Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][NH:5][CH2:4][C@@H:3]1[N:8]1[C:12]2=[C:13]3[CH:19]=[CH:18][NH:17][C:14]3=[N:15][CH:16]=[C:11]2[NH:10][C:9]1=[O:20].[Cl:21][C:22]1[N:27]=[C:26](Cl)[CH:25]=[CH:24][N:23]=1.C(N(CC)CC)C.O>C(O)C>[Cl:21][C:22]1[N:27]=[C:26]([N:5]2[CH2:6][CH2:7][C@@H:2]([CH3:1])[C@@H:3]([N:8]3[C:12]4=[C:13]5[CH:19]=[CH:18][NH:17][C:14]5=[N:15][CH:16]=[C:11]4[NH:10][C:9]3=[O:20])[CH2:4]2)[CH:25]=[CH:24][N:23]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: C[C@@H]1CCNC[C@@H]1n1c(=O)[nH]c2cnc3[nH]ccc3c21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: C[C@@H]1CCN(c2ccnc(Cl)n2)C[C@@H]1n1c(=O)[nH]c2cnc3[nH]ccc3c21
Temperature: 25 °C
Reaction time: 17 h
Yield: 45.9 %

Procedure:
To the mixture of rel-1-[(3R,4R)-4-methyl-3-piperidinyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one-(100 mg) and 2,4-dichloropyrimidine (82 mg) in ethanol (2 mL), triethylamine (75 mg) was added at ambient temperature. Then After the mixture was stirred at ambient temperature for 17 hours, water (10 mL) was added. The resulting precipitate was collected, to afford rel-1-[(3R,4R)-1-(2-chloro-4-pyrimidinyl)-4-methyl-3-piperidinyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (65 mg) as yellow powder. From NMR, it was found that the obtained powder was mixture of regioisomer (4:1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>CO.C1COCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(-c2ccncn2)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cccc(-c2ccncn2)c1
Reaction time: 1 h
Yield: 96.1 %

Procedure:
To a suspension of (36) (6.3 g, 31 mmol) in a mixture of MeOH (60 ml) and THF (30 ml) was added 5% palladium on activated carbon (300 mg) and the mixture was hydrogenated at ambient pressure for 1 hr. The mixture was filtered and concentrated under reduced pressure. The residue was purified by column-chromatography on silica gel using a mixture of hexane and ethylcetate (3:1) as the eluent to give (37) (5.1 g, 96%).
Reaction SMILES: [SH:1][CH2:2][CH2:3][C@H:4]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:5](=[O:13])[NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:13]=[C:5]1[C@@H:4]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:3][CH2:2][S:1][C@H:7]2[CH2:8][CH2:9][CH2:10][CH2:11][N:6]12
Reactant: O=CCCCCNC(=O)[C@H](CCS)NC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@H]1CCS[C@H]2CCCCN2C1=O)OCc1ccccc1
Temperature: 50 °C
Yield: 80.8 %

