Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([O:10]C)[CH:7]=[CH:6][C:4]=1[NH2:5].C[O:13][C:14]1[CH:22]=[CH:21][C:17](C(Cl)=O)=[CH:16][CH:15]=1>>[OH:13][C:14]1[CH:22]=[CH:21][C:17]([C:1]2[O:2][C:3]3[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:4]=3[N:5]=2)=[CH:16][CH:15]=1
Reactant: COc1ccc(N)c(OC)c1
Reactant: COc1ccc(C(=O)Cl)cc1
Product: Oc1ccc(-c2nc3ccc(O)cc3o2)cc1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 1, from 2,4-dimethoxyaniline, and 4-methoxybenzoyl chloride and was obtained as a white solid, m.p. greater than 300° C.; MS m/e 226 (M−H)+.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH2:21][CH2:20][C:15]4([O:19][CH2:18][CH2:17][O:16]4)[CH2:14][CH2:13]3)=[CH:8][CH:7]=2)=[N:4][N:3]=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>CN(C=O)C>[CH2:33]([O:32][C:30](=[O:31])[CH2:29][N:3]1[N:2]=[N:1][C:5]([C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH2:13][CH2:14][C:15]4([O:19][CH2:18][CH2:17][O:16]4)[CH2:20][CH2:21]3)=[CH:8][CH:7]=2)=[N:4]1)[CH3:34].[CH2:33]([O:32][C:30](=[O:31])[CH2:29][N:4]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH2:13][CH2:14][C:15]4([O:19][CH2:18][CH2:17][O:16]4)[CH2:20][CH2:21]3)=[CH:8][CH:7]=2)=[N:1][N:2]=[N:3]1)[CH3:34]
Reactant: c1cc(N2CCC3(CC2)OCCO3)ccc1-c1nnn[nH]1
Reactant: CCOC(=O)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1nnc(-c2ccc(N3CCC4(CC3)OCCO4)cc2)n1
Product: CCOC(=O)Cn1nnnc1-c1ccc(N2CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Yield: 16 %
Yield: 73 %

Procedure:
To a solution of 8-[4-(1H-tetrazol-5-yl)-phenyl]-1,4-dioxa-8-aza-spiro[4.5]decane (0.57 g, 2 mmol) (which was obtained in Example 46) in DMF (10 mL) was added cesium carbonate (0.81 g, 2.5 mmol) and ethyl iodoacetate (0.43 g, 2 mmol). The mixture was stirred at room temperature over night, then the reaction was quenched with water, extracted with ethyl acetate. The products from the organic phase was seperated by silica gel chromatography (ethyl acetate/hexanes) to yield ethyl{5-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl]-2H-tetraazol-2-yl}acetate as a colorless crystal (0.55 g, 73%) and ethyl{5-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl]-1H-tetraazol-1-yl}acetate as a gum (0.12 g, 16%).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:3]=1[O:4][C:5]1[C:10]([C:11]([NH:13][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[NH:22][CH2:21][CH2:20][CH2:19]3)=[O:12])=[CH:9][N:8]=[CH:7][CH:6]=1.[CH3:29]CCCCCC.C(OCC)(=O)C>>[Cl:1][C:2]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]([CH3:29])[C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[NH:22][CH2:21][CH2:20][CH2:19]3)=[O:12])=[CH:9][N:8]=[CH:7][CH:6]=1
Reactant: CCCCCCC
Reactant: O=C(Nc1cccc2c1NCCC2)c1cnccc1Oc1cc(Cl)ccc1Cl
Solvent: CCOC(C)=O
Product: CN(C(=O)c1cnccc1Oc1cc(Cl)ccc1Cl)c1cccc2c1NCCC2

