Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C@@H:41]([CH2:61][CH3:62])[C@H:42]([N:46]1[CH2:50][C:49](=[O:51])[N:48]([CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([CH3:59])[N:54]=2)[C:47]1=[O:60])[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[OH:32][C@H:3]([C@@H:2]([NH:1][C:43](=[O:44])[C@@H:42]([N:46]1[CH2:50][C:49](=[O:51])[N:48]([CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([CH3:59])[N:54]=2)[C:47]1=[O:60])[CH:41]([CH3:40])[CH2:61][CH3:62])[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1
Reactant: CC[C@H](C)[C@@H](C(=O)O)N1CC(=O)N(Cc2cccc(C)n2)C1=O
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)N1CC(=O)N(Cc2cccc(C)n2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.3 %

Procedure:
A solution containing the product from Example 2C (0.025 g, 0.047 mmol) in THF (0.5 mL) was treated with the product from Example 36E (0.020 g, 0.061 mmol), DEPBT (0.021 g, 0.071 mmol), and N,N-diisopropylethylamine (0.041 mL, 0.235 mmol), stirred at 25° C. for 2 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane, followed by 0-10% methanol in ethyl acetate, to give the title compound (0.026 g, 68% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.76 (m, 18 H), 1.16 (m, 1 H), 1.29 (m, 1 H), 1.52 (m, 1 H), 1.76 (s, 1 H), 2.39 (s, 3 H), 2.68 (m, 4 H), 3.20 (m, 2 H), 3.50 (s, 3 H), 3.83 (m, 2 H), 4.13 (m, 2 H), 4.67 (m, 2 H), 6.66 (d, J=9.56 Hz, 1 H), 7.07 (m, 7 H), 7.22 (d, J=8.09 Hz, 2 H), 7.31 (m, 1 H), 7.66 (t, J=7.72 Hz, 1 H), 7.86 (m, 6 H), 8.63 (d, J=4.04 Hz, 1 H).
Reaction SMILES: [C:1]([C:5]1[CH: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].[C:38]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)(=[O:40])[CH3:39]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:44]3[CH2:45][CH2:46][N:41]([C:38](=[O:40])[CH3:39])[CH2:42][CH2:43]3)=[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)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CC(=O)N1CCNCC1
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C(C)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 4) was reacted with 1-acetyl-piperazine (Aldrich) to give the title compound. LR-MS: 649.2 [(M+H)+]
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11]1=[O:19])[CH2:7][CH2:8][CH3:9])[CH3:2].[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][C:29]=2[CH2:31]O)[C:24]([CH3:33])=[C:23]1[CH3:34].N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:31][C:29]2[CH:28]=[CH:27][CH:26]=[C:25]3[C:30]=2[N:22]([CH3:21])[C:23]([CH3:34])=[C:24]3[CH3:33])[C:11]1=[O:19])[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: Cc1c(C)n(C)c2c(CO)cccc12
Reactant: CCCC(CC(=O)OCC)n1c(=O)[nH]c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC(CC(=O)OCC)n1c(=O)n(Cc2cccc3c(C)c(C)n(C)c23)c2ccccc21
Reaction time: 12 h
Yield: 49.7 %

Procedure:
To a solution of 3-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)-hexanoic acid ethyl ester (100 mg, 0.36 mmol) in THF (10 mL) were added (1,2,3-Trimethyl-1H-indol-7-yl)-methanol (103 mg, 0.54 mmol), DIAD (diisoproyl azo-dicarboxylate) (0.14 mL, 0.7 mmol) and triphenylphosphine (95 mg, 0.36 mmol) at room temperature. The solution was stirred at the same temperatrue for 12 hours. The solution was filtered and the filtrate was concentrated. The residue was purified by combFlash with 10% EtOAc in Hexane as the eluent to afford the desirable product 3-[2-Oxo-3-(1,2,3-trimethyl-1H-indol-7-ylmethyl)-2,3-dihydro-benzoimidazol-1-yl]-hexanoic acid ethyl ester (80 mg, 49%) as a white foam.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[F:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>>[F:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:9](=[O:11])[CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=2)=[CH:15][CH:14]=1
Reactant: O=C(O)Cc1cccc(O)c1
Reactant: Nc1ccc(F)cc1
Product: O=C(Cc1cccc(O)c1)Nc1ccc(F)cc1
Yield: 88.6 %