Procedure:
To a solution of (S)-benzyl 4-mercapto-1-oxo-1-(5-oxopentylamino)butan-2-ylcarbamate (150 mg, 0.426 mmol) in DCM (5 mL) at rt was added a couple drops of TFA (by pipette). The mixture was stirred at 50° C. (gentle refluxing) for 1.5 hr. The reaction mixture was cooled to rt and concentrated. The residue was diluted with EtOAc. The EtOAc solution was washed with saturated aqueous NaHCO3, saturated aqueous NaCl (2×), dried over Na2SO4, filtered and concentrated. The residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-70% EtOAc/Hex to give benzyl (4S,10aS)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamate (115 mg, 0.344 mmol, 81% yield). Anal. Calcd. for C12H22N2O3S m/z 334.3. found: 335.3 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.43-7.26 (m, 5H), 6.25 (d, J=6.5 Hz, 1H), 5.28 (dd, J=7.7, 3.0 Hz, 1H), 5.10 (d, J=2.5 Hz, 2H), 4.86 (ddd, J=10.3, 6.8, 3.3 Hz, 1H), 4.28 (d, J=13.8 Hz, 1H), 3.19 (ddd, J=14.1, 11.0, 2.7 Hz, 1H), 3.07-2.87 (m, 1H), 2.70 (ddd, J=14.4, 6.1, 3.0 Hz, 1H), 2.44-2.25 (m, 1H), 2.06-1.89 (m, 2H), 1.86-1.60 (m, 3H), 1.60-1.39 (m, 2H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23]CC)=[O:22].C(O)C.[OH-].[Na+]>C(OC(=O)C)(=O)C>[N+:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)CCCCCCc1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: CCO
Product: O=C(O)CCCCCCc1ccc2ccccc2c1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Fuming nitric acid (81 ml) was ice-cooled and acetic anhydride (4.5 ml) was added dropwise. The mixture was cooled to -78° C. and a solution of ethyl 7-(2-naphthyl)heptanoate (10 g) in acetic anhydride (20 ml) was added. The temperature was then increased to -20° C. over a period of 2 hours, after which ethanol (10 ml) was added dropwise. The mixture was stirred for 30 minutes. Then, 2N aqueous sodium hydroxide solution (300 ml) was added under ice-cooling and the mixture was further stirred for 2 hours and, then, extracted with ether. The organic layer was washed with water, dried, and concentrated to dryness. The solid residue (11 g) was added to 5N aqueous sodium hydroxide solution (66 ml)-tetrahydrofuran (264 ml) and the mixture was refluxed for 6 hours. The reaction mixture was acidified with HCl and extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated to dryness and the residue was recrystallized from hexane-ethyl acetate to provide 7-(1-nitro-2-naphthyl)heptanoic acid (3.4 g).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)[CH3:3].[CH:18]1([C:24](Cl)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C(N(CC)CC)C>>[CH:18]1([C:24]([O:17][C@H:14]2[CH2:15][CH2:16][C@H:11]([C:8]3[CH:9]=[CH:10][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])=[CH:6][CH:7]=3)[CH2:12][CH2:13]2)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: CN(C)Cc1ccc([C@H]2CC[C@H](O)CC2)cc1
Solvent: CCN(CC)CC
Product: CN(C)Cc1ccc([C@H]2CC[C@H](OC(=O)C3CCCCC3)CC2)cc1

Procedure:
from trans-4-(4-dimethylaminomethylphenyl)-cyclohexanol and cyclohexane carboxylic acid chloride/triethylamine. White crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[F:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[S:37]([NH:40][C:41]1[CH:46]=[C:45](B2OC(C)(C)C(C)(C)O2)[CH:44]=[C:43]([OH:56])[CH:42]=1)(=[O:39])=[O:38].C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:1][C:2]1[C:3]([C:45]2[CH:46]=[C:41]([NH:40][S:37]([C:31]3[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:30]=3[F:29])(=[O:39])=[O:38])[CH:42]=[C:43]([OH:56])[CH:44]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: CC1(C)OB(c2cc(O)cc(NS(=O)(=O)c3ccc(F)cc3F)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cc(O)cc(NS(=O)(=O)c4ccc(F)cc4F)c3)n(-c3ccccc3)c(=O)c12
Yield: 8.6 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (80 mg, 0.18 mmol) was treated with 2,4-difluoro-N-(3-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzenesulfonamide (180 mg, 0.37 mmol), sodium carbonate (2M, 200 μl, 0.40 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (30 mg, 0.04 mmol) according to the method described in Example 3 to give 10 mg (8% yield) of the title compound. Purity 94%.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].[H-].[Na+]>CN(C=O)C>[CH3:21][O:20][C:18](=[O:19])[C:17]1[CH:22]=[CH:23][C:14]([NH:13][C:2]2[S:3][C:4]3[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=3[N:6]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc2nc(Cl)sc2c1
Reactant: COC(=O)c1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Nc2nc3ccc(OC)cc3s2)cc1
Temperature: 120 °C
Reaction time: 24 h
Yield: 9.5 %

