Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:3]=[N:2]1.Cl[C:16]1[N:21]=[N:20][C:19]([N:22]2[CH2:27][CH2:26][CH:25]([N:28]3[C:36]4[C:31](=[CH:32][CH:33]=[C:34]([F:37])[CH:35]=4)[CH2:30][CH2:29]3)[CH2:24][CH2:23]2)=[CH:18][CH:17]=1>>[NH:2]1[CH:3]=[C:4]([C:16]2[N:21]=[N:20][C:19]([N:22]3[CH2:23][CH2:24][CH:25]([N:28]4[C:36]5[C:31](=[CH:32][CH:33]=[C:34]([F:37])[CH:35]=5)[CH2:30][CH2:29]4)[CH2:26][CH2:27]3)=[CH:18][CH:17]=2)[CH:5]=[N:1]1
Reactant: Fc1ccc2c(c1)N(C1CCN(c3ccc(Cl)nn3)CC1)CC2
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: Fc1ccc2c(c1)N(C1CCN(c3ccc(-c4cn[nH]c4)nn3)CC1)CC2

Procedure:
1-(1-(6-(1H-pyrazol-4-yl)pyridazin-3-yl)piperidin-4-yl)-6-fluoroindoline was prepared according to the procedure described in Example 1, Method A, STEP 4, reacting pyrazole-4-boronic acid pinacol ester and 1-(1-(6-chloropyridazin-3-yl)piperidin-4-yl)-6-fluoroindoline.
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([C:10]([OH:12])=O)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:44]([O:47][C:48]1[C:57]([CH3:58])=[CH:56][C:51]([C:52]([NH:54][NH2:55])=[O:53])=[CH:50][C:49]=1[CH3:59])[CH:45]=[CH2:46]>C(Cl)Cl.CCOCC>[CH2:1]([C:5]1[S:9][C:8]([C:10]([NH:55][NH:54][C:52](=[O:53])[C:51]2[CH:50]=[C:49]([CH3:59])[C:48]([O:47][CH2:44][CH:45]=[CH2:46])=[C:57]([CH3:58])[CH:56]=2)=[O:12])=[CH:7][CH:6]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: C=CCOc1c(C)cc(C(=O)NN)cc1C
Reactant: CC(C)Cc1ccc(C(=O)O)s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOc1c(C)cc(C(=O)NNC(=O)c2ccc(CC(C)C)s2)cc1C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
To a solution of 5-isobutyl-thiophene-2-carboxylic acid (830 mg, 4.51 mmol) and DIPEA (680 mg, 5.27 mmol) in DCM (20 mL) is added TBTU (1.59 g, 4.96 mmol) at rt. The mixture is stirred at rt for 45 min before 4-allyloxy-3,5-dimethyl-benzoic acid hydrazide (993 mg, 4.50 mmol) is added. Stirring is continued for 2 h. The mixture is diluted with ether (200 mL) and washed with 1M aq. HCl (3×50 mL), 1M aq. NaOH (3×50 mL) and brine (50 mL). The org. extract is dried over MgSO4, filtered and evaporated to give the crude 4-allyloxy-3,5-dimethyl-benzoic acid N′-(5-isobutyl-thiophene-2-carbonyl)-hydrazide (1.40 g) as a yellow oil that slowly solidifies; LC-MS: tR=1.02 min, [M+1]+=387.10.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@H:5]23)[CH:10]=1.[Cl:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=1B(O)O>>[Cl:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=1[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[CH2:16][C@H:5]23)[CH:10]=1
Reactant: COc1ccc(B(O)O)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cc(Br)cc3c1N2CC3
Product: COc1ccc(-c2cc3c4c(c2)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@H]2N4CC3)c(Cl)c1