Procedure:
The title compound was prepared as described in Example 44.A, using 3-hydroxyphenyl acetic acid (80 g, 0.52 mol) and 4-fluoroaniline (49.3 ml, 0.52 mol) to provide the title compound (113 g, 89% yield): ES-MS (m/z) 246 [M+H]+.
Reaction SMILES: ClN1C(=O)CCC1=O.O=[C:10]([CH3:14])[CH:11]=[N:12][OH:13].[CH3:15][S-:16].[Na+].[Cl:18][C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([Cl:29])[C:20]=1[NH:30][NH2:31]>CN(C)C=O.O>[Cl:18][C:19]1[CH:24]=[C:23]([C:25]([F:26])([F:28])[F:27])[CH:22]=[C:21]([Cl:29])[C:20]=1[NH:30][N:31]=[C:10]([CH2:14][S:16][CH3:15])[CH:11]=[N:12][OH:13]
Reactant: CC(=O)C=NO
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: C[S-]
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSCC(C=NO)=NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
N-Chlorosuccinimide (7.3 g) was added, portionwise, to a solution of 2-oxopropanal 1-oxime (4.8 g) in dimethylformamide (30 ml). The reaction was heated to 50° and hydrochloric acid gas bubbled through to initiate the reaction. The mixture was then stirred at room temperature for an hour. Poured into water, extracted with ether and the extracts worked up to give crude 1-chloro--oxopropanal 1-oxime. This (1.5 g) in dimethylformamide (25 ml) was then reacted with sodium methanethiolate (0.86 g). After 5 hours at below 5°, the mixture was poured into water and extracted with ether and the extracts worked up to give crude 1-methylthio-oxopropanal 1-oxime. This (1.0 g) was then reacted with 2,6-dichloro-4-trifluoromethylphenylhydrazine (1.84 g), in a similar to that described in Example 1, to give 2-(2,6-dichloro-4-trifluoromethylphenylhydrazono)-methylthiopropanal-1-oxime. This (1.4 g) was then reacted with acetic anhydride, in a similar manner to Example 5, to give 2-(2,6-dichloro-4-trifluoromethyl-phenylhydrazono)-1-methylthiopropanal 1-acetyloxime. This (1.4 g) was then stirred with a mixture of caesium carbonate (1.1 g) and tetrahydrofuran (40 ml) at room temperature for 2 hours. Solvent was removed and the residue worked up to give compound 3.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:20](=[O:48])[NH:21][C@@H:22]([C:34]1[S:35][C:36]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[C:37]([C:39](=[O:41])[NH2:40])[N:38]=1)[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1)[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][C@H:8]([CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)[C:20]([NH:21][C@@H:22]([C:34]1[S:35][C:36]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[C:37]([C:39]([NH2:40])=[O:41])[N:38]=1)[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1)=[O:48]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc2ccccc2c1)C(=O)N[C@H](Cc1ccc2ccccc2c1)c1nc(C(N)=O)c(-c2ccccc2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1nc([C@@H](Cc2ccc3ccccc3c2)NC(=O)[C@H](N)Cc2ccc3ccccc3c2)sc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.8 %

