Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([CH:8]1[S:20][C:11]23[CH:19]=[CH:18][CH:17]=[CH:16][C:12]2=[N:13][CH2:14][CH2:15][CH:10]3[CH:9]1[C:21]([OH:23])=O)=O)(C)(C)C.Cl.CN.[CH2:27]([N:29](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O.C(OCC)(=O)C>[CH3:27][NH:29][C:21]([CH:9]1[CH:10]2[C:11]3([CH:19]=[CH:18][CH:17]=[CH:16][C:12]3=[N:13][CH2:14][CH2:15]2)[S:20][CH2:8]1)=[O:23]
Reactant: CC(C)(C)OC(=O)C1SC23C=CC=CC2=NCCC3C1C(=O)O
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)C1CSC23C=CC=CC2=NCCC13
Temperature: 50 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
In 5 ml of dimethylformamide were dissolved 0.32 g of 2-tert-butoxycarbonyl-1,2,3,4-tetrahydro-benzo[b]thieno[2,3-c]pyridine-3-carboxylic acid, 0.08 g of methylamine.hydrochloride, and 0.17 ml of triethylamine, and after adding dropwise thereto 5 ml of a dimethylformamide solution of 0.33 g of diphenylphosphorylazide under ice-cooling and further adding dropwise thereto 2 ml of a dimethylformamide solution of 0.17 ml of triethylamine, the mixture was stirred for 2 hours at room temperature. To the reaction mixture was added 50 ml of ethyl acetate and the mixture was washed thrice with 10 ml of an aqueous 5% citric acid solution, thrice with an aqueous 5% sodium hydrogencarbonate solution and then twice with a saturated sodium chloride solution, and thereafter dried with sodium sulfate. After filtering away sodium sulfate, 5 ml of a mixture of 1N hydrochloric acid in ethyl acetate were added to the filtrate and the mixture was heated to 50° C. for one hour. Then, the reaction mixture was allowed to stand overnight in a refrigerator and crystals thus deposited were collected by filtration to provide 0.23 g (yield of 65%) of N-methyl-1,2,3,4-tetrahydrobenzo[b]thieno[2,3-c]pyridine-3-carboamide. (See Table 11, Table 12).
Reaction SMILES: [F:1][C:2]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:3]=1[CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:20]=[C:21]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=4)[CH:17]=3)[N:12](S(C3C=CC(C)=CC=3)(=O)=O)[CH:11]=2)[CH:7]=[N:6]1.[OH-].[Li+]>C1COCC1.O.CO>[F:1][C:2]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:3]=1[CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:20]=[C:21]([NH:25][S:26]([CH3:29])(=[O:27])=[O:28])[CH:22]=[CH:23][CH:24]=4)[CH:17]=3)[NH:12][CH:11]=2)[CH:7]=[N:6]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cc(F)ccc4F)c3)c3cc(-c4cccc(NS(C)(=O)=O)c4)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cccc(-c2cnc3[nH]cc(-c4cnn(Cc5cc(F)ccc5F)c4)c3c2)c1
Yield: 90.9 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(3-(3-(1-(2,5-difluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl) methanesulfonamide (250 mg, 0.39 mmol) was hydrolyzed with lithium hydroxide (66 mg, 1.57 mmol) in THF/water/methanol (5/4/3 ml) mixture to afford 170 mg (89.94% yield) of the pure product. 1H NMR (DMSO-d6, 300 MHz): δ 11.83 (s, 1H), 8.47-8.32 (m, 3H), 7.97 (s, 1H), 7.799-7.794 (d, 1H), 7.64-7.55 (m, 3H), 7.49-7.44 (m, 3H), 7.32-7.21 (m, 2H), 5.44 (s, 2H), 3.03 (s, 3H) MS: m/z=479.8 (M+1), HPLC: 73.14% in method A.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]([F:26])([F:25])[C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[NH2:17]>>[F:12][C:13]([F:25])([F:26])[C:14]1[CH:15]=[C:16]([NH:17][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[OH:11])[CH:18]=[C:19]([C:21]([F:22])([F:24])[F:23])[CH:20]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(O)c1cc(Br)ccc1O
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(Br)ccc1O
Yield: 88.5 %

Procedure:
