Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C(N(C)C)=N.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]12[CH2:24][NH:23][CH2:22][CH:21]1[CH2:20][S:19][C:18]([NH:25][C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[N:17]2.[F:34][C:35]1[CH:36]=[N:37][C:38](Cl)=[N:39][CH:40]=1.C(OCC)(=O)C>CS(C)=O.O>[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]12[CH2:24][N:23]([C:38]3[N:39]=[CH:40][C:35]([F:34])=[CH:36][N:37]=3)[CH2:22][CH:21]1[CH2:20][S:19][C:18]([NH:25][C:26](=[O:33])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[N:17]2
Reactant: O=C(NC1=NC2(c3ccccc3F)CNCC2CS1)c1ccccc1
Reactant: Fc1cnc(Cl)nc1
Agent: CN(C)C(=N)N(C)C
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C(NC1=NC2(c3ccccc3F)CN(c3ncc(F)cn3)CC2CS1)c1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 42.8 %

Procedure:
N,N,N′,N′-tetramethylguanidine (0.44 mL, 3.5 mmol) is added to a solution of racemic N-[7a-(2-fluorophenyl)-4a,5,6,7-tetrahydro-4H-pyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (1.0 g, 2.9 mmol) and 5-fluoro-2-chloropyrimidine (0.46 g, 3.5 mmol) in dimethylsulfoxide (10 mL). The reaction is stirred at 100° C. for 2 hours, and cooled to room temperature. To the crude reaction is added ethyl acetate (7.5 ml) and water (2.5 ml), the mixture is passed through diatomaceous earth (10 g), and the solvent removed under reduced pressure. The residue is purified by silica gel chromatography eluting with a gradient of 40% to 60% ethyl acetate in hexanes to give the title compound (560 mg, 43%). ES/MS (m/e): 452 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[NH:5][CH:6]=[N:7]2.[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:15]=1[CH2:16]Cl>>[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:15]=1[CH2:16][N:7]1[CH:6]=[N:5][C:4]2[C:8]1=[N:9][CH:10]=[N:11][C:3]=2[N:2]([CH3:12])[CH3:1]
Reactant: CN(C)c1ncnc2nc[nH]c12
Reactant: Fc1cccc(Cl)c1CCl
Product: CN(C)c1ncnc2c1ncn2Cc1c(F)cccc1Cl

Procedure:
Employing N6,N6 -dimethyladenine prepared in Example 17 and 2-chloro-6-fluorobenzyl chloride, the same procedures as in Example 39, (1) were repeated to give a crude 9-(2-chloro-6-fluorobenzyl)-N6, N6 -dimethyladenine, in which the purity was 73.1% by weight and the content of the 3-isomer was 26.9% by weight.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[CH2:10][OH:11].[N+:12]([C:15]1[CH:20]=[CH:19][C:18](F)=[CH:17][CH:16]=1)([O-:14])=[O:13]>>[CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[CH2:10][O:11][C:18]1[CH:19]=[CH:20][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cn1c([N+](=O)[O-])cnc1CO
Product: Cn1c([N+](=O)[O-])cnc1COc1ccc([N+](=O)[O-])cc1

