Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([CH2:12][C:11](=[O:13])[O:10][C:8](=[O:9])[CH2:7]1)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2.[CH:14]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.Cl>ClCCl.O>[CH:14]1([NH:20][C:11]([CH2:12][C:1]2([CH2:7][C:8]([OH:10])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:13])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: NC1CCCCC1
Reactant: O=C1CC2(CCCCC2)CC(=O)O1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: O=C(O)CC1(CC(=O)NC2CCCCC2)CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 115.9 %

Procedure:
A mixture of 1,1-cyclohexanediacetic anhydride (0.911 g, 5.0 mmol) and cyclohexylamine (0.63 mL, 5.5 mmol) in dichloromethane (10.0 mL) was stirred overnight at room temperature. The reaction mixture was diluted with H2O (5 mL) and the aqueous layer was acidified to pH-5 using 6 N HCl. The organic layer was collected. The aqueous layer was extracted with additional dichloromethane (5 mL). The organic extracts were combined, dried with sodium sulfate, filtered and concentrated to dryness to give crude title compound (1.63 g, 95% purity). (m/z): [M+H]+ calcd for C16H27NO3, 282.21; found 282.5.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]#[C:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:21])[C:5]([O:7][CH3:8])=[O:6]>C(#N)C.C(#N)C.C(#N)C.[Pd](Cl)Cl>[Cl:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[C:13]1[NH:1][C:2]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=2
Reactant: COC(=O)c1ccc(C#Cc2c(Cl)cccc2Cl)c(N)c1
Agent: Cl[Pd]Cl
Solvent: CC#N
Product: COC(=O)c1ccc2cc(-c3c(Cl)cccc3Cl)[nH]c2c1
Temperature: 65 °C

Procedure:
A mixture of methyl 3-amino-4-(2,6-dichlorophenylethynyl)-benzoate (450 mg, 1.41 mmol) and palladium (II) chloride bis(acetonitrile) (90 mg, 347 μmol) in acetonitrile (5 mL) was heated at 65° C. for 2 h. The solvent was removed on under reduced pressure and the residue was purified by chromatography using a gradient of 10-30% heptane/ethyl acetate to give methyl 2-(2,6-dichlorophenyl)-1H-indole-6-carboxylate.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1.[CH3:18][N:19]1C(=O)CCC1>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][C:9]1[CH:10]=[C:2]([C:18]#[N:19])[C:3]2[CH:4]=[N:5][N:6]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[C:7]=2[CH:8]=1
Reactant: CN1CCCC1=O
Reactant: Cc1cc(Br)c2cnn(C3CCCCO3)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1cc(C#N)c2cnn(C3CCCCO3)c2c1
Temperature: 100 °C
Yield: 50 %

Procedure:
A mixture of 4-bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1.1 g, 3.74 mmol), Zn(CN)2 (873 mg, 7.46 mmol), and Pd(PPh3)4 (646 mg, 0.56 mmol) in NMP (25 mL) under nitrogen was heated at 100° C. overnight. After it was cooled to RT, the reaction mixture was partitioned between EtOAc (300 mL) and water (50 mL). The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel chromatography using petroleum ether:EtOAc (10:1) as eluting solvents to afford 6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonitrile as white solid (400 mg, 50%). MS (ESI): m/z=242.3 [M+1]+.
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:42][C:43]([N:45]([CH2:47][CH3:48])[CH3:46])=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:42][CH2:43][N:45]([CH2:47][CH3:48])[CH3:46])=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CCN(C)C(=O)CCl
Product: CCN(C)CCOc1ccc(CN(CC)c2cc(OC)c(OC)cc2[C@@H]2CCc3cc(O)ccc3C2)cc1F
Yield: 28 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (15 mg) and 2-chloro-N-ethyl-N-methylacetamide (7.4 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (4.1 mg) was obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=2[NH2:20])=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([N:8]1[C:12]([C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=2[NH:20][S:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:29])=[O:28])=[N:11][N:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1cccc(N)c1-c1nnnn1Cc1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1cccc(NS(=O)(=O)c2ccccc2)c1-c1nnnn1Cc1ccccc1
Reaction time: 8 h
Yield: 98.7 %

