Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28][C:29]1[CH:30]=[CH:31][C:32]([S:35]([NH2:38])(=[O:37])=[O:36])=[CH:33][CH:34]=1>>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:38][S:35]([C:32]3[CH:31]=[CH:30][C:29]([CH3:28])=[CH:34][CH:33]=3)(=[O:37])=[O:36])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and p-toluenesulfonamide in accordance with Procedure 1, Method B described hereinabove. Yield (42%); 1H NMR (CD3 OD) δ 7.87 (d, J=8.2 Hz, 2H), 7.37–7.08 (m, 15H), 6.87 (d, J=8.2 Hz, 2H), 6.32 (d, J=15.7 Hz, 1H), 2.44 (q, J=7.4 Hz, 2H), 2.40 (s, 3H), 0.89 (t, J=7.3 Hz, 3H); APcI m/z: 508 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[S:4][C:3]=1[C:17](OCC)=O.Br([O-])(=O)=[O:23].[Na+].S(=O)(O)[O-].[Na+]>C1CCCCC1.O>[CH3:17][C:3]1[S:4][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)=[CH:6][C:2]=1[CH2:1][OH:23]
Reactant: [O-][Br+2]([O-])[O-]
Reactant: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)cc1C
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCCCC1
Product: Cc1sc(-c2ccc(C(F)(F)F)cc2)cc1CO
Reaction time: 2 h

Procedure:
Ethyl 3-methyl-5-[4-(trifluoromethyl)phenyl]thiophene-2-carboxylate (intermediate 35, 0.100 g) and sodium bromate (0.144 g) were suspended in a mixture of cyclohexane and water (1:1 v/v, 4 ml). To this was added a solution sodium bisulfite (0.99 g) in water (1 ml). The mixture was stirred for 2 hours, quenched with 1M sodium thiosulfate solution, then extracted with ethyl acetate. The organic layer was taken and washed with water, sodium thiosulfate and dried with brine and over MgSO4 and concentrated to give the title compound as a white crystalline solid.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:12]2[NH:13][C:14](=[O:21])[C:15]3[C:20]([C:11]=2[C:10]2[CH:9]=[C:8]([Cl:22])[CH:7]=[CH:6][C:5]1=2)=[CH:19][CH:18]=[CH:17][CH:16]=3.[CH3:23]I>CN(C)C=O>[CH3:23][O:21][C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]2[C:10]3[CH:9]=[C:8]([Cl:22])[CH:7]=[CH:6][C:5]=3[N:4]([CH3:3])[C:12]=2[N:13]=1
Reactant: CI
Reactant: Cn1c2ccc(Cl)cc2c2c3ccccc3c(=O)[nH]c21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nc2c(c3ccccc13)c1cc(Cl)ccc1n2C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a stirred suspension of 0.08 g of 65% sodium hydride (in oil) in 5 ml of dimethylformamide, 0.5 g of 7-methyl-10-chloroindolo(2,3-c)isoquinolin-5(6H)-one is added at room temperature. The reaction mixture is stirred for 30 minutes and 2.5 g of methyl iodide in 30 ml of dimethylformamide is added dropwise thereto at room temperature. After addition, stirring is continued for further 16 hours at room temperature and then dimethylformamide is removed under reduced pressure. The residue is treated with water and extracted with dichloromethane. The organic layer is dried over magnesium sulfate and the solvent is evaporated in vacuo to give 404 mg of 5-methoxy-7-methyl-10-chloro-7H-indolo(2,3-c)isoquinoline, which is recrystallized from ethyl acetate, melting point 179°-180.5° C.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si](C(C)(C)C)(C)C)[CH2:12][C@@H:11]([O:23][C:24]2[N:29]=[CH:28][N:27]=[C:26]([NH:30][C@@H:31]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH2:33][C@@H:32]3[O:40][CH3:41])[CH:25]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(O)(=O)C>C1COCC1.O>[Si:1]([O:8][C@H:9]1[CH2:10][C@H:11]([O:23][C:24]2[CH:25]=[C:26]([NH:30][C@@H:31]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH2:33][C@@H:32]3[O:40][CH3:41])[N:27]=[CH:28][N:29]=2)[CH2:12][C@H:13]1[CH2:14][OH:15])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CO[C@H]1Cc2ccccc2[C@H]1Nc1cc(O[C@@H]2C[C@@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)C2)ncn1
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CO[C@H]1Cc2ccccc2[C@H]1Nc1cc(O[C@@H]2C[C@@H](CO)[C@@H](O[Si](C)(C)C(C)(C)C)C2)ncn1
Yield: 77.7 %

