Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH2:11][C:12](=O)[CH2:13][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:15]([NH:22][CH:12]1[CH2:11][CH2:10][CH2:9][C:8]2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=2[CH2:13]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc2c1CCCC(=O)C2
Reactant: NCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc2c1CCCC(NCc1ccccc1)C2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 1-methoxy-5,7,8,9-tetrahydro-6H-benzocyclohepten-6-one (6.0 g) and benzylamine (3.4 ml) in toluene (60 ml) in the presence of a catalytic amount of p-toluenesulfonic acid monohydrate was refluxed for 2 hours to remove water as the toluene azeotrope, and then the mixture was evaporated in vacuo. To the residue in methanol (60 ml) was added sodium borohydride (1.2 g) under nitrogen at 5° C., and the mixture was stirred at room temperature for 12 hours. The resulting mixture was poured into ice-cold water and stirred for 30 minutes before adding ethyl acetate and brine. After separation, the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was chromatographed (hexane-ethyl acetate-methanol) over silica gel to afford N-benzyl-(1-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine (7.27 g).
Reaction SMILES: [C:1]1([O:7][P:8]([CH2:17][NH:18][C@@H:19]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:38][CH:37]=2)[C:20]([NH:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])=[O:21])([O:10]C2C=CC=CC=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>C1COCC1>[C:1]1([O:7][P:8]([CH2:17][NH:18][C@@H:19]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[CH:40][CH:41]=2)[C:20]([NH:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:26])=[O:21])([OH:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(CCNC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NCP(=O)(Oc1ccccc1)Oc1ccccc1)OCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(CCNC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NCP(=O)(O)Oc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzyl (S)-N-[2-(diphenylphosphonomethylamino)-3-(4-biphenylyl)-propionyl]-3-aminopropionate (720 mg, 1.1 mmol) is dissolved in THF (15 mL) and treated with 2N hydrochloric acid. The solution is stirred at room temperature for 8 hours. The precipitate is filtered. It can be further purified by column chromatography on silica gel, eluting with a mixture of methylene chloride-methanol-acetic acid (95/5/25), to obtain benzyl (S)-N-[2-(monophenylphosphonomethylamino)-3-(4-biphenylyl)-propionyl]-3-aminopropionate m.p. 243°-244°.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH:11]=O)[S:8][C:6]=2[N:7]=1.[Cl-].[CH3:20][S:21]([N:24]1[CH2:29][CH2:28][NH2+:27][CH2:26][CH2:25]1)(=[O:23])=[O:22].C([O-])(=O)C.[Na+].C(OC)(OC)OC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:27]3[CH2:28][CH2:29][N:24]([S:21]([CH3:20])(=[O:23])=[O:22])[CH2:25][CH2:26]3)[S:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)N1CC[NH2+]CC1
Reactant: O=Cc1cc2c(N3CCOCC3)nc(Cl)nc2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: CS(=O)(=O)N1CCNCC1
Solvent: COC(OC)OC
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Temperature: 25 °C
Yield: 80 %

