Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([CH:15]([CH3:17])[CH3:16])[C:13]2[C:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:19]([F:22])[CH:20]=[CH:21][C:12]=2[N:11]=1)[CH3:9])(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:22][C:19]1[CH:20]=[CH:21][C:12]2[N:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[N:14]([CH:15]([CH3:16])[CH3:17])[C:13]=2[C:18]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: CC(C)n1c([C@H](C)NC(=O)OC(C)(C)C)nc2ccc(F)c(-c3ccccn3)c21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)n1c([C@H](C)N)nc2ccc(F)c(-c3ccccn3)c21
Reaction time: 1 h
Yield: 76 %

Procedure:
[(S)-1-(6-Fluoro-1-isopropyl-7-pyridin-2-yl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tert-butyl ester (0.6 g, 1.5 mmol) was dissolved in 20% TFA in DCM (10 mL). The resulting solution was stirred for 1 h then the mixture was passed through an SCX column. The column was washed with DCM and MeOH to remove non-basic impurities and the product was then eluted with 2M NH3 in MeOH. The product fractions were concentrated to give a yellow solid (0.34 g, 76%). 1H NMR (CDCl3, 400 MHz): δ 8.77 (1H, d, J=6.1 Hz), 7.85 (1H, td, J=10.5, 2.4 Hz), 7.69 (1H, dd, J=11.4, 6.4 Hz), 7.57 (1H, d, J=10.8 Hz), 7.38 (1H, dd, J=9.8, 6.9 Hz), 7.07 (1H, dd, J=13.7, 11.6 Hz), 4.35 (1H, q, J=8.7 Hz), 4.03 (1H, sept, J=9.3 Hz), 1.60 (3H, d, J=8.8 Hz), 1.40-1.29 (6H, m)
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][C@@H:5]([CH:8]([CH3:10])[CH3:9])[C@H:4]([O:11][CH2:12][C:13]([OH:15])=O)[CH2:3]1.[CH2:16]([N:18]([CH2:24][CH3:25])[CH2:19][CH2:20][NH:21][CH2:22][CH3:23])[CH3:17].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH2:16]([N:18]([CH2:24][CH3:25])[CH2:19][CH2:20][N:21]([CH2:22][CH3:23])[C:13](=[O:15])[CH2:12][O:11][C@H:4]1[C@H:5]([CH:8]([CH3:9])[CH3:10])[CH2:6][CH2:7][C@@H:2]([CH3:1])[CH2:3]1)[CH3:17]
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OCC(=O)O
Reactant: CCNCCN(CC)CC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CCN(CC)CCN(CC)C(=O)CO[C@@H]1C[C@H](C)CC[C@H]1C(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.4 %

Procedure:
5.0 g of ((1R,3R,4S)-1-methyl-4-isopropylcyclohex-3-yloxy)acetic acid were dissolved in 100 ml of tetrahydrofuran. 3.4 g (=4.2 ml) of N,N,N'-triethylethylenediamine and 5.3 g of dicyclohexylcarbodiimide were added to the solution, and the reaction mixture was stirred at room temperature for 24 hours. The mixture was worked up by concentrating it under reduced pressure. The remaining residue was purified by chromatography on silica gel using dichloromethane/methanol as the eluent. 4.8 g of N-(2- diethylaminoethyl)-N-(ethyl)-((1R,3R,4S)-1-methyl-4-isopropylcyclohex-3-yloxy)acetamide were obtained.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[C:6](#[N:10])[C:7]([CH3:9])=[CH2:8]>>[N:1]1([CH2:8][CH:7]([CH3:9])[CH2:6][NH2:10])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: C=C(C)C#N
Product: CC(CN)Cn1ccnc1

Procedure:
A mixture of 15.0 g. of imidazole and 25 ml. of methacrylonitrile was heated at reflux temperature for 18 hours and then concentrated to remove the volatile material. The residue was mixed with 150 ml. of ethanol, 75 ml. of ammonium hydroxide and 6 g. of Raney Nickel catalyst and reduced in a Parr hydrogenator under hydrogen pressure until reduction was complete. The catalyst was removed by filtration and the mother liquor was concentrated to remove the solvents. The residual oil was used in reactions without further purification.
Reaction SMILES: [CH:1](=O)[CH3:2].C([BH3-])#N.[Na+].C(O)(=O)C.[NH2:12][C@H:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1.C(=O)([O-])O.[Na+]>CO>[C:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][C@H:13]([NH:12][CH2:1][CH3:2])[CH2:14]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC=O
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCN[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.6 %