Procedure:
The title compound was prepared in analogy to Example 12, from 4-(2,5-dichloro-phenoxy)-N-(1,2,3,4-tetrahydro-quinolin-8-yl)-nicotinamide (Example 22) and using a gradient of n-heptane:ethyl acetate (100:0 to 0:100) for the chromatographic purification. Colorless foam (42%). MS (ESI): m/z=428.092 [M+H]+.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[S:15][C:16]([C:19]#[N:20])=[CH:17][N:18]=3)[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:22][C:23]([NH:25][CH:26]1[CH2:28][CH2:27]1)=[O:24]>C(Cl)(Cl)Cl>[C:19]([C:16]1[S:15][C:14]([NH:13][C:9]2[N:10]=[CH:11][N:12]=[C:7]([N:1]3[CH2:6][CH2:5][N:4]([CH2:22][C:23]([NH:25][CH:26]4[CH2:28][CH2:27]4)=[O:24])[CH2:3][CH2:2]3)[CH:8]=2)=[N:18][CH:17]=1)#[N:20]
Reactant: N#Cc1cnc(Nc2cc(N3CCNCC3)ncn2)s1
Reactant: O=C(CBr)NC1CC1
Solvent: ClC(Cl)Cl
Product: N#Cc1cnc(Nc2cc(N3CCN(CC(=O)NC4CC4)CC3)ncn2)s1
Temperature: 100 °C

Procedure:
12-3 (0.2 g, 0.39 mmol) and 2-bromo-N-cyclopropylacetamide 38-1 (0.069 g, 0.39 mmol) were suspended in chloroform/2M Na2CO3 in a sealed tube and heated in a Smith Personal Chemistry microwave reactor at 100° C. for 20 minutes. The solid was then filtered off and purified on a silica column to afford 38-2. Hi-Res MS: calc: 385.1554 found: 385.1548. 1H-NMR (CD3OD): 8.39(s, 1H); 7.99(s, 1H); 6.14(s, 1H); 3.68(m, 4H); 3.05(s, 2H); 2.70(m, 1H); 2.58(m, 4H); 0.75(m, 2H); 0.55(m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[CH:11][NH:10][N:9]=2)=[C:4]([F:13])[C:3]=1[CH3:14].[O:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1>O1CCCC1.C(OCC)(=O)C.CS(O)(=O)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20][O:15]3)[CH:11]=[N:10][N:9]=2)=[C:4]([F:13])[C:3]=1[CH3:14]
Reactant: Cc1c(Br)ccc(-c2nc[nH]n2)c1F
Reactant: C1=COCCC1
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(Br)ccc(-c2nncn2C2CCCCO2)c1F
Temperature: 85 °C
Reaction time: 20 h
Yield: 94.8 %

Procedure:
Methanesulfonic acid (0.090 mL, 1.390 mmol) was added to a stirred solution of 3-(4-bromo-2-fluoro-3-methylphenyl)-1H-1,2,4-triazole (7.0 g, 27.3 mmol) and 3,4-dihydro-2H-pyran (12.68 mL, 139 mmol) in tetrahydrofuran (33 mL). The resulting mixture stirred at 85° C. under a reflux condenser under nitrogen for 20 h. The mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified using flash chromatography (20-30-50% ethyl acetate in hexane). Product containing fractions were combined and solvent removed under reduced pressure to afford desired product (8.8 g, 95% yield) as a yellow solid. MS (ESI) m/z 340.0 [M]+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C@@:12]3([CH2:17][CH2:16][N:15]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21](I)[CH:20]=4)[C@@H:14]([CH3:26])[CH2:13]3)[C:11]([NH:27][CH3:28])=[N:10][C:9]2=[O:29])[CH:5]=[CH:6][CH:7]=1.[C:30]1([CH3:39])[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O.C([O-])([O-])=O.[K+].[K+].[ClH:46]>>[Cl-:46].[Cl-:46].[F:1][C:2]1[CH:3]=[C:4]([N:8]2[C@@:12]3([CH2:17][CH2:16][NH+:15]([CH2:18][C:19]4[CH:20]=[C:21]([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=5[CH3:39])[CH:22]=[CH:23][CH:24]=4)[C@@H:14]([CH3:26])[CH2:13]3)[C:11]([NH2+:27][CH3:28])=[N:10][C:9]2=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: CNC1=NC(=O)N(c2cccc(F)c2)[C@@]12CCN(Cc1cccc(I)c1)[C@@H](C)C2
Reactant: Cl
Reactant: Cc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C[NH2+]C1=NC(=O)N(c2cccc(F)c2)[C@@]12CC[NH+](Cc1cccc(-c3ccccc3C)c1)[C@@H](C)C2
Product: [Cl-]
Temperature: 120 °C