Procedure:
To a suspension of 2-chloro-4-morpholinothieno[2,3-d]pyrimidine-6-carbaldehyde 19 (90.8 g, 0.320 mol, 1.0 equiv.), 4-(methylsulfonyl)piperazin-1-ium chloride 8 (alternatively named as 1-(methylsulfonyl)piperazine hydrochloride, 92.3 g, 0.460 mol, 1.45 equiv.) and sodium acetate (anhydrous powder, 37.7 g, 0.460 mol, 1.45 equiv.) in 1,2-dichloroethane (anhydrous, 1.8 L) was added trimethyl orthoformate (340 g, 3.20 mol, 10 equiv.). The slurry was stirred at ambient temperature for at least 6 hours. Sodium triacetoxyborohydride (assay>90%, 101.3 g, 0.430 mol, 1.35 equiv.) was added and the reaction was stirred for 24 hours. LC/MS indicated that the reaction was complete. The reaction was quenched with water (4.4 L) and methylene chloride (4.4 L). The phases were separated and the organic phase was dried over MgSO4, filtered and concentrated to give a yellow solid. The crude solid was then stirred in ethyl acetate (2.0 L) at 80° C. for 2 hours. The slurry was cooled to 30-40° C., filtered and rinsed with ethyl acetate (50 ml). The cake was dried in vacuum oven at 45° C. to give 4-(2-chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[2,3-d]pyrimidin-4-yl)morpholine 20 as an off-white solid (110.2 g, 80% yield). 1H NMR (400 MHz, DMSO-d6) δ 2.52-2.55 (m, 4H), 2.89 (s, 3H), 3.12-3.14 (m, 4H), 3.73 (t, J=4.4 Hz, 4H), 3.81 (s, 2H), 3.86 (t, J=4.8 Hz, 4H), 7.59 (s, 1H). LCMS (ESI pos) m/e 432 (M+1).
Reaction SMILES: C([O:8][C:9](=[O:32])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:31])[C@H:16]([CH3:30])[NH:17][CH:18]1[CH2:22][CH:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[O:20][C:19]1=[O:29])C1C=CC=CC=1>CO.[Pd]>[O:29]=[C:19]1[CH:18]([NH:17][C@H:16]([C:15]([N:11]2[CH2:12][CH2:13][CH2:14][C@H:10]2[C:9]([OH:32])=[O:8])=[O:31])[CH3:30])[CH2:22][CH:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[O:20]1
Reactant: CCCCCCC1CC(N[C@@H](C)C(=O)N2CCC[C@H]2C(=O)OCc2ccccc2)C(=O)O1
Agent: [Pd]
Solvent: CO
Product: CCCCCCC1CC(N[C@@H](C)C(=O)N2CCC[C@H]2C(=O)O)C(=O)O1
Reaction time: 2 h

Procedure:
Dissolved in 50 ml of methanol was 3.80 g of Isomer B of N-(2-oxo-5-hexyl-3-tetrahydrofuranyl)-L-alanyl-L-proline benzyl ester (Compound 7). Thereafter, 0.40 g of 10% palladium-charcoal was added and the reaction mixture was hydrogenated at room temperature and normal pressure for 2 hours. The palladium-charcoal was then filtered off and the filtrate was distilled under reduced pressure to obtain as white powder 2.80 g of N-(2-oxo-5-hexyl-3-tetrahydrofuranyl)-L-alanyl-L-proline (Isomer B) [in the formula (I), R1 =--(CH2)5CH3, R2 =H, R3 =CH3, R4 and R5 =--(CH2)3 --, R6 =H (Compound 14)].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([CH:15]=2)[C:13]2[CH:16]=[CH:17][C:18]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:19][C:12]=2[S:11]3)=[CH:4][CH:3]=1.[C:27]([C:31]1[O:35][N:34]=[C:33]([N:36]=[C:37]=[O:38])[CH:32]=1)([CH3:30])([CH3:29])[CH3:28]>C1(C)C=CC=CC=1>[C:27]([C:31]1[O:35][N:34]=[C:33]([NH:36][C:37]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[N:9]=[C:10]4[N:14]([CH:15]=3)[C:13]3[CH:16]=[CH:17][C:18]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:19][C:12]=3[S:11]4)=[CH:6][CH:7]=2)=[O:38])[CH:32]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CCOC(=O)CCc1ccc2c(c1)sc1nc(-c3ccc(N)cc3)cn12
Reactant: CC(C)(C)c1cc(N=C=O)no1
Solvent: Cc1ccccc1
Product: CCOC(=O)CCc1ccc2c(c1)sc1nc(-c3ccc(NC(=O)Nc4cc(C(C)(C)C)on4)cc3)cn12
Temperature: 110 °C
Yield: 91.4 %

Procedure:
A mixture of ethyl 3-[2-(4-aminophenyl)imidazo[2,1-b][1,3]benzothiazol-7-yl]propanoate (3.80 g, 10.4 mmol) from Step C and 5-tert-butyl-3-isocyanatoisoxazole (2.08 g, 12.5 mmol) in toluene (80 mL) was heated at 110° C. over night. A precipitate was formed, collected by filtration, washed with ether, and dried under high vacuum to give the title compound as a white solid (5.056 g, 91%). 1H NMR (DMSO-d6) δ 9.62 (s, 1H), 9.08 (s, 1H), 8.70 (s, 1H), 7.91 (s, 1H), 7.89 (d, 1H), 7.79 (d, 2H), 7.54 (d, 2H), 7.46 (d, 1H), 6.53 (s, 1H), 4.06 (q, 2H), 2.98 (t, 2H), 2.70 (t, 2H), 1.30 (s, 9H), 1.15 (t, 3H); LC-MS: ESI 532 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6](=[O:22])[CH2:7][C:8]([OH:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:35]1[CH:40]=[CH:39][CH2:38][CH2:37][CH2:36]1>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6](=[O:22])[CH2:7][C:8]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([O:21][CH:36]1[CH2:37][CH2:38][CH2:39][CH2:40][O:35]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH3:2]
Reactant: C1=COCCC1
Reactant: CCOC(=O)CC(=O)CC(O)(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC(=O)CC(=O)CC(OC1CCCCO1)(c1ccccc1)c1ccccc1

