Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([C:9]2[CH:33]=[C:32]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])[C:12]([C:13]([N:15]([CH2:17][C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=3)[CH3:16])=[O:14])=[CH:11][N:10]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+].O1CCCC1>C(O)C>[F:31][C:28]([F:29])([F:30])[C:20]1[CH:19]=[C:18]([CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=1)[CH2:17][N:15]([CH3:16])[C:13](=[O:14])[C:12]1[C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH3:40])=[CH:33][C:9]([C:7]2[S:8][C:4]([CH:1]([OH:3])[CH3:2])=[CH:5][CH:6]=2)=[N:10][CH:11]=1
Reactant: CC(=O)c1ccc(-c2cc(-c3ccccc3C)c(C(=O)N(C)Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccccc1-c1cc(-c2ccc(C(C)O)s2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 95.4 %

Procedure:
A mixture of 50 mg (0.087 mmol) 6-(5-acetyl-thiophen-2-yl)-N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-4-o-tolyl-nicotinamide (Example 38), 7 mg (0.2 mmol) sodium borohydride in 1 ml ethanol and a small amount of tetrahydrofuran was stirred at room temperature for 2 h. The reaction was quenched by addition of water, followed by 1 N aqueous hydrochloric acid solution. The mixture was basified with sodium carbonate and extracted with 3 portions of ethyl acetate. The combined organic extracts were dried with sodium sulfate, filtered and concentrated to give 48 mg (96%) of the title compound as a slightly yellow solid.
Reaction SMILES: [CH:1]([C:4]1[N:9]=[C:8]([CH2:10][N:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([NH2:20])[C:14]=3[C:13]([CH3:21])=[N:12]2)[CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[F:22][C:23]1[CH:28]=[CH:27][N:26]2[C:29]([C:32](OCC)=[O:33])=[CH:30][N:31]=[C:25]2[CH:24]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:22][C:23]1[CH:28]=[CH:27][N:26]2[C:29]([C:32]([NH:20][C:15]3[CH:16]=[CH:17][CH:18]=[C:19]4[C:14]=3[C:13]([CH3:21])=[N:12][N:11]4[CH2:10][C:8]3[CH:7]=[CH:6][CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:9]=3)=[O:33])=[CH:30][N:31]=[C:25]2[CH:24]=1
Reactant: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc(N)c12
Reactant: CCOC(=O)c1cnc2cc(F)ccn12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc(NC(=O)c3cnc4cc(F)ccn34)c12
Temperature: 0 °C
Yield: 73 %

Procedure:
1-((6-Isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-amine (Preparation D; 0.673 g, 2.40 mmol) and ethyl 7-fluoroimidazo[1,2-a]pyridine-3-carboxylate (Step C, 0.500 g, 2.40 mmol) were dissolved in dry THF (24 mL) and chilled to 0° C. LiHMDS (5.28 mL, 5.28 mmol, 1M in THF) was added by syringe over a five-minute period. Once the addition was complete, the reaction mixture was removed from the cooling bath and allowed to warm to ambient temperature. The mixture was quenched with saturated ammonium chloride solution and extracted with EtOAc. The combined organic extracts were washed with saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated. The crude material was purified by column chromatography (100% ethyl acetate) to afford 775 mg (73%) of 7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([C@:8]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)([CH3:11])[CH2:9][OH:10])[CH:7]=1.C(N(CC)CC)C.[C:30]([Si:34]([CH3:37])([CH3:36])Cl)([CH3:33])([CH3:32])[CH3:31]>ClCCl.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([C@:8]([NH:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)([CH3:11])[CH2:9][O:10][Si:34]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:37])[CH3:36])[CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(CN[C@@](C)(CO)c2cc(Br)ccc2F)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CN[C@@](C)(CO[Si](C)(C)C(C)(C)C)c2cc(Br)ccc2F)cc1

Procedure:
A solution of (R)-2-(5-bromo-2-fluoro-phenyl)-2-(4-methoxy-benzylamino)-propan-1-ol (6.95 g, 18.9 mmol) in dichloromethane (170 ml) was treated at room temperature with triethylamine (5.78 ml, 41.5 mmol), 4-dimethylaminopyridine (1.15 g, 9.43 mmol), and tert-butyldimethylchlorosilane (1.15 g, 37.7 mmol). After 16 hours at room temperature the reaction mixture was consecutively extracted with saturated sodium hydrogen carbonate solution (100 ml), water (100 ml), and brine (100 ml). The aqueous layers were re-extracted with dichloromethane (100 ml). The combined organic layers were dried over sodium sulfate and evaporated at reduced pressure. After chromatography on Silicycle-Si-amine column using heptane as the eluent, [(R)-1-(5-bromo-2-fluoro-phenyl)-2-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethyl]-(4-methoxy-benzyl)-amine (intermediate C8A) was obtained as a colourless oil (8.0 g, 88% of theory). MS (ISP): m/z=482.2, 484.3 [M+H]+.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].Br[C:13]1[S:14][CH:15]=[CH:16][N:17]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(O)cc1
Reactant: Brc1nccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)Oc1ccc(Oc2nccs2)cc1
Temperature: 160 °C
Yield: 54.8 %

Procedure:
To a solution of 4-isopropoxyphenol (CAS #7495-77-4. 3 g, 19.7 mmole), at room temperature in DMSO (30 mL) was added in turn, 2-bromothiazole (3.23 g, 19.7 mmole) and potassium carbonate (5.44 g, 39.4 mmole), heated at 160° C. for 3 hours. The reaction mixture was cooled, diluted with ethyl acetate, washed with water and brine sequentially, dried over magnesium sulfate, filtered and concentrated. The residue was purified on Silica gel column using a gradient of 5 to 25% ethyl acetate in hexane and provided 2.54 g (55%) of the title compound as yellowish oil. 1H NMR (300 MHz, CDCl3) δ ppm 7.22 (d, J=3.68 Hz, 1H) 7.15-7.21 (m, 2H) 6.86-6.95 (m, 2H) 6.76 (d, J=4.04 Hz, 1H) 4.43-4.60 (heptet, J=6.25 Hz, 1H) 1.34 (d, J=6.25 Hz, 6H). MS (ESI) m/z 236 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:23])[C@H:10]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH2:12][CH2:13][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:25](OCC)(=O)[CH3:26]>C1COCC1>[CH2:1]([N:8]1[CH:26]=[CH:25][N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:10]([CH2:11][CH2:12][CH2:13][CH3:14])[C:9]1=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)NCc1ccccc1
Reactant: CCOC(C)=O
Agent: Cl
Solvent: C1CCOC1
Product: CCCC[C@H]1C(=O)N(Cc2ccccc2)C=CN1C(=O)OC(C)(C)C

Procedure:
A solution of N-benzyl 2(R)-tert-butoxycarbonylaminohexanamide (1.0 g, 2.29 mmol) in THF (10 mL) was vigorously stirred with 6N HCl(10 mL) for 24h. Ethyl acetate was added, and the layers separated. The organic phase was washed with water, then saturated sodium chloride solution. The crude product was chromatographed on silica gel with 30% ethyl acetate in hexane. The title compound was obtained as an oil (0.140 g). NMR (CDCl3, 300 MHz) δ 7.3 (5H, m), 6.31, 6.14 (1H, 2 ds, J=7, 7 Hz), 5.55, 5.42 (1H, 2 ds, J=7, 7 Hz), 4.68 (2H, AB q, J=15 Hz, D n=36 Hz), 4.78 (1H, m), 1.66 (2H, m), 1.47 (9H, d), 1.33 (4H, m), 0.89 (3H, brt, J=7 Hz).
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:8]([O:9][Si](C)(C)C)[CH2:7][N:6](C(=O)C(F)(F)F)[CH2:5]1)=[N+:2]=[N-:3].C([O-])([O-])=O.[K+].[K+]>CO>[N:1]([C@H:4]1[CH2:5][NH:6][CH2:7][C@@H:8]1[OH:9])=[N+:2]=[N-:3]
Reactant: C[Si](C)(C)O[C@H]1CN(C(=O)C(F)(F)F)C[C@@H]1N=[N+]=[N-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: [N-]=[N+]=N[C@H]1CNC[C@@H]1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.8 %

Procedure:
A solution of (3S,45)-1-(3-azido-4-trimethylsilanyloxy-pyrrolidin-1-yl)-2,2,2-trifluoro-ethanone (5.8 g, 19.57 mmol, prepared according to J. Org. Chem. 1997, 62, 4197) in MeOH (200 mL) was treated with K2CO3 (2.7 g, 1 eq) and the mixture stirred at rt for 4 h. concentrated in vacuo and purified by CC (DCM/MeOH 4:1+1% NH4OH) to give the title intermediate (2 g, 80% yield) as a brownish oil.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=O)[CH2:2]1.Cl.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18]N)=[CH:14][CH:13]=1>C(O)C.O>[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:15](=[CH:16][CH:17]=1)[NH:18][C:3]1[CH2:4][CH2:5][CH2:6][C:1](=[O:8])[C:2]2=1
Reactant: O=C1CCCC(=O)C1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1ccc2[nH]c3c(c2c1)C(=O)CCC3
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.7 %

Procedure:
1,3-Cyclohexanedione (8 g) was added to a solution of 4-methoxyphenylhydrazine hydrochloride (10 g) in ethanol (350 ml) and water (70 ml). The resulting solution was stirred at room temperature for 3 h and then at reflux for 14 h. On cooling to ambient temperature, the reaction mixture was poured into water (3 l) to give a solid, which was dried in vacuo to give the title compound, (6.0 g) m.p. 279°-279.5°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH2:13])=[S:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>>[CH3:16][N:17]([CH:19]=[N:13][C:11]([NH:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[S:12])[CH3:18]
Reactant: NC(=S)Nc1ccc([N+](=O)[O-])cc1
Reactant: COC(OC)N(C)C
Product: CN(C)C=NC(=S)Nc1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 74.3 %

Procedure:
A mixture of 5 g (25.3 mmol) (4-nitro-phenyl)-thiourea and 33.8 ml (253 mmol) N,N-Dimethylformamide dimethyl acetal was heated to 100° C. for 1 h. The precipitate was filtered off, washed with diethyl ether and dried to yield 4.74 g (74%) the title compound as orange solid.
Reaction SMILES: [CH3:1][C:2]1[C:15]([N:16]=[C:17]=S)=[C:14]([CH3:19])[CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8].[NH2:20][C:21]1[C:22]([NH2:45])=[N:23][C:24]([O:40][CH2:41][CH:42]([F:44])[F:43])=[C:25]([CH:39]=1)[C:26]([NH:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([C:35]([F:38])([F:37])[F:36])[CH2:31][CH2:30]1)=[O:27].CC(C)N=C=NC(C)C>>[CH3:1][C:2]1[C:15]([NH:16][C:17]2[NH:20][C:21]3[C:22]([N:45]=2)=[N:23][C:24]([O:40][CH2:41][CH:42]([F:44])[F:43])=[C:25]([C:26](=[O:27])[NH:28][C@H:29]2[CH2:30][CH2:31][C@H:32]([C:35]([F:37])([F:36])[F:38])[CH2:33][CH2:34]2)[CH:39]=3)=[C:14]([CH3:19])[CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: Nc1cc(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)c(OCC(F)F)nc1N
Reactant: Cc1ccc(CNC(=O)C(C)(C)C)c(C)c1N=C=S
Agent: CC(C)N=C=NC(C)C
Product: Cc1ccc(CNC(=O)C(C)(C)C)c(C)c1Nc1nc2nc(OCC(F)F)c(C(=O)N[C@H]3CC[C@H](C(F)(F)F)CC3)cc2[nH]1

Procedure:
The title compound is prepared from N-(2,4-dimethyl-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (65 mg, 0.24 mmol) and 5,6 diamino-2-(2,2-difluoro-ethoxy)-N-(trans-4-trifluoromethyl-cyclohexyl)-nicotinamide (90 mg, 0.24 mmol) with DIC in analogy to examples 8a/8b.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[CH2:16][OH:17])=[CH:10][CH:9]=2)[CH:2]=1.[H][H]>C(O)C.[C].[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][OH:17])=[CH:12][CH:13]=2)[CH:2]=1
Reactant: OC/C=C/c1ccc(Cc2cccnc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: OCCCc1ccc(Cc2cccnc2)cc1
Yield: 99.1 %

Procedure:
In 10 ml of ethanol was dissolved 500 mg of (E)-3-[4-(pyridin-3-ylmethyl)phenyl]allyl alcohol, and to the resulting solution was added 100 mg of 5% palladium-carbon, and the resulting mixture was stirred at room temperature in a hydrogen atmosphere for 2.5 hours. The reaction mixture thus obtained was filtered and the filtrate thus obtained was concentrated under reduced pressure to obtain 500 mg (yield 99.1%) of colorless, oily 3-[4-(pyridin-3-ylmethyl)phenyl]propanol.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:26](N)=[O:27])=[N:4][C:5]([C:16]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH:23]([CH3:25])[CH3:24])[CH:17]=2)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[N:7]=1.[OH-:29].[Na+].Cl>O1CCOCC1>[NH2:1][C:2]1[C:3]([C:26]([OH:27])=[O:29])=[N:4][C:5]([C:16]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH:23]([CH3:25])[CH3:24])[CH:17]=2)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[N:7]=1
Reactant: COc1ccc(-c2nc(N)c(C(N)=O)nc2-c2ccc(=O)n(C(C)C)c2)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(-c2nc(N)c(C(=O)O)nc2-c2ccc(=O)n(C(C)C)c2)cc1
Temperature: 100 °C

