Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([OH:6])[CH3:5].[Br:7][C:8]1[CH:13]=[C:12](F)[CH:11]=[C:10]([Br:15])[CH:9]=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[Br:7][C:8]1[CH:13]=[C:12]([O:6][CH:4]([CH3:5])[CH3:3])[CH:11]=[C:10]([Br:15])[CH:9]=1
Reactant: Fc1cc(Br)cc(Br)c1
Reactant: CC(C)O
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(Br)cc(Br)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of NaH 60% dispersion in mineral oil (1.89 g, 47.25 mmol) in dry DMF (20 mL) under inert atmosphere was added dropwise at 0° C. i-PrOH (3.62 mL, 47.25 mmol). The mixture was stirred at 0° C. for 15 min. Then, a solution of 1,3-dibromo-5-fluoro-benzene (1.98 mL, 15.75 mmol) in dry DMF (20 mL) was added dropwise at 0° C. The reaction mixture was stirred for 16 h at room temperature. A saturated solution of NaHCO3 was added dropwise and the crude product was extracted with Et2O (2 times), the organic layer was washed with a saturated solution of NaHCO3 (3 times), then with a saturated solution of NaCl, dried over MgSO4 and concentrated to give I-a as yellow oil in quantitative yield. 1H RMN (300 MHz, CDCl3) δ 7.21 (t, J=1.4 Hz, 1H), 6.97 (d, J=1.5 Hz, 2H), 4.61-4.40 (m, 1H), 1.32 (d, J=6.0 Hz, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[OH:12].[C:13](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[O:12][CH3:13]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cc(F)cc(Br)c1O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1c(Br)cc(F)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 61.8 %

Procedure:
2-Bromo-4-fluoro-6-nitro-phenol 2b (24.7 g, 104.7 mmol) and potassium carbonate (17.34 g, 125.6 mmol) were dissolved in 300 mL of acetone followed by addition of iodomethane (9.8 mL, 157.1 mmol). The reaction mixture was heated to reflux at 80° C. for 22 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was concentrated under reduced pressure and diluted with 200 mL of ethyl acetate and 200 mL of water. The aqueous layer was extracted with ethyl acetate (100 mL×2). The combined organic extracts were washed with 4 N hydrochloric acid and saturated aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 1-bromo-5-fluoro-2-methoxy-3-nitro-benzene 2c (16.18 g, yield 61.8%) as a white solid.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([C@@H:13]([CH2:23][C@H:24]3[CH2:28][CH2:27][NH:26][CH2:25]3)[C:14]([NH:16][C:17]3[S:18][C:19]([F:22])=[CH:20][N:21]=3)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH3:29][NH:30][C:31](=O)[O:32]C1C=CC=CC=1.[OH-].[Na+].O>O1CCCC1>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([C@H:13]([C:14]([NH:16][C:17]3[S:18][C:19]([F:22])=[CH:20][N:21]=3)=[O:15])[CH2:23][C@H:24]3[CH2:28][CH2:27][N:26]([C:31]([NH:30][CH3:29])=[O:32])[CH2:25]3)=[CH:11][CH:12]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(Nc1ncc(F)s1)[C@H](C[C@H]1CCNC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: CNC(=O)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)N1CC[C@H](C[C@@H](C(=O)Nc2ncc(F)s2)c2ccc(S(=O)(=O)C3CC3)cc2)C1
Reaction time: 1.5 h
Yield: 74.7 %

Procedure:
(R)-2-(4-(Cyclopropylsulfonyl)phenyl)-N-(5-fluorothiazol-2-yl)-3-((S)-pyrrolidin-3-yl)propanamide (500 mg, 1.05 mmol) was dissolved in tetrahydrofuran (40 mL), and thereafter, phenyl N-methylcarbamate (636 mg, 4.21 mmol) and an aqueous solution of sodium hydroxide (2 M, 2 mL) were added to the above obtained solution under ice-cold condition. The obtained mixture was stirred for 1.5 hours. Thereafter, water was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and was then concentrated in vacuo. The obtained residue was purified by silica gel chromatography (chloroform/methanol=1%→15%) to obtain the captioned compound (377 mg, 75%) in the form of a white solid.
Reaction SMILES: C[Al](C)C.[C:5]([NH2:9])([CH3:8])([CH3:7])[CH3:6].C[O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[C:22]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=3)=[N:23][O:24][C:25]=2[CH2:26][OH:27])=[N:15][CH:14]=1.C(OCC)(=O)C>O1CCOCC1.CCCCCCC>[C:5]([NH:9][C:12](=[O:11])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[C:22]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=3)=[N:23][O:24][C:25]=2[CH2:26][OH:27])=[N:15][CH:14]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2CO)nc1
Reactant: CC(C)(C)N
Agent: C[Al](C)C
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)NC(=O)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2CO)nc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 12 %

