Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[CH3:41][N:42]([CH2:44][C:45]1[CH:51]=[CH:50][C:48]([NH2:49])=[CH:47][CH:46]=1)[CH3:43]>ClCCl>[CH3:43][N:42]([CH2:44][C:45]1[CH:46]=[CH:47][C:48]([NH:49][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[NH:10]2)=[O:30])=[CH:50][CH:51]=1)[CH3:41]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CN(C)Cc1ccc(N)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)Cc1ccc(NC(=O)C2NC(CC(C)(C)C)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)cc1
Reaction time: 1 h
Yield: 70.5 %

Procedure:
To a stirred solution of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (60 mg, 0.128 mmol) in dichloromethane (5.00 ml) were added N,N-DIISOPROPYLETHYLAMINE (100 mg) and 4-((dimethylamino)methyl)aniline (29.8 mg, 0.198 mmol) followed by N,N,N′,N′-tetramethyl-O-(7-aza-benzotriazol-1-yl)uranium hexafluorophosphate (HATU) (90.3 mg, 0.237 mmol, Chem-Impex) and the reaction mixture was stirred for 1 hr. The reaction mixture was diluted with CH2Cl2 (80 mL), washed with sat Na2CO3 (2×15 mL), water (2×15 mL) and evaporated. The crude material was purified by flash chromatography (silica gel, 4 g, 4% to 50% EtOAc in hexanes) to give rac-(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-dimethylaminomethyl-phenyl)-amide as white solid (54.1 mg, 70%). MS (ES+) m/z Calcd: [(M+H)+]: 599. found: 599.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][CH2:11][N:12]1[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[C:16]([NH2:25])[C:15]=2[N:14]=[C:13]1[CH2:26][O:27][CH2:28][CH3:29].O[N:31]1[C:52](=[O:53])[NH:51][C@H:50]2[C@@H:32]1[CH2:33][S:34][C@H:35]2[CH2:36][CH2:37][CH2:38][CH:39](N1C(=O)CCC1=O)[C:40](=O)[OH:41]>C(Cl)(Cl)Cl>[NH2:25][C:16]1[C:15]2[N:14]=[C:13]([CH2:26][O:27][CH2:28][CH3:29])[N:12]([CH2:11][CH2:10][NH:9][C:40](=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]3[CH:50]4[CH:32]([NH:31][C:52](=[O:53])[NH:51]4)[CH2:33][S:34]3)[C:24]=2[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:17]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CCN
Reactant: O=C(O)C(CCC[C@@H]1SC[C@H]2[C@@H]1NC(=O)N2O)N1C(=O)CCC1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCNC(=O)CCCCC1SCC2NC(=O)NC21
Temperature: 25 °C
Yield: 13.3 %

Procedure:
Triethylamine (1.2 g, 11.4 mmol) was added in a single portion to a slurry of 1-(2-aminoethyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine hydrochloride (3.39 g, 10.53 mmol) in chloroform (150 mL). The reaction mixture became clear. N-hydroxysuccinimidobiotin (3.0 g, 8.79 mmol) was then slowly added. After 2 hours the turbid reaction mixture was heated to reflux. The reaction mixture was maintained at reflux overnight and became clear. The reaction mixture was allowed to cool to ambient temperature and then it was quenched with water. The layers were separated. The organic layer was dried over magnesium sulfate and then concentrated to provide an off-white solid. This material was recrystallized from 8:2 ethanol:water to provide a white solid. A portion of this material was purified by prep HPLC eluting with water/acetonitrile/trifluoroacetic acid to provide 0.6 g of N1-[2-(4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-5-(2-oxoperhydrothieno[3,4-d]imidazol-4-yl)pentanamide as the ditrifluoroacetate salt, m.p. 171-175° C. Analysis: Calculated for: C25H33N7O3S.2 C2HF3O2: % C, 47.09; % H, 4.77; % N, 13.26. Found: % C, 47.06; % H, 5.17; % N, 13.31.
Reaction SMILES: C[N:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[N:4][C:3]1=O.P(Cl)(Cl)([Cl:23])=O.P(Cl)(Cl)(Cl)(Cl)Cl>>[Cl:23][C:3]1[N:2]=[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:5][N:4]=1
Reactant: Cn1c(-c2ccccc2)c(-c2ccccc2)cnc1=O
Reactant: O=P(Cl)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: Clc1ncc(-c2ccccc2)c(-c2ccccc2)n1