Procedure:
A Biotage microwave vial was charged with intermediate (5R,7S)-1-(3-fluorophenyl)-8-(3-iodobenzyl)-7-methyl-4-(methylamino)-1,3,8-triazaspiro[4.5]dec-3-en-2-one (60 mg, 0.118 mmol) from step 3 above, PdCl2dppf (4.3 mg, 0.01 mmol) and 2-tolylboronic acid (21 mg, 0.15 mmol). The vial was sealed and put under a nitrogen atmosphere. To the solids was added aqueous 1.5M K2CO3 (0.24 mL, 0.35 mmol) and degassed THF (0.7 mL). The mixture was briefly vortexed and heated in an Optimizer microwave for 5 min. at 120° C. The reaction enclosure was removed and the reaction diluted with EtOAc and water. The organic layer was washed with brine, dried over Na2SO4 and the solvent removed under reduce pressure. Purification over silica via automated flash chromatography (0 to 10% MeOH/CH2Cl2) afforded, after solvent removal under reduced pressure, the product as a white solid. The salt was prepared by mixing the free base with ethereal HCl and evaporating to give the product as a solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[CH3:20])[N:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:21])[C:3]=1[CH2:22][CH2:23]Cl>NC(CC)CC>[CH2:7]([CH:6]([N:5]1[C:2]2[C:11]3[CH:10]=[CH:9][N:8]=[C:7]([C:12]4[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=4[CH3:20])[C:6]=3[N:5]=[C:4]([CH3:21])[C:3]=2[CH2:22][CH2:23]1)[CH2:11][CH3:10])[CH3:12]
Reactant: Cc1cc(C)c(-c2nccc3c(Cl)c(CCCl)c(C)nc23)c(C)c1
Agent: CCC(N)CC
Product: CCC(CC)N1CCc2c(C)nc3c(-c4c(C)cc(C)cc4C)nccc3c21
Reaction time: 8 h
Yield: 198.9 %

Procedure:
A solution of 4-chloro-3-(2-chloroethyl)-8-mesityl-2-methyl[1,7]naphthyridine (100 mg, 0.28 mmol) in 3-aminopentane (5.0 mL) was stirred at 200° C. for six hours in a sealed tube. After overnight, the residue was purified by silica gel column chromatography (30-50% ethyl acetate/hexane), to give the title compound (104 mg) as pale brown crystals.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[OH:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[C:15]([CH3:18])[CH:14]=[CH:13]2.[Cl:19][C:20]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[C:24]([Cl:31])[C:21]=1[CH2:22]Br.O>CN(C=O)C>[Cl:19][C:20]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[C:24]([Cl:31])[C:21]=1[CH2:22][O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[C:15]([CH3:18])[CH:14]=[CH:13]2
Reactant: O=[N+]([O-])c1ccc(Cl)c(CBr)c1Cl
Reactant: Cc1ccc2cccc(O)c2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2cccc(OCc3c(Cl)ccc([N+](=O)[O-])c3Cl)c2n1
Reaction time: 0.5 h

