Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:25]([NH:29][S:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[CH:38]=[C:37]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:9]=[C:10]([CH3:24])[CH:11]=[C:12]([C:14]4[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=4)[N:13]=3)[CH:3]=2)[CH:36]=[CH:35][CH:34]=1)(=[O:32])=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(Br)c2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-(4-trifluoromethylphenyl)-6-methyl-pyrimidine (example E.47) (0.39 g, 1.0 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.31 g, 1.2 mmol) according to the general procedure VI. Obtained as a white solid (0.4 g, 76%). MS (ISP) 526.3 [(M+H)+]; mp 163° C.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:14])[CH:8]=2)[N:3]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17](B(O)O)[CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1.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>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:14])[CH:8]=2)[N:3]=[C:2]([C:17]2[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=2)[C:11]=1[CH3:12]
Reactant: OB(O)c1cccnc1
Reactant: Cc1c(Cl)nc2ccc(F)cc2c1Cl
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: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(-c2cccnc2)nc2ccc(F)cc2c1Cl

Procedure:
Prepared according to general Procedure F using 2,4-dichloro-6-fluoro-3-methylquinoline (300 mg, 1.3 mmol), 3-pyridylboronic acid (160 mg, 1.3 mmol), tetrakis(triphenylphosphine)palladium(0), sodium carbonate (242 mg, 2.28 mmol) in toluene:water (5 mL:2 mL) and heating at 130° C. overnight. After purification 4-chloro-6-fluoro-3-methyl-2-(pyridin-3-yl)quinoline was obtained as a white solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1([N:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[C:18]([NH2:20])=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>O1CCCC1>[CH:7]1([N:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[CH2:18][NH2:20])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: NC(=O)[C@H]1CCCN1C1CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NC[C@H]1CCCN1C1CCCCC1
Yield: 96 %

Procedure:
Lithium aluminum hydride (7.3 ml, 1M in tetrahydrofuran, 7.3 mmol) was added dropwise to a solution of (2R)-1-cyclohexyl-2-pyrrolidinecarboxamide (preparation 147) (950 mg, 4.85 mmol) in tetrahydrofuran (15 ml) and once addition was complete, the reaction was heated under reflux for 20 hrs. The cooled mixture was carefully quenched with water, and extracted with ethyl acetate. The combined organic extracts were then dried over MgSO4 and evaporated under reduced pressure. The residue was suspended in dichloromethane, filtered through Whatman® fibre and the filtrate evaporated under reduced pressure to give the desired product as an oil (849 mg, 96%).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH:12]([CH3:14])[CH3:13])=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[N:3]=1.O.[NH2:24][NH2:25]>>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:4]2[N:3]=[C:2]([NH:24][NH2:25])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:17][CH:18]=1
Reactant: NN
Reactant: CC(C)Cn1cnc2c(Nc3ccc(Cl)cc3)nc(Cl)nc21
Solvent: O
Product: CC(C)Cn1cnc2c(Nc3ccc(Cl)cc3)nc(NN)nc21

Procedure:
Was prepared according to Example 8 from (2-chloro-9-isobutyl-9H-purin-6-yl)-(4-chloro-phenyl)-amine and hydrazine monohydrate.
Reaction SMILES: [CH3:1][CH:2]1[CH:10]([CH3:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C(N(CC)CC)C.[N+:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)([O-:21])=[O:20]>ClCCl>[CH3:1][CH:2]1[CH:10]([CH3:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:26](=[O:27])[C:25]1[CH:24]=[CH:23][C:22]([N+:19]([O-:21])=[O:20])=[CH:30][CH:29]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CC1Nc2ccccc2C1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1c2ccccc2N(C(=O)c2ccc([N+](=O)[O-])cc2)C1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 5616.2 %

Procedure:
To a mixture of 2,3-dimethylindoline (736 mg) and triethylamine (0.836 ml) in dichloromethane (20 ml) was added p-nitrobenzoyl chloride (928 mg) and the solution was stirred at ambient temperature for 4 hours. The solution was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate, water and brine, and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was solidified with n-hexane to give 2,3-dimethyl-1-(4-nitrobenzoyl)indoline (83.2 g).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.O[CH2:9][NH:10][C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[N:14][CH:13]=1>FC(F)(F)C(O)=O>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([C:11]([NH:10][CH2:9][S:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)=[O:18])[CH:13]=1
Reactant: O=C(NCO)c1cccnc1
Reactant: Sc1ccncc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCSc1ccncc1)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.9 %