Procedure:
A solution of 1-methyl-5,6-diphenyl-1H-pyrimidin-2-one (106, 314 mg, 1.20 mmol), phosphorus oxychloride (0.6 ml, 6.4 mmol) and phosphorus pentachloride (55 mg, 0.26 mmol) was heated at 120° C. for 3 hours. The excess amount of phosphorus oxychloride was removed under reduced pressure and cold water was added to the residue. The resulting precipitate was extracted with CH2Cl2. The organic layer was washed with brine, and dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (20% ethyl acetate in hexane) to produce the title compound as a white solid.
Reaction SMILES: CN1C=CN=C1.[NH2:7][C:8]1[S:9][CH:10]=[C:11]([C:13](=[N:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])[C:14]([O:16]CC)=[O:15])[N:12]=1.CO.O1CCCC1>[OH-].[Na+]>[NH2:7][C:8]1[S:9][CH:10]=[C:11]([C:13](=[N:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])[C:14]([OH:16])=[O:15])[N:12]=1
Reactant: CCOC(=O)C(=NOCc1ccc(Cl)cc1Cl)c1csc(N)n1
Agent: Cn1ccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1nc(C(=NOCc2ccc(Cl)cc2Cl)C(=O)O)cs1
Reaction time: 6 h
Yield: 90.1 %

Procedure:
A solution of 1-methylimidazole (0.5 g.) in 1 N sodium hydroxide aqueous solution (48 ml.) was added to a solution of ethyl 2-(2-aminothiazol-4-yl)-2-(2,4-dichorobenzyloxyimino)acetate (syn isomer, 12.0 g.), methanol (120 ml.) and tetrahydrofuran (100 ml.) at 15° to 20° C., and stirred at 35° to 40° C. for 6 hours. After removing methanol and tetrahydrofuran in vacuo from the resultant mixture, the aqueous residue was washed with ethyl acetate. Ethyl acetate was completely removed from the aqueous solution and adjusted to pH 2.0 with hydrochloric acid. The precipitates were collected by filtration to give 2-(2-aminothiazol-4-yl)-2-(2,4-dichlorobenzyloxyimino)acetic acid (syn isomer, 10.0 g.).
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]([C:5]1[N:22]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[CH3:29][C@@H:30]1[CH2:35][NH:34][CH2:33][C@H:32]([CH3:36])[N:31]1[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>>[C:40]([O:39][C:37]([N:31]1[C@H:32]([CH3:36])[CH2:33][N:34]([CH2:20][C:17]2[CH:16]=[N:15][C:14]([NH:13][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:1])[CH3:28])[N:22]([CH:23]5[CH2:24][CH2:25][CH2:26][CH2:27]5)[C:8]=4[N:9]=3)=[CH:19][CH:18]=2)[CH2:35][C@@H:30]1[CH3:29])=[O:38])([CH3:43])([CH3:41])[CH3:42]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C=O)cn3)nc2n1C1CCCC1
Reactant: C[C@@H]1CNC[C@H](C)N1C(=O)OC(C)(C)C
Product: C[C@@H]1CN(Cc2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)C[C@H](C)N1C(=O)OC(C)(C)C
Yield: 74.4 %

Procedure:
Following General Procedure B, 7-cyclopentyl-2-(5-formyl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (150 mg, 0.396 mmol) and tert-butyl (2R,6S)-2,6-dimethylpiperazine-1-carboxylate (93 mg, 0.436 mmol) gave (2S,6R)-4-[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-ylmethyl]-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (170 mg, 74%) [following SiO2 chromatography, eluting with 0-10% MeOH)/dichloromethane]. MS (ESI) m/z 577.3 (M+H)+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C([Li])CCC.[O:14]1[CH2:17][C:16](=[O:18])[CH2:15]1.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:16]2([OH:18])[CH2:17][O:14][CH2:15]2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: O=C1COC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: OC1(c2ccc(Br)cn2)COC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 51.9 %