Procedure:
A solution of 6-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]oxy}-N-[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]pyrimidin-4-amine (0.32 g, 0.00053 mol) in THF (2.88 mL), water (2.88 mL), and acetic acid (8.64 mL) was stirred for 3 days. The reaction was concentrated and azeotroped 2× with toluene. The residue was purified by flash chromatography (30 to 80% EtOAc/hexanes) give 0.20 g (77%) of the title compound. LC/MS: Rt=1.59 min, ES+ 486 (FA standard).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:12](=[O:31])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16](/[CH:26]=[CH:27]/[C:28]([OH:30])=O)=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C([N:39]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1.O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:12](=[O:31])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16](/[CH:26]=[CH:27]/[C:28]([NH2:39])=[O:30])=[CH:15][CH:14]=2)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(/C=C/C(=O)O)ccc2c1=O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(/C=C/C(N)=O)ccc2c1=O
Yield: 93.1 %

Procedure:
A solution of (E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-2-propenic acid (0.33 g, 0.7 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.27 g, 1.4 mmol) and 1-hydroxybenzotriazole ammonium salt (0.21 g, 1.4 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give (E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-2-propenamide (0.31 g, 93.9%) as crystals.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[F:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[CH2:14]Br)[C:9]#[N:10]>CN(C=O)C>[F:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[CH2:14][N:1]=[N+:2]=[N-:3])[C:9]#[N:10]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(CBr)c(F)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(CN=[N+]=[N-])c(F)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 86.9 %

Procedure:
Sodium azide (Aldrich, 0.63 g, 9.8 mmol) was added to a solution of 3-fluoro-4-(bromomethyl)benzonitrile (compound 5-3, 1.4 g, 6.5 mmol) in DMF (15 ml). After stirring at ambient temperature for 20 hours, the reaction mixture was partitioned in EtOAc and water (100 ml, each). Organic layer was then dried (MgSO4), and solvent was removed under vacuum to give the title compound (0.995 g, 86%). 1H NMR (CDCl3): δ 4.50 (s, 2H), 7.38 (d, 2H, J=8.1 Hz), 7.52 (m, 2H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH2:6][NH2:7].[CH2:13]([O:15][C:16]([C:18]1[C:19](=[O:38])[C:20]2[CH:25]=[N:24][C:23](S(C)(=O)=O)=[N:22][C:21]=2[N:30]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)=[O:17])[CH3:14]>>[CH2:13]([O:15][C:16]([C:18]1[C:19](=[O:38])[C:20]2[CH:25]=[N:24][C:23]([NH:7][CH2:6][C:5]3[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:22][C:21]=2[N:30]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)=[O:17])[CH3:14]
Reactant: COc1cc(CN)cc(OC)c1
Reactant: CCOC(=O)c1cn(C2CCCCC2)c2nc(S(C)(=O)=O)ncc2c1=O
Product: CCOC(=O)c1cn(C2CCCCC2)c2nc(NCc3cc(OC)cc(OC)c3)ncc2c1=O

Procedure:
Using the procedure outlined in Example 28 Step F, the title compound was prepared from 3,5-dimethoxy-benzylamine and 8-cyclohexyl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (33 mg, 0.08 mmol). 8-Cyclohexyl-5-oxo-2-(3,5-dimethoxy-benzylamino)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester was obtained as a white solid (29 mg, 90%). Mass Spectrum (LCMS, ESI pos.) Calcd. For C25H30N4O5: 467.22 (M+H). Found: 467.2.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:6](=O)[N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:3]1.[Li].I[CH3:23]>C1COCC1>[CH3:23][C:4]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:3][C:2]([CH3:20])([CH3:1])[CH2:6][N:5]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: CI
Reactant: CCOC(=O)[C@@H]1CC(C)(C)C(=O)N1C(=O)OC(C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CC(C)(C)CN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
To a solution of(s)-1-tert-butyl 2-ethyl 4,4-dimethyl-5-oxopyrrolidine-1,2-dicarboxylate (163D) (10 g, 0.035 mol) in dry THF (60 mL) stirred at −78° C. under nitrogen was added a 1 M solution of lithium hexmethyldisilazide in THF (38.5 mL, 0.038 mol). The mixture was stirred at −78° C. for 30 min, iodomethane (5.4 g, 0.038 mol) in THF (5 mL) was added, and the mixture was then stirred 1 h, warmed up to room temperature and continued stirring for additional 3 h. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with CH2Cl2 (3×100 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by flash chromatography (10-20% EtOAc/hexane) to furnish (163E) (8.2 g, 72%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]#[C:8][C:9]12[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][C:11]([NH2:19])([CH2:12]3)[CH2:10]1)[CH2:16]2.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26](O)=[O:27].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]#[C:8][C:9]12[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][C:11]([NH:19][C:26]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=4)=[O:27])([CH2:12]3)[CH2:10]1)[CH2:16]2
Reactant: O=C(O)c1ccccn1
Reactant: NC12CC3CC(C1)CC(C#Cc1cnccn1)(C3)C2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC12CC3CC(CC(C#Cc4cnccn4)(C3)C1)C2)c1ccccn1
Temperature: 25 °C
Yield: 116.2 %

