Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([CH3:19])([CH2:5][N:6]1[C:14]([O:15][CH2:16][CH3:17])=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([Cl:18])=[CH:12]2)=[N:7]1)[C:3]#[N:4].[F:20][C:21]([F:32])([F:31])[C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[S:27])=[CH:24][CH:23]=1>>[Cl:18][C:11]1[CH:10]=[CH:9][C:8]2[C:13](=[C:14]([O:15][CH2:16][CH3:17])[N:6]([CH2:5][C:2]([NH:1][C:26](=[S:27])[C:25]3[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:31])[F:32])=[CH:30][CH:29]=3)([C:3]#[N:4])[CH3:19])[N:7]=2)[CH:12]=1
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: CCOc1c2cc(Cl)ccc2nn1CC(C)(N)C#N
Product: CCOc1c2cc(Cl)ccc2nn1CC(C)(C#N)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(5-chloro-3-ethoxy-2H-indazol-2-yl)-2-methylpropionitrile (52 mg, described in Example 120) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (83 mg, 93%). MS (ES): M/Z [M+H]=483. 1H NMR: (400 MHz, DMSO-d6): 1.26 (t, J=7.0 Hz, 3H), 1.71 (s, 3H), 4.52 (q, J=7.0 Hz, 2H), 4.78 (d, 1H), 4.93 (d, 1H), 7.16 (dd, J=9.3, 1.9 Hz, 1H), 7.47 (d, J=9.3 Hz, 1H), 7.85-7.89 (m, 3H), 7.96 (d, J=8.8 Hz, 2H) and 8.99 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −42.0 (s, 3F).
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[N:7][C:6]=1[Br:12])C.[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOC(C)=O.O>CCOCC>[Br:12][C:6]1[C:5]([CH2:4][OH:3])=[CH:10][C:9]([CH3:11])=[CH:8][N:7]=1
Reactant: CCOC(=O)c1cc(C)cnc1Br
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: O
Product: Cc1cnc(Br)c(CO)c1
Reaction time: 1 h

Procedure:
A solution of 2-bromo-5-methyl-nicotinic acid ethyl ester (0.4 g, 1.63 mmol) (synthesized according to Ponticello's procedure J. Org. Chem., 1978, 43, 2529-2535) in Et2O (10 mL) was dropwise added LiAlH4 (1.0 M in THF, 1.79 mL, 1.79 mmol) at −78° C. After the addition was completed, the suspension was stirred at −78 C for 1 h. EtOAc was carefully added at −78° C. and then water was dropwise added. The organic portion was brought to the usual work-up to give the product without further purification. 1H NMR (300 MHz, CDCl3) 8.13 (s, 1H), 7.68 (s, 1H), 4.73 (s, 2H), 2.33 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][C:5]2[O:10][C:9](=[O:11])[CH:8]=[C:7]([CH:12]([CH3:14])[CH3:13])[C:6]=2[CH:15]=1.Cl[CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[CH3:17][O:16][C:3]1[C:2]([O:1][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:24][CH2:23]2)=[CH:15][C:6]2[C:7]([CH:12]([CH3:13])[CH3:14])=[CH:8][C:9](=[O:11])[O:10][C:5]=2[CH:4]=1
Reactant: COc1cc2oc(=O)cc(C(C)C)c2cc1O
Reactant: ClCCCN1CCN(c2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2oc(=O)cc(C(C)C)c2cc1OCCCN1CCN(c2ccccc2)CC1
Yield: 88 %

Procedure:
4.0 g (17 mmol) 6-hydroxy-7-methoxy-4-(1-methylethyl)-2H-1-benzopyran-2-one (example 105), 4.7 g (20.5 mmol) 1-(3-chloropropyl)-4-phenylpiperazine, 4.7 g (34 mmol) potassium carbonate and 1.0 g potassium iodide are agitated in 300 ml DMF for 44 h under nitrogen at 60° C. After filtration and removal of the solvent in vacuum, the residue is taken up in chloroform and washed with dilute sodium hydroxide solution and with water, dried over sodium sulfate and then evaporated again. Yield 5.5 g (74%) of crystals with a fusion point of 94°-96° C. (from isopropanol and TBME). Fumarate: method E; yield 88%; fusion point 175°-176° C. (from isopropanol and ethanol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].OS(O)(=O)=O.[N+:16]([O-])([OH:18])=[O:17]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:16]([O-:18])=[O:17])=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)c1ccccc1F
Agent: O=S(=O)(O)O
Product: CC(=O)c1cc([N+](=O)[O-])ccc1F
Temperature: -15 °C
Reaction time: 0.25 h

