Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Br:10][C:11]1[CH:19]=[C:18]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[O:21])[CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH3:56][O:57][C:58](=[O:70])[C@H:59]([CH2:61][NH:62][C:63]([C:65]1[S:66][CH:67]=[CH:68][CH:69]=1)=[O:64])[NH2:60].C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[Br:10][C:11]1[CH:19]=[C:18]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[O:21])[CH:17]=[CH:16][C:12]=1[C:13]([NH:60][C@H:59]([C:58]([O:57][CH3:56])=[O:70])[CH2:61][NH:62][C:63]([C:65]1[S:66][CH:67]=[CH:68][CH:69]=1)=[O:64])=[O:15]
Reactant: O=C(NCc1cccc(O)c1)c1ccc(C(=O)O)c(Br)c1
Reactant: COC(=O)[C@@H](N)CNC(=O)c1cccs1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Br
Reaction time: 6 h
Yield: 82.5 %

Procedure:
Diisopropylethylamine (305 μL, 1.71 mmol) was added dropwise to a solution of 2-bromo-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoic acid (Example 47; 150 mg, 0.428 mmol), HBTU (179 mg, 0.471 mmol), 3-(thiophene-2-carbonyl)amino-L-alanine methyl ester HCl salt (Example 301; 125 mg, 0.471 mmol), and HOBT (64 mg, 0.471 mmol) in N,N-dimethylformamide (6.5 mL) at 25° C. The solution was stirred for 6 h. The solvent was concentrated under vacuum to remove most of the N,N-dimethylformamide. The residue was diluted with ethyl acetate (60 mL) and washed with 1 N HCl (10 mL), water (10 mL), saturated aqueous NaHCO3 (10 mL) and brine (10 mL). The organic layer was dried (MgSO4), filtered, evaporated and flash chromatographed (silica, 60-75% ethyl acetate in petroleum ether) to give N-[2-bromo-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine, methyl ester (198 mg, 83%) as an off-white foam.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([C:13]2[S:23][C:22]3[N:24]4[C:15](=[CH:16][N:17]=[C:18]4[CH:19]=[CH:20][CH:21]=3)[CH:14]=2)=[O:12])[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(O)C>[CH2:32]([N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([C:13]2[S:23][C:22]3[N:24]4[C:15](=[CH:16][N:17]=[C:18]4[CH:19]=[CH:20][CH:21]=3)[CH:14]=2)=[O:12])[CH2:5][CH2:4]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(NCC1CCNCC1)C1=Cc2cnc3cccc(n23)S1
Reactant: BrCc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(NCC1CCN(Cc2ccccc2)CC1)C1=Cc2cnc3cccc(n23)S1

Procedure:
To a solution of 0.58 g (1.5 mM) of N-(piperidin-4-ylmethyl)-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride and 1.0 ml (7.5 mM) of triethylamine in ethanol was added 0.19 ml (1.6 mM) of benzyl bromide at room temperature, and the mixture was refluxed under nitrogen for 6 hours. The solvent was then distilled off under reduced pressure and the residue was diluted with water and extracted with methylene chloride. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4. The resulting crude product was purified by column chromatography (methanol/ethyl acetate 40%) to provide the title compound.
Reaction SMILES: Cl[C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:19]=[CH:18][C:10]([O:11][CH:12]([CH2:16]C)[C:13]([Cl:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.ClC1C=CC(OC2C=CC(OC(CCC)C(Cl)=O)=CC=2)=CC=1.BrC1C=CC([N+:51]([O-:53])=[O:52])=CC=1>>[N+:51]([C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:19]=[CH:18][C:10]([O:11][CH:12]([CH3:16])[C:13]([Cl:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1)([O-:53])=[O:52]
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: CCC(Oc1ccc(Oc2ccc(Cl)cc2)cc1)C(=O)Cl
Agent: CCCC(Oc1ccc(Oc2ccc(Cl)cc2)cc1)C(=O)Cl
Product: CC(Oc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1)C(=O)Cl