Procedure:
To a solution of intermediate 11, 3-(pyrazin-2-ylethynyl)-1-adamantylamine (30 mg, 0.12 mmol) and picolinic acid (18 mg, 0.15 mmol) in DMF (2 mL) was added DIEA (50 mg, 0.38 mmol) and HATU (60 mg, 0.12 mmol) under N2. After stirring at room temperature for an hour, the reaction was quenched with brine and extracted with ethyl acetate (2×20 mL). The combined organic phase was washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give a residue, which was purified by Prep HPLC to give 50 mg (95%) of the title compound, pyridine-2-carboxylic acid (3-pyrazin-2-ylethynyl-adamantan-1-yl)-amide, as an off-white solid. 1H NMR (500 MHz, CDCl3): δ 8.60-8.43 (m, 4H), 8.17 (d, J=8.0 Hz, 1H), 7.96 (s, 1H), 7.85-7.82 (m, 1H), 7.42-7.39 (m, 1H), 2.45 (s, 2H), 2.26-2.20 (m, 4H), 2.11-1.97 (m, 6H), 1.76-1.69 (m, 2H); ESI-MS m/z: 359 (M+H)+.
Reaction SMILES: Br[Mg][CH:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1.[Cl:8][C:9]1[C:10]([O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])=[CH:11][C:12]2[O:16][C:15](=[O:17])[NH:14][C:13]=2[CH:18]=1>O1CCCC1>[Cl:8][C:9]1[C:10]([O:19][Si:20]([CH:24]([CH3:26])[CH3:25])([CH:27]([CH3:29])[CH3:28])[CH:21]([CH3:22])[CH3:23])=[CH:11][C:12]([OH:16])=[C:13]([NH:14][C:15]([CH:3]2[CH2:7][CH2:6][CH2:5][CH2:4]2)=[O:17])[CH:18]=1
Reactant: CC(C)[Si](Oc1cc2oc(=O)[nH]c2cc1Cl)(C(C)C)C(C)C
Reactant: Br[Mg]C1CCCC1
Solvent: C1CCOC1
Product: CC(C)[Si](Oc1cc(O)c(NC(=O)C2CCCC2)cc1Cl)(C(C)C)C(C)C
Temperature: 70 °C
Yield: 86.9 %

Procedure:
Bromo(cyclopentyl)magnesium (0.58 mL, 1.16 mmol, 2 M in diethylether) was added under inert atmosphere to a solution of 5-chloro-6-[(triisopropylsilyl)oxy]-1,3-benzoxazol-2(3H)-one (66 mg, 0.19 mmol) in tetrahydrofuran (3 mL). After stirring over night at 70° C., the solution was evaporated and dissolved in ethylacetate. The organic layer was washed with water and 1M hydrochloric acid, dried and finally concentrated to give 68 mg (89%) of the subtitled compound as a brown solid.
Reaction SMILES: [I-].[F:2][C:3]([F:26])([F:25])[CH2:4][CH2:5][P+:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:37]([O:39][C:40](Cl)=[O:41])[CH3:38]>C1COCC1>[CH2:37]([O:39][C:40](=[O:41])[C:5](=[P:6]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:4][C:3]([F:2])([F:25])[F:26])[CH3:38]
Reactant: CCOC(=O)Cl
Reactant: FC(F)(F)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CC(F)(F)F)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -5 °C
Yield: 88.8 %

