Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OCC[C:4]1[N:8]([CH2:9][C:10]2[CH:27]=[CH:26][C:13]3/[C:14](=[CH:23]/[C:24]#[N:25])/[C:15]4[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=4[CH2:17][CH2:18][C:12]=3[CH:11]=2)[C:7]2[CH:28]=[C:29]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:30]=[C:31]([CH3:32])[C:6]=2[N:5]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(Cl)(Cl)Cl.C(=O)([O-])O.[Na+]>C(#N)C>[CH3:32][C:31]1[C:6]2[N:5]=[CH:4][N:8]([CH2:9][C:10]3[CH:27]=[CH:26][C:13]4/[C:14](=[CH:23]/[C:24]#[N:25])/[C:15]5[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=5[CH2:17][CH2:18][C:12]=4[CH:11]=3)[C:7]=2[CH:28]=[C:29]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:30]=1
Reactant: Cc1cc(-c2ccccc2)cc2c1nc(CCO)n2Cc1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: Cc1cc(-c2ccccc2)cc2c1ncn2Cc1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Temperature: 25 °C
Reaction time: 4 h
Yield: 15.5 %

Procedure:
[step 1] (E)-{2-[2-(2-Hydroxyethyl)-4-methyl-6-phenylbenzimidazol-1-yl]methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile (100 mg, 0.20 mmol) obtained in Example 59, step 1 was dissolved in acetonitrile (2 mL), 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (128 mg, 0.30 mmol) was added, and the mixture was stirred at room temperature for 4 hr. Chloroform (20 mL) and saturated aqueous sodium hydrogen carbonate solution (20 mL) were added to the mixture, and the mixture was stirred at room temperature for 30 min. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 95/15) to give (E)-[2-(4-methyl-6-phenylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (14 mg, 15%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6](Cl)(=[O:8])=[O:7].[CH3:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=1[N:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1>CC(C)=O>[CH3:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][S:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)(=[O:8])=[O:7])=[CH:14][C:13]=1[N:19]1[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Solvent: CC(C)=O
Product: COc1ccc(NS(=O)(=O)c2cccs2)cc1N1CCN(C)CC1
Reaction time: 8 h

Procedure:
A solution of thiophene-2-sulfonyl chloride (82 mg; 0.45 mmol) in acetone (2 ml) was added to a solution of 4-methoxy-3-(4-methylpiperazin-1-yl)aniline (100 mg; 0.45 mmol) in acetone (2 ml) and the mixture stood overnight at room temperature. The resultant crystalline solid was filtered off and washed with acetone, then diethyl ether, to afford the title compound as the hydrochloride salt. (153 mg; 84%). MS: m/z=368.
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.[CH2:9]([C:13]1[S:17][C:16]([CH:18]2[CH2:20][CH:19]2[C:21](Cl)=[O:22])=[CH:15][CH:14]=1)[CH2:10][CH2:11][CH3:12].O>[Na]>[CH2:9]([C:13]1[S:17][C:16]([CH:18]2[CH2:20][CH:19]2[C:21]([N:4]2[CH2:5][CH:6]([CH3:8])[O:7][CH:2]([CH3:1])[CH2:3]2)=[O:22])=[CH:15][CH:14]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCc1ccc(C2CC2C(=O)Cl)s1
Reactant: CC1CNCC(C)O1
Agent: [Na]
Solvent: O
Product: CCCCc1ccc(C2CC2C(=O)N2CC(C)OC(C)C2)s1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
2,6-Dimethylmorpholine (5.0 g, 0.043 mol) was added dropwise to a solution of 2-(5-n-butylthiophen-2-yl)-cyclopropanecarbonyl chloride (4.85 g, 0.02 mol) in sodium dried ether (40 ml) at 10° C. and after complete addition the solution was stirred at 20° C. for 3 hours. The reaction mixture was poured into water and extracted with diethyl ether (2×100 ml). The ethereal extracts were washed with water, dried over anhydrous sodium sulphate, and the solvent removed to give 2-(5-n-butylthiophen-2-yl)-cyclopropanecarbonyl-2,6-dimethylmorpholine (5.8 g, 90% as a yellow oil. A solution of 2-(5-n-butylthiophen-2-yl)-chclopropanecarbonyl-2,6-dimethylmorpholine (5.8 g, 0.018 mol) in sodium dried ether (30 ml) was added dropwise to a suspension of lithium aluminium hydride (0.8 g, 0.02 mol) in sodium dried ether (20 ml) and the reaction mixture stirred at room temperature for 3 hours. The reaction mixture was poured carefully into water and extracted with diethyl ether. The ethereal extracts were washed with water, dried over anhydrous sodium sulphate, and the solvent removed to give a colourless oil. This oil was purified by column chromatography (silica eluted with ethyl acetate/petroleum ether 2:3) to give the title compound (1.3 g, 24%).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:19]=[CH:20][C:21]4[N:22]([C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][N:26]=4)[N:23]=3)[CH2:14][CH2:13]2)=[CH:4]1.Cl.Cl[CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>CN(C=O)C>[N:35]1([CH2:34][CH2:33][N:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH:12]3[CH2:13][CH2:14][N:15]([C:18]4[CH:19]=[CH:20][C:21]5[N:22]([C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][N:26]=5)[N:23]=4)[CH2:16][CH2:17]3)=[CH:4]2)[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: ClCCN1CCCC1
Reactant: FC(F)(F)c1nnc2ccc(N3CCC(c4c[nH]c5ccccc45)CC3)nn12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1nnc2ccc(N3CCC(c4cn(CCN5CCCC5)c5ccccc45)CC3)nn12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27.6 %