Procedure:
2,5-Dibromopyridine (10 g, 35.2 mmol) is dissolved in dry toluene (200 mL) under a nitrogen atmosphere and cooled to −78° C. n-Butyllithium (2.5M in hexanes, 2.5 mL, 38.7 mmol) is added at −78° C. over 20 minutes. The reaction mixture is stirred at −78° C. for 20 minutes. Oxetane-3-one (2.79 g, 38.7 mmol) in toluene (100 mL) is added then stirred at −78° C. for 30 minutes. Saturated aqueous ammonium chloride solution (50 mL) is added. The mixture extracted with ethyl acetate (2×200 mL), separated, washed with brine solution (50 mL) and the solvent evaporated under reduced pressure. The crude material is purified using flash chromatography (35% ethyl acetate in hexane) to give the title compound (4.2 g): 1H NMR (400 MHz, DMSO-d6):δ 4.64 (2H, d), 4.87 (2H, d), 6.68 (1H, s), 7.55 (1H, d), 8.06 (1H, dd), 8.76 (1H, d).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]2[C:14]3[S:15][CH:16]=[CH:17][C:13]=3[CH:12]=[C:11]([O:19][CH3:20])[C:10]=2[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[CH:4]=1.[C:21](Cl)(=[O:33])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].[Cl-].[Cl-].[Cl-].[Al+3].CCCCCC>ClCCl>[CH3:20][O:19][C:11]1[C:10]2[C:6]3[S:7][C:8]([C:21](=[O:33])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:9][C:5]=3[CH:4]=[C:3]([O:2][CH3:1])[C:18]=2[C:14]2[S:15][CH:16]=[CH:17][C:13]=2[CH:12]=1
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: COc1cc2ccsc2c2c(OC)cc3ccsc3c12
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCC
Solvent: ClCCl
Product: CCCCCCCCCCCC(=O)c1cc2cc(OC)c3c4sccc4cc(OC)c3c2s1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 53.9 %

Procedure:
4,9-Dimethoxynaphtho[1,2-b:5,6-b′]dithiophene (0.90 g, 3.0 mmol) was solubilized in anhydrous dichloromethane (20 mL). Dodecanoyl chloride (0.765 g, 3.5 mmol) was then added and stirring was continued for 10 minutes at this temperature. Aluminum trichloride (0.465 g, 3.5 mmol) was then added in 3 portions. The mixture was stirred overnight at room temperature. The mixture was cooled in ice water and extracted with chloroform (200 mL) and washed with water (100 mL) and brine (50 mL). After the solvent was removed, the residual was purified using a silica column with dichloromethane:hexane (1/3) to give compound 1-(4,9-dimethoxynaphtho[1,2-b:5,6-b′]dithiophen-2-yl)dodecan-1-one as a pale yellow solid (0.78 g, ˜54% yield). 1H NMR (500 MHz, CDCl3): δ 8.72 (s, 1H), 7.69 (d, J=5.5 Hz, 1H), 7.50 (m, 2H), 7.42 (s, 1H), 4.24 (s, 3H), 4.22 (s, 3H) 3.07. (t, J=7.0 Hz, 2H), 1.83 (m, 2H), 1.39 (m, 18H); 0.88 (m, J=6.0 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1)=[O:3].Br.[OH2:15]>CS(C)=O>[F:13][C:10]([F:11])([F:12])[C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH:1]=[O:15])=[CH:5][CH:6]=1
Reactant: O
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Agent: Br
Solvent: CS(C)=O
Product: O=CC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 70 °C
Reaction time: 9.5 h
Yield: 59 %

Procedure:
4-Trifluoromethylacetophenone (11.14 mmol, 2.096 g) was dissolved in dimethyl sulfoxide (13 mL), and 48% hydrobromic acid (5.4 mL) was gradually added at room temperature. After 9.5 hours of stirring at 70° C., the reactor was cooled to room temperature. The reaction solution was poured into water and stirred for about 16 hours. The precipitated solid was recovered by filtration, washed with water and dried by means of a vacuum pump to give the desired product as a yellow solid (1.3116 g, yield 59%).
Reaction SMILES: [CH2:1]([C:4]1([N:17]([CH2:22][C:23]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:24]=2[CH:25]=[CH:26][N:27]3[S:32]([C:35]2[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[C:18](=[O:21])C=C)[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]>ClCCl.Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1>[O:21]=[C:18]1[CH:3]=[CH:2][CH2:1][C:4]2([CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH2:6][CH2:5]2)[N:17]1[CH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[CH:26][N:27]2[S:32]([C:35]1[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=1)(=[O:34])=[O:33]
Reactant: C=CCC1(N(Cc2cccc3c2ccn3S(=O)(=O)c2ccc(C)cc2)C(=O)C=C)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3c(CN4C(=O)C=CCC45CCN(C(=O)OC(C)(C)C)CC5)cccc32)cc1
Reaction time: 8 h
Yield: 84 %

