Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]1.[Cl:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][N:16]2[CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[C:12]([NH:24][C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=2)[N:11]=1>O>[ClH:9].[ClH:9].[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:10]2[N:18]=[C:17]3[C:13]([N:14]=[CH:15][N:16]3[CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)=[C:12]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([C:29]#[N:30])=[CH:31][CH:32]=3)[N:11]=2)[CH2:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: N#Cc1ccc(Nc2nc(Cl)nc3c2ncn3C2CCCC2)cc1
Solvent: O
Product: Cl
Product: N#Cc1ccc(Nc2nc(N[C@H]3CC[C@H](N)CC3)nc3c2ncn3C2CCCC2)cc1
Temperature: 140 °C

Procedure:
2 g of trans-1,4-diaminocyclohexane is taken to approximately 150° C. then 1.18 g of the product obtained in Stage 1 above is added, the reaction medium is maintained under agitation to 140° C. for 6 hours then left to return to ambient temperature. Then 30 ml of water is added, followed by extracting with dichloromethane, drying and evaporating the solvent. The residue is chromatographed on silica (eluent: MeOH/NH4OH 98/2), 130 mg of the product obtained is removed and taken up in 10 ml of ethanol, 4 ml of an ethanolic solution of hydrochloric acid is added, followed by separating, washing with ether, drying under reduced pressure at 50° C. and 144 mg of expected product is recovered.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([OH:16])(=[O:15])[CH2:11]C(O)=O.C([O-])(=O)C.[NH4+:21]>C(O)C>[NH2:21][CH:6]([C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:11][C:10]([OH:16])=[O:15]
Reactant: [NH4+]
Reactant: O=Cc1ccc(F)cc1
Reactant: O=C(O)CC(=O)O
Agent: CC(=O)[O-]
Solvent: CCO
Product: NC(CC(=O)O)c1ccc(F)cc1
Yield: 23.6 %

Procedure:
A solution of 24.8 g (0.2 mol) of 4-fluorobenzaldehyde, 20.8 g (0.2 mol) of malonic acid, 30.8 g (0.4 mol) of ammonium acetate and 550 ml of ethanol was refluxed for approximately seven hours. The mixture was cooled and the precipitated solid was collected by vacuum filtration. The solid was recrystallized from 500 ml of water to provide 8.66 g of 3-amino-3-(4-fluorophenyl)propionic acid. mp=225° C. dec.
Reaction SMILES: [OH:1][C@H:2]1[CH2:22][C@@:21]2([CH3:23])[C@@H:13]([CH2:14][CH2:15][C@:16]2([O:24][C:25](=[O:27])[CH3:26])[C:17](=[O:20])[CH2:18][OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:30])[C:9]([C@@H:10]([CH3:28])[CH2:11]2)=[CH:8][C:7](=[O:29])[CH:6]=[CH:5]1.C(N(CC)CC)C.[C:38](Cl)(=[O:43])[CH2:39][CH:40]([CH3:42])[CH3:41].CO>C(Cl)Cl>[C:25]([O:24][C@:16]1([C@:21]2([CH3:23])[C@H:13]([C@H:12]3[C@H:3]([C@@H:2]([OH:1])[CH2:22]2)[C@:4]2([CH3:30])[C:9](=[CH:8][C:7](=[O:29])[CH:6]=[CH:5]2)[C@@H:10]([CH3:28])[CH2:11]3)[CH2:14][CH2:15]1)[C:17](=[O:20])[CH2:18][O:19][C:38](=[O:43])[CH2:39][CH:40]([CH3:42])[CH3:41])(=[O:27])[CH3:26]
Reactant: CC(=O)O[C@]1(C(=O)CO)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Reactant: CC(C)CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=O)O[C@]1(C(=O)COC(=O)CC(C)C)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Reaction time: 1.5 h
Yield: 78 %