Procedure:
((1R)-1-((1R)-1-(4-Carbamoyl-5-phenyl-1,3-thiazol-2-yl)-2-(2-naphthyl)ethylcarbamoyl)-2-(2-naphthyl)ethyl)carbamic acid tert-butylester (0.22 g; 0.328 mmol) was dissolved in methylene chloride (2.5 ml) and trifluoroacetic acid (2.5 ml) was added. The reaction mixture was stirred 1 h at room temperature and the solvent was removed in vacuo. The residue was dissolved in methylene chloride and evaporated (2×5 ml). The residue was dissolved in methylene chloride (10 ml) and washed with sodium hydrogencarbonate (satd; 10 ml), water (10 ml) and dried (magnesium sulfate). The solvent was removed in vacuo to afford 0.155 g of 2-((1R)-1-((2R)-2-amino-3-(2-naphthyl)propionylamino)-2-(2-naphthyl)ethyl)-5-phenyl-1,3-thiazole-4-carboxylic acid amide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C1(C)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(O[C:43](=[O:49])[O:44][C:45](Cl)(Cl)Cl)Cl.[CH3:51][O:52][C:53]1[CH:63]=[CH:62][CH:61]=[CH:60][C:54]=1[O:55][CH2:56][CH2:57]CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:43](=[O:49])[O:44][CH2:45][CH2:57][CH2:56][O:55][C:54]2[CH:60]=[CH:61][CH:62]=[CH:63][C:53]=2[O:52][CH3:51])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: COc1ccccc1OCCCO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCCCOc4ccccc4OC)c(C)c3C)c2cc1OC
Temperature: 25 °C
Yield: 67 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (70 mg) was added to toluene/triethylamine=10/1 (7 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (97 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-(2-methoxyphenoxy)-1-propanol (60 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (77 mg, yield 63%).
Reaction SMILES: [CH2:1]([Br:4])[C:2]#[CH:3].[CH3:5][N:6]([CH3:10])[CH2:7][CH2:8][OH:9].[CH2:11]1[CH2:15][O:14][CH2:13][CH2:12]1>>[CH2:1]([O:9][CH2:8][CH2:7][N+:6]([CH3:11])([CH3:10])[CH3:5])[C:2]#[CH:3].[Br-:4].[CH2:13]([O:14][CH2:15][CH2:11][N+:6]([CH3:10])([CH3:7])[CH3:5])[C:12]#[CH:1]
Reactant: C1CCOC1
Reactant: CN(C)CCO
Reactant: C#CCBr
Product: C#CCOCC[N+](C)(C)C
Product: [Br-]
Reaction time: 8 h

Procedure:
Propargyl-choline was synthesized by the following procedure: 4 grams of propargyl bromide (80% solution in toluene, 34 mmoles) were slowly added to 3 grams of dimethyl-ethanolamine (34 mmoles) in 10 mL of dry THF, while stirring on ice. The mix was allowed to reach room temperature and stirring was continued overnight. The resulting white solid was filtered and washed extensively with cold THF (10 times, 20 mL), to afford pure propargyl-choline bromide (5.9 grams, 84% yield) as a white solid. Propargyl-choline: white crystals, molecular weight: 128.19, ES-API LC/MS: [M]+=128.1, 1H NMR (600 MHz, CD3OD): 4.78 (1H, b), 4.49 (2H, d, J=2.4 Hz), 4.03 (2H, t, J=4.5 Hz), 3.64 (2H, m), 3.30 (6H, s), 13C NMR (600 MHz, CD3OD): δ3.2 (CH, d, J=101.4 Hz), 72.7 (C, d, J=21.0 Hz), 66.4 (CH2, t, J=60.3 Hz), 56.7 (CH2, t, J=47.4 Hz), 56.5 (CH2, t, J=45.9 Hz), 52.2 (C2H6, q, J=31.2 Hz), 49.05 (CD3OD).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[O:28]=[C:29]1[NH:37][C:32]2=[N:33][CH:34]=[CH:35][CH:36]=[C:31]2[C@@:30]21[CH2:48][C:40]1=[N:41][CH:42]=[C:43]([C:45]([OH:47])=O)[CH:44]=[C:39]1[CH2:38]2.Cl.[NH2:50][C@H:51]1[CH2:56][C@@H:55]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C@@H:54]([CH3:63])[N:53]([CH2:64][C:65]([F:68])([F:67])[F:66])[C:52]1=[O:69].C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:63][C@H:54]1[N:53]([CH2:64][C:65]([F:68])([F:66])[F:67])[C:52](=[O:69])[C@@H:51]([NH:50][C:45]([C:43]2[CH:44]=[C:39]3[CH2:38][C@@:30]4([C:31]5[C:32](=[N:33][CH:34]=[CH:35][CH:36]=5)[NH:37][C:29]4=[O:28])[CH2:48][C:40]3=[N:41][CH:42]=2)=[O:47])[CH2:56][C@H:55]1[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1
Reactant: O=C(O)c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Reactant: C[C@@H]1[C@H](c2ccccc2)C[C@H](N)C(=O)N1CC(F)(F)F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H]1[C@H](c2ccccc2)C[C@H](NC(=O)c2cnc3c(c2)C[C@@]2(C3)C(=O)Nc3ncccc32)C(=O)N1CC(F)(F)F
Temperature: 23 °C
Reaction time: 3 h