Using 5-bromosalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2](C)=[CH2:3].O[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18](=[O:22])[C:19](C)=[CH2:20])=[CH:11][C:10]=1N1N=C2C=CC=CC2=N1.C(OCCC[Si](OC)(OC)OC)(=O)C(C)=C.N(C(C)(C)C#N)=NC(C)(C)C#N>CCCCCC.COCCOC>[CH3:13][CH2:14][CH2:9][CH2:10][CH:11]([CH2:7][O:6][C:1]([CH:2]=[CH2:3])=[O:5])[CH2:12][CH3:15].[CH3:11][CH2:12][CH2:15][CH2:16][O:17][C:18]([CH:19]=[CH2:20])=[O:22]
Reactant: C=C(C)C(=O)OCCc1ccc(O)c(-n2nc3ccccc3n2)c1
Reactant: C=C(C)C(=O)OC
Agent: C=C(C)C(=O)OCCC[Si](OC)(OC)OC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: COCCOC
Solvent: CCCCCC
Product: C=CC(=O)OCC(CC)CCCC
Product: C=CC(=O)OCCCC

Procedure:
A flask having a reflux condenser and a stirrer and having nitrogen substituted for air inside was charged with 65 parts of methyl methacrylate (to be abbreviated as “MMA” hereinafter), 25 parts of 2-(2′-hydroxy-5′-methacryloxyethylphenyl)benzotriazole (to be abbreviated as “MEBT” hereinafter), 10 parts of 3-methacryloxypropyl-trimethoxysilane (to be abbreviated as “MPTMS” hereinafter), 0.16 part of azobisisobutyronitrile and 200 parts of 1,2-dimethoxyethane, and these contents were mixed and dissolved. Then, the mixture was allowed to react under nitrogen current at 70° C. for 6 hours. The resultant reaction mixture was added to n-hexane for re-precipitation and purification, to give 86 parts of an acrylic copolymer resin (to be abbreviated as “AC-1” hereinafter) having an MMA/MEBT/MPTMS composition ratio of 65/25/10 by weight ratio (85/10/5 by molar ratio). The above copolymer had a weight average molecular weight of 90,000.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[CH2:5][C:6]3[CH2:10][N:9]([C@@H:11]([CH2:15][CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)[C:12](O)=[O:13])[C:8](=[O:22])[C:7]=3[O:23][C:24]=2[CH:25]=[CH:26][CH:27]=1.C(Cl)(=O)C(Cl)=O.[Cl:34][C:35]1[CH:36]=[CH:37][C:38]([NH2:41])=[N:39][CH:40]=1>C(Cl)Cl.O>[Cl:34][C:35]1[CH:36]=[CH:37][C:38]([NH:41][C:12](=[O:13])[C@@H:11]([N:9]2[CH2:10][C:6]3[CH2:5][C:4]4[C:3]([O:2][CH3:1])=[CH:27][CH:26]=[CH:25][C:24]=4[O:23][C:7]=3[C:8]2=[O:22])[CH2:15][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[N:39][CH:40]=1
Reactant: COc1cccc2c1CC1=C(O2)C(=O)N([C@@H](CC2CCCCC2)C(=O)O)C1
Reactant: Nc1ccc(Cl)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Product: COc1cccc2c1CC1=C(O2)C(=O)N([C@@H](CC2CCCCC2)C(=O)Nc2ccc(Cl)cn2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22 %

Procedure:
A solution of (S)-2-(8-methoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-propionic acid (200 mg, 0.64 mmol) (from Example 7, Step 2c), in methylene chloride (10 mL) was treated with oxalyl chloride (0.07 mL, 0.64 mmol) at 0° C. The mixture was warmed to 25° C. and stirred for additional 2 hours. Then, the reaction mixture was cooled to 0° C., and N,N′-diisopropylethyl amine (0.34 mL, 1.92 mmol) and commercially available 5-chloro-pyridin-2-ylamine (83 mg, 0.64 mmol), were added. The reaction mixture was stirred for 16 hours at 25° C. The reaction mixture was diluted with water and extracted with ethyl acetate (2×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue, upon silica gel flash chromatography using hexane-ethyl acetate gradiant elution, afforded (S)—N-(5-chloro-pyridin-2-yl)-3-cyclohexyl-2-(8-methoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-propionamide (68 mg, 26.3%), as a white solid. 1H NMR (DMSO-d6) δ: 11.07 (s, 1H), 8.39 (s, 1H), 8.04 (d, J=8.8 Hz, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.22 (t, J=8.3 Hz, 1H), 6.77 (d, J=8.3 Hz, 1H), 6.68 (d, J=8.3 Hz, 1H), 5.07 (d, J=5.9 Hz, 1H), 4.37 (d, J=18.6 Hz, 1H), 4.03 (d, J=19.1 Hz, 1H), 3.82 (s, 3H), 3.55 (s, 2H), 1.48-2.00 (m, 7H), 0.85-1.32 (m, 6H).