Procedure:
The title compound was prepared by the method of Example 90 from tert-butyl(±)-cis-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate (121 mg, 0.27 mmol) and corresponding 2-chloro-4-methoxyphenylboronic acid (100 mg, 0.54 mmol), to afford after chromatographic purification the title compound (141 mg, 68%) as a white amorphous solid. 1H NMR (CDCl3, 300 MHz) δ 7.21 (d, 1H, J=8.4 Hz), 6.94–6.99 (m, 3H), 6.82 (dd, 1H, J=2.9 Hz, 8.8 Hz), 3.75–4.00 (m, 7H), 3.60–3.70 (m, 1H), 3.10–3.50 (m, 7H), 2.80–3.00 (m, 1H), 1.70–1.90 (m, 2H), 1.48 (s, 9H) ppm. MS (CI, NH3): 441 (base, M+H).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[O:12][CH2:11][CH2:10][NH:9][CH2:8][C:7]=2[CH:13]=1.Cl[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C>C(O)CCC.C(OCC)(=O)C>[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[O:12][CH2:11][CH2:10][N:9]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=[CH:17][CH:16]=3)[CH2:8][C:7]=2[CH:13]=1
Reactant: Clc1ccnc2ccccc12
Reactant: Brc1ccc2c(c1)CNCCO2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: Brc1ccc2c(c1)CN(c1ccnc3ccccc13)CCO2
Yield: 84.4 %

Procedure:
A solution of 7-bromo-2,3,4,5-tetrahydro-1,4-benzoxazepine hydrochloride (1.50 g, 5.67 mmol) (example 2, step 1), 4-chloroquinoline (0.973 g, 5.95 mmol), diisopropylethylamine (2.93 g, 22.7 mmol) in 1-butanol (15 mL) was stirred at 170° C. for 1 hour in a microwave synthesizer. The reaction mixture was diluted with ethyl acetate (100 mL), washed with saturated sodium bicarbonate (50 mL) and brine (50 mL), dried over sodium sulfate. Filtration and concentration afforded a crude brown oil that was purified by silica gel chromatography (9:1 dichloromethane/methanol) to provide 7-bromo-4-quinolin-4-yl-2,3,4,5-tetrahydro-1,4-benzoxazepine (1.70 g, 84.6% yield) as a yellow oil. MS (EI) for C18H15BrN2O: 356 (MH+).
Reaction SMILES: Cl[C:2]([F:27])([F:26])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([O:18][CH:19]([CH3:21])[CH3:20])[C:4]=1[C:22]([O:24][CH3:25])=[O:23].C(N(CC)CC)C.[H][H]>C(O)C.[Pd]>[F:27][CH:2]([F:26])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([O:18][CH:19]([CH3:21])[CH3:20])[C:4]=1[C:22]([O:24][CH3:25])=[O:23]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1OC(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1OC(C)C
Yield: 90.8 %

Procedure:
A mixture of 3.0 g (0.007 mol) of product of Example 12, 0.72 g (0.007 mol) of triethylamine and 0.36 g of Pd/C (10%) in 30 ml of ethanol was hydrogenated with 501 kPa hydrogen pressure at 50° C. for 1 hour and filtered. The filtrate was concentrated, the residue dissolved in ether, washed with 3.7% aqueous HCl, dried (MgSO4) and concentrated in vacuo to 2.74 g of a brown oil. This oil was kugelrohr distilled at 67 Pa, pot temperature 90° C., to give 2.45 g (90.8%) of product as a yellow solid; mp 29°-31° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=O)[CH2:8][CH2:9][C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=O)[CH:2]=1.[CH3:19][Si:20]([CH3:29])([CH3:28])[CH2:21][CH2:22][O:23][C:24]([NH:26][NH2:27])=[O:25].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:19][Si:20]([CH3:29])([CH3:28])[CH2:21][CH2:22][O:23][C:24](=[O:25])[NH:26][N:27]1[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:8][CH:9]=[C:10]1[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(CCC(=O)c1cccnc1)c1cccnc1
Reactant: C[Si](C)(C)CCOC(=O)NN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C[Si](C)(C)CCOC(=O)Nn1c(-c2cccnc2)ccc1-c1cccnc1
Temperature: 25 °C

