Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Cl:9][C:10]1[C:11]2[S:18][CH:17]=[CH:16][C:12]=2[N:13]=[CH:14][N:15]=1.[I:19]I.O>C1COCC1>[Cl:9][C:10]1[C:11]2[S:18][C:17]([I:19])=[CH:16][C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: II
Reactant: Clc1ncnc2ccsc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Clc1ncnc2cc(I)sc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.6 %

Procedure:
To a solution of LDA (1.8M, 20.6 mL, 37.1 mmol) in THF (65 mL) at −78° C. was added 4-chloro-thieno[3,2-d]pyrimidine (5.26 g, 31 mmol) in THF (50 mL) dropwise over 1 hour. After stirring for 20 minutes, I2 (12.7 g, 50 mmol) in THF (40 mL) was added to the mixture at −78° C. dropwise. The mixture was stirred at the same temperature for 20 minutes and then warmed up to room temperature for 2 hours. The mixture was poured into water (100 mL) and stirred for 30 minutes. The solid was filtered and washed with water and Hexane-Hexanes/DCM (50:1) to afford the product 4-Chloro-6-iodothieno[3,2-d]pyrimidine (6.86 g, 75%). 1H NMR (DMSO, 400 Hz) δ 8.97 (s, 1H), 8.15 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH2:9])=[C:7]([O:10][CH3:11])[N:6]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([O:18][CH3:19])[CH2:14][CH2:13]2)[N:4]=1.C(N(CC)CC)C.[C:27]([CH2:31][C:32](Cl)=[O:33])([CH3:30])([CH3:29])[CH3:28].O>C(OCC)(=O)C.COC(C)(C)C.CCCCCCC>[CH3:11][O:10][C:7]1[C:8]([NH:9][C:32](=[O:33])[CH2:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[C:3]([O:2][CH3:1])[N:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([O:18][CH3:19])[CH2:14][CH2:13]2)[N:6]=1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: COc1nc(N2CCC(OC)CC2)nc(OC)c1N
Solvent: COC(C)(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: COc1nc(N2CCC(OC)CC2)nc(OC)c1NC(=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
To a solution of 4,6-dimethoxy-2-(4-methoxypiperidin-1-yl)pyrimidin-5-amine (36.97 g, 137.8 mmol), triethylamine (15.25 g, 21.0 mL, 150.7 mmol) in ethyl acetate (370 mL) was added tert-butylacetyl chloride (20.26 g, 21.0 mL, 150.5 mmol, 1.1 equiv) dropwise over 15 min. The resulting suspension was stirred overnight at RT, then poured into water, stirred 30 min, and subsequently transferred to a separatory funnel rinsing with ethyl acetate (100 mL). The organic extract was separated and washed with brine (100 mL), dried over magnesium sulfate, filtered, and concentrated to provide yellow-orange solids, which were taken up in 1:1 heptane: methyl tert-butylether (500 mL) and stirred at RT. The resulting suspension was filtered, and the solids were washed with 1:1 heptane: methyl tert-butylether (100 mL) and dried to afford 39.76 g of N-(4,6-dimethoxy-2-(4-methoxypiperidin-1-yl)pyrimidin-5-yl)-3,3-dimethylbutanamide, Example 1, as a white solid. 1H NMR (CDCl3) δ 6.14 (br. s., 1H) 4.23 (ddd, J=14.2, 5.7, 4.5 Hz, 2H) 3.87 (s, 6H) 3.40-3.48 (m, 1H) 3.39 (s, 3H) 3.37 (assumed ddd, J=13.5, 9.2, 3.3 Hz, 2H partially obscured by singlet) 2.20 (s, 2H) 1.83-1.99 (m, 2H) 1.47-1.61 (m, 2H) 1.10 (s, 9H). MS: (ESI) m/z=367.2 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][C:13](=[O:17])[NH:14]2)=[CH:9][CH:8]=1.[Cl:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH:22]1[CH:21]=[C:20]([N:26]2[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]3[CH:8]=[CH:9][C:10]4[CH2:11][CH2:12][C:13](=[O:17])[NH:14][C:15]=4[CH:16]=3)[CH2:28][CH2:27]2)[C:19]([Cl:18])=[C:24]([Cl:25])[CH:23]=1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Reactant: O=C1CCc2ccc(OCCCCBr)cc2N1
Product: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1