Procedure:
(Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (1.89 g, 4.28 mmol) was added to a solution of (6S)-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxylic acid (described in Intermediate 1) (1.10 g, 3.92 mmol), (3S,5S,6R)-3-amino-6-methyl-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-2-one hydrochloride (described in Intermediate 4) (1.15 g, 3.56 mmol), and N,N-diisopropylethylamine (3.11 mL, 17.8 mmol) in DMF (40 mL), and the resulting mixture was stirred at 23° C. for 3 h. The reaction mixture was then partitioned between saturated aqueous sodium bicarbonate solution (200 mL) and ethyl actetate (3×200 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with hexanes initially, then grading to 100% EtOAc before stepping to 5% MeOH in EtOAc to afford the title compound as an amorphous solid, which was further purified by the following crystallization procedure. A solution of the amorphous product in a minimal amount of methanol required for dissolution was diluted with 10 volumes water, and the resulting slurry was seeded with crystalline product and stirred at 23° C. for 4 h. The solids were filtered, washed with water, and dried under a stream of nitrogen to give the title compound as a crystalline solid. HRMS: m/z=550.2068, calculated m/z=550.2061 for C29H27F3N5O3. 1H NMR (500 MHz, CDCl3) δ 8.91 (s, 1H), 8.70 (s, 1H), 8.17 (dd, 1H, J=5.4, 1.5 Hz), 8.04 (s, 1H), 7.37 (m, 3H), 7.29 (t, 1H, J=7.3 Hz), 7.21 (d, 2H, J=7.3 Hz), 7.13 (dd, 1H, J=7.3, 1.2 Hz), 6.89 (dd, 1H, J=7.3, 5.4 Hz), 4.99-4.90 (m, 1H), 4.53 (dt, 1H, J=10.7, 6.6 Hz), 3.94 (p, 1H, J=5.9 Hz), 3.78 (d, 1H, J=17.1 Hz), 3.67 (d, 1H, J=16.4 Hz), 3.65 (m, 1H), 3.34-3.26 (m, 1H), 3.28 (d, 1H, J=17.1 Hz), 3.17 (d, 1H, J=16.6 Hz), 2.79 (m, 1H), 2.58 (q, 1H, J=12.7 Hz), 1.07 (d, 3H, J=6.6 Hz).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]1=[O:14].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C1COCC1>[O:14]=[C:6]1[N:5]([CH2:4][CH2:3][NH:2][S:23]([CH3:22])(=[O:25])=[O:24])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7]1
Reactant: NCCn1c(=O)[nH]c2ccccc21
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCCn1c(=O)[nH]c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.1 %

