Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][C@@H:12]([O:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([C:25]3[C:26](=[O:35])[NH:27][C:28]4[C:33]([CH:34]=3)=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.C(N(C(C)C)CC)(C)C.[NH:45]1[CH2:50][CH2:49][CH:48]([N:51]2[CH2:56][CH:55]=[CH:54][CH2:53][CH2:52]2)[CH2:47][CH2:46]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C)C=O.ClCCl>[O:35]=[C:26]1[C:25]([CH:22]2[CH2:23][CH2:24][N:19]([C:17]([O:16][C@H:12]([CH2:11][C:4]3[CH:5]=[C:6]4[C:10](=[C:2]([CH3:1])[CH:3]=3)[NH:9][N:8]=[CH:7]4)[C:13]([N:45]3[CH2:50][CH2:49][CH:48]([N:51]4[CH2:56][CH2:55][CH:54]=[CH:53][CH2:52]4)[CH2:47][CH2:46]3)=[O:14])=[O:18])[CH2:20][CH2:21]2)=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27]1
Reactant: C1=CCN(C2CCNCC2)CC1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)O)cc2cn[nH]c12
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)N2CCC(N3CC=CCC3)CC2)cc2cn[nH]c12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of (R)-3-(7-methyl-1H-indazol-5-yl)-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carbonyloxy)propanoic acid (50 mg, 0.11 mmol), diisopropylethylamine (37 μL, 0.21 mmol), and 1-(piperidin-4-yl)-1,2,3,6-tetrahydropyridine (75.7 mg, 2.0 equiv) in dimethylformamide (0.50 mL) and dichloromethane (0.50 mL) at 0° C. was added PyBOP® (57.6 mg, 0.11 mmol). The reaction was stirred at 0° C. for 4 h. The reaction was concentrated and purified by column chromatography (95:5:1 to 90:10:1 dichloromethane/methanol/triethylamine). The resulting residue was dissolved in 5% methanol/dichloromethane and passed through a basic alumina column to give 35.9 mg (53%) as a white powder. 1H-NMR (CD3OD, 500 MHz) δ −0.35-0.15 (m, 0.7H), 0.60-0.93 (m, 1H), 1.15-2.20 (m, 11H), 2.30-3.25 (m, 11H), 3.75-4.58 (m, 4H), 5.35-5.75 (m, 3H), 7.01-7.14 (m, 1H), 7.18 (m, 1H), 7.28 (m, 1H), 7.36-7.50 (m, 2H), 7.53-7.73 (m, 2H), 7.90-8.01 (m, 1H). Mass spec.: 623.33 (MH)+.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[CH:11]=[C:12]([C:16]2[N:20]([CH3:21])[N:19]=[C:18]([C:22]([N:24]3[CH2:28][CH2:27][CH:26]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[CH2:25]3)=[O:23])[C:17]=2[CH3:34])[CH:13]=[CH:14][CH:15]=1.[Cl:35][C:36]1[CH:41]=[CH:40][C:39](/[CH:42]=[CH:43]/B(O)O)=[CH:38][CH:37]=1>>[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([CH:42]=[CH:43][C:10]2[CH:11]=[C:12]([C:16]3[N:20]([CH3:21])[N:19]=[C:18]([C:22]([N:24]4[CH2:28][CH2:27][CH:26]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[CH2:25]4)=[O:23])[C:17]=3[CH3:34])[CH:13]=[CH:14][CH:15]=2)=[CH:38][CH:37]=1
Reactant: OB(O)/C=C/c1ccc(Cl)cc1
Reactant: CCN(CC)C1CCN(C(=O)c2nn(C)c(-c3cccc(Br)c3)c2C)C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CCN(CC)C1CCN(C(=O)c2nn(C)c(-c3cccc(C=Cc4ccc(Cl)cc4)c3)c2C)C1
Yield: 67 %