Reaction SMILES: C([C:4]1[C:12]([CH2:13]/[CH:14]=[C:15](\[CH3:22])/[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:11]([O:23][CH3:24])[C:10]([CH3:25])=[C:9]2[C:5]=1[C:6](=[O:26])[O:7][CH2:8]2)(O)=O.C([N:29]([CH2:32]C)CC)C.C1([O:40]P(Cl)(OC2C=CC=CC=2)=O)C=CC=CC=1.[N-]=[N+]=[N-].[Na+]>CN(C)C=O>[N:29]([C:4]1[C:12]([CH2:13]/[CH:14]=[C:15](\[CH3:22])/[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:11]([O:23][CH3:24])[C:10]([CH3:25])=[C:9]2[C:5]=1[C:6](=[O:26])[O:7][CH2:8]2)=[C:32]=[O:40]
Reactant: CCN(CC)CC
Reactant: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Reactant: COC(=O)CC/C(C)=C/Cc1c(OC)c(C)c2c(c1C(=O)O)C(=O)OC2
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CC/C(C)=C/Cc1c(N=C=O)c2c(c(C)c1OC)COC2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
To a stirred, 0° C. solution of 6.0 g (16.6 mmol) of methyl (E)-6-(1,3-dihydro-4-carboxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4hexenoate in 150 ml of dimethylformamide was added 4.62 ml (33.1 mmol) of triethylamine followed by drop-wise addition of 4.5 ml (21.8 mmol) of diphenylchlorophosphate. The mixture was allowed to stir at room temperature for 1 hour and then recooled to 0° C., and treated with 10..3 g (166 mmol) of sodium azide. This mixture was stirred for 24 hours at 0° C and then partitioned between aqueous sodium hydrogen sulfate and ethyl acetate. The organic phase was washed four times with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was triturated with hexane to give 5.8 g of methyl (E)-6-(1,3-dihydro-4-isocyanato-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4hexenoate. A small sample was further purified by rapid silica gel chromatography with an eluant of 1:1 hexaneethyl acetate followed by recrystallization from hexane-ethyl acetate to give purified methyl (E)-6(1,3-dihydro-4-isocyanato-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate, mp 95°-101° C.
Reaction SMILES: N1([CH:7]([CH3:28])[CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][C:16](B4OC(C)(C)C(C)(C)O4)=[CH:17][C:12]=3[NH:11][C:10]2=[O:27])CCOCC1.Br[CH:30]=[C:31]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[CH2:35][O:34][C:33]2[CH:42]=[C:43]([F:46])[CH:44]=[CH:45][C:32]1=2.[C:47]([O-:50])([O-])=O.[Na+].[Na+]>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.O1CCOCC1>[F:46][C:43]1[CH:44]=[CH:45][C:32]2[C:31](=[CH:30][C:16]3[CH:15]=[CH:14][C:13]4[N:9]([CH2:8][CH2:7][CH2:28][N:9]5[CH2:10][CH2:47][O:50][CH2:7][CH2:8]5)[C:10](=[O:27])[NH:11][C:12]=4[CH:17]=3)[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=3[CH2:35][O:34][C:33]=2[CH:42]=1
Reactant: CC(Cn1c(=O)[nH]c2cc(B3OC(C)(C)C(C)(C)O3)ccc21)N1CCOCC1
Reactant: O=C([O-])[O-]
Reactant: Fc1ccc2c(c1)OCc1ccccc1C2=CBr
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: C1COCCO1
Product: O=c1[nH]c2cc(C=C3c4ccccc4COc4cc(F)ccc43)ccc2n1CCCN1CCOCC1

Procedure:
Following procedures essentially as described in Example 219, mix 1-(2-morpholin-4-yl-propyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-benzoimidazol-2-one (205 mg, 0.53 mmol)(prepared following procedures essentially as described in Preparation 36), 11-bromomethylene-3-fluoro-6,11-dihydro-dibenzo[b,e]oxepine (E-isomer, 150 mg, 0.5 mmol), 2N Na2CO3 (0.5 mL), dioxane (5 mL) and (Ph3P)4Pd (53 mg, 0.046 mmol). Purify the crude product by column chromatography using 2N NH3 in MeOH/dichloromethane. Triturate the product obtained (192 mg) with hexane to give 170 mg pure title compound, HPLC (ISO80-10M) t=1.72 (100%). MS (ES) 486 (M+1), 484 (M−1). H NMR (DMSO-d6)10.68 (s, 1H), 7.57 (m, 2H), 7.35 (t, 1H, J=7.5 Hz), 7.22 (t, 1H, J=7.7 Hz), 6.96 (m, 3H), 6.78 (td, 1H, J=12.0, 4.2 Hz), 6.71 (d, 1H, J=7.5 Hz), 6.60 (m, 2H), 5.31 (br d, 2H), 3.72 (t, 2H, J=6.6 Hz), 3.46 (t, 4H, J=4.2 Hz), 2.48 (m, 4H), 1.71 (m, 2H), 2.20 (m, 6H).