Procedure:
2-bromoacetic acid, (b) 2-bromobutyric acid, and (c) 2-bromovaleric acid in the above (A), were used to obtain (a'), 4-(4-chlorophenoxy)phenoxyacetic acid chloride, (b') 2-(4-(4-chlorophenoxy)phenoxybutyric acid chloride, (c') 2-(4-(4-chlorophenoxy)phenoxy)valeric acid chloride, respectively. Also, by using (d) 4-bromonitrobenzene instead of 4-bromochlorobenzene in the above (a), (d') 2-(4-(4-nitrophenoxy)phenoxy)propionic acid chloride was obtained.
Reaction SMILES: O.NN.[C:4]([O:8][C:9](=[O:31])[NH:10][CH2:11][CH2:12][CH:13]([N:20]1C(=O)C2C(=CC=CC=2)C1=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:7])([CH3:6])[CH3:5]>C1COCC1.CO>[C:4]([O:8][C:9](=[O:31])[NH:10][CH2:11][CH2:12][CH:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:7])([CH3:5])[CH3:6]
Reactant: CC(C)(C)OC(=O)NCCC(c1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCCC(N)c1ccccc1
Temperature: 65 °C

Procedure:
Hydrazine hydrate (85%, 5.1 mL, 74 mmol) was added to a solution of [3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-phenyl-propyl]-carbamic acid tert-butyl ester (2.8 g, 7.4 mmol) in THF (25 mL) and MeOH (25 mL). The resulting mixture was heated to 65° C. for 6 hours. Then the precipitate was filtered, and the filtrate was concentrated under reduced pressure to give crude product which was purified by column chromatography on silica gel (dichloromethane:MeOH, 100:1, 1% NH3 H2O) to give (3-amino-3-phenyl-propyl)-carbamic acid tert-butyl ester as an off-white solid. (Yield 1.7 g, 92%). 1H NMR (300 MHz, CDCl3): δ 7.31-7.18 (m, 5H), 6.82 (brs, 1H), 3.78-3.74 (m, 1H), 2.92 (brs, 2H), 1.82 (s, 2H), 1.63-1.61 (m, 2H), 1.37 (s, 9H). LC-MS: [M+H]+ 251.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:15][CH2:16][CH2:17][N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[NH:20][C:19]1=[O:27].C(N(C(C)C)CC)(C)C.O>CN(C=O)C.C1(C)C=CC=CC=1>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([N:1]2[CH2:2][CH2:3][N:4]([CH2:15][CH2:16][CH2:17][N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[NH:20][C:19]3=[O:27])[CH2:5][CH2:6]2)=[N:8][CH:9]=1
Reactant: O=c1[nH]c2ccccc2n1CCCCl
Reactant: Clc1ccc(N2CCNCC2)nc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccccc2n1CCCN1CCN(c2ccc(Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 116.6 %

Procedure:
A mixture of 1.14 gm of 2-piperazino 5-chloro pyridine, 1.35 gm of 1-(3-chloro propyl)-2,3-dihydro-1H-benzimidazol-2-one (available from Janssen) and 1.49 gm of diisopropylethylamine in 3 ml DMF and 30 ml toluene is kept for 12 hours at 110° C. Upon cooling to ambient temperature, 30 ml water is added and the mixture is extracted with chloroform (CHCl3) and the extract is collected, washed with 20 ml water and dried over sodium sulfate (Na2SO4). The crude product (2.5 gm) which is obtained after removing the solvents is purified using chromatography: solid phase (SiO2 ; 40 μm; Baker); eluant 2% methanol (CH3OH) in methylene chloride (CH2Cl2). A sample of this purified material (1.2 gm) was transferred into its hydrochloride (mp: 200° C.) by treating an ethanolic suspension of this material with a mixture of ethyl ether/HCl.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[NH2:10][C:11]1[C:12]([C:33](O)=[O:34])=[N:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:15][N:16]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.[ClH:78]>CN(C)C=O.C(Cl)Cl.C(OCC)C>[ClH:78].[NH2:10][C:11]1[C:12]([C:33]([NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=2[O:2][CH3:1])=[O:34])=[N:13][C:14]([C:17]2[CH:18]=[CH:19][C:20]([S:23]([N:26]3[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]3)(=[O:25])=[O:24])=[CH:21][CH:22]=2)=[CH:15][N:16]=1
Reactant: CN1CCN(S(=O)(=O)c2ccc(-c3cnc(N)c(C(=O)O)n3)cc2)CC1
Reactant: COc1ccccc1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccccc1NC(=O)c1nc(-c2ccc(S(=O)(=O)N3CCN(C)CC3)cc2)cnc1N
Reaction time: 13 h
Yield: 12 %