Procedure:
Sodium hydride (60% dispersion in oil, 31 mg, 0.75 mmol) was added to 6-[4-(1H-indol-3-yl)piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (obtained as described in Example 507) (150 mg, 0.39 mmol) suspended in DMF (2 mL) at 0° C. under nitrogen. The resulting mixture was stirred at 0° C. for 30 minutes, then 1-(2-chloroethyl)pyrrolidine hydrochloride (72.6 mg, 0.43 mmol) in DMF (1 mL) was added. The resulting mixture was stirred at ambient temperature for 18 hours. The reaction mixture was evaporated to afford crude product. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD 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 give 6-[4-[1-(2-pyrrolidin-1-ylethyl)-1H-indol-3-yl]piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (52.0 mg, 27.7%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([OH:21])=[C:10]([C:17](OC)=[O:18])[N:11]=[C:12]2[C:15]#[N:16])=[CH:7][CH:6]=1.[NH2:26][CH2:27][C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30]>CCO>[Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([OH:21])=[C:10]([C:17]([NH:26][CH2:27][C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:18])[N:11]=[C:12]2[C:15]#[N:16])=[CH:7][CH:6]=1
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3Cl)ccc2c1O
Reactant: CCOC(=O)C(C)(C)CN
Solvent: CCO
Product: CCOC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3Cl)ccc2c1O

Procedure:
Methyl 7-(2-chlorophenoxy)-1-cyano-4-hydroxyisoquinoline-3-carboxylate (20 mg, 0.06 mmol) and ethyl 3-amino-2,2-dimethylpropanoate (33 mg, 0.23 mmol) in EtOH (3 mL) were heated at 150° C. in a microwave for 1.5 hours. The solvent was removed in vacuo and the residue oil was purified by flash chromatography (0-50% EtOAc/hexanes) to give the title compound in 30 mg. 1H NMR (CDCl3, 200 MHz): δ=8.41 (d, 1H, J=8.5 Hz), 8.30 (t, 1H, J=6.6 Hz), 7.57-7.48 (m, 2H), 7.42-7.17 (m, 4H), 4.23 (q, 2H, J=7.0 Hz), 3.60 (d, 2H, J=6.6 Hz), 1.35 (t, 3H, J=7.0 Hz), 1.28 (s, 6H).
Reaction SMILES: [C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:11][C@@H:10]([NH:25][C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31](C)[CH:30]=2)=[O:27])[C:9]1=[O:36])=[O:6])([CH3:4])([CH3:3])[CH3:2].[N+:37](C1C=C(N=C=O)C=CC=1)([O-:39])=[O:38]>>[C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:11][C@@H:10]([NH:25][C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([N+:37]([O-:39])=[O:38])[CH:30]=2)=[O:27])[C:9]1=[O:36])=[O:6])([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1cccc(NC(=O)N[C@@H]2N=C(c3ccccc3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Product: CC(C)(C)C(=O)CN1C(=O)[C@H](NC(=O)Nc2cccc([N+](=O)[O-])c2)N=C(c2ccccc2)c2ccccc21
Yield: 94 %

