Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].CCN(CC)CC.[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:22]=1)[C:17]([OH:19])=O.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[Br:13][C:14]1[CH:22]=[C:21]([CH:20]=[C:16]([C:17](=[O:19])[N:3]([O:4][CH3:5])[CH3:2])[CH:15]=1)[C:23]([O:25][CH3:26])=[O:24]
Reactant: CNOC
Reactant: COC(=O)c1cc(Br)cc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(Br)cc(C(=O)N(C)OC)c1
Reaction time: 0.5 h
Yield: 77.4 %

Procedure:
N,O-Dimethylhydroxylamine hydrochloride (1.15 g, 11.8 mmol) was dissolved in CH2Cl2 (50 mL) and Et3N (4.8 mL, 34.4 mmol) was added. The solution was stirred for 30 min. The resultant solution was cooled to 0° C. and compound 3-bromo-5-(methoxycarbonyl)benzoic acid (2.55 g, 9.84 mmol) was added followed by EDC.HCl (3.77 g, 19.6 mmol) and HOBt (0.26 g, 1.96 mmol). The reaction mixture was allowed to come to room temperature and stirred for another 4 h. After completion, the reaction mixture was diluted with CH2Cl2. The organic layer was washed with water and brine solution and dried over anhydrous sodium sulfate. Solvent was removed under reduced pressure and the crude product was purified by column chromatography (silica 60-120 mesh, eluent 20% EtOAc in petroleum ether) to get methyl 3-bromo-5-(methoxy(methyl)carbamoyl)benzoate (2.3 g, yield 77%) as colorless liquid. 1H NMR (400 MHz, CDCl3) δ 8.29 (m, 1H), 8.27 (t, J=1.8 Hz, 1H), 8.02 (t, J=1.6 Hz, 1H), 3.95 (s, 3H), 3.57 (s, 3H), 3.39 (s, 3H). MS (ESI) m/z: Calculated for C11H12BrNO4: 300.99. found: 302.0 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[O:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[O:11]2)=[CH:6][CH:5]=1.O=[C:28]([CH3:42])[CH2:29][CH2:30][N:31]1C(=O)C2C(=CC=CC=2)C1=O>>[F:26][C:2]([F:1])([F:25])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([CH:19]3[CH2:20][CH2:21][N:22]([CH:28]([CH3:42])[CH2:29][CH2:30][NH2:31])[CH2:23][CH2:24]3)[O:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[O:11]2)=[CH:8][CH:9]=1
Reactant: CC(=O)CCN1C(=O)c2ccccc2C1=O
Reactant: FC(F)(F)Oc1ccc(C2(C3CCNCC3)Oc3ccccc3O2)cc1
Product: CC(CCN)N1CCC(C2(c3ccc(OC(F)(F)F)cc3)Oc3ccccc3O2)CC1

Procedure:
Using general procedure B with the above amine (260 mg, 0.712 mmol) and 2-(3-oxo-butyl)-isoindole-1,3-dione (309 mg, 1.42 mmol) and then using general procedure D gave 3-{4-[2-(4-trifluoromethoxy-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butylamine as a white solid (193 mg, 63% over 2 steps).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:13]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[CH:11][C:5]2=[N:6][C:7]=1[CH2:8][NH:9][CH3:10].Cl[C:23]1[N:28]=[C:27]([NH:29][C:30]2[CH:34]=[C:33]([CH:35]3[CH2:37][CH2:36]3)[NH:32][N:31]=2)[CH:26]=[CH:25][N:24]=1.CCN(C(C)C)C(C)C>CC(C(O)C(C)C)C>[CH:35]1([C:33]2[NH:32][N:31]=[C:30]([NH:29][C:27]3[CH:26]=[CH:25][N:24]=[C:23]([N:9]([CH2:8][C:7]4[N:6]=[C:5]5[CH:11]=[CH:12][N:13]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:4]5=[CH:3][C:2]=4[F:1])[CH3:10])[N:28]=3)[CH:34]=2)[CH2:37][CH2:36]1
Reactant: CNCc1nc2ccn(COCC[Si](C)(C)C)c2cc1F
Reactant: Clc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Agent: CC(C)C(O)C(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1nc2ccn(COCC[Si](C)(C)C)c2cc1F)c1nccc(Nc2cc(C3CC3)[nH]n2)n1
Temperature: 135 °C
Yield: 46.3 %