Procedure:
2-Methoxyaniline (80 mg, 318 mmol) was added to a mixture of 3-amino-6-[4-[(4-methyl-1-piperazinyl)sulfonyl]phenyl]-2-pyrazinecarboxylic acid (80 mg, 212 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (82 mg, 255 mmol), 1-hydroxybenzotriazole hydrate (34 mg, 255 mmol) and N-ethyl-N,N-diisopropylamine (0.111 mL, 0.637 mmol) in N,N-dimethylformamide (2 mL). The reaction mixture was stirred for 13 h. The reaction was quenched with water (1 mL) and the solvent was evaporated. Purification by preparative HPLC (column: XTerra C8 19×300 mm, eluent: a acetonitrile/water, (20:80 to 80:20), gradient) followed by evaporation of the solvent gave a yellowish solid that was dissolved in methylene chloride (10 mL). HCl in diethyl ether (1 M, 2.5 mL) was added while stirring. Filtration and drying gave 12 mg (12% yield) of the title compound: MS (ESI) 483 m/z (M++1).
Reaction SMILES: I[C:2]1[N:11]=[C:10]2[N:4]([CH2:5][CH2:6][C:7]3[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=3[CH:9]2[O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[CH:3]=1.[C:24]([NH:31][CH2:32][C:33]#[CH:34])([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].N(CC)CC.N>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:27]([O:26][C:24](=[O:25])[NH:31][CH2:32][C:33]#[C:34][C:2]1[N:11]=[C:10]2[N:4]([CH2:5][CH2:6][C:7]3[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=3[CH:9]2[O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[CH:3]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CN1CCC(OC2c3ccccc3CCn3cc(I)nc32)CC1
Reactant: C#CCNC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: N
Solvent: CCNCC
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCC(OC2c3ccccc3CCn3cc(C#CCNC(=O)OC(C)(C)C)nc32)CC1
Temperature: 50 °C

Procedure:
To a solution of compound 2-iodo-4-(1-methyl piperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene (example 2A) (80 mg, 0.19 mmoles) in DMF (0.5 mL) in a screw-capped vial under argon are added CuI (7.2 mg, 0.038 mmole), (PPh3)2PdCl2 (13.3 mg, 19 μmole), N-Boc-propargylamine (91 mg, 0.57 mmole) and Et2NH (58 μL, 0.57 mmole). The reaction mixture is heated at 50° C. overnight. Water is added and pH adjusted to 9-10 with concentrated aqueous ammonia solution. The aqueous phase is extracted three times with AcOEt. The organic phase is dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is pre-purified by silica gel chromatography using (CH2Cl2:MeOH) as eluent with a gradient from (95:5) to (90:10) and the residue is submitted to a preparative thin-layer chromatography eluting with (CH2Cl2:MeOH:NH4OH) (9:1:1) to afford {3-[4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]-prop-2-ynyl}-carbamic acid tert-butyl ester.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[CH:27]=[CH:26][C:23](C=O)=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C2(C3C=CC=CC=3)CCP(C3C=CC=CC=3)[C:35]2=[CH:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])C=CC=CC=1>C1C=CC=CC=1.CCCCCC.C(OCC)C.C(O)(=O)C1C=CC=CC=1>[Si:1]([O:18][CH2:19][C:20]1[CH:27]=[CH:26][C:23](/[CH:35]=[CH:45]/[C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=C1P(c2ccccc2)CCC1(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](OCc1ccc(C=O)cc1)(c1ccccc1)c1ccccc1
Agent: O=C(O)c1ccccc1
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: CCCCCC
Product: CCOC(=O)/C=C/c1ccc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Reaction time: 2 h
Yield: 347.8 %