Procedure:
7-(4-bromobutoxy)-3,4-dihydrocarbostyril, is reacted with 1-(2,3-dichlorophenyl)piperazine and the thus obtained crude aripiprazole crystals are recrystallized from ethanol.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][SH:12])=[CH:9][CH:8]=1)[CH2:4][CH3:5].[C:15]([N:19]1[C:24](=[O:25])[C:23]([CH3:26])=[C:22](Cl)[CH:21]=[N:20]1)([CH3:18])([CH3:17])[CH3:16].O>CN(C)C=O>[C:15]([N:19]1[C:24](=[O:25])[C:23]([CH3:26])=[C:22]([S:12][CH2:11][C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:3][CH2:4][CH3:5])=[CH:14][CH:13]=2)[CH:21]=[N:20]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: Cc1c(Cl)cnn(C(C)(C)C)c1=O
Reactant: CCCOc1ccc(CS)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1ccc(CSc2cnn(C(C)(C)C)c(=O)c2C)cc1
Yield: 46.3 %

Procedure:
To 5 ml of dry N,N-dimethylformamide was added 0.24 g of 55% sodium hydride. The resulting mixture was kept at 0° C. and added dropwise with a solution of 0.91 g of p-propoxybenzyl mercaptan dissolved in 5 ml of N,N-dimethylformamide. After ten minutes passed, the resulting mixture was added dropwise with a solution of 1.0 g of 2-t-butyl-5-chloro-4-methyl-3(2H)-pyridazinone dissolved in 5 ml of N,N-dimethylformamide. After completion of dropwise addition, the resulting mixture was reacted at room temperature for four hours. The resulting solution was poured into 50 ml of water and extracted twice with 50 ml of diethyl ether. The resulting organic layer was dried over anhydrous sodium sulfate, and freed of solvent by distillation under reduced pressure to give 1.7 g of crude product. The crude product was fractionated on thin layer chromatography to obtain 0.8 g of 2-t-butyl-4-methyl-5-(p-propoxybenzylthio)-3(2H)-pyridazinone.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[C:19]([C:21]3[N:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[C:23]([C:30]4[CH:31]=[N:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=4)[N:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:29][CH:27]([F:28])[C:25]1[CH:24]=[C:23]([C:30]2[CH:31]=[N:32][C:33]([C:36]([F:37])([F:39])[F:38])=[CH:34][CH:35]=2)[N:22]=[C:21]([C:19]2[CH:18]=[CH:17][N:16]=[C:15]([C:11]3[CH:10]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:14]=[CH:13][CH:12]=3)[CH:20]=2)[N:26]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)F)n3)ccn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)F)n3)ccn2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 38.9 %