Procedure:
To a mixture of 1.11 g (10 mmol) of 4-mercaptopyridine and 1.52 g (10 mmol) of N-(hydroxymethyl)nicotinamide, 30 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off and 30 ml of ethanol was added to the residue. The solvent was distilled off and water was added to the residue. The mixture was neutralized with saturated aqueous sodium bicarbonate, followed by extraction with chloroform. After washing with saturated saline, the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography (eluent: ethyl acetate/ethanol=5:1) to give 390 mg of the desired compound (15.9% yield, yellow solid).
Reaction SMILES: [CH3:1][NH2:2].Cl.[N:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10]Cl)[CH:5]=1>>[CH3:1][NH:2][CH2:10][C:6]1[CH:5]=[N:4][CH:9]=[CH:8][CH:7]=1
Reactant: CN
Reactant: ClCc1cccnc1
Agent: Cl
Product: CNCc1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.6 %

Procedure:
To 25 ml of a 20% aqueous solution of NAOH stirred under cooling with ice-water, a 40% aqueous solution of methylamine (13.6 g, 0.175 mole) was added dropwise over 5 minutes, followed by further dropwise addition of an aqueous solution (10 ml) of 8.2 g (0.05 mole) of 3-pyridylmethyl chloride hydrochloride over 10 minutes. The mixture was further stirred at room temperature for 2 hours and, then, extracted with CH2Cl2 (100 ml×3). The extract was dried over MgSO4 and distilled to remove the solvent. The residue was subjected to vacuum distillation to give 2.6 g of the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:36])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:33][CH3:34])[CH2:25][NH:26][S:27]([CH:30]([CH3:32])[CH3:31])(=[O:29])=[O:28])[C:5]1=[O:35])[CH:2]=[CH2:3].I[CH2:38][CH3:39]>>[CH2:1]([C@@:4]1([CH3:36])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:33][CH3:34])[CH2:25][N:26]([CH2:38][CH3:39])[S:27]([CH:30]([CH3:31])[CH3:32])(=[O:28])=[O:29])[C:5]1=[O:35])[CH:2]=[CH2:3]
Reactant: CCI
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CNS(=O)(=O)C(C)C)C1=O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN(CC)S(=O)(=O)C(C)C)C1=O

Procedure:
The title compound was prepared from N-((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butyl)propane-2-sulfonamide (Example 183, Step A) by a procedure similar to the one described in Example 182, Step A, replacing iodomethane with iodoethane. MS (ESI) m/z=579 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[CH3:8][C:9]1(C)O[C@]2(OC[C@@H]3OC(C)(C)O[C@@H]3C2=O)C[O:10]1>>[C:9]([NH:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4])(=[O:10])[CH3:8]
Reactant: CC1(C)O[C@H]2CO[C@@]3(COC(C)(C)O3)C(=O)[C@H]2O1
Reactant: N[C@@H](CS)C(=O)O
Product: CC(=O)N[C@@H](CS)C(=O)O

Procedure:
Cysteine is an amino acid with one chiral carbon atom. It exists as an L-enantiomer, a D-enantiomer or a racemic mixture of the L- and D-enantiomers. The L-enantiomer is the naturally occurring configuration.
Reaction SMILES: O.[C:2]1([CH3:19])[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.C[O:22][C:23](=[O:36])[C@H:24]([CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)[NH2:25].[Li+].[OH-]>C1COCC1.O>[C:2]1([CH3:19])[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([NH:25][C@H:24]([C:23]([OH:36])=[O:22])[CH2:26][C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[NH:29][CH:28]=2)=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)O)cc1

Procedure:
N-(Toluene-4-sulfonyl)-L-proline hydrate was coupled to L-tryptophan methyl ester hydrochloride using the procedure described in Method 3. The title compound was prepared via hydrolysis of the methyl ester using LiOH in THF/water.
Reaction SMILES: C([O:4][CH:5]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:6]=[CH:7][CH2:8][N:9]([CH2:14][CH2:15][CH2:16][C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23]CC)=[O:22])=[CH:19][CH:18]=1)[S:10]([CH3:13])(=[O:12])=[O:11])(=O)C.[OH-].[Na+]>O.CO>[OH:4][CH:5]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:6]=[CH:7][CH2:8][N:9]([CH2:14][CH2:15][CH2:16][C:17]1[CH:27]=[CH:26][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1)[S:10]([CH3:13])(=[O:11])=[O:12]
Reactant: CCCCCC(C=CCN(CCCc1ccc(C(=O)OCC)cc1)S(C)(=O)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCC(O)C=CCN(CCCc1ccc(C(=O)O)cc1)S(C)(=O)=O