Procedure:
A suspension of (3,3,3-trifluoropropyl)triphenylphosphonium iodide (194.5 g, 0.4 mol) in THF (anhydrous, 800 mL) was cooled to −5° C. in an ice/brine bath under nitrogen. To this suspension, lithium bis(trimethylsilyl)amide (1.0 M in THF, 800 mL, 0.8 mol) was added drop-wise over 2 h. The temperature was maintained below 5° C. throughout the addition. The reaction mixture was then cooled to −75° C. in a dry ice/acetone bath. To this solution, ethylchloroformate (76.5 mL, 0.8 mol) was added drop-wise over 30 min. The reaction was stirred at −75° C. for an additional hour and allowed to warm to 25° C. overnight. The reaction mixture was poured onto brine (1.5 L) and stirred for 30 min. The layers were separated and the organic layer was washed with brine (200 mL). The aqueous layer was washed with CH2Cl2 (2×200 mL) and the combined organics were concentrated to a residue. This residue was redissolved in CH2Cl2 (500 mL), dried over MgSO4, and filtered through a plug of magnasol. The solvent was reduced to a minimum (˜100 mL) in vacuo and the product was precipitated with hexanes (250 mL). The solvent was completely removed in vacuo and the solid product was triturated with hexanes (500 mL). The solid was isolated by filtration and dried overnight in vacuo at 25° C. to give a beige powder (152.8 g, 89%).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@@H:12]([CH3:26])[C@@H:13]([CH3:25])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)=[CH:7][C:6]=1[O:27][CH3:28].C[O-].[Na+].[N+:32]([C:35]1[N:36]=[CH:37][NH:38][CH:39]=1)([O-:34])=[O:33]>>[CH3:24][O:23][C:17]1[CH:16]=[C:15]([CH2:14][C@H:13]([CH3:25])[C@H:12]([CH3:26])[CH2:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:38]3[CH:39]=[C:35]([N+:32]([O-:34])=[O:33])[N:36]=[CH:37]3)=[C:6]([O:27][CH3:28])[CH:7]=2)[CH:20]=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: COc1ccc(C[C@H](C)[C@H](C)Cc2ccc(OCCBr)c(OC)c2)cc1OC
Reactant: O=[N+]([O-])c1c[nH]cn1
Agent: C[O-]
Agent: [Na+]
Product: COc1ccc(C[C@H](C)[C@H](C)Cc2ccc(OCCn3cnc([N+](=O)[O-])c3)c(OC)c2)cc1OC
Yield: 65 %

Procedure:
The Standard Procedure 2 was followed by use of 9a (72.2 mg, 0.160 mmol, 1.0 equiv), sodium methoxide (19.1 mg, 0.353 mmol, 2.2 equiv), and 4-nitroimidazole (6a, 36.3 mg, 0.321 mmol, 2.0 equiv). After workup and purification with column chromatography (80% EtOAc in hexanes as eluant), 10a (50.3 mg, 0.104 mmol) was obtained in 65% yield as white solids: mp (recrystallized from methanol) 98.3-98.8° C.; 1H NMR (CDCl3, 400 MHz) δ 0.80 (d, J=6.8 Hz, 3H, CH3), 0.83 (d, J=6.8 Hz, 3H, CH3), 1.74 (m, 2H, 2×CH), 2.22-2.34 (m, 2H, 2×ArCH), 2.69-2.76 (m, 2H, 2×ArCH), 3.81 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 4.25 (t, J=4.8 Hz, 2H, CH2N), 4.37 (t, J=4.8 Hz, 2H, CH2O), 6.62-6.68 (m, 4H, 4×ArH), 6.71-6.78 (m, 2H, 2×ArH), 7.60 (d, J=1.4 Hz, 1H, nitroimidazole C5-H), 8.13 (d, J=1.4 Hz, 1H, nitroimidazole C2-H); 13C NMR (CDCl3, 100 MHz) δ 16.03, 16.16, 38.70, 38.93, 39.06, 39.25, 47.92, 55.61, 55.73, 55.82, 68.38, 110.98, 112.23, 112.78, 114.90, 120.62, 120.85, 120.93, 134.26, 136.55, 137.02, 144.90, 146.99, 147.98, 148.61, 149.66; IR (neat) 2957 (s), 2933 (s), 1590 (w), 1543 (s), 1516 (m), 1456 (w), 1337 (s), 1262 (m), 1235 (s), 1031 (s) cm−1; HRMS (FAB) m/z calcd for C26H34N3O6 (M+H)+: 484.2448. found: 484.2444.
Reaction SMILES: [C:1]1([C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH:2]=1.Cl[C:15]1[N:24]=[C:23]([NH2:25])[C:22]2[C:17](=[CH:18][C:19]([O:28][CH3:29])=[C:20]([O:26][CH3:27])[CH:21]=2)[N:16]=1>>[NH2:25][C:23]1[C:22]2[C:17](=[CH:18][C:19]([O:28][CH3:29])=[C:20]([O:26][CH3:27])[CH:21]=2)[N:16]=[C:15]([N:11]2[CH2:10][CH2:9][N:8]([C:6]([C:1]3[CH2:5][CH2:4][CH2:3][CH:2]=3)=[O:7])[CH2:13][CH2:12]2)[N:24]=1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: O=C(C1=CCCC1)N1CCNCC1
Product: COc1cc2nc(N3CCN(C(=O)C4=CCCC4)CC3)nc(N)c2cc1OC