Procedure:
The title compound (J. W. Wolfe, et al, J. Org. Chem. 29, 3249 (1964) ) was prepared from δ-hydroxy-β-oxo-δ-phenylbenzenepentanoic acid ethyl ester (2.0 g, 0.006 mol), p-toluenesulfonic acid (0.014 g, 0.60 mmol), and 3,4-dihydro-2H-pyran (0.77 g, 0.009 mol) using the procedure described in Example 6, Step A.
Reaction SMILES: C([N:3]([CH2:14][CH3:15])[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7](C)[C:6]=1[CH3:12])C.[OH:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23]CC#N)[CH2:19][CH2:18]1>>[OH:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:15][C:14]2[NH:3][C:4](=[O:13])[C:5]3[C:6]([CH:12]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:19][CH2:18]1
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Reactant: N#CCCN1CCC(O)CC1
Product: O=c1[nH]c(CCN2CCC(O)CC2)cc2ccccc12
Yield: 8.2 %

Procedure:
By the reaction in the same manner as in Example 1a, using N,N-diethyl-2,3-dimethylbenzamide (5.6017 g) and 3-(4-hydroxypiperidin-1-yl)propionitrile (2.26 g), 3-[2-(4-hydroxypiperidin-1-yl)ethyl]-2H-isoquinolin-1-one (327.5 mg) was obtained.
Reaction SMILES: O[C:2]1[C:3]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[N:6][N:7]=1.[NH2:15][CH:16]1[CH:21]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]1>>[F:31][C:28]([F:29])([F:30])[C:25]1[CH:24]=[CH:23][C:22]([CH:21]2[CH2:20][CH2:19][NH:18][CH2:17][CH:16]2[NH:15][C:2]2[C:3]3[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[N:6][N:7]=2)=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(F)(F)F)cc2)C(N)C1
Reactant: NC(=O)c1cccc2c(O)nnnc12
Product: NC(=O)c1cccc2c(NC3CNCCC3c3ccc(C(F)(F)F)cc3)nnnc12

Procedure:
Compound 22 was prepared following general synthesis scheme 9 wherein 4-hydroxybenzo[d][1,2,3]triazine-8-carboxylic acid amide was reacted with tert-butyl 3-amino-4-(4-(trifluoromethyl)phenyl)piperidine-1-carboxylate to give the title compound. LC-MS [417 (M+H)], 1H NMR (400 MHz, DMSO-d6) δ 9.21 (s, 1H), 9.04-8.92 (m, 1H), 8.61-8.43 (m, 3H), 8.11-7.92 (m, 2H), 7.72 (d, 1H), 7.64-7.46 (m, 5H), 5.58-5.44 (m, 1H), 3.71-3.44 (m, 4H), 3.30-3.09 (m, 1H), 2.81-2.60 (m, 1H), 2.08 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([NH2:17])=[N:14][C:13]=2[CH3:18])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[CH2:19]([N:21]=[C:22]=[O:23])[CH3:20]>CN(C=O)C>[CH2:19]([NH:21][C:22]([NH:17][C:15]1[S:16][C:12]([C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([F:1])[CH:3]=2)=[C:13]([CH3:18])[N:14]=1)=[O:23])[CH3:20]
Reactant: CCN=C=O
Reactant: Cc1nc(N)sc1-c1ccc(S(C)(=O)=O)c(F)c1
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(F)c2)s1
Temperature: 85 °C

Procedure:
A mixture of 5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (0.40 g, 1.4 mmol) and ethyl isocyanate (0.121 ml, 1.5 mmol) in dry DMF (3 ml) is heated at 85° C. for 1 hour. The solvent is removed and the product is purified by chromatography on silica eluting with hexane—ethyl acetate (1:1) to give the title compound.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][N:27]=1>>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([C:26]3[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][N:27]=3)=[O:5])[N:7]=[CH:8]2)[CH:12]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3Cl)c2)cn1
Reactant: Cc1ccnc(Br)c1
Product: Cc1ccnc(C(=O)c2cn(-c3cccc(-c4ccccc4Cl)c3)cn2)c1