Procedure:
367 μL (6.5 mmol) of acetaldehyde, 817 mg (13 mmol) of sodium cyanoborohydride and 3.75 mL (65 mmol) of acetic acid are added to a solution of 1.47 mL (8.4 mmol) of (S)-3-amino-1-tert-butoxycarbonylpyrrolidine in 30 mL of anhydrous methanol. The solution is stirred at room temperature for 24 hours then a saturated aqueous solution of sodium hydrogencarbonate is added to adjust the pH to 7. The compound is extracted with ethyl acetate. The organic phases are dried over magnesium sulfate, filtered then evaporated and the residue is purified by chromatography on silica (eluent dichloromethane/methanol 94/6) to give 970 mg (70%) of (S)-1-tert-butoxycarbonyl-3-ethylamino-pyrrolidine in the form of a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17](O)=[O:18].[CH:20]([NH:23][NH:24][C:25]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)=[O:26])([CH3:22])[CH3:21].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]([N:23]([CH:20]([CH3:22])[CH3:21])[NH:24][C:25]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)=[O:26])=[O:18]
Reactant: CC(C)NNC(=O)c1cccs1
Reactant: Cc1cccc(-c2ccccc2CCC(=O)O)c1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cccc(-c2ccccc2CCC(=O)N(NC(=O)c2cccs2)C(C)C)c1C
Yield: 50.8 %

Procedure:
A solution of 3-(2′,3′-dimethyl-biphenyl-2-yl)-propionic acid (207 mg, 0.81 mmoles) and thiophene-2-carboxylic acid N′-isopropyl-hydrazide (150 mg, 0.81 mmoles) in DMF (8 mL) was treated with triethylamine (0.34 mL, 2.44 mmoles), HOBT (132 mg, 0.98 mmoles) and EDCI (156 mg, 0.98 mmoles) at room temperature for 48 h. The reaction mixture was partitioned between 1N HCl and dichloromethane. The organic layer was washed successively with 1N NaOH and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexanes gradient to afford the product (173 mg, 51%). LC-MS m/e 421.46 (M+H+)
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:12])[CH2:4][C@H:3]1[OH:13].N[C@@H]1CC2C(=C(O)C=CC=2)C[C@H]1O.[Cl:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32]([C:37](O)=[O:38])=[CH:31]2.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[Cl:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32]([C:37]([NH:1][C@@H:2]1[CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][C:9]=3[OH:12])[CH2:4][C@H:3]1[OH:13])=[O:38])=[CH:31]2
Reactant: N[C@@H]1Cc2c(O)cccc2C[C@H]1O
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N[C@@H]1Cc2cccc(O)c2C[C@H]1O
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1Cc2c(O)cccc2C[C@H]1O)c1cc2cc(Cl)ccc2[nH]1

Procedure:
A mixture of trans 3-amino-2,5-dihydroxy-1,2,3,4-tetrahydronaphthalene and trans 3-amino-2,8-dihydroxy-1,2,3,4-tetrahydronaphthalene (278 mg, prepared in the manner disclosed in GB 1442851) was dissolved at room temperature with stirring under argon in N,N-dimethylformamide (2 mL) along with 5-chloroindole-2-carboxylic acid (315 mg), 1-hydroxy-7-azabenzotriazole (230 mg), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (330 mg). After 3 days the reaction mixture was purified without work-up by reverse phase preparative HPLC to provide the two isomers as off-white solids, trans 3-(5-chloroindole-2-carbonylamino)-2,5-dihydroxy-1,2,3,4-tetrahydronaphthalene, Example 2 (eluted first, 130 mg) and trans 3-(5-chloroindole-2-carbonylamino)-2,8-dihydroxy-1,2,3,4-tetrahydronaphthalene, Example 3 (eluted second, 104 mg). HPLC/MS for both isomers [M+H]+, 357; [M−H]−, 355.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1([CH:11](O)[CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:19]1([CH3:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCCl>[CH3:25][C:19]1[CH:24]=[CH:23][C:22]([CH:11]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)=[CH:21][CH:20]=1
Reactant: Cc1ccccc1
Reactant: OC(Cn1cncn1)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cc1ccc(C(Cn2cncn2)c2ccccc2)cc1
Temperature: 80 °C

