Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.[NH2:13][C:14]1[CH:18]=[C:17]([CH:19]2[CH2:21][CH2:20]2)[NH:16][N:15]=1.C(N(CC)CC)C.[I-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[N:11]=[C:10]([NH:13][C:14]2[NH:15][N:16]=[C:17]([CH:19]3[CH2:21][CH2:20]3)[CH:18]=2)[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: Clc1nc(Cl)c2c(n1)CCCC2
Reactant: Nc1cc(C2CC2)[nH]n1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Clc1nc2c(c(Nc3cc(C4CC4)n[nH]3)n1)CCCC2
Temperature: 90 °C

Procedure:
To a solution of 2,4-dichloro-5,6,7,8-tetrahydroquinazoline (500 mg, 2.46 mmol) and 3-amino-5-cyclopropylpyrazole (303 mg, 2.46 mmol) in DMF (10 mL) is added triethylamine (0.357 mL, 2.56 mmol) followed by sodium iodide (368 mg, 2.46 mmol) and the reaction mixture is heated at 90° C. for 20 h. The reaction mixture is partitioned between ethyl acetate and aqueous saturated NaHCO3. The organic layer is washed with brine and evaporated in vacuo. The residue is purified by flash chromatography (SiO2, hexane/AcOEt gradient) to give (2-chloro-5,6,7,8-tetrahydroquinazolin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[CH:23]=2)=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:23]2[C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[O:20][C:19]=2[C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2cc3ccccc3o2)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: COc1ccc(-c2oc3ccccc3c2C(=O)c2ccc(Cl)cc2)cc1

Procedure:
Reaction of p-chlorobenzoyl chloride with 2-p-methoxyphenylbenzofuran gave 3-p-chlorobenzoyl-2-p-methoxyphenylbenzofuran.
Reaction SMILES: [N+:1]([C:4]1[CH:40]=[CH:39][C:7]([O:8][C:9]2[CH:38]=[CH:37][C:12]([O:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]4[CH:26]=[CH:25][C:24]([O:27][C:28]5[CH:33]=[CH:32][C:31]([N+:34]([O-])=O)=[CH:30][CH:29]=5)=[CH:23][CH:22]=4)=[CH:16][CH:15]=3)=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-])=O>[Pd].C1COCC1>[NH2:34][C:31]1[CH:32]=[CH:33][C:28]([O:27][C:24]2[CH:25]=[CH:26][C:21]([O:20][C:17]3[CH:16]=[CH:15][C:14]([O:13][C:12]4[CH:37]=[CH:38][C:9]([O:8][C:7]5[CH:39]=[CH:40][C:4]([NH2:1])=[CH:5][CH:6]=5)=[CH:10][CH:11]=4)=[CH:19][CH:18]=3)=[CH:22][CH:23]=2)=[CH:29][CH:30]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(Oc3ccc(Oc4ccc(Oc5ccc([N+](=O)[O-])cc5)cc4)cc3)cc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccc(Oc3ccc(Oc4ccc(Oc5ccc(N)cc5)cc4)cc3)cc2)cc1

Procedure:
A 150 ml hydrogenation bottle was charged with 11.3 g (0.021 mol) 1,4-bis[4-(4-nitrophenoxy)phenoxy]benzene, 100 ml dry THF, and 0.5 g 10% Pd—C. The bottle was placed in a Parr-hydrogenator and the nitro group was reduced under H2-atmosphere (50 psi) in 5 h. at room temperature. The THF solution was filtered over a short silica-gel/celite patch and the THF was removed by distillation. Pure 1,4-bis[4-(4-aminophenoxy)phenoxy]benzene (P3) was obtained after recrystallization from acetone/water (95/5) as off white crystals. Yield: 8.6 g (86%). Mp: 170° C.; IR(KBr): vmax 3384, 3316, 1499, 1275, 1223, 1193, 1105, 1097, 865, 846, 827 cm−1; 1H-NMR (CDCl3) δ (ppm): 3.55 (s, 4H), 6.64 (d, 4H, J=9 Hz), 6.83 (d, 4H, J=9 Hz), 6.87-6.93 (m, 12H); 13C-NMR (CDCl3) δ (ppm); 116.2. 118.6, 119.5, 119.7, 119.8, 120.5, 142.4, 149.1, 152.2, 153.1, 154.3.
Reaction SMILES: [N+:1]([O-])([OH:3])=[O:2].[CH2:5]([O:12][C:13]1[CH:18]=[C:17](/[CH:19]=[CH:20]/[N+:21]([O-:23])=[O:22])[CH:16]=[CH:15][C:14]=1[O:24][CH2:25][CH2:26][O:27][CH2:28][CH3:29])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(O)(=O)C>[CH2:5]([O:12][C:13]1[CH:18]=[C:17](/[CH:19]=[CH:20]/[N+:21]([O-:23])=[O:22])[C:16]([N+:1]([O-:3])=[O:2])=[CH:15][C:14]=1[O:24][CH2:25][CH2:26][O:27][CH2:28][CH3:29])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCOCCOc1ccc(/C=C/[N+](=O)[O-])cc1OCc1ccccc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CCOCCOc1cc([N+](=O)[O-])c(/C=C/[N+](=O)[O-])cc1OCc1ccccc1
Reaction time: 6 h

