Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6](=[O:13])[N:7]2[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]2)=O.[N:19]1([C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(O)(=O)C.ClC(Cl)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[C:29]([C:28]1[CH:27]=[CH:26][C:25]([N:19]2[CH2:24][CH2:23][N:22]([CH2:1][C:3]3[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6](=[O:13])[N:7]4[C:12]=3[CH:11]=[CH:10][CH:9]=[CH:8]4)[CH2:21][CH2:20]2)=[CH:32][CH:31]=1)#[N:30]
Reactant: CCOC(=O)c1cc(C=O)c2ccccn2c1=O
Reactant: N#Cc1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(CN2CCN(c3ccc(C#N)cc3)CC2)c2ccccn2c1=O

Procedure:
A mixture of the ethyl 1-formyl-4-oxo-4H-quinolizine-3-carboxylate (0.891 g, 3.63 mmol), 4-piperazin-1-ylbenzonitrile (0.952 g, 5.09 mmol), glacial acetic acid (1.25 mL, 21.8 mmol) and 18.2 mL of dichloroethane was stirred vigorously. To the stirring mixture was added sodium triacetoxyborohydride (1.08 g, 5.09 mmol), which was stirred for 18 hours. The mixture was quenched with a 10% sodium carbonate solution, extracted with dichloromethane (1×40 mL), and partitioned between water and dichloromethane. The organic layer was dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography eluting with EtOAc to yield ethyl 1-{[4-(4-cyanophenyl)piperazin-1-yl]methyl}-4-oxo-4H-quinolizine-3-carboxylate.
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:9](SC)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:27]([NH2:35])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CO>[C:21]([O:20][C:18]([N:10]1[C@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[C:9]1[NH:35][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: NCCc1ccccc1
Reactant: CSC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1C(=O)OC(C)(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)N1C(NCCc2ccccc2)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Temperature: 100 °C
Yield: 44.2 %

Procedure:
A mixture of intermediate 59 (2.0 g, 5.43 mmol), phenethylamine (2.04 mL, 16.3 mmol) and MeOH (0.5 mL) is heated at 100° C. for 2 days. The reaction mixture is cooled to RT, and is purified by chromatography on silica gel; gradient elution with heptane:EtOAc (75:25-60:40) gives 1.06 g of the product 93. 1H NMR (CDCl3) δ 7.40-7.30 (m, 4 H), 7.30-7.10 (m, 2 H), 7.10-6.90 (m, 8 H), 6.80-6.65 (m, 2 H), 5.45-5.25 (m, 2 H), 3.90-3.60 (m, 2 H), 3.05 (t, 2 H), 1.13 (s, 9 H); MS: m/z 442 (M++1).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.[Cl:31][C:32]1[N:37]=[C:36](Cl)[CH:35]=[CH:34][N:33]=1>CC#N>[Cl:31][C:32]1[N:37]=[C:36]([O:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[CH:4][CH:3]=2)[CH:35]=[CH:34][N:33]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c2ccccc12
Reactant: Clc1ccnc(Cl)n1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(Cl)n2)c2ccccc12
Yield: 35.7 %

Procedure:
To a degassed solution of tert-butyl 4-hydroxynaphthalen-1-ylcarbamate (13.3 g, 51.3 mmol) and DBU (12.6 mL, 51.3 mmol) in MeCN (80 mL) under nitrogen was added 2,4-dichloropyrimidine (7.65 g, 51.3 mmol) in acetonitrile (19 mL) and the reaction mixture was heated to reflux for 4 hr. The solvent was evaporated in vacuo and the residue was taken up into DCM (100 mL) and was washed with water (2×100 mL) and brine (100 mL), then dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 330 g, EtOAc in isohexane, 0-50%, gradient elution) to afford the title compound as a pale pink solid (6.80 g, 34%); Rt 2.50 min (Method 2); m/z 372/374 (M+H)+, (ES+)+.
Reaction SMILES: C([C:5]1[C:10]([NH2:11])=[C:9]([N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:13]2)[CH:8]=[CH:7][N:6]=1)(C)(C)C.[NH2:26][C:27]1[C:28]([C:34](O)=[O:35])=[N:29][C:30]([Br:33])=[CH:31][CH:32]=1>>[NH2:26][C:27]1[C:28]([C:34]([NH:11][C:10]2[CH:5]=[N:6][CH:7]=[CH:8][C:9]=2[N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([O:18][Si:19]([C:22]([CH3:23])([CH3:24])[CH3:25])([CH3:21])[CH3:20])[CH2:13]2)=[O:35])=[N:29][C:30]([Br:33])=[CH:31][CH:32]=1
Reactant: CC(C)(C)c1nccc(N2CCCC(O[Si](C)(C)C(C)(C)C)C2)c1N
Reactant: Nc1ccc(Br)nc1C(=O)O
Product: CC(C)(C)[Si](C)(C)OC1CCCN(c2ccncc2NC(=O)c2nc(Br)ccc2N)C1