Procedure:
2′-Fluoroacetophenone (11.04 g) was dropwise added to concentrated H2SO4 (46 mL) at −20° C. After the addition was complete, a thoroughly mixed solution of fuming nitric acid (6.4 mL) and concentrated H2SO4 (18 mL) was added dropwise at −15° C. The reaction mixture was stirred at −15° C. for 15 minutes and then poured into 500 g of ice. The resulting solid was collected, washed with and dissolved in CH2Cl2. The organic layer was washed with water, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (25% ethyl acetate in hexane) to give 8 g of the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[CH2:17]O)=[N:9]2)=[CH:4][CH:3]=1.CO.C(Cl)(Cl)[Cl:25]>O=S(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[CH2:17][Cl:25])=[N:9]2)=[CH:4][CH:3]=1
Reactant: OCc1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Reactant: ClC(Cl)Cl
Solvent: CO
Solvent: O=S(Cl)Cl
Product: ClCc1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 813 mg (2.75 mmol) of trans-3-[2-(7-chloroquinolin-2-yl)ethenyl]benzyl alcohol in 40 ml of CHCl3, 1.0 ml of SOCl2 was added, followed by stirring at room temperature for 24 hours. A small amount of MeOH was added to the reaction mixture and the solvent was distilled off under reduced pressure, whereby trans-3-[2-(7-chloroquinolin-2-yl)ethenyl]benzyl chloride was obtained as pale yellow powder.
Reaction SMILES: [CH2:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14].[C:15]12([C:25](Cl)=[O:26])[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2.C(N(CC)CC)C>O1CCCC1>[CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:14][C:25]([C:15]12[CH2:24][CH:19]3[CH2:18][CH:17]([CH2:23][CH:21]([CH2:20]3)[CH2:22]1)[CH2:16]2)=[O:26]
Reactant: NC1CCc2oc3ccccc3c2C1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc2oc3c(c2c1)CCCC3)C12CC3CC(CC(C3)C1)C2
Yield: 56.1 %

Procedure:
Following the procedure of Example 1, tetrahydro-dibenzofuran-2-ylamine (0.94 g, 5.0 mmol), adamantanecarbonyl chloride (1.1 g, 5.3 mmol), and triethylamine (2.1 mL, 15 mmol) in tetrahydrofuran (20 mL) provided adamantane-1-carboxylic acid (6,7,8,9-tetrahydro-dibenzofuran-2-yl)-amide (0.98 g). Mp 247-248° C.; Anal. Calcd. for C23H27NO2: C, 79.05; H, 7.79; N, 4.01; Found: C, 78.75; H, 7.73; N, 3.75.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([NH:23][C:24](=[O:36])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH:32]([CH3:34])[CH3:33])=[C:27]([Cl:35])[CH:26]=1)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[C:18]([CH:19]([OH:21])[CH3:20])=[CH:17][CH:16]=[CH:15][N:14]3[CH:22]=2)=[CH:7][CH:6]=1.CCN=C=NCCCN(C)C.C(N(CC)C(C)C)(C)C.[CH3:57][N:58]([CH3:63])[CH2:59][C:60](O)=[O:61]>C(Cl)Cl.O>[Cl:35][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=1[O:31][CH:32]([CH3:33])[CH3:34])[C:24]([NH:23][C@@H:3]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[C:18]([CH:19]([OH:21])[CH3:20])=[CH:17][CH:16]=[CH:15][N:14]3[CH:22]=2)=[CH:7][CH:6]=1)[CH2:2][NH:1][C:60](=[O:61])[CH2:59][N:58]([CH3:63])[CH3:57])=[O:36]
Reactant: CC(C)Oc1ccc(C(=O)N[C@H](CN)Cc2ccc(-c3cn4cccc(C(C)O)c4n3)cc2)cc1Cl
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1ccc(C(=O)N[C@H](CNC(=O)CN(C)C)Cc2ccc(-c3cn4cccc(C(C)O)c4n3)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.3 %