Procedure:
To a solution of 2-chloro-6-methoxybenzothiazole (1.00 g, 5.03 mmol) in DMF (10 mL) was added methyl 4-aminobenzoate (760 mg, 5.03 mmol) followed by addition of powdered K2CO3 (1.81 g, 15.09 mmol). The mixture was stirred at 90° C. for 16 h and at 120° C. for 24 h and then at 140° C. for 3 days. It was allowed to cool down to rt and NaH (60% in mineral oil, 201 mg, 5.03 mmol) was added. The mixture was stirred at rt for 16 h and quenched with H2O. The solvent was removed in vacuo at 80° C. and the residue was partitioned between H2O and EtOAc. The organic layer was washed with HCl 1N, saturated NaHCO3 and brine, dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography using EtOAc/Hex and increasing polarity from 20:80 to 50:50 throughout elution, affording the title compound 161 (150 mg, 9% yield). m/z: 315.2 (MH+)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.CC(O)(C)C.ClCCCl.[NH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[CH2:27][CH2:26]2.C(N(CC)CC)C>[Cl-].[Cl-].[Zn+2].ClCCCl>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([NH:22][C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[NH:29][C:28](=[O:33])[CH2:27][CH2:26]3)[N:7]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: Nc1ccc2c(c1)CCC(=O)N2
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C1CCc2cc(Nc3ncc(C(F)(F)F)c(Cl)n3)ccc2N1
Yield: 71.5 %

Procedure:
To a solution of 2,4-Dichloro-5-trifluoromethyl-pyrimidine (963 mg, 4.43 mmol) in 30 mL of 50/50 mixture of t-BuOH/DCE was added a solution of ZnCl2 (1M in THF;4.43 mL). After one hour 6-Amino-3,4-dihydro-1H-quinolin-2-one (480 mg;2.95 mmol) was added followed by the dropwise addition of triethylamine (0.617 ml, 4.43 mmol) in 2 mL t-BUOH/DCE. Following removal of the solvent under reduced pressure, the crude reaction was triturated from methanol and the product filtered off as a yellow solid 723 mg (72% yield). 1H NMR (DMSO-d6, 400 MHz) δ 2.39 (t, J=12 Hz; 2H), 2.80 (t, J=8 Hz; 2H), 6.78 (d, J=8 Hz; 1H), 7.35 (d, J=8 Hz; 1H), 7.40 (br s, 1H), 8.70 (s, 1H), 10.02 (s, 1H), 10.48 (s, 1H). HPLC ret. time: 6.074 (96% purity), LRMS (M+) 343.2/345.2.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:11]=[C:10]2[C:6]([C:7]3[CH:15]([CH2:16][N:17]([C:19](OC(C)(C)C)=O)C)[CH2:14][CH2:13][S:12][C:8]=3[NH:9]2)=[CH:5][CH:4]=1.Br[CH2:29][CH2:30][CH2:31][Cl:32]>>[Cl:32][CH2:31][CH2:30][CH2:29][N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([C:2]([F:26])([F:27])[F:1])[CH:11]=2)[C:7]2[CH:15]([CH2:16][NH:17][CH3:19])[CH2:14][CH2:13][S:12][C:8]1=2
Reactant: CN(CC1CCSc2[nH]c3cc(C(F)(F)F)ccc3c21)C(=O)OC(C)(C)C
Reactant: ClCCCBr
Product: CNCC1CCSc2c1c1ccc(C(F)(F)F)cc1n2CCCCl