Procedure:
N-(1-cyclopenten-1-ylcarbonyl)piperazine (1.8 g., 0.01 mole) and 2-chloro-4-amino-6,7-dimethoxyquinazoline (2.4 g., 0.01 mole) are reacted according to the procedure of Example 127(a). The isolated product crystallized from methanol affords analytically pure 4-amino-2-[4-(1-cyclopenten-1-ylcarbonyl)piperazinyl]-6,7-dimethoxyquinazoline, m.p. 256.5°-258.0° C. (corr.).
Reaction SMILES: CN1C2C(=CC(NS(C(F)(F)F)(=O)=O)=CC=2)C=C1C(O)=O.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C([O:38][C:39](=[O:47])[C:40]1[CH:45]=[CH:44][CH:43]=[C:42](N)[CH:41]=1)C>CN(C=O)C.C(Cl)Cl>[C:39]([OH:47])(=[O:38])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CCOC(=O)c1cccc(N)c1
Agent: Cn1c(C(=O)O)cc2cc(NS(=O)(=O)C(F)(F)F)ccc21
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(O)c1ccccc1
Temperature: 25 °C

Procedure:
To 1-Methyl-5-Trifluoromethansulfonylamino-1H-Indole-2-Carboxylic Acid (0.51 g, 1.6 mmol) in 8 ml of DMF was added HOBt (240 mg, 1.8 mmol), EDC (370 mg, 1.9 mmol), TEA (0.445, 3.2 mmol), and 3-aminobenzoic acid ethyl ester (265 mg, 1.6 mmol). The reaction mixture was stirred at room temperature for a day. The reaction was diluted with 200 ml of methylene dichloride and washed with water and brine, then concentrated. The residue was treated with 40 ml of MeOH and 20 ml of 1H NaOH. The reaction mixture was stirred at room temperature for 4 hr and then concentrated via a rotor-evaporator to remove the methanol. The aqueous solution was adjusted pH to 4 with 6N HCl. The solid was filtered, washed with water, and purified by either recrystalization with CH2Cl2/Hexane or flash column using 30% EtOAc/Hexane with 1% AcOH to give 0.19 g of 3-[1-Methyl-5-trifluoromethansulfonylamino-1H-indole-2-carbonyl)-amino]-benzoic acid as a beige solid. 1H-NMR (400 MHz, DMSO-d6) δ 12.75 (s, 1H, COOH), 11.68 (s, 1H, SNH), 10.65 (s, 1H, NHCO), 7.93 (m, 4H, ArH), 7.64 (m, 2H, H-7 & H-4), 7.38 (s, 1H, H-3), 7.20 (dd, J=1.6, 9 Hz, H-6), 4.01 (s, 3H, CH3), MS, m/z, 440 (M−H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[CH2:17]([O:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]=1[CH:30]=O)[CH3:18].C(N(C(C)C)CC)(C)C.C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:30][C:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:28]=[CH:29][C:20]=2[O:19][CH2:17][CH3:18])[CH2:13][CH2:12]1
Reactant: CCOc1ccc2ccccc2c1C=O
Reactant: c1ccc2sc(NC3CCNCC3)nc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: CCOc1ccc2ccccc2c1CN1CCC(Nc2nc3ccccc3s2)CC1
Temperature: 40 °C
Reaction time: 1 h
Yield: 8 %