Procedure:
Cs2CO3 (10.8 g, 33.3 mmol) was added at room temperature to 8-hydroxy-2-methylquinoline (5 g, 33.3 mmol) in DMF (65 ml). After 30 min, 2,6-dichloro-3-nitrobenzyl bromide (13 g, 45.6 mmol) was added. After 18 h, H2O was added and the precipitate was filtered off with suction and washed with EA (50 ml), the title compound being obtained as an amorphous substance.
Reaction SMILES: BrCBr.[NH2:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]2[NH:11][N:12]=[CH:13][C:6]=12.N(OCCC(C)C)=O.C(N(CC)CC)C.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40]N[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][N:4]([C:5]2[N:10]=[CH:9][N:8]=[C:7]3[NH:11][N:12]=[CH:13][C:6]=23)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]
Reactant: Nc1ncnc2[nH]ncc12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(C)CCON=O
Solvent: BrCBr
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc3[nH]ncc23)CC1
Reaction time: 3 h
Yield: 2.3 %

Procedure:
A dibromomethane suspension (5 mL) of commercially available 4-aminopyrazolo[3,4-d]pyrimidine (420.8 mg, 3.11 mmol) was heated to 80° C., and isoamyl nitrite (0.43 mL, 3.20 mmol) was added thereto, followed by stirring at the same temperature for 3 hours. Isoamyl nitrite (0.43 mL, 3.20 mmol) was further added thereto, followed by heating under reflux for 3.5 hours, and then the insoluble matter was removed by filtration. The filtrate was concentrated, the resulting residue was dissolved in dimethylformamide (5 mL), and then triethylamine (2.00 mL, 14.3 mmol) and N-tert-butoxycarbonylpiperazine (1.00 g, 5.37 mmol) were added thereto, followed by stirring at room temperature overnight. After the reaction solution was concentrated, the resulting residue was purified by silica gel column chromatography to give the target compound (20.4 mg, 0.07 mmol).
Reaction SMILES: [S:1]1[C:5](=[O:6])[CH2:4][C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]1=2.[OH-].[Na+].[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1.C(O)(=[O:24])C>O>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][S:1][C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=2[CH2:4][C:5]([OH:24])=[O:6])=[CH:16][CH:15]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CC(=O)O
Reactant: O=C1Cc2ccccc2S1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)Cc1ccccc1SCc1ccc(Cl)cc1

Procedure:
Benzo[b]thiophen-2(3H)-one (6 g) and sodium hydroxide (3.2 g) were refluxed in water (40 ml) for one hour. 4-Chlorobenzyl chloride (6.44 g) was added and the mixture refluxed for a further 11/2 hours and allowed to cool overnight. Water (25 ml) was added, followed by acetic acid (100 ml). The solid was collected, washed with water and dried to give [2-(4-chlorobenzylthio)phenyl]-acetic acid, m.p. 149°-51°. A solution of this product (10.4 g) in methanol (250 ml) containing concentrated sulphuric acid (0.5 ml) was heated under reflux overnight and excess methanol evaporated. Ether and water were added and the organic phase was washed with aqueous sodium hydroxide, dried and evaporated. The product which solidified was re-crystallised from hexane to give the methyl ester of the starting acid, m.p. 52°-4°. This was treated with methyl formate and sodium hydride in a similar manner to the procedure described in Example 1 to give methyl (E)-3-methoxy- 2-[2-(4-chlorobenzylthio)phenyl]-prop-2-enoate, m.p. 81°-4°, (Compound 3) and the corresponding Z-isomer, m.p. 127°-8°. (Compound 4), which were separated by silica gel column chromatography.
Reaction SMILES: C([O:8][C:9](=[O:36])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:21][C:20](=[O:22])[N:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=3[O:32][CH3:33])[S:18]2(=[O:35])=[O:34])=[CH:12][CH:11]=1)C1C=CC=CC=1.[H][H]>CCOC(C)=O.CCO.[Pd]>[CH3:33][O:32][C:25]1[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:24]=1[CH2:23][N:19]1[S:18](=[O:35])(=[O:34])[N:17]([CH2:16][C:13]2[CH:14]=[CH:15][C:10]([C:9]([OH:36])=[O:8])=[CH:11][CH:12]=2)[CH2:21][C:20]1=[O:22]
Reactant: [H][H]
Reactant: COc1ccc(CN2C(=O)CN(Cc3ccc(C(=O)OCc4ccccc4)cc3)S2(=O)=O)c(OC)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(CN2C(=O)CN(Cc3ccc(C(=O)O)cc3)S2(=O)=O)c(OC)c1