Procedure:
Ethyl 4-{3-[N-(4-Acetoxy-2-nonenyl)methanesulfonamido]propyl}benzoate (23.4 g., 0.05 mole) is added to a solution of sodium hydroxide (6.0 g., 0.15 mole) in water (30 ml.) and methanol (300 ml.). The resulting solution is boiled under reflux for 2 hours.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](/[CH:11]=[CH:12]/[CH2:13][CH2:14]C2C3C(=CC=CC=3)C=N2)=[CH:3][N:2]=1.O.[NH2:25]N>C(O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](/[CH:11]=[CH:12]/[CH2:13][CH2:14][NH2:25])=[CH:3][N:2]=1
Reactant: NN
Reactant: C1=NC(CC/C=C/c2cncc3ccccc23)c2ccccc21
Solvent: CCO
Solvent: O
Product: NCC/C=C/c1cncc2ccccc12

Procedure:
To a refluxing solution of 1.75 g of (E)-1-[4-(4-isoquinolinyl)-3-butenyl]-1H-isoindole-1,3-(2H-dione in 80 mL of ethanol was added 1.1 mL of hydrazine hydrate and the reaction was stirred at reflux for 17 hours. The solvent was removed in vacuo and the residue was triturated with chloroform. The extract was concentrated to yield 1 g of (E)-4-(4-isoquinolinyl)-3-buten-1-amine as an oil.
Reaction SMILES: Br[CH:2]([CH3:10])[C:3]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)=O.C(=O)([O-])O.[Na+].[Si:16]([O:23][CH2:24][C:25]1[CH:26]=[C:27]([C:31]2[CH:32]=[CH:33][C:34]([NH2:37])=[N:35][CH:36]=2)[CH:28]=[CH:29][CH:30]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>C(O)C>[Si:16]([O:23][CH2:24][C:25]1[CH:26]=[C:27]([C:31]2[CH:32]=[CH:33][C:34]3[N:35]([C:2]([CH3:10])=[C:3]([C:5]4[S:6][CH:7]=[CH:8][CH:9]=4)[N:37]=3)[CH:36]=2)[CH:28]=[CH:29][CH:30]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(Br)C(=O)c1cccs1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(-c2ccc(N)nc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1c(-c2cccs2)nc2ccc(-c3cccc(CO[Si](C)(C)C(C)(C)C)c3)cn12
Temperature: 100 °C
Yield: 67.2 %

Procedure:
In a glass tube, 280 mg of 5-[3-(tert-butyldimethylsilanyloxymethyl)phenyl]pyridin-2-ylamine, 390 mg of 2-bromo-1-thiophen-2-ylpropan-1-one and 190 mg of sodium hydrogencarbonate are dissolved in 5 ml of ethanol. The tube is closed and heated at 100° C. for 20 h. After cooling, the mixture is concentrated under reduced pressure. The residue is purified by silica gel chromatography, elution being carried out with a heptane/ethyl acetate mixture. 260 mg of compound are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:17][O:18][CH2:19][CH2:20]Br>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:20][CH2:19][O:18][CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Amine preparation: To 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (1.5 g) in dry DMF (15 mL) was added sodium hydride (447 mg). After stirring for 2 hrs at room temperature, 2-bromoethyl methyl ether (0.7 mL) was added. The reaction mixture was heated to 40° C. overnight, and then diluted with ethyl acetate, washed with water and dried (MgSO4). The solvent was evaporated and the residue purified by flash chromatography to give 4-(2-methoxy-ethoxy)-piperidine-1-carboxylic acid tert-butyl ester (447 mg). Treatment of this compound with HCl in DCM/MeOH yielded the desired amine, which was isolated as the hydrochloride salt.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:10](=[O:11])[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18]O)[CH:13]=2)=[C:8]([CH3:20])[N:7]([CH:21]([C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)[CH3:22])[CH:6]=1)=[O:4].COCCN(S(F)(F)[F:41])CCOC>ClCCl>[CH3:1][NH:2][C:3]([C:5]1[C:10](=[O:11])[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][F:41])[CH:13]=2)=[C:8]([CH3:20])[N:7]([CH:21]([C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)[CH3:22])[CH:6]=1)=[O:4]
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CNC(=O)c1cn(C(C)c2ccc(C#N)cc2)c(C)c(-c2cccc(CO)c2)c1=O
Solvent: ClCCl
Product: CNC(=O)c1cn(C(C)c2ccc(C#N)cc2)c(C)c(-c2cccc(CF)c2)c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of preparation 31a (60 mg, 149 μmol) and [bis(2-methoxyethyl)amino]sulfur trifluoride (50% in toluene, 74 μL, 202 μmol) in dichloromethane (1 mL) is stirred for 3 h at room temperature. The reaction mixture is quenched with 1N HCl, extracted twice with dichloromethane and the organic phase is concentrated under reduced pressure. The remaining residue is purified by preparative reversed-phase HPLC (Stable Bond, gradient of acetonitrile in water, 0.1% TFA, 60° C.). Yield: 30 mg (50% of theory); ESI mass spectrum: [M+H]+=404; Retention time HPLC: 0.95 min (Z017—504).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:19]([C:31]([OH:33])=O)=[C:20]([CH3:30])[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]=23)[CH2:3][CH2:2]1.[NH2:34][C@H:35]1[CH2:40][CH2:39][C@H:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:37][CH2:36]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:19]([C:31]([NH:34][C@H:35]4[CH2:40][CH2:39][C@H:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:46])([CH3:45])[CH3:47])[CH2:37][CH2:36]4)=[O:33])=[C:20]([CH3:30])[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:28])[CH3:29])[C:14]=23)[CH2:3][CH2:2]1
Reactant: Cc1c(C(=O)O)c2nccc(-c3ccc(F)cc3OCC3CC3)c2n1COCC[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Product: Cc1c(C(=O)N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)c2nccc(-c3ccc(F)cc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-fluorophenyl]-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (example D.c2) and commercially available tert-butyl trans-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1.[CH2:15]([O:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:16]#[CH:17]>CN(C=O)C.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.[Cu]I>[N:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C:17]#[C:16][CH2:15][O:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH:10]=1
Reactant: C#CCOCCNC(=O)OC(C)(C)C
Reactant: Brc1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCOCC#Cc1cccnc1
Temperature: 80 °C
Yield: 73.5 %