Procedure:
A solution of 1,4-di-Pyridin-3-yl-butane-1,4-dione (1 g, 4.2 mmol) in toluene (40 mL) is treated with hydrazinecarboxylic acid 2-trimethylsilanyl-ethyl ester (888 mg, 5.0 mmol) and p-toluenesulfonic acid (30 mg). The reaction vessel is fitted with a Dean Stark trap, and the resulting solution is heated to reflux, with azeotropic removal of water until no starting materials are detected by TLC. The solution is cooled to rt, and washed with water. The organic layer is dried over Na2SO4, filtered and concentrated to afford (2,5-di-pyridin-3-yl-pyrrol-1-yl)-carbamic acid 2-trimethylsilanyl-ethyl ester, which is not purified further.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][C:20]=1Cl)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[CH:10]=1)=O)([O-])=O.C(O)C.[H][H]>C(O)(C)C.[Pd]>[CH:13]1[CH:12]=[C:11]([NH2:15])[CH:10]=[C:9]([CH2:7][C:6]2[CH:18]=[CH:19][CH:20]=[C:4]([NH2:1])[CH:5]=2)[CH:14]=1
Reactant: [H][H]
Reactant: O=C(c1cccc([N+](=O)[O-])c1)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: CC(C)O
Product: Nc1cccc(Cc2cccc(N)c2)c1
Temperature: 25 °C
Yield: 82.2 %

Procedure:
30.7 g (0.1 mol) of 3,3'-dinitro-4-chlorobenzophenone, 1.5 g of 5% Pd/C and 100 ml of ethanol were charged in a closed glass vessel equipped with a thermometer and a stirrer. While stirring the mixture at a temperature of 65° to 70° C., hydrogen was introduced thereto and 20.1 l (0.9 mol) of hydrogen was absorbed in 6 hours. Since no more absorption of hydrogen was observed, the reaction was terminated at this point. The reaction mixture was cooled to room temperature and filtered to obtain a black filter cake. This filter cake was dissolved in 100 ml of a 90% aqueous isopropyl alcohol solution with heating. The catalyst was removed by filtration with heating. The filtrate was cooled to precipitate 3,3'-diaminodiphenylmethane hydrochloride as a crystal. This crystal was recovered by filtration, washed with 10 ml of isopropanol and neutralized with dilute aqueous ammonia to precipitate a white crystal. The crystal was recovered by filtration and dried in vacuo to give 16.3 g (yield 82.2%) of 3,3'-diaminodiphenylmethane.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][CH:7]([P:12]([OH:15])(=[O:14])[OH:13])[P:8]([OH:11])(=[O:10])[OH:9].[OH-].[Na+:17]>O>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][CH:7]([P:8]([OH:11])(=[O:9])[OH:10])[P:12]([O-:14])(=[O:13])[O-:15].[Na+:17].[Na+:17]
Reactant: O=P(O)(O)C(Nc1nccs1)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=P([O-])([O-])C(Nc1nccs1)P(=O)(O)O

Procedure:
2.74 g of 1-(thiazol-2-ylamino)methane-1,1-diphosphonic acid (example 1 ) are suspended in 10 ml of water. While stirring, 10 ml of 2N aqueous sodium hydroxide solution are added dropwise to the suspension. The resulting solution is evaporated to dryness. 40 ml of methanol are added to the resulting viscous residue and the mixture is stirred thoroughly. The resulting crystalline precipitate is filtered off and dried, yielding the disodium 1-(thiazol-2-ylamino)methane-1,1-diphosphonate of the formula ##STR10## which has a melting point of more than 320°.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[CH:7][N:8]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)[CH:9]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]=[CH:19][C:10]=1[N:8]1[CH:9]=[C:5]([CH2:3][OH:2])[N:6]=[CH:7]1
Reactant: COC(=O)c1cn(-c2ccc3ccccc3c2)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCc1cn(-c2ccc3ccccc3c2)cn1

Procedure:
Following the general method described in example 298) 1-naphthalen-2-yl-1H-imidazole-4-carboxylic acid methyl ester was reacted with lithium aluminum hydride followed by hydrolytic workup and chromatography. The title compound was obtained as a light brown gum. MS: m/e=225 (M+).
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13]/[CH:14]=[C:15](/[C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)\[CH3:16])[CH:7]=1)C.C(O)C>[OH-].[Na+].Cl.C(OCC)(=O)C>[Br:29][C:26]1[CH:27]=[CH:28][C:23]([C:20]2[CH:19]=[CH:18][C:17](/[C:15](/[CH3:16])=[CH:14]/[CH2:13][O:12][C:8]3[CH:7]=[C:6]([CH2:5][C:4]([OH:30])=[O:3])[CH:11]=[CH:10][CH:9]=3)=[CH:22][CH:21]=2)=[CH:24][CH:25]=1
Reactant: CCOC(=O)Cc1cccc(OC/C=C(\C)c2ccc(-c3ccc(Br)cc3)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: C/C(=C\COc1cccc(CC(=O)O)c1)c1ccc(-c2ccc(Br)cc2)cc1
Yield: 98.6 %