Procedure:
To a solution of 4-(t-butyldiphenylsilyloxymethyl)benzaldehyde (3.26 g, 8.71 mmol) in benzene (80 mL) were added ethyl (triphenylphospholanylidene)acetate (3.19 g, 9.14 mmol) and benzoic acid (116.0 mg, 0.950 mmol) at room temperature, and the mixture was heated under reflux with stirring for 2 h. The reaction mixture was directly concentrated under reduced pressure, and the residue thus obtained was diluted with hexane (80 mL) and diethyl ether (40 mL) and stirred for 8 h. Precipitated solids were filtered, and the residue obtained by concentrating the filtrate under reduced pressure was subjected to silica gel column chromatography (hexane-ethyl acetate 25:1) to give 13.47 g of ethyl (E)-3-{4-[(t-butyldiphenylsilyloxy)methyl]phenyl}acrylate as oil (yield: 90%).
Reaction SMILES: CN(C1C=CC=CN=1)C.[N+:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[C:16]2[NH2:22])([O-:12])=[O:11].[C:23]([O:27][C:28](OC([O-])=O)=[O:29])([CH3:26])([CH3:25])[CH3:24].C(N(CC)CC)C>C1COCC1>[C:23]([O:27][C:28]([N:18]1[C:19]2[C:15](=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:21][CH:20]=2)[C:16]([NH2:22])=[N:17]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: Nc1n[nH]c2ccc([N+](=O)[O-])cc12
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1nc(N)c2cc([N+](=O)[O-])ccc21
Reaction time: 0.5 h
Yield: 49.6 %

Procedure:
Dimethylaminopyridine (4 g, 36 mmol) was added to a solution of 5-nitro-1H-indazol-3-ylamine (32.2 g, 181 mmol), tert-butyldicarbonate (39.4 g, 181 mmol) and triethylamine (25 mL, 181 mmol) in THF (1 L) at room temperature under nitrogen. After stirring for 30 minutes, the reaction mixture was concentrated and the residue partitioned between EtOAc and saturated ammonium chloride solution. The layers were separated and the organic phase washed with brine, dried (MgSO4), and concentrated to an orange solid. Recrystallisation from ethyl acetate provided the title product as a yellow solid (25 g, 50%). 1H NMR (400 MHz, DMSO) 1.60 (9H, s), 6.75 (2H, brs), 8.10 (1H, d), 8.36 (1H, d), 8.96 (1H, s); MS (ES−) m/e=277.
Reaction SMILES: [BrH:1].N1C=CC=CC=1.[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH:10]=[C:9]1[C:17]([CH3:19])=[O:18]>CO>[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH:10]=[C:9]1[C:17](=[O:18])[CH2:19][Br:1]
Reactant: CC(=O)c1cc2ccccc2o1
Reactant: Br
Solvent: CO
Solvent: c1ccncc1
Product: O=C(CBr)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 7 h
Yield: 120.5 %

Procedure:
A polymer of perbromide of pyridine hydrobromide (8.75 g; 17.5 mmol; 1.4 equivalent) is added to a solution of (benzofuran-2-yl)methylketone (2 g; 12.5 mmol) in methanol (40 ml). The resulting mixture is stirred at ambient temperature for 7 hours and the reaction is stopped by filtration. The methanol is eliminated under reduced pressure and an additional addition of diethyl ether allows crystallization of the expected product (3.6 g; yield=60%).
Reaction SMILES: NC(CCCCCCCCC(N)CCC)CCC.C(C1CC=CCCC=CCC(CCC)N=N1)CC.[CH:37]1([CH:43]2[CH2:54][CH:53]=[CH:52][CH2:51][CH2:50][CH:49]=[CH:48][CH2:47][CH:46]([CH:55]3[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]3)[N:45]=[N:44]2)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>>[NH2:44][CH:43]([CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH:46]([NH2:45])[CH:55]1[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]1
Reactant: C1=CCC(C2CCCCC2)N=NC(C2CCCCC2)CC=CCC1
Agent: CCCC(N)CCCCCCCCC(N)CCC
Agent: CCCC1CC=CCCC=CCC(CCC)N=N1
Product: NC(CCCCCCCCC(N)C1CCCCC1)C1CCCCC1
Yield: 90.3 %