Procedure:
Under a nitrogen atmosphere, anhydrous triethylamine (45.5 mL, 326 mmol) and 3-bromopyridine (12.9 mL, 138 mmol) were added to a solution of tert-butyl 2-(prop-2-ynyloxy)ethylcarbamate (26.0 g, 125 mmol) in anhydrous DMF (400 mL), and the reaction was heated at 80° C. Dichlorobis(triphenylphosphine)palladium (II) (1.76 g, 2.51 mmol) and copper (I) iodide (0.96 g, 5.02 mmol) were then added, and the reaction was heated at 80° C. for one hour. The volatiles were removed under reduced pressure, and the residual black oil was dissolved in ethyl acetate (500 mL). The solution was washed with dilute aqueous sodium bicarbonate (1×200 mL) and brine (2×100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide a dark brown oil. The oil was purified by column chromatography on silica gel (350 g, eluting with 50:50 ethyl acetate:hexane), and the resulting dark oil was dissolved in hot methanol (200 mL) and treated with 10 g of activated charcoal. The mixture was filtered through a layer of CELITE filter aid, and the filtrate was treated with additional activated charcoal (10 g) and filtered in the same way to provide 25.4 g of tert-butyl {2-[3-(pyridin-3-yl)prop-2-ynyloxy]ethyl}carbamate as a light amber-colored oil.
Reaction SMILES: [N+]([N:4]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([N+:13]([O-:15])=[O:14])[CH:9]=[CH:10]2)=[N:5]1)([O-])=O.[CH3:16][O-:17].[Na+]>C1COCC1.C(OCC)(=O)C>[CH3:16][O:17][C:12]1[C:11]2[C:6](=[CH:7][C:8]([N+:13]([O-:15])=[O:14])=[CH:9][CH:10]=2)[NH:5][N:4]=1
Reactant: C[O-]
Reactant: O=[N+]([O-])c1ccc2cn([N+](=O)[O-])nc2c1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1n[nH]c2cc([N+](=O)[O-])ccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 2,6-dinitro-2H-indazole(1 mmol) (prepared by nitration of 6-nitroindazole; Wrzeciono, et al., E. Pharmazie, 1980, 35, 593-596) in dry THF (4 mL) at 0° C., solid sodium methoxide (4 mmol) was added in portions. The reaction mixture was allowed to warm to room temperature and stirred for 12 h. The contents were diluted with ethyl acetate (20 mL), washed with water (2×10 mL) and brine (10 mL) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to yield 3-methoxy-6-nitro-1H-indazole as a brown solid, which was reduced to 3-methoxy-1H-indazol-6-ylamine by hydrogenation following general procedure F.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[C:8]([CH2:10][NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18](=[O:27])[NH:19][O:20][CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:7]=[CH:6][C:5]=1[F:28].[OH-].[Li+]>C1COCC1.O>[CH:22]1([CH2:21][O:20][NH:19][C:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][CH2:10][C:8]2[CH:7]=[CH:6][C:5]([F:28])=[C:4]([CH:9]=2)[C:3]([OH:29])=[O:2])=[O:27])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: COC(=O)c1cc(CNc2ccccc2C(=O)NOCC2CCCC2)ccc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(CNc2ccccc2C(=O)NOCC2CCCC2)ccc1F
Temperature: 60 °C
Reaction time: 15 h
Yield: 77.1 %