Procedure:
A mixture of (6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-5-yl)-N-methylmethanamine (50 mg, 0.17 mmol), 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (38 mg, 0.17 mmol), and DIPEA (66 mg, 0.51 mmol) in 2,4-dimethylpentan-3-ol (2 mL) was heated at 135° C. for 15 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by SiO2 chromatography eluting with DCM/MeOH (10:1) to afford 40 mg (30%) of N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-((6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-5-yl)methyl)-N2-methylpyrimidine-2,4-diamine as a brown oil (40 mg, 30%). MS (ESI): m/z=509.4 [M+H]+.
Reaction SMILES: C([O:8][C:9](=[O:34])[C@H:10]([N:20]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)C1C=CC=CC=1>CO.[Pd]>[CH2:32]([O:31][C:29]([CH2:28][N:20]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[C@H:10]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)[C:9]([OH:34])=[O:8])=[O:30])[CH3:33]
Reactant: CCOC(=O)CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc(OC)cc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc(OC)cc1)C(=O)O
Yield: 86.5 %

Procedure:
N-Ethoxycarbonylmethyl-N-tert.-butoxycarbonyl-2-(R)-amino-3-(4-methoxyphenyl)-propionic acid benzyl ester (1.50 g) were dissolved in 40 mL of methanol and hydrogenated for 4 h at room temperature using 0.3 g palladium on charcoal (10%) as catalyst. Filtration followed by concentration in vacuo affords 1.05 g (87%) of the title compound as a colorless oil. (−)-APCI-MS: 381 ([M−H]−).
Reaction SMILES: FC(F)(F)C(O)=O.[O-:8][C:9]#[N:10].[Na+].NN.[CH3:14][C:15]1[CH:16]=[C:17]([N:22]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[NH2:23])[CH:18]=[C:19]([CH3:21])[CH:20]=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[NH2:10][C:9]([NH:23][N:22]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:17]1[CH:16]=[C:15]([CH3:14])[CH:20]=[C:19]([CH3:21])[CH:18]=1)=[O:8]
Reactant: N#C[O-]
Reactant: COC(=O)CN(N)c1cc(C)cc(C)c1
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CN(NC(N)=O)c1cc(C)cc(C)c1
Reaction time: 2 h
Yield: 76 %

Procedure:
Trifluoroacetic acid (1.06 ml, 13.9 mmol) was added under nitrogen to a stirred suspension of sodium cyanate (1.00 g, 15.2 mmol) in a solution of the hydrazine (Intermediate 36; 1.00 g, 4.8 mmol) in dry toluene (30 ml). The mixture was stirred for ca. 2 h, causing formation of a viscous insoluble gum. Saturated aqueous sodium hydrogen carbonate (25 ml) was added (causing effervescence and dissolution of the gum) and the mixture was extracted with ethyl acetate (3×75 ml). The combined extracts were washed with saturated brine (50 ml) dried and evaporated to afford a light yellow solid which was triturated with hexane/ethyl acetate (1:1) to give the title compound as a white powder (0.92 g, 76%), m.p. 139°-141°.
Reaction SMILES: [C:1]([O:18][C@@H:19]1[C@@H:23]([CH2:24][O:25][C:26](=[O:42])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[O:22][C@@H:21]([N:43]2[CH:50]=[C:49]([F:51])[C:47](=[O:48])[NH:46][C:44]2=[O:45])[CH2:20]1)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(N(CC)CC)C.[CH3:59][O:60][C:61]1[C:69]([O:70][CH3:71])=[CH:68][CH:67]=[CH:66][C:62]=1[C:63](Cl)=[O:64]>O1CCOCC1>[CH3:59][O:60][C:61]1[C:69]([O:70][CH3:71])=[CH:68][CH:67]=[CH:66][C:62]=1[C:63]([N:46]1[C:47](=[O:48])[C:49]([F:51])=[CH:50][N:43]([C@@H:21]2[O:22][C@H:23]([CH2:24][O:25][C:26](=[O:42])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C@@H:19]([O:18][C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:20]2)[C:44]1=[O:45])=[O:64]
Reactant: COc1cccc(C(=O)Cl)c1OC
Reactant: CCCCCCCCCCCCCCCC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OC(=O)CCCCCCCCCCCCCCC
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)n(C(=O)c3cccc(OC)c3OC)c2=O)C[C@@H]1OC(=O)CCCCCCCCCCCCCCC
Reaction time: 1.5 h
Yield: 80.2 %

Procedure:
3.0 Grams of 2'-deoxy-3',5'-di-O-palmitoyl-5-fluorouridine are dissolved in 25 ml of dry dioxane and the solution is ice cooled. 2 Milliliters of triethylamine and 1.9 g of 2,3-dimethoxybenzoyl chloride are added to the solution and the mixture is subjected to reaction at room temperature for 10 minutes and then at 70° C. for 90 minutes. The reaction liquid is cooled and the precipitated triethylamine hydrochloride is filtered off. The filtrate is concentrated under reduced pressure and the residue is dissolved under heating in ethanol and the solution is allowed to stand whereby crystals are obtained which, after recrystallization from ethanol, affords 2.95 g (yield: 80.2%) of 3-(2,3-dimethoxybenzoyl)-2'-deoxy-3',5'-di-O-palmitoyl-5-fluorouridine. M.P. 77°-78° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17](=O)[CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)[CH2:23][CH2:22]3)[CH2:13][CH2:12]2)=[N:8][CH:9]=1)([O-:3])=[O:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:47])=CC=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17](=[S:47])[CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)[CH2:23][CH2:22]3)[CH2:13][CH2:12]2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C(CCCN1CCN(c2ccc(C(F)(F)F)cc2)CC1)N1CCC(Nc2ccc([N+](=O)[O-])cn2)CC1
Product: O=[N+]([O-])c1ccc(NC2CCN(C(=S)CCCN3CCN(c4ccc(C(F)(F)F)cc4)CC3)CC2)nc1

Procedure:
1-[4-(5-Nitro-pyridin-2-ylamino)-piperidin-1-yl]-4-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-butan-1-one (20 mg; 0.038 mmol, prepared in accordance with Example 95) is reacted with Lawesson's reagent (8 mg; 0.019 mmol) according to the general conditions described in Example 109. The desired product is obtained following purification by preparative HPLC (8 mg; 0.015 mmol). The structure was confirmed using Protocol I-B. Calculated mass=537; observed mass=537; HPLC retention time=4.39 min.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N+:15]=2[O-])[CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:22]1C=CC=CC=1.CS(OS(C)(=O)=O)(=O)=O.C(CN)O>CC#N.O>[C:1]([O:5][C:6](=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([NH2:22])[N:15]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc[n+]([O-])c1-c1cccc(C(=O)OC(C)(C)C)c1
Reactant: c1ccncc1
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: O
Solvent: CC#N
Solvent: NCCO
Product: Cc1ccc(N)nc1-c1cccc(C(=O)OC(C)(C)C)c1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
A solution of compound 5 (1 eq) and pyridine (4 eq) in MeCN (8 vol) is heated to 70° C. A solution of methanesulfonic anhydride (1.5 eq) in MeCN (2 vol) is added over 50 min via addition funnel maintaining the temperature at less than 75° C. The mixture is stirred for an additional 0.5 hours after complete addition. The mixture is then allowed to cool to ambient. Ethanolamine (10 eq) is added via addition funnel. After stirring for 2 hours, water (6 vol) is added and the mixture is cooled to 10° C. After stirring for NLT 3 hours, the solid is collected by filtration and washed with water (3 vol), 2:1 MeCN/water (3 vol), and MeCN (2×1.5 vol). The solid is dried to constant weight (<1% difference) in a vacuum oven at 50° C. with a slight N2 bleed to afford compound 6 as a red-yellow solid (53% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]4[N:26]=[CH:25][N:24](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:23]=4)[CH:20]=3)[N:15](C3CCCCO3)[N:14]=2)[CH:8]=1)=[O:5]>O1CCOCC1.Cl>[NH:24]1[CH:25]=[N:26][C:22]([C:19]2[CH:20]=[C:21]3[C:16](=[CH:17][CH:18]=2)[NH:15][N:14]=[C:13]3[C:9]2[CH:8]=[C:7]([NH:6][C:4](=[O:5])[CH2:3][O:2][CH3:1])[CH:12]=[CH:11][CH:10]=2)=[N:23]1
Reactant: COCC(=O)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: Cl
Solvent: C1COCCO1
Product: COCC(=O)Nc1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1
Reaction time: 18 h
Yield: 46 %

Procedure:
Hydrolysis was performed by stirring 2-methoxy-N-(3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)](1H-indazol-3-yl)}phenyl)acetamide (0.141 g, 0.207 mmol) in 4 mL of 4.0 N commercial solution of HCl in dioxane and 2 mL of 6.ON aqueous HCl, at room temperature for 18 hours. The title compound was purified by preparative HPLC (15–80% acetonitrile in water) (0.033 g, 46% yield) 1H NMR (DMSO-d6) δ 13.5 (br s, 1H), 10.0 (s, 1H), 8.7 (s, 1H), 8.4 (br s, 1H), 8.3 (s, 1H), 8.1 (d, 1H), 7.8 (d, 1H), 7.7 (d, 2H), 7.5 (dd, 1H), 4.06 (s, 2H), 3.4 (s, 3H); ES-MS (m/z) 349 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:7]2([CH2:10][O:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[CH2:9][O:8]2)=[CH:5][CH:6]=1.[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[S:3][C:4]([C:7]([OH:8])([CH2:9][N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)[CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:5][CH:6]=1
Reactant: c1nc[nH]n1
Reactant: Clc1ccc(OCC2(c3ccc(Br)s3)CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OC(COc1ccc(Cl)cc1)(Cn1cncn1)c1ccc(Br)s1
Yield: 54.7 %

Procedure:
16 g of crude 2-(2-bromo-thien-5-yl)-2-(4-chlorophenoxymethyl)-oxirane in 200 ml of acetonitrile are heated under reflux with 11 g (0.157 mol) of 1,2,4-triazole and 5 g of potassium carbonate for 4 hours. Thereafter, the reaction mixture is poured onto water, and extracted with methylene chloride. The methylene chloride phase is dried over sodium sulphate and evaporated down in vacuo. The residue is chromatographed over silica gel using the chloroform/ethyl acetate (1:1) system. 10.5 g (55% of theory) of 2-(2-bromo-thien-5-yl)-1-(4-chlorophenoxy)-3-(1,2,4-triazol-1-yl)-propan-2-ol are obtained in the form of a yellow resin which crystallizes after standing for a long time. Melting point 108°-112° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[CH:5]2.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>O1CCOCC1.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>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:6]2[NH:7][C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:10][CH:9]=3)=[CH:12][CH:13]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1ccc(-c2cc3cc(Br)ccc3[nH]2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: Clc1ccc(-c2cc3cc(-c4ccccc4)ccc3[nH]2)cc1
Temperature: 160 °C
Yield: 10.6 %

Procedure:
To a suspension of 5-bromo-2-(4-chlorophenyl)-1H-indole (200 mg, 0.65 mmol) in dioxane/water 4:1 v/v (5 mL) was added phenylboronic acid (87 mg, 0.72 mmol) and a few milligrams of tetrakis(triphenylphosphine)palladium(0). The resulting suspension was heated in the microwave at 160° C. for 15 min. After cooling, the reaction was poured into water to give a precipitate, which was filtered off and washed with water. The resulting solid was purified by column chromatography eluting using a gradient (hexanes to ethyl acetate/hexanes 30:70 v/v), followed by a recrystallisation from hot ethyl acetate to afford 21 mg (11%) of the title compound (LCMS RT=8.54 min, MH+ 304.1)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)=[CH:20][C:19]([CH3:32])=[C:18]([C:33]([N:35]3[CH2:40][CH2:39][CH:38]([N:41]4[CH2:45][CH2:44][CH2:43][CH2:42]4)[CH2:37][CH2:36]3)=[O:34])[N:17]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>CO>[CH3:32][C:19]1[CH:20]=[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:29])[F:30])[CH:23]=2)[C:16]([C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:15])=[N:17][C:18]=1[C:33]([N:35]1[CH2:40][CH2:39][CH:38]([N:41]2[CH2:45][CH2:44][CH2:43][CH2:42]2)[CH2:37][CH2:36]1)=[O:34]
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)nc1C(=O)N1CCC(N2CCCC2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(C(=O)N2CCNCC2)nc1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for the preparation of example 60, 4-[5-methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromethyl-phenyl)-pyridine-2-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (example 59) was reacted with HCl/dioxane in methanol to give the title compound as light yellow solid. MS: 530.2 (MH+).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:16][CH2:15][CH:14]([NH:17]C(=O)OC(C)(C)C)[CH2:13][C:12]3[CH:25]=[CH:26][CH:27]=[CH:28][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>ClCCl>[C:1]1([S:7]([N:10]2[CH2:16][CH2:15][CH:14]([NH2:17])[CH2:13][C:12]3[CH:25]=[CH:26][CH:27]=[CH:28][C:11]2=3)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccccc2)c2ccccc2C1
Agent: Cl
Solvent: ClCCl
Product: NC1CCN(S(=O)(=O)c2ccccc2)c2ccccc2C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 1 tert-butyl 1-(phenylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-4-ylcarbamate in dichloromethane (2 mL) was added HCl (4 M in 1,4-dioxane, 2 mL, 8.0 mmol). The mixture was stirred at room temperature for 20 hours before being filtered and evaporated to dryness to yield 1-(phenylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-4-amine.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:7][CH2:6][C:5]([CH3:11])([C:8]([OH:10])=O)[CH2:4][O:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:48]=1[C:59]([NH2:61])=[O:60]>C(Cl)Cl>[C:59]([C:48]1[C:47]([NH:46][C:8]([C:5]2([CH3:11])[CH2:4][O:3][C:2]([CH3:1])([CH3:12])[O:7][CH2:6]2)=[O:10])=[CH:52][CH:51]=[CH:50][C:49]=1[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)(=[O:60])[NH2:61]
Reactant: NC(=O)c1c(N)cccc1-c1ccccc1
Reactant: CC1(C)OCC(C)(C(=O)O)CO1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)OCC(C)(C(=O)Nc2cccc(-c3ccccc3)c2C(N)=O)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.9 %

Procedure:
To a solution of the commercially available 2,2,5-trimethyl-1,3-dioxane-5-carboxylic acid (0.6 g, 4 mmol) in DCM (30 mL) was added HATU (1.8 g, 4.7 mmol) and DIPEA (1.6 mL, 23.5 mmol). The reaction mixture was stirred at room temperature for 1 h. After this time, 3-aminobiphenyl-2-carboxamide (0.6 g, 2.35 mmol) was added and the resulting solution was stirred for 16 h. At the conclusion of this period, the reaction mixture was washed with water, dried, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (25% ethyl acetate in hexanes) to yield N-(2-carbamoylbiphenyl-3-yl)-2,2,5-trimethyl-1,3-dioxane-5-carboxamide (0.25 g, 24% yield) as a white solid. LCMS Method Y: retention time 1.69 min; [M+1]=367.2.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH2:7][CH:3]([C:4]([OH:6])=[O:5])[CH2:2]1.[OH-].[Na+].[CH2:12]([O:19][C:20](Cl)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O.O1CCCC1>[CH2:12]([O:19][C:20]([N:1]1[CH2:9][CH2:8][CH2:7][CH:3]([C:4]([OH:6])=[O:5])[CH2:2]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)C1CCCNC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C