Procedure:
If there are used in the manner described under (a), instead of 942 g (3.79 mols) of 3,12-dipropyl-1,2-diaza-1,5,9-cyclododecatriene, 328.5 g (1 mol) of 3,12-dicyclohexyl-1,2-diaza-1,5,9-cyclododecatriene (diastereoisomeric mixture) and correspondingly reduced amounts of catalyst and solvent, using otherwise the same procedure, there is obtained, as the main fraction, 304 g (90% of theory) of 1,10-diamino-1,10-dicyclohexyldecane as colourless oil [b.p. 190°-193° C./0.05 Torr; nD20 =1.4944; IR (liquid) inter alia bands at 3355, 3278 and 1613 cm-1 ].
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([NH:10][C:11]([C:13]2[C:14]([CH3:23])=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=2)=[O:12])[CH:7]=[CH:6][C:5]=1[Cl:24].[BH4-].[Li+].C(=O)(O)[O-].[Na+]>O1CCCC1>[Cl:24][C:5]1[CH:6]=[CH:7][C:8]([NH:10][C:11](=[O:12])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[N:15][C:14]=2[CH3:23])=[CH:9][C:4]=1[CH2:3][OH:2]
Reactant: COC(=O)c1cc(NC(=O)c2ccc(C(F)(F)F)nc2C)ccc1Cl
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(CO)c1
Temperature: 45 °C
Yield: 53 %

Procedure:
A solution of 2-chloro-5-[(2-methyl-6-trifluoromethyl-pyridine-3-carbonyl)-amino]-benzoic acid methyl ester (6.68 g; 18 mmol) in tetrahydrofuran (100 ml) was cooled to 0° C. Lithium borohydride (0.98 g; 45 mmol) was added portionwise and the reaction mixture allowed to warn to room temperature, followed by heating at 45° C. for 4 hours. The reaction was allowed to cool to room temperature and saturated sodium bicarbonate solution (100 ml) was added. This was extracted with ethyl acetate (3×50 ml). The organic layers were dried (magnesium sulphate), filtered and evaporated. The residue was purified by column chromatography (50% ethyl acetate in heptane) to give N-(4-chloro-3-hydroxymethyl-phenyl)-2-methyl-6-trifluoromethyl-nicotinamide (3.29 g, 54%).
Reaction SMILES: NC1N(C2C=C(CC(OCC)=O)C=CC=2)N=C(C2C=CSC=2)C=1.[NH2:24][C:25]1[N:29]([C:30]2[CH:31]=[C:32]([CH:36]([CH3:42])[C:37]([O:39]CC)=[O:38])[CH:33]=[CH:34][CH:35]=2)[N:28]=[C:27]([C:43]2[CH:47]=[CH:46][S:45][CH:44]=2)[CH:26]=1.[Cl:48][C:49]1[C:54]([Cl:55])=[CH:53][CH:52]=[CH:51][C:50]=1[N:56]=[C:57]=[O:58]>>[Cl:48][C:49]1[C:54]([Cl:55])=[CH:53][CH:52]=[CH:51][C:50]=1[NH:56][C:57](=[O:58])[NH:24][C:25]1[N:29]([C:30]2[CH:31]=[C:32]([CH:36]([CH3:42])[C:37]([OH:39])=[O:38])[CH:33]=[CH:34][CH:35]=2)[N:28]=[C:27]([C:43]2[CH:47]=[CH:46][S:45][CH:44]=2)[CH:26]=1
Reactant: O=C=Nc1cccc(Cl)c1Cl
Reactant: CCOC(=O)C(C)c1cccc(-n2nc(-c3ccsc3)cc2N)c1
Agent: CCOC(=O)Cc1cccc(-n2nc(-c3ccsc3)cc2N)c1
Product: CC(C(=O)O)c1cccc(-n2nc(-c3ccsc3)cc2NC(=O)Nc2cccc(Cl)c2Cl)c1

