Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[C:15](=O)([O-])[O-].[K+].[K+].IC>C(#N)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]1
Reactant: Fc1cccc(C2CCNCC2)c1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CN1CCC(c2cccc(F)c2F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(2,3-difluorophenyl)piperidine (0.2 g, 1.01 mmol) in acetonitrile (10 ml), was added potassium carbonate (0.28 g, 2.0 mmol) and 1-iodomethane (0.06 ml, 1.0 mmol) and the mixture was stirred at ambient temperature for 1 h. MS m/z (rel. intensity, 70 eV) 211 (M+, 78), 210 (bp), 2140 (8), 127 (12), 97 (11).
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[C:38]([CH2:43][OH:44])[CH:37]=1)[CH2:10][NH:11][C@H:12]([CH3:35])[CH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])=[O:24])=[CH:17]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:45][O:46]C1C=CC=C(OC)C=1CN>>[Si:1]([O:8][C@H:9]([C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[C:38]([CH2:43][OH:44])[CH:37]=1)[CH2:10][NH:11][C@H:12]([CH3:35])[CH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([C:23]([NH:25][CH2:26][C:27]1[C:32]([O:46][CH3:45])=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])=[O:24])=[CH:17]2)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: COc1cccc(OC)c1CN
Reactant: COc1ccccc1CNC(=O)c1cc2cc(C[C@@H](C)NC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(O)c(CO)c3)ccc2[nH]1
Product: COc1cccc(OC)c1CNC(=O)c1cc2cc(C[C@@H](C)NC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(O)c(CO)c3)ccc2[nH]1

Procedure:
Prepared analogously to 5-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]-N-(2-methoxybenzyl)-1H-indole-2-carboxamide using 2,6-dimethoxybenzylamine to give the title compound as a pale yellow foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:15])[CH3:14])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21]([CH:26]=O)=[CH:22][NH:23]2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21](/[CH:26]=[CH:14]/[C:13]([C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[O:15])=[CH:22][NH:23]2)=[CH:19][CH:18]=1
Reactant: O=Cc1c[nH]c2cc(Cl)ccc12
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Product: COc1cc(C(=O)/C=C/c2c[nH]c3cc(Cl)ccc23)cc(OC)c1OC
Yield: 69.2 %

Procedure:
Substantially the same procedure as in Example 1 was repeated using 3',4',5'-trimethoxyacetophenone (2.1 g) and 6-chloroindole-3-carboxaldehyde (1.8 g) except that the obtained product was recrystallized from ethyl acetate, to give Compound 42 (2.57 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:11][CH2:12][CH:13]([OH:20])[C:14]2[N:15]=[C:16]([CH3:19])[S:17][CH:18]=2)[CH3:10])=[CH:4][CH:3]=1.[C:21]([O:25][CH3:26])(=[O:24])[CH:22]=O>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([N:11]2[CH2:12][CH:13]([C:14]3[N:15]=[C:16]([CH3:19])[S:17][CH:18]=3)[O:20][CH:22]2[C:21]([O:25][CH3:26])=[O:24])[CH3:10])=[CH:4][CH:3]=1
Reactant: Cc1nc(C(O)CNC(C)Cc2ccc(O)cc2)cs1
Reactant: COC(=O)C=O
Product: COC(=O)C1OC(c2csc(C)n2)CN1C(C)Cc1ccc(O)cc1

Procedure:
Prepared by analogy to Example 18 by reaction of N-[2-(4-hydroxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-methyl-thiazol-4-yl)ethanamine with methyl glyoxylate, followed by purification of the base on a silica gel column using ether/petroleum ether=8:2 as eluant.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([NH:15][CH2:16][C:17]([N:19]([C:21]2[C:22]([Cl:38])=[C:23]([C:34]([Cl:37])=[CH:35][CH:36]=2)[CH2:24][O:25][C:26]2[C:27]([NH2:33])=[C:28]([CH:30]=[CH:31][CH:32]=2)[NH2:29])[CH3:20])=[O:18])=[O:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:39](OC)(OC)(OC)[O:40][CH3:41]>C(O)(=O)C>[C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([NH:15][CH2:16][C:17]([N:19]([C:21]2[C:22]([Cl:38])=[C:23]([C:34]([Cl:37])=[CH:35][CH:36]=2)[CH2:24][O:25][C:26]2[C:27]3[N:33]=[C:39]([O:40][CH3:41])[NH:29][C:28]=3[CH:30]=[CH:31][CH:32]=2)[CH3:20])=[O:18])=[O:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: COC(OC)(OC)OC
Reactant: CC(=O)Nc1ccc(/C=C/C(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc(N)c3N)c2Cl)cn1
Solvent: CC(=O)O
Product: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)/C=C/c4ccc(NC(C)=O)nc4)c3Cl)cccc2[nH]1
Reaction time: 8 h
Yield: 83 %