Procedure:
(E)-{3-[3-(4′-Bromo-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-acetic acid ethyl ester (example 22) (150 mg, 0.32 mmol) was suspended in 1N NaOH (0.82 mL) and ethanol (5 mL) and stirred for 24 h at room temperature. The mixture was diluted with 1N HCl (0.82 mL) and ethyl acetate (10 mL). The aqueous layer was separated and extracted with ethyl acetate (20 mL) The organic layers were combined, washed with brine, dried (MgSO4) and evaporated to give 138 mg (98%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[CH:15]1([NH:21][C:22]([C@H:24]2[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]2)=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.O1CCOCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:15]1([NH:21][C:22]([C@H:24]2[CH2:29][CH2:28][CH2:27][N:26]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:25]2)=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: O=C(NC1CCCCC1)[C@H]1CCCNC1
Reactant: Brc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: O=C(NC1CCCCC1)[C@H]1CCCN(c2ccccc2)C1

Procedure:
A mixture of bromobenzene (13 μL, 0.00012 mol), (3S)—N-cyclohexylpiperidine-3-carboxamide trifluoroacetate (40 mg, 0.0001 mol), sodium tert-butoxide (28 mg, 0.00030 mol), palladium acetate (0.8 mg, 0.000004 mol) and 2-(di-tert-butylphosphino)biphenyl (1 mg, 0.000004 mol) was vacuumed and charged with nitrogen. To the mixture was added 1,4-dioxane (1 mL, 0.01 mol) and the resulting mixture was refluxed overnight. After cooling, the mixture to ambient temperature the inorganics were filtered and the filtrate was adjusted with TFA to pH=7.0. The crude product was chromatographed by combiflash (ethyl acetate in hexanes: 60%) to afford the desired product. LCMS: m/z 287.3 (M+H)+.
Reaction SMILES: OC(C(F)(F)F)=O.[F:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:24])[NH:16][N:15]=2)=[CH:11][C:10]=1[C:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:28].[CH:35]1([C:38](=[O:42])[C:39](O)=[O:40])[CH2:37][CH2:36]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:35]1([C:38](=[O:42])[C:39]([N:32]2[CH2:33][CH2:34][N:29]([C:27](=[O:28])[C:10]3[CH:11]=[C:12]([CH2:13][C:14]4[C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[C:17](=[O:24])[NH:16][N:15]=4)[CH:25]=[CH:26][C:9]=3[F:8])[CH2:30][CH2:31]2)=[O:40])[CH2:37][CH2:36]1
Reactant: O=C(O)C(=O)C1CC1
Reactant: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(C(=O)N1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.2 %

Procedure:
4-(4-fluoro-3-(piperazine-1-carbonyl)benzyl)phthalazin-1(2H)-one TFA salt (1.24 g, 2.68 mmol), 2-cyclopropyl-2-oxoacetic acid (2.84 g, 24.84 mmol), DIPEA (6.9 ml, 41.4 mmol), and HATU (4.08 g, 10.8 mmol) were mixed in DMF (100 ml), the resulting reaction mixture was stirred at room temperature for overnight until the reaction finished (monitored by TLC). The reaction mixture was then partitioned between DCM and water (100 ml each, the water phase was extracted with DCM (100 ml). The combined organic phase was washed with water, sat. aqueous sodium bicarbonate, and brine, dried over sodium sulphate, filtered, and concentrated to yield the crude product. Then the crude product was purified by column chromatography on silica gel (DCM: MeOH=100:1) and re-crystallized from methanol to afford the desired product (610 mg, 49.3%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[N+:22]([O-])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[NH2:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)c1
Reaction time: 2 h
Yield: 99.4 %