Procedure:
In 4 ml of methylene chloride was dissolved 208 mg of 11β,21-dihydroxy-17α-acetoxy-6α-methyl-1,4-pregnadiene-3,20-dione obtained according to the method as described in Example 6. To this solution was added 202 mg of triethylamine and the solution was cooled externally with ice. To this solution was added slowly a solution of 120 mg of isovaleryl chloride in 1 ml of methylene chloride, and the mixture was stirred for 1.5 hours. To the reaction liquid was added 1 ml of methanol, and the mixture was further stirred for one hour. The reaction liquid was concentrated under reduced pressure and the resultant residue was directly subjected to preparative thin layer chromatography (silica gel) for purification and then recrystallized from ether-hexane whereby 195 mg (yield: 78.0%) of the title compound was obtained as colorless fine needle crystals. Shown below are physical properties and various analytical data of this compound.
Reaction SMILES: [C:1]([O:5][C@H:6]([CH3:19])[C@H:7]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:8]([OH:10])=O)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.Cl.Cl.[N:53]1[CH:58]=[CH:57][CH:56]=[N:55][C:54]=1[C:59]1([NH2:62])[CH2:61][CH2:60]1>CN(C=O)C.O>[C:15]([O:14][C:12](=[O:13])[NH:11][C@H:7]([C:8](=[O:10])[NH:62][C:59]1([C:54]2[N:55]=[CH:56][CH:57]=[CH:58][N:53]=2)[CH2:61][CH2:60]1)[C@H:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:19])([CH3:18])([CH3:17])[CH3:16]
Reactant: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NC1(c2ncccn2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OC(C)(C)C)C(=O)NC1(c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.9 %

Procedure:
To a solution of (2S,3R)-3-tert-butoxy-2-tert-butoxycarbonylamino-butyric acid (0.20 g, 0.72 mmol) in DMF (1 mL) was added HATU (0.27 g, 0.72 mmol), Et3N (0.30 mL, 2.2 mmol) and 1-pyrimidin-2-yl-cyclopropylamine dihydrochloride (0.15 g, 0.72 mmol.). The reaction was allowed to stir at RT for 24 h. The mixture was diluted with water and extracted with EtOAc (3×50 mL). The combined extracts were washed with satd NaHCO3, 2N HCl, water and brine. The solution was dried with MgSO4, filtered and concentrated to give [(1S,2R)-2-tert-butoxy-1-(1-pyrimidin-2-yl-cyclopropylcarbamoyl)-propyl]-carbamic acid tert-butyl ester (0.23 g, 0.59 mmol).
Reaction SMILES: [CH2:1]([C:8]1([CH2:18][N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][C:9]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:24].[K+].I[CH3:27].Cl>O.CO>[CH3:27][O:24][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:8]([CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([OH:10])=[O:17]
Reactant: [OH-]
Reactant: O=C1Oc2ccccc2C1(Cc1ccccc1)Cn1cncn1
Reactant: CI
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ccccc1C(Cc1ccccc1)(Cn1cncn1)C(=O)O
Temperature: 25 °C
Yield: 57 %

Procedure:
To a clear solution of 3-benzyl-3-[(1,2,4-triazol-1-yl)methyl]-2(3H)-benzofuranone (11 g, 0.0360 mole) and methanol (100 mL), potassium hydroxide (45% solution) (0.5 g, 0.0750 mole) was added and the reaction mixture heated with stirring at reflux for 3 hours. The reaction mixture was then cooled to 25° C. and iodomethane (6.1 g, 0.0750 mole) added and the reaction mixture continued to stir at 50° C. for an additional 3 hours. The reaction solvent was then removed by distillation, and the residue stirred with hydrochloric acid (5 g, 0.37 mole) and 100 mL of water. The precipitated solid was filtered by suction and washed by 100 mL of hot ethyl acetate. The remaining solid was dried and gave 7.0 g, melting point 250°-252° C. (yield 57%), Example 95 of Table 1.
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH:10]=O)=[CH:8][C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([O-:3])=[O:2].C1(C)C=CC=CC=1.C(O)(=O)C.[NH2:27][C:28]1[S:29][CH:30]=[CH:31][N:32]=1>O>[N+:1]([C:4]1[C:9]([CH:10]=[S:29]2[CH:30]=[CH:31][N:32]=[C:28]2[NH2:27])=[CH:8][C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([O-:3])=[O:2]
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Reactant: Nc1nccs1
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1cc(C=S2C=CN=C2N)c([N+](=O)[O-])cc1OC
Yield: 71.1 %