Procedure:
To a solution of 3-[3-[N-[(E)-3-(6-acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-aminoaniline (735 mg) in acetic acid (7.4 ml) was added tetramethyl orthocarbonate (215 mg) at ambient temperature, and the mixture was stirred for 8 hours at the same temperature. The solvent was removed, and the residue was dissolved in chloroform. The solution was washed with saturated sodium bicarbonate solution, water and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (chloroform-methanol) to give 4-[3-[N-[(E)-3-(6-acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methoxy-1H-benzimidazole (654 mg).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH:18]([C:20](=[O:22])[CH3:21])[CH3:19])[C:4]2[C:9]([C:10]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:23][Li]>>[OH:22][C:20]([CH3:23])([CH3:21])[CH:18]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])=[C:2]1[CH3:1])[CH3:19]
Reactant: CC(=O)C(C)n1c(C)c(C(=O)OC(C)(C)C)c2ccccc21
Reactant: [Li]C
Product: Cc1c(C(=O)OC(C)(C)C)c2ccccc2n1C(C)C(C)(C)O
Temperature: -78 °C

Procedure:
A 50 mL round bottom flask was charged with (±)-tert-butyl 2-methyl-1-(3-oxobutan-2-yl)-1H-indole-3-carboxylate (0.2441 g, 0.810 mmol), vac/purged with N2, diluted with THF (5 mL) and cooled to −78° C. Methyllithium (0.648 ml, 0.972 mmol) was then added slowly, drop-wise, and the solution was allowed to slowly warm to ambient temperature. The reaction was then quenched with 1N HCl, extracted with EtOAc. The org layer was washed with water then brine, dried over Na2SO4, filtered, concentrated, purified by column chromatography using 10% EtOAc in Hex (10 CV), 15% (10 CV) to elute (±)-tert-butyl 1-(3-hydroxy-3-methylbutan-2-yl)-2-methyl-1H-indole-3-carboxylate (157.2 mg, 61.1%). LRMS (M+H+) m/z: calcd 318.42. found 318.2.
Reaction SMILES: N1C2C(=NC=CC=2)N(O[C:11]([C:13]2[C:17]([CH3:18])=[C:16](/[CH:19]=[C:20]3\[C:21](=[O:41])[NH:22][C:23]4[C:28]\3=[CH:27][C:26]([S:29]([CH2:32][C:33]3[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:40])(=[O:31])=[O:30])=[CH:25][CH:24]=4)[NH:15][C:14]=2[CH3:42])=[O:12])N=1.[N:43]1[CH:48]=[CH:47][CH:46]=[C:45]([CH2:49][CH2:50][NH2:51])[CH:44]=1>CC(N(C)C)=O>[N:43]1[CH:48]=[CH:47][CH:46]=[C:45]([CH2:49][CH2:50][NH:51][C:11]([C:13]2[C:17]([CH3:18])=[C:16](/[CH:19]=[C:20]3\[C:21](=[O:41])[NH:22][C:23]4[C:28]\3=[CH:27][C:26]([S:29]([CH2:32][C:33]3[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:40])(=[O:31])=[O:30])=[CH:25][CH:24]=4)[NH:15][C:14]=2[CH3:42])=[O:12])[CH:44]=1
Reactant: NCCc1cccnc1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)On1nnc2cccnc21
Solvent: CC(=O)N(C)C
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NCCc1cccnc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [1,2,3]triazolo[4,5-b]pyridin-3-yl ester (100 mg, 0.162 mmol) in DMA (2 mL) was added 2-pyridin-3-yl-ethylamine (39 mg, 2 eq.). The mixture was stirred at rt for 18 hours. The reaction was concentrated, diluted with DCM, washed with sat. NaHCO3 and water, concentrated and triturated with ethanol to give the titled compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]2[CH2:6][CH:7]([CH3:20])[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[O-:23][C:24]#[N:25].[K+]>C(O)(=O)C>[Br:1][C:2]1[CH:22]=[CH:21][C:5]2[CH2:6][CH:7]([CH3:20])[N:8]([C:24](=[O:23])[NH2:25])[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=3)[C:4]=2[CH:3]=1
Reactant: CC1Cc2ccc(Br)cc2C(c2ccc([N+](=O)[O-])cc2)=NN1
Reactant: N#C[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CC1Cc2ccc(Br)cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(N)=O
Reaction time: 1 h
Yield: 77.4 %