Procedure:
5-[(2-Cyclopentylmethoxycarbamoyl-phenylamino)-methyl]-2-fluoro-benzoic acid methyl ester (Example 493, 511 mg) was dissolved in THF (15 ml) and water (5 ml). Lithium hydroxide (122 mg) was added and the mixture was heated to 60° C. The reaction mixture was stirred at this temperature for 15 hours, cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water and 1M hydrochloric acid was added until a precipitate formed. The solid material was isolated by filtration and washed with water and dried under high vacuum and gave the title compound (380 mg) as a white powder. 13C-NMR (DMSO-d6) δ 166.9, 165.0, 160.0, 148.4, 135.9, 133.0, 132.4, 130.1, 128.0, 119.1, 116.9, 114.6, 113.4, 111.5, 79.4, 44.8, 37.6, 28.9, 24.9.
Reaction SMILES: [CH2:1]([Si:5]([CH:18]1[S:23][CH2:22][CH2:21][CH2:20][S:19]1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:2][CH:3]=[CH2:4].C([Li])CCC.Br[CH2:30][CH:31]([CH3:33])[CH3:32]>C1COCC1>[CH2:1]([Si:5]([C:18]1([CH2:30][CH:31]([CH3:33])[CH3:32])[S:19][CH2:20][CH2:21][CH2:22][S:23]1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:2][CH:3]=[CH2:4]
Reactant: CC(C)CBr
Reactant: C=CCC[Si](c1ccccc1)(c1ccccc1)C1SCCCS1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCC[Si](c1ccccc1)(c1ccccc1)C1(CC(C)C)SCCCS1
Reaction time: 3 h
Yield: 92.5 %

Procedure:
To a solution of 32 (4.68 g, 13.1 mmol) in THF (100 mL) at -78° C. was added dropwise over 10 min n-butyllithium (1.6M in hexanes, 18.4 mmol). After 3 h of stirring under argon, 1-bromo-2-methylpropane (2.14 mL, 19.7 mmol) was added dropwise over 5 min, and the mixture was stirred for 2 h at -78° C. and overnight at rt. The reaction mixture was quenched with water (10 mL) and the excess organic solvent was removed under reduced pressure. The crude mixture was extracted with three 100-mL portions of EtOAc. The combined organic extracts were washed with saturated aqueous NaCl, dried over Na2SO4, and concentrated. Flash chromatography over silica gel (1/9 EtOAc:hexane) gave pure 26 as a colorless solid (5.0 g, 92%): R.function. =0.75 (1/9 EtOAc:hexane); mp 67°-69° C. 1H NMR (300 MHz, CDCl3) δ7.83 (d, J=6.0 Hz, 4H), 7.41 (m, 6H), 5.88 (m, 1H), 4.97 (dd, J=17.1, 1.7 Hz, 1H), 4.88 (dd, J=10.1, 1.7 Hz, 1H), 3.04 (m, 2H), 2.49 (t, J=4.3 Hz 1H), 2.44 (t, J=4.1 Hz, 1H), 2.08 (d, J=5.1 Hz, 2H), 1.98 (m, 4H), 1.79 (m, 1H), 1.54 (m, 2H), 0.82 (d, J=6.7 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ141.5, 136.7, 132.9, 129.9, 127.7, 113.0, 45.7, 39.9, 28.3, 27.2, 24.6, 24.3, 24.2, 11.0; IR (film) 3068 (m), 3043 (m), 2951 (s), 2912 (s), 2863 (m), 1432 (s), 1274 (w), 1113 (s), 997 (m), 913 (m), 738 (s), 705 (s) cm-1 ; MS (EI) m/e (rel. intensity) 289 (M+ -123, 3), 237 (8), 183 (72), 175 (100), 159 (32), 143 (17), 119 (16), 105 (35); HRMS (FAB) calcd for C24H32S2Si: 412.1715 (MH+ -1), found: 412.1727. Anal. Calcd for C24H32S2 Si: C, 69.84; H, 7.82. Found: C, 70.08; H, 8.07.