Procedure:
A mixture of N-[(1S)-2-amino-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)ethyl]-3-chloro-4-[(1-methylethyl)oxy]benzamide (0.912 g, 1.80 mmol), EDCI (0.69 g, 3.6 mmol), N,N-diisopropylethylamine (0.466 g, 3.6 mmol), and N,N-dimethylglycine (0.372 g, 3.6 mmol) in methylene chloride (17 mL) was stirred overnight at room temperature. The reaction was diluted with water, washed with brine, dried (Na2SO4), and concentrated. The residue was purified by flash chromatography on silica gel (8%-10% MeOH:CH2Cl2) to give the title compound (0.515 g, 48%) as a pale yellow solid. MS (ES+) m/e 592 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]2[C:18]([C:19]#[N:20])=[CH:17][N:16]=[CH:15][C:14]=2I)[C:5]([CH3:11])=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.C([Sn](CCCC)(CCCC)[C:27]1[O:28][C:29]2[CH:35]=[CH:34][C:33]([CH:36]=[O:37])=[CH:32][C:30]=2[CH:31]=1)CCC.C(OCC)(=O)C>CN(C=O)C.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>[Cl:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]2[C:18]([C:19]#[N:20])=[CH:17][N:16]=[CH:15][C:14]=2[C:27]2[O:28][C:29]3[CH:35]=[CH:34][C:33]([CH:36]=[O:37])=[CH:32][C:30]=3[CH:31]=2)[C:5]([CH3:11])=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2
Reactant: Cc1c(Nc2c(I)cncc2C#N)cc(Cl)c2[nH]ccc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2cc(C=O)ccc2o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(Nc2c(C#N)cncc2-c2cc3cc(C=O)ccc3o2)cc(Cl)c2[nH]ccc12
Temperature: 110 °C
Yield: 82.2 %

Procedure:
To a stirred solution of 4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]-5-iodonicotinonitrile (405 mg, 1 mmol) in DMF (7 mL) was added 2-(tributylstannyl)-1-benzofuran-5-carbaldehyde (609 mg, 1.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (110 mg, 0.1 mmol) under nitrogen atmosphere, the reaction mixture was heated at 110° C. for 1.5 h and cooled to room temperature and ethyl acetate was added to the resulting mixture. The organic phase was washed with water, saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated and the residue was purified by flash column chromatography (ethyl acetate/hexane) to give 4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]-5-(5-formyl-1-benzofuran-2-yl)nicotinonitrile as a yellow solid (351 mg, 82%). HPLC retention time: 12.4 min.(g); and MS: 427.3 (M+H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23](=[O:25])[NH2:24])[CH:5]=[CH:6][CH:7]=1.Br[CH2:27][C:28]([O:30][CH3:31])=[O:29]>CN(C=O)C.C(OCC)(=O)C>[I:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH2:27][C:28]([O:30][CH3:31])=[O:29])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23](=[O:25])[NH2:24])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CBr
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(I)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cccc(I)c1
Reaction time: 0.05 h
Yield: 86 %

Procedure:
40% Methanolic Triton B (0.07 mL, 0.15 mM) was added to a solution of the 9-[(3-iodophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (60 mg, 0.13 mM) in 8 mL DMF at room temperature. After 3 minutes, methyl bromoacetate (30 mg, 0.19 mM) was added and the resultant mixture stirred at room temperature for 17 hours. The mixture was diluted with ethyl acetate, washed with H2O and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 60 mg (86%) of the {9-[(3-iodophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a white solid. 1H NMR (DMSO-d6) δ7.6-7.0 (m, 11H), 6.6 (d, 1H, J=8 Hz), 5.7 (s, 2H), 4.9 (s, 2H), and 3.75 (s, 3H). IR (KBr, cm−1) 3500, 3350, 1727, 1642, 1291, 1236, and 772. MS (ES) m/e 515.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([OH:11])[CH2:6]1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCCCCC.CN(C)C=O>[CH2:12]([O:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([OH:11])[CH2:6]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: OCC1CCCC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: OC1CCCC(COCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 5 h
Yield: 56.4 %