Procedure:
69% Nitric acid (11 mL, 171 mmol) was added to a solution of (E)-2-(benzyloxy)-1-(2-ethoxyethoxy)-4-(2-nitrovinyl)benzene described in Production Example 24-3 (15.4 g, 44.9 mmol) and acetic acid (100 mL) at 25° C., and the mixture was stirred for 6 hours. The reaction liquid was poured onto ice. The suspension was subjected to suction filtration and the product was washed with water to quantitatively obtain the title compound.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]#[C:11][C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH:5]=1.CO>[OH-].[Na+].O>[CH3:30][O:29][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[C:20]3[C:12]([C:11]#[C:10][C:6]4[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=4)[C:3]([OH:31])=[O:2])=[CH:13][NH:14][C:15]3=[N:16][CH:17]=2)[CH:26]=[CH:25][C:24]=1[O:27][CH3:28]
Reactant: COC(=O)c1cccc(C#Cc2c[nH]c3ncc(-c4ccc(OC)c(OC)c4)cc23)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(-c2cnc3[nH]cc(C#Cc4cccc(C(=O)O)c4)c3c2)cc1OC

Procedure:
Into a microwave safe tube, 3-[5-(3,4-Dimethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-ylethynyl]-benzoic acid methyl ester (0.049 g, 0.00012 mol) was dissolved in 5.00 M of Sodium hydroxide in Water (1.78 mL) and Methanol (7.1 mL, 0.18 mol). The reaction was warmed at 60 watts to 100° C. for 10 minutes. The resulting clear yellow solution was concentrated under reduced pressure. The resulting aqueous slurry was acidified to pH 5 with 1 M HCl (aq) and was extracted into ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, then concentrated under reduced pressure. The resulting residue was recrystalized from ethyl acetate and methanol to yield the titled compound as a white solid. MS(ESI) [M+H+]+=399.20
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Br:13][C:14]1[C:15]([CH3:32])=[N:16][O:17][C:18]=1[NH:19][S:20]([C:23]1[CH:27]=[CH:26][S:25][C:24]=1[C:28]([O:30][CH3:31])=[O:29])(=[O:22])=[O:21].[CH2:33]1[O:37][C:36]2[CH:38]=C(O)[CH:40]=[CH:41][C:35]=2[O:34]1.N1C=CN=C1>C1COCC1>[Br:13][C:14]1[C:15]([CH3:32])=[N:16][O:17][C:18]=1[NH:19][S:20]([C:23]1[CH:27]=[CH:26][S:25][C:24]=1[C:28]([O:30][C:31]1[CH:40]=[CH:41][C:35]2[O:34][CH2:33][O:37][C:36]=2[CH:38]=1)=[O:29])(=[O:21])=[O:22]
Reactant: Oc1ccc2c(c1)OCO2
Reactant: COC(=O)c1sccc1S(=O)(=O)Nc1onc(C)c1Br
Agent: O=C(n1ccnc1)n1ccnc1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: Cc1noc(NS(=O)(=O)c2ccsc2C(=O)Oc2ccc3c(c2)OCO3)c1Br
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Carbonyldiimidazole (530 mg., 3.26 mmol.) was added to a solution of N-(4-bromo-3-methyl-5-isoxazolyl)-2-carboxylthiophene-3-sulfonamide (Example 17) (1.0 g, 2.72 mmol) in dry THF (10 ml). The mixture was stirred at room temperature for 15 minutes. Sesamol (767 mg., 5.44 mmol) and imidazole (185 mg, 2.72 mmol) were added simultaneously. The resulting mixture was refluxed for 1 hour and allowed to cool to room temperature. The solvent was evaporated. The residue was partitioned between 1N HCl and EtOAc. The organic layer was dried (MgSO4). The solid was filtered and the filtrate concentrated to give a yellow oil which was recrystalized from EtOAc/Et2O/Hexane. N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)phenoxycarbonyl]thiophene-3-sulfonamide was obtained as a white powder (494 mg, 37% yield), m.p. 174-176° C.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23](Cl)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:27]1([NH:30][C:31]([CH:33]2[O:38][CH2:37][CH2:36][NH:35][CH2:34]2)=[O:32])[CH2:29][CH2:28]1.CCN(C(C)C)C(C)C>ClCCCl>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:35]3[CH2:36][CH2:37][O:38][CH:33]([C:31]([NH:30][CH:27]4[CH2:28][CH2:29]4)=[O:32])[CH2:34]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCC(F)(F)CC1
Reactant: O=C(NC1CC1)C1CNCCO1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CCOC(C(=O)NC4CC4)C3)ccc2n1CC1CCC(F)(F)CC1
Reaction time: 1 h