Procedure:
A trimethylaluminium solution (2 M in toluene, 798 μL, 1.6 mmol) in dioxane (7.5 mL) was added to tert-butylamine (174 μL, 1.6 mmol) and the mixture was stirred for 1 h at 50° C. 6-[3-(3,4-Difluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (150 mg, 0.4 mmol) in dioxane (7.5 mL) was added and stirring was continued overnight at 85° C. Chromatography (silica, ethyl acetate: heptane=1:4 to 1:1) afforded the title compound (20 mg, 13%) as a colourless solid. MS: m/e=416.4 [M−H]−.
Reaction SMILES: [CH2:1]([N:5]([CH2:35][CH2:36][CH2:37][CH3:38])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([N:25]2[CH2:34][CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)=[O:24])[NH:11][CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[C:39]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.CC(OC)(C)C>[CH2:35]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([N:25]2[CH2:34][CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)=[O:24])[N:11]([CH3:39])[CH:12]=1)=[O:7])[CH2:36][CH2:37][CH3:38]
Reactant: CCCCN(CCCC)C(=O)c1c[nH]c(-c2ccc(C(=O)OC)cc2C(=O)N2CCc3ccccc3C2)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: CCCCN(CCCC)C(=O)c1cn(C)c(-c2ccc(C(=O)OC)cc2C(=O)N2CCc3ccccc3C2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.7 %

Procedure:
To a stirred solution of methyl 4-(4-(dibutylcarbamoyl)-1H-imidazol-2-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (80 mg, 0.15 mmol) in dry DMF (3 mL) was added K2CO3 (42 mg, 0.30 mmol) and methyl iodide (22 mg, 0.15 mmol, a solution in 100 μL of DMF) at 0° C. The reaction mixture was allowed to warm to room temperature and stirring was continued for 4 h. The reaction mixture was diluted with MTBE and washed with water. The organic layer was dried over Na2SO4 and concentrated in vacuo to give crude product. The crude material was purified by flash chromatography (gradient from 0% to 2% MeOH/CHCl3) to provide the title compound (65 mg, 79%). 1H NMR (CD3OD) δ 8.25-8.00 (m, 2H), 7.92-7.00 (m, 6H), 4.80-4.60 (m, 2H), 4.02 (s, 3H), 3.70-3.40 (m, 6H), 3.01 (s, 3H), 2.90-2.80 (m, 2H), 1.60-1.50 (m, 4H), 1.50-1.30 (m, 4H), 1.05-0.90 (m, 6H); MS(ESI+) m/z 531.4 (M+H)+.
Reaction SMILES: [CH:1]1([CH:6]([NH:18][C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)[C:7]2[O:8][C:9]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:10]=3[C:11]=2[CH3:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:29]([O:31][C:32](=[O:36])[CH2:33][CH2:34][NH2:35])[CH3:30].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl-].[NH4+]>CN(C)C=O.C(N(CC)CC)C>[CH:1]1([CH:6]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([NH:35][CH2:34][CH2:33][C:32]([O:31][CH2:29][CH3:30])=[O:36])=[O:24])=[CH:26][CH:27]=2)[C:7]2[O:8][C:9]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:10]=3[C:11]=2[CH3:12])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1c(C(Nc2ccc(C(=O)O)cc2)C2CCCC2)oc2ccc(F)cc12
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3ccc(F)cc3c2C)C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.7 %

Procedure:
A solution of 4-{[cyclopentyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyl]amino}benzoic acid (483 mg) synthesized above, β-alanine ethyl ester hydrochloride (241 mg), 1-hydroxybenzotriazole monohydrate (240 mg), triethylamine (438 μL) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (301 mg) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 3 hr. 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 subjected to silica gel column chromatography (hexane-ethyl acetate 100:0-60:40, v/v) to give the title compound (397 mg, 65%) as a colorless amorphous form.
Reaction SMILES: O[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[N:6]=1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[N:6]=1
Reactant: Oc1nc(-c2ccncc2)cs1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nc(-c2ccncc2)cs1
Temperature: 140 °C
Yield: 29 %