Procedure:
2-(1-Benzyl-1H-tetrazol-5-yl)-3-methylphenylamine (Intermediate 16, 0.15 g) was dissolved in pyridine (5 mL) and benzenesulfonyl chloride (0.07 g, 0.4 mmol) was added. The mixture was stirred overnight, then diluted with ethyl acetate and washed with 1N hydrochloric acid, dried with magnesium sulfate and filtered. The filtrate was evaporated to dryness and the residue was purified by flash chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane. The fractions containing the desired product were combined and evaporated to give the title compound as a white powder (0.16 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[F:9][C:10]([F:23])([O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O)[CH:11]([F:13])[F:12].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[F:9][C:10]([F:23])([O:14][C:15]1[CH:16]=[C:17]([CH2:18][NH:1][C:2]2[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=2)[CH:20]=[CH:21][CH:22]=1)[CH:11]([F:12])[F:13]
Reactant: Nc1cccc(O)c1
Reactant: O=Cc1cccc(OC(F)(F)C(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Oc1cccc(NCc2cccc(OC(F)(F)C(F)F)c2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 83.3 %

Procedure:
EX-20A) To a solution of 3-aminophenol (4.91 g, 45.0 mmol) and 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (10.0 g, 45.0 mmol) in 100 mL of 1,2-dichloroethane was added sodium triacetoxyborohydride (14.28 g 67.5 mmol) and glacial acetic acid (2.7 mL, 47.3 mmol). The reaction mixture was stirred at room temperature for 6 h then quenched with water and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over MgSO4, and concentrated in vacuo to give 11.82 g (83%) of the desired 3-[[[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]phenol product as a dark orange oil. 1H NMR (acetone-d6) δ 7.01-7.38 (m, 5H), 6.26-6.44 (m, 3H), 6.08 (t, 1H), 5.88 (tt, 1H), 4.34 (s, 2H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:2]1[O:4][CH2:3]1.[CH3:18][C:19]([NH2:30])([CH3:29])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1>>[CH2:6]([O:5][CH2:1][CH:2]([OH:4])[CH2:3][NH:30][C:19]([CH3:29])([CH3:18])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCCOCC1CO1
Reactant: COc1ccc(CC(C)(C)N)cc1
Product: CCCCCCCCCCCCOCC(O)CNC(C)(C)Cc1ccc(OC)cc1
Yield: 28.7 %