Procedure:
This compound is prepared by method C using compound 12e and 2-bromo-4-methylpyridine
Reaction SMILES: [F:1][CH2:2][CH2:3]I.C(=O)([O-])[O-].[K+].[K+].[C:11]([O:15][C:16]([NH:18][C@H:19]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:20][C@H:21]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][N:31]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:17])([CH3:14])([CH3:13])[CH3:12]>CN(C)C=O>[C:11]([O:15][C:16]([NH:18][C@H:19]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:20][C@H:21]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:3][CH2:2][F:1])=[CH:32][N:31]=1)[C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])=[O:17])([CH3:12])([CH3:13])[CH3:14]
Reactant: FCCI
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(O)cn1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(OCCF)cn1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.4 %

Procedure:
To a solution of 196 mg 1-fluoro-2-iodoethane (1.13 mmol) in N,N-dimethylformamide (25 mL) was subsequently added 363 mg potassium carbonate (2.63 mmol), followed by 350 mg di-tert-butyl (4R)—N-(tert-butoxycarbonyl)-4-[(5-hydroxypyridin-2-yl)methyl]-L-glutamate 0.75 mmol), and the resulting mixture was stirred for 4 h at room temperature. The mixture was than partitioned between water and dichloromethane, and the organic layer was washed with brine, dried over magnesium sulfate, and evaporated. Purification of the crude product by preparative HPLC (method A) gave 313 mg of the target compound (81% yield).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][C:15]([CH:18]3[CH2:27][CH2:26][C:21]4(OCC[O:22]4)[CH2:20][CH2:19]3)=[CH:14][CH2:13]2)=[C:8]([F:28])[C:7]=1[F:29])[CH2:2][CH2:3][CH3:4].C(O)=O.O>C1(C)C=CC=CC=1>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:13][CH2:14][CH:15]([CH:18]3[CH2:27][CH2:26][C:21](=[O:22])[CH2:20][CH2:19]3)[CH2:16][CH2:17]2)=[C:8]([F:28])[C:7]=1[F:29])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(C2CC=C(C3CCC4(CC3)OCCO4)CC2)c(F)c1F
Solvent: O
Solvent: O=CO
Solvent: Cc1ccccc1
Product: CCCCOc1ccc(C2CCC(C3CCC(=O)CC3)CC2)c(F)c1F
Temperature: 30 °C
Yield: 98.5 %

Procedure:
The compound (23) (7.7 g), formic acid (87%; 8.7 g) and toluene (100 ml) were mixed and the mixture was heated to reflux for 2 hours. After the reaction mixture had been cooled to 30° C., water (200 ml) and toluene (200 ml) were added to the mixture and mixed with it. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and the extraction into an organic phase was carried out. The resulting organic phase was separated, and washed successively with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. Then the solvent was distilled off under reduced pressure, and the residue was purified by recrystallization from heptane solvent and dried to give 4′-(4-butoxy-2,3-difluorophenyl)-bicyclohexyl-4-one (24) (6.8 g). The yield based on the compound (23) was 99.0%.
Reaction SMILES: [CH3:1][N:2]([C@H:16]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH:25]3[CH2:29][CH2:28][CH2:27][NH:26]3)[CH:22]=2)[CH2:17]1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:7][N:6]=1)=[O:4].[CH:30](=O)[CH3:31]>>[CH2:30]([N:26]1[CH2:27][CH2:28][CH2:29][CH:25]1[C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[CH2:17][C@@H:16]([N:2]([CH3:1])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH:13]3[CH2:14][CH2:15]3)=[CH:7][N:6]=1)=[O:4])[CH2:24]2)[CH3:31]
Reactant: CC=O
Reactant: CN(C(=O)c1ccc(OCC2CC2)cn1)[C@@H]1Cc2ccc(C3CCCN3)cc2C1
Product: CCN1CCCC1c1ccc2c(c1)C[C@H](N(C)C(=O)c1ccc(OCC3CC3)cn1)C2

Procedure:
According to method A, N-methyl-N-((R)-5-pyrrolidin-2-ylindan-2-yl)-5-cyclopropylmethoxypyridine-2-carboxamide was reacted with acetaldehyde. The product was thus obtained with the monoisotopic molecular weight of 419.26 (C26H33N3O2); MS (ESI): 420.4 (M+H+).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:16]=2[CH:17]2[CH2:33][CH:21]3[N:22](C(OC(C)(C)C)=O)C(=O)[O:24][CH:20]3[CH2:19][CH2:18]2)=[O:9])[CH:5]=[CH:4][C:3]=1[F:34].[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:37]=1B(O)O.C(N(CC)CC)C>CCO.C1(C)C=CC=CC=1>[NH2:22][CH:21]1[CH:20]([OH:24])[CH2:19][CH2:18][CH:17]([C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[NH:10][C:8](=[O:9])[C:6]2[CH:5]=[CH:4][C:3]([F:34])=[C:2]([C:37]3[C:36]([F:35])=[CH:41][CH:40]=[CH:39][C:38]=3[F:42])[N:7]=2)[CH2:33]1
Reactant: CC(C)(C)OC(=O)N1C(=O)OC2CCC(c3ccncc3NC(=O)c3ccc(F)c(Br)n3)CC21
Reactant: OB(O)c1c(F)cccc1F
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CCO
Product: NC1CC(c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)CCC1O

Procedure:
A solution of tert-butyl 5-(3-(6-bromo-5-fluoropicolinamido)pyridin-4-yl)-2-oxohexahydrobenzo[d]oxazole-3(2H)-carboxylate (1.0 equiv), 2,6-difluorophenyl boronic acid (3.0 equiv.), tetrakistriphenylphosphine (0.2 equiv.) and triethylamine (3.0 equiv.) in 1:1 EtOH/toluene (0.1 M) was heated at 120° C. with microwave irradiation for 1200 seconds. Upon cooling, removal of the volatiles in vacuo, the Suzuki product was directly purified by reverse phase HPLC. The product fraction was lyophilized and the resulting cyclic carbamate and Boc groups were deprotected as described in Method 9 yielding, after RP HPLC purification and lyophilization, N-(4-(3-amino-4-hydroxycyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamideas the TFA salt. LCMS (m/z): 443.2 (MH+); LC Rt=2.11 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].CS(O[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)(=O)=O>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)=[CH:22][CH:21]=2)[CH2:15][CH2:16][CH:17]([CH3:18])[CH3:19])[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)CCN(c1ccc(O)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CS(=O)(=O)OCc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)CCN(c1ccc(OCc2ccc(F)cc2)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.13 h
Yield: 90.6 %

Procedure:
4-[(4-hydroxy-phenyl)-(3-methyl-butyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (In, 1.18 g, 3.26 mmol) was dissolved in DMF (7 mL), treated with NaH (0.26 g, 6.52 mmol, 60% dispersion in mineral oil), and stirred for 8 minutes. 4-Fluorobenzyl methanesulfonate (Ie, 0.93 g, 4.56 mmol) was added and the reaction was stirred for 5 minutes, then diluted with EtOAc (100 mL), washed with saturated sodium bicarbonate solution and with brine, dried over Na2SO4, and concentrated. The residue was chromatographed on silica gel eluting with 4:1 hexane/EtOAc to give 1.39 g (91%) of the desired product.
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:24][CH3:25])[C:12]2[CH:13]=[C:14]([CH3:23])[C:15]3[O:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:16]=3[CH:22]=2)=[CH:7][CH:6]=1)C.[OH-].[K+]>C(O)C>[CH2:24]([N:11]([C:12]1[CH:13]=[C:14]([CH3:23])[C:15]2[O:19][CH2:18][C:17]([CH3:20])([CH3:21])[C:16]=2[CH:22]=1)[C:8]1[CH:7]=[CH:6][C:5]([C:4]([OH:26])=[O:3])=[CH:10][CH:9]=1)[CH3:25]
Reactant: CCOC(=O)c1ccc(N(CC)c2cc(C)c3c(c2)C(C)(C)CO3)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCN(c1ccc(C(=O)O)cc1)c1cc(C)c2c(c1)C(C)(C)CO2
Yield: 7.5 %