Procedure:
m.p. 150° C, from 15.7 g (0.1 mole) of 1-methyl-2-hydroxymethyl-5-nitro-imidazole (MHNI) and 14.1 g (0.1 mole) of 4-nitrofluorobenzene.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.N1C=CN=C1NC(C1C2N=C(N[C:24]([C:26]3[N:27]=[CH:28][C:29]4[C:34]([CH:35]=3)=[CH:33][CH:32]=[CH:31][C:30]=4[O:36][CH3:37])=[O:25])NC=2C=CC=1)=O.CC[O:40][CH2:41]C>C(O)(=O)C>[CH3:41][O:40][C:24]([C:26]1[N:27]=[CH:28][C:29]2[C:34]([CH:35]=1)=[CH:33][CH:32]=[C:31]([Cl:4])[C:30]=2[O:36][CH3:37])=[O:25]
Reactant: CCOCC
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1cccc2cc(C(=O)Nc3nc4c(C(=O)Nc5ncc[nH]5)cccc4[nH]3)ncc12
Solvent: CC(=O)O
Product: COC(=O)c1cc2ccc(Cl)c(OC)c2cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
0.083 mL (1 mmol) of sulfuryl chloride was added to a solution of 90 mg (0.41 mmol) of 8-methoxy-isoquinoline-3-carboxylic acid methyl ester (from Example 295) in 1 mL of acetic acid and stirred at room temperature overnight. Ether was added to the reaction mixture, and the precipitated solid was filtered, washed with ether, then partitioned between ethyl acetate (30 mL) and saturated NaHCO3 solution (30 mL) and extracted. The organic layer was dried over sodium sulfate, and evaporation of the solvent in vacuo gave 47.3 mg (46%) of 7-chloro-8-methoxy-isoquinoline-3-carboxylic acid methyl ester. LCMS: 252 (M+1)+. The ester was hydrolyzed according to the general procedure B to provide 40 mg (88%) of the 7-chloro-8-methoxy-isoquinoline-3-carboxylic acid. LCMS: 238 (M+1)+.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:31]([O:33][CH3:34])=[O:32])[CH2:19][C:20]3[CH:25]=[C:24]([N+:26]([O-])=O)[C:23]([NH2:29])=[C:22]([CH3:30])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:35]=[CH:36][CH:37]=[CH:38][C:4]=2[NH:3]1.[H][H]>CO.[Pd]>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@@H:18]([C:31]([O:33][CH3:34])=[O:32])[CH2:19][C:20]3[CH:21]=[C:22]([CH3:30])[C:23]([NH2:29])=[C:24]([NH2:26])[CH:25]=3)=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:35]=[CH:36][CH:37]=[CH:38][C:4]=2[NH:3]1
Reactant: COC(=O)[C@@H](Cc1cc(C)c(N)c([N+](=O)[O-])c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H](Cc1cc(C)c(N)c(N)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Reaction time: 3.5 h

Procedure:
A suspension of 2.00 g (3.24 mmol) (R)-2-(4-amino-3-methyl-5-nitro-phenyl)-1-methoxycarbonyl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 300 mg 10% Pd/C in 100 mL MeOH was hydrogenated for 3.5 h at 50° C. and 50 psi hydrogen pressure. The catalyst was filtered off, the filtrate was evaporated down i. vac. and the residue was purified by chromatography (silica gel, gradient DCM/MeOH 30:1 to DCM/MeOH 15:1).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Br:13]Br>CCOCC>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH:8]([Br:13])[CH2:7]1)=[O:5])[CH3:2]
Reactant: BrBr
Reactant: CCOC(=O)C1CCC(=O)CC1
Solvent: CCOCC
Product: CCOC(=O)C1CCC(=O)C(Br)C1

Procedure:
To a 1 l. three-necked flask provided with a stirrer, condenser and dropping funnel and containing a solution of 25.5 g. of 4-ketocyclohexanecarboxylic acid ethyl ester in 450 ml. of anhydrous ether cooled to -10° was added dropwise over 45 minutes 24 g. of bromine. The resulting colorless solution was washed with 3×100 ml. of water, then with 2×50 ml. of 5% sodium bicarbonate solution and finally with 2×100 ml. of water. The ether solution was dried over anhydrous magnesium sulfate and then the solvent was removed on a steam bath. The yield of crude 3-bromo-4-ketocyclohexanecarboxylic acid ethyl ester was 37 g.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][C:13]=1[OH:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[Ni]>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])=[C:13]([OH:21])[CH:14]=1
Reactant: [H][H]
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1O)OCc1ccccc1
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc(NC(=O)OCc2ccccc2)c(O)c1
Reaction time: 1 h