Procedure:
Using the method of Example 5, supra, dodecyl glycidyl ether (242 mg, 1.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (197 mg, 1.1 mmol) were used to prepare 121 mg of the title compound as a clear, colorless oil: GC/EI-MS, m/z (rel. int.) 422 (M+1, 1), 406 (4), 300 (100), 222 (11), 163 (23), 121 (34); 1H-NMR (CDCl3) δ 7.09 (2H, d, J=8.6), 6.83 (2H, d, J=8.6), 3.79 (3H, s), 3.76 (1H, m), 3.45 (4H, m), 2.81 (1H, dd, J=7.6 and 4.0), 2.65 (4H, m), 1.53 (2H, m), 1.26 (20H, m), 1.06 (3H, s), 1.05 (3H, s), 0.88 (3H, t, J=6.4); 13C-NMR (CDCl3) δ 1.58.1, 131.3, 130.0, 113.4, 73.5, 71.7, 69.0, 55.1, 53.4, 46.4, 44.6, 31.9, 29.6, 29.4, 29.3, 26.7, 26.6, 26.1, 22.7, 14.1; FT-IR (film) cm−1 3415 (broad, s), 1612, 1512, 1246, 1121, 825.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[C:8](C(O)=O)=[N:9][C:10]([Cl:14])=[C:11]([Cl:13])[N:12]=1.[N+:18]([O-])([OH:20])=[O:19]>>[Cl:14][C:10]1[N:9]=[C:8]([N+:18]([O-:20])=[O:19])[C:7]([NH2:6])=[N:12][C:11]=1[Cl:13]
Reactant: Nc1nc(Cl)c(Cl)nc1C(=O)O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Nc1nc(Cl)c(Cl)nc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
To 450 ml concentrated sulfuric acid cooled to 10° is added 50.0 g (0.2 m) 3-amino-5,6-dichloropyrazine carboxylic acid. To this solution cooled to 0°-5°, is added a cold solution of 15 ml fuming sulfuric acid in 15 ml fuming nitric acid dropwise over 15 minutes. The reaction mixture is stirred at 0°-5° for 2 hours and then at ambient temperature for 2 hours. The reaction mixture is then poured onto ice and the yellow solid is collected. This solid is taken up in ethyl acetate, washed twice with saturated sodium carbonate solution and then the solution is filtered through a pad of silica gel. The resulting solution is evaporated in vacuo to afford 35 g of 5,6-dichloro-3-nitropyrazinamine, m.p. 169°-170° C.
Reaction SMILES: [C:1]([N:5]1[N:9]=[N:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]([NH:37][C:38](=[O:49])[C@H:39]([C:45]([CH3:48])([CH3:47])[CH3:46])[NH:40][C:41]([O:43][CH3:44])=[O:42])[CH2:18][C@H:19]([OH:36])[C@@H:20]([NH:28]C(OC(C)(C)C)=O)[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:12][CH:11]=2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[ClH:50]>C1COCC1>[ClH:50].[C:1]([N:5]1[N:9]=[N:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]([NH:37][C:38](=[O:49])[C@H:39]([C:45]([CH3:48])([CH3:47])[CH3:46])[NH:40][C:41]([O:43][CH3:44])=[O:42])[CH2:18][C@H:19]([OH:36])[C@@H:20]([NH2:28])[CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:12][CH:11]=2)=[N:6]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)N[C@H](C(=O)NN(Cc1ccc(-c2nnn(C(C)(C)C)n2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)NN(Cc1ccc(-c2nnn(C(C)(C)C)n2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere, 200 mg (0.293 mmol) of 1-[4-(2-tert-butyl-2H-tetrazol-5-yl)-phenyl]-4(S)-hydroxy-5(S)-N-(tert-butyloxycarbonyl)amino-2-N-[N-methoxycarbonyl-(L)-tert-leucyl]amino-6-phenyl-2-azahexane are dissolved in 2.3 ml of THF; 1.6 ml of aqueous 2N HCl are added and the mixture is stirred at 50° C. for 8 hours. The reaction solution is concentrated by evaporation; the residue is taken up several times in ethanol and concentrated by evaporation again (→title compound): TLC: Rf=0.08 (CH2Cl2/MeOH 30:1); HPLC20-100(12′): tRet=9.9; 1H-NMR (CD3OD) d 8.03 and 7.50 (2d, J=8, each 2H), 7.32 (m, 5H), 4.18 and 3.91 (2d, J=4, 2H), 3.80 (m, 1H), 3.68 (s, 1H), 3.58 (s, 3H), 3.57 (m, 1H), 3.3-2.9 (m, 4H), 1.81 and 0.75 (2s, each 9H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4](Cl)[N:3]=1.[C:17]([O:21][C:22](=[O:39])[C:23]1[CH:28]=[CH:27][C:26]([NH:29][CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[C:25]([N+:36]([O-:38])=[O:37])[CH:24]=1)([CH3:20])([CH3:19])[CH3:18]>C(O)CCCC>[C:17]([O:21][C:22](=[O:39])[C:23]1[CH:28]=[CH:27][C:26]([NH:29][CH:30]2[CH2:35][CH2:34][N:33]([C:4]3[N:3]=[C:2]([NH2:1])[C:11]4[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=3)[CH2:32][CH2:31]2)=[C:25]([N+:36]([O-:38])=[O:37])[CH:24]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)c1ccc(NC2CCNCC2)c([N+](=O)[O-])c1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Solvent: CCCCCO
Product: COc1cc2nc(N3CCC(Nc4ccc(C(=O)OC(C)(C)C)cc4[N+](=O)[O-])CC3)nc(N)c2cc1OC
Temperature: 120 °C
Yield: 63.5 %