Procedure:
Following Method 11 of Example 305, tert-butyl (+/−)-4-(3-(tert-butyldimethylsilyloxy)piperidin-1-yl)pyridin-3-amine was coupled to 3-amino-6-bromopicolinic acid yielding 3-amino-6-bromo-N-(4-(3-(tert-butyldimethylsilyloxy)piperidin-1-yl)pyridin-3-yl)picolinamide. LCMS (m/z): 506.2 (MH+); LC Rt=4.03 min.
Reaction SMILES: C(OC(=O)[N:10]([CH2:25][CH3:26])[C:11]1[C:16]([O:17][CH3:18])=[CH:15][C:14]([C:19]([O:21][CH3:22])=[O:20])=[CH:13][C:12]=1[O:23][CH3:24])C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:22][O:21][C:19](=[O:20])[C:14]1[CH:15]=[C:16]([O:17][CH3:18])[C:11]([NH:10][CH2:25][CH3:26])=[C:12]([O:23][CH3:24])[CH:13]=1
Reactant: [H][H]
Reactant: CCN(C(=O)OCc1ccccc1)c1c(OC)cc(C(=O)OC)cc1OC
Agent: [Pd]
Solvent: CO
Product: CCNc1c(OC)cc(C(=O)OC)cc1OC

Procedure:
A suspension of 77.5 g. of N-ethyl-2,6-dimethoxy-4-(methoxy-carbonyl)carbanilic acid benzyl ester in 1 liter of methanol was hydrogenated in the presence of 2 g. of palladium on carbon (5%) until hydrogen uptake ceased. The suspension was heated to boiling and filtered. The filtrate was evaporated under vacuum. After recrystallization of the residue from cyclohexane, there was obtained 4-(ethylamino)-3,5-dimethoxy-benzoic acid methyl ester having a melting point of 50°-51° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:28])[CH:12]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[S:8][CH:9]=1>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:28])[CH:12]([C:19]2[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=2)[CH2:13][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18]2)[S:8][CH:9]=1
Reactant: COC(=O)Cc1csc(NC(=O)C(CC2CCCC2)c2ccc([N+](=O)[O-])cc2)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)Cc1csc(NC(=O)C(CC2CCCC2)c2ccc(N)cc2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.5 %

Procedure:
A solution of {2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazol-4-yl}-acetic acid methyl ester (prepared as in Example 24, 75.3 mg, 0.18 mmol) in ethyl acetate (25 mL) was treated with 10% palladium on activated carbon. The reaction mixture was stirred under hydrogen gas at 60 psi at 25° C. for 4 h. The catalyst was then filtered off through a pad of celite, which was washed well with ethyl acetate. The resulting filtrate was concentrated in vacuo to give {2-[2-(4-amino-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl}-acetic acid methyl ester (64.5 mg, 93.3%) as a tan oil: EI-HRMS m/e calcd for C20H25N3O3S (M+) 387.1616, found 387.1612.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:14][C:13](CO)([C:15]([OH:17])=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([CH2:15][O:17][S:21]([CH3:20])(=[O:23])=[O:22])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CC(CO)(C(=O)O)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CN(C(=O)OCc2ccccc2)C1