Procedure:
4-(4-methyl-2-nitrophenylamino)-piperidine-1-carboxylic acid tert-butyl ester (3.0 g, 8.96 mmol) was dissolved in a mixture of THF and CH3OH (100 mL). Then 10% of Pd on carbon (0.60 g) was added. The mixture was hydrogenated at 50 psi for 2 hrs. The mixture was filtered through a pad of Celite® and washed with CH3OH. The filtrate was evaporated to dryness to give a pink residue as 4-(2-amino-4-methylphenylamino)-piperidine-1-carboxylic acid tert-butyl ester (2.72 g, 100%).
Reaction SMILES: [C:1]([NH:4]/[C:5](=[CH:10]/[C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([NH2:18])=[C:13]([Cl:19])[CH:12]=1)/[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1CC=CCCC=C1.C1CC=CCCC=C1.[Cl-].[Cl-].[Rh].[Rh]>[C:1]([NH:4][CH:5]([CH2:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([NH2:18])=[C:13]([Cl:19])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2]
Reactant: COC(=O)/C(=C\c1cc(C)c(N)c(Cl)c1)NC(C)=O
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: [Cl-]
Solvent: C1=CCCC=CCC1
Product: COC(=O)C(Cc1cc(C)c(N)c(Cl)c1)NC(C)=O

Procedure:
20.6 g (73.0 mmol) methyl (E)-2-acetylamino-3-(4-amino-3-chloro-5-methyl-phenyl)-acrylate, 0.445 g (0.90 mmol) bis(1,5-cyclooctadiene)-di-rhodium(I)-dichloride, 0.744 g (1.8 mmol) 1,3-bis(diphenylphosphino)-propane were dissolved in 400 ml degassed methanol and 12 ml degassed triethylamine and then hydrogenated at ambient temperature under 3 bar hydrogen pressure. The reaction mixture was evaporated down under reduced pressure and taken up in ethyl acetate. The insoluble precipitate was removed by suction filtering and the filtrate was evaporated down under reduced pressure. The residue was purified by column chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[C:17]([F:18])=[C:16]([F:19])[CH:15]=[CH:14][C:13]=2[F:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]=[CH2:27].CC(C)([O-])C.[K+].O>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]([C:12]2[C:13]([F:20])=[CH:14][CH:15]=[C:16]([F:19])[C:17]=2[F:18])[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]=[CH2:22])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cc1c(F)ccc(F)c1F)c1ccc(Cl)cc1
Reactant: C=CCCCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCCCCC(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(4-Chloro-benzenesulfonylmethyl)-1,3,4-trifluoro-benzene (1.0 g, 3.1 mmol, from example 8, step 2) and 6-bromo-1-hexene (1.5 g, 6.3 mmole) were dissolved in 20 mL THF and potassium t-butoxide (1M in THF, 6.2 mL) was added. The reaction mixture was stirred at room temperature for three hours. 50 mL water and 50 mL EtOAc were added. The organic layer washed with brine (50 mL), dried over Na2SO4 and concentrated. The product was purified by column chromatography using EtOAc/Hexane as eluent (gradient from 0/100 to 25/75 in 40 minutes, 0.65 g, 52%). 1H NMR (CDCl3, 400 MHz) δ 7.63 (d, j=8.05 Hz, 2H), 7.45 (d, j=8.05 Hz, 2H), 7.14 (m, 1H), 6.83 (m, 0.5H), 6.74 (m, 0.5H), 5.70 (m, 1H), 4.93 (m, 2H), 4.58 (d, j=5.1 and 6.5 Hz, 1H), 2.43 (m, 1H), 2.31 (m, 1H), 1.99 (m, 2H), 1.39 (m, 2H), 1.25 (m, 2H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][NH:5][CH2:4][C@H:3]1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].[Cl:16][C:17]1[CH:22]=[CH:21][C:20](I)=[CH:19][N:18]=1>>[Cl:16][C:17]1[N:18]=[CH:19][C:20]([N:5]2[CH2:6][CH2:7][C@@H:2]([CH3:1])[C@H:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4]2)=[CH:21][CH:22]=1
Reactant: C[C@H]1CCNC[C@H]1NC(=O)OC(C)(C)C
Reactant: Clc1ccc(I)cn1
Product: C[C@@H]1CCN(c2ccc(Cl)nc2)C[C@H]1NC(=O)OC(C)(C)C
Yield: 24.4 %