Procedure:
To a cooled and stirred solution of 3-{4-[4-difluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonic acid tert-butylamide (0.16 g) in dichloromethane (4 ml) was added TFA (4 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (25 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by column chromatography on silica gel (dichloromethane/MeOH/NH4OH 16:1:0.1) and trituration (diethyl ether) yielded the title compound as a white solid (0.056 g, 22%). MS (ISP) 508.1 [(M+H)+]; mp 264.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:21]([O-:23])=[O:22])[CH:5]=[C:6]([Cl:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]C)=[C:11]([CH:17]([CH3:19])[CH3:18])[CH:10]=1.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N+:21]([O-:23])=[O:22])[CH:5]=[C:6]([Cl:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH:17]([CH3:19])[CH3:18])[CH:10]=1
Reactant: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1C(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)c1cc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)ccc1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3,5-Dichloro-4-(3'-isopropyl-4'-methoxyphenoxy)-nitrobenzene (10.63 g) in 100 ml. dichloromethane is cooled in a dry ice/acetone bath and 60 ml of 1M boron tribromide in dichloromethane is added at less than -40°. After addition is completed, the mixture is stirred 18 hours at room temperature, poured into ice, and extracted twice with ethyl acetate. The combined organic layers are dried, filtered, and stripped to yield 3,5-dichloro-4-(3'-isopropyl-4'-hydroxyphenoxy)-nitrobenzene. NMR(CDCl3): δ1.2 (6H,d), 3.3 (1H,m), 6.5 (1H, d of d), 6.7 (1H,d), 6.8 (1H,d), 8.3 (2H,s).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N:12]2[CH:16]=[N:15][N:14]=[CH:13]2)=[CH:4][C:3]=1Br.[CH3:18][N:19]1CCCC1=O>>[NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N:12]2[CH:16]=[N:15][N:14]=[CH:13]2)=[CH:4][C:3]=1[C:18]#[N:19]
Reactant: CN1CCCC1=O
Reactant: Nc1c(Br)cc(-n2cnnc2)cc1C(F)(F)F
Product: N#Cc1cc(-n2cnnc2)cc(C(F)(F)F)c1N

Procedure:
The following compound, m.p. 283°, was similarly prepared to the previous Preparation using 4-(4-amino-3-bromo-5-trifluoromethylphenyl)-1,2,4-triazole, cuprous cyanide and 1-methyl-2-pyrrolidone as the starting materials: ##STR148##
Reaction SMILES: [CH2:1]([NH:3][C:4]([N:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([O:20]C)=[O:19])[CH:13]=2)[C:10]([C:22]#[N:23])=[C:9]([CH3:24])[NH:8][C:7]1=[O:25])=[O:5])[CH3:2].CO.[OH-].[Li+].Cl>O>[CH2:1]([NH:3][C:4]([N:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([OH:20])=[O:19])[CH:13]=2)[C:10]([C:22]#[N:23])=[C:9]([CH3:24])[NH:8][C:7]1=[O:25])=[O:5])[CH3:2]
Reactant: CCNC(=O)N1C(=O)NC(C)=C(C#N)C1c1cccc(C(=O)OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCNC(=O)N1C(=O)NC(C)=C(C#N)C1c1cccc(C(=O)O)c1
Reaction time: 1 h
Yield: 91.4 %

Procedure:
To a mixture of 6-(3-carbomethoxyphenyl)-5-cyano-3,6-dihydro-4-methyl-2-oxo-1-(2H)-pyrimidinecarboxylic acid, 1-ethyl amide (0.34 g, 1.0 mmol), MeOH (9 mL) and water (3 mL) at 0° C. was added lithium hydroxide (0.84 g, 20.0 mmol). The reaction mixture was stirred for 1 h, acidified to pH 2 with 1 N HCl and extracted with EtOAc. The extract was dried (MgSO4) and concentrated in vacuo to give 6-(3-carboxyphenyl)-5-cyano-3,6-dihydro-4-methyl-2-oxo-1-(2H)-pyrimidinecarboxylic acid, 1-ethyl amide as a colorless solid (0.30 g, 92%): 1H NMR (MeOH-d4, 400 MHz) δ 8.98 (s, 1H), 7.89 (m, 2H), 7.46 (d, 1H, J=7.5 Hz), 7.42 (t, 1H, J=7.5 Hz), 6.12 (s, 1H), 3.16 (m, 2H), 2.06 (s, 3H), 1.03 (t, 3H, J=7.0 Hz).
Reaction SMILES: [SH:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:23])[CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:8]=2)=[N:4][N:3]=1.Cl[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:34][CH3:35])=[C:30]([CH:33]=1)[C:31]#[N:32]>>[C:31]([C:30]1[CH:33]=[C:26]([CH:27]=[CH:28][C:29]=1[O:34][CH3:35])[CH2:25][S:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:23])[CH2:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:8]=2)=[N:4][N:3]=1)#[N:32]
Reactant: O=C(CCc1ccccc1)Nc1cc(-c2nnc(S)o2)ccn1
Reactant: COc1ccc(CCl)cc1C#N
Product: COc1ccc(CSc2nnc(-c3ccnc(NC(=O)CCc4ccccc4)c3)o2)cc1C#N
Yield: 39 %