Procedure:
By the same procedure as in Example 39(2), 7-trifluoromethyl-4-(N-t-butoxycarbonyl-N-methylaminomethyl)-2,3,4,9-tetrahydrothiopyrano[2,3-b]indole (1.5 g) is made to react with 3-bromopropyl chloride followed by the reaction to remove the butoxycarbonyl group to give 9-(3-chloropropyl)-7-trifluoromethyl-4-methylaminomethyl-2,3,4,9-tetrahydrothiopyrano[2,3-b]indole. Ethanol (15 ml) and a 50% aqueous solution of dimethylamine are added to the product. The solution is heated at 90°-95° C. in a sealed-tube for 8 hours and evaporated to remove the solvent. The residue is dissolved in chloroform and extracted with dilute hydrochloric acid. The extract is adjusted to pH 8 with an aqueous solution of sodium hydroxide and extracted with chloroform. The extract is washed with water, dried and condensed to give the title compound (1.28 g).
Reaction SMILES: [C:1]1([CH:7]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24][N:25]1[CH:29]=[C:28]([C:30]([O:32]CC)=[O:31])[CH:27]=[N:26]1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(C(C)=O)C>[C:1]1([CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:14]2[CH2:15][CH2:16][N:17]([CH2:21][CH2:22][CH2:23][CH2:24][N:25]3[CH:29]=[C:28]([C:30]([OH:32])=[O:31])[CH:27]=[N:26]3)[CH2:18][CH2:19]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: CCOC(=O)c1cnn(CCCCBr)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(O)c1cnn(CCCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Under reflux for 4 hours is placed a mixture of 6.3 g (25 mmoles) of diphenylmethyl piperazine, 6.87 g (25 mmoles) of 1-(4-bromobutyl)-4-ethyloxycarbonylpyrazole, 5.17 g (37.5 moles) of potassium carbonate and 5.06 g (33.7 mmoles) of sodium iodide in 100 ml of methyl ethyl ketone. It is cooled, filtered and the filtrate evaporated to dryness. The residue is taken up again with chloroform and water, the organic phase is dried with Na2SO4, it is filtered and evaporated under vacuum. The resulting product is purified on a chromatographic silica column (eluant: chloroform-methanol 95:5) and in this way 7.4 g of 1-[4-(4-Diphenylmethyl-1-piperazinyl)butyl]-4-ethyloxycarbonylpyrazole is obtained, with a melting point 70°-74° C.
Reaction SMILES: [OH-].[Na+].Cl[C:4]1[C:7]([F:9])([F:8])[C:6]([F:11])([F:10])[C:5]=1[Cl:12].[CH:13]([OH:16])([CH3:15])[CH3:14]>>[CH:13]([O:16][C:4]1[C:7]([F:9])([F:8])[C:6]([F:11])([F:10])[C:5]=1[Cl:12])([CH3:15])[CH3:14]
Reactant: CC(C)O
Reactant: FC1(F)C(Cl)=C(Cl)C1(F)F
Agent: [Na+]
Agent: [OH-]
Product: CC(C)OC1=C(Cl)C(F)(F)C1(F)F
Reaction time: 2 h

Procedure:
200 g (5 mol) of powdered sodium hydroxide are metered into a solution of 786 g (3.94 mol) of 1,2-dichloro-3,3,4,4-tetrafluorocyclobutene and 328 g (5.47 mol) of technical grade isopropanol at -10° C. The mixture is stirred for a further 2 hours, the solid is filtered off with suction and the filtrate is distilled.
Reaction SMILES: [CH2:1]([O:7][N:8]=[C:9]([C:15](=[O:17])[CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].S(Cl)([Cl:21])(=O)=O>C(O)(=O)C>[CH2:1]([O:7][N:8]=[C:9]([C:15](=[O:17])[CH2:16][Cl:21])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCCCCCON=C(C(C)=O)C(=O)OCC
Solvent: CC(=O)O
Product: CCCCCCON=C(C(=O)CCl)C(=O)OCC
Yield: 80.2 %

Procedure:
Ethyl 2-n-hexyloxyimino-3-oxobutyrate (syn isomer, 60.7 g.), acetic acid (61 ml.) and sulfuryl chloride (34.7 g.) were treated in a similar manner to that of Example F-(2) to give ethyl 2-n-hexyloxyimino-4-chloro-3-oxobutyrate (syn isomer, 55.6 g.).
Reaction SMILES: Cl.N1C=CC=CC=1.C[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[N:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:23]=2)[CH:19]=[CH:18][CH:17]=1.[OH-].[Na+]>O>[C:28]1([C:24]2[N:23]=[C:22]([C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[OH:9])[N:21]=3)[CH:27]=[CH:26][CH:25]=2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COc1ccccc1-c1cccc(-c2cccc(-c3ccccc3)n2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: Oc1ccccc1-c1cccc(-c2cccc(-c3ccccc3)n2)n1
Temperature: 120 °C
Reaction time: 2 h
Yield: 93.5 %