Procedure:
0.53 mole (153 g) of 2-(benzyloxycarbonylamino) -5-nitrophenol in 1 liter of ethanol is subjected to a hydrogen pressure of 8×105 pascals (8 bars) in an autoclave in the presence of 60 g of Raney nickel (water content 50%). After 1 hour at 65° C., the reaction medium is filtered while hot in order to remove the catalyst. On cooling the filtrate, the expected product crystallizes. After draining and drying, the product obtained is recrystallized in 96° strength ethanol. It melts at 148° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[C:16]([Cl:23])=[CH:15][N:14]=1.[O:24]1CCCC1>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:24][C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[C:16]([Cl:23])=[CH:15][N:14]=2)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: C1CCOC1
Reactant: FC(F)(F)c1cc(Cl)ncc1Cl
Agent: [H-]
Agent: [Na+]
Product: FC(F)(F)c1cc(OCc2ccc(Br)cc2)ncc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
To a solution of 4-bromobenzylbromide (0.43 g, 2.3 mmol) in tetrahydrofuran (8 mL) at 0° C. was added sodium hydride (60% w/w dispersion in oil; 138 mg, 3.45 mmol). The mixture was stirred for 1 hour at room temperature, then 2,5-dichloro-4-trifluoromethylpyridine (0.5 g, 2.3 mmol) was added in one portion and the reaction heated under reflux for 4 hours. The reaction mixture was cooled and partitioned between ethyl acetate (30 mL) and water (10 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo to give the crude title compound (0.61 g, 71%). This was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH:11]=O)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[CH3:29][C:30]1([C:35]([N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)=[O:36])[CH2:34][CH2:33][NH:32][CH2:31]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CO>[CH3:29][C:30]1([C:35]([N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)=[O:36])[CH2:34][CH2:33][N:32]([CH2:11][C:10]2[N:2]([CH3:1])[C:3]3[C:8]([N:9]=2)=[C:7]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[N:6]=[C:5]([N:19]2[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[C:20]2[CH3:28])[N:4]=3)[CH2:31]1
Reactant: CC1(C(=O)N2CCCC2)CCNC1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C)(C(=O)N4CCCC4)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
A mixture of 9-methyl-2-(2-methylbenzoimidazol-1-yl)-6-morpholin-4-yl-9H-purine-8-carbaldehyde (100 mg, 0.26 mmol), (3-methylpyrrolidin-3-yl)pyrrolidin-1-ylmethanone (58 mg, 0.32 mmol), trimethoxyorthoformate (0.29 mL, 2.65 mmol) and acetic acid (15 μL, 0.26 mmol) in DCE (5 mL) was stirred at room temperature for 1 hour then sodium triacetoxyborohydride (90 mg, 0.42 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours then diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was washed with MeOH and the desired product was eluted with 2M NH3 in MeOH. The solvents were removed and the residue was subjected to flash chromatography (Si—PCC, 0-20% MeOH in EtOAc) to give 396 as a white solid (107 mg, 76%). LCMS (Method G): RT 6.69 min; [M+H]+ 544. 1H NMR (400 MHz, CHCl3-d): δ 8.12-8.07 (m, 1 H); 7.74-7.70 (m, 1 H); 7.30-7.26 (m, 2 H); 4.35 (m, 4 H); 3.90 (s, 3 H); 3.87 (t, J=4.75 Hz, 5 H); 3.49 (m, 5 H); 2.96 (s, 3 H); 2.64 (s, 2 H); 2.46-2.37 (m, 2 H); 1.89 (m, 4 H); 1.81 (m, 2 H); 1.41 (s, 3 H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.[CH2:14]([N:16]([CH2:27][CH3:28])[CH2:17][CH2:18][O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)[CH3:15]>C1COCC1.CC(O)C>[CH2:27]([N:16]([CH2:14][CH3:15])[CH2:17][CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([NH:24][C:2]2[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=2)=[CH:25][CH:26]=1)[CH3:28]
Reactant: CCN(CC)CCOc1ccc(N)cc1
Reactant: CCNc1nc(Cl)ncc1[N+](=O)[O-]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CCNc1nc(Nc2ccc(OCCN(CC)CC)cc2)ncc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 88.1 %

Procedure:
To a solution of 1.013 g (5 mmol) of 2-chloro-4-(ethylamino)-5-nitropyrimidine in 50 mL THF at −78° C. is added a solution of 2.48 g (12 mmol) of 4-[2-(diethylamino)ethoxy]aniline in 50 mL of 2-propanol, and the resulting mixture is allowed to warm slowly to room temperature. After removal of the solvent, the residue is dissolved in aqueous acetic acid and filtered through celite. The aqueous solution is then basified with aqueous ammonia, and the resulting precipitate is collected, washed with water, and dried to give 1.65 g (95%) of the title compound: mp (MeOH) 134–136° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:13])=[N:7][C:8]([Cl:12])=[CH:9][C:10]=1[CH3:11])=[O:4].[Br:14]N1C(=O)CCC1=O.C(O)(=O)C>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH2:13][Br:14])=[N:7][C:8]([Cl:12])=[CH:9][C:10]=1[CH3:11])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c(C)cc(Cl)nc1C
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(C)cc(Cl)nc1CBr