Reaction SMILES: OC(C(F)(F)F)=O.[Cl:8][C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:16][C:17]1[C:18]([NH2:26])=[N:19][NH:20][C:21]=1[C:22]([F:25])([F:24])[F:23].O=[C:28]([CH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)[CH2:29][C:30](OCC)=[O:31]>C(O)(=O)C>[Cl:8][C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:16][C:17]1[C:21]([C:22]([F:25])([F:23])[F:24])=[N:20][N:19]2[C:30]([OH:31])=[CH:29][C:28]([CH:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[N:26][C:18]=12
Reactant: Nc1n[nH]c(C(F)(F)F)c1Cc1cccc(Cl)c1Cl
Reactant: CCOC(=O)CC(=O)C1CCOCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: Oc1cc(C2CCOCC2)nc2c(Cc3cccc(Cl)c3Cl)c(C(F)(F)F)nn12
Reaction time: 8 h

Procedure:
To a suspension of 4-[(2,3-dichlorophenyl)methyl]-5-(trifluoromethyl)-1H-pyrazol-3-amine TFA salt (201 mg, 0.48 mmol) in acetic acid (2 mL) was added ethyl 3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanoate (100 mg, 0.50 mmol). The reaction vessel was sealed, stirred and irradiated (microwave) at 140° C. for 40 minutes. The reaction mixture was cooled and diluted with acetic acid (5 mL). It was stood still overnight. The precipitate was collected, washed with acetic acid (2 mL), then with cooled methanol (2 mL) and dried to give crude product. The crude material was purified by reverse-phase HPLC to provide titled compound. (16 mg, 7.5%); LC/MS: MS (ES+) m/e 446 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.75-1.77 (m, 4H) 2.82 (s, 1H) 3.38-3.41 (m, 2H) 3.96 (dd, J=10.99, 2.91 Hz, 2H) 4.21 (s, 2H) 5.84 (s, 1H) 6.77-6.83 (m, 1H) 7.25 (t, J=7.96 Hz, 1H) 7.54 (dd, J=7.96, 1.39 Hz, 1H) 12.22 (s, 1H).
Reaction SMILES: C([O:5][C:6](=O)[CH2:7][CH2:8][N:9]([C:16]1[C:21]([N+:22]([O-])=O)=[CH:20][N:19]=[C:18]([Cl:25])[N:17]=1)[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)(C)(C)C.C(O)C.Cl>C(OCC)(=O)C.O>[Cl:25][C:18]1[N:19]=[CH:20][C:21]2[NH:22][C:6](=[O:5])[CH2:7][CH2:8][N:9]([CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[C:16]=2[N:17]=1
Reactant: CC(C)(C)OC(=O)CCN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCCC1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C1CCN(C2CCCCC2)c2nc(Cl)ncc2N1
Reaction time: 8 h
Yield: 41.9 %

Procedure:
A solution of 1.53 g (0.004 mole) of 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclohexyl-amino]-propionic acid tert-butyl ester (IV-20) in 20 mL of ethyl acetate was added in portions over 10 minutes to a mixture of 2.69 g (0.012 mole) of stannous chloride dihydrate, 12 mL of ethanol and 0.5 mL of hydrochloric acid. The mixture was stirred overnight and then diluted with 30 mL of water and extracted with ethyl acetate. The ethyl acetate extract was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (100:0-92:8) to give 0.47 g of 2-chloro-9-cyclohexyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-20).