Procedure:
4-Amino-2-chloro-6,7-dimethoxyquinazoline (0.08 g, 0.33 mmol) was added to a solution of (44) (0.11 g, 0.35 mmol) in n-pentanol (5 mL) at 25° C. The mixture was heated to 120° C. and maintained at that temperature for 12 h. The reaction mixture was then cooled to room temperature and the desired product was filtered and rinsed with acetone to give 0.11 g (64%) of the title compound: TLC (Rf =0.30; 5% MeOH/CH2Cl2); 1H NMR (DMSO) δ 12.23 (s, 1H), 8.89 (s, 1H), 8.65 (s, 1H), 8.56 (s, 1H, J=2.0), 8.23 (d, 1H, J=7.8), 7.94 (d, 1H, J=9.2), 7.74 (s, 1H), 7.55 (s, 1H), 7.34 (d, 1H, J=9.3), 4.62 (d, 2H, J=13.3), 4.15 (m, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 3.35 (t, 2H, J=11.6), 2.10 (d, 2H, J=11.3), 1.74 (m, 2H), 1.53 (s, 9H); 13C NMR (DMSO) δ 163.5, 161.4, 155.2, 151.2, 146.8, 146.2, 136.3, 135.8, 130.6, 128.2, 117.9, 115.1, 104.9, 101.6, 99.1, 80.8, 56.2, 56.0, 48.8, 43.5, 30.5, 27.8; HRMS (FAB) m/z 525.2456 (M+H)+ (C26H32N6O6 requires 525.2454); Anal. (C26H32N6O6 ·1HCl) C, H, N.
Reaction SMILES: C([O:5][C:6](=[O:59])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH:14]([NH:28][C:29](=[O:56])[CH2:30][C:31]2([OH:55])[CH2:36][CH2:35][CH:34]([N:37](C(OC(C)(C)C)=O)[CH2:38][CH2:39][NH:40]C(OC(C)(C)C)=O)[CH2:33][CH2:32]2)[B:15]2[O:23]C3C(C)(C4CC(C3)C4(C)C)[O:16]2)[C:8]=1OC)(C)(C)C.B(Cl)(Cl)Cl>>[NH2:40][CH2:39][CH2:38][NH:37][CH:34]1[CH2:33][CH2:32][C:31]([CH2:30][C:29]([NH:28][CH:14]2[CH2:13][C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([C:6]([OH:5])=[O:59])[C:8]=3[O:16][B:15]2[OH:23])=[O:56])([OH:55])[CH2:36][CH2:35]1
Reactant: COc1c(CC(NC(=O)CC2(O)CCC(N(CCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Agent: ClB(Cl)Cl
Product: NCCNC1CCC(O)(CC(=O)NC2Cc3cccc(C(=O)O)c3OB2O)CC1

Procedure:
Prepared from 3-[2-(2-{4-[tert-Butoxycarbonyl-(2-tert-butoxycarbonylamino-ethyl)-amino]-1-hydroxy-cyclohexyl}-acetylamino)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-2-methoxy-benzoic acid tert-butyl ester and BCl3 following the procedure described in Step 2 of Example 1. The crude product was purified by reverse phase preparative HPLC and dried using lyophilization. ESI-MS m/z 406 (MH)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][O:8][NH2:9].[NH2:10][C:11]1[S:12][CH:13]=[C:14]([C:16](=O)[C:17]([OH:19])=[O:18])[N:15]=1>>[NH2:10][C:11]1[S:12][CH:13]=[C:14](/[C:16](=[N:9]/[O:8][CH2:7][C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=2)/[C:17]([OH:19])=[O:18])[N:15]=1
Reactant: Cn1ccnc1CON
Reactant: Nc1nc(C(=O)C(=O)O)cs1
Product: Cn1ccnc1CO/N=C(\C(=O)O)c1csc(N)n1

Procedure:
N.m.r. in solvent B: 4.73 (q, 2H), 6.93 (s, 1H). 15. The method of condensation was that described in Footnote 11. 16. N.m.r. in solvent B: 3.5 (d, 1H), 3.75 (d, 1H), 3.95 (d, 1H), 4.5 (d, 1H), 4.75 (d, 1H), 4.95 (d, 1H), 5.3 (d, 1H), 5.9 (d, 1H), 7.2 (s, 1H). 17. The starting material was prepared by reaction of O-(1-methylimidazol-2-yl)methylhydroxylamine with 2-(2-aminothiazol-4-yl)glyoxylic acid to give 2-(2-aminothiazol-4-yl)-2-[(Z)-(1-methylimidazol-2-yl)-methoxy-imino]acetic acid.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[F:7][C:8]([F:20])([F:19])[C:9]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][NH:11][N:10]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1>CC(C)=O>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][N:11]2[CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([C:8]([F:7])([F:19])[F:20])=[N:10]2)=[CH:24][CH:25]=1
Reactant: COc1ccc(CBr)cc1
Reactant: CCOC(=O)c1c[nH]nc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cn(Cc2ccc(OC)cc2)nc1C(F)(F)F
Yield: 100.1 %