Procedure:
To an ice cooled solution of nipecotic acid (10.0 g, 77.5 mmol), sodium hydroxide (3.4 g, 85 mmol), and tetrahydrofuran (50 mL) in water (100 mL) was added by simultaneous dropwise addition benzylchloroformate (13.3 mL, 93 mmol) in tetrahydrofuran (50 mL) and sodium hydroxide (3.4 g, 85 mmol) in water (50 mL). Warmed slowly to room temperature. After 24 hours tetrahydrofuran was removed in vacuo and the resulting aqueous mixture acidified with 3 N hydrochloric acid and extracted with dichloromethane (3×). The combined organic portions were dried with anhydrous magnesium sulfate. Filtration followed by evaporation of the filtrate in vacuo gave the titled compound. 1HNMR (CHCl3, 300 MHz) □ 7.45-7.20 (m, 5H); 5.14 (m, 2H); 4.21 (br s, 1H); 3.96 (m, 1H), 3.15 (br s, 1H); 2.93 (m, 1H); 2.51 (m, 1H); 2.09 (m, 1H); 1.80-1.60 (m, 2H); 1.50 (m, 1H) ppm.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:14][CH3:15].[Cl:20][C:21]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([Cl:33])[C:22]=1[CH:23]=[O:24]>O1CCCC1>[Cl:20][C:21]1[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[C:25]([Cl:33])[C:22]=1[CH:23]([OH:24])[CH:14]([CH3:15])[C:13]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CC
Reactant: O=Cc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)C(O)c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 3.8 ml of anhydrous diisopropylamine in 50 ml anhydrous tetrahydrofuran was added 14.7 ml of n-butyllithium (1.61 moles/liter in hexane) at 0° C., the mixture was stirred at 0° C. for 30 minutes, and 2.4 ml of ethyl propionate in 10 ml of anhydrous tetrahydrofuran was thereafter added to the mixture. The resulting mixture was stirred at -78° C. for 1 hour, and 5.0 g of 2,6-dichloro-4-trifluoromethylbenzaldehyde (7) in 10 ml of anhydrous tetrahydrofuran was thereafter added to the mixture, followed by stirring at -78° C. for 30 minutes and then at room temperature for 1 hour. The reaction mixture was poured into ice water, followed by extraction with ethyl acetate, washing with brine, drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/6), affording 7.2 g of the desired product in the form of a yellow oil (yield 91.1%).
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][C:10](=[CH:17][C:18]1([CH3:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[C:11]2=[O:16]>[Ni].O.C(O)C>[C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH:10]([CH2:17][C:18]1([CH3:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1)[C:11]2=[O:16]
Reactant: CC1(C=C2Cc3c(cccc3-c3ccccc3-c3ccccc3)C2=O)CCCCC1
Agent: [Ni]
Solvent: O
Solvent: CCO
Product: CC1(CC2Cc3c(cccc3-c3ccccc3-c3ccccc3)C2=O)CCCCC1
Yield: 88.2 %

Procedure:
A mixture of Raney nickel (a slurry in water, 4.4 g), compound 20 (4.4 g, 11.21 mmol, 1 equiv) in ethanol (450 mL) was hydrogenated @ 50 psi at room temperature overnight. The mixture was filtered through Celite and the filter cake was washed with ethanol (200 mL). The filtrate was concentrated under reduced pressure to give crude compound 21 (3.9 g, 88% yield) as a pale-yellow oil. This material was used subsequently.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][Si:12]([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([F:29])[CH:6]=1)(=O)C.[OH-].[Na+].Cl>CO>[Si:12]([O:11][C:8]1[CH:9]=[CH:10][C:5]([OH:4])=[CH:6][C:7]=1[F:29])([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(=O)Oc1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)[Si](Oc1ccc(O)cc1F)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
4-{[t -Butyl(diphenyl)silyl]oxy}-3-fluorophenyl acetate (5.28 g, 12.92 mmol) was dissolved in methanol (100 mL). 1N NaOH (15.5 mL) was added. The solution was stirred for 30 minutes at ambient temperature. 1N HCl (16 mL) was added. The solvent was removed in vacuo and the solid partitioned between dichloromethane and water. The aqueous phase was washed with dichloromethane. The organic layers were combined and the solvent dried over anhydrous magnesium sulfate. The solution was filtered and the solvent evaporated to dryness in vacuo to yield crude title compound (4.5 g, 12.28 mmol).