Procedure:
The resolved aminobenzodiazepine of Example 26 was treated with m-nitrophenyl isocyanate as described in Example 45 to provide a colourless oil (490 mg, 94%).
Reaction SMILES: [C:1]1([C@:11]23[CH2:16][CH:15]2[CH2:14][O:13][C:12]3=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.ClCCl>O1CCCC1>[C:1]1([C@:11]2([CH2:12][OH:17])[CH2:16][CH:15]2[CH2:14][OH:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1OCC2C[C@]12c1cccc2ccccc12
Solvent: C1CCOC1
Solvent: ClCCl
Product: OCC1C[C@@]1(CO)c1cccc2ccccc12
Yield: 98.6 %

Procedure:
BMS (0.2 mL, 0.8 mmol) was added to (1S)-1-(1-naphthyl)-3-oxabicyclo[3.1.0]hexan-2-one (90 mg, 0.4 mmol) in dry tetrahydrofuran (1 mL), under nitrogen atmosphere. The reaction mass was refluxed for 5 hours and monitored by TLC (dichloromethane (100%)). The reaction mass was quenched with 10% potassium carbonate solution. The aqueous layer was extracted with dichloromethane (2×10 mL). The combined organic layer was dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to yield 90 mg (98.5%) of desired product. 1H NMR δ(300 MHz,CDCl3): 1.09-1.43 (3H,m), 1.67-1.69 (2H,m,) 1.83-1.90 (1H,m), 3.5-3.7 (2H,m), 4.25-4.27 (2H,m), 7.4-7.65 (4H,m), (1H,m) 7.77-7.89 (2H,m), 8.25 (1H,brs).
Reaction SMILES: [ClH:1].Cl.[O:3]([C:10]1[CH:11]=[C:12]([CH:16]([C:24]2([OH:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:17][N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[ClH:1].[ClH:1].[O:3]([C:10]1[CH:11]=[C:12]([C@H:16]([C:24]2([OH:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)[CH2:17][N:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]2)[CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OC1(C(CN2CCNCC2)c2cccc(Oc3ccccc3)c2)CCCCC1
Agent: Cl
Solvent: CO
Product: OC1([C@H](CN2CCNCC2)c2cccc(Oc3ccccc3)c2)CCCCC1

Procedure:
Racemic 1-[1-(3-phenoxyphenyl)-2-piperazin-1-ylethyl]cyclohexanol (see Example 311) was dissolved in methanol at a concentration of approximately 50 mg/mL. The resulting solution was injected onto the Preparative High Performance Liquid Chromatography instrument. The baseline resolved enantiomers, using the conditions described below, were collected. The enantiomeric purity of each enantiomer was determined under the same HPLC conditions using a Chiralcel OD-H 5 u, 250 mm×4.6 mm ID column at 1.0 mL/min flow rate using an HP 1100 HPLC (Agilent Technologies. Palo Alto, Calif., USA).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]1[C:13]2[C:8](=[CH:9][C:10]([CH2:14]O)=[CH:11][CH:12]=2)[CH2:7][CH2:6]1>C(Cl)(Cl)Cl>[Cl:3][CH2:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[CH2:5][CH2:6][CH2:7]2
Reactant: OCc1ccc2c(c1)CCC2
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: ClCc1ccc2c(c1)CCC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.7 %

Procedure:
Thionyl chloride (120 ml, 1.65 mol) was added drop-wise to a rapidly stirred mixture of (2,3-dihydro-1H-inden-5-yl)methanol (81.4 g, 0.55 mol) in chloroform (500 ml) at 0° C. After the addition was complete, the resulting mixture was allowed to warm to room temperature and the stirring was continued for an additional 12 h. The chloroform was evaporated under reduced pressure to give a residue, that was purified by column chromatography (petroleum ether:ethyl acetate=15:1) to afford 5-(chloromethyl)-2,3-dihydro-1H-indene (90.5 g, 99%). 1H NMR (300 MHz, CDCl3) δ 2.06-2.19 (m, 4H), 2.93 (t, J=7.5, 4H), 4.54 (s, 2H), 7.15-7.31 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19](Cl)[N:18]=1>>[Cl:16][C:17]1[N:18]=[C:19]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: Clc1cccc(Cl)n1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2cccc(Cl)n2)ccc1-n1cnc(C)c1