Procedure:
A mixture of 2-hydroxy-4-(4-pyridyl)thiazole (17.8 g, 0.10 mol) in phosphorous oxychloride (175 mL) was heated at 140° C. for 48 hours then quenched by carefully pouring onto ice (4000 mL). The resulting mixture was basified with 50% sodium hydroxide to pH 9 and extracted with methylene chloride (5×400 mL). The combined extracts were dried over sodium sulfate, concentrated, and chromatographed over silica gel (ethyl acetate as eluant). Recrystallization from ethyl acetate/hexane afforded 2-chloro-4-(4-pyridyl)thiazole (5.70 g, 29%). mp. 124°-125° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(O[CH:10]1[CH2:18][CH2:17][C:16]2[N:12]([C:13]3[N:32]=[CH:31][N:30]=[C:29]([NH2:33])[C:14]=3[C:15]=2[C:19]2[CH:20]=[N:21][C:22]3[C:27]([CH:28]=2)=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:11]1)(=O)=O.O>CN(C=O)C>[N:1]([CH:10]1[CH2:18][CH2:17][C:16]2[N:12]([C:13]3[N:32]=[CH:31][N:30]=[C:29]([NH2:33])[C:14]=3[C:15]=2[C:19]2[CH:20]=[N:21][C:22]3[C:27]([CH:28]=2)=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:11]1)=[N+:2]=[N-:3]
Reactant: CS(=O)(=O)OC1CCc2c(-c3cnc4ccccc4c3)c3c(N)ncnc3n2C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NC1CCc2c(-c3cnc4ccccc4c3)c3c(N)ncnc3n2C1
Temperature: 80 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
Sodium azide (361 mg) was added to a solution of 4-amino-5-(quinolin-3-yl)-6,7,8,9-tetrahydropyrimido[5,4-b]indolizin-8-yl methanesulfonate (758 mg) obtained in Step 9 in DMF (9 ml) at room temperature, and the mixture was stirred at 80° C. for 4 hours. After cooling, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as a yellow solid (508 mg).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].[OH:15][CH2:16][C:17]([C@@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1[C:24]([C@@H:26]1[CH2:30][CH2:29][CH2:28][N:27]1[C:31]([NH:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])=[O:25])=[O:18].S([O-])(O)(=O)=O.[K+]>C(Cl)Cl>[C:35]1([CH2:34][NH:33][C:31]([N:27]2[CH2:28][CH2:29][CH2:30][C@H:26]2[C:24]([N:20]2[CH2:21][CH2:22][CH2:23][C@H:19]2[C:17](=[O:18])[CH2:16][O:15][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[O:25])=[O:32])[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C(CO)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)NCc1ccccc1
Reactant: CC(C)(C)C(=O)Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)OCC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)NCc1ccccc1
Reaction time: 17 h

Procedure:
Triethylamine (0.59 ml), pivaloyl chloride (0.43 ml) were added, under ice-cooling, to a methylene chloride solution (25 ml) of (S)-2-[[(S)-2-(hydroxyacetyl)-1-pyrrolidinyl]carbonyl]-N-(phenylmethyl)-1-pyrrolidinecarboxamide (1.26 g) obtained in Example 5 and the mixture was stirred for 17 hours. The reaction mixture was poured into 5% potassium hydrogensulfate and extracted with methylene chloride. The extract was washed with saturated sodium hydrogencarbonate and water in order, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to give the title compound (1.21 g) (see Table 1).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:38]1([NH:41][C:42](=[O:50])[CH2:43][N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:47]3[CH2:48][CH2:49][N:44]([CH2:43][C:42]([NH:41][CH:38]4[CH2:40][CH2:39]4)=[O:50])[CH2:45][CH2:46]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=C(CN1CCNCC1)NC1CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)NC2CC2)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with N-cyclopropyl-2-piperazin-1-yl-acetamide (Enamine) to give the title compound. HR-MS (ES, m/z) calculated for C38H47Cl2N6O3 [(M+H)+] 705.3081, observed 705.308.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:31]=[C:32]([O:34]CC2C=CC=CC=2)[CH:33]=1)[CH2:12][N:13]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15](/[CH:24]=[CH:25]/[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:14]1)C1C=CC=CC=1.C(O)C>[C].[Pd].O1CCCC1>[OH:8][C:9]1[CH:10]=[C:11]([CH:31]=[C:32]([OH:34])[CH:33]=1)[CH2:12][N:13]1[CH:17]=[C:16]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:15]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:14]1
Reactant: CCOC(=O)/C=C/c1cn(Cc2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)cc1-c1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CCc1cn(Cc2cc(O)cc(O)c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.7 %