Procedure:
2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazole-5-sulfonyl chloride (0.95 g, 2.35 mmol) was added to a solution of N-cyclopropylmorpholine-2-carboxamide (0.8 g, 2.6 mmol) (see following steps B and C for preparation) and DIPEA (0.82 mL, 4.7 mmol) in DCE (80 mL) at 80° C. The reaction mixture was stirred for 1 h and the solvent was concentrated. The product was purified by MPLC on silica gel using 60-90% EtOAc/Heptane to provide the title compound as white solid. Yield: 1.1 g (71%); 1H NMR (400 MHz, CDCl3) δ 0.39-0.54 (m, 2 H), 0.69-0.80 (m, 2 H), 1.49-1.69 (m, 3 H), 1.72 (s, 9 H), 1.75-1.86 (m, 3 H), 2.09 (t, J=10.84 Hz, 1 H), 2.2 (m, 3 H), 2.38-2.50 (m, 1 H), 2.61-2.71 (m, 1 H), 3.56 (d, J=11.91 Hz, 1 H), 3.67 (td, J=11.52, 1.95 Hz, 1 H), 3.91-4.06 (m, 3 H), 4.44 (d, J=7.03 Hz, 2 H), 6.58 (d, J=3.12 Hz, 1 H), 7.63-7.73 (m, 2 H), 8.04 (s, 1 H); MS (ESI) (M+H)+=538.8; Anal. Calcd for C26H36F2N4O4S+2.2 TFA: C, 46.25; H, 4.88; N, 7.10. Found: C, 46.26; H, 5.00; N, 6.95.
Reaction SMILES: [F:1][CH2:2][CH:3]([OH:5])[CH3:4].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25]>C1COCC1.O.CCOC(C)=O>[F:23][C:21]1[CH:22]=[CH:17][C:18]([N+:24]([O-:26])=[O:25])=[C:19]([O:5][CH:3]([CH3:4])[CH2:2][F:1])[CH:20]=1
Reactant: CC(O)CF
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(CF)Oc1cc(F)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.29 g (3.77 mmol) 1-fluoro-propan-2-ol in 20 mL THF is cooled down to 0° C. 4.90 mL (1 M in THF; 4.90 mmol) LiHMDS is added drop wise. After 60 minutes of stirring at 0° C. 0.60 g (3.77 mmol) 2,4-difluoro-1-nitro-benzene is added. The mixture is stirred for 2 h. The mixture is diluted with water and EtOAc. The organic layer is washed with brine, separated, dried and evaporated giving rise to the crude 4-fluoro-2-(2-fluoro-1-methyl-ethoxy)-1-nitro-benzene. 80.0 mg palladium on charcoal (10%) and MeOH are added hydrogenated in a Parr apparatus (RT; 50 psi; 5 h). The catalyst is filtered off and the solvent is evaporated.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([CH3:6])([OH:5])[CH3:4].[O-:13][C:14]#[N:15].[K+]>O>[OH:5][C:3]([CH3:6])([CH3:4])[C@@H:2]([NH:1][C:14]([NH2:15])=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N#C[O-]
Reactant: CC(C)(O)[C@@H](N)c1ccccc1
Agent: [K+]
Solvent: O
Product: CC(C)(O)[C@@H](NC(N)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-1-amino-2-methyl-1-phenylpropan-2-ol (2.0 g, 10 mmol) in H2O (10 mL) was added potassium cyanate (0.85 g, 12 mmol) and the contents were stirred at ambient temperature for 2 h. The solid thus obtained was filtered and washed successively with H2O (2×5 mL) and dried in air to afford (S)-1-(2-hydroxy-2-methyl-1-phenylpropyl)urea. 1H NMR (400 MHz, DMSO-d6) δ 7.25-7.15 (m, 5H), 6.52 (d, J=9.2 Hz, 1H), 5.50 (s, 2H), 4.50 (s, 1H), 4.41 (d, J=9.2 Hz, 1H), 1.10 (s, 3H), 0.93 (s, 3H). Anal. Calcd. C11H16N2O2 208.3. Found 209.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH:9]=[N+]=[N-])=[CH:4][C:3]=1[S:13](=[O:17])(=[O:16])[NH:14][CH3:15].[ClH:18]>COCCOCCOC>[Cl:18][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([S:13](=[O:17])(=[O:16])[NH:14][CH3:15])[CH:4]=1)=[O:12]
Reactant: CNS(=O)(=O)c1cc(C(=O)C=[N+]=[N-])ccc1Cl
Reactant: Cl
Solvent: COCCOCCOC
Product: CNS(=O)(=O)c1cc(C(=O)CCl)ccc1Cl