Procedure:
In analogy to the procedure described in example 14C] but with 2.8 eq of K3PO4, [5-(3-bromo-phenyl)-1,4-dimethyl-1H-pyrazol-3-yl]-(3-diethylamino-pyrrolidin-1-yl)-methanone and trans-2-(4-chlorophenyl)vinylboronic acid gave (5-{3-[2-(4-chloro-phenyl)-vinyl]-phenyl}-1,4-dimethyl-1H-pyrazol-3-yl)-(3-diethylamino-pyrrolidin-1-yl)-methanone in 67% yield as light brown oil. MS: 477.0 (MH+, 1 Cl).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:13]([O-])=O)=[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:7]=1>[Ni].CO.C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])[C:5]([NH2:13])=[CH:4][CH:3]=1
Reactant: CC(C)(C)Nc1cc(Br)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)Nc1cc(Br)ccc1N
Temperature: 25 °C
Reaction time: 9 h
Yield: 82.4 %

Procedure:
A suspension of (5-bromo-2-nitro-phenyl)-tert-butyl-amine (Step 123.3) (6 g, 21.97 mmol) and Raney nickel (2 g) in MeOH/THF (1:1 v/v, 600 mL) is stirred for 9 h at rt, under a hydrogen atmosphere. The reaction mixture is filtered through a pad of celite and concentrated. The residue purified by silica gel column chromatography (Hex/EtOAc, 97:3→3:1) to afford 4.4 g of the title compound as a black oil: ESI-MS: 243.0/245.0 [M+H]+; tR=2.75 min (System 1); TLC: Rf=0.89 (Hex/EtOAc, 1:1).
Reaction SMILES: B(F)(F)F.CSC.[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[N:25][N:26]([CH2:37][C:38]#[N:39])[C:27]=2[C:28]2[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]([O:35]C)[CH:29]=2)=[CH:19][N:18]=1)(=[O:10])[CH3:9]>ClCCl>[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[N:25][N:26]([CH2:37][C:38]#[N:39])[C:27]=2[C:28]2[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]([OH:35])[CH:29]=2)=[CH:19][N:18]=1)(=[O:10])[CH3:9]
Reactant: COc1cc(C)cc(-c2c(-c3ccc(-c4ccccc4C(C)=O)nc3)cnn2CC#N)c1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CSC
Product: CC(=O)c1ccccc1-c1ccc(-c2cnn(CC#N)c2-c2cc(C)cc(O)c2)cn1
Reaction time: 24 h

Procedure:
Borontrifluoride-dimethylsulfide (0.13 mL, 1.2 mmol) was dropwise added to a solution of the methoxy compound (50.7 mg, 0.12 mmol) prepared in Example 70 in dichloromethane (4 mL) at room temperature under nitrogen atmosphere, and stirred for 24 hours. The reaction mixture was concentrated by vacuum distillation. The residue was treated in ethyl acetate (100 mL) and brine (50 mL), and the organic layer was dried over anhydrous magnesium sulfate and distilled under vacuum. Purification through column chromatography (silica gel, ethyl acetate) afforded pure hydroxy products (30 mg, 62%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15]([SH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CS(C)=O>[CH2:15]([S:22][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: SCc1ccccc1
Reactant: Cc1cccc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cccc(SCc2ccccc2)n1
Temperature: 25 °C
Yield: 87 %

Procedure:
2-Chloro-6-methylpyridine (1.30 g), potassium carbonate (2.12 g) and benzylmercaptan (1.8 mL) were stirred in dimethyl sulfoxide (10 mL) at 150° C. for 3 hr. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=15:1) to give the title compound as a pale-red oil (yield 1.90 g, 87%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH2:25])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:33]1(N)[CH2:35][CH2:34]1.C(OCC)(=O)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH:25][CH:33]3[CH2:35][CH2:34]3)=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: NC1CC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2cn(-c3cccc(F)c3)cc2NC(N)=O)C1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2cn(-c3cccc(F)c3)cc2NC(=O)NC2CC2)C1
Yield: 78 %

Procedure:
Following general method 7, employing (S)-3-{[1-(3-fluorophenyl)-4-ureido-1H-pyrrole-3-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester and cyclopropylamine, afforded the crude desired product. Column chromatography (silica, 12 g column, ISCO, 0-50% ethyl acetate in DCM) afforded the title compound as a glass (64 mg, 78%); LCMS (method B): RT=3.70 min, M+H+=486.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][O:6][C:7]2=[O:12].CN1CCOCC1.[C:20]12([CH2:30][C:31](Cl)=[O:32])[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH2:21]1)[CH2:27]2>O1CCOCC1>[C:20]12([CH2:30][C:31]([NH:1][C:2]3[CH:11]=[CH:10][CH:9]=[C:8]4[C:3]=3[CH:4]=[CH:5][O:6][C:7]4=[O:12])=[O:32])[CH2:27][CH:26]3[CH2:25][CH:24]([CH2:23][CH:22]([CH2:28]3)[CH2:21]1)[CH2:29]2
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: Nc1cccc2c(=O)occc12
Solvent: C1COCCO1
Solvent: CN1CCOCC1
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nc1cccc2c(=O)occc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.3 %