Procedure:
A mixture of ethyl(E)-3-[1-(3,5-dibenzyloxybenzyl)-4-phenyl-3-pyrrolyl]propenoate (19.0 g), 5% palladium-carbon (40.0 g), ethanol (200 ml), and tetrahydrofuran (200 ml) was stirred for 4 hours at room temperature under a hydrogen atmosphere. After the palladium-carbon was removed by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[1-(3,5-dihydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (12.10 g, yield: 95%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (3:2, volume ratio).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:14]([CH3:17])([OH:16])[CH3:15])[C:11]3[CH:24]=[C:25]([F:29])[C:26]([F:28])=[CH:27][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.F[C:31]1[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:14]([CH3:15])([CH3:17])[O:16][C:31]3[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=3)[C:11]3[CH:24]=[C:25]([F:29])[C:26]([F:28])=[CH:27][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: N#Cc1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(Oc1ccc(C#N)cc1)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A solution of 1.0 g (2.39 mmol) (−)-1-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-1-cyclohexyl-2-methyl-propan-2-ol and 0.289 g (2.39 mmol) 4-fluorobenzonitrile (commercially available) in 10 ml anhydrous tetrahydrofuran was cooled down to 0° C. Then, 4.77 ml (2.39 mmol) potassium bis(trimethylsilyl)amide (0.5 M solution in toluene) were added dropwise to the reaction mixture. The cooling bath was removed and the reaction stirred at room temperature for 5 days. The yellow suspension was poured onto 10% aqueous ammonium chloride solution and the phases were separated. The aqueous layer was extracted three times with ethyl acetate, the combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The compound was purified twice by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting first with n-heptane for 5 min, then with a gradient of dichloromethane:ethyl acetate (100:0 to 90:10). Colorless foam (40%). MS (Turbo Spray): m/z=520.2 [M+H].
Reaction SMILES: CC(C)(OC([NH:7][C@H:8]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=1)[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[N:20]=[C:14]2[CH2:13]1)=[O:11])=O)C.[ClH:35]>CO>[ClH:35].[ClH:35].[NH2:7][C@H:8]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=1)[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[CH:18]=[C:19]([C:21]([F:22])([F:24])[F:23])[N:20]=[C:14]2[CH2:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2cc(C(F)(F)F)nc2C1)Cc1ccc(F)c(F)c1
Agent: Cl
Solvent: CO
Product: N[C@@H](CC(=O)N1CCn2cc(C(F)(F)F)nc2C1)Cc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 7-[(3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(3,4-difluorophenyl)butanoyl]-2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-α]pyrazine (110.8 mg, 0.226 mmol, from Step C) was added 2 mL of methanol saturated with hydrogen chloride. The reaction was stirred at ambient temperature for 1 h. Concentration gave 89.5 mg of the title compound as a foamy solid. 1H NMR (500 MHz, CD3OD) δ 2.97–3.10 (m, 4H), 3.91–4.34 (m, 5H), 4.90–5.04 (m, 2H), 7.16–7.33 (m, 2H), 8.01–8.08 (m, 1H). ESI-MS 389 (M+1).
Reaction SMILES: [Br:1][C:2]1([CH:9]=[CH:8][CH:7]=[C:6]([F:10])[CH2:5]1)[CH2:3]O.N1C=CC=CC=1.P(Br)(Br)[Br:18]>C(Cl)(Cl)Cl>[Br:1][C:2]1([CH:9]=[CH:8][CH:7]=[C:6]([F:10])[CH2:5]1)[CH2:3][Br:18]
Reactant: BrP(Br)Br
Reactant: OCC1(Br)C=CC=C(F)C1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: FC1=CC=CC(Br)(CBr)C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 83 %

Procedure:
To a solution of 1-bromo-3-fluorobenzyl alcohol (1.61 kg, 7.85 mol) in chloroform (14 L) at 0° C. add pyridine (770 mL, 9.52 mol) in one portion (slight exotherm) and stir at 0° C. for 5 min. Add phosphorus tribromide (900 mL, 9.49) dropwise while maintaining the internal temperature below 20° C. and stir the resulting solution overnight while allowing to warm to room temperature. Cool the reaction to 0° C. and quench slowly with ice water (2 L). Transfer to a 50 L flask, separate the layers and then extract the aqueous layer with chloroform (1 L). Wash the combined organic phases with 5% sulfuric acid (2 L), saturated aqueous sodium bicarbonate (2 L), brine (2 L), dry over magnesium sulfate, filter, and concentrate to obtain the title compound as a yellow oil (1753 g, 83%). 1H NMR (CDCl3) δ 7.43 (d, 1H), 7.21 (m, 1H), 7.09 (t, 1H), 4.68 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[Cl-].[Al+3].[Cl-].[Cl-].[C:18](#[N:20])[CH3:19]>>[O:11]1[CH2:12][CH2:13][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:18](=[NH:20])[CH3:19])[CH2:9][CH2:10]1
Reactant: CC#N
Reactant: Nc1ccccc1N1CCOCC1
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=N)Nc1ccccc1N1CCOCC1

Procedure:
A mixture of 4-(2-aminophenyl)morpholine (5.3 g), acetonitrile (4.52 ml) and anhydrous aluminium chloride (12 g) was heated at 160°-170° C. for 4 hours to yield N-(2-morpholinophenyl)acetamidine (m.p. 140°-141° C.) which was recrystallised from hexane.
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[Cl:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:31][C:32]1[CH:37]=[C:36]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][S:2](=[O:1])(=[O:30])[CH2:3][CH2:4]2)=[O:9])[CH:35]=[CH:34][CH:33]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCS(=O)(=O)CC2)n3-c2cccc(Cl)c2)CC1
Yield: 21 %

Procedure:
The title compound was synthesized in analogy to example 66, from [2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 1), 3-chlorphenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light brown solid (21%).
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.Cl.[CH2:27]([C:29]1[CH:30]=[C:31]([NH:35][CH:36]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:37]([OH:39])=[O:38])[CH:32]=[CH:33][CH:34]=1)[CH3:28].[N:46]12[CH2:53][CH2:52][CH:49]([CH2:50][CH2:51]1)[C@@H:48](O)[CH2:47]2>C1COCC1>[N:46]12[CH2:53][CH2:52][CH:49]([CH2:50][CH2:51]1)[C@@H:48]([O:38][C:37](=[O:39])[CH:36]([NH:35][C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([CH2:27][CH3:28])[CH:30]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:47]2
Reactant: CCc1cccc(NC(C(=O)O)c2ccccc2)c1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCc1cccc(NC(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 29.1 %

Procedure:
PS-DCC (1097 mg, 1.371 mmol, loading: 1.25 mmol/g) is suspended in THF (15 mL). HOBT (210 mg, 1.37 mmol), (3-ethyl-phenylamino)-phenyl-acetic acid hydrochloride (I42) (200 mg, 0.68 mmol), and (R)-quinuclidin-3-ol (262 mg, 2.06 mmol) are added and the suspension is shaken at RT for 16 hours. PS-DCC is filtered off and the filtrate is evaporated. The resulting residue is dissolved in EtOAc and washed with water, sat. NaHCO3, water and brine. The organic phase is dried over Na2SO4, filtered and evaporated. The crude is purified by flash chromatography (DCM/MeOH=95/5) to obtain the title compound as a colorless oil (72 mg, 30% yield, mixture of diastereoisomers).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C@H:10]([C:19]([O:21]CC)=[O:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C@H:10]([C:19]([OH:21])=[O:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1c1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H](C(=O)O)[C@H](c2ccccn2)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of 1-tert-butyloxycarbonyl-trans-3-ethoxycarbonyl-4-(2-pyridyl)pyrrolidine from step 4 above (4.2 g, 13 mmol) in methanol (30 mL) was added aqueous NaOH (4.7 mL of a 4.0 N solution, 19 mmol). The resulting solution was stirred at ambient temperature for 48 h. The solution was acidified with aqueous HCl (3.1 mL of a 6.0 N solution, 19 mmol) and the solvents were removed in vacuo to give the title compound as an amorphous solid containing NaCl (HPLC RT=4.42 min, method A).