Procedure:
Add K2CO3 (503 mg, 3.60 mmol) to a solution of ethyl 3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (500 mg, 2.40 mmol) in acetone (8 mL) at ambient temperature under N2. Add 1-bromomethyl-4-methoxybenzene (0.51 mL, 3.6 mmol) dropwise to the mixture, and stir overnight under N2. Quench the reaction with H2O, and extract twice with EtOAc. Dry the combined organic layers over MgSO4, filter, and concentrate under reduced pressure. Purify the residue by flash silica gel chromatography (gradient of 0 to 15% EtOAc in hexanes) to yield the title compound (789 mg, quantitative). ES/MS m/z 351.0 (M+Na).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.Cl[C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18]>C1(C)C=CC=CC=1>[CH:20]([O:19][C:17]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:18])([CH3:22])[CH3:21]
Reactant: CC(C)OC(=O)Cl
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)Nc1ccc(C2=NNC(=O)CC2C)cc1
Yield: 50.4 %

Procedure:
6.0 g (29.5 millimoles) of 6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone, 4.0 g (32.6 millimoles) of isopropyl chloroformate and 100 ml of absolute toluene are refluxed for 16 hours. The product is filtered off at 10° C., washed first with toluene and then with water, and recrystallized twice from dimethylformamide/water. 4.3 g (50% of theory) of 4,5-dihydro-6-(p-isopropoxycarbonylaminophenyl)-5-methyl-3(2H)-pyridazinone are obtained as colorless crystals, of melting point 236°-237° C.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)/[CH:7]=[CH:8]/[C:9]1[S:10][C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1.[C:21]1(=[O:25])[O:24][CH2:23][CH2:22]1>CN(C)C=O>[C:21]([CH2:22][CH2:23][O:3][C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)/[CH:7]=[CH:8]/[C:9]1[S:10][C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1)([OH:25])=[O:24]
Reactant: O=C1CCO1
Reactant: Oc1cccc(/C=C/c2nc3ccccc3s2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)CCOc1cccc(/C=C/c2nc3ccccc3s2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
To 3 ml of dimethylformamide were added 47 mg of 60% sodium hydride and 300 mg of 2-(trans-3-hydroxystyryl)benzothiazole, and the mixture was stirred at room temperature for 30 minutes. Then, 74 μl of β-propiolactone was added and the mixture was further stirred for 4.5 hours. The acidic portion was extracted in a conventional manner with chloroform, and after drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure and the crude crystals were washed with ethyl ether, followed by drying under reduced pressure to give 118 mg (yield 31%) of the title compound.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].CN(C)C1C=C(N(C)C)C=CC=1[C:16]1(C2C=CC(N(C)C)=CC=2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:18](=[O:19])[O:17]1>S(=O)(=O)(O)O>[N+:1]([C:22]1[CH:21]=[C:20]2[C:25]([CH2:16][O:17][C:18]2=[O:19])=[CH:24][CH:23]=1)([O-:4])=[O:2]
Reactant: CN(C)c1ccc(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3ccccc32)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C1OCc2ccc([N+](=O)[O-])cc21

Procedure:
Three portions of a mixture of concentrated nitric acid (0.6 ml. each portion) and concentrated sulfuric acid (0.66 ml. each portion) were added to a mixture of 3-(2,4-bis(dimethylamino)phenyl)-3-(4-(dimethylamino)phenyl)phthalide (4.17 g.) and concentrated sulfuric acid (20 ml.) with cooling. After each addition the temperature was allowed to rise to room temperature. The resulting mixture was poured onto ice and the resulting mixture was basified, affording 3-(2,4-bis(dimethylamino)phenyl)-3-(4-(dimethylamino)phenyl)-5 or 6-nitrophthalide (I: X=Y4 =(CH3)2N, Y2 =Z4 =Z7 =H, Z5 or Z6 =O2N and the other of Z5 or Z6 =H) or a mixture of both.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][C@@H:19]3[CH3:24])[N:15]=[C:14]([C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32](=O)[O:33]C4C=CC=CC=4)=[CH:27][CH:26]=3)[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.FC1C=CC(S(C(C2C=C(N3CCOC[C@@H]3C)N=C([C:67]3[CH:72]=[CH:71][C:70]([NH:73]C(=O)OC4C=CC=CC=4)=CC=3)N=2)(C)C)(=O)=O)=CC=1>>[CH:70]1([NH:73][C:32](=[O:33])[NH:31][C:28]2[CH:27]=[CH:26][C:25]([C:14]3[N:13]=[C:12]([CH2:11][S:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)(=[O:10])=[O:9])[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][C@@H:19]4[CH3:24])[N:15]=3)=[CH:30][CH:29]=2)[CH2:71][CH2:72][CH2:67]1
Reactant: C[C@H]1COCCN1c1cc(CS(=O)(=O)c2ccc(F)cc2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)c2ccc(F)cc2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Product: C[C@H]1COCCN1c1cc(CS(=O)(=O)c2ccc(F)cc2)nc(-c2ccc(NC(=O)NC3CCC3)cc2)n1