Procedure:
Prepared in analogy to example 62 from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine and 2,6-dichloropyridine. The title compound was obtained as a yellow solid (Yield=60%). MS ISP (m/e): 315.1 & 317.1 (100 & 37) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): 8 (ppm)=7.63 (s, 1H), 7.48 (t, 1H), 7.37 (s, 1H), 7.18 (d, 1H), 6.95-6.80 (m, 2H), 6.82 (d, 1H), 6.72 (d, 1H), 6.64 (s, 1H), 3.86 (s, 3H), 2.30 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([NH:21][C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=[C:14]3C=2C[N:16]([CH3:19])[C:15]3=[O:20])[CH:7]=[N:6]1.[NH2:50]C1C(C(NC)=O)=NC(C2C=NN(CCCO)C=2)=CC=1>>[OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[N:50]=[C:14]([C:15](=[O:20])[NH:16][CH3:19])[C:13]([NH:21][C:22]3[C:27]([C:28]([F:29])([F:31])[F:30])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=[CH:12][CH:11]=2)[CH:7]=[N:6]1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Reactant: CNC(=O)c1nc(-c2cnn(CCCO)c2)ccc1N
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)nc3C(=O)NC)n2)c(OC)c1)OCC
Yield: 68 %

Procedure:
Prepared analogously to Compound 1B replacing Compound 1C with 3-amino-6-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-N-methylpyridine-2-carboxamide (Compound 6C, 220.0 mg, 0.7991 mmol) to afford 337 mg of the title compound (68%). 1H NMR (400 MHz, CDCl3) δ 12.19 (s, 1H), 9.04 (d, J=9.1 Hz, 1H), 8.36-8.44 (m, 2H), 8.21 (s, 1H), 8.08 (s, 1H), 8.04 (br. s., 1H), 7.63 (d, J=8.8 Hz, 1H), 7.52 (s, 1H), 6.95 (td, J=2.3, 8 Hz, 1H), 6.86 (t, J=1.9 Hz, 1H), 4.40 (t, J=6.2 Hz, 2H), 3.97-4.11 (m, 4H), 3.91 (s, 3H), 3.65 (q, J=5.3 Hz, 2H), 3.18 (d, J=21.1 Hz, 2H), 3.09 (d, J=5.1 Hz, 3H), 2.11 (quin, J=5.9 Hz, 2H), 1.26 (t, J=7.1 Hz, 6H) [OH proton obscured]. MS (ES+): m/z 693.75 [M+H]+. UPLC: tR=1.24 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][C:6]([CH2:7][CH:8]([C:11]#[N:12])[C:9]#[N:10])=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:20][CH2:21][C:22]([F:26])=[C:23]([F:25])[F:24]>CN(C)C=O>[F:26][C:22](=[C:23]([F:25])[F:24])[CH2:21][CH2:20][C:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:15])([F:16])[F:1])=[CH:14][CH:13]=1)([C:11]#[N:12])[C:9]#[N:10]
Reactant: FC(F)=C(F)CCBr
Reactant: N#CC(C#N)Cc1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)=C(F)F)Cc1ccc(C(F)(F)F)cc1
Yield: 21.6 %

Procedure:
Using 0.50 g of (4-(trifluoromethyl)benzyl)malononitrile, 6 ml of N,N-dimethylformamide, 98 mg of sodium hydride (60% in oil), and 0.46 g of 4-bromo-1,1,2-trifluoro-1-butene, and according to the process described in the Production Example 1, there was obtained 0.16 g of 2-(3,4,4-trifluoro-3-butenyl)-2-(4-(trifluoromethyl)benzyl)malononitrile (the present compound (73)).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.CCCCCC.C([Li])CCC.[C:19]1(=[O:24])[O:23][CH2:22][CH2:21][CH2:20]1>CCOCC>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:22](=[O:23])[CH2:21][CH2:20][CH2:19][OH:24])[CH:3]=1
Reactant: Brc1cccnc1
Reactant: O=C1CCCO1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: O=C(CCCO)c1cccnc1
Yield: 76.5 %