Procedure:
To a solution of benzothiazol-2-yl-piperidin-4-yl-amine (23.3 mg, 0.1 mmol, 1.0 equiv) and 2-ethoxy-naphthalene-1-carbaldehyde (commercially available, 24.0 mg, 0.12 mmol, 1.2 equiv) in ethanol (2 mL) was added diisopropylethylamine (23.42 μL, 25.9 mg, 0.2 mmol, 2.0 equiv) and acetic acid (18.0 mg, 0.3 mmol, 3.0 equiv) and the mixture stirred at 40° C. After 1 h, sodium cyano borohydride (7.54 mg, 0.12 mmol, 1.2 equiv) was added and the mixture stirred at 40° C. over night. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 3.3 mg (8%) of the title compound. MS (ESI): 418.4 [M+H]+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6]([N+:21]([O-])=O)=[C:7]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)[C:8]([F:12])=[C:9]([F:11])[CH:10]=1)[CH:2]=[CH2:3].[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C.O>[CH2:1]([O:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[C:7]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)[C:6]=1[NH2:21])[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(F)c(F)c(Nc2ccc(I)cc2)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C=CCOc1cc(F)c(F)c(Nc2ccc(I)cc2)c1N
Temperature: 70 °C
Yield: 61.7 %

Procedure:
A suspension of (3-allyloxy-5,6-difluoro-2-nitro-phenyl)-(4-iodo-phenyl)-amine (Intermediate 9, 1.1 g, 2.5 mmol) in ethanol (15 mL) was stirred at 70° C. to obtain a clear solution. To this hot solution, was added a freshly prepared solution of Na2S2O4 (1.3 g, 7.6 mmol) in water (3.1 mL) and stirred the reaction mixture at 90° C. for 1 h. The progress of reaction was monitored by TLC. After completion, the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, and the organic phase was dried over anhydrous Na2SO4 and concentrated to yield 6-allyloxy-3,4-difluoro-N2-(4-iodo-phenyl)-benzene-1,2-diamine as a brown solid (620 mg). 1H-NMR (400 MHz, CDCl3): δ 4.54 (2H, d, J=4.8), 5.24 (1H, s), 5.32 (1H, d, J=10.8), 5.42 (1H, d, J=17.2), 6.06-6.02 (1H, m), 6.45 (2H, d, J=8.4), 6.57-6.62 (1H, m), 7.47 (2H, d, J=8.4).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1Br)([CH3:4])([CH3:3])[CH3:2].[C:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)#[N:19]>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:17])=[C:10]([C:23]2[CH:24]=[CH:25][C:20]([C:18]#[N:19])=[CH:21][CH:22]=2)[CH:11]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1Br
Reactant: N#Cc1ccc(B(O)O)cc1
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1-c1ccc(C#N)cc1

Procedure:
The subtitle compound was prepared by the method of example 1 step (ii) using the product from example 1 step (i) and 4-cyanophenylboronic acid. Yield 0.524 g
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH2:12][OH:13])[CH:8]=[C:9]([F:11])[CH:10]=1)[CH3:3]>C(Cl)(Cl)Cl.[O-2].[Mn+4].[O-2]>[CH3:3][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:8]=[C:9]([F:11])[CH:10]=1)[CH:12]=[O:13])[CH3:1]
Reactant: CN(C)Cc1cc(F)cc(CO)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CN(C)Cc1cc(F)cc(C=O)c1
Reaction time: 7 h

Procedure:
To a solution of {3-[(dimethylamino)methyl]-5-fluorophenyl}methanol (0.100 g, 0.546 mmol, from Step 1) in Chloroform (3 mL) was added manganese(IV) oxide (0.145 g, 1.42 mmol) and the mixture was heated in an oil bath held at 80° C. for 7 hours, The reaction mixture was filtered, rinsing with copious CHCl3 and the solvent was removed from the filtrate in vacuo. The product of the reaction, containing approximately 50% aldehyde and 50%) unreacted alcohol was used without further purification in Step 3. H NMR (300 MHz, CDCl3): δ 9.99 (d, 1H), 7.78 (dd, 1H), 7.67 (ddd, 1H), 7.52 (ddd, 1H), 4.28 (s, 2H), 2.84 (s, 6H); LCMS (M+H)+: 182.0.