Procedure:
To a solution of 1-(2-aminoethyl)-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (2.8 g, 13 mmoles) in THF (30 ml) and triethyl amine (5.5 ml, 39 mmoles) was added methanesulfonyl chloride (1.12 ml, 14 mmoles) and the reaction mixture was stirred for 2 hours at room temperature. The organic solvent was evaporated and the residue was partitioned into water and ethyl acetate. The organic layer was washed with saturated aqueous Na2CO3 solution and taken to dryness. The crude residue was purified by flash chromatography (CH2Cl2-methanol 96-4) to give 0.5 g of the title compound as a white solid. M.p. 162-170° C.
Reaction SMILES: [Mg].II.[F:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7]Cl.[CH2:13]([N:20]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCOCC>[CH2:13]([N:20]1[CH2:24][CH2:23][C:22]([CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[F:4])([OH:25])[CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Fc1ccccc1CCl
Reactant: O=C1CCN(Cc2ccccc2)C1
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: OC1(Cc2ccccc2F)CCN(Cc2ccccc2)C1

Procedure:
To a suspension of 3.4 g of magnesium shavings in 50 ml of ether is added a crystal of iodine followed by a few mls of a solution of 20.6 g of 2-fluorobenzyl chloride in 100 ml of ether. Thereafter, the reaction is initiated via a hot air gun before adding dropwise, while maintaining the reaction at reflux, the remaining 2-fluorobenzylchloride-ether solution. After total addition the reaction is maintained at reflux with stirring for an additional hour before successively adding 100 ml of ether and adding dropwise with vigorous stirring a solution of 25.0 g of N-benzyl-3-pyrrolidinone in 100 ml of ether. After complete addition the resulting suspension is refluxed for an additional 2 hours, stirred at ambient temperature for 16 more hours, and then filtered. The filter cake is washed well with ether and then hydrolyzed by stirring in an ice-ammonium chloride solution. The aqueous solution is extracted thrice with ether and the combined ether extracts are washed, successively, with water and a sodium chloride solution and dried. The solvent is removed and the residue is distilled at 135°-140° C., 0.1 mm pressure to provide a viscous yellow oil which solidifies upon standing. The solid is recrystallized twice from an ethanol-water mixture to give the product, 1-benzyl-3-(2-fluorobenzyl)-3-pyrrolidinol, mp 75°-77° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[N:15]=[C:16](Cl)[CH:17]=[CH:18][C:13]=2[N:12]2[CH:20]=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1.[CH3:23][NH:24][CH3:25].C(O)C>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[N:15]=[C:16]([N:24]([CH3:25])[CH3:23])[CH:17]=[CH:18][C:13]=2[N:12]2[CH:20]=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1
Reactant: Clc1ccc2c(n1)C(c1ccccc1Cl)=NCc1nncn1-2
Reactant: CNC
Solvent: CCO
Solvent: CO
Product: CN(C)c1ccc2c(n1)C(c1ccccc1Cl)=NCc1nncn1-2

Procedure:
This compound was obtained in an analogous manner to that given in Example 10a from 15 grams of 6-(o-chloro-phenyl)-8-chloro-4H-s-triazolo-(4,3-a)-pyrido-(2,3-f)-(1,4)-diazepine and 55 grams of dimethylamine in 500 ml. of ethanol by heating for 5 hours at 120° C. M.P. 240°-242° C. (from methanol); Yield 8.5 grams.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:24]3[CH2:27][C@H:26]([OH:28])[CH2:25]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12.[N+:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1)([O-:31])=[O:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[N+:29]([C:32]1[CH:33]=[CH:34][C:35]([C:36]([O:28][C@H:26]2[CH2:25][C@H:24]([N:8]3[C:4]4=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]4[C:10]([C:11]4[CH:12]=[CH:13][C:14]([O:17][C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)=[CH:15][CH:16]=4)=[N:9]3)[CH2:27]2)=[O:37])=[CH:39][CH:40]=1)([O-:31])=[O:30]
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2[C@H]1C[C@@H](O)C1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2[C@H]1C[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)C1

Procedure:
A solution of cis 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-cyclobutanol (0.113 g, 0.000302 mol), 4-nitrobenzoic acid (0.101 g, 0.000605 mol) and triphenylphosphine (0.159 g, 0.000605 mol) in tetrahydrofuran (5 mL) was cooled to 0° C. Diethyl azodicarboxylate (0.096 mL, 0.159 g, 0.000605 mol) was added dropwise, keeping the temperature below 10° C. The mixture was allowed to come to room temperature over eighteen hours. The solvent was removed in vacuo and the residue was purified by flash column chromatography on silica using heptane/ethyl acetate (3:1). The solvent was removed in vacuo to give trans 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]cyclobutyl 4-nitrobenzoate (0.081 g, 0.000164 mmol) as a tan solid.
Reaction SMILES: [N:1]1([OH:6])[CH:5]=[CH:4][CH:3]=[N:2]1.CCN(C(C)C)C(C)C.[CH:16]1[CH:21]=[CH:20][C:19]([CH2:22]Br)=[CH:18][CH:17]=1>C(Cl)Cl>[CH2:22]([O:6][N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1)[C:19]1[CH:20]=[CH:21][CH:16]=[CH:17][CH:18]=1
Reactant: On1cccn1
Reactant: BrCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: c1ccc(COn2cccn2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 56.4 %

Procedure:
To a mixture of pyrazol-1-ol (1 g, 11.9 mmol) and i-Pr2NEt (2.02 mL, 11.9 mL) in DCM (15 mL) at 0° C. was added BnBr (4.09 mL, 23.8 mmol). The mixture was allowed to warm up to r.t. and stirred at this temperature for 22 h. The mixture was concentrated in vacuo to afford a yellow paste. The crude product was purified by flash chromatography (silica gel, hexanes/DCM/Et2O (100:0:0 to 80:10:10), Rf 0.23 in hexanes/DCM/Et2O (34:3:3)) to provide the title product as a yellow oil (1.17 g, 56%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](F)[C:3]=1[C:4]#[N:5].[CH3:11][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:15]2[CH:16]=[C:12]([CH3:11])[N:13]=[CH:14]2)[C:3]=1[C:4]#[N:5]
Reactant: Cc1c[nH]cn1
Reactant: N#Cc1c(F)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cn(-c2cccc(Cl)c2C#N)cn1
Yield: 73 %

Procedure:
In analogy to example 5a, 2-chloro-6-fluoro-benzonitrile was reacted with 4-methylimidazole and potassium carbonate for 16 h at 90° C. After aqueous workup and crystallization from Ethyl acetate/diisopropylether the title compound was obtained as an off-white solid (yield: 73%). MS: m/e=218.2 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([CH:15]=[O:16])[CH2:11][CH2:10]2)=[CH:5][C:4]=1[F:17])#[N:2].[CH2:18]([CH:21]([CH2:24]O)[CH2:22][OH:23])[CH2:19][CH3:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:10][CH2:11][C@H:12]([CH:15]3[O:23][CH2:22][CH:21]([CH2:18][CH2:19][CH3:20])[CH2:24][O:16]3)[CH2:13][CH2:14]2)=[CH:5][C:4]=1[F:17])#[N:2]
Reactant: N#Cc1ccc([C@H]2CC[C@H](C=O)CC2)cc1F
Reactant: CCCC(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCC1COC([C@H]2CC[C@H](c3ccc(C#N)c(F)c3)CC2)OC1
Reaction time: 3 h

Procedure:
A mixture of 2.3 g of trans-4-(4-cyano-3-fluorophenyl)-cyclohexanecarbaldehyde, 1.2 g of 2-propylpropane-1,3-diol, 0.01 g of p-toluenesulfonic acid and 15 ml of toluene is boiled for 3 hours under a water separator and is cooled. Working up in the customary manner gives 2-[trans-4-(4-cyano-3-fluorophenyl)-cyclohexyl]-5-propyl-1,3-dioxane.