Procedure:
12 g of 4'-chloro-3'-methylsulfamoyl-diazoacetophenone were reacted as prescribed in Example 66b) with concentrated HCl in diethyleneglycol dimethyl ether und worked up. Colorless crystals, melting point: 153° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]1([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[CH2:20][C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:34][CH2:33][C@@H:32]([N:35]([CH3:37])[CH3:36])[CH2:31]2)=[CH:26][CH:25]=1)=[O:22]>C(#N)C.CN(C=O)C>[CH3:37][N:35]([CH3:36])[C@@H:32]1[CH2:33][CH2:34][N:30]([C:27]2[CH:28]=[CH:29][C:24]([NH:23][C:21](=[O:22])[CH2:20][N:16]3[CH2:15][CH2:14][CH:13]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH2:18][CH2:17]3)=[CH:25][CH:26]=2)[CH2:31]1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: CN(C)[C@@H]1CCN(c2ccc(NC(=O)CCl)cc2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CN(C)[C@@H]1CCN(c2ccc(NC(=O)CN3CCC(c4ccccc4)CC3)cc2)C1
Reaction time: 12 h

Procedure:
Cesium carbonate (100 mg) and 4-phenylpiperidine (48 mg) were added to a solution of (R)-2-chloro-N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]acetamide (80 mg) in acetonitrile (5 ml) and DMF (1 ml), and the mixture was kept at 65° C. for 12 hours. The mixture was freed of volatile fractions and the residue was partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (silica gel, eluent: methanol/dichloromethane). This resulted in the product with the molecular weight of 406.58 (C25H34N4O); MS (ESI): 407 (M+H+).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([C:7]1([CH3:31])[CH2:13][C:12]2[CH:14]=[C:15]3[O:20][CH2:19][O:18][C:16]3=[CH:17][C:11]=2[C:10]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[C:23]([CH3:30])[CH:22]=2)=[N:9][NH:8]1)#[N:6]>>[C:1]([N:8]1[C:7]([C:5]#[N:6])([CH3:31])[CH2:13][C:12]2[CH:14]=[C:15]3[O:20][CH2:19][O:18][C:16]3=[CH:17][C:11]=2[C:10]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[C:23]([CH3:30])[CH:22]=2)=[N:9]1)(=[O:3])[CH3:2]
Reactant: Cc1cc(C2=NNC(C)(C#N)Cc3cc4c(cc32)OCO4)ccc1[N+](=O)[O-]
Reactant: CC(=O)Cl
Product: CC(=O)N1N=C(c2ccc([N+](=O)[O-])c(C)c2)c2cc3c(cc2CC1(C)C#N)OCO3
Yield: 67 %