Procedure:
To a solution of tert-butyl 4-allyl-4-(N-((1-tosyl-1H-indol-4-yl)methyl)acrylamido)piperidine-1-carboxylate (0.075 g, 0.13 mmol) in dichloromethane (5.0 mL) was added Grubbs 2nd generation catalyst (0.006 g, 0.006 mmol) under argon and the reaction mixture was stirred at it overnight. The dark brown solution was concentrated under reduced pressure and the crude product was purified by column chromatography (eluent: 25% ethyl acetate in hexane) to yield the title compound as a solid (0.060 g, 84%). [LCMS RtE=0.523 min, [M+H]+=549.8]
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[Si:9]([N:16]1[C@H:19]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[C@@H:18]([C@H:25]([OH:27])[CH3:26])[C:17]1=[O:28])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].C(N(CC)CC)C>CN(C)C=O>[Si:9]([N:16]1[C@H:19]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[C@@H:18]([C@H:25]([O:27][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7])[CH3:26])[C:17]1=[O:28])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)C[C@@H]1[C@@H]([C@@H](C)O)C(=O)N1[Si](C)(C)C(C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C[C@@H]1[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N1[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
t-Butyldimethylchlorosilane (940 mg, 6.25 mmol) is added in one portion to a solution of (3S, 4R)-1-(t-butyldimethylsilyl)-3-[(R)-1-hydroxyethyl]-4-carbomethoxymethylazetidin-2-one (1.88 g, 6.25 mmol) and triethylamine (1.27 g, 6.25 mmol) in 15 ml of anhydrous dimethylformamide at 0° C. After 15 min. at 0° C. the cooling bath is removed and the reaction mixture is stirred at room temperature for 24 hrs. Ether (100 ml) is added and the mixture is filtered, then washed with 2.5 N hydrochloric acid (20 ml), water (3×20 ml) and brine. The organic phase is dried over magnesium sulfate, then concentrated in vacuo. The residue is chromatographed on silica gel (7:3 petroleum ether:ether) to yield (3S, 4R)-1-(t-butyldimethylsilyl)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-carbomethoxymethylazetidin-2-one. n.m.r. (CDCl3)δ4.1(m,2), δ3.68(S,3), δ3.03(dd,1,J=4.3,2.7 ), δ2.8(ABq,2), δ1.17(d,3,J=6.6), δ0.98(s,9), δ0.89(s,9), δ0.23(s,6), δ0.1(s,6).
Reaction SMILES: [Sn](Cl)Cl.[CH3:4][C:5]1[C:12]([CH3:13])=[C:11]([N+:14]([O-])=O)[CH:10]=[CH:9][C:6]=1[C:7]#[N:8]>C(O)C>[NH2:14][C:11]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([CH3:4])[C:12]=1[CH3:13]
Reactant: Cc1c(C#N)ccc([N+](=O)[O-])c1C
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Cc1c(N)ccc(C#N)c1C
Reaction time: 5 h
Yield: 93.6 %

Procedure:
Tin dichloride (12.24 g, 54.2 mmol) was added to a solution of 2,3-dimethyl-4-nitrobenzonitrile (2.73 g, 15.5 mmol) in ethanol (94 ml) at room temperature, and the reaction was carried out for 5 hours under reflux conditions. After cooling, the reaction mixture was concentrated, and the resulting residue was diluted with ethyl acetate and then washed with a saturated aqueous sodium hydrogencarbonate solution. After the insoluble material was filtered off, the filtrate was separated and the organic layer was washed with a saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate and distilled to remove the solvent, whereby 4-amino-2,3-dimethylbenzonitrile (2.12 g, 93.6%) was obtained.
Reaction SMILES: F[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]2[C:10]3([CH2:31][O:32][C:4]=2[CH:3]=1)[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[N:12]([CH2:19][C:20]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][N:21]=1)[C:11]3=[O:30].FC1C(C#[N:41])=CC2C3(COC=2C=1)C1C(=CC=CC=1)N(CC1C=CC=CC=1C(F)(F)F)C3=O>>[F:29][C:26]([F:28])([F:27])[C:25]1[C:20]([CH2:19][N:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10]3([C:5]4[CH:6]=[C:7]5[C:2](=[CH:3][C:4]=4[O:32][CH2:31]3)[NH:41][N:9]=[CH:8]5)[C:11]2=[O:30])=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: N#Cc1cc2c(cc1F)OCC21C(=O)N(Cc2ncccc2C(F)(F)F)c2ccccc21
Reactant: N#Cc1cc2c(cc1F)OCC21C(=O)N(Cc2ccccc2C(F)(F)F)c2ccccc21
Product: O=C1N(Cc2ncccc2C(F)(F)F)c2ccccc2C12COc1cc3[nH]ncc3cc12