Procedure:
The trans product from Example 39C (0.146 g, 0.68 mmol) and 2-chloro-5-iodopyridine (0.21 g, 0.88 mmol; Aldrich) were processed according to the procedure in Example 1A to provide the title compound (0.054 g, 24%). MS (CI/NH3) m/z 326/328 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:9][C:10]2[CH:11]=[C:12]([CH:25]=[CH:26][C:27]=2[CH3:28])[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH3:24])[CH3:23])[CH:17]=2)=[O:14])=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[N-:29]=[N+:30]=[N-:31].[Na+].[Cl-].[NH4+]>CN(C=O)C>[NH:29]1[C:1]([C:3]2[C:4]([NH:9][C:10]3[CH:11]=[C:12]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH3:24])[CH3:23])[CH:17]=3)=[O:14])=[N:5][CH:6]=[CH:7][CH:8]=2)=[N:2][N:31]=[N:30]1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(C(=O)Nc2cccc(C(C)C)c2)cc1Nc1ncccc1C#N
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2cccc(C(C)C)c2)cc1Nc1ncccc1-c1nnn[nH]1
Temperature: 130 °C

Procedure:
To 3-(3-cyanopyridin-2-ylamino)-N-(3-isopropylphenyl)-4-methylbenzamide (11 mg, 0.03 mmol), sodium azide (21 mg, 0.30 mmol) and ammonium chloride (17 mg, 0.30 mmol) was added DMF (0.5 mL). The mixture was heated to 130° C. in the microwave for 10 minutes. The reaction was quenched with saturated sodium bicarbonate and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to yield 3-(3-(1H-tetrazol-5-yl)pyridin-2-ylamino)-N-(3-isopropylphenyl)-4-methylbenzamide. MS m/z [M+H]+=414; Calc'd for C23H23N7O: 413.49.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[N:12]=[C:11]([C:21]([OH:23])=O)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[O:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][NH2:32])[CH2:26][CH2:25]1.[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]/[C:36]([OH:38])=[O:37]>C(O)C>[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]/[C:36]([OH:38])=[O:37].[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([C:21](=[O:23])[NH:32][CH2:31][CH2:30][N:27]3[CH2:28][CH2:29][O:24][CH2:25][CH2:26]3)[N:12]=[C:13]([CH3:20])[C:14]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)c1c(-c2cccc(C#N)c2)cc(C(=O)O)nc1C
Reactant: NCCN1CCOCC1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Product: CCOC(=O)c1c(-c2cccc(C#N)c2)cc(C(=O)NCCN2CCOCC2)nc1C
Yield: 52.1 %

Procedure:
Ethyl 4-(3-cyanophenyl)-2-methyl-6-(2-morpholinoethylcarbamoyl)-3-pyridinecarboxylate, which was obtained according to a similar manner to that of Example 18 from 4-(3-cyanophenyl)-5-ethoxycarbonyl-6-methyl-2-pyridinecarboxylic acid (0.93 g) and 2-morpholinoethylamine (0.39 g), was treated with a solution of fumaric acid (0.54 g) in ethanol (11 ml) to give ethyl 4-(3-cyanophenyl)-2-methyl-6-(2-morpholinoethylcarbamoyl)-3-pyridinecarboxylate fumarate (0.84 g).
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11]=1[CH2:12][CH2:13][C:14]([OH:16])=[O:15])=O.[Br:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21]2.N1CCCC1.C(O)(=O)C>C(O)C>[Br:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[C:21]2=[CH:1][C:3]1[NH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11]=1[CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: O=Cc1[nH]c2c(c1CCC(=O)O)CCCC2
Reactant: O=C1Cc2cc(Br)ccc2N1
Solvent: CCO
Solvent: CC(=O)O
Solvent: C1CCNC1
Product: O=C(O)CCc1c(C=C2C(=O)Nc3ccc(Br)cc32)[nH]c2c1CCCC2
Temperature: 25 °C
Yield: 98.3 %

Procedure:
A mixture of 3-(2-Formyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propionic acid (3.4 g), 2.7 g of 5-bromo-2-oxindole and 1.4 g of pyrrolidine in 25 mL of ethanol was refluxed for 4 hours. Upon slow addition of acetic acid (8 mL), a precipitate formed. The mixture was refluxed for 5 minutes and cooled to ambient temperature. The precipitate was collected by vacuum filtration and washed with 20 mL of ethanol. The solids were slurry-washed by refluxing in 30 mL of ethanol, cooled, collected by vacuum filtration, washed with 30 mL of ethanol and dried under vacuum to give 5.2 g (98% yield) of 3-[2-(5-bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-propionic acid as a red-orange solid, mp 286-289° C.