Procedure:
To a suspention of 3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)-5-(4-methoxyphenyl)-2-pyrazinecarboxamide (210 mg) in dioxane (2 ml) was added an aq. NaOH (2M, 4 ml) and this solution was heated at 100° C. for 4 hours. This reaction mixture was cooled to room temperature and the pH of this solution was adjusted to 2.5 with 2N aq. HCl. The precipitate was collected by filtration and washed with water to give 3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)-5-(4-methoxyphenyl)-2-pyrazinecarboxylic acid (203 mg) as a yellow powder.
Reaction SMILES: [CH3:1][C:2]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]2[C:23](=[O:24])[C:22]3([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:21]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:20]2)=[CH:14][CH:13]=1)([CH3:10])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].I[CH2:43][CH2:44][CH2:45][N:46]1[C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=2[NH:48][C:47]1=[O:55]>CN(C)C=O.C(OCC)(=O)C>[CH3:10][C:2]([O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][N:19]2[C:23](=[O:24])[C:22]3([CH2:29][CH2:28][N:27]([CH2:43][CH2:44][CH2:45][N:46]4[C:50]5[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=5[NH:48][C:47]4=[O:55])[CH2:26][CH2:25]3)[N:21]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:20]2)=[CH:16][CH:17]=1)([CH3:1])[C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4]
Reactant: O=c1[nH]c2ccccc2n1CCCI
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CN2CN(c3ccccc3)C3(CCN(CCCn4c(=O)[nH]c5ccccc54)CC3)C2=O)cc1
Temperature: 55 °C
Reaction time: 16 h
Yield: 86.4 %

Procedure:
To a solution of tert-butyl 2-methyl-2-(4-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)phenoxy)propanoate (0.22 g, 0.46 mmol) and potassium carbonate (0.095 g, 0.69 mmol) in N,N-dimethylformamide (4 mL), was added 1-(3-iodopropyl)-1,3-dihydro-2H-benzimidazol-2-one (0.139 g, 0.46 mmol). After stirring at 55° C. for 16 hours, the reaction mixture was diluted with ethyl acetate (100 mL), washed with water and brine. The organic phase was dried over MgSO4, filtered, concentrated and isolated by preparatory TLC (10% methanol/dichloromethane) to obtain the title compound (0.26 g, 86%); 1H NMR (DMSO-d6): δ 1.35 (s, 9H), 1.49 (s, 6H), 1.56 (d, 2H, J=13.6 Hz), 1.82 (t, 2H, J=6.4 Hz), 2.32-2.34 (m, 2H), 2.45-2.50 (m, 2H), 2.66-2.72 (m, 4H), 3.85 (t, 2H, J=6.8 Hz), 4.45 (s, 2H), 4.53 (s, 2H), 6.77-6.84 (m, 5H), 6.96 (d, 3H, J=3.2 Hz), 7.17-7.24 (m, 5H), 10.79 (s, 1H); MS for C38H47N5O5 m/z 654.18 (M+H)+.
Reaction SMILES: C(=O)([O-])O.[Na+].[CH:6]1([N:12]([CH3:19])[CH2:13][CH2:14][C:15]([CH3:18])([NH2:17])[CH3:16])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C1COCC1.[C:25](ON1C(=O)CCC1=O)([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>O>[CH:6]1([N:12]([CH3:19])[CH2:13][CH2:14][C:15]([NH:17][C:25](=[O:26])[O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([CH3:16])[CH3:18])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CN(CCC(C)(C)N)C1CCCCC1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(CCC(C)(C)NC(=O)OCc1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.9 %

Procedure:
Sodium hydrogen carbonate (15.0 g, 0.18 mol) dissolved in water (200 mL) was added to reaction containing crude N1-cyclohexyl-N1,3-dimethylbutane-1,3-diamine (14.0 g, 46.1 mmol) was dissolved into THF (200 mL). CbzOSu (11.0 g, 1 equiv, 44.2 mmol) was added in one portion to the reaction and left to stir at room temperature for 16 h. The organic solvent was removed and the aqueous residue was extracted with DCM (3×150 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated to a pale yellow oil (12.7 g). The crude oil was purified on an ISCO purification system with gradient elution from 20-100% ethyl acetate then1-10% methanol in ethyl acetate. The desired fraction was collected and concentrated to give a colorless oil (5.27 g, yield: 34.4%). 1H NMR (CDCl3, 400 MHz): δ 1.0-1.49 (m, 5H), 1.37 (s, 6H), 1.55 (t, 2H), 1.6-1.64 (m, 1H), 1.76 (bs, 4H), 2.21 (s, 3H), 2.32-2.4 (m, 1H), 2.60 (t, 2H), 5.03 (s, 2H), 7.2-7.4 (m, 5H), 7.96 (s, 1H). LRMS (ESI+) for C20H32N2O2 (332.3); Found: 333 (MH+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)=[O:7].[NH:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31]([CH:33]3[CH2:35][CH2:34]3)=[O:32])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1>>[O:7]=[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)[CH2:5][CH2:4][CH2:3][CH2:2][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31]([CH:33]3[CH2:34][CH2:35]3)=[O:32])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Reactant: O=C(CCCCCl)c1cccc(C(F)(F)F)c1
Product: O=C(CCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1)c1cccc(C(F)(F)F)c1

Procedure:
Prepared by Procedure K and Scheme B1 using 5-chloro-1-[3-(trifluoromethyl)phenyl]-1-pentanone and N-[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e: 473.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]([NH:14][C:15]3[CH:16]=[C:17]([CH:28]=[CH:29][CH:30]=3)[O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]([OH:27])=O)[CH:20]=3)=[O:13])=[CH:8][CH:9]=2)[CH:4]=[N:3]1.[NH2:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>CN(C=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]([NH:14][C:15]3[CH:16]=[C:17]([CH:28]=[CH:29][CH:30]=3)[O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]([NH:31][CH2:32][CH2:33][N:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)=[O:27])[CH:20]=3)=[O:13])=[CH:8][CH:9]=2)[CH:4]=[N:3]1
Reactant: Cn1ncc2cc(NC(=O)Nc3cccc(Oc4ccnc(C(=O)O)c4)c3)ccc21
Reactant: NCCN1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cn1ncc2cc(NC(=O)Nc3cccc(Oc4ccnc(C(=O)NCCN5CCCCC5)c4)c3)ccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.2 %

Procedure:
4-[3-({[(1-methyl-1H-indazol-5-yl)amino]carbonyl}amino)phenoxy]-pyridine-2-carboxylic acid (0.07 g, 0.17 mmol) was dissolved in DMF (2.5 mL), followed by sequential addition of 1-(2-aminoethyl)piperidine (0.02 g, 0.17 mmol), 1-hydroxybenzotriazole (0.05 g, 0.38 mmol), 1-[3-(dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride (0.05 g, 0.26 mmol), and N-methylmorpholine (0.04 g, 0.38 mmol). The mixture was stirred at room temperature for 12 h, and the solvent was removed in vacuo. The crude residue was dissolved in CH2Cl2 (10 mL), and washed with H2O (3 mL). The solvent was removed in vacuo, and the crude product was purified by preparative HPLC. The isolated product was washed with aq. Na2CO3 to give 0.07 g (78%) of the title compound. 1H-NMR (CD3OD) δ 8.51 (d, 1H), 7.91 (s, 1H), 7.84 (d, 1H), 7.59 (d, 1H), 7.50-7.46 (m, 2H), 7.41-7.36 (m, 2H), 7.26 (dd, 1H), 7.10 (dd, 1H), 6.81-6.77 (dd, 1H), 4.03 (s, 3H), 3.60 (t, 2H), 2.78-2.71 (m, 6H), 1.69-1.51 (m, 6H); MS LC-MS (M+H)+=514.3, RT=2.62 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:36]=[CH:35][C:25]2[N:26]([CH3:34])[C:27](=[O:33])[CH2:28][CH2:29][C:30]([CH3:32])([CH3:31])[C:24]=2[CH:23]=1.Cl>O1CCOCC1.COCCO>[Cl:20][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[N:7][C:2]([NH:21][C:22]2[CH:36]=[CH:35][C:25]3[N:26]([CH3:34])[C:27](=[O:33])[CH2:28][CH2:29][C:30]([CH3:32])([CH3:31])[C:24]=3[CH:23]=2)=[N:3][CH:4]=1
Reactant: CN1C(=O)CCC(C)(C)c2cc(N)ccc21
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: COCCO
Solvent: C1COCCO1
Product: CN1C(=O)CCC(C)(C)c2cc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)ccc21
Yield: 19.9 %

Procedure:
Combined N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (85 mg, 0.251 mmol), 7-Amino-1,5,5-trimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (80 mg, 0.251 mmol), 4 N HCl in dioxane (80 ul) and 2-methoxyethanol (3 mL). Heated reaction to 120° C. for 4 hours. Added CH2Cl2/MeOH/NH4OH, evaporated off solvent and purified with normal phase chromatography eluting with 1% to 3% MeOH in CH2Cl2 to yield a yellow solid, N-{(1R,2R)-2-[5-Chloro-2-(1,5,5-trimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide (26 mg, 20%). mp 165° C.; LCMS: m/z=521.59 (M+H+), 1H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.68 (m, 2H), 7.25 (s, 1H), 7.06 (d, 1H, J=8.6 Hz), 6.06 (d, 1H, J=6.6 Hz), 5.73 (d, 1H, J=7.3 Hz), 3.83 (m, 1H), 3.26 (s, 3H), 2.85 (s, 3H), 2.11 (m, 7H), 1.80 (s, 2H), 1.30 (m, 10H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:33]=[CH:32][C:10]([O:11][CH2:12][CH:13]([OH:31])[CH2:14][N:15]2[CH2:22][CH:21]3[CH2:23][CH:17]([CH2:18][N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20]3)[CH2:16]2)=[CH:9][CH:8]=1>N1C=CC=CC=1>[OH:31][CH:13]([CH2:12][O:11][C:10]1[CH:32]=[CH:33][C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:8][CH:9]=1)[CH2:14][N:15]1[CH2:22][CH:21]2[CH2:23][CH:17]([CH2:18][N:19]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:20]2)[CH2:16]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC2CC(CN(CC(O)COc3ccc(N)cc3)C2)C1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CC2CC(CN(CC(O)COc3ccc(NS(C)(=O)=O)cc3)C2)C1
Reaction time: 2.5 h
Yield: 87 %

Procedure:
MsCl (0.50 g; 4.40 mmol) was added to a stirred solution of tert-butyl 7-[3-(4-aminophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (1.68 g; 4.29 mmol; see Example 13 above) in pyridine (20 mL). The reaction mixture was stirred for 2.5 h and subsequently concentrated. The residue was partitioned between DCM and NaHCO3 (sat.), the organic layer separated, dried and concentrated. Purification using column chromatography (gradient 0 to 10% MeOH in DCM) gave the title compound in a 87% yield. 13C NMR (CDCl3): δ 28.70, 28.70, 28.84, 29.09, 29.42, 31.93, 38.77, 47.64, 49.42, 57.01, 60.29, 61.84, 65.20, 70.79, 79.50, 115.48, 116.32, 124.53, 129.40, 155.94, 157.28.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=2[F:23])=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13])(=O)=O.O[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[C:27]([CH3:38])[C:26]=1[CH3:39]>>[F:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[C:8]1[C:7]([CH2:6][O:5][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[C:27]([CH3:38])[C:26]=2[CH3:39])=[C:11]([C:12]([F:15])([F:14])[F:13])[S:10][N:9]=1
Reactant: Cc1ccc(-c2nsc(C(F)(F)F)c2COS(C)(=O)=O)c(F)c1
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Product: Cc1ccc(-c2nsc(C(F)(F)F)c2COc2ccc(CCC(=O)O)c(C)c2C)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting following Step 5 and 6 coupling (3-(2-fluoro-4-methylphenyl)-5-(trifluoromethyl)isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (300 MHz, CD3OD) δ 7.36 (t, J=7.6 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 7.07 (d, J=11.4 Hz, 1H), 6.90 (d, J=8.4 Hz, 1H), 6.50 (d, J=8.7 Hz, 2H), 5.05 (s, 2H), 2.85 (t, J=8.4 Hz, 2H), 2.42 (s, 3H), 2.34 (t, J=8.4 Hz, 2H), 2.18 (s, 3H), 1.88 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C23H21F4NO3S, 466.1 (M−H). found 466.2.