Procedure:
To 60 ml of acetyl chloride 9.11 g (25.0 millimoles) of (±)-8-cyano-7,8-dihydro-8-methyl-5-(3-methyl-4-nitro-phenyl)-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepine are added at 15° C. under stirring. The suspension formed turns into a solution within 5 minutes, but after a further period of 5 minutes a suspension is re-formed. The reaction mixture is stirred at 25° C. for 6 days, whereupon it is evaporated in vacuo. To the residue 90 ml of water are added and the mixture is stirred under cooling with icecold water for half an hour. The precipitated crystals are filtered and washed with icecold water. The crude product is crystallized from 150 ml of acetonitrile. The crystals are filtered, washed with acetonitrile and ether and dried. Thus 6.84 g of the desired compound are obtained, yield 67%, mp.: 253–255° C.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].FC(F)(F)S(O[C:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH:18]=1)(=O)=O.[N+:28]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)([O-:30])=[O:29].[Cl-].[Li+]>C(COC)OC>[N+:28]([C:31]1[CH:36]=[C:35]([C:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH:18]=2)[CH:34]=[CH:33][CH:32]=1)([O-:30])=[O:29]
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2cccc([N+](=O)[O-])c2)CC1
Yield: 82.7 %

Procedure:
According to the procedure used for the synthesis of tert-butyl 4-[3-(amino)phenyl]-1,2,3,6-tetrahydro-1-pyridinecarboxylate,a mixture of 2 M aqueous Na2CO3 solution (2.2 mL), tert-butyl 4-{[(trifluoromethyl)sulfonyl]oxy}-1,2,3,6-tetrahydro-1-pyridine-carboxylate (0.500 g, 1.51 mmol), 3-nitrophenylboronic acid (0.353 g, 2.11 mmol), lithium chloride (0.191 9, 4.50 mmol) and tetrakis-triphenylphosphine palladium(0) (0.080 g, 0.075 mmol) in dimethoxyethane (5 mL) afforded 0.380g of the desired product.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1.[CH:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([CH3:29])[CH3:28].C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:27]([C:30]1[CH:35]=[CH:34][C:33]([N:3]2[C:4](=[O:26])[C:5]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:14][CH:13]=3)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=[C:2]2[CH3:1])=[CH:32][CH:31]=1)([CH3:29])[CH3:28]
Reactant: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC(C)c1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCc1nc(C)n(-c2ccc(C(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g), (4-isopropylphenyl)boronic acid (1.0 g), triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (3.0 g) in methylene chloride (10 mL) was added copper(II) acetate (1.0 g), and the mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (1.21 g, 90%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].C(=O)(O)[O-].[Na+].O1[CH2:22][CH2:21]OCC1>>[F:8][C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[C:22]1[CH:21]=[CH:2][CH:3]=[CH:4][N:9]=1
Reactant: C1COCCO1
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(F)c(-c2ccccn2)c1

Procedure:
0.55 g of Tetrakis-triphenylphosphine palladium was added to a 1,4-dioxane (20 ml) solution of 2.1 g of 3-bromo-4-fluoro-nitrobenzene and 2.3 g of 2-trimethyltin-pyridine, and the reaction liquid was heated overnight under reflux. Aqueous saturated sodium bicarbonate was added to the reaction liquid, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=7/1) to obtain the entitled compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4](I)[CH:3]=1.C(N(CC)C(C)C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[P:62]([O-:67])([O:65]C)[O:63][CH3:64]>C(#N)C.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:21]([O:20][C:19]1[C:18](=[O:28])[N:17]2[C:12]([C:13]([CH3:30])([CH3:29])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:8]([NH:7][CH2:6][C:5]1[CH:31]=[CH:32][C:2]([F:1])=[CH:3][C:4]=1[P:62](=[O:65])([OH:67])[O:63][CH3:64])=[O:9])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1I)c(OCc1ccccc1)c2=O
Reactant: COP([O-])OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COP(=O)(O)c1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C
Temperature: 120 °C
Yield: 64.5 %