Procedure:
The following compounds were made in an analogous fashion from phenyl N-[4-[4-[(4-fluorophenyl)sulfonylmethyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate or phenyl N-[4-[4-[2-(4-fluorophenyl)sulfonylpropan-2-yl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate and the appropriate amine.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[C:12]([NH:22][CH3:23])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>ClCCl.C(N(C(C)C)C(C)C)C>[CH2:28]([O:27][C:25](=[O:26])[N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[C:12]([NH:22][CH3:23])=[CH:11][N:10]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CNc1cnc(NCc2ccccc2)cc1-c1ccccc1C
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNc1cnc(N(Cc2ccccc2)C(=O)OCc2ccccc2)cc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
To a solution of 2.03 g (6.7 mmol) N2-benzyl-N5-methyl-4-o-tolyl-pyridine-2,5-diamine in 100 ml dichloromethane and 40 ml N-ethyldiisopropylamine a solution of 2.1 ml (14.09 mmol) benzyl chloroformate in 50 ml dichloromethane was added dropwise at 0° C. After stirring for 2 h at room temperature the reaction mixture was washed with water (2×50 ml), brine (50 ml), dried (magnesium sulfate) and evaporated. Chromatography of the residue afforded 2.36 g (80%) of the title compound as light brown crystals. M.p. 110-112° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:35])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15]([C:17]3([C:20]4[CH:30]=[CH:29][C:23]5[O:24][C:25]([F:28])([F:27])[O:26][C:22]=5[CH:21]=4)[CH2:19][CH2:18]3)=[O:16])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:31]([CH3:34])([CH3:33])[CH3:32]>CO.C(N(CC)CC)C>[C:31]([C:6]1[N:5]([CH2:4][C@@H:3]([OH:35])[CH2:2][NH:1][C:25](=[O:26])[O:24][CH3:23])[C:13]2[C:8]([CH:7]=1)=[CH:9][C:10]([NH:14][C:15]([C:17]1([C:20]3[CH:30]=[CH:29][C:23]4[O:24][C:25]([F:28])([F:27])[O:26][C:22]=4[CH:21]=3)[CH2:19][CH2:18]1)=[O:16])=[CH:11][CH:12]=2)([CH3:32])([CH3:34])[CH3:33]
Reactant: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2n1C[C@H](O)CN
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)NC[C@H](O)Cn1c(C(C)(C)C)cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc21
Reaction time: 0.5 h

Procedure:
To a stirred solution (R)- N-(1-(3-amino-2-hydroxypropyl)-2-tert-butyl-1H-indol-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (0.10 g, 0.20 mmol) in methanol (1 mL) was added 2 drops of triethylamine and methylchloroformyl chloride (0.020 mL, 0.25 mmol). After 30 min, the reaction mixture was filtered and purified using reverse phase HPLC providing (S)-methyl 3-(2-tert-butyl-5-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclo-propanecarboxamido)-1H-indol-1-yl)-2-hydroxypropylcarbamate. The retention time on a three minute run is 1.40 mM. LC/MS (M+1)=544.3. 1 H NMR (400 MHz, CDCl3) δ 7.52 (d, 1H, J=2 Hz), 7.30(dd, 1H, J=2, 8 Hz), 7.28(m, 1H), 7.22(d, 1H, J=8 Hz), 7.14(d, 1H, J=8 Hz), 7.04(br s, 1H), 6.97(dd, 1H, J=2, 8 Hz), 6.24(s, 1H), 5.19(1H, br s), 4.31(dd, 1H, J=6, 15 Hz), 4.28(dd, 1H, J=11, 15 Hz), 4.18(m, 1H), 3.70(s, 3H), 3.40(dd, 1H, J=3, 6 Hz), 3.36(dd, 1H, J=3, 6 Hz), 3.26(m, 1H), 1.74(m, 2H), 1.40(s, 9 H), 1.11(m, 2 H).