Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH:5]1[O:11][CH:10]2[N:7]([C:8](=[O:12])[CH2:9]2)[CH2:6]1)=[N+]=[N-].[C:13](O)(=[O:18])[CH2:14][CH2:15][CH:16]=[CH2:17].C1(N=C=NC2CCCCC2)CCCCC1>[Pd].C(OCC)(=O)C>[C:13]([NH:1][CH2:4][CH:5]1[O:11][CH:10]2[N:7]([C:8](=[O:12])[CH2:9]2)[CH2:6]1)(=[O:18])[CH2:14][CH2:15][CH:16]=[CH2:17]
Reactant: C=CCCC(=O)O
Reactant: [N-]=[N+]=NCC1CN2C(=O)CC2O1
Agent: [Pd]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: C=CCCC(=O)NCC1CN2C(=O)CC2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 15 %

Procedure:
600 mg of (3RS,5RS)-3-Azidomethyl-4-oxa-1-azabicyclo[3.2.0]heptan-7-one was hydrogenated with 1.0 g of 10% Palladium on activated carbon in Ethyl acetate at 50 psi for 1 hr. After removal of catalyst by filtration, 360 mg (3.6 mmol) of 4-Pentenoic acid and 300 mg (1.8 mmol) of 1,3-Dicyclohexyl carbodiimide were added under ice-cooling. The reaction mixture was then stirred at room temperature for 2 hrs. Resulted solid was filtered off and the filtrate was concentrated in vacuo. The residue was purified by flash silicagel column using Hexane-Ethyl acetate (1:1) as eluent and the title compound was obtained as oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[C:13]1([CH3:22])[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][C:3]1[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH3:22]
Reactant: Cc1ccccc1B(O)O
Reactant: COC(=O)c1ccc(Br)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(-c2ccccc2C)c(C)c1
Temperature: 120 °C
Yield: 96 %

Procedure:
To a solution of methyl 4-bromo-3-methylbenzoate (ABCR, 15.0 g, 65 mmol) in toluene (200 mL) and water (200 mL), was added o-tolylboronic acid (10.7 g, 78 mmol) followed by potassium carbonate (45.3 g, 32.7 mmol) and tetrakis(triphenylphosphine)palladium(0) (3.78 g, 3.3 mmol). The mixture was degassed with N2 and refluxed at 120° C. for 6 hours. After the completion of reaction, the reaction mixture was cooled to RT. The organic phase was separated and evaporated under reduced pressure. The crude compound was passed through a silica column using hexane as eluent to get the title compound as a white solid (15 g, 95%). 1H NMR (DMSO-d6, 400 MHz) δ 7.91 (s, 1H), 7.82 (m, 1H), 7.32 (m, 2H), 7.27 (m, 1H), 7.24 (m, 1H), 7.06 (m, 1H), 3.84 (s, 3H), 2.09 (s, 3H), 1.95 (s, 3H). HPLC (Method B), Rt 3.01 min (purity: 98.71%).
Reaction SMILES: [CH:1]([C:3]1[CH2:4][S:5][C@@H:6]2[CH:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C:25](=[O:36])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])=O.Cl.[C:38]([CH2:43][NH:44][NH2:45])([O:40][CH2:41][CH3:42])=[O:39]>O1CCCC1.O>[S:31]1[CH:32]=[CH:33][CH:34]=[C:30]1[CH2:29][C:28]([NH:27][CH:26]1[C:25](=[O:36])[N:7]2[C:8]([C:9]([O:11][CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:10])=[C:3]([CH:1]=[N:45][NH:44][CH2:43][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:4][S:5][C@H:6]12)=[O:35]
Reactant: O=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Reactant: CCOC(=O)CNN
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CNN=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Reaction time: 48 h
Yield: 69.8 %

Procedure:
To a solution of diphenylmethyl 3-formyl-7-(2-thienylacetamido)-3-cephem-4-carboxylate (155 mg) in tetrahydrofuran (15 ml) is added a solution of carbethoxymethylhydrazine hydrochloride (69 mg) in water (2.5 ml), and the mixture is kept at room temperature for 2 days. The crystals obtained by concentration of the reaction mixture are collected by filtration, washed with ether and water, and dried to give diphenylmethyl 7-(2-thienylacetamido)-3-(2-carbethoxymethylhydrazono)methyl-3-cephem-4-carboxylate (129 mg). m.p. 70°-75° C. Yield: 69%. IR: νmaxNujol 3270, 1780, 1745, 1670; 1540cm-1. NMR: δd 6-DMSO (60MHz) 1.435 (6Hz) 3H, 3.52ABq (24; 17Hz) 2H, 3.48s2H, 3.60s2H, 4.17 quintet (6Hz) 2H, 4.95d(5Hz)1H, 5.70dd(8;4Hz)1H, 6.67-7.63m16H, 8.03s1H. [ α]D24.5 - 144° (c=0.340, CHCl3).
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[C:23]([CH3:33])=[CH:24][C:25]([O:31][CH3:32])=[C:26]([CH:30]=1)[C:27]([OH:29])=O.[CH3:34][C:35]1[CH:40]=[C:39]([CH3:41])[N:38]=[C:37]([C:42]2([NH2:45])[CH2:44][CH2:43]2)[N:36]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[CH3:41][C:39]1[CH:40]=[C:35]([CH3:34])[N:36]=[C:37]([C:42]2([NH:45][C:27]([C:26]3[C:25]([O:31][CH3:32])=[CH:24][C:23]([CH3:33])=[C:22]([C:3]4[CH:4]=[CH:5][C:6]5[O:10][C:9]([C:11]6[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=6)=[C:8]([C:18]([NH:19][CH3:20])=[O:21])[C:7]=5[C:2]=4[F:1])[CH:30]=3)=[O:29])[CH2:43][CH2:44]2)[N:38]=1
Reactant: Cc1cc(C)nc(C2(N)CC2)n1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)c(F)c12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5nc(C)cc(C)n5)CC4)c(OC)cc3C)c(F)c12
Reaction time: 8 h

Procedure:
To a mixture of 5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (50 mg, 0.11 mmol), crude 1-(4,6-dimethylpyrimidin-2-yl)cyclopropanamine (100 mg) in 2 ml DMF at room temperature was added BOP (100 mg, 0.22 M, 2.0 eq.) and triethyl amine (0.046 ml 0.33 M, 3.0 eq.), and the mixture stirred overnight under an N2 atmosphere. The mixture was poured into crushed ice, and the solid precipitate was filtered and dried. The product obtained was further purified by preparative HPLC. Yield: 15 mg (24%) 1H NMR (400 MHz, CD3OD): δ 7.97-7.94 (m, 2H), 7.89 (s, 1H), 7.51 (d, J=8.5 Hz, 1H), 7.31-7.25 (m, 3H), 7.19 (s, 1H), 7.14 (s, 1H), 4.11 (s, 3H), 2.96 (s, 3H), 2.48 (s, 6H), 2.31 (s, 3H), 1.86-1.83 (m, 2H), 1.55-1.52 (m, 2H). 19F NMR (376.57 MHz, CD3OD) δ−77.40 (TFA), −112.33, −122.75 (CFCl3 as reference).
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]([O:16]C)=O)(C)C.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[Pb](SC#N)[S:30][C:31]#[N:32]>ClCCl>[C:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]([N:32]=[C:31]=[S:30])=[O:16])#[CH:5]
Reactant: N#CS[Pb]SC#N
Reactant: COC(=O)Cc1ccccc1C#C[Si](C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C#Cc1ccccc1CC(=O)N=C=S
Reaction time: 1 h

Procedure:
To acid 319 (0.34 g, 2.1 mmol) in dry dichloromethane (25 mL) was added oxalyl chloride (0.39 mL, 0.57 g, 4.5 mmol) and dry DMF (0.05 mL). The mixture was stirred for 1 h, then concentrated under reduced pressure. The residue was re-dissolved in toluene (40 mL) and lead thiocyanate (0.75 g, 2.3 mmol) was added. The resulting suspension was heated to reflux with vigorous stirring for 3 h, then cooled, filtered through celite, and concentrated to afford crude 317 which was used without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])(=[O:5])=[O:4].C([Li])CCC.[F:24][C:25]1[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27]Br>O1CCCC1.CCCCCC>[CH3:1][N:2]([CH3:18])[S:3]([N:6]1[CH:10]=[C:9]([CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[C:32]([F:33])[C:25]=2[F:24])[N:8]=[C:7]1[Si:11]([C:14]([CH3:15])([CH3:17])[CH3:16])([CH3:13])[CH3:12])(=[O:4])=[O:5]
Reactant: Fc1cccc(CBr)c1F
Reactant: CN(C)S(=O)(=O)n1ccnc1[Si](C)(C)C(C)(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1cc(Cc2cccc(F)c2F)nc1[Si](C)(C)C(C)(C)C
Reaction time: 8 h
Yield: 49.8 %