Reaction SMILES: [Cl:1][CH:2]([Cl:5])[C:3]#[N:4].C[O-].[Na+].Cl.[CH2:10]([O:12][C:13](=[O:18])[C@H:14]([CH2:16][SH:17])N)[CH3:11].O>CO.C(Cl)Cl>[Cl:1][CH:2]([Cl:5])[C:3]1[S:17][CH2:16][CH:14]([C:13]([O:12][CH2:10][CH3:11])=[O:18])[N:4]=1
Reactant: N#CC(Cl)Cl
Reactant: CCOC(=O)[C@@H](N)CS
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C1CSC(C(Cl)Cl)=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
Dichloroacetonitrile (33.67 mL, 420 mmol) was added slowly, whilst maintaining the temperature below 0° C., over 30 min. to a solution of sodium methoxide ((25% w/w) 9.63 mL, 43 mmol) in methanol (84.5 mL) which was precooled to −10° C. This was allowd to stir for 30 min. before the addition of L-cysteine ethyl ester hydrochloride (78.32 g, 422 mmol) dissolved in methanol (67.4 mL) and then stirred overnight at RT. Water (136 mL) followed by DCM (136 mL) was added to the mixture and stirred vigorously. The organic layer was separated and the aqueous layer was reextracted with a further 136 mL of DCM. This was concentrated in vacuo to give the crude product (94.1 g, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]#[N:15])=[C:12]([CH3:16])[O:11][N:10]=1.C(O[CH:22](N(C)C)[N:23]([CH3:25])[CH3:24])(C)(C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]#[N:15])=[C:12](/[CH:16]=[CH:22]/[N:23]([CH3:25])[CH3:24])[O:11][N:10]=1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: Cc1onc(-c2c(F)cccc2Cl)c1C#N
Solvent: Cc1ccccc1
Product: CN(C)/C=C/c1onc(-c2c(F)cccc2Cl)c1C#N

Procedure:
To a solution of 1.5 g (6.3389 mmol) 3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonitrile in 100 mL dry toluene, were added 2.10 g (12.6779 mmol) tert-Butoxy-bis(dimethylamino)methane. The reaction mixture was heated under reflux for 12 h. The mixture was concentrated in vacuo and was dried in the high vacuum. Petroleum ether was added to the crystallized residue. The product was collected by filtration and 1.791 g (yield of theory: 95.9%) of clean product were obtained. Result of LC/MS MH+: 292.0; 1H NMR (DMSO-d6; CCl4): 2.93 (3H, s, N—CH3), 3.17 (3H, s, N—CH3), 5.15-5.20 (1H, d, C2H2), 7.74-7.78 (1H, d, C2H2), 7.45-7.52 (1H, dd, CH-arom.), 7.57-7.59 (1H, d, CH-arom.), 7.65-7.71 (1H, d, CH-arom.)
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:7]=[CH:6][NH:5][N:4]=1.N#N.[O:12]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1)[CH3:13].C(OCC)(=O)C.CCCCCC>CN(C=O)C>[CH3:13][O:12][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][N:5]2[CH:6]=[CH:7][C:3]([C:2]([F:9])([F:8])[F:1])=[N:4]2)=[CH:16][CH:15]=1
Reactant: COc1ccc(CCl)cc1
Reactant: FC(F)(F)c1cc[nH]n1
Agent: N#N
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2ccc(C(F)(F)F)n2)cc1
Temperature: 0 °C
Yield: 69.5 %

Procedure:
NaH (33.08 g (19.85 mol, 60%) was washed with n-hexane, then dry DMF (500 mL) was added drop wise under N2 atmosphere and the mixture was stirred well. A solution of 3-(trifluoromethyl)-1H-pyrazole (75 g, 0.55 mol) in DMF (125 mL) was added drop wise under N2 atmosphere. Then a solution of 4-methoxylbenzyl chloride (86.3 g, 0.55 mol) in DMF (125 mL) was added drop wise and the overall reaction mixture was allowed to stir for 12 h at room temperature. Progress of the reaction was monitored by TLC (10% ethyl acetate/hexane, Rf˜0.4). On completion of the reaction, the reaction contents were poured into ice water (500 mL) and the product was extracted with ethyl acetate (2×400 mL). The ethyl acetate layer was washed with 2N HCl (2×200 ml). Then the contents were dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by CC with 10% ethyl acetate/n-hexane to yield 1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-pyrazole as a brown colored liquid (98 g, 70%).
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[CH2:3][CH:4]([NH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][N:23]=1)[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.CC(S(N)=O)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1.[NH2:70][CH2:71][CH2:72][S:73]([OH:76])(=[O:75])=[O:74]>O.CN(C)C=O>[CH3:1][CH:2]([CH3:31])[CH2:3][CH:4]([NH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:70][CH2:71][CH2:72][S:73]([OH:76])(=[O:75])=[O:74])=[O:27])=[CH:24][N:23]=1)[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:20])[F:19])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1
Reactant: NCCS(=O)(=O)O
Reactant: CC(C)CC(Nc1ccc(C(=O)O)cn1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: CC(C)(C)S(N)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CC(Nc1ccc(C(=O)NCCS(=O)(=O)O)cn1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 35.8 %

Procedure:
A 5 mL vial equipped with magnetic stirrer was charged with 6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butylamino)nicotinic acid (0.200 g, 0.467 mmol) as prepared in Example 1.1 using racemic 2-methylpropane-2-sulfinamide in Step B, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl uronium hexafluorophosphate (266.0 mg, 0.700 mmol), N-methylmorpholine (236.1 mg, 2.334 mmol), N,N-dimethylformamide (2.4 mL). The mixture was purged with nitrogen, heated to 30° C. and stirred for 30 minutes. Then 2-aminoethanesulfonic acid (58.4 mg, 0.467 mmol) was added. The mixture was stirred at 30° C. for 2 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with water (2×20 mL) and dried over sodium sulfate, filtered and concentrated. Purification by prep-HPLC provided (+/−)-2-(6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butylamino)nicotinamido) ethanesulfonic acid (89.6 mg, 35.8%) as a white solid. 1H NMR (400 MHz, CD3OD, δ): 8.41 (s, 1H), 8.29 (m, 1H), 8.25-8.19 (m, 1H), 7.88 (d, 2H), 7.78-7.70 (m, 4H), 7.54 (d, 2H), 7.13 (d, 1H), 5.05-4.92 (m, 1H), 3.76 (t, 2H), 3.06 (t, 2H), 1.88-1.82 (m, 1H), 1.72-1.62 (m, 2H), 1.07 (d, 3H), 1.04 (d, 3H) ppm. MS (M+1): 536.2.
Reaction SMILES: [I:1]I.[C:3]1(=NN)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1.C(N=C(N(C)C)N(C)C)(C)(C)C>CCOCC>[I:1][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH:4]=1
Reactant: NN=C1CCCc2ccccc21
Reactant: II
Agent: CN(C)C(=NC(C)(C)C)N(C)C
Solvent: CCOCC
Product: IC1=CCCc2ccccc21
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
A solution of I2 (14 g, 56 mmol) in ether (100 mL) added slowly at 5° C. over a 50 minute period to a solution of (3,4-dihydro-2H-naphthalen-1-ylidene)-hydrazine (4.5 g, 28 mmol, prepared from α-tetralone and hydrazine) and tert-butyl-tetramethylguanidine (43 g, 251 mmol, prepared from tetramethylurea, triphosgene, and tert-butylamine) in ether (100 mL). After the addition is complete, the mixture is stirred for 30 minutes and the ether (100 mL) is removed. The residue is heated for 1 hout at 90° C. and then cooled to room temperature. The mixture is diluted with ether and washed successively with 1N HCl, aq. Na2S2O3, aq. NaHCO3, and then saturated brine. The organic layers are dried, concentrated, and purified by flash chromatography (elution with hexane only) to give 6.4 g 4-iodo-1,2-dihydro-naphthalene: 1H NMR (CDCl3) 7.42 (d, 1H), 7.26-7.14 (m, 2H), 7.01 (d, 1H), 6.83 (t, 1H), 2.84 (t, 2H), 2.39-2.32 (m, 2H).
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O[CH:19](O)[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21].[BH3-]C#N.[Na+]>CO>[C:22]1([CH:20]([OH:21])[CH2:19][NH:15][C:14]2[CH:16]=[CH:17][C:11]([CH2:10][CH2:9][NH:8][C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])=[CH:12][CH:13]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(N)cc1
Reactant: O=C(c1ccccc1)C(O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCc1ccc(NCC(O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
4-(N-Boc-2-aminoethyl)aniline 28 (1.25 g, 5.29 mmole) was dissolved in methanol (30 mL), followed by addition of phenyl glyoxal 24 (0.708 g, 5.28 mmