Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.CCN(C(C)C)C(C)C.[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)([CH3:33])[CH3:32])=[CH:27][CH:26]=1>CN(C=O)C>[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([N:34]2[CH2:35][CH2:36][N:37]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=4)[N:7]=3)[CH2:38][CH2:39]2)([CH3:33])[CH3:32])=[CH:27][CH:26]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: CC(C)(c1ccc(F)cc1)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(c1ccc(F)cc1)N1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Temperature: 80 °C
Yield: 70.3 %

Procedure:
6-Chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (120 mg, 0.54 mmol), DIPEA (0.094 mL, 0.54 mmol) and 1-[2-(4-fluorophenyl)propan-2-yl]piperazine (obtained as described in J. Med. Chem. 2007, 50, 3528) (120 mg, 0.54 mmol) in DMF (1.5 mL) were stirred and heated at 80° C. for 1 hour. The resulting solution was cooled to room temperature then applied to an SCX column and eluted with MeOH followed by 2M ammonia in methanol. Fractions containing product were combined and evaporated, then purified by preparative HPLC (Waters XTerra C18 column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 6-[4-[1-(4-fluorophenyl)-1-methylethyl]piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (155 mg, 70%) as a colourless solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1(/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1(/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:8][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH3:25])[CH:19]=3)=[C:20]([C:25]([F:28])([F:26])[F:27])[CH:19]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1(/C=C/c2ccc(O)c(C(F)(F)F)c2)COC(C)(C)OC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(CCCOc2ccc(/C=C/C3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)cc2C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 212.7 %

Procedure:
Compound 93-8 (400 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (397 mg) and compound 15-2 (246 mg) were added, and the mixture was stirred at 50° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (560 mg) as a white solid.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH2:24])=[CH:18][CH:17]=1>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:24][CH2:23][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=1)#[N:2]
Reactant: CC(C)OC(=NC#N)c1cccnc1
Reactant: NCCc1ccc(Cl)cc1
Solvent: CO
Product: N#CNC(=NCCc1ccc(Cl)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 78.1 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.60 g, 3.2 mmol) was dissolved in methanol (10 ml), and 2-(4-chlorophenyl)ethylamine (0.55 g, 3.5 mmol) was added. The mixture was stirred at room temperature for 2.5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residual concentrate was subjected to chromatography on a silica gel column (WAKO GEL C-200, 50 g) eluting with chloroform-methanol (100:1). The eluted fractions were concentrated under reduced pressure, and the concentrated residue thus obtained was further crystallized from methanol-diethyl ether to give the title compound (0.71 g, 2.5 mmol, yield: 79%) as colorless powder.
Reaction SMILES: C(O[CH:4]=[CH:5][C:6](O)([C:10]([F:13])([F:12])[F:11])[CH2:7][C:8]#[N:9])C.[NH3:15]>>[NH2:15][C:4]1[CH:5]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:8][N:9]=1
Reactant: CCOC=CC(O)(CC#N)C(F)(F)F
Reactant: N
Product: Nc1cc(C(F)(F)F)ccn1
Temperature: 125 °C
Yield: 67.9 %

Procedure:
50 g of 5-ethoxy-3-hydroxy-3-(trifluoromethyl)pent-4-enenitrile were mixed with 600 g of aqueous ammonia (25%), and the resulting mixture was heated to 125° C. in an autoclave for 24 h, in the course of which a pressure of approx. 14 bar built up. Subsequently, the reaction mixture was cooled and the resulting biphasic mixture was extracted repeatedly with dichloromethane. The combined organic phases were cautiously concentrated by rotary evaporation, and the product was subsequently recrystallized from cyclohexane. 26.3 g of 2-amino-4-(trifluoromethyl)pyridine (68%) were thus obtained as a yellowish-brown solid. The spectroscopic data agreed with those reported in the literature (A. D. Dunn et al. in J. Fluorine Chem. 1999, 93, 153-157).
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[C:24]2[CH2:25][CH2:26][N:27]([CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:28][C:23]=2[C:5]2[C:6]([OH:22])=[CH:7][C:8]([C:10]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([CH3:14])[CH2:11][CH2:12][CH3:13])=[CH:9][C:4]=2[O:3]1.Cl.[N:39]1([CH2:44][CH2:45][CH2:46][C:47](O)=[O:48])[CH2:43][CH2:42][CH2:41][CH2:40]1.C1(N=C=NC2CCCCC2)CCCCC1>>[ClH:21].[CH3:37][C:2]1([CH3:1])[C:24]2[CH2:25][CH2:26][N:27]([CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:28][C:23]=2[C:5]2[C:6]([O:22][C:47](=[O:48])[CH2:46][CH2:45][CH2:44][N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)=[CH:7][C:8]([C:10]([C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)([CH3:14])[CH2:11][CH2:12][CH3:13])=[CH:9][C:4]=2[O:3]1
Reactant: CCCC(C)(c1ccc(Cl)cc1)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(CCc2ccccc2)CC1
Reactant: O=C(O)CCCN1CCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Product: CCCC(C)(c1ccc(Cl)cc1)c1cc(OC(=O)CCCN2CCCC2)c2c(c1)OC(C)(C)C1=C2CN(CCc2ccccc2)CC1

Procedure:
5,5-Dimethyl-10-hydroxy-2-phenethyl-8-(4-chlorophenyl-1-methylbutyl)-1,2,3,4-tetrahydro-5H[1]benzopyrano [3,4-d]pyridine, γ-pyrrolidino-butyric acid hydrochloride and dicyclohexylcarbodiimide are reacted in equimolar amounts according to Example 7 to produce the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:20][CH2:21][CH:22]([CH3:24])[CH3:23])=[C:14]([NH2:19])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](OCC)(OCC)(OCC)[CH3:26]>C(OCC)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:20]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:25]([CH3:26])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Reactant: CCOC(C)(OCC)OCC
Solvent: CCOCC
Product: Cc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)C
Temperature: 160 °C

Procedure:
The preparation of 7-benzyloxy-N4-(2-methylpropyl)quinoline-3,4-diamine is described in Parts A-F of Example 1. Under a nitrogen atmosphere, triethyl orthoacetate (4.59 mL, 25.0 mmol) was added to a solution of 7-benzyloxy-N4-(2-methylpropyl)quinoline-3,4-diamine (8.05 g, 25.0 mmol) in xylenes (130 mL), and the resulting solution was heated at reflux (160° C.) overnight. The solvent volume was reduced to 70 mL using a Dean-Stark trap. Over a period of a few days, a precipitate formed. Diethyl ether was added, and the precipitate was isolated by filtration and washed with diethyl ether to provide 6.81 g of 7-benzyloxy-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline as a light-brown powder.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([CH3:17])[CH3:16])=[C:10]([CH3:18])[CH:9]=1)=O)C.[CH3:20][NH:21][NH2:22]>C1(C)C=CC=CC=1>[OH:3][C:4]1[N:21]([CH3:20])[N:22]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([CH3:17])[CH3:16])=[C:10]([CH3:18])[CH:9]=2)[CH:5]=1
Reactant: CNN
Reactant: CCOC(=O)CC(=O)c1ccc(OC(C)C)c(C)c1
Solvent: Cc1ccccc1
Product: Cc1cc(-c2cc(O)n(C)n2)ccc1OC(C)C
Yield: 84.3 %

Procedure:
At room temperature, to a mixture of 3-(4-isopropoxy-3-methyl-phenyl)-3-oxo-propionic acid ethyl ester (described in Reference Preparation example 94) 12.1 g and toluene 100 ml was added N-methyl hydrazine 21 g, and the resulting mixture was stirred for twelve hours. The toluene was distilled off under reduced pressure. At room temperature, to the reaction mixture was added water 100 ml and the resulting mixture was acidified with 10% aqueous hydrochloric acid solution and was stirred for three hours. The precipitates were filtered and were washed with water 400 ml and ethyl acetate 500 ml, and then were dried under reduced pressure to give 5-hydroxy-3-(4-isopropoxy-3-methyl-phenyl)-1-methyl-1H-pyrazole 9.5 g.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[CH3:22][N:23]1[C:27]([C:28](Cl)=[O:29])=[CH:26][C:25]([CH3:31])=[N:24]1>>[CH3:22][N:23]1[C:27]([C:28]([N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)=[O:29])=[CH:26][C:25]([CH3:31])=[N:24]1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: Cc1cc(C(=O)N2CCC3(CC2)CSC2=C(O3)c3ccccc3C(=O)C2=O)n(C)n1

Procedure:
Compound 42 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride and conditions outlined in procedure N. M.p.=244-245° C.; 300 MHz 1H NMR (DMSO-d6) δ 8.07 (d, 1H), 7.67 (d, 1H), 7.65 (t, 1H), 7.56 (t, 1H), 6.16 (s, 1H), 3.40 (m, 2H), 3.86 (s, 3H), 3.01 (s, 2H), 2.26 (s, 3H), 2.24 (m, 2H), 1.92 (m, 2H), 1.62 (m, 2H); LCMS: 424 [M+H].
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][C:9]1[N:10]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:11](=[O:26])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15](Br)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].[CH3:32][S-:33].[Na+].CN(C)C=O>O>[C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][C:9]1[N:10]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:11](=[O:26])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([S:33][CH3:32])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(Br)ccc2c1=O
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ccc2c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccccc3)c2c1
Temperature: 85 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
A mixture of tert-butyl(6-bromo-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.24 g, 0.5 mmol), sodium thiomethoxide (0.080 g, 1.1 mmol) and N,N-dimethylformamide (4 mL) was stirred at 85° C. for 1 h, and the reaction mixture was poured into water (50 mL) and extracted twice with ethyl acetate (25 mL). The extracts were combined, washed with saturated aqueous sodium hydrogencarbonate (15 mL) and saturated brine (15 mL), dried over anhydrous magnesium sulfate (12 g) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1 (v/v)) to give tert-butyl[2-isobutyl-6-(methylsulfanyl)-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.17 g, 73%) as a colorless powder.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:24]3[C:19](=[CH:20][C:21]([O:27][CH2:28][CH3:29])=[C:22]([O:25][CH3:26])[CH:23]=3)[C@@H:18]3[C@@H:13]([CH2:14][CH2:15][C@@H:16]([OH:30])[CH2:17]3)[N:12]=2)=[CH:7][N:6]=1)=N.O[Li].O.P(=O)(O)(O)[OH:35].P([O-])([O-])(O)=O.[Na+].[Na+]>C1COCC1>[CH2:28]([O:27][C:21]1[CH:20]=[C:19]2[C:24]([C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:3]([OH:2])=[O:35])=[N:6][CH:7]=3)=[N:12][C@H:13]3[C@@H:18]2[CH2:17][C@H:16]([OH:30])[CH2:15][CH2:14]3)=[CH:23][C:22]=1[O:25][CH3:26])[CH3:29]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=N)OC)nc1)=N[C@@H]1CC[C@@H](O)C[C@H]21
Reactant: O=P(O)(O)O
Agent: O=P([O-])([O-])O
Agent: [Li]O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)nc1)=N[C@@H]1CC[C@@H](O)C[C@H]21
Temperature: 60 °C
Reaction time: 18 h

Procedure:
In a second step, 443 mg (1.08 mmol) of 5-((2R,4aR,10bR)-9-ethoxy-2-hydroxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-6-yl)-pyridine-2-carboximidic acid methyl ester are dissolved in 3 ml of THF. A solution of 51 mg (2.16 mmol) LiOH.H2O is added and the solution stirred at 60° C. for 18 hrs. The pH is adjusted to 5 using phosphoric acid and Disodiumhydrogenphosphate. The solvent is removed and the solid residue extracted with chloroform/methanol. After filtering off and removing the volatiles 350 mg (82%) of the title compound are obtained.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[F:39][C:40]1[CH:41]=[CH:42][C:43]([O:49][CH3:50])=[C:44](B(O)O)[CH:45]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:39][C:40]1[CH:45]=[CH:44][C:43]([O:49][CH3:50])=[C:42]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:41]=1
Reactant: COc1ccc(F)cc1B(O)O
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc(F)cc1-c1cn(COCC[Si](C)(C)C)c2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c12
Yield: 66.1 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (80 mg, 0.13 mmol) was treated with (5-fluoro-2-methoxyphenyl)boronic acid (55 mg, 0.32 mmol), sodium carbonate (34 mg, 0.32 mmols) and bis(triphenylphosphine)palladium(II) dichloride (10 mg, 0.01 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 30%, hexane-ethyl acetate) to give 55 mg (64% yield) of the title compound. Purity 92%.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4](=[O:20])[CH2:5][C:6]([OH:19])([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1.N1C=CN=C1.Cl[Si:27]([CH3:30])([CH3:29])[CH3:28]>CN(C)C=O>[CH3:1][S:2][C:3]1[C:4](=[O:20])[CH2:5][C:6]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)([O:19][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:7]=1
Reactant: CSC1=CC(O)(CCCCOc2ccccc2)CC1=O
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CSC1=CC(CCCCOc2ccccc2)(O[Si](C)(C)C)CC1=O
Yield: 89 %

Procedure:
To a solution of 400 mg of 2-methylthio-4-hydroxy-4-(4-phenoxybutyl)-2-cyclopentenone obtained in Example 52 or Example 53 dissolved in 4 ml of dimethylformamide were added 279 mg of imidazole and 260 μl of chlorotrimethylsilane, under ice-cooling and stirring, and the mixture was stirred at 0° C. for 3 hours. The reaction mixture was extracted with an addition of water and hexane. The organic layer was washed with saturated aqueous sodium chloride, and the product dried over anhydrous sodium sulfate, filtered and concentrated, followed by silica gel column chromatography, to give 445 mg (yield 89%) of 2-methylthio-4-(4-phenoxybutyl)-4-trimethylsilyloxy-2-cyclopentenone.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[Si:10]([O:17][CH:18]1[CH2:21][N:20]([CH2:22][C@H:23]([O:28][C:29]2[N:34]=[CH:33][N:32]=[C:31]3[N:35]([C:38]4[C:43]([Cl:44])=[CH:42][CH:41]=[CH:40][C:39]=4[Cl:45])[N:36]=[CH:37][C:30]=23)[C:24](OC)=[O:25])[CH2:19]1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]>>[Si:10]([O:17][CH:18]1[CH2:19][N:20]([CH2:22][C@H:23]([O:28][C:29]2[N:34]=[CH:33][N:32]=[C:31]3[N:35]([C:38]4[C:39]([Cl:45])=[CH:40][CH:41]=[CH:42][C:43]=4[Cl:44])[N:36]=[CH:37][C:30]=23)[C:24]([NH:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=2)=[O:25])[CH2:21]1)([C:13]([CH3:15])([CH3:16])[CH3:14])([CH3:11])[CH3:12]
Reactant: N#Cc1ccc(N)nc1
Reactant: COC(=O)[C@H](CN1CC(O[Si](C)(C)C(C)(C)C)C1)Oc1ncnc2c1cnn2-c1c(Cl)cccc1Cl
Product: CC(C)(C)[Si](C)(C)OC1CN(C[C@H](Oc2ncnc3c2cnn3-c2c(Cl)cccc2Cl)C(=O)Nc2ccc(C#N)cn2)C1

Procedure:
Using a procedure analogous to that described for Intermediate BD12 using 6-aminonicotinonitrile and (S)-methyl 3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-(1-(2,6-dichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate (Intermediate BJ1).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:16]([CH:18]1[O:20][CH2:19]1)Cl.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:16]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:14][CH:15]=1)[CH:18]1[O:20][CH2:19]1
Reactant: ClCC1CO1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(c1ccccc1)c1ccc(OCC2CO2)cc1
Temperature: 25 °C

Procedure:
As illustrated in FIG. 6, 100 mL of dried acetone were added to a dry, 250-mL round bottom flask, equipped with a magnetic stirrer, along with 15.05 grams of 4-hydroxybenzophenone, 32.1 grams of epichlorohydrin, and 6.2 grams of potassium carbonate. The solution was heated to reflux for 6 hours and then cooled to room temperature. The precipitated potassium chloride was filtered off, and the solution was evaporated to remove excess epichlorohydrin. The crude product was recrystallized from methanol. 1H NMR data confirmed the formation of the desired product.
Reaction SMILES: [CH:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:10]([CH2:12][N:13]1[C:19]3[C:20]([Cl:24])=[CH:21][CH:22]=[CH:23][C:18]=3[C:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])=[N:16][CH:15]([NH:32]C(OC(C)(C)C)=O)[C:14]1=[O:40])=[O:11])[CH2:2]2.Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[NH2:32][CH:15]1[N:16]=[C:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=2[N:13]([CH2:12][C:10]([N:3]2[CH2:4][CH:5]3[CH2:8][CH2:9][CH:1]([CH2:7][CH2:6]3)[CH2:2]2)=[O:11])[C:14]1=[O:40]
Reactant: CC(C)(C)OC(=O)NC1N=C(c2ccccc2F)c2cccc(Cl)c2N(CC(=O)N2CC3CCC(CC3)C2)C1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: NC1N=C(c2ccccc2F)c2cccc(Cl)c2N(CC(=O)N2CC3CCC(CC3)C2)C1=O
Temperature: 0 °C
Reaction time: 5.5 h
Yield: 100.9 %

Procedure:
A mixture of (3RS)-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-9-chloro-2,3-dihydro-5-(2-fluorophenyl)-3-tert-butoxycarbonylamino-1H-1,4-benzodiazepin-2-one (660 mg) and 4N aqueous hydrochloric acid in ethyl acetate (3 ml) was stirred at 0° C. for 5.5 hours. A saturated aqueous solution of sodium bicarbonate and ethyl acetate were added to the reaction mixture. The separated organic layer was washed with water and brine, and then dried over sodium sulfate. The solvent was evaporated in vacuo to afford (3RS)-3-amino-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-9-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one (549.0 mg) as a crystalline powder.
Reaction SMILES: O.[Na+].[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:10][CH:11]=2)[CH:6]=[C:5]1[C:32]([O-:34])=[O:33].Cl.C(O)C>O>[OH2:15].[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:24][CH:23]=4)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:10][CH:11]=2)[CH:6]=[C:5]1[C:32]([OH:34])=[O:33]
Reactant: Cn1c(C(=O)[O-])cc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc21
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cn1c(C(=O)O)cc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc21
Reaction time: 8 h
Yield: 169.1 %

Procedure:
1-methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxylic acid sodium salt hydrate (0.62 g), from the previous alternative, and aqueous hydrochloric acid (2 molar) were combined in refluxing ethanol (13 mL) and water (1.3 mL). The mixture was cooled, granulating overnight, chilled in ice and the resulting slurry was filtered. The product solids were dried, yielding the title compound, 1-methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxylic acid hydrate (0.5 g, 83%, containing 2% water by weight). Anhydrous Mol wt (calc) 438.41, MS: 439.35 (MH+), 437.20 (M−). 1H NMR (DMSO-d6): δ 3.97 (s, 3H), 7.13 (s, 1H), 7.30-7.75 (complex, 10H), 7.92 (s, 1H), 10.21 (s,1H).; HPLC retention time 9.29 minutes.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH:30]4[CH2:32][CH2:31]4)=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[O:16])=[C:6]([N:8]2[CH2:12][CH2:11][N:10]([CH3:13])[C:9]2=[O:14])[CH:7]=1.[NH:33]1[CH2:37][CH2:36][CH2:35][C:34]1=[O:38]>>[CH:30]1([C:26]2[CH:27]=[C:28]([CH3:29])[C:23]([N:20]3[CH2:21][CH2:22][N:17]([C:15]([C:5]4[CH:4]=[CH:3][C:2]([N:33]5[CH2:37][CH2:36][CH2:35][C:34]5=[O:38])=[CH:7][C:6]=4[N:8]4[CH2:12][CH2:11][N:10]([CH3:13])[C:9]4=[O:14])=[O:16])[CH2:18][CH2:19]3)=[N:24][CH:25]=2)[CH2:32][CH2:31]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Cl)cc2N2CCN(C)C2=O)CC1
Reactant: O=C1CCCN1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCC3=O)cc2N2CCN(C)C2=O)CC1
Yield: 47.4 %

Procedure:
Using 1-{5-chloro-2-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-3-methylimidazolidin-2-one (82 mg) described in Preparation Example 242 and pyrrolidin-2-one (23 mg) and by the reaction and treatment in the same manner as in Example 666, the title compound (43 mg) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C=O)C>[CH2:14]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc2ccncc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(COc2ccc3ccncc3c2)cc1
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a solution of 7-hydroxyisoquinoline (prepared by the method of R. B. Woodward and W. D. Doering, J. Am. Chem. Soc., 1945, 67, 860) (1.45 g, 10 mmol) in DMF (20 ml) was added sodium hydride (60% dispersion in oil, 0.4 g, 10 mmol) portionwise. After stirring for 30 minutes, benzyl bromide (1.2 ml, 10 mmol) was added and the reaction mixture stirred for 2 h. The reaction mixture was poured into water and extracted with diethyl ether (3×100ml). The ether extracts were combined, washed with 2N sodium hydroxide solution (2×50 ml), brine (50 ml), dried over magnesium sulphate, filtered and evaporated under reduced pressure to give the title compound (1.6 g, 68%); δH (CDCl3) 5.21 (2H, s, OCH2), 7.30-7.51 (7H, m, ArH), 7.59 (1H, d, J 8.3 Hz, ArH), 7.75 (1H, d, J 13 Hz, ArH), 8.42 (1H, d, J 8 Hz, ArH), and 9.14 (1H, s, ArH).