Procedure:
To a solution of 4.2 g (14.5 mmol) 2-(tert-butyl-dimethyl-silanyl)-imidazole-1-sulfonic acid dimethylamide in 50 ml tetrahydrofuran were added 10.9 ml (17.4 mmol) of a 1.6M butyl lithium solution in hexane at −75° C. After stirring for 20 min 3.6 g (17.4 mmol) 2,3-difluorobenzylbromide was added at −75° C. and the mixture was allowed to reach room temperature overnight. The mixture was partitioned between water and ethyl acetate, re-extracted with ethyl acetate and the combined organic layers are dried over MgSO4, filtered and evaporated. The residue was purified by flash chromatography (silica gel, hexane/ethyl acetate=4:1) to yield 3.0 g (49%) of 2-(tert-butyl-dimethyl-silanyl)-4-(2,3-difluoro-benzyl)-imidazole-1-sulfonic acid dimethylamide as a light yellow solid; MS (ISP): 416.1 ((M+H)+.).
Reaction SMILES: [CH3:1][C@@H:2]([N:9]1[C:13](=[O:14])[CH2:12][C@@H:11]([C:15](O)=[O:16])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CSC.B>O1CCCC1>[OH:16][CH2:15][C@H:11]1[CH2:10][N:9]([C@@H:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH3:1])[C:13](=[O:14])[CH2:12]1
Reactant: C[C@H](c1ccccc1)N1C[C@H](C(=O)O)CC1=O
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1C[C@H](CO)CC1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
5 g (1′R,3R)-1-(1′Phenylethyl)-5-oxo-3-pyrrolidine carboxylic acid was dissolved in 50 mL tetrahydrofuran, then the solution was cooled to 0° C. 16.5 mL borane dimethyl sulfide (2 M in tetrahydrofuran) was added dropwise over 30 min and the reaction solution was slowly warmed to 25° C. and stirred for a further 2 h at 25° C. The reaction mixture was concentrated, diluted in dichloromethane and washed with sodium bicarbonate solution. The water phase was extracted with dichloromethane (×2) and the combined organic phases were dried over magnesium sulfate and concentrated.
Reaction SMILES: Cl.[CH2:2]([NH:18][C:19]1[CH:29]=[CH:28][C:22]([CH2:23][CH2:24][C:25](Cl)=[O:26])=[CH:21][CH:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[CH2:30]([O:32][CH2:33][CH2:34][OH:35])[CH3:31]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:2]([NH:18][C:19]1[CH:29]=[CH:28][C:22]([CH2:23][CH2:24][C:25]([O:35][CH2:34][CH2:33][O:32][CH2:30][CH3:31])=[O:26])=[CH:21][CH:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCOCCO
Reactant: CCCCCCCCCCCCCCCCNc1ccc(CCC(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCNc1ccc(CCC(=O)OCCOCC)cc1

Procedure:
Prepared as described in Example 18, 10.0 g. of 4-(hexadecylamino)hydrocinnamoyl chloride hydrochloride in 80. ml. of methylene chloride is treated with 9.5 g. of 4-dimethylaminopyridine and 2.1 g. of 2-ethoxyethanol, analogous to the method of Example 19. Workup and filtration through alumina provides 2-ethoxyethyl 4-(hexadecylamino)hydrocinnamate.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH:6]=[C:7]2[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[CH2:9][C:8]2=[O:15])=[CH:4][CH:3]=1.[Br:18]Br>ClCCl>[Br:18][CH:6]([CH:7]1[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[CH2:9][C:8]1=[O:15])[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:17][CH:16]=1
Reactant: BrBr
Reactant: CC1(C)CCC(=Cc2ccc(Cl)cc2)C(=O)C1
Solvent: ClCCl
Product: CC1(C)CCC(C(Br)c2ccc(Cl)cc2)C(=O)C1
Temperature: 7.5 °C