Procedure:
50% Sodium hydride (5.77 g; 120 mmol) is washed with n-hexane, and dimethylformamide (50 ml) is added thereto. To the resultant mixture, 3-hydroxymethylcyclohexanol (9) (10.0 g; 76.8 mmol) is dropwise added under ice-cooling, and then benzyl bromide (13.15 g; 76.8 mmol) is dropwise added thereto under ice-cooling. The resulting mixture is stirred at a temperature of 0° to 10° C. for 5 hours. The reaction mixture is poured into ice-water, extracted with toluene. The organic layer is washed with water, dried and concentrated under reduced pressure. The residue is chromatographed on a silica gel column to give 3-benzyloxymethylcyclohexanol (10) (9.55 g).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[NH:4][CH:3]=1.[H-].[Na+].[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C)C=O>[C:15]1([S:21]([N:4]2[C:5]3=[N:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[C:10]3[C:2]([I:1])=[CH:3]2)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1cnc2[nH]cc(I)c2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cnc2c(c1)c(I)cn2S(=O)(=O)c1ccccc1
Reaction time: 0.17 h
Yield: 70.7 %

Procedure:
To a solution of 3-iodo-5-methoxy-1H-pyrrolo[2,3-b]pyridine (15, 4.30 g, 15.7 mmol) in 53.6 mL of N,N-dimethylformamide under nitrogen, sodium hydride (0.690 g, 60% in mineral oil, 17.2 mmol) was added. After 10 minutes, benzenesulfonyl chloride (11, 2.20 mL, 17.2 mmol) was added and the reaction was cooled in a water bath. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate purified by silica gel column chromatography, eluting with 30-100% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (16, 4.60 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][C:7]=1[CH3:14]>C(Cl)(Cl)Cl.O=[Mn]=O>[CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[O:13])=[CH:8][C:7]=1[CH3:14]
Reactant: COC(=O)CCc1ccc(CO)cc1C
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: COC(=O)CCc1ccc(C=O)cc1C
Temperature: 25 °C
Reaction time: 96 h
Yield: 60 %

Procedure:
A mixture of 3-(4-Hydroxymethyl-2-methyl-phenyl)-propionic acid methyl ester (0.49 g, 2.35 mmol) and MnO2 (0.80 g, 9.20 mmol) in chloroform (5 mL) is stirred at RT for 4 days. The mixture is filtered through Celite; the Celite is washed with copious amounts of EtOAc. The filtrate is concentrated and purified by flash chromatography to yield the title compound (0.29.g, 60%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[CH2:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)[CH:17]=1)=[O:14].[N:31]1[CH:36]=[CH:35][CH:34]=[C:33](B(O)O)[CH:32]=1>>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:13](=[O:14])[CH2:12][C:7]2[C:8]3[C:3](=[C:2]([C:33]4[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=4)[CH:11]=[CH:10][CH:9]=3)[CH:4]=[CH:5][CH:6]=2)=[CH:17][C:18]=1[N:24]1[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]1
Reactant: COc1ccc(NC(=O)Cc2cccc3c(Br)cccc23)cc1N1CCN(C)CC1
Reactant: OB(O)c1cccnc1
Product: COc1ccc(NC(=O)Cc2cccc3c(-c4cccnc4)cccc23)cc1N1CCN(C)CC1

Procedure:
The title compound was prepared from 5-bromo-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]naphth-1-ylacetamide (E20) and 3-pyridylboronic acid using a similar procedure to Example 4 (13%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].[Cl:10][C:11]1[N:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14]>>[Cl:10][C:11]1[C:12]([C:13]([NH:1][C:2]2[C:3]([Cl:9])=[N:4][CH:5]=[CH:6][C:7]=2[CH3:8])=[O:14])=[CH:16][CH:17]=[CH:18][N:19]=1
Reactant: Cc1ccnc(Cl)c1N
Reactant: O=C(Cl)c1cccnc1Cl
Product: Cc1ccnc(Cl)c1NC(=O)c1cccnc1Cl

Procedure:
3-Amino-2-chloro-4-methylpyridine of Formula A is condensed with 2-chloronicotinoyl chloride of Formula B to give 2-chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridine carboxamide of Formula II, which is then reacted with cyclopropylamine to give N-(2-chloro-4-methyl-3-pyridyl)-2 -cyclopropylamino) -3-pyridine carboxamide of Formula III. Then N-(2-chloro-4-methyl-3-pyridyl)-2-(cyclopropylamino)-3-pyridine carboxamide was cyclized in the presence of sodium hydride to give nevirapine of Formula I. The disadvantage of the above process is use of large excess of cyclopropylamine. Further, with the above process undesirable side products are obtained during the reaction, which makes the product impure.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[N:10]N[C:8]=2N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(CC#N)C=CC=CC=1.C([O:24]C(OCC)OCC)C>>[O:24]=[CH:8][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:11]#[N:10]
Reactant: CCOC(OCC)OCC
Reactant: Nc1[nH]ncc1-c1ccccc1
Solvent: N#CCc1ccccc1
Product: N#CC(C=O)c1ccccc1