Procedure:
Hydrochloric acid (14.8 ml, 177.2 mmol) was added to pyridine (14.3 ml, 177.2 mmol), and the mixture was heated with removing water till an internal reaction temperature reach to 180° C. After the reaction mixture was cooled to 120° C., 6-(2-methoxyphenyl)-6′-phenyl-2,2′-bipyridine (3.0 g, 8.9 mmol) obtained by Example 13 was added to the reaction mixture and stirred for at 180° C. for 2 hours. After the reaction mixture was cooled, to which was then added an aqueous 1 mol/L sodium hydroxide solution, the mixture was extracted with dichloromethane, the solvent was distilled off, and the residue was purified by silica gel column chromatography and recrystallization, thereby obtaining 2.7 g of 2-(6′-phenyl-2,2′-bipyridine-6-yl)phenol as yellow crystal. Yield: 93.9%.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:18]([NH:20][C@H:21]([C:34]([O:36]CC1C=CC=CC=1)=[O:35])[CH2:22][CH2:23][C:24](=[O:33])[O:25]CC1C=CC=CC=1)=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9].O>CO.C(O)(=O)C.[Pd]>[NH2:1][C@H:2]([C:18]([NH:20][C@H:21]([C:34]([OH:36])=[O:35])[CH2:22][CH2:23][C:24](=[O:25])[OH:33])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:9])=[O:10]
Reactant: Cc1ccc(S(=O)(=O)NCCCC[C@H](NC(=O)OCc2ccccc2)C(=O)N[C@@H](CCC(=O)OCc2ccccc2)C(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)NCCCC[C@H](N)C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1
Reaction time: 8 h

Procedure:
5.21 Grams of Z-Lys(Tos)-Glu(OBzl)-OBzl was dissolved in a mixture of 80 ml of methanol with 20 ml of 10% acetic acid, and a small amount of palladium black was added thereto and stirred overnight under introducing hydrogen gas. After the reaction was completed, the catalyst was removed by vacuum filtration, and the filtrate was distilled under a reduced pressure to obtain the rresidue. To the residue was poured water and was lyophilized to obtain the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=2[CH3:36])=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=[C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[CH:16][C:8]=4[C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[NH:12][C:11]3=[O:17])[NH:30][C:29]=2[CH3:36])=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C1Cc2c(cccc2-c2ccc(F)cc2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(F)cc4)c32)c(C)c1C(=O)NCCN1CCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 76.2 %

Procedure:
To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (68.5 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellow solid (90.0 mg, 76%).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@@H:7](O)C(N[C@@H]2C(=O)N3C(C(O)=O)=C(CSC4N(CS(O)(=O)=O)N=NN=4)CS[C@H]23)=O)=[CH:5][CH:6]=1.C(O)(=O)C.C(O)(=O)C.[CH2:44]([N:51](CC1C=CC=CC=1)[CH2:52][CH2:53][NH2:54])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>O.CO>[CH2:44]([NH:51][CH2:52][CH2:53][NH:54][CH2:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: O=C(O)C1=C(CSc2nnnn2CS(=O)(=O)O)CS[C@@H]2[C@H](NC(=O)[C@H](O)c3ccccc3)C(=O)N12
Reactant: NCCN(Cc1ccccc1)Cc1ccccc1
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: c1ccc(CNCCNCc2ccccc2)cc1
Reaction time: 3 h
Yield: 99.4 %