Procedure:
To a solution of 5-amino-1H-isochromen-1-one (2.95 g, 18.3 mmol) and NMM (2.02 mL, 18.3 mmol) in 1,4 dioxane (55 mL) was added dropwise at room temperature a solution of 1-adamantaneacetic acid chloride (3.9 g, 18.3 mmol) in 1,4-dioxane (40 mL). The reaction mixture was stirred at room temperature for 3 h and then partitioned between DCM (400 mL) and water (200 mL). The layers were separated. The aqueous phase was washed with DCM (100 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was suspended in hexane (100 mL) and filtered off. The solid was collected on the filter and dried in vacuo to yield 2-adamantan-1-yl-N-(1-oxo-1H-isochromen-5-yl)-acetamide as a yellow solid (5.6 g, 16.7 mmol, 91%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:10]=2)[CH:7]=1.[C:16]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])[CH:17]=[CH2:18].[B-](F)(F)(F)F.CC([PH+](C(C)(C)C)C(C)(C)C)(C)C.C1(CNCC2CCCCC2)CCCCC1>O1CCOCC1>[C:21]([O:20][C:16](=[O:19])[CH:17]=[CH:18][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:10]=2)[CH:7]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1cnc2ccc(Br)cn12
Agent: C1CCC(CNCC2CCCCC2)CC1
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc2ccc(C=CC(=O)OC(C)(C)C)cn12
Temperature: 95 °C

Procedure:
A stirring mixture of ethyl 6-bromoimidazo[1,2-a]pyridine-3-carboxylate (24s) (500 mg, 1.86 mmol), tert-butyl acrylate (408 uL, 2.79 mmol), tris(dibenzylideneacetone)diplalladium(0) (51 mg, 0.056 mmol), [(t-Bu)3PH]BF4 (27 mg, 0.093 mmol) and N,N-dicyclohexylmethylamine (738 uL, 3.48 mmol) in anhydrous 1,4-dioxane (5 mL) was heated at 95° C. overnight. The reaction was cooled to room temperature and filtered. The solvent was concentrated and the crude product was purified by silica chromatography to yield ethyl 6-(3-(tert-butoxy)-3-oxoprop-1-en-1-yl)imidazo[1,2-a]pyridine-3-carboxylate (70). MS m/z 317.14 (M+1)+.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:7][CH2:6][NH:5][C:4]1=[O:8].[CH:9]1([C:12]2[C:13]([N:21]3[CH2:26][CH2:25][N:24]([C:27]([C:29]4[CH:30]=[N:31][C:32](F)=[CH:33][C:34]=4[CH3:35])=[O:28])[CH2:23][CH2:22]3)=[N:14][CH:15]=[C:16]([CH:18]3[CH2:20][CH2:19]3)[CH:17]=2)[CH2:11][CH2:10]1.O>CN(C)C=O>[CH:9]1([C:12]2[C:13]([N:21]3[CH2:22][CH2:23][N:24]([C:27]([C:29]4[C:34]([CH3:35])=[CH:33][C:32]([N:5]5[CH2:6][CH2:7][O:3][C:4]5=[O:8])=[N:31][CH:30]=4)=[O:28])[CH2:25][CH2:26]3)=[N:14][CH:15]=[C:16]([CH:18]3[CH2:20][CH2:19]3)[CH:17]=2)[CH2:10][CH2:11]1
Reactant: O=C1NCCO1
Reactant: Cc1cc(F)ncc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(N2CCOC2=O)ncc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Temperature: 25 °C
Yield: 45.7 %

Procedure:
To a solution of sodium hydride (168 mg, 60% in oil) in N,N-dimethylformamide (10 mL) was added oxazolidin-2-one (367 mg) under ice-cooling, and the mixture was stirred at room temperature. Thereto was added a solution of [4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl](6-fluoro-4-methylpyridin-3-yl)methanone (400 mg) described in Preparation Example 139 in N,N-dimethylformamide (5 mL) and the mixture was stirred at 90° C. for 5 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with water, washed with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (ethyl acetate:hexane). Then, diethyl ether was added and the mixture was stirred at room temperature. The solid was collected by filtration to give the title compound (215 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[C:13]([Br:14])=[CH:12][C:11]([NH2:15])=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](Cl)=[O:22].C(N(CC)C(C)C)(C)C>C(Cl)Cl.Cl.C(Cl)Cl>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[C:13]([Br:14])=[CH:12][C:11]([NH:15][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][CH:26]=[C:18]([F:17])[CH:19]=2)=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: CC(C)(C)OC(=O)Nc1ncc(N)cc1Br
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1ncc(NC(=O)c2cccc(F)c2)cc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.4 %

Procedure:
(5-Amino-3-bromo-pyridin-2-yl)-carbamic acid tert-butyl ester (50 mg, 0.17 mmol), 3-fluoro-benzoyl chloride (28 mg, 0.17 mmol), and N,N-diisopropylethylamine (0.03 mL, 0.19 mmol) were dissolved in CH2Cl2 (2 mL), and stirred or 1 h at 0° C. The reaction solution was diluted with 1 M HCl/CH2Cl2, and filtered through an Extrelut column. The column was washed with CH2Cl2, and the filtrate was concentrated. The crude product was purified via Biotage eluting with a gradient of 20 to 70% EtOAc/hexanes to provide of [3-bromo-5-(3-fluoro-benzoylamino)-pyridin-2-yl]-carbamic acid tert-butyl ester (47 mg, 66% yield) as a solid.
Reaction SMILES: [CH2:1]([N:8]([CH3:17])[C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:18](O)=O.[OH-:21].[Na+].[CH3:23][C:24]1[CH:25]=[CH:26][C:27]([S:30]([OH:33])(=[O:32])=[O:31])=[CH:28][CH:29]=1>CCOCC>[C:24]1([CH3:23])[CH:25]=[CH:26][C:27]([S:30]([OH:33])(=[O:31])=[O:32])=[CH:28][CH:29]=1.[CH2:1]([N:8]([C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[N:15]([CH3:18])[CH3:16])[CH:17]=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: O=CO
Reactant: CN[C@@H]1CCCC[C@H]1N(C)Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CCOCC
Product: CN(C)[C@@H]1CCCC[C@H]1N(C=O)Cc1ccccc1

Procedure:
A solution of trans-N-benzyl-N,N'-dimethyl-1,2-cyclohexanediamine (9.29 g.; 0.04 mole) in 40 ml. of formic acid was refluxed 20 hours, added and poured into 200 g. of ice. It was basified with 15% NaOH and extracted well with ether. The extract was washed with H2O, saturated salt solution, dried (MgSO4) and evaporated. The residue (9.7 g.) was converted to the salt with 2 mole of p-TSA in ether. The resulting gum was crystallized from MeOH-ether to give 13.64 g.; of the titled compound, m.p. 201°-202.5°. The analytical sample melted at 202°-203°. uv sh 210 nm (ε 27,850); sh 222 (25,600); sh 227 (12,350); sh 243 (302); sh 248 (375) λ max 254 (472); 258 (556); 261 (562); 268 (399); sh 272 (175). ir N+H 2720, 2560; C=O 1670; 1650; C=C 1600, 1495; SO3 other 1225, 1170, 1120, 1030, 1010, 815, 705, 685. nmr in D2O (100 MHz) was in accord. Mass spectrum M+ 260.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](N1C=CN=C1)=[O:11])[CH2:2]2.[F:17][C:18]1[CH:19]=[C:20]([CH:24]([C:26]2[CH:31]=[CH:30][C:29]([S:32][CH3:33])=[CH:28][CH:27]=2)[OH:25])[CH:21]=[CH:22][CH:23]=1>>[F:17][C:18]1[CH:19]=[C:20]([CH:24]([O:25][C:10](=[O:11])[O:9][C@@H:3]2[CH:4]3[CH2:5][CH2:6][N:1]([CH2:8][CH2:7]3)[CH2:2]2)[C:26]2[CH:31]=[CH:30][C:29]([S:32][CH3:33])=[CH:28][CH:27]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: O=C(O[C@H]1CN2CCC1CC2)n1ccnc1
Reactant: CSc1ccc(C(O)c2cccc(F)c2)cc1
Product: CSc1ccc(C(OC(=O)O[C@H]2CN3CCC2CC3)c2cccc(F)c2)cc1

Procedure:
The desired product was prepared by reacting imidazole-1-carboxylic acid (R)-1-aza-bicyclo[2.2.2]oct-3-yl ester with (3-fluoro-phenyl)-(4-methylsulfanyl-phenyl)-methanol.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][NH2:18].[OH2:19]>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([CH:13]([CH2:14][NH:15][CH2:16][CH2:17][NH2:18])[N:12]([S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:8])=[O:19])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O
Reactant: NCCNCCN
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)C(CNCCN)N(S(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
115 g (0.6 mol) of p-toluenesulfonyl chloride are dissolved in 250 ml of pyridine at ambient temperature. A solution of diethylenetriamine (21.5 ml, 0.2 mol) in pyridine (30 ml) is added dropwise. The reaction mixture is stirred at 50° C. for 90 minutes and then transferred under warm conditions to an erlenmeyer flask. After returning to ambient temperature, 200 ml of water are added. The mixture is left stirring overnight at ambient temperature and is then placed in an ice bath for 2 hours. The orange solid which then forms is filtered off and washed with cold (0° C.) 95% ethanol. After drying under vacuum at 40° C. (rotary evaporator), the desired product is obtained in the form of a light yellow solid (92 g, yield 81%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:24])[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C@H:4]([C@@H:25]([OH:29])[CH:26]([CH3:28])[CH3:27])[CH2:3]1.[CH3:30][C:31]([CH3:33])=O.[C:34]([BH3-])#N.[Na+].C=O>C(Cl)Cl>[OH:29][C@H:25]([C@@H:4]1[CH2:3][C@H:2]([N:1]([CH:31]([CH3:33])[CH3:30])[CH3:34])[CH2:7][CH2:6][C@@H:5]1[NH:8][C:9](=[O:24])[CH2:10][NH:11][C:12](=[O:23])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)[CH:26]([CH3:27])[CH3:28]
Reactant: [BH3-]C#N
Reactant: CC(C)[C@H](O)[C@@H]1C[C@H](N)CC[C@@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Reactant: CC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)[C@H](O)[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
The entirety of N-(2-((1S,2R,4R)-4-amino-2-((S)-1-hydroxy-2-methylpropyl)cyclohexylamino)-2-oxoethyl)-3-(trifluoromethyl)benzamide te prepared in previous Step (1 eq) in CH2Cl2 (20 mL). The resultant solution was charged with acetone (10 eq) and stirred at RT for 10 min before sodium cyanoborohydride (2 eq) was added in one portion. The reaction was stirred at RT for 10 h and then charged successively with formaldehyde (10 eq in 37 wt % aq soln) and sodium cyanoborohydride (2 eq). The reaction was stirred for another 9 h at RT and then quenched with sat. NaHCO3. The aqueous mixture was extracted with EtOAc (40 mL, then 2×40 mL). The organic extracts were combined, washed with brine (30 mL), dried (MgSO4), filtered, and concentrated in vacuo. After the resulting oil stood, some paraformaldehyde-related products solidified; these were removed by dissolving the mixture in a minimal volume of EtOAc and filtering. Subsequent concentration provided N-(2-((1S,2R,4R)-2-((S)-1-hydroxy-2-methylpropyl)-4-(isopropyl(methyl)amino)cyclohexylamino)-2-oxoethyl)-3-(trifluoromethyl)benzamide. MS found: (M+H)+=472.
Reaction SMILES: [C:1]([O-:4])([O-])=O.[Na+].[Na+].[N:7]1[CH:12]=[CH:11][CH:10]=[C:9](B(O)O)[CH:8]=1>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][C:11]1[CH:10]=[CH:9][CH:8]=[C:9]2[C:8]=1[N:7]=[C:12]([C:9]1[CH:8]=[N:7][CH:12]=[CH:11][CH:10]=1)[C:11]([CH:1]=[O:4])=[CH:10]2
Reactant: OB(O)c1cccnc1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cccc2cc(C=O)c(-c3cccnc3)nc12
Yield: 281.9 %