Procedure:
To a solution of 710 mg, (3.6 mmol) 6-chloro-2,4-dimethyl-pyridine-3-carboxylic acid methylester in CCl4 (16 ml) were added 688 mg (3.90 mmol) N-bromosuccinimide, 59 mg (0.36 mmol) AlBN and 210 μl (3.72 mmol) acetic acid. The reaction mixture was irradiated with a 200 W Wolfram lamp at 60° C. for 24 h. The mixture was then filtered through celite, washed with CCl4 and concentrated in vacuo. After CC (hexane/EtOAc 97:3) of the residue a mixture of 6-chloro-2,4-dimethyl-pyridine-3-carboxylic acid methylester, 4-(bromomethyl)-6-chloro-2-methyl-pyridine-3-carboxylic acid methylester and 2-(bromomethyl)-6-chloro-4-methyl-pyridine-3-carboxylic acid methylester was obtained. This mixture was dissolved in dioxane (10 ml) and added at 0° C. to a solution prepared by dissolving 594 mg (25.8 mmol) sodium in MeOH (11 ml) at 0° C. This reaction mixture was stirred at RT for 3 h. Then the reaction solution was poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. After CC (hexane/EtOAc 97:3) of the residue again a mixture of 6-chloro-4-(methoxymethyl)-2-methyl-pyridine-3-carboxylic acid methylester and 6-chloro-2-(methoxymethyl)-4-methyl-pyridine-3-carboxylic acid methylester was obtained. This material was dissolved in NMP (7.8 ml) and 860 μl (9.85 mmol) morpholine and 1.36 g (9.85 mmol) K2CO3 were added followed by heating at 100° C. for 5 h. Then the mixture was poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 9:1) provided 90 mg (0.32 mmol, 9%) 2-(methoxymethyl)-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid methylester.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:22][CH2:21][C:8]2([CH2:11][CH:10]([N:12]3[CH2:17][CH2:16][CH:15]([C:18](O)=[O:19])[CH2:14][CH2:13]3)[CH2:9]2)[CH2:7]1)=[O:5])[CH3:2].C[N:24]([CH:26]=O)C.CN(C(ON1N=N[C:38]2[CH:39]=CC=N[C:37]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:37][CH:38]([CH3:39])[CH2:26][NH:24][C:18]([CH:15]1[CH2:14][CH2:13][N:12]([CH:10]2[CH2:9][C:8]3([CH2:21][CH2:22][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7]3)[CH2:11]2)[CH2:17][CH2:16]1)=[O:19]
Reactant: CCOC(=O)N1CCC2(CC(N3CCC(C(=O)O)CC3)C2)C1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CN(C)C=O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCC2(CC(N3CCC(C(=O)NCC(C)C)CC3)C2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.5 %