Procedure:
10 g (0.04 mole) of 2-(4-chlorobenzylidene)-5,5-dimethycyclohexanone prepared according to Example 1(a) were dissolved in 50 ml dichloromethane and cooled to 5-10° C. Bromine (6.4 g, 0.04 mole) was added over 5 minutes to give 2-bromo-2-(α-bromo-4-chlorobenzyl-5,5-dimethylcyclohexanone in solution.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH3:12][N:13]([CH3:18])[CH2:14][CH2:15][CH2:16]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:16][CH2:15][CH2:14][N:13]([CH3:18])[CH3:12])=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CN(C)CCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCCCN(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
To a solution of methyl 4-hydroxybenzoate (1.0 g, 6.58 mmol), 3-dimethylamino-1-propanol (1.01 g, 9.87 mmol), and triphenylphosphine (2.6 g, 9.87 mmol) at 0° C. in THF (20 mL) was added dropwise diisopropyl azodicarboxylate (1.99 g, 9.87 mmol). After stirring for 16 h at room temperature the solution was concentrated and the residue purified by column chromatography (silica gel, methanol/dichloromethane) to yield the title compound as an oily solid (1.25 g, 5.2 mmol). MS(ESI): 238.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:19][C:20]3[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=3)=[O:18])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1.O.[NH2:28][NH2:29]>C(O)CCC>[NH2:9][C:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][C:6]=2[C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=3)=[O:18])=[CH:12][CH:11]=2)[NH:29][N:28]=1
Reactant: NN
Reactant: Cc1cccc(NC(=O)Nc2ccc(-c3ccnc(Cl)c3C#N)cc2)c1
Solvent: CCCCO
Solvent: O
Product: Cc1cccc(NC(=O)Nc2ccc(-c3ccnc4[nH]nc(N)c34)cc2)c1

Procedure:
A mixture of Example 35D (0.08 g, 0.22 mmol) and hydrazine hydrate (0.11 mL, 2.2 mmol) in n-butanol (5 mL) was heated at 110° C. for 2 h, then concentrated. The residue was purified via HPLC on an Agilent Zorbax Stablebond C-18 (7 micron particle size) preparative column using a solvent gradient of 20% to 100% acetonitrile in 0.1% aqueous TFA at a flow rate of 15 ml/min over 50 min, to give the title compound. 1H NMR (500 MHz, DMSO-D6) δ ppm 2.29 (s, 3H) 6.81 (d, J=7.32 Hz, 1H) 6.93 (d, J=4.58 Hz, 1H) 7.17 (t, J=7.63 Hz, 1H) 7.26 (d, J=7.63 Hz, 1H) 7.33 (s, 1H) 7.54 (d, J=8.24 Hz, 2H) 7.66 (d, J=7.93 Hz, 2H) 8.38 (d, J=4.27 Hz, 1H) 8.80 (s, 1H) 9.04 (s, 1H); MS (ESI(+)) m/e 359 (M+H)+.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])[CH3:4].[CH:23]1([CH2:26]Br)[CH2:25][CH2:24]1>CN(C=O)C>[CH2:3]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:26][CH:23]3[CH2:25][CH2:24]3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])[CH3:4]
Reactant: BrCC1CC1
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ccccc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC(c2cn(CC3CC3)c3ccccc23)CC1
Reaction time: 0.5 h
Yield: 96 %

Procedure:
To a suspension of 0.76 g (19 mmol) of a 60% suspension of sodium hydroxide, in mineral oil, in 15 mL of anhydrous DMF, a solution of 4 g (15 mmol) of 4-(1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester in 5 mL of anhydrous DMF was added. After 30 minutes at room temperature, a solution of 1.71 mL (18 mmol) of cyclopropylmethyl bromide in 5 mL of DMF was added. The crude mixture was stirred at room temperature for 14 h and the solvent was removed under reduced pressure. The crude mixture was extracted between water and ethyl acetate. The organic layer was dried over magnesium sulfate, and after filtration the solvent was removed under reduced pressure affording 4.7 g of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:13](Cl)(=[O:15])=[O:14])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[OH:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[NH2:21]>CO>[OH:17][C:18]1[CH:19]=[C:20]([NH:21][S:13]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=2)(=[O:15])=[O:14])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: COc1ccc(N)cc1O
Reactant: COc1cc(S(=O)(=O)Cl)cc(OC)c1OC
Solvent: CO
Product: COc1ccc(NS(=O)(=O)c2cc(OC)c(OC)c(OC)c2)cc1O
Reaction time: 1 h
Yield: 61.9 %