Procedure:
A solution of N-(4-fluoro-2-iodobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.200 g, 0.35 mmol) in acetonitrile (5 ml) was flushed with argon and then treated with N,N-diisopropylethylamine (0.25 ml, 1.4 mmol), triphenylphosphine (0.030 g), palladium(II) acetate (0.040 g). and dimethyl phosphite (0.10 ml, 1.06 mmol). The reaction mixture was then heated in a microwave oven at 120° C. for 40 min. The reaction mixture was then diluted with ethyl acetate, washed with 0.1 N hydrochloric acid, brine, dried over anhydrous magnesium sulfate and concentrated. Purification of the residue by preparative HPLC (column YMC Pack C-18, 5μ, 20×250 mm, elution gradient acetonitrile-water 0.1% trifluoroacetic acid) gave 0.120 g (64% yield) of the title material as a white solid. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.62 (6H, s, 2×CH3), 3.77 and 3.79 (3H, 2 s, OCH3), 3.95-4.05 (4H, m, 2×CH2), 4.75 (2H, d, J=4.6 Hz, NCH2), 5.32 (2H, s, OCH2), 7.22 (1H, m, aromatic), 7.3-7.35 (3H, m, aromatics), 7.38-7.42 (2H, m, aromatics), 7.48-7.54 (1H, m, aromatic), 7.55-7.62 (1H, m, aromatic), 8.54 (1H, broad t, NH). HRMS (ESI+) calculated for C25H28FN3O7P [M+H+]: 532.1649; found: 532.1642.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][CH:18]=[CH:17]3)[CH3:9])[C:5]([CH3:23])=[CH:4][N:3]=1.[H-].[Na+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CN(C=O)C.O>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][N:19]1[C:20]2[C:16](=[CH:15][C:14]([O:13][CH2:12][CH2:11][CH2:10][N:8]([C:6]3[C:5]([CH3:23])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH3:9])=[CH:22][CH:21]=2)[CH:17]=[CH:18]1)[CH3:32]
Reactant: CCOC(=O)CBr
Reactant: Cc1cnc(Cl)nc1N(C)CCCOc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cn1ccc2cc(OCCCN(C)c3nc(Cl)ncc3C)ccc21
Reaction time: 1 h

Procedure:
(2-Chloro-5-methyl-pyrimidin-4-yl)-[3-(1H-indol-5-yloxy)-propyl]-methyl-amine (Example 88, 0.117 g, 0.35 mmol) was dissolved in DMF (2 mL) at rt, and sodium hydride was added (0.017 g, 60% in mineral oil, 0.42 mmol). The reaction solution immediately turned purple. The resulting mixture was stirred for 1 h and ethyl bromoacetate (0.065 g, 0.39 mmol) was added. The reaction mixture was stirred for 60 h, diluted with water, and extracted with EtOAc. The organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as an orange oil without purification (103 mg, 70%). LC/MS m/z 417.4 (M+H)+, RT 3.05 min.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.[C:9]([N:13]1[CH2:16][CH:15]([OH:17])[CH2:14]1)([CH3:12])([CH3:11])[CH3:10].[OH-].[K+]>Cl>[NH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:8][CH2:16][CH:15]([OH:17])[CH2:14][NH:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:2][CH:1]=1
Reactant: Nc1ccc(O)cc1
Reactant: CC(C)(C)N1CC(O)C1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CC(C)(C)NCC(O)COc1ccc(N)cc1
Temperature: 140 °C
Yield: 19.7 %

Procedure:
A mixture of 21.8 g of p-aminophenol, 22 g of 1-(tert.-butyl)-3-azetidinol and 0.73 g of potassium hydroxide was heated under nitrogen gas at 140° C. for 8 hours with agitation. The reaction mixture was cooled and dissolved in concentrated hydrochloric acid and the solution was extracted with ether. The hydrochloric acid aqueous solution was made alkaline with 10% -NaOH aqueous solution and then extracted with ether. The ether solution was washed with water and dried over anhydrous sodium sulfate. Then ether was distilled off and the residue was recrystallized from benzene. as a result, 8 g of 1-(p-aminophenoxy)-3-(tert.-butylamino)-2-propanol melting at 125°-127° C. were obtained. The results of infra-red spectrum analysis and nuclear magnetic resonance analysis are as follows:
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH2:19]([O:21][C:22]([C:24]1[C:25]([NH2:29])=[N:26][NH:27][CH:28]=1)=[O:23])[CH3:20]>O1CCCC1>[CH2:19]([O:21][C:22]([C:24]1[C:25]([NH:29][CH:8]=[C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])=[N:26][NH:27][CH:28]=1)=[O:23])[CH3:20]
Reactant: CCOC(=O)c1c[nH]nc1N
Reactant: O=C1Nc2ccccc2/C1=C/O
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: CCOC(=O)c1c[nH]nc1NC=C1C(=O)Nc2ccccc21

Procedure:
The named compound is prepared by substituting 3-amino-1H-pyrazole-4-carboxylic acid ethyl ester for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.100 gms.) is reacted with 0.2001 gms. of 3-amino-1H-pyrazole-4-carboxylic acid ethyl ester by refluxing in tetrahydrofuran (2.5 mL).