Procedure:
To a heated solution of 6-nitroveratraldehyde (84 g, 0.4 mole), 500 ml of toluene, and 1 ml of acetic acid was added a suspension of 2-aminothiazole (50 g, 0.44 mole) and 250 ml of toluene. The material was refluxed until 7 ml of water was collected using a Dean-Stark apparatus. The solid was removed and the filtrate was concentrated leaving a light solid which was recrystallized from benzene to yield 84 g (71%) of the product, m.p. 125°-130°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([NH2:7])=[O:6].[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([Cl:21])=[CH:16][N:15]=1>O1CCCC1>[Cl:13][C:14]1[N:19]=[C:18]([NH:1][C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=2[O:11][CH3:12])[C:5]([NH2:7])=[O:6])[C:17]([Cl:21])=[CH:16][N:15]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: COc1ccc(C(N)=O)cc1N
Solvent: C1CCOC1
Product: COc1ccc(C(N)=O)cc1Nc1nc(Cl)ncc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.8 %

Procedure:
3-Amino-4-methoxy-benzamide (1.00 g, 0.00602 mol) in tetrahydrofuran (40 mL) was treated with 2,4,5-trichloro-pyrimidine (0.8278 mL, 0.007221 mol), and the reaction was stirred overnight at room temperature, then for 4 hours at 50° C. The mixture was partitioned between water and dichloromethane, and the aqueous phase was extracted twice with dichloromethane. The organics were dried (MgSO4) and concentrated, and the product was isolated by chromatography (Silica, MeOH/dichloromethane 0-3%), followed by crystallization from methanol to give 3-(2,5-dichloro-pyrimidin-4-ylamino)-4-methoxy-benzamide as a white solid (1.26 g, 64%). LC/MS (ESI+): 313.04 (M+H).
Reaction SMILES: C([O:5][C:6](=[O:32])[NH:7][CH2:8][C:9]1[N:10]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:24]([NH2:26])=[S:25])=[CH:14][CH:13]=2)(C)(C)C.Cl.C(N(CC)CC)C.[CH:41]1[C:53]2[CH:52]([CH2:54]OC(Cl)=O)[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:45]=2[CH:44]=[CH:43][CH:42]=1>C(OCC)(=O)C.O>[NH2:26][C:24]([C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:27])[N:10]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:9]([CH2:8][NH:7][C:6](=[O:32])[O:5][CH2:54][CH:52]1[C:53]3[CH:41]=[CH:42][CH:43]=[CH:44][C:45]=3[C:46]3[C:51]1=[CH:50][CH:49]=[CH:48][CH:47]=3)=[C:18]2[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[S:25]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(C(N)=S)cc12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCOc1c(CNC(=O)OCC2c3ccccc3-c3ccccc32)n(CC(C)C)c(=O)c2ccc(C(N)=S)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
Tert-butyl[6-(aminothiocarbonyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (Example 189 (1)) (1.38 g, 3 mmol) was dissolved in a solution of 4N hydrogen chloride in ethyl acetate (10 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was suspended in tetrahydrofuran (20 ml). To the obtained mixture were added triethylamine (0.84 ml, 6 mmol) and 9-fluorenylmethylchloroformate (1.16 g, 4.5 mmol) and the mixture was stirred at 0° C. for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 9H-fluoren-9-ylmethyl [6-(aminocarbothioyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (1.52 g, 86.9%) as an amorphous.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:21])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([CH:19]=[CH2:20])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:22][C:23]1[N:24]=[CH:25][N:26]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:27]=1[C:28](O)=[O:29].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[Cl:22][C:23]1[N:24]=[CH:25][N:26]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:27]=1[C:28]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:18]=[C:17]([CH:19]=[CH2:20])[CH:16]=[C:13]([C:14]#[N:15])[CH:12]=2)[C:4]=1[F:21])=[O:29]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)O
Reactant: C=Cc1cc(C#N)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: C=Cc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3c(Cl)ncn3COCC[Si](C)(C)C)c2F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
To a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-ethenylbenzonitrile (630 mg, 2.081 mmol), 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (576 mg, 2.081 mmol) and HOBT (414 mg, 2.71 mmol) in DMF (10.0 ml) was added EDC (479 mg, 2.497 mmol) and the reaction mixture was stirred at rt for 30 minutes. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 4-chloro-N-({4-chloro-3-[(3-cyano-5-ethenylphenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (1125 mg, 2.004 mmol, 96% yield), 1H NMR (400 MHz, DMSO-d6) δ ppm 8.76 (t, 1H), 7.92 (s, 1H), 7.77 (s, 1H), 7.43-7.49 (m, 1H), 7.32-7.42 (m, 2H), 7.22 (s, 1H), 6.72 (dd, 1H), 6.02 (d, 1H), 5.48 (s, 2H), 5.41 (d, 1H), 4.47 (d, 2H), 3.37 (t, 2H), 0.74 (t, 2H), −0.10 (s, 9H)
Reaction SMILES: [CH:1]1[CH:6]=[N:5][CH:4]=[C:3]([N:7]=[C:8]=[S:9])[CH:2]=1.[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[C:19]([NH2:28])[C:18]=2[N:17]=[C:16]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)(Cl)Cl.N1C=CC=CC=1>[NH2:28][C:19]1[C:18]2[N:17]=[C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][NH:10][C:8]([NH:7][C:3]3[CH:4]=[N:5][CH:6]=[CH:1][CH:2]=3)=[S:9])[C:27]=2[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1
Reactant: S=C=Nc1cccnc1
Reactant: NCCCCn1c(-c2ccccc2)nc2c(N)nc3ccccc3c21
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Nc1nc2ccccc2c2c1nc(-c1ccccc1)n2CCCCNC(=S)Nc1cccnc1
Temperature: 25 °C
Yield: 42.8 %