Procedure:
The title A compound, 4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzoic acid benzyl ester (2.04 g, 4.0 mmol) is suspended in EtOAc/EtOH (1:1, 100 mL) along with 10% palladium on carbon (300 mg) and treated with hydrogen (48 psi) for 4 h on a Parr Shaker. The reaction mixture is filtered through celite and concentrated to give a white solid which is recrystallized from MeOH to yield 4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzoic acid: [M-1]-=419.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH:14]1([CH2:20][C@H:21]([N:25]2[C:29](=[O:30])[C@H:28]([CH2:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[NH:27][C:26]2=[O:38])[C:22](O)=[O:23])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH2:11]([O:10][C:8](=[O:9])[C:7]([C:5]1[N:6]=[C:2]([NH:1][C:22](=[O:23])[C@@H:21]([N:25]2[C:29](=[O:30])[C@H:28]([CH2:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[NH:27][C:26]2=[O:38])[CH2:20][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)[S:3][CH:4]=1)=[O:13])[CH3:12]
Reactant: O=C(O)[C@H](CC1CCCCC1)N1C(=O)N[C@@H](CC2CCCCC2)C1=O
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Product: CCOC(=O)C(=O)c1csc(NC(=O)[C@H](CC2CCCCC2)N2C(=O)N[C@@H](CC3CCCCC3)C2=O)n1

Procedure:
By using the conditions described in Step (iv) of Example 17, ethyl 2-amino-4-thiazoleglyoxylate was condensed with (S,S)-3-cyclohexyl-2-[4-(cyclohexyl)methyl-2,5-dioxoimidazolidinyl]propanoic acid [Example 17, Step (iii)] to give the title compound as a colorless foam: EI-HRMS m/e calcd. for C26H36N4O6S (M+) 533.2434, found 533.2431.
Reaction SMILES: [CH2:1]([N:8]1[C@H:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:10][C:9]1=[C:20]([CH2:31][C:32]([O:34]CC1C=CC=CC=1)=[O:33])C(OCC1C=CC=CC=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])=O.[NH4+].C(Cl)Cl>CO.[Pd]>[CH2:1]([N:8]1[C@H:12]([C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[CH2:11][CH2:10][C@@H:9]1[CH2:20][CH2:31][C:32]([OH:34])=[O:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCC(=C(CC(=O)OCc2ccccc2)C(=O)OCc2ccccc2)N1Cc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)[C@@H]1CC[C@H](CCC(=O)O)N1Cc1ccccc1
Reaction time: 12 h
Yield: 22.2 %