Procedure:
A solution of 10.0 g (63.3 mmol) of 3-bromopyridine in 100 ml of ether was cooled to -78° C., to which 40 ml (64 mmol) of 1.6 M n-butyllithium hexane solution was added dropwise with stirring. After completion of the addition, the mixture was stirred for further 15 minutes, to which the solution of 5.45 g (63.3 mmol) of γ-butyrolactone in 15 ml of ether was added dropwise, and stirred for further 1 hour at -78° C.-room temperature. To the reaction mixture an aqueous solution of ammonium chloride, and the resultant substance was extracted with ethyl acetate. The extract was washed with water and dried, and the solvent was evaporated off. The residue was purified with silica gel column chromatography (CHCl3 -MeOH (9:1)) and recrystallized from ethyl acetate-isopropyl ether, to give 8.0 g (77%) of 4-(3-pyridyl)-4-oxobutanol. m.p. 36°-37° C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:4][N:3]=[CH:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:24]([O:26][C:27](=[O:32])[CH2:28]C(O)=O)[CH3:25]>O1CCCC1>[CH2:24]([O:26][C:27](=[O:32])[CH2:28][C:9](=[O:11])[CH2:8][CH2:7][CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[CH3:25]
Reactant: O=C(O)CCCn1ccnc1
Reactant: CCOC(=O)CC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CCCn1ccnc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 44 %

Procedure:
To a suspension of 4-(1-imidazolyl)butyric acid (0.5 g) in tetrahydrofuran (35 ml), 1,1'-carbonyldiimidazole (0.578 g) was added, followed by stirring at room temperature for 6 hours. After magnesium salt of malonic acid monoethyl ester [Mg(OCOCH2COOC2H5)2 ] (1.02 g) was added, the mixture was stirred at room temperature for 18 more hours. After the reaction mixture was concentrated under reduced pressure, the residue was dissolved in dichloromethane. The dichloromethane layer was washed with water and dried (MgSO4), after which the solvent was distilled off. The residual oily substance was subjected to silica gel column chromatography and eluted with chloroform-methanol (30:1, v/v) to yield 6-(1-imidazolyl)-3-oxohexanoic acid ethyl ester (0.32 g, 44%) as an oily substance.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][C:14]=3[Cl:22])[C:9]([CH3:11])=[N:10][C:5]2=[CH:4][CH:3]=1.[C:23](Cl)(=O)[C:24](Cl)=O.CN(C)C=O>ClCCl>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([O:21][CH:24]4[CH2:23][CH2:5][CH2:4][CH2:3][CH2:2]4)=[O:20])=[CH:15][C:14]=3[Cl:22])[C:9]([CH3:11])=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: Cc1nc2ccc(Br)nc2n1Cc1ccc(C(=O)O)cc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc2ccc(Br)nc2n1Cc1ccc(C(=O)OC2CCCCC2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-bromo-3-(2-chloro-4-carboxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine (525 mg) in dichloromethane (5 ml) were added oxalyl chloride (0.36 ml) and N,N-dimethylformamide (0.03 ml), and the mixture was stirred at room temperature for 1 hr and concentrated under reduced pressure. Dichloromethane (5 ml) was added and dissolved, and trimethylamine (698 mg), 4-dimethylaminopyridine (10 mg) and cyclohexanol (1.38 g) were successively added under ice-cooling. The mixture was stirred under ice-cooling for 30 min and at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and water and ethyl acetate were added for partitioning. The organic layer was successively washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Hexane (20 ml) was added to the residue and the mixture was heated. The black insoluble matter was removed by filtration and the filtrate was allowed to cool. The precipitated crystals were collected by filtration, dried under reduced pressure and by heating to give the objective compound (533 mg) as colorless crystals.
Reaction SMILES: C(OC([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][N:12]([CH2:16][C:17]3[S:18][C:19]4[C:24]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[N:23][C:22]([Cl:31])=[N:21][C:20]=4[N:32]=3)[CH2:13]2)[CH2:9]1)=O)(C)(C)C.N1(C2CCNCC2)C[CH2:35][CH2:34]1>>[N:8]1([CH:9]2[CH2:10][CH2:11][N:12]([CH2:16][C:17]3[S:18][C:19]4[C:24]([N:25]5[CH2:26][CH2:27][O:28][CH2:29][CH2:30]5)=[N:23][C:22]([Cl:31])=[N:21][C:20]=4[N:32]=3)[CH2:35][CH2:34]2)[CH2:15][CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CC2CN(Cc3nc4nc(Cl)nc(N5CCOCC5)c4s3)CC2C1
Reactant: C1CN(C2CCNCC2)C1
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCC(N4CCC4)CC3)nc2n1