Procedure:
3-Hydroxymethyl-azetidine-1,3-dicarboxylic acid monobenzyl ester (6.6 g) was dissolved in CH2Cl2 (100 mL) and brought to −15 C. While stirring, TEA was added (3 eq, 9.43 g) followed by methanesulphonic chloride (2.0 eq, 7.69 g) and allowed to come to RT and stirred for 1 h. The resulting organic solution was extracted with water (3×100 mL). The organic layer was dried over Na2SO4 and evaporated to give the desired product as a clear oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[CH:17]=[C:16]([S:18][C:19]([F:22])([F:21])[F:20])[C:15]([CH:23]([OH:25])[CH3:24])=[N:14]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.CCOCC>ClCCl>[C:23]([C:15]1[C:16]([S:18][C:19]([F:20])([F:21])[F:22])=[CH:17][N:13]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:9])([F:11])[F:10])=[CH:5][C:4]=2[Cl:12])[N:14]=1)(=[O:25])[CH3:24]
Reactant: CC(O)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1SC(F)(F)F
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1SC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.5 %

Procedure:
To a solution of 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-(1-hydroxyethyl)-4-trifluoromethylthiopyrazole (1.1 g) in dichloromethane (40 ml) was added pyridinium chlorochromate (0.62 g), and the mixture stirred at room temperature overnight. Ether (50 ml) was added and the mixture filtered on diatomaceous earth. Evaporation of the filtrate in vacuo gave a brown solid, which was triturated with hexane and filtered. The filtrate was evaporated in vacuo to give a yellow solid, which recrystallised from cyclohexane to give 3-acetyl-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylthiopyrazole (0.4 g) in the form of a yellow solid, m.p. 89-91° C.
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][C:5]1[CH:10]=[C:9]([O:11][CH:12]([F:14])[F:13])[C:8]([O:15][CH3:16])=[CH:7][C:6]=1[Br:17].[OH-].[Li+].Cl>CO.O>[Br:17][C:6]1[CH:7]=[C:8]([O:15][CH3:16])[C:9]([O:11][CH:12]([F:14])[F:13])=[CH:10][C:5]=1[CH2:4][C:3]([OH:18])=[O:2]
Reactant: COC(=O)Cc1cc(OC(F)F)c(OC)cc1Br
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(Br)c(CC(=O)O)cc1OC(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.4 %

Procedure:
(2-Bromo-5-difluoromethoxy-4-methoxy-phenyl)-acetic acid methyl ester (400 mg) was dissolved in 5 ml methanol and treated with 150 mg lithium hydroxide in 1 ml of water. The mixture was stirred at room temperature for 18 hours, acidified with 10% aqueous hydrochloric acid, filtered and dried to yield 350 mg of (2-bromo-5-difluoromethoxy-4-methoxy-phenyl)-acetic acid.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:29][C:30]([NH2:32])=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34].O.N>ClCCl>[C:33]([N:25]1[CH2:26][CH2:27][CH2:28][N:22]([C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:13]3[N:12]=[CH:11][C:10]([CH2:29][C:30]([NH2:32])=[O:31])=[C:9]([NH:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:14]=3)=[CH:21][CH:20]=2)[CH2:23][CH2:24]1)(=[O:35])[CH3:34]
Reactant: NC(=O)Cc1cnc(Nc2ccc(N3CCCNCC3)cc2)cc1NCc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: N
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1CCCN(c2ccc(Nc3cc(NCc4ccccc4)c(CC(N)=O)cn3)cc2)CC1
Reaction time: 0.5 h
Yield: 72.9 %