Procedure:
4-Aryl-3-aminopyrazoles such as 4-phenyl-2H-pyrazol-3-ylamine may be prepared according to the procedures described in patent EP269,859 and illustrated in scheme 8, by reacting benzeneacetonitrile with orthoformic acid triethyl ester to give 3-oxo-2-phenyl-propionitrile which is reacted with hydrazine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[CH:11][N:12]=2)=[CH:4][C:3]=1[CH2:13][C:14]([OH:16])=O.CN(C)C=O.C(Cl)(=O)C([Cl:25])=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[CH:11][N:12]=2)=[CH:4][C:3]=1[CH2:13][C:14]([Cl:25])=[O:16]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1cc(-c2ncco2)ccc1Br
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1cc(-c2ncco2)ccc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the title compound of Step (B) and 0.048 ml dimethylformamide (DMF) in 19 ml CH2Cl2, oxalyl chloride (2M in CH2Cl2, 2.38 ml, 4.75 mmol) was added. The reaction was stirred at room temperature for 1 hour and concentrated to give the title compound of this step as a gum.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH:2]=[CH:3][CH2:4][CH2:5][CH3:6].[CH:9](=O)CCCC>O>[C:1]([OH:8])(=[O:7])[CH:2]=[CH:3][CH2:4][CH2:5][CH2:6][CH3:9]
Reactant: CCCC=CC(=O)O
Reactant: CCCCC=O
Solvent: O
Product: CCCCC=CC(=O)O
Yield: 84.8 %

Procedure:
The procedure followed was analogous to part (b) of Example 1, with the exception that (before the cracking reaction) the mixture was heated with 50 g of water at 90° C. for 60 minutes. 268 g of heptenoic acid (boiling point 139°-141° C./25) were obtained, corresponding to a yield of 84.8%, relative to valeraldehyde which had reacted.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:26])[CH2:9][NH:10][C@H:11]([CH3:25])[CH2:12][C:13]2[C:21]3[C:16](=[C:17]([C:22]([OH:24])=[O:23])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[CH2:32](O)[CH3:33]>>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:26])[CH2:9][NH:10][C@H:11]([CH3:25])[CH2:12][C:13]2[C:21]3[C:16](=[C:17]([C:22]([O:24][CH2:32][CH3:33])=[O:23])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: C[C@H](Cc1c[nH]c2c(C(=O)O)cccc12)NC[C@H](O)c1cccc(Cl)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cccc2c(C[C@@H](C)NC[C@H](O)c3cccc(Cl)c3)c[nH]c12
Temperature: 150 °C
Yield: 93 %

Procedure:
3-{(2R)-2-[2-(3-Chlorophenyl)-(2R)-2-hydroxyethylamino]propyl}-1H-indole-7-carboxylic acid (50 mg, 0.134 mmol) is dissolved in ethanol (5 mL), and thereto are added conc. sulfuric acid (0.05 mL) and Molecular Sieves 4A powder (trade name, 0.3 g), and the mixture is heated at 150° C. for 16 hours. After cooling, the insoluble materials are removed by filtration, and a saturated aqueous sodium hydrogen carbonate solution is added to the filtrate. The mixture is evaporated under reduced pressure to remove ethanol, and the resultant is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over sodium sulfate, and concentrated. The residue is purified by silica gel column chromatography (chloroform/ethanol=4/1) to give the title compound (50 mg, yield: 93%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]([C:11]#[N:12])=[C:6](SC)[S:7][CH3:8])[CH3:2].FC(F)(F)C(O)=O.[CH:21]1([NH:24][C:25](=[O:35])[C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([NH:33][NH2:34])[CH:27]=2)[CH2:23][CH2:22]1.C(N(C(C)C)CC)(C)C>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[C:6]([S:7][CH3:8])=[N:34][N:33]([C:28]2[CH:27]=[C:26]([C:25](=[O:35])[NH:24][CH:21]3[CH2:23][CH2:22]3)[CH:31]=[CH:30][C:29]=2[CH3:32])[C:11]=1[NH2:12])=[O:13])[CH3:2]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NN
Reactant: CCOC(=O)C(C#N)=C(SC)SC
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)c1c(SC)nn(-c2cc(C(=O)NC3CC3)ccc2C)c1N
Temperature: 65 °C
Yield: 68.3 %