Procedure:
Following general procedure G and using 4-[ethyl-(3,3,7-trimethyl-2,3-dihydro-benzofuran-5-yl)-amino]-benzoic acid ethyl ester (Compound 20, 0.013 g, 0.37 mmol) and 1 mL (4 mmol) of 4M potassium hydroxide solution in 1.1 mL of ethanol, the title compound (0.009 g, 75%) was obtained as a solid. 1H NMR (300 MHz, CDCl3): δ 7.86 (d, 2H, J=9.0 Hz), 6.77 (s, 1H), 6.75 (s, 1H), 6.57 (d, 2H, J=9.0 Hz), 4.29 (s, 2H), 3.72 (q, 2H, J=7.1 Hz), 2.21 (s, 3H), 1.33 (s, 6H), 1.25 (t, 3H, J=7.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5](O)=[O:6].O1CCCC1.B>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:8]=[C:9]([CH3:11])[CH:10]=1
Reactant: Cc1cc(Cl)cc(C(=O)O)c1
Agent: B
Solvent: C1CCOC1
Product: Cc1cc(Cl)cc(CO)c1
Temperature: 0 °C

Procedure:
To a stirred solution/suspension of 3-chloro-5-methylbenzoic acid (800 mg, 4.69 mmol) in THF (5 ml) at 0° C. under nitrogen was added dropwise borane tetrahydrofuran complex (1 M in THF, 23.45 ml, 23.45 mmol) over 30 mins maintaining the temperature around 0° C. The reaction mixture was then allowed to warm to RT over 20 hrs. On cooling in an ice/water bath the reaction mixture was quenched dropwise with water and after a few minutes the THF was removed under reduced pressure. Water was added to the residue and on cooling a few drops of 1M HCl were added until effervescence ceased. The mixture was diluted with water and extracted into EtOAc, the organic portion dried over MgSO4, filtered and concentrated under reduced pressure. Purification was carried out by chromatography on silica using 0-50% EtOAc in hexanes as eluent and azeotroping with toluene to afford the title product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[O:12][CH2:11][CH:10]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=3)[C:9]=2[C:8]([CH3:23])=[C:7]([NH:24][C:25](=[O:32])OCC(Cl)(Cl)Cl)[C:6]=1[CH3:33].[NH2:34][CH2:35][CH2:36][OH:37]>CCCCCC.C(OCC)(=O)C>[OH:37][CH2:36][CH2:35][NH:34][C:25]([NH:24][C:7]1[C:6]([CH3:33])=[C:5]([CH2:4][CH2:3][CH2:2][OH:1])[C:13]2[O:12][CH2:11][CH:10]([C:14]3[CH:15]=[CH:16][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:18][CH:19]=3)[C:9]=2[C:8]=1[CH3:23])=[O:32]
Reactant: Cc1c(CCCO)c2c(c(C)c1NC(=O)OCC(Cl)(Cl)Cl)C(c1ccc(C(C)C)cc1)CO2
Reactant: NCCO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(CCCO)c2c(c(C)c1NC(=O)NCCO)C(c1ccc(C(C)C)cc1)CO2
Yield: 53 %

Procedure:
Using 2,2,2-trichloroethyl (7-(3-hydroxypropyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 141 and 2-aminoethanol, the title compound was synthesized in the same manner as in Example 143. Yield: 53%. Melting point: 153-154° C. (hexane-ethyl acetate).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:13][CH2:12]2)=[C:7]([O:14][CH2:15][CH2:16][O:17][CH3:18])[N:6]=1)=[O:4].[OH-].[Na+]>C(O)C>[CH:11]1([C:8]2[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][C:7]=2[O:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:13][CH2:12]1
Reactant: COCCOc1nc(C(=O)OC)ccc1C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCCOc1nc(C(=O)O)ccc1C1CC1
Yield: 83.3 %

Procedure:
A solution of 5-cyclopropyl-6-(2-methoxyethoxy)-pyridine-2-carboxylic acid methyl ester (0.16 g, 0.6 mmol) and sodium hydroxide (31 mg, 0.7 mmol) in ethanol (40 mL) was heated to 90° C. for 2 h. The reaction mixture was evaporated, dissolved in water and extracted with ethyl acetate (30 mL). The pH of the aqueous layer was adjusted to 2 by addition of 1 N hydrochloric acid, the resulting precipitate was collected by filtration and dried in vacuo to give the title compound (0.11 g, 0.5 mmol; 73%) as yellow oil; MS: m/e=238.1 [M+H]+.