Procedure:
To a degassed solution of (S)-dibenzyl 2-(1-benzyl-5-(tert-butoxycarbonyl)pyrrolidin-2-ylidene)succinate (1500 mg, 2.70 mmol) was added 10% Pd/C (900 mg, 0.846 mmol) and ammonium formate (2,550 mg, 40.5 mmol) in MeOH (20 ml). The reaction mixture was then heated to reflux under argon. After 12 hrs, heating was stopped and the reaction mixture was left to stand at rt overnight. The next day another 0.5 g of ammonium formate was added to the reaction and reaction was heated for another 5 hrs. The reaction mixture was diluted with MeOH and filtered. The catalyst was rinsed with MeOH and the filtrate was concentrated to give a yellow solid. CH2Cl2 was added to the residue and the mixture was stirred for 5 min. The mixture was then filtered to remove ammonium formate. The filtrate was concentrated to give 3-((2R,5S)-1-benzyl-5-(tert-butoxycarbonyl)pyrrolidin-2-yl)propanoic acid (200 mg, 0.60 mmol, 22.2% yield) as a yellow syrup. 1H NMR (400 MHz, CDCl3) δ ppm 8.20 (2 H, d, J=13.7 Hz), 7.36-7.26 (5 H, m), 3.97 (1 H, d, J=13.7 Hz), 3.75 (1 H, d, J=13.7 Hz), 3.36 (1 H, t, J=7.4 Hz), 3.14-3.05 (1 H, m), 2.61-2.52 (1 H, m), 2.40-2.31 (1 H, m), 2.10-1.98 (1 H, m), 1.96-1.77 (4 H, m), 1.77-1.65 (1 H, m), 1.34 (9 H, s).
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[CH:10]1[CH:15]=[CH:14]C=CC=1.[CH3:16]O>>[CH:16](=[C:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C:1]1=[O:7])[CH:15]([CH3:14])[CH3:10]
Reactant: CO
Reactant: c1ccccc1
Reactant: O=C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)C=C1CCCCC1=O
Yield: 37 %

Procedure:
While stirring a mixture of 52.5 g (0.536 mol) of cyclohexanone and 13.5 g (0.188 mol) of isobutylaldehyde, a solution prepared by dissolving 2.2 g of sodium hydroxide in 50 ml of methanol is dropwise added to the mixture at a temperature of from room temperature to 40° C., and reacted at room temperature for 2 hours. After the reaction, 20 ml of benzene was added, and the reaction mixture was washed three times with 100 ml of water. From the organic layer, benzene and unreacted cyclohexanone were recovered by distillation, and the distillation was continued, whereby 2-isobutylidene cyclohexanone was obtained in the yield of 37% (based on the isobutylaldehyde) under reduced pressure of 6 mmHg at a temperature of from 95° to 105° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([N:9]([CH3:11])[NH2:10])[N:3]=1.[C:12](OC)(=[O:16])[C:13]([CH3:15])=O>CO>[NH2:8][C:6]1[C:5]2[C:12](=[O:16])[C:13]([CH3:15])=[N:10][N:9]([CH3:11])[C:4]=2[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: COC(=O)C(C)=O
Reactant: CN(N)c1cc(N)nc(N)n1
Solvent: CO
Product: Cc1nn(C)c2nc(N)nc(N)c2c1=O
Reaction time: 5 h
Yield: 76 %

Procedure:
To a refluxing solution of 2,4-diamino-6-(1-methylhydrazino)pyrimidine (500 mg) in anhydrous methanol (15 ml) was added methyl pyruvate (496 mg) over a five minute period. Reflux was continued for 5 hours after which time the solid which had separated was collected by suction filtration of the hot mixture, washed with methanol, and dried under vacuum at 70° C. to yield tan crystals of 5,7-diamino-1,3-dimethylpyrimido(4,5-c)-pyridazine-4(1H)-one (508 mg; 76% of theoretical yield; m.p.>275° C.).
Reaction SMILES: [C:1]1([C:7]#[C:8][CH2:9][C:10]2([OH:16])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=1.C(N(CC)CC)C>>[N+:24]([C:23]1[C:18]([N:13]2[CH2:14][CH2:15][C:10]([CH2:9][C:8]#[C:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([OH:16])[CH2:11][CH2:12]2)=[N:19][CH:20]=[CH:21][CH:22]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: OC1(CC#Cc2ccccc2)CCNCC1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccnc1N1CCC(O)(CC#Cc2ccccc2)CC1
Yield: 99.5 %