Procedure:
Prepared according to the procedure described for Intermediate 1, utilising Intermediate 32 (10 g, 48.7 mmol), Na2CO3 (7.74 g, 73 mmol), 3-pyridylboronic acid (5.98 g, 48.7 mmol) and tetrakis(triphenylphosphine)palladium(0) (2.81 g, 2.43 mmol) in DME (150 mL) and water (40 mL). The title compound (11.36 g, 94%) was obtained as a brown solid. δH (CDCl3) 10.20 (s, 1H), 9.02 (dd, J 2.3, 0.8 Hz, 1H), 8.86 (s, 1H), 8.80 (dd, J 4.9, 1.7 Hz, 1H), 8.10 (ddd, J 7.9, 2.3, 1.7 Hz, 1H), 7.90 (d, J 8.3 Hz, 1H), 7.78-7.75 (m, 1H), 7.58 (dd, J 8.1, 7.2 Hz, 1H), 7.53 (ddd, J 7.9, 4.9, 0.8 Hz, 1H), 2.88 (s, 3H). LCMS (ES+) 249 (M+H)+, RT 1.41 minutes.
Reaction SMILES: C(S([N:7]1[CH2:12][CH2:11][C:10]([C:19]#[N:20])(N2CCCCC2)[CH2:9][CH2:8]1)(=O)=O)CC.[ClH:21].O1CCOCC1>C(OCC)C>[Cl-:21].[C:19]([CH:10]1[CH2:11][CH2:12][NH2+:7][CH2:8][CH2:9]1)#[N:20].[ClH:21]
Reactant: CCCS(=O)(=O)N1CCC(C#N)(N2CCCCC2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: N#CC1CC[NH2+]CC1
Product: [Cl-]
Reaction time: 8 h

Procedure:
In a round bottom flask was placed tert-butyl 4-cyanopiperidine-1-carboxylate (1) (15 g, 71.3 mmol) and diethyl ether (500 ml). To this was added HCl in dioxane (4M, 35.7 ml, 143 mmol) and the solution stirred overnight. A fine white solid was formed in suspension and filtered with a medium frit to give 4-cyanopiperidinium chloride (13) as an HCl salt in quantitative yield after washing with diethyl ether (3×50 ml). MS 111 (M+1)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:29])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[CH:12][N:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)=[CH:23][C:22]=1[C:30]([F:31])([F:32])[F:33]
Reactant: NC(=O)c1[nH]c2cnccc2c1-c1ccc(N)cc1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Product: NC(=O)c1[nH]c2cnccc2c1-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
103 mg of solid yellow 3-{4-[3-(4-chloro-3-trifluoromethylphenyl)ureido]-phenyl}-1H-pyrrolo[2,3-c]pyridine-2-carboxamide are prepared as described in Example 1 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide and 4-chloro-3-trifluoromethylphenyl isocyanate.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10]O)[CH2:4][CH2:3]1.[ClH:12].[Cl:13][C:14]([O:16][C:17](Cl)(Cl)Cl)=[O:15]>C(#N)C.O1CCOCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH3:10])[CH2:4][CH2:3]1.[ClH:13].[ClH:12].[Cl:13][C:14]([O:16][CH2:17][CH3:1])=[O:15]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CN1CCN(CCCO)CC1
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: CCCN1CCN(C)CC1
Product: CCOC(=O)Cl
Temperature: 6 °C
Reaction time: 15 h

Procedure:
9.7 g (61.2 mmol) of N-methyl-N′-(3-hydroxypropyl)piperazine dissolved in 10 ml of acetonitrile are added dropwise to a solution of 100 ml of acetonitrile and 40 ml of 4 N HCl in dioxane and cooled using a water bath that the internal temperature did not exceed 40° C. 8 ml (66.3 mmol) of trichloromethyl chloroformate in 10 ml of acetonitrile are subsequently added dropwise with ice-cooling at an internal temperature of 2-10° C., and the mixture is subsequently stirred at room temperature for 15 h. The precipitate formed is filtered off with suction, washed with acetonitrile, and the residue is dried in vacuo.