Procedure:
To a solution of 2-cyano-3,3-bis-methylsulfanyl-acrylic acid ethyl ester 15 (78.0 mg, 0.359 mmol) in ethanol (3 ml) was added N-cyclopropyl-3-hydrazino-4-methyl-benzamide trifluoroacetic acid salt (0.100 g, 0.313 mmol) and diisopropylethylamine (0.0626 ml, 0.359 mmol). The mixture was heated to 65° C. for 2 h. The mixture was cooled to room temperature. Solvents were removed in vacuo. EtOAc and ether was added to the residue and a solid precipitated. The solid was collected on a flitted funnel and was washed with EtOAc and ether to give the desired 5-amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-3-methylsulfanyl-1H-pyrazole-4-carboxylic acid ethyl ester 16 as a white solid (80 mg, 59%). HPLC (4 minute 10-90 gradient) tR 2.18 min; MS m/z 375.1 [M+H]+; 1H NMR (DMSO-d6, 300 MHz) δ 8.47 (d, J=3.7, 1H), 7.90 (d, J=7.9, 1H), 7.78 (s, 1H), 7.49 (d, J=8.0, 1 H), 6.81 (bs, 2H), 6.30 (s, 2H), 2.86 (m, 1H), 2.45 (s, 3H), 2.11 (s, 3H), 0.68 (m, 2H), 0.57 (m, 2H) ppm.HPLC (4 minute 10-90 gradient) tR 1.66 min; MS m/z 378.1 [M+H]+; 1H NMR (DMSO-d6, 300 MHz) δ 8.50 (d, J=2.6, 1H), 7.92 (d, J=7.9, 1 H), 7.81 (s, 1H), 7.51 (d, J=7.9, 1H), 6.24 (bs, 2H), 4.22 (q, J=6.6, 2 H), 2.88 (m, 1H), 2.35 (s, 3H), 2.14 (s, 3H), 1.29 (t, J=6.7, 3 H), 0.72 (m, 2H), 0.58 (m, 2H) ppm; 13C NMR (DMSO-d6, 125 MHz) δ 166.0, 163.1, 151.8, 148.5, 139.4, 135.8, 132.9, 131.1, 128.2, 126.7, 91.3, 58.9, 23.0, 17.2, 14.4, 12.3, 5.6 ppm.
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][CH2:5][NH:6][C:7](=[O:38])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]=3)=[CH:28][CH:27]=2)[C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[CH:20]=2)=[O:17])=[CH:10][CH:9]=1.[OH-].[Li+].Cl>C1COCC1.O>[Br:25][C:21]1[CH:20]=[C:19]([NH:18][C:16](=[O:17])[N:15]([CH2:14][C:11]2[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:39])=[O:2])=[O:38])=[CH:13][CH:12]=2)[C:26]2[CH:27]=[CH:28][C:29]([C:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]=3)=[CH:30][CH:31]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)CCNC(=O)c1ccc(CN(C(=O)Nc2cccc(Br)c2)c2ccc(C3=CCCCC3)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCNC(=O)c1ccc(CN(C(=O)Nc2cccc(Br)c2)c2ccc(C3=CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.7 %

Procedure:
3-{4-[3-(3-Bromophenyl)-1-(4-cyclohex-1-enylphenyl)ureidomethyl]benzoylamino}propionic acid methyl ester (0.64 g, 1.08 mmol) was dissolved in THF (10 ml) and lithium hydroxide (0.043 g, 1.08 mmol) in water (1 ml) was added and the resulting mixture was stirred at room temperature for 16 hours. More lithium hydroxide (0.043 g, 1.08 mmol) in water (1 ml) was added and, after 4 hours, 1N hydrochloric acid (2.2 ml) was added. The mixture was concentrated in vacuo and the residue was triturated with water, filtered and dried in vacuo at 40° C. to afford 0.378 g (61%) of 3-{4-[3-(3-bromophenyl)-1-(4-cyclohex-1-enylphenyl)ureidomethyl]benzoylamino}propionic acid.