Procedure:
A well homogenised mixture of the Compound 256c (115 mg, 0.53 mmol), 2-chloro-3-nitropyridine (93.1 mg, 0.587 mmol) and triethyl amine (0.092 mL, 0.641 mmol) was stirred at 25° C. for 24 h. The reaction crude was purified by flash chromatography (EtOAc—Petroleum Ether 8:2) affording the title product (178 mg).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([OH:18])(=[O:17])[CH:14]([CH3:16])[CH3:15].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH3:15][C:14]([CH3:16])([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:13]([OH:18])=[O:17]
Reactant: BrCc1ccccc1
Reactant: CC(C)C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(Cc1ccccc1)C(=O)O
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of diisopropylamine (12.6 g, 125 mmol) in tetrahydrofuran (100 ml) under anhydrous conditions at 0° C. was added n-butyllithium (80.6 ml, 1.55M in hexane, 125 mmol). The reaction mixture was stirred for 30 minutes at 5° C. and then isobutyric acid (4.4 g, 50 mmol) was added. The reaction mixture was stirred at 0° C. for 30 minutes and then benzyl bromide (17.1 g, 100 mmol) was added dropwise. The reaction mixture was stirred for 2 hours at ambient temperature, quenched with saturated aqueous ammonium chloride (60 ml) and then acidified with 6N hydrochloric acid with cooling. The aqueous phase was saturated with sodium chloride and extracted with diethyl ether (2×100 ml). The combined organic phase was washed with saturated aqueous sodium chloride (2×25 ml) and then dried over magnesium sulfate and concentrated in vacuo to give viscous oil. The oil was distilled at 0.2 mmHg and the product was collected at 160°-170° C. The product was purified by chromatography on a 5×15 cm column of silica gel eluted with 10 percent diethyl ether/hexane (1 L) and 50 percent diethyl ether/hexane (1 L) to afford the desired product as a colorless solid. m.p. 58°-9° C.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH2:10])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:12][CH2:13][CH2:14][CH3:15]>>[C:1]([C:5]1[O:9][N:8]([CH2:12][CH2:13][CH2:14][CH3:15])[C:7](=[NH:10])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCBr
Reactant: CC(C)(C)c1cc(N)no1
Product: CCCCn1oc(C(C)(C)C)cc1=N
Temperature: 85 °C
Reaction time: 70 h
Yield: 100 %

Procedure:
A mixture of 5-tert-butylisoxazol-3-amine (3.0 g, 21 mmol) and 1-bromobutane (3.5 mL, 32 mmol) was warmed to 85° C. and was allowed to stir for 70 h. The mixture was cooled to ambient temperature and was purified by column chromatography (silica gel, 60% hexanes/EtOAc) to give the title compound (4.2 g, 21 mmol, 99% yield). MS (DCI/NH3) m/z 197 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH2:10][C:4]=2[C:3]=1[S:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=O)[NH:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:17][CH:16]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:37]2)=CC=1>O1CCOCC1>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH2:10][C:4]=2[C:3]=1[S:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[S:37])[NH:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:17][CH:16]=1
Reactant: CC(C)(C)NC(=O)c1ccc(CSc2c(Cl)ccc3c2CCNCC3)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: CC(C)(C)NC(=S)c1ccc(CSc2c(Cl)ccc3c2CCNCC3)cc1
Temperature: 25 °C

Procedure:
Combine 7-chloro-6-(4-tert-butylcarbamoyl-benzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (53 mg, 0.13 mmol) with 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's reagent) (53 mg, 0.13 mmol) in anhydrous 1,4-dioxane (1 mL) in a sealed tube and heat at 100° C. for 2 h. Cool the reaction mixture to room temperature, concentrate in vacuo and purify the residue by SCX chromatography to obtain 7-chloro-6-(4-tert-butylthiocarbamoyl-benzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow oil. Purify by reverse phase preparative HPLC [Zorbax SB-Phenyl 21.2×250 mm, 5 micron, 22 mL/min of 0.1% aqueous HCl /acetonitrile (9:1 to 1:9) over 3 0 min, detector at 230 nm].