Procedure:
25 mg of 4-(benzylamino)-6-{[4-(1,4-diazepan-1-yl)phenyl]amino}pyridine-3-carboxyamide (the compound of Example 226) was dissolved in 1.5 mL of dichloromethane, to which, under ice cooling, 15.1 mg of acetic anhydride was added, and stirred for 30 minutes. To the reaction mixture 1.5 mL of ammonia water was added, extracted with chloroform, the extract was washed with saturated saline, and dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel thin layer chromatography (chloroform:methanol=10:1), recrystallized from chloroform-methanol-diethylether to obtain 20 mg (73%) of the title compound as light brown needle crystals.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([O:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[NH:19][C:18]4=[O:25])[C:11](O)=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:38]([C:42]1[CH:47]=[CH:46][C:45]([S:48]([NH2:51])(=[O:50])=[O:49])=[CH:44][CH:43]=1)([CH3:41])([CH3:40])[CH3:39].N12CCCN=C1CCCCC2>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([O:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[NH:19][C:18]4=[O:25])[C:11]([NH:51][S:48]([C:45]3[CH:46]=[CH:47][C:42]([C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:43][CH:44]=3)(=[O:49])=[O:50])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)c1ccc(S(N)(=O)=O)cc1
Reactant: O=C1NC(=O)c2cc(OC(C(=O)O)c3ccc4c(c3)OCO4)ccc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)c1ccc(S(=O)(=O)NC(=O)C(Oc2ccc3c(c2)C(=O)NC3=O)c2ccc3c(c2)OCO3)cc1
Reaction time: 1 h

Procedure:
A solution of 1 g of 2-(1,3-benzodioxol-5-yl)-2-(1,3-dihydro-1,3-dioxoisoindol-5-yloxy)acetic acid and 0.71 g of carbonyldiimidazole in 100 ml of THF is heated at 60° for 2 hours. 0.93 g of 4-tert-butylbenzenesulfonamide and 0.67 g of 1,8-diaza-bicyclo[5.4.0]-undec-7-ene are then added and the mixture is stirred for a further 1 hour at this temperature. After customary working up, 2-(1,3-benzodioxol-5-yl)-2-(1,3-dihydro-1,3-dioxo-isoindol-5-yloxy)-N-(4-tert-butylphenylsulfonyl)acetamide, m.p. 215°, is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[CH2:11]3)=[CH:4][CH:3]=1.[F:26][C:27]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:28]=1[C:29](Br)=[O:30]>>[F:26][C:27]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:28]=1[C:29]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[CH2:11]3)=[CH:4][CH:3]=1)=[O:30]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Reactant: O=C(Br)c1ccc(F)cc1F
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)c4ccc(F)cc4F)cc3)ccc2C1=O

Procedure:
The compound of example 316 was prepared analogous to compound of example 304 by reaction of compound of example 223 with 2,4-difluoro benzoyl bromide. The compound of example 316 was used directly without isolation, for the preparation of compound of example 317.
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]2[C:12]([C:13](=[O:15])[CH:14]=1)=[CH:11][CH:10]=[C:9]([OH:16])[C:8]=2[CH2:17][CH2:18][CH3:19])([O:3][CH3:4])=[O:2].[CH2:20]([C:23]1[C:35]([OH:36])=[C:34]([C:37](=[O:39])[CH3:38])[CH:33]=[CH:32][C:24]=1[O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br)[CH2:21][CH3:22]>>[C:1]([C:5]1[O:6][C:7]2[C:12]([C:13](=[O:15])[CH:14]=1)=[CH:11][CH:10]=[C:9]([O:16][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][O:25][C:24]1[CH:32]=[CH:33][C:34]([C:37](=[O:39])[CH3:38])=[C:35]([OH:36])[C:23]=1[CH2:20][CH2:21][CH3:22])[C:8]=2[CH2:17][CH2:18][CH3:19])([O:3][CH3:4])=[O:2]
Reactant: CCCc1c(OCCCCCBr)ccc(C(C)=O)c1O
Reactant: CCCc1c(O)ccc2c(=O)cc(C(=O)OC)oc12
Product: CCCc1c(OCCCCCOc2ccc3c(=O)cc(C(=O)OC)oc3c2CCC)ccc(C(C)=O)c1O
Yield: 66.7 %