Procedure:
In the same manner as in Example 1 and using N-[4-(5-mercapto-1,3,4-oxadiazol-2-yl)-2-pyridyl]-3-phenylpropionamide instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 5-(chloromethyl)-2-methoxybenzonitrile instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 39%) was obtained as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].[CH:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].O1CCCC1.C(N(CC)CC)C>C(OCC)(=O)C.[Cu]I>[C:9]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8])#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: Fc1ccccc1Br
Reactant: C#CCCCCCCCCC
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCC#Cc1ccccc1F
Temperature: 55 °C
Reaction time: 3 h
Yield: 53.2 %

Procedure:
To a solution of 2-bromofluorobenzene (17.5 g), 1-undecyne (18.3 g), tetrahydrofuran (50 ml), and triethylamine (70 ml) was added bistriphenylphosphine palladium(II)chloride (1.2 g)and copper(I) iodide (162 mg). The reaction mixture was stirred at 55° C. for 3 hr, and an additional 2-bromofluorobenzene (2.0 g) and bistriphenylphosphine palladium(II)chloride (200 mg) were added. The mixture was stirred at 55° C. overnight, allowed to cool to room temperature, diluted with ethyl acetate and washed with water. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was chromatographed over silica gel (eluted with hexane). The appropriate fractions were collected and evaporated. The residue was distilled twice under vacuum to give 13.1 g (53%) of product.
Reaction SMILES: Cl[C:2]1[C:3](=[O:24])[O:4][C:5]([CH2:14][CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:6][C:7]=1[OH:8].ClC1C(=O)OC(CCC2CCCCC=2)(C2CCCC2)CC=1O.ClC1C=CC2N(C(C)C)C(S)=NC=2C=1.[N:61]1[CH:66]=[CH:65][C:64]([C:67]2[NH:68][C:69]([SH:72])=[N:70][N:71]=2)=[CH:63][CH:62]=1>>[CH:18]1([CH2:17][CH2:16][CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:24])[C:2]([S:72][C:69]3[NH:68][C:67]([C:64]4[CH:65]=[CH:66][N:61]=[CH:62][CH:63]=4)=[N:71][N:70]=3)=[C:7]([OH:8])[CH2:6]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C1OC(CCCCC2CCCCC2)(C2CCCC2)CC(O)=C1Cl
Reactant: Sc1nnc(-c2ccncc2)[nH]1
Agent: CC(C)n1c(S)nc2cc(Cl)ccc21
Agent: O=C1OC(CCC2=CCCCC2)(C2CCCC2)CC(O)=C1Cl
Product: O=C1OC(CCCCC2CCCCC2)(C2CCCC2)CC(O)=C1Sc1nnc(-c2ccncc2)[nH]1

Procedure:
The title compound was prepared analogously to Example C(4), where 3-Chloro-6-(4-cyclohexyl-butyl)-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-one (described in Step 2 of example C(32) was substituted in place of 3-Chloro-6-(2-cyclohex-1-enyl-ethyl)-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-one and 5-Chloro-1-isopropyl-2-mercapto benzimidazole was substituted in place of 5-Pyridin-4-yl-4H-[1,2,4]triazole-3-thiol of that example. 1H NMR (DMSO-d6): δ 0.73-1.36 (m, 23H), 1.43 (d, J=7.4, 6H), 1.49-1.55 (m, 2H), 1.84-1.88 (m, 2H), 2.18-2.23 (m 1H), 2.41 (d, J=17.0, 1H), 2.77 (d, J=17.0, 1H), 4.65-4.74 (m, 1H), 7.02 (dd, J=8.6, 1.9, 1H), 7.22 (d, J=1.9, 1H), 7.54 (d, J=8.6, 1H), 12.9 (brs, 1H); Anal. Calcd. For C30H41ClN2O3S.1.25H2O: C, 63.47; H, 7.72; N, 4.93; Found: C, 63.27; H, 7.44; N, 4.80. ESIMS (MH+): 546.
Reaction SMILES: CC1NC=NC=1C(OCC)=O.C1([Mg]Br)C=CC=CC=1.[CH2:20]([O:22][C:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[N:25]=[CH:26][NH:27][C:28]=1[CH3:29])[CH3:21].[CH3:42][N:43]([CH3:48])[S:44](Cl)(=[O:46])=[O:45]>>[CH3:42][N:43]([CH3:48])[S:44]([N:27]1[C:28]([CH3:29])=[C:24]([C:23]([O:22][CH2:20][CH3:21])([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:25]=[CH:26]1)(=[O:46])=[O:45]
Reactant: CCOC(c1ccccc1)(c1ccccc1)c1nc[nH]c1C
Reactant: CN(C)S(=O)(=O)Cl
Agent: Br[Mg]c1ccccc1
Agent: CCOC(=O)c1nc[nH]c1C
Product: CCOC(c1ccccc1)(c1ccccc1)c1ncn(S(=O)(=O)N(C)C)c1C

Procedure:
Ethyl 5-methylimidazole-4-carboxylate was converted by a Grignard reaction, using phenylmagnesium bromide, to 4-[ethoxy(diphenyl)methyl]-5-methylimidazole, m.p. 205°. This was then treated with dimethylsulphamoyl chloride in a similar manner to that described in Example 1, to give 1-dimethylsulphamoyl-4-[ethoxy(diphenyl)methyl)-5-methylimidazole, m.p. 150°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][O:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1.[N:20]([O-])=O.[Na+].[ClH:24]>O>[ClH:24].[CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][O:6][C:7]1[CH:13]=[CH:12][C:10]([NH:11][NH2:20])=[CH:9][CH:8]=1
Reactant: O=N[O-]
Reactant: COc1ccc(COc2ccc(N)cc2)c(OC)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1ccc(COc2ccc(NN)cc2)c(OC)c1

Procedure:
p-(2,4-Dimethoxybenzyloxy)aniline (2.5 g, 0.01 M) is diazotized with concentrated hydrochloric acid (6 ml) and sodium nitrite (1 g) in water (2 ml) at 0° C. This solution is treated with stannous chloride dihydrate (7 g) in concentrated hydrochloric acid (20 ml) at 0° C. for 2 hours. After 12 hours at 0° C. the precipitate is filtered off and recrystallized from ethanol to afford p-(2,4-dimethoxybenzyloxy)phenyl hydrazine hydrochloride. The free base is liberated by treatment with aqueous sodium carbonate and extraction into chloroform.
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH2:14][C:15]1[CH:16]=[C:17]([C:21]2[C:30]3[C:25](=[C:26]([C:31]([F:34])([F:33])[F:32])[CH:27]=[CH:28][CH:29]=3)[N:24]=[CH:23][C:22]=2[C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:36])[CH:18]=[CH:19][CH:20]=1.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[C:35]([C:22]1[CH:23]=[N:24][C:25]2[C:30]([C:21]=1[C:17]1[CH:16]=[C:15]([NH:14][S:2]([C:5]3[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=3)(=[O:4])=[O:3])[CH:20]=[CH:19][CH:18]=1)=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([F:34])([F:32])[F:33])(=[O:36])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(S(=O)(=O)Nc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1
Reaction time: 8 h
Yield: 52 %

Procedure:
4-(Chlorosulfonyl)benzoic acid (0.11 g, 0.5 mmol) in 5 mL of THF was added dropwise to a stirred solution of [4-(3-aminophenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone (0.098 g, 0.25 mmol) and triethylamine (0.4 mL, 0.29 mmol) in 5 mL of THF at room temperature. The reaction mixture was stirred overnight, diluted with ethyl acetate, washed with water, and concentrated. The residue was purified by semi-preparative HPLC (Column: Phenomenex C18 Luna 21.6 mm×60 mm, 50M; Solvent A: Water (0.1% TFA buffer); Solvent B: Acetonitrile (0.1% TFA buffer); Solvent Gradient: Time 0: 0% B; 10 min: 100% B; Hold 100% B 5 min. Flow Rate: 22.5 mL/min). The product was collected based on UV absorption and concentrated to give the title compound as a brown solid (0.075 g, 50%): MS (EI) m/z 601.1 (M+H)+; 1H NMR (DMSO-d6): δ 7.03 (d, J=7.7 Hz, 1H), 7.33 (t, J=8.0 Hz, 1H), 7.39 (t, J=7.8 Hz, 2H), 7.56 (t, J=7.4 Hz, 1H), 7.60-8.75 (m, 9H), 8.06 (d, J=8.6 Hz, 1H), 8.36 (d, J=7.3 Hz, 1H), 9.16 (s, 1H), 10.34 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[C:9]([CH2:19][CH3:20])=[N:10][N:11]([CH2:15][C:16]([OH:18])=O)[C:12]=2[CH2:13][CH3:14])=[CH:5][CH:4]=1)#[N:2].[C:23]([NH:26][NH2:27])(=[O:25])[CH3:24].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[C:23]([NH:26][NH:27][C:16](=[O:18])[CH2:15][N:11]1[C:12]([CH2:13][CH3:14])=[C:8]([O:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:22][CH:21]=2)[C:9]([CH2:19][CH3:20])=[N:10]1)(=[O:25])[CH3:24]
Reactant: CCc1nn(CC(=O)O)c(CC)c1Oc1ccc(C#N)cc1
Reactant: CC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCc1nn(CC(=O)NNC(C)=O)c(CC)c1Oc1ccc(C#N)cc1
Yield: 72 %

Procedure:
The acid of step (a) above (400 mg, 1.34 mmol), acetic hydrazide (109 mg, 1.47 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (372 mg, 1.47 mmol), 1-hydroxybenzotriazole hydrate (192 mg, 1.47 mmol) and N-methylmorpholine (525 mg, 5.36 mmol) were stirred in N,N-dimethylformamide (6 ml) at room temperature for 18 hours. The reaction mixture was then evaporated under reduced pressure and the residue was partitioned between dichloromethane (40 ml) and water (30 ml). The organic layer was dried over magnesium sulphate, filtered, and then concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (93:7:0.5, by volume) to provide the title compound (345 mg, 72%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[C:20]([C:36]([F:39])([F:38])[F:37])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:41]>C(O)C>[ClH:41].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH3:35])=[C:20]([C:36]([F:37])([F:38])[F:39])[CH:19]=1)([CH2:13][OH:12])[CH2:9][OH:10]
Reactant: COc1ccccc1CCCOc1ccc(CCC2(NC(=O)OC(C)(C)C)COC(C)(C)OC2)cc1C(F)(F)F
Agent: Cl
Solvent: CCO
Product: COc1ccccc1CCCOc1ccc(CCC(N)(CO)CO)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Compound 17-3 (780 mg) was dissolved in ethanol (20 ml), concentrated hydrochloric acid (2 ml) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (560 mg) as a white powder.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:24])[CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[C:10](/[CH:17]=[CH:18]/[C:19]([O:21][CH3:22])=[O:20])[CH:11]=[CH:12][C:13]=2[O:15][CH3:16])[N:8]([CH3:23])[CH:7]=1>CO.[Pd]>[CH3:24][N:3]([CH3:2])[CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[C:10]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:11]=[CH:12][C:13]=2[O:15][CH3:16])[N:8]([CH3:23])[CH:7]=1
Reactant: COC(=O)/C=C/c1ccc(OC)c2c(CCN(C)C)cn(C)c12
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)CCc1ccc(OC)c2c(CCN(C)C)cn(C)c12
Temperature: 25 °C
Reaction time: 6 h
Yield: 84.2 %

Procedure:
A mixture of 25-2 (78.6 mg, 0.25 mmol) and Pd/C (5%, 50 mg) in MeOH was purged with nitrogen and hydrogen, and then the reaction was stirred at room temperature. After 6 h, the reaction mixture was filtered and concentrated to give the compound 25-3 as a pale yellow semi-solid (67 mg), which was used for the next step without purification. 1H NMR (CDCl, 300 MHz) δ (ppm) 6.82 (d, J=8.0 Hz, 1H), 6.64 (s, 1H), 6.37 (d, J=8.0 Hz, 1H), 3.93 (s, 3H), 3.87 (s, 3H), 3.28-3.34 (m, 2H), 2.99-3.05 (m, 2H), 2.57-2.69 (m, 4H), 2.35 (s, 6H).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O)([CH3:5])[CH3:4])#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Br:48][C:49]1[CH:55]=[CH:54][C:52]([NH2:53])=[CH:51][C:50]=1[N+:56]([O-:58])=[O:57]>CN(C=O)C>[Br:48][C:49]1[CH:55]=[CH:54][C:52]([NH:53][C:9](=[O:11])[C:8]2[CH:12]=[CH:13][CH:14]=[C:6]([C:3]([C:1]#[N:2])([CH3:4])[CH3:5])[CH:7]=2)=[CH:51][C:50]=1[N+:56]([O-:58])=[O:57]
Reactant: Nc1ccc(Br)c([N+](=O)[O-])c1
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(Br)c([N+](=O)[O-])c2)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 249.8 %

Procedure:
A solution of 3-(2-cyanopropan-2-yl)benzoic acid 3 (436 mg, 2.304 mmol), HATU (1.051 g, 2.76 mmol) and DIPEA (0.762 mL, 4.61 mmol) in DMF (9 mL) was stirred 15 min at rt. 4-bromo-3-nitroaniline (200 mg, 0.922 mmol) was added and stirred overnight at 60° C. The reaction mixture was cooled to rt and extracted with CH2Cl2. Organic layer was washed (3×) with water, dried and evaporated. Purification by chromatography heptane:EtOAc (1:1) gave N-(4-bromo-3-nitrophenyl)-3-(2-cyanopropan-2-yl)benzamide 61 (894 mg, 89%). (m/z)=388 and 390 (M+H)+.
Reaction SMILES: [NH2:1]/[C:2](/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:3]1\[C:4](=[O:12])[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[S:7]\1.[C:19]([O-])(=O)C.C[NH3+].CS(C)=O>CO>[CH3:19][NH:1]/[C:2](/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:3]1\[C:4](=[O:12])[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[S:7]\1
Reactant: CC(=O)[O-]
Reactant: N/C(=C1/Sc2ccccc2C1=O)c1ccccc1
Agent: C[NH3+]
Solvent: CS(C)=O
Solvent: CO
Product: CN/C(=C1/Sc2ccccc2C1=O)c1ccccc1
Yield: 58 %

Procedure:
A mixture of 2.53 gm (0.01 mol) of (E)-2-[(amino)phenylmethylene]-benzo[b]thiophen-3(2H)-one, 40.0 gm (0.44 mol) of methylammonium acetate and 10 ml of dimethylsulfoxide was heated for 5 hours to a reaction temperature of 130° to 140° C. Working up was in accordance with Example 65, and the desired compound, m.p. 154°-155° C. (methanol), was obtained with a yield of 58% of theory. The product was identical to that of Example 2 according to elemental analysis and thin-layer chromatogram.