Procedure:
To a stirred solution of cefonicid (5.76 g, 9.8 mmol) in water (6.3% w/w), at pH 5-6 and ambient temperature, methanol (50 ml) was added, followed by a suspension of N,N-dibenzylethylene diamine diacetate (8.6 g, 24 mmol) in methanol (50 ml). The reaction mixture was stirred for 3 h at 20°-25° C., resulting in formation of a white solid. The reaction mixture was cooled to 10°-15° C. and filtered. The white solid was washed with water (3×15 ml) and methanol (3×10 ml). The solid was dried at 30°-35° C. under vacuum. (7.63 g, 99.4% yield). The melting range of the crystals was 191°-193° C. Washed salt with water (50 ml×2) followed by methanol (120 ml) to yield a product with a melting range of 195°-198° C. Elemental Analysis (C34H38N8 O8S3) calcd: C, 52.16; H, 4.89; N, 14.31; S, 12.26. found: C, 52.06; H, 4.89; N, 14.01; S, 12.27.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[C:16]([S:20]([N:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=2)[N:8]=1)=O.[NH:27]([C:29]1[CH:30]=[C:31]([NH:35][C:36](=[O:38])[CH3:37])[CH:32]=[CH:33][CH:34]=1)[NH2:28]>>[CH3:25][N:23]([CH3:24])[S:20]([C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:27]([C:29]4[CH:30]=[C:31]([NH:35][C:36](=[O:38])[CH3:37])[CH:32]=[CH:33][CH:34]=4)[N:28]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1)(=[O:21])=[O:22]
Reactant: CC(=O)Nc1cccc(NN)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(=O)(=O)N(C)C)c2)ccc1=O
Product: CC(=O)Nc1cccc(-n2nccc2-c2nn(-c3cccc(S(=O)(=O)N(C)C)c3)ccc2=O)c1

Procedure:
The product was obtained starting from 3-[3-((E)-3-Dimethylamino-acryloyl)-4-oxo-4H-pyridazin-1-yl]-N,N-dimethyl-benzenesulfonamide (A-12) and N-(3-hydrazino-phenyl)-acetamide according to the method described for example 91. MS: M=479.1 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=1)=[O:4].[NH2:14][C@H:15]([CH3:31])[CH2:16][N:17]1[CH:21]=[CH:20][C:19]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([Cl:30])[CH:23]=2)=[N:18]1>>[Cl:30][C:24]1[CH:23]=[C:22]([C:19]2[CH:20]=[CH:21][N:17]([CH2:16][C@H:15]([NH:14][C:11]([C:9]3[N:10]=[C:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[S:7][CH:8]=3)=[O:13])[CH3:31])[N:18]=2)[CH:29]=[CH:28][C:25]=1[C:26]#[N:27]
Reactant: COC(=O)Nc1nc(C(=O)O)cs1
Reactant: C[C@@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: COC(=O)Nc1nc(C(=O)N[C@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cs1
Yield: 27.2 %

Procedure:
(R)-methyl 4-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl-carbamoyl)thiazol-2-ylcarbamate was prepared using the method of Example 34(d) starting from 2-(methoxycarbonylamino)thiazole-4-carboxylic acid (0.36 g, 1.460 mmol) and (R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.334 g, 1.217 mmol). The product was triturated using diethyl ether and DCM, respectively. Yield 27.2%. 1H-NMR (400 MHz; DMSO-d6): δ 1.13 (d, 3H), 3.77 (s, 3H), 4.33 (d, 1H), 4.34 (d, 1H), 4.37-4.45 (m, 1H), 6.96 (d, 1H), 7.72 (s, 1H), 7.83 (d, 1H), 7.87 (d, 1H), 7.93-7.94 (m, 2H), 8.04 (t, 1H), 11.85 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[C:4]([F:10])[CH:3]=1.[C:11]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C:15]1=O)(=O)[CH3:12].C1(C)C(C)=CC=CC=1>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11]([CH3:12])=[C:14]3[C:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)=[N:9]2)=[C:4]([F:10])[CH:3]=1
Reactant: CC(=O)C1CCCCC1=O
Reactant: NNc1ccc(Cl)cc1F
Solvent: CC(=O)O
Solvent: Cc1ccccc1C
Product: Cc1c2c(nn1-c1ccc(Cl)cc1F)CCCC2

Procedure:
A solution of 19.7 parts of 4-chloro-2-fluorophenylhydrazine and 14.0 parts of 2-acetylcyclohexanone in 50 parts of xylene and 1 part of glacial acetic acid were refluxed for 24 hours with a Dean Stark trap to collect the water formed. The xylene was distilled from the mixture. The residual oil was dissolved in arm hexane solution. On cooling, 6.2 parts of crude product was obtained. Recrystallization of this product yielded white crystals of 2-(4-chloro-2-fluorophenyl)-3-methyl-4,5,6,7-tetrahydro-2H-indazole, melting point 84.5°-87.5° C; ir bands (1570 cm-1, 905 cm-1, 822 cm-1).