Procedure:
Using the procedure of Example 2, 5.25 g (20 mmoles) of 2-carbomethoxy-7-hydroxy-8-propylchromone and 8.24 g (24 mmoles) of 5-(2-n-propyl-3-hydroxy-4-acetylphenoxy)-1-bromopentane gave 7.0 g (66%) of the title compound, mp 86°-87° C. Calc: C, 68.69; H, 6.92; Found: C, 68.80; H, 6.89.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]([N+:15]([O-])=O)[CH2:12][N:11]([CH3:18])[CH2:10][CH:9]1[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](O)(=[O:22])[CH3:21]>C(O)C.[Ni]>[C:20]([NH:15][CH:13]1[CH2:14][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:9]([CH3:19])[CH2:10][N:11]([CH3:18])[CH2:12]1)(=[O:22])[CH3:21]
Reactant: CC1CN(C)CC([N+](=O)[O-])CN1Cc1ccccc1
Reactant: CC(=O)O
Agent: [Ni]
Solvent: CCO
Product: CC(=O)NC1CN(C)CC(C)N(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-Benzyl-2,4-dimethyl-6-nitrohexahydro-1H-1,4-diazepine (5.1 g) is dissolved in ethanol (100 ml) and acetic acid (5 ml) and hydrogenerated over Raney-nickel (about 1 g) at 25° C. After the calculated amount of the hydrogen is absorbed, the catalyst is filtered off. The filtrate is evaporated under reduced pressure. The residue is dissolved in chloroform (100 ml), and acetic anhydride (4.0 g) is added to the solution. The reaction mixture is stirred for 2 hours at 25° C., diluted with aqueous sodium hydroxide solution, and extracted with chloroform. The organic layer is washed successively with water, aqueous sodium hydroxide solution, and saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent is evaporated under reduced pressure, the residue is chromatographed on silica gel with.elution of chloroform-methanol (9:1). Fractions containing the object compound are pooled and evaporated under reduced pressure to give 6-acetylamino-1-benzyl-2,4-dimethylhexahydro-1H-1,4-diazepine (1.8 g) as an oil. The above compound is dissolved in 10% hydrochloric acid (20 ml) and is refluxed for 2 hours. After cooling, the reaction mixture is basified with aqueous sodium hydroxide solution and extracted with chloroform. The organic layer is washed successively with water and saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent is evaporated under reduced pressure to give the title compound (1.5 g).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[CH:12]=[CH:11][C:10]=1[N:20]1[S:24](=[O:26])(=[O:25])[NH:23][C:22](=[O:27])[CH2:21]1)C1C=CC=CC=1.B(Br)(Br)Br.O>C(Cl)Cl>[OH:8][C:9]1[CH:14]=[C:13]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[CH:12]=[CH:11][C:10]=1[N:20]1[S:24](=[O:26])(=[O:25])[NH:23][C:22](=[O:27])[CH2:21]1
Reactant: O=C1CN(c2ccc(-c3nccs3)cc2OCc2ccccc2)S(=O)(=O)N1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=C1CN(c2ccc(-c3nccs3)cc2O)S(=O)(=O)N1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 5-(2-benzyloxy-4-thiazol-2-yl-phenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (50 mg, 0.125 mmol) in CH2Cl2 (5 mL) at −10° C. is added BBr3 (1.0M in CH2Cl2, 0.68 mL) dropwise. The yellow mixture is stirred at −10° C. for 30 min. Water is added to the reaction mixture and the aqueous layer is separated and neutralized with 1N NaOH. The water is removed under reduced pressure and the residue is purified by reverse phase HPLC (MeCN/water/0.1% TFA) to afford the title compound as a light yellow solid: 1H NMR (D24.45 (s, 1H), 7.48-7.54 (m, 3H), 7.61 (d, J=4 Hz, 1H), 7.85 (d, J=4 Hz, 1H); (M−1)−=310.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:12][N:7]2[CH2:8][CH2:9][NH:10][CH2:11][C@@H:6]2[CH2:5][CH2:4]1.Cl[C:14]1[N:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[OH:1][CH2:2][C@@H:3]1[CH2:12][N:7]2[CH2:8][CH2:9][N:10]([C:14]3[N:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=3)[CH2:11][C@@H:6]2[CH2:5][CH2:4]1
Reactant: Fc1cnc(Cl)nc1
Reactant: OC[C@H]1CC[C@H]2CNCCN2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: OC[C@H]1CC[C@H]2CN(c3ncc(F)cn3)CCN2C1
Temperature: 25 °C
Yield: 74.5 %