Procedure:
To a solution of 3,4,5-trimethoxybenzenesulfonyl chloride (500 mg, 1.88 mmol) in methanol (10 mL) was added 3-hydroxy4-methoxyaniline (523 mg, 3.76 mmol) at ambient temperature. After stirring for 1 h, the reaction mixture was concentrated and the crude residue was purified by chromatography over silica to afford 430 mg (62%) of product as fme white needles, m.p. 145-146° C. 1H—NMR (CDCl3): δ9.74 (1H, s), 9.15 (1H, s), 6.98 (2H, s), 6.78 (1H, d, J=8.8 Hz), 6.63 (1H, d, J=2.6 Hz), 6.50 (1H, dd, J=8.8, 2.6 Hz), 3.76 (6H, s), 3.70 (3H, s), 3.68 (3H, s). Anal. Calcd. for C16H19N1O7S: C, 52.03; H, 5.18; N, 3.79; S, 8.68. Found: C, 51.87; H, 5.28; N, 3.76; S, 8.77.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([C:17]([OH:19])=[O:18])([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1.S(Cl)(Cl)=O.[CH3:24]O.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([C:17]([O:19][CH3:24])=[O:18])([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1
Reactant: CO
Reactant: O=C(O)C12CC(c3ccccc31)c1ccc(Cl)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: COC(=O)C12CC(c3ccccc31)c1ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a solution of 2-chloro-9,10-dihydro-9,10-methano-9-anthracenecarboxylic acid (described in example 1j) (10.03 g, 37.1 mmol) in toluene (100 mL) was added thionyl chloride (4.05 mL, 55.7 mmol, 1.5 eq). The reaction was heated to reflux monitoring gas evolution with a bubbler of mineral oil. Gas evolution ceased after 30 min at which time the reaction was cooled slightly under nitrogen and a large excess of methanol (10 mL) was added. The solution was again heated to reflux for 1 h, cooled to room temperature under nitrogen, and stirred for 18 h. Aqueous NaOH (2.5N, 60 mL) was added and the aqueous phase was extracted with ethyl acetate (2×70 mL). Combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and reduced to a solid. The reaction product was purified by flash chromatography over silica gel (250 mL, eluent: 15% ethyl acetate in hexane) to yield 10.2 g (97%) of the title compound as a highly crystalline white solid. TLC (Rf 0.45, 10% ethyl acetate in hexane). MS (CI, CH4) m/z 285 (M+1,100), 287 (31), 313 (M+29,11), 253 (14), 225 (14), 205 (8)
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[NH2:41][C:42]1[CH:47]=[CH:46][C:45]([N:48]2[CH2:53][CH2:52][CH:51]([C:54]([O:56][CH2:57][CH3:58])=[O:55])[CH2:50][CH2:49]2)=[CH:44][CH:43]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:57]([O:56][C:54]([CH:51]1[CH2:50][CH2:49][N:48]([C:45]2[CH:46]=[CH:47][C:42]([NH:41][C:28]([C@H:9]3[C@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=4[F:31])[C@:12]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10]3)=[O:30])=[CH:43][CH:44]=2)[CH2:53][CH2:52]1)=[O:55])[CH3:58]
Reactant: CCOC(=O)C1CCN(c2ccc(N)cc2)CC1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCN(c2ccc(NC(=O)[C@@H]3N[C@@H](CC(C)(C)C)[C@](C#N)(c4ccc(Cl)cc4F)[C@H]3c3cccc(Cl)c3F)cc2)CC1
Reaction time: 0.5 h
Yield: 291.1 %

Procedure:
To a stirred solution of (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (20.0 mg) in dichloromethane (5 ml) were added N,N-DIISOPROPYLETHYLAMINE (33 mg) and ethyl 1-(4-aminophenyl)piperidine-4-carboxylate (63.8 mg, 0.257 mmol, Bionet Research Intermediates) followed by N,N,N′,N′-tetramethyl-O-(7-aza-benzotriazol-1-yl)uranium hexafluorophosphate (HATU) (29 mg, Chem-Impex) and the reaction mixture was stirred for 30 min; Another portion of N,N-DIISOPROPYLETHYLAMINE (33 mg), (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (20.0 mg) and HATU (29 mg) was added and stirring was continued for 30 min before the addition of the last portion of N,N-DIISOPROPYLETHYLAMINE (33 mg), (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (20.0 mg) and HATU (29 mg). 1 hr later, the reaction mixture was diluted with CH2Cl2 (80 mL), washed with sat Na2CO3 (2×15 mL), water (2×15 mL) and evaporated. The crude material was purified by flash chromatography (silica gel, 4 g, 4% to 50% EtOAc in hexanes) to give 1-(4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-phenyl)-piperidine-4-carboxylic acid ethyl ester as off-white solid (86.9 mg, 97%). MS (ES+) m/z Calcd: [(M+H)+]: 697. found: 697.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]([NH2:15])=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:16][CH2:17][C:18](O)=O>>[CH2:1]([N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]=[C:18]1[CH2:17][Cl:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCl
Reactant: Nc1ccccc1NCc1ccccc1
Product: ClCc1nc2ccccc2n1Cc1ccccc1
Yield: 61.7 %

Procedure:
The title compound was prepared in accordance with the general method of Example 191(C), from N1-benzylbenzene-1,2-diamine (2.93 g, 14.78 mmol) and 2-chloroacetic acid (2.10 g, 22 mmol). The crude residue was purified over silicagel chromatography (prepacked 70 g silicagel column, Cyclohexane/AcOEt: from 80/20 to 70/30 as eluent) to afford 2.34 g of 1-benzyl-2-(chloromethyl)-1H-benzo[d]imidazole (Yield: 61%) as a yellow oil.
Reaction SMILES: C(O)C[OH:3].[C:5]([N:9]1[C:14](=[O:15])[C:13]([CH3:16])=[C:12](Cl)[CH:11]=[N:10]1)([CH3:8])([CH3:7])[CH3:6].[OH-].[K+].Cl>O>[C:5]([N:9]1[C:14](=[O:15])[C:13]([CH3:16])=[C:12]([OH:3])[CH:11]=[N:10]1)([CH3:8])([CH3:7])[CH3:6]
Reactant: Cc1c(Cl)cnn(C(C)(C)C)c1=O
Reactant: OCCO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1c(O)cnn(C(C)(C)C)c1=O
Temperature: 130 °C
Reaction time: 4 h

Procedure:
To 30 ml of ethylene glycol were added 20 g (0.01 mol) of 2-t-butyl-5-chloro-4-methyl-3(2H)-pyridazinone and 2.8 g (0.05 mol) of potassium hydroxide and the mixture was stirred at 130° C. for 4 hours. After allowing to cool, the mixture was poured into 200 ml of water and added with 20 ml of 6N hydrochloric acid. The precipitated crystals were gathered by filtration. After drying, the crystals were washed with 30 ml of hot isopropyl ether to obtain 1.7 g of 2-t-butyl-5-hydroxy-4-methyl-3(2H)-pyridazinone, m.p. 236.0°~239.0° C.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[C:5]([C:7]1[CH:8]=[CH:9][C:10]2[C:20](=[C:21]3[CH2:26][CH2:25][N:24]([CH2:27][C:28]([O:30]CC)=O)[CH2:23][CH2:22]3)[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[CH2:13][CH2:12][C:11]=2[CH:33]=1)#[N:6]>O>[C:5]([C:7]1[CH:8]=[CH:9][C:10]2[C:20](=[C:21]3[CH2:22][CH2:23][N:24]([CH2:27][C:28](=[O:30])[NH:3][CH2:2][CH2:1][NH2:4])[CH2:25][CH2:26]3)[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[CH2:13][CH2:12][C:11]=2[CH:33]=1)#[N:6]
Reactant: CCOC(=O)CN1CCC(=C2c3ccc(C#N)cc3CCc3cccnc32)CC1
Reactant: NCCN
Solvent: O
Product: N#Cc1ccc2c(c1)CCc1cccnc1C2=C1CCN(CC(=O)NCCN)CC1
Reaction time: 3 h
Yield: 62 %

Procedure:
Ethylenediamine (4 ml) was added to 0.5 g of 8-cyano-11-(1-ethoxycarbonylmethyl-4-piperidylidene)6,11-dihydro-5H-benzo[5,6]-cyclohepta[1,2-b]pyridine, followed by stirring at 70°-80° C. for 3 hours. After the reaction, water was added and the resulting mixture was extracted with ethyl acetate. The extract was dried over anhydrous Na2SO4. The ethyl acetate was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column and, from relevant fractions eluted with chloroform:methanol (20:1 - 10:1), 0.32 g of 8-cyano-11-[1-(2-aminoethylcarbamoylmethyl)-4-piperidylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine was obtained (yield: 62%).