Procedure:
Using the same general approach as for Example 524, ethyl 2-(3-(5-amino-3-(thiophen-3-yl)-1H-pyrazol-1-yl)phenyl)acetate (0.2258 g, 0.450 mmol, 1.00 eq) was transformed to ethyl 2-(3-(5-amino-3-(thiophen-3-yl)-1H-pyrazol-1-yl)phenyl)propanoate. This, in turn, was combined with 2,3-dichlorophenyl isocyanate, according to general method A, to afford 2-(3-(5-(3-(2,3-dichlorophenyl)ureido)-3-(thiophen-3-yl)-1H-pyrazol-1-yl)phenyl)propanoic acid. Using general method J, this product was combined with 0.5M NH3 in dioxane (4.50 ml, 2.25 mmol, 5.00 eq). to afford 0.1731 g (77%) of pure 1-(1-(3-(1-amino-1-oxopropan-2-yl)phenyl)-3-(thiophen-3-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea. 1H NMR (DMSO-d6): δ 9.38 (s, 1H), 8.82 (s, 1H), 8.12-8.09 (m, 1H), 7.88-7.87 (m, 1H), 7.62-7.60 (m, 1H), 7.57-7.42 (m, 6H), 7.36-7.31 (m, 2H), 6.89 (brs, 1H), 6.86 (s, 1H), 3.69 (q, 1H, J=7.2 Hz), 1.36 (d, 3H, J=7.2 Hz); MS (ESI) m/z: 500.0 (M+H+), 502.0 (M+2+H+).
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO>[Cl:17][C:14]1[CH:15]=[CH:16][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][CH:10]([CH3:12])[C:9]=2[CH:13]=1
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2ccc(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1CNCCc2ccc(Cl)cc21
Temperature: 60 °C
Reaction time: 3.5 h
Yield: 81.3 %

Procedure:
A solution of N-trifluoroacetyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (65 mg, 0.22 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH (2 mL), and stirred for 3.5 hours at 60° C. The product mixture was concentrated, extracted 3 times with CH2Cl2 (5 mL), dried with Na2SO4 and concentrated to give 35 mg of a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.11 (s, 1H), 7.05 (d, J=8 Hz, 1H), 6.98 (d, J=8 Hz, 1H), 3.1-2.9 (m, 6H), 2.71 (m, 1H), 2.68 (bs, 1H), 1.32 (d, J=8 Hz, 3H). MS calculated for C11H14ClN+H: 196, observed: 196.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]2[N:10]([Si](C(C)C)(C(C)C)C(C)C)[CH:11]=[CH:12][C:3]=12.[CH3:23][NH2:24]>COC(O)C>[CH3:23][NH:24][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]2[NH:10][CH:11]=[CH:12][C:3]=12
Reactant: CN
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)c(C=O)cnc21
Agent: COC(C)O
Product: CNc1c(C=O)cnc2[nH]ccc12
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A mixture of 4-chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (5.9 g, 17.5 mmol), methyl amine (40 wt. % solution in water, 40 mL) in methoxyethanol (10 mL) is heated at 120° C. in a sealed tube. After overnight, the reaction mixture is cooled to room temperature and concentrated. The residue is dissolved in HCl solution (1N, 20 mL) and heated at 50° C. After stirring for 1.5 hours, the reaction mixture is basified with saturated sodium bicarbonate solution to pH=8. The solid is collected by filtration and washed with water, then hexanes, dried to afford the title compound as a solid. MS m/z 176.2 (M+1).
Reaction SMILES: Cl.[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]21[CH2:16][CH2:15][CH:14]([NH2:17])[CH2:13][CH2:12]2.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>N1C=CC=CC=1>[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]21[CH2:12][CH2:13][CH:14]([NH:17][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:16]2
Reactant: CCOC(=O)Cl
Reactant: NC1CCC2(CCc3ccccc3C2)CC1
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)NC1CCC2(CCc3ccccc3C2)CC1
Temperature: 0 °C

Procedure:
To an ice cooled solution of the free base prepared from 1.5 g. of 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-ylamine hydrochloride [I(c)] (prepared as in Example 10C) in 12 ml. of pyridine, 1 ml. of ethyl chloroformate is added. The mixture is allowed to stand in the cold for about 5 hours and then poured into ice water. The solid that precipitates is collected on a filter and recrystallized from methylene chloride: benzene to give ethyl 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalene]-4-carbamate [I(c)].
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][OH:28])[CH:22]=4)[CH:19]=3)[NH:14][N:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2]>C1COCC1.O=[Mn]=O>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=[O:28])[CH:22]=4)[CH:19]=3)[NH:14][N:13]=2)[CH2:10][CH2:11]1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4cccc(CO)c4)cc23)CC1
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(hydroxymethyl)phenyl]-1H-indazole-7-carboxamide (Intermediate 23) (130 mg, 0.294 mmol) in THF (50 mL) was added MnO2 (900 mg, 8.8 mmol). The reaction mixture was stirred at room temperature overnight and filtered. The filtrate was concentrated at reduced pressure to give the crude title compound, which was used in the next step without further purification.