Procedure:
A solution of 1.80 g (5 mmoles) of 8-bromo-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine in 10 ml of glacial acetic acid is treated with 0.53 g (6.5 mmoles) of potassium cyanate. After 1 hour, the solution is poured onto water, and the precipitated crystals are filtered. The crude product is suspended in 15 ml of hot ethanol. After filtration and drying, 1.56 g (77%) of the title compound are obtained. M.p.: 193°-203° C.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][O:4][N:3]=1.[Br:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[N:18]1[C:27]2[C:22](=[CH:23][C:24]([S:28](Cl)(=[O:30])=[O:29])=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]1=[O:32].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Br:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[N:18]1[C:27]2[C:22](=[CH:23][C:24]([S:28]([NH:1][C:2]3[CH:6]=[CH:5][O:4][N:3]=3)(=[O:30])=[O:29])=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]1=[O:32]
Reactant: O=c1ccc2cc(S(=O)(=O)Cl)ccc2n1-c1ccc(C(F)(F)F)cc1Br
Reactant: Nc1ccon1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1ccc2cc(S(=O)(=O)Nc3ccon3)ccc2n1-c1ccc(C(F)(F)F)cc1Br
Reaction time: 0.5 h
Yield: 33.2 %

Procedure:
A solution of 3-aminoisoxazole (0.380 ml, 5.14 mmol) and 1-(2-bromo-4-(trifluoromethyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonyl chloride (1.200 g, 2.57 mmol) in 10 mL THF was cooled to 0° C. and was treated with LHMDS 1N in THF (2.57 ml, 2.57 mmol). After stirring for 30 minutes, the reaction mixture was concentrated. Purification of the crude residue by reverse phase column chromatography [Puriflash C18, 10-100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] gave 1-(2-bromo-4-(trifluoromethyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.438 g, 0.852 mmol, 33.1% yield) with minor impurities. m/z (ESI) 514.0 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1.[F:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1>>[O:29]=[C:27]1[NH:26][C:25](=[O:30])[CH:24]([CH2:23][C:20]2[CH:19]=[CH:18][C:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][N:9]([CH3:8])[C:36](=[O:37])[C:35]4[CH:39]=[CH:40][C:32]([F:31])=[CH:33][CH:34]=4)[CH:12]=3)=[CH:22][CH:21]=2)[S:28]1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CNCc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1
Solvent: O=C(O)C(F)(F)F
Product: CN(Cc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1)C(=O)c1ccc(F)cc1

Procedure:
In a manner similar to that of Example 37(e), by reacting 1 g (2.2 mmol) of 5-(3′-methylaminomethyl-biphenyl-4-ylmethyl)thiazolidine-2,4-dione trifluoro-acetate with 290 μl (2.5 mmol) of 4-fluorobenzoyl chloride, and after purification, 1 g (98%) of N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-4-fluoro-N-methylbenzamide, with a melting point of 212° C., is obtained.
Reaction SMILES: O=[C:2]1[N:6]([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:8])[CH2:5][CH:4]([C:15](OC)=[O:16])[CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[C:9]1([CH:7]([N:6]2[CH2:2][CH2:3][CH:4]([CH2:15][OH:16])[CH2:5]2)[CH3:8])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COC(=O)C1CC(=O)N(C(C)c2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(c1ccccc1)N1CCC(CO)C1
Yield: 87.2 %