Procedure:
1-[6-(Ethoxycarbonyl)-6-azaspiro[3.4]oct-2-yl]piperidine-4-carboxylic acid (0.200 g, 0.65 mmol) was dissolved in DMF (5 mL) isobutylamine (0.071 g, 0.97 mmol), HATU (0.270 g, 0.71 mmol) and DIPEA (0.417 g, 3.23 mmol) were added. The reaction mixture was stirred at rt overnight under nitrogen. The solvents were removed in vacuo, and the residue was partitioned between DCM and sat. NaHCO3 sol., organic layer washed with sat. NaCl sol. and dried over MgSO4. The solvents were removed in vacuo, and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 25 g, 40-63 μm, 60 A, 12 mL per min, gradient 0% to 10% MeOH in DCM]) to give ethyl 2-{4-[(2-methylpropyl)carbamoyl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate (0.089 g, 37.7%) as a pale yellow gum as a mixture of diastereomers.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([C@@H:23]3[CH2:27][CH2:26][NH:25][CH2:24]3)[C:7]([CH2:9][N:10]3[C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:11]3)=[N:8][C:4]=2[CH:3]=1.[OH:30][C:31]([CH3:36])([CH3:35])[C:32](O)=[O:33].OCC(O)=O>>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([C@@H:23]3[CH2:27][CH2:26][N:25]([C:32](=[O:33])[C:31]([OH:30])([CH3:36])[CH3:35])[CH2:24]3)[C:7]([CH2:9][N:10]3[C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[C:12]([S:19]([CH3:22])(=[O:20])=[O:21])=[N:11]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CC(C)(O)C(=O)O
Reactant: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2[C@@H]2CCNC2)c2cnccc12
Agent: O=C(O)CO
Product: CC(C)(O)C(=O)N1CC[C@@H](n2c(Cn3nc(S(C)(=O)=O)c4ccncc43)nc3cc(Cl)ccc32)C1

Procedure:
The title compound was prepared in analogy to Example 2-17 by using 1-({5-chloro-1-[(3R)-(pyrrolidin-3-yl)]-1H-benzo[d]imidazol-2-yl}methyl)-3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine and 2-hydroxy-2-methylpropanoic acid instead of 1-{[5-chloro-1-(pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl]methyl}-3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine and 2-hydroxyacetic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:17]([O:19][CH2:20][CH2:21][CH2:22][Cl:23])=[O:18].O>CC(C)=O>[OH:6][CH2:5][C:4]1[CH:3]=[C:2]([NH:1][C:17](=[O:18])[O:19][CH2:20][CH2:21][CH2:22][Cl:23])[CH:9]=[CH:8][CH:7]=1
Reactant: Nc1cccc(CO)c1
Reactant: O=C(Cl)OCCCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(Nc1cccc(CO)c1)OCCCCl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3.7 g (30 mmol) of 3-aminobenzyl alcohol are dissolved in 50 ml of acetone, and 3.2 g (30 mmol) of sodium carbonate are added. 5.7 g (36 mmol) of 3-chloropropyl chloroformate are metered into this suspension at 25° C. The reaction mixture is stirred at room temperature for a further 18 h. Water is added to the reaction mixture for hydrolysis, and the solid is subsequently filtered off. The solution is concentrated by distillation, during which the product deposits as an oil. The product phase is separated off. The aqueous phase is extracted with ethyl acetate. The organic phases are combined, washed with water and dried over sodium sulfate. The mixture is subsequently evaporated to dryness. The crude product is reacted further directly without further purification;
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([NH2:14])[C:10]([NH2:13])=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.Cl.[CH:16]1([C:19](=N)OCC)[CH2:18][CH2:17]1.C(O)C.N>CO>[CH:16]1([C:19]2[NH:13][C:10]3[CH:11]=[CH:12][C:7]([CH2:6][N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)=[CH:8][C:9]=3[N:14]=2)[CH2:18][CH2:17]1
Reactant: Nc1ccc(Cn2ccnc2)cc1N
Reactant: CCOC(=N)C1CC1
Agent: Cl
Agent: N
Solvent: CO
Solvent: CCO
Product: c1cn(Cc2ccc3[nH]c(C4CC4)nc3c2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.6 %

Procedure:
A mixture of 3.3 parts of 4-(1H-imidazol-1-ylmethyl)-1,2-benzenediamine, 2.88 parts of ethyl cyclopropanecarboximidate hydrochloride and 64 parts of ethanol was stirred first for 4 hours at room temperature and further for 1 hour at reflux. The reaction mixture was cooled, treated with methanol, saturated with ammonia, and evaporated. The residue was purified twice by column chromatography over silica gel using first a mixture of trichloromethane and methanol (90:10 by volume) and then a mixture of trichloromethane and methanol (92:8 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from ethyl acetate, yielding 2.57 parts (61.6%) of 2-cyclopropyl-5-(1H-imidazol-1-ylmethyl)-1H-benzimidazole; mp. 184.3° C. (compound 168).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[C:16]([CH2:20][S:21]([NH2:24])(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=3)[N:8]=2)[CH2:6][CH2:5]C[CH2:3][CH2:2]1.Cl[C:26]1N=CN=C(NC2C=C(CS(N)(=O)=O)C=CC=2)[N:27]=1.CN1CCNCC1>>[CH3:26][N:27]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[C:16]([CH2:20][S:21]([NH2:24])(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=3)[N:8]=2)[CH2:2][CH2:3]1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCCCC3)n2)c1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Agent: CN1CCNCC1
Product: CN1CCN(c2ncnc(Nc3cccc(CS(N)(=O)=O)c3)n2)CC1

Procedure:
B12 was prepared following the procedure reported for B1 using A1 and N-methylpiperazine. MS (ES) C15H21N7O3S requires: 363. found: 364 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([O:10][CH2:11][CH2:12][F:13])[N:7]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[N:15]=3)[C:6]=2[CH:21]=1.[C:22]([Si:24]([CH3:27])([CH3:26])[CH3:25])#[CH:23].C(N(CC)CC)C>CS(C)=O.ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:13][CH2:12][CH2:11][O:10][C:8]1[N:7]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[N:15]=2)[C:6]2[CH:21]=[C:2]([C:23]#[C:22][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:3]=[CH:4][C:5]=2[N:9]=1
Reactant: Nc1nccc(-n2c(OCCF)nc3ccc(Br)cc32)n1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: C[Si](C)(C)C#Cc1ccc2nc(OCCF)n(-c3ccnc(N)n3)c2c1
Yield: 37.8 %

Procedure:
A solution of 4-[6-bromo-2-(2-fluoroethoxy)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (150 mg, 0.43 mmol), ethynyltrimethylsilane (126 mg, 1.28 mmol), bis(triphenylphosphine) palladium(II) dichloride (120 mg, 0.17 mmol) and triethylamine (0.5 mL) in dimethylsulfoxide (1 mL) was irradiated with microwave radiation under nitrogen in a sealed tube at 80° C. for 40 min. The reaction mixture was diluted with 10 mL of dichloromethane and the solid material was removed by filtration. The filtrate was concentrated under vacuum and the residue was purified on a silica gel column (ethyl acetate/petroleum ether, 3:1) to give 60 mg (38%) of 4-[2-(2-fluoroethoxy)-6-[2-(trimethylsilyl)ethynyl]-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine as a yellow solid: LC-MS: m/z=+370 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:35][CH2:34][CH2:33][C@@H:32]2[C:36]2[N:40](C3CCCCO3)[N:39]=[CH:38][CH:37]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:35][CH2:34][CH2:33][C@@H:32]2[C:36]2[NH:40][N:39]=[CH:38][CH:37]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(O[C@H]3CCC[C@@H]3c3ccnn3C3CCCCO3)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1ccncn1)c1cc(Cl)c(O[C@H]2CCC[C@@H]2c2ccn[nH]2)cc1F
Yield: 76.9 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)-4-({(1S*,2R*)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]cyclopentyl}oxy)benzenesulfonamide (126 mg, 0.187 mmol) prepared in Example 140a, triethylsilane (0.30 mL), trifluoroacetic acid (2.0 mL) and dichloromethane (3.0 mL), to yield the title compound (63 mg, 77%) as a colorless solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:33]=[CH:32][C:23]([O:24][C:25]2[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=2)=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]([O:39][CH2:40][CH2:41][CH2:42][CH3:43])(=[O:38])[CH:35]([CH3:37])O>>[CH2:1]([N:8]([CH2:19][C:20]1[CH:33]=[CH:32][C:23]([O:24][C:25]2[CH:26]=[C:27]([CH:28]=[CH:29][CH:30]=2)[O:31][CH:35]([CH3:37])[C:34]([O:39][CH2:40][CH2:41][CH2:42][CH3:43])=[O:38])=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3cccc(O)c3)cc2)cccc1[N+](=O)[O-]
Reactant: CCCCOC(=O)C(C)O
Product: CCCCOC(=O)C(C)Oc1cccc(Oc2ccc(CN(Cc3ccccc3)c3cccc([N+](=O)[O-])c3C)cc2)c1

Procedure:
The product from Example 61F and butyl lactate was processed as described in Example 62A to provide the title compound.