Procedure:
Following the procedure as described in EXAMPLE 46 and making non-critical variations using 6-fluoro-2′-oxo-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile to replace 6-fluoro-2′-oxo-1′-[2-(trifluoromethyl)benzyl]-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile, 1′-((3-(trifluoromethyl)pyridin-2-yl)methyl)-1,6-dihydrospiro[furo[3,2-f]indazole-5,3′-indolin]-2′-one was obtained (47%): mp 152-154° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 12.79 (br s, 1H), 8.80 (d, J=6.0 Hz, 1H), 8.24-8.21 (m, 1H), 7.87 (s, 1H), 7.57-7.53 (m, 1H), 7.26-7.17 (m, 3H), 7.02-6.89 (m, 3H), 5.25 (ABq, 2H), 4.87 (ABq, 2H); 13C NMR (75 MHz, DMSO-d6) δ 172.5, 160.1, 153.2, 152.9, 143.5, 141.6, 135.5, 135.4, 134.1, 132.7, 129.1, 126.7, 124.0, 123.6, 123.2, 122.5, 119.1, 116.0, 109.5, 89.4, 80.0, 56.9, 42.4; MS (ES+) m/z 436.9 (M+1).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:17]3[C:16]([CH3:18])=[N:15][NH:14][C:13]=3[C:12](=[O:19])[N:11]2[C:20]2[CH:21]=[C:22]([CH3:30])[C:23]3[N:24]([C:26]([CH3:29])=[N:27][N:28]=3)[CH:25]=2)=[CH:6][CH:5]=1.I[CH2:32][CH3:33]>CN(C=O)C.CCOCC>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:17]3[C:13](=[N:14][N:15]([CH2:32][CH3:33])[C:16]=3[CH3:18])[C:12](=[O:19])[N:11]2[C:20]2[CH:21]=[C:22]([CH3:30])[C:23]3[N:24]([C:26]([CH3:29])=[N:27][N:28]=3)[CH:25]=2)=[CH:6][CH:5]=1
Reactant: Cc1n[nH]c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c3nnc(C)n3c1)C2=O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCn1nc2c(c1C)C(c1ccc(Cl)cc1)N(c1cc(C)c3nnc(C)n3c1)C2=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 18 %

Procedure:
NaH (21.18 mg, 0.529 mmol) was added to a stirred solution of 4-(4-chlorophenyl)-5-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Example 98) (160 mg, 0.407 mmol) in DMF (4 mL) at 0° C. and the resulting mixture was stirred at 0° C. for 30 min. Iodoethane (0.039 mL, 0.489 mmol) was added and the reaction mixture was stirred at RT for 30 min. The reaction was quenched with water, diluted with EtOAc and both phases were separated. The aq. layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude material was purified by preparative achiral SFC (column NH2, gradient 19-24% in 6 min, total 11 min) to afford, after trituration in Et2O, 31 mg, 0.074 mmol, 18% yield) as white solid. tR: 0.88 min (LC-MS 2); ESI-MS: 421 [M+H]+ (LC-MS 2); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38 (t, J=7.2 Hz, 3H) 2.13 (s, 3H) 2.46 (s, 3H) 2.63 (s, 3H) 4.20 (q, J=7.2 Hz, 2H) 6.49 (s, 1H) 7.33-7.40 (m, 5H) 8.46 (s, 1H).
Reaction SMILES: [ClH:1].Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[N:12][CH:13]=[CH:14][N:15]=2)=[CH:6][CH:5]=1.[CH2:22]([N:24]1[C:28]([CH3:29])=[C:27]([CH:30]=O)[C:26]([CH3:32])=[N:25]1)[CH3:23].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].Cl>O1CCCC1.C(#N)C.C(Cl)Cl>[ClH:1].[CH2:22]([N:24]1[C:28]([CH3:29])=[C:27]([CH2:30][N:19]2[CH2:18][CH2:17][N:16]([C:11]3[C:10]([C:7]4[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=4)=[N:15][CH:14]=[CH:13][N:12]=3)[CH2:21][CH2:20]2)[C:26]([CH3:32])=[N:25]1)[CH3:23]
Reactant: Fc1ccc(-c2nccnc2N2CCNCC2)cc1
Reactant: CCn1nc(C)c(C=O)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCn1nc(C)c(CN2CCN(c3nccnc3-c3ccc(F)cc3)CC2)c1C
Temperature: 25 °C
Reaction time: 19 h
Yield: 14.9 %