Procedure:
A solution of 10.0 g (40.5 mmol) [3R-(R*,R*)]methyl 5-oxo-1-(-1-phenylethyl)-3-pyrrolidinecarboxylate in 75 ml dry tetrahydrofuran was added dropwise to a mixture of 6.50 g (171 mmol) lithium aluminum hydride in 100 ml tetrahydrofuran. The mixture was refluxed overnight, diluted with 50 ml tetrahydro furan and treated dropwise with 6.5 ml water, 6.5 ml 15% sodium hydroxide and 19.5 ml water. Solids were removed by filtration and the filtrate was evaporated to a syrup which was dissolved in dichloromethane, dried (MgSO4), and reevaporated to give 8.06 g of crude crystalline product. Recrystallization from hexane afforded 7.25 g (87%) of the title compound, mp 86°-88° C. [α]D +51.3° C. (C, 1.06, methanol).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:19])[CH2:6][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:8]([CH3:11])([CH3:10])[CH3:9]>CO>[CH3:17][C:15]([CH3:18])([O:14][C:12]([N:7]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:6][C:5]([OH:19])=[O:4])=[O:13])[CH3:16]
Reactant: COC(=O)CN(C(=O)OC(C)(C)C)C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N(CC(=O)O)C(C)(C)C
Temperature: 25 °C
Reaction time: 40 h
Yield: 84.4 %

Procedure:
Aqueous sodium hydroxide (4M, 5 mL) was added to a solution of N-[(1,1-dimethylethoxy)carbonyl]-N-(1,1-dimethylethyl)glycine methyl ester (Description 158, 2.0 g, 8.2 mmol) in methanol (10 mL) and the mixture was stirred at room temperature for 40 hours. The solvent was evaporated under reduced pressure, hydrochloric acid (2M, 20 mL) was added and the mixture was extracted with dichloromethane (3×40 mL). The combined organic fractions were washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a colorless oil (1.6 g, 88%). 1H NMR (400 MHz, CDCl3) δ 1.41 (9H, s), 1.46 (9H, s), and 4.08 (2H, s).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH3:13][S:14][C:15]1[CH:16]=[C:17]([CH:28]=[CH:29][CH:30]=1)[O:18][C:19]1[N:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([OH:23])=O.[NH2:31][C@H:32]1[CH2:37][CH2:36][CH2:35][CH2:34][C@H:33]1[OH:38].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[OH:38][C@@H:33]1[CH2:34][CH2:35][CH2:36][CH2:37][C@@H:32]1[NH:31][C:21](=[O:23])[C:20]1[CH:24]=[CH:25][CH:26]=[N:27][C:19]=1[O:18][C:17]1[CH:28]=[CH:29][CH:30]=[C:15]([S:14][CH3:13])[CH:16]=1
Reactant: CSc1cccc(Oc2ncccc2C(=O)O)c1
Reactant: N[C@H]1CCCC[C@H]1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1cccc(Oc2ncccc2C(=O)N[C@H]2CCCC[C@H]2O)c1
Reaction time: 18 h
Yield: 48.5 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (293 mg, 1.53 mmol) was added to a solution of 2-(3-methylsulfanyl-phenoxy)-nicotinic acid (200 mg, 0.765 mmol), (1R,2S)-2-aminocyclohexanol hydroformate [8151/195/2] (123 mg, 0.765 mmol), 1-hydroxybenzotriazole (114 mg, 0.842 mmol) and triethylamine (430□l, 3.10 mmol) in dimethylformamide (5 ml) under nitrogen at room temperature. The reaction was stirred for 18 h and partitioned between diethyl ether (25 ml) and water (25 ml). The organic phase was washed with brine (30 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography using ethyl acetate:cyclohexane (50:50 as eluant) to give N-[(1 S,2R)-2-hydroxycyclohexyl]-2-[3-(methylsulfanyl)phenoxy]nicotinamide (133 mg) as a gum.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[C:5](#N)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O>[C:6]1([C:5]2[NH:3][CH2:2][CH2:1][N:4]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NCCN
Reactant: N#Cc1ccccc1
Solvent: O
Product: c1ccc(C2=NCCN2)cc1
Temperature: 200 °C
Yield: 87 %

Procedure:
In a 2,000 ml four-necked flask equipped with a reflux condenser and a thermometer were charged 515 g of benzonitrile and 10 g of titanium diisopropoxybis(acetonate). After addition of 4 g of water, the mixture was heated up to 185°-190° C. with stirring. Then, 300 g of ethylenediamine were added dropwise for 10 hours with stirring while maintaining the temperature at 185° C. or above. After completion of the addition of the diamine, the reaction mixture was heated up to 200° C. and maintained at that temperature for 6 hours. The resulting mixture was then subjected to vacuum distillation at 0.7 mmHg and at 160°-180° C. to obtain 635 g of 2-phenyl-2-imidazoline with a yield of 87%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[CH2:8][CH:7]([NH:13][CH:14]([CH2:18][CH2:19][CH3:20])[C:15]([OH:17])=O)[CH2:6][CH2:5]2.[CH3:21][N:22]([CH3:33])[CH2:23][C:24]([N:27]1[CH:31]=[C:30]([NH2:32])[N:29]=[CH:28]1)([CH3:26])[CH3:25]>>[CH3:33][N:22]([CH3:21])[CH2:23][C:24]([N:27]1[CH:31]=[C:30]([NH:32][C:15](=[O:17])[CH:14]([NH:13][CH:7]2[CH2:6][CH2:5][C:4]3[C:9](=[C:10]([F:12])[CH:11]=[C:2]([F:1])[CH:3]=3)[CH2:8]2)[CH2:18][CH2:19][CH3:20])[N:29]=[CH:28]1)([CH3:26])[CH3:25]
Reactant: CN(C)CC(C)(C)n1cnc(N)c1
Reactant: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)O
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(C)(C)CN(C)C)cn1

Procedure:
Following the procedure for Example 86, 2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid (diastereomer 2) was reacted with 1-(2-Dimethylamino-1,1-dimethyl-ethyl)-1H-imidazol-4-ylamine to afford the title compound: C13 NMR (100 MHz, CDCl3) 14.1, 19.5, 26.2, 28.2, 28.8, 28.9, 29.8, 36.6, 48.0, 52.8, 59.0, 60.9, 70.0, 100.8, 101.1, 101.3, 104.6, 110.7, 110.8, 131.3, 137.4, 172.3; MS m/z 448.3 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[C:5]#[N:6].O.S(=O)(=O)(O)[OH:15].N>C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[C:5]([NH2:6])=[O:15]
Reactant: N#Cc1cc(F)cc([N+](=O)[O-])c1
Reactant: O=S(=O)(O)O
Agent: N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cc(F)cc([N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 24 h
Yield: 36 %

Procedure:
To a solution of 3-fluoro-5-nitrobenzonitrile (1.0 g, 6.02 mmoL) in TFA (8 mL) was added water (1 mL) and conc. sulfuric acid (2 mL). The reaction mixture was heated to 70° C. and stirred for 24 h. Then the reaction mixture was cooled to 0° C. and liquid ammonia solution was added. The solidified solid was filtered through Celite® (diatomaceous earth) and washed with water to obtain 3-fluoro-5-nitrobenzamide (0.400 g, 36%) as an off white solid. Observed mass (M−1): 183.02.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7](/[C:10](=[N:16]/[OH:17])/[C:11]([O:13]CC)=[O:12])=[CH:6][CH:5]=1.Cl[CH2:19][C:20]1[CH:39]=[CH:38][C:23]([O:24][CH2:25][C:26]2[N:27]=[C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:29][C:30]=2[CH3:31])=[CH:22][CH:21]=1.Cl.C(=O)(O)[O-].[Na+]>CN(C)C=O>[F:3][C:4]1[CH:5]=[CH:6][C:7](/[C:10](=[N:16]/[O:17][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:24][CH2:25][C:26]3[N:27]=[C:28]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[O:29][C:30]=3[CH3:31])=[CH:38][CH:39]=2)/[C:11]([OH:13])=[O:12])=[CH:8][CH:9]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: CCOC(=O)/C(=N\O)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\C(=O)O)c2ccc(F)cc2)cc1
Reaction time: 1 h
Yield: 82.8 %

Procedure:
Sodium hydride (60% in oil, 209 mg) was added under a nitrogen atmosphere to a solution of ethyl Z-2-(4-fluorophenyl)-2-hydroxyiminoacetate (920 mg) and 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.37 g) in N,N-dimethylformamide-(10 ml) at room temperature and the mixture was stirred for 1 hour. After adding 1N HCl (7 ml), aqueous sodium bicarbonate was added, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residue was subjected to column chromatography on silica gel to obtain an oil from a fraction eluted with ethyl acetate-hexane (1:3, v/v). This oil was dissolved in tetrahydrofuran (20 ml)-methanol (10 ml), and 1N aqueous solution of sodium hydroxide (10 ml) was added and the mixture was stirred at 40° C. for 2 hours. 1N HCl (10.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residual crystal was recrystallized from ethyl acetate to obtain Z-2-(4-fluorophenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]acetic acid (1.66 g, yield 83%) as colorless crystals. m.p. 182-183° C. (decomposition)
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(N[S:23]([C:26]3[C:31](F)=[CH:30][CH:29]=[CH:28][C:27]=3F)(=[O:25])=[O:24])C=CC=2)C=CN=1.[NH2:34][C:35]1[C:36]([F:57])=[C:37]([C:41]2[N:42]=[C:43]([C:53]([CH3:56])([CH3:55])[CH3:54])[S:44][C:45]=2[C:46]2[CH:51]=[CH:50][N:49]=[C:48]([NH2:52])[N:47]=2)[CH:38]=[CH:39][CH:40]=1.C1(S(Cl)(=O)=O)C=CC=CC=1>>[NH2:52][C:48]1[N:47]=[C:46]([C:45]2[S:44][C:43]([C:53]([CH3:54])([CH3:56])[CH3:55])=[N:42][C:41]=2[C:37]2[C:36]([F:57])=[C:35]([NH:34][S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:40]=[CH:39][CH:38]=2)[CH:51]=[CH:50][N:49]=1
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(N)n2)s1
Agent: O=S(=O)(Cl)c1ccccc1
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3ccccc3)c2F)c(-c2ccnc(N)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 4 4-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine (65 mg, 0.189 mmol) and benzenesulfonyl chloride (0.029 mL, 0.227 mmol), the title compound was obtained as an off white solid (60 mg, 65% yield). MS (ESI): 484 [M+H]+.
Reaction SMILES: [CH2:1]1[C:4]2([CH2:7][CH2:6][CH2:5]2)[C:3](C(O)=O)(C(O)=O)[CH2:2]1.[C:14](=[O:16])=[O:15]>>[CH2:5]1[C:4]2([CH2:1][CH2:2][CH2:3]2)[CH2:7][CH:6]1[C:14]([OH:16])=[O:15]
Reactant: O=C(O)C1(C(=O)O)CCC12CCC2
Reactant: O=C=O
Product: O=C(O)C1CC2(CCC2)C1
Temperature: 220 °C

Procedure:
Crude spiro[3.3]heptane-3,3-dicarboxylic acid (8.3 g, 0.046 mole) was thermally decarboxylated by heating the material at 220° C for 30 min. Heating was discontinued when the evolution of carbon dioxide ceased. The mixture was cooled to yield 5.38 g of spiro[3.3]heptane-2-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][CH2:10]2)=[CH:5][CH:4]=1.C1(=O)[N:19](CC=O)[C:18](=O)[C:17]2=CC=CC=C12.CC([O-])=O.[Na+].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[NH2:19][CH2:18][CH2:17][N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[C:12]([O:13][CH3:14])[C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:10]1
Reactant: O=CCN1C(=O)c2ccccc2C1=O
Reactant: COc1ccc2c(c1OC)CNCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc2c(c1OC)CN(CCN)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
To a solution of 7,8dimethoxy-1,2,3,4-tetrahydroisoquinoline (421 mg, 2.2 mmol), 2-phthalimidoacetaldehyde (410 mg, 2.2 mmol) and NaOAc (180 mg, 2.2 mmol) in 27 mL of CH2Cl2 was added 690 mg (3.25 mmol) of NaBH(OAc)3 in small portions. After stirring 1 hour at room temperature, the reaction mixture was diluted with CH2Cl2 and washed with a saturated Na2CO3 solution and brine. The residue obtained after evaporation of CH2Cl2 was dissolved in 25 mL of EtOH and treated with 1.2 mL of hydrazine hydrate overnight. The reaction mixture was then filtered and evaporated to give 510 mg (100%) of the title compound; MS m/e 327 (M+1).