Procedure:
20 g (0.15 mole) of AlCl3 were added in portions to a solution of 18.9 g (0.1 mole) of 1-phenyl-2-(1,2,4-triazol-1-yl)-ethanol in 50 ml of toluene and 50 ml of 1,2-dichloroethane at -10° C. Thereafter, the mixture was heated to 80° C., until the evolution of gas was no longer observed. The mixture was poured onto 200 ml of ice-water, the organic phase was separated off and concentrated, and the residue was triturated with diisopropyl ether. Yield 23.8 g (90%), m.p. 98°-100° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[N:9]2)=[CH:4][C:3]=1[C:18]#[N:19].C1C(=O)N([Br:27])C(=O)C1.C(OOCC1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][Br:27])=[CH:11][C:10]([C:14]([F:16])([F:15])[F:17])=[N:9]2)=[CH:4][C:3]=1[C:18]#[N:19]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C(F)(F)F)nn1-c1ccc(F)c(C#N)c1
Agent: c1ccc(COOCc2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(-n2nc(C(F)(F)F)cc2CBr)ccc1F
Yield: 50.1 %

Procedure:
To a solution of 1-(4-fluoro-3-cyanophenyl)-3-trifluoromethyl-5-methylpyrazole (4.0 g, 14.9 mmol) in CCl4 (75 mL) was added NBS (5.3 g, 29.7 mmol) and benzylperoxide (0.2 g, 1.49 mmol). The reaction was brought to reflux overnight. The next day the CCl4 was evaporated and the residue was partitioned between ethyl acetate and sodium bicarbonate (sat.). The organic phase was washed with water, brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography gave 1-(4-fluoro-3-cyanophenyl)-3-trifluoromethyl-5-bromomethylpyrazole (2.6 g, 50% yield) as pure compound: MS (CI): 348 (M+H)+ (100%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1)[CH2:6][CH3:7])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=1)[CH2:6][CH3:7])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C(CC)Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CC)Cc1ccc(N)cc1

Procedure:
28 g of 2-(p-nitrobenzyl)-butyric acid ethyl ester are dissolved in 200 ml ethyl acetate. The solution is added with 1 g of 10% Pd/C and hydrogenated in a Parr apparatus until complete absorption of hydrogen. After filtering and evaporation from solvent about 25 g of product are obtained as a sufficiently pure oil for the successive reactions.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH2:15])(=[O:14])=[O:13])#[C:2][CH2:3][CH2:4][CH3:5].[CH:16]1([O:21][C:22]([NH:24][C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[N:30]([CH3:34])[CH:29]=[C:28]3[CH2:35][C:36]2[CH:44]=[CH:43][C:39]([C:40](O)=[O:41])=[CH:38][C:37]=2[O:45][CH3:46])=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:16]1([O:21][C:22]([NH:24][C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[N:30]([CH3:34])[CH:29]=[C:28]3[CH2:35][C:36]2[CH:44]=[CH:43][C:39]([C:40]([NH:15][S:12]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[C:1]#[C:2][CH2:3][CH2:4][CH3:5])(=[O:13])=[O:14])=[O:41])=[CH:38][C:37]=2[O:45][CH3:46])=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COc1cc(C(=O)O)ccc1Cc1cn(C)c2ccc(NC(=O)OC3CCCC3)cc12
Reactant: CCCC#Cc1ccccc1S(N)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCC#Cc1ccccc1S(=O)(=O)NC(=O)c1ccc(Cc2cn(C)c3ccc(NC(=O)OC4CCCC4)cc23)c(OC)c1
Reaction time: 20 h
Yield: 74 %

Procedure:
1.07 g of 2-(pent-1-yn-1-yl)-benzenesulfonamide and 0.94 g of 3-[N-dimethylaminopropyl]-N-ethylcarbodiimide hydrochloride as well as 0.6 g of 4-dimethylaminopyridine are added to a solution of 2.0 g of 4-[5-(cyclopentyloxycarbonylamino)-1-methyl-indol-3-yl-methyl]-3-methoxy-benzoic acid in 50 ml of methylene chloride. The reaction mixture is stirred for 20 hours under argon and then diluted with 50 ml of methylene chloride. The methylene chloride phase is washed in a separating funnel twice with 1N hydrochloric acid and once with water. The methylene chloride phase is dried over magnesium sulfate and concentrated by evaporation at 20 torr and 40°. The residue is chromatographed on 80 g of silica gel (Merck Si60, 40-63 μm), ethyl acetate being used as eluant. The fractions containing the product are concentrated by evaporation at 20 torr and 40° to yield 2.2 g of the title compound in the form of a white amorphous solid. 1H-NMR (400 MHz, DMSO-d6): 8.76 (s, b, 1H); 8.00 (d, 1H); 7.56 (m, 2H); 7.44 (m, 4H); 7.21 (d, 1H); 7.16 (d, d, 1H); 7.08 (d, 1H); 6.91 (s, 1H); 5.07 (m, 1H); 3.94 (s, 2H); 3.88 (s, 3H); 3.66 (s, 3H); 2.33 (t, 2H); 1.90-1.53 (m, 8H); 1.47 (m, 2H); 0.89 (t, 3H).
Reaction SMILES: CC1(C)CO[CH:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([O:15][CH2:16][CH2:17][CH3:18])[CH:9]=2)[O:4]C1.C1(C)C=CC=CC=1>C(O)=O>[OH:14][C:11]1[CH:12]=[CH:13][C:8]([CH:5]=[O:4])=[CH:9][C:10]=1[O:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCOc1cc(C2OCC(C)(C)CO2)ccc1O
Solvent: Cc1ccccc1
Solvent: O=CO
Product: CCCOc1cc(C=O)ccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
A mixture of 1.26 g (4.74 mmol) of 4-(5,5-dimethyl-1,3-dioxan-2-yl)-2-propoxyphenol, 20 ml of toluene and 20 ml of formic acid was vigorously stirred for 2 hours at room temperature. Thereafter, the reaction mixture was partitioned between toluene and water and the organic phase was washed several times with water, dried over magnesium sulfate, filtered and evaporated down. Crystallization of the residue from a mixture of 10 ml of diethyl ether and 20 ml of hexane gave 0.78 mg of 4-hydroxy-3-propoxybenzaldehyde.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](Cl)=O)=[CH:6][CH:5]=1)[CH3:2].[NH2:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[NH:23][CH2:24][CH:25]1[CH2:27][CH2:26]1)[C:18]#[N:19]>C(O)(=O)C>[CH:25]1([CH2:24][N:23]2[C:22]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=3[N:14]=[C:11]2[CH2:10][C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=2)[CH2:26][CH2:27]1
Reactant: N#Cc1ccc(NCC2CC2)c(N)c1
Reactant: CCOc1ccc(CC(=O)Cl)cc1
Solvent: CC(=O)O
Product: CCOc1ccc(Cc2nc3cc(C#N)ccc3n2CC2CC2)cc1
Yield: 78.3 %

Procedure:
Following the general procedure 2D, the freshly prepared (4-ethoxyphenyl)acetyl chloride (from 793 mg of acid, 4.4 mmol) and crude 3-amino-4-[(cyclopropylmethyl)amino]benzonitrile (750 mg, 4.01 mmol) were heated in acetic acid (HOAc) overnight. After work-up, the crude residue was purified by silica gel column chromatography to afford pure product (1.04 g, 78%) as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 8.08 (s, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.38 (d, J=8.4 Hz, 1H), 7.14 (d, J=8.4 Hz, 2H), 6.84 (d, J=8.4 Hz, 2H), 4.29 (s, 2H), 4.01 (d, J=7.6 Hz, 2H), 3.96 (q, J=7.6 Hz, 2H), 1.39 (t, J=7.6 Hz, 3H), 1.04–1.00 (m, 1H), 0.58–0.53 (m, 2H), 0.29–0.25 (m, 2H). MS (ESI) (M+H)+=332. Anal. Calcd for C21H21N3O.0.1H2O: C, 75.50; H, 6.41; N, 12.61. Found: C, 75.76; H, 6.72; N, 12.45.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:12]=3[C:13]=2[CH3:14])O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)(Cl)=O.C(=O)([O-])O.[Na+].[NH2:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]([O:38][CH3:39])=[O:37])=[N:34][CH:35]=1.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[NH4+]>C1(C)C=CC=CC=1.CN(C)C=O>[CH:1]1([CH:7]([NH:29][C:30]2[CH:31]=[CH:32][C:33]([C:36]([O:38][CH3:39])=[O:37])=[N:34][CH:35]=2)[C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:12]=3[C:13]=2[CH3:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(C(O)C2CCCCC2)oc2ccc(F)cc12
Reactant: COC(=O)c1ccc(N)cn1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(c2oc3ccc(F)cc3c2C)C2CCCCC2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.1 %

Procedure:
To a solution (15 mL) of cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methanol (1.50 g) synthesized in Example A37(2) in toluene was added thionyl chloride (625 μL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into ice-cooled saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a brown oil. To a mixture of the obtained oil, methyl 5-aminopyridine-2-carboxylate (957 mg), sodium iodide (1.71 g) and N,N-dimethylformamide (15 mL) was added sodium carbonate (1.21 g), and the mixture was stirred at 80° C. overnight. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10-50% ethyl acetate/hexane) to give the title object compound (909 mg, 40%) as a pale-brown solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[F:18])[N:14]=[C:13](Cl)[C:12]([Cl:20])=[N:11]2>CCO>[Cl:20][C:12]1[C:13]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:14][C:15]2[C:10](=[CH:9][C:8]([F:7])=[C:17]([F:18])[CH:16]=2)[N:11]=1
Reactant: C1CNCCN1
Reactant: Fc1cc2nc(Cl)c(Cl)nc2cc1F
Solvent: CCO
Product: Fc1cc2nc(Cl)c(N3CCNCC3)nc2cc1F
Temperature: 75 °C

Procedure:
Piperazine (0.86 g, 10 mmol) was added to a stirred suspension of 6,7-difluoro-2,3-dichloroquinoxaline* (1.18 g, 5 mmol) in EtOH (50 mL) at room temperature. The mixture was heated at 75° C. for 17 h, allowed to cool and filtered to give the product as a pale yellow solid: yield 0.40 g (28%); mp 294-297° C. (dec). MS m/z 285/287 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]([C:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([C:18]4[C:26]5[O:25][CH2:24][O:23][C:22]=5[CH:21]=[CH:20][C:19]=4[O:27][CH2:28][CH3:29])[C:12]=3[NH:11][CH:10]=2)=[O:8])[CH2:2]1.Cl[C:31]([C@@H:33]([O:35]C(=O)C)[CH3:34])=[O:32]>>[OH:35][C@@H:33]([CH3:34])[C:31]([N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]([C:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([C:18]4[C:26]5[O:25][CH2:24][O:23][C:22]=5[CH:21]=[CH:20][C:19]=4[O:27][CH2:28][CH3:29])[C:12]=3[NH:11][CH:10]=2)=[O:8])[CH2:2]1)=[O:32]
Reactant: CCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@@H]4CCNC4)c[nH]c13)OCO2
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Product: CCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@@H]4CCN(C(=O)[C@H](C)O)C4)c[nH]c13)OCO2

Procedure:
Starting from 4-(5-ethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide (example A176) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound was obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][C:6]1([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[O:11])[CH2:9][CH2:8][CH2:7]1.[BH4-].[Na+].[CH3:23]O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]([C:6]2([CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[OH:11])[CH2:9][CH2:8][CH2:7]2)[CH3:23])[CH:18]=[CH:19][CH:20]=1
Reactant: CO
Reactant: O=C(c1ccccn1)C1(Cc2cccc(Cl)c2)CCC1
Agent: [BH4-]
Agent: [Na+]
Product: CC(c1cccc(Cl)c1)C1(C(O)c2ccccn2)CCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 23.6 %

Procedure:
To a solution of Example 44C (0.5 g, 1.67 mmol) in 20 mL of methanol was added NaBH4 (0.076 g, 2 mmol) in small portions at 0° C. The mixture was stirred at 0° C. for 2 h. The mixture was concentrated and the residue was purified by prep TLC (petroleum ether: ethyl acetate=7:1) to afford the title compound (0.35 g, total yield 23.6%). 1H NMR (400 MHz, CDCl3): δ=8.58 (d, J=2.0 Hz, 1H), 7.65-7.62 (m, 1H), 7.27-7.12 (m, 6H), 4.78 (s, 1H), 4.16 (brs, 1H), 3.12-3.00 (m, 1H), 2.17-1.80 (m, 4H), 1.36 (d, J=6.0 Hz, 3H), 1.26-1.17 (m, 1H), 0.95-0.80 (m, 1H). LC-MS: m/z 302 (M+H).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][NH:4]1.[S:13](=O)(=[O:16])([OH:15])[OH:14]>O>[OH:16][S:13]([O:1][CH2:2][C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][NH:4]1)(=[O:15])=[O:14]
Reactant: OC[C@@H]1Cc2ccccc2CN1
Reactant: O=S(=O)(O)O
Solvent: O
Product: O=S(=O)(O)OC[C@@H]1Cc2ccccc2CN1
Temperature: 110 °C

Procedure:
A solution of (S)-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline (41 g.) in a mixture of sulphuric acid (d = 1.83; 13 cc.) and water (70 cc.) is heated at 110° C. Water (about 50 cc.) is distilled off and the mixture is then concentrated under reduced pressure (20 mm. Hg) at 100° C. The brown oily residue is taken up in a mixture of sulphuric acid (d = 1.83; 13 cc. ) and water (70 cc.); water (50 cc.) is again distilled off and the mixture is then concentrated as previously described, after which the concentration is finished at 100° C. under reduced pressure (1 mm. Hg). The residue, which crystallises on cooling, is recrystallised from a mixture of ethanol (140 cc.) and water (60 cc.) After cooling for 15 hours at about 5° C., the crystals which have appeared are filtered off and washed with a mixture of ethanol and water (3:1 by volume) (20 cc.) and then with ethanol (2 × 25 cc.). After drying at 60° C . under reduced pressure (1 mm. Hg), (S)-3-hydroxysulphonyloxymethyl-1,2,3,4-tetrahydroisoquinoline (48 g.) is obtained in the form of white crystals.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>C(#N)C>[CH3:25][CH:26]1[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][O:4][C:5]2[CH:6]=[C:7]([C:11]3[C:15]4[S:16][CH:17]=[CH:18][C:14]=4[O:13][N:12]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:28][CH2:27]1
Reactant: CC1CCNCC1
Reactant: BrCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1CCN(CCOc2cccc(-c3noc4ccsc34)c2)CC1
Temperature: 75 °C
Yield: 96.3 %

Procedure:
Mix 3-[3-(2-bromo-ethoxy)-phenyl]-thieno[2,3-d]isoxazole (0.250 g, 0.77 mmol), potassium carbonate (0.22 g, 1.59 mmol), 4-methylpiperidine (0.382 g, 3.85 mmol) and acetonitrile (4.0 mL) and heat at 75° C., overnight. Cool the reaction mixture and filter through a Waters Sep-Pak 1 g silica cartridge (ethyl acetate). Combine the appropriate fractions and concentrate to give a residue. Purify the residue by column (10 g silica) chromatography using a solvent gradient of dichloromethane to 10% methanol in dichloromethane to obtain the title compound (0.254 g, 96% Yield) as an amber oil. Purity by LC/MS (APCI)=99%, [M+H]+=343.
Reaction SMILES: [F:1][C:2]1[C:24]([N:25]2[CH2:31][CH2:30][CH2:29][N:28]([CH3:32])[CH2:27][CH2:26]2)=[CH:23][C:5]2[NH:6][C:7]([C:9]3[C:13]([N+:14]([O-])=O)=[CH:12][N:11]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][O:18]4)[N:10]=3)=[N:8][C:4]=2[CH:3]=1.[H][H]>CO.[Pd]>[F:1][C:2]1[C:24]([N:25]2[CH2:31][CH2:30][CH2:29][N:28]([CH3:32])[CH2:27][CH2:26]2)=[CH:23][C:5]2[NH:6][C:7]([C:9]3[C:13]([NH2:14])=[CH:12][N:11]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][O:18]4)[N:10]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: [H][H]
Reactant: CN1CCCN(c2cc3[nH]c(-c4nn(C5CCCCO5)cc4[N+](=O)[O-])nc3cc2F)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCCN(c2cc3[nH]c(-c4nn(C5CCCCO5)cc4N)nc3cc2F)CC1
Yield: 98.2 %

Procedure:
A suspension of 11.9 g of 5-fluoro-6-(4-methylperhydro-1,4-diazepin-1-yl)-2-[4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazol-3-yl]-1H-benzimidazole in 260 mL of methanol and 1.2 g of palladium-on-charcoal is hydrogenated under 1 bar of hydrogen pressure at ambient temperature for 18 hours. The reaction medium is filtered through celite and the filtrate is concentrated under reduced pressure in a rotary evaporator. 10.9 g of 3-[5-fluoro-6-(4-methylperhydro-1,4-diazepin-1-yl)-1H-benzimidazol-2-yl]-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-ylamine are obtained in the form of a brown powder. 1H NMR (300 MHz, DMSO-d6, δ in ppm): 1.43 to 2.17 (m, 8H); 2.33 (s, 3H); 2.64 (m, 2H); 2.73 (m, 2H); from 3.20 to 3.40 (m masked, 4H); 3.62 (m, 1H); 3.95 (m, 1H); 4.92 (broad s, 2H); 5.31 (dd, J=2.5 and 10.0 Hz, 1H); from 6.91 to 7.36 (m, 2H); 7.31 (s, 1H); 12.4 (broad m, 1H). ES mass spectrum: m/z=414: MH+ (base peak)—m/z=330: (MH−C5H8O)+