Procedure:
A mixture of 2.31 g (13.6 mmol) of (7S,9aS)-7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (Preparation 2), 1.98 g (15.0 mmol) of 2-chloro-5-fluoropyrimidine (B. Baasner, E. Klauke, J. Fluorine Chem., 1989, 45, 417), 4.32 g (40.8 mmol) of sodium carbonate and 50 mL of water was heated at reflux for 16 h. The mixture was cooled to room temperature and extracted with chloroform (3×). The combined organic layers were dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with 95:5 chloroform:methanol gave 2.7 g (75%) of the title compound. mp (base) 111-112° C. 13C NMR (base, CDCl3): δ26.5, 27.3, 34.2, 44.3, 49.8, 54.8, 58.8, 60.7, 68.2, 145.0, 145.3, 149.9, 153.2, 158.6. HRMS calcd for C13H19FN4O: 266.1543, found: 266.1530.
Reaction SMILES: CI.[C:3](=O)([O-])[O-].[K+].[K+].[CH2:9]([O:12][C:13](=[O:45])[CH:14]([CH2:32][CH2:33][N:34]1[C:38](=[O:39])[C:37]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:36]2[C:35]1=[O:44])[NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH:10]=[CH2:11]>CN(C)C=O>[CH2:9]([O:12][C:13](=[O:45])[CH:14]([CH2:32][CH2:33][N:34]1[C:38](=[O:39])[C:37]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:36]2[C:35]1=[O:44])[N:15]([CH3:3])[S:16]([C:19]1[CH:20]=[CH:21][C:22]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:23][CH:24]=1)(=[O:17])=[O:18])[CH:10]=[CH2:11]
Reactant: C=CCOC(=O)C(CCN1C(=O)c2ccccc2C1=O)NS(=O)(=O)c1ccc(Oc2ccccc2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: C=CCOC(=O)C(CCN1C(=O)c2ccccc2C1=O)N(C)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
Methyl iodide (0.83 g, 5.8 mmol) and potassium carbonate (5.34 g, 38.4 mmol) were added to a solution of (±)-N-(4-phenoxybenzenesulfonyl)-2-(2-phthalimidoethyl)glycine allyl ester (2.00 g, 3.8 mmol), the product of (2) above, in N,N-dimethylformamide (20 ml). This mixture was stirred at room temperature for 1 hour. The insoluble material was removed by filtration. The filtrate was extracted with ethyl acetate and the organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=3/1 as the eluant to afford the desired compound (1.90 g, yield 93%) as a colorless oil.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][C:5]1[S:9][C:8]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=1.[BH4-].[Na+]>O1CCCC1.CO>[CH3:2][NH:3][CH2:4][C:5]1[S:9][C:8]([CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[OH:11])=[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=1
Reactant: CNCc1cc(-c2ccccc2)c(C(=O)c2ccccc2)s1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CNCc1cc(-c2ccccc2)c(C(O)c2ccccc2)s1
Reaction time: 3 h
Yield: 43 %

Procedure:
The free base of {5-[(methylamino)methyl]-3-phenyl-2-thienyl}(phenyl)methanone (274 mg) obtained in Example 13 was dissolved in tetrahydrofuran (3 mL) and methanol (2 mL), and sodium borohydride (51 mg) was added at room temperature. After stirring for 3 hr, the solvent was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent:hexane-ethyl acetate=1:1→1:9) to give a free base of the title compound (106 mg) as a pale-yellow oil. To a solution of fumaric acid (40 mg) in ethanol (3 mL) was added a solution of the obtained free base in ethyl acetate (4 mL), and the solvent was evaporated under reduced pressure. The residue was crystallized from a mixed solvent of ethyl acetate and 2-propanol and recrystallized from ethanol to give the title compound as colorless crystals (yield 40 mg, yield 32%).