Procedure:
Prepared according to the method used in the preparation of 5-(5-chloro-7-morpholin-4-ylthiazolo[4,5-d]pyrimidin-2-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester using 4-azetidin-1-yl piperidine in place of hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester. The title compound was obtained as a yellow solid (97 mg, 33%).
Reaction SMILES: C([O:4][CH2:5][C:6]1[NH:7][N:8]2[C:17]([CH:18]=1)=[C:16]1[C:11]([CH:12]=[CH:13][CH:14]=[CH:15]1)=[N:10][C:9]2=[O:19])(=O)C.[OH-].[Na+].Cl.O>CO>[OH:4][CH2:5][C:6]1[NH:7][N:8]2[C:17]([CH:18]=1)=[C:16]1[C:11]([CH:12]=[CH:13][CH:14]=[CH:15]1)=[N:10][C:9]2=[O:19]
Reactant: CC(=O)OCc1cc2c3ccccc3nc(=O)n2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=c1nc2ccccc2c2cc(CO)[nH]n12
Reaction time: 5 h

Procedure:
The crude acetate product from Example 5 is slurried in a solution of 0.3 g of sodium hydroxide in 10 ml of aqueous methanol (1:1). After stirring for 5 hours, the reaction mixture is neutralized with concentrated hydrochloric acid followed by the addition of 13 ml of distilled water. After stirring overnight, the product is filtered, washed with cold distilled water and dried under vacuum at 60° C. to 0.62 g (72%) of white product, m.p. 285.0°-288.0° C.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20].Cl.[O:23]1[CH2:28][CH2:27][CH:26]([CH2:29][NH2:30])[CH2:25][CH2:24]1>C1COCC1>[N+:19]([C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:9]=1[NH:30][CH2:29][CH:26]1[CH2:27][CH2:28][O:23][CH2:24][CH2:25]1)=[CH:17][CH:16]=[CH:15][CH:14]=2)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: NCC1CCOCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnc2ccccc2c1NCC1CCOCC1
Reaction time: 1 h
Yield: 89.2 %

Procedure:
Under a nitrogen atmosphere THF (90 mL) and triethylamine (17.5 mL, 125.6 mmol) were added sequentially to a mixture of crude 4-chloro-3-nitroquinoline (13.10 g, 62.81 mmol) and 1-tetrahydro-2H-pyran-4-ylmethylamine hydrochloride (10.0 g, 65.95 mmol). The reaction mixture was placed in an oil bath at 45° C. for 1 hour and then concentrated under reduced pressure. The residue was diluted with THF (30 mL) and water (200 mL). The THF was removed under reduced pressure. A solid was isolated by filtration and dried to provide 16.10 g of 3-nitro-N-(tetrahydro-2H-pyran-4-ylmethyl)quinolin-4-amine as a light yellow solid.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([O:14][C:15](=[O:23])[NH:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([CH3:13])([CH3:12])[CH3:11].Cl[S:25]([C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=1)(=[O:27])=[O:26]>C1COCC1>[C:10]([O:14][C:15]([NH:16][CH:17]1[CH2:22][CH2:21][N:20]([S:25]([C:28]2[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:35][CH:36]=2)(=[O:27])=[O:26])[CH2:19][CH2:18]1)=[O:23])([CH3:13])([CH3:11])[CH3:12]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc(C(=O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 119.7 %

Procedure:
Diisopropylethylamine (10.9 ml, 62.4 mmol) was added in one portion to a stirred solution of piperidin-4-yl-carbamic acid tert-butyl ester (5.0 g, 20.0 mmol) in THF (150 ml) at room temperature. To this mixture was added 4-(chlorosulfonyl)benzoic acid (5.52 g, 25.0 mmol) portion wise and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After this time the mixture was concentrated and the resulting residue suspended in HCl (1M solution, 100 ml), the resulting solid precipitate was collected by filtration, washed with water and dried under vacuum give the title compound (9.2 g, 96% yield) as a white solid. Tr=1.28 min m/z (ES+) (M+Na+) 407.