Procedure:
To a stirred suspension of 3′-(4-fluoro-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl dihydrochloride (0.3 g, 0.906 mmol, 1 eq) and 1-ethyl-3,5-dimethyl-1H-pyrazole-4-carbaldehyde (207 mg, 1.36 mmol, 1.5 eq) in tetrahydrofuran (10 mL) add sodium triacetoxyborohydride (480 mg, 2.26 mmol, 2.5 eq) in one portion as a solid. Stir the mixture at room temperature under nitrogen for 19 hr. Add 2M aqueous sodium hydroxide solution (10 ml) and DCM (20 ml) separate and extract the aqueous layer with DCM (20 ml). Combine the organics, dry over magnesium sulfate, filter and concentrate. Purify by high pH reverse phase HPLC. Dissolve this material (49 mg, 0.12 mmol), in the minimum quantity of 50% aqueous acetonitrile. Add 2M aqueous hydrogen chloride (60 μL, 0.12 mmol) and lyophilize to give the title compound (58 mg, 15%). MS (ES): m/z=395.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.Br[CH2:11][CH2:12][CH2:13][N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9][CH2:11][CH2:12][CH2:13][N:14]2[C:18](=[O:19])[C:17]3[C:16](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:15]2=[O:24])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(S)c1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cccc(SCCCN2C(=O)c3ccccc3C2=O)c1

Procedure:
A solution of 3-methoxybenzenethiol (1.52 mL, 12.2 mmol), N-(3-bromopropyl)phthalimide (3.28 g, 12.2 mmol), and potassium carbonate (2.53 g, 18.3 mmol) in acetone (50 mL) was heated to reflux for 88 hours. The solvent was removed in vacuo and the residue partitioned between water (50 mL) and methylene chloride (50 mL). The layers were separated and the aqueous layer washed with methylene chloride (2×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to provide a yellow oil. The crude product was purified by column chromatography (0→50% ethyl acetate/hexane) to provide the title compound as a clear oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]#[N:13].[CH:14](OC)=[O:15]>>[C:12]([CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][CH:14]=[O:15])[CH:3]=2)[NH:7][CH:6]=1)#[N:13]
Reactant: COC=O
Reactant: N#CCc1c[nH]c2ccc(N)cc12
Product: N#CCc1c[nH]c2ccc(NC=O)cc12

Procedure:
A solution of 5-amino-1H-indole-3-acetonitrile (0.5 g) in methyl formate (20 ml) was stirred at room temperature for 24 h. The resulting solid precipitate was filtered off, washed with ether (2×20 ml) and dried in vacuo to give the title compound (0.41 g) as a white microcrystalline solid m.p. 196°6-200° (softens 194°).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=1>C(#N)C>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:9][CH:10]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: C1CNCCN1
Solvent: CC#N
Product: FC(F)(F)c1ccc(N2CCNCC2)nc1
Temperature: 25 °C
Yield: 69.5 %

Procedure:
A stirred solution of 7.1 grams (0.083 mole) of piperazine (commercially available) and 5.0 grams (0.028 mole) of 2-chloro-5-(trifluoromethyl)pyridine (commercially available) in 75 mL of acetonitrile was heated at reflux during a two-hour period. After this time the reaction mixture was allowed to cool to ambient temperature, and then it was filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was dissolved in 75 mL of methylene chloride and washed with two 50 mL portions of water. The organic layer was dried with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using 100% methylene chloride, then 5% methanol in methylene chloride as eluants. The appropriate fractions were combined and concentrated under reduced pressure, yielding 4.5 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.