Procedure:
A solution of pyridine-3-isothiocyanate (0.136 g, 1.0 mmol) in chloroform (5 mL) was added at ambient temperature to a solution of 1-(4-aminobutyl)-2-phenyl-1H-imidazo[4,5-c]quinolin-4-amine (0.331 g, 1.0 mmol) in a mixture of chloroform (25 mL) and pyridine (5 mL). The reaction mixture was maintained at ambient temperature over the weekend. The reaction was quenched with ethanol and then concentrated under vacuum to provide an off-white solid. This material was purified by flash chromatography (silica gel, eluting with 10% methanol in dichloromethane). The pure fractions were combined and concentrated under vacuum to provide 0.2 g of N-[4-(4-amino-2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-(3-pyridyl)thiourea as a white solid, m.p. 118-120° C. Mass spec M+1=468.3. Analysis: Calculated for C26H25N7S: % C, 66.79; % H, 5.39; % N, 20.97. Found: % C, 64.29; % H, 5.46; % N, 20.06.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:26]([CH3:34])[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:25])=[CH:20][CH:19]=3)[CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)=[C:7]([CH3:35])[C:6]=2[CH:36]=1.C(N(CC)CC)C.[CH2:44]([N:46]=[C:47]=[O:48])[CH3:45]>O1CCCC1>[CH:11]1([CH:10]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]([CH3:34])[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:25])=[CH:20][CH:19]=2)[C:8]2[O:9][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:47](=[O:48])[NH:46][CH2:44][CH3:45])=[CH:36][C:6]=3[C:7]=2[CH3:35])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CCN=C=O
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(N)cc3c2C)C2CCCCC2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCNC(=O)Nc1ccc2oc(C(Nc3ccc(C(=O)N(C)CCC(=O)OCC)cc3)C3CCCCC3)c(C)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
To a solution (10 mL) of ethyl 3-{[(4-{[(5-amino-3-methyl-1-benzofuran-2-yl)(cyclohexyl)methyl]amino}phenyl)carbonyl](methyl)amino}-propanoate (280 mg) synthesized in Example A110(5) in tetrahydrofuran were added triethylamine (95 μL) and ethyl isocyanate (54 μL), and the mixture was stirred at room temperature for 1 day. Triethylamine (95 μL) and ethyl isocyanate (54 μL) were additionally added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (60-100% ethyl acetate/hexane) to give the title object compound (304 mg, 95%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]([NH2:12])=[O:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([N:23]1[CH2:27][C@@H:26]([F:28])[CH2:25][C@H:24]1[C:29]#[N:30])=[O:22]>CN(C)C=O>[C:10]([C:5]12[CH2:4][CH2:3][C:2]([NH:1][CH2:20][C:21]([N:23]3[CH2:27][C@@H:26]([F:28])[CH2:25][C@H:24]3[C:29]#[N:30])=[O:22])([CH2:9][CH2:8]1)[CH2:7][CH2:6]2)(=[O:11])[NH2:12]
Reactant: NC(=O)C12CCC(N)(CC1)CC2
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(N)=O)(CC1)CC2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 98.2 %

Procedure:
4-Aminobicyclo[2.2.2]octane-1-carboxamide (50.0 mg) was dissolved in N,N-dimethylformamide (2 mL). To this solution, potassium carbonate (50.0 mg) was added, followed by dropwise addition of (2S,4S)-1-(2-bromoacetyl)-4-fluoropyrrolidine-2-carbonitrile (70.0 mg) in N,N-dimethylformamide (1 mL) at room temperature. The mixture was stirred at room temperature for 2.5 hours and was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluant:chloroform:methanol=10:1) to give (2S,4S)-1-[[(4-carbamoylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (94.1 mg).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[C:18](Br)[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.B([C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=1)(O)O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([C:27]5[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=5)[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(C(=O)O)cc1
Temperature: 80 °C
Yield: 94.6 %

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-methylphenyl)cyclopropanecarbox-amide (B-8) (5.1 g, 14 mmol), 4-boronobenzoic acid (3.4 g, 20 mmol), 1 M K2CO3 (54 mL, 54 mmol), Pd-FibreCat 1007 (810 mg, 1.35 mmol), and DMF (135 mL) were combined. The mixture was heated at 80° C. for 3 h. After cooling, the mixture was filtered and DMF was removed in vacuo. The residue was partitioned between dichloromethane (250 mL) and 1N HCl (250 mL). The organics were separated, washed with saturated NaCl solution (250 mL), and dried over Na2SO4. Evaporation of organics yielded 4-[5-(1-benzo[1,3]dioxol-5-ylcyclopropyl)carbonylamino-2-methyl-phenyl]benzoic acid (5.5 g, 98%). ESI-MS m/z calc. 415.1, found 416.5 (M+1)+; Retention time 3.19 minutes. 1H NMR (400 MHz, DMSO-d6) δ 13.06 (s, 1H), 8.83 (s, 1H), 8.06-8.04 (m, 2H), 7.58-7.56 (m, 1H), 7.50-7.48 (m, 3H), 7.27-7.24 (m, 1H), 7.05-7.04 (m, 1H), 6.98-6.94 (m, 2H), 6.07 (s, 2H), 2.22 (s, 3H), 1.46-1.44 (m, 2H), 1.12-1.09 (m, 2H).
Reaction SMILES: Br[CH:2]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[F:18][C:19]1[CH:20]=[C:21]([C:26](=[C:31]2[CH2:34][NH:33][CH2:32]2)[C:27]([CH3:30])([CH3:29])[CH3:28])[CH:22]=[C:23]([F:25])[CH:24]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH:2]([N:33]2[CH2:34][C:31](=[C:26]([C:21]3[CH:20]=[C:19]([F:18])[CH:24]=[C:23]([F:25])[CH:22]=3)[C:27]([CH3:30])([CH3:28])[CH3:29])[CH2:32]2)[C:3]2[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=2)[C:6]#[N:7])=[CH:12][CH:13]=1
Reactant: N#Cc1cccc(C(Br)c2ccc(Cl)cc2)c1
Reactant: CC(C)(C)C(=C1CNC1)c1cc(F)cc(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)C(=C1CN(C(c2ccc(Cl)cc2)c2cccc(C#N)c2)C1)c1cc(F)cc(F)c1

Procedure:
A mixture of 99 mg (0.32 mmol) of 3-[bromo(4-chlorophenyl)methyl]benzonitrile, 80 mg (0.216 mmol) of 3-[1-(3,5-difluorophenyl)-2,2-dimethylpropylidene]azetidine and 113 uL (0.65 mmol) of N,N-diisopropylethylamine in 3 mL of acetonitrile was heated at reflux for 3 h. Then the reaction was concentrated and the residue was dissolved in 5 ml of hexane/ether. A solution of 1 mL of 1N HCl in ether was added to above solution to make the salt. The mixture was filtered and the solids were washed with hexane/ether. The residue was neutralized with NaOH and the free base was purified by silica gel chromatography with hexanes/ethyl acetate to afford the title compound as a white solid; 1H-NMR (CDCl3) δ 1.07 (s, 9H), 3.37 (m, 2H), 4.06 (m, 2H), 4.50 (s, 1H), 6.58 (d, J=8 Hz, 2H), 6.74 (m, 1H), 7.28 (d, J=8.5 Hz, 2H), 7.34 (d, J=8.5 Hz, 2H), 7.39 (t, J=7.7 Hz, 1H), 7.50 (d, J=7.8 Hz, 1H), 7.62 (d, J=7.8 Hz, 1H), 7.72 (s, 1H); Mass Spectrum: m/e=463 (M+1 35Cl) and 465 (M+1 37Cl).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C@H:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[N:19]=3)[N:14]=[CH:13][CH:12]=2)[OH:10])[CH2:4]1.[O:23]=[C:24]1[CH2:29][S:28][C:27]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[N:33][C:26]=2[NH:25]1.[BH4-].[Na+]>C(Cl)Cl.CCO>[OH:10][C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[N:19]=2)[N:14]=[CH:13][CH:12]=1)[CH2:8][N:5]1[CH2:6][CH2:7][C@@H:3]([CH2:2][NH:1][CH2:34][C:32]2[CH:31]=[CH:30][C:27]3[S:28][CH2:29][C:24](=[O:23])[NH:25][C:26]=3[N:33]=2)[CH2:4]1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Reactant: COc1ccc2nccc([C@H](O)CN3CC[C@@H](CN)C3)c2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc2nccc([C@H](O)CN3CC[C@@H](CNCc4ccc5c(n4)NC(=O)CS5)C3)c2n1
Reaction time: 24 h
Yield: 52.9 %

Procedure:
To a stirred solution of (1S)-2-[(3S)-3-(aminomethyl)-1-pyrrolidinyl]-1-[6-(methyloxy)-1,5-naphthyridin-4-yl]ethanol (72 mg, 0.24 mmole) in dry CH2Cl2 (25 mL) and dry EtOH (20 mL) at RT was added 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde (47 mg, 0.24 mmole). After 24 h at RT, was added NaBH4 (10 mg, 0.26 mmole). After 2 h, silica gel (5 g) was added to the reaction solution and the suspension was concentrated under vacuum to a dry solid. Purification on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) afforded the title compound (61 mg, 54%) as light yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.81 (d, J=4.5 Hz, 1H), 8.23 (d, J=9.1 Hz, 1H), 7.84 (d, J=4.5 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.12 (d, J=9.1 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 5.74 (m, 1H), 4.04 (s, 3H), 3.82 (s, 2H), 3.46 (s, 2H), 3.00-3.11 (m, 1H), 2.58-2.83 (m, 6H), 2.33-2.58 (m, 1H), 2.01 (m, 2H), 1.65 (m, 1H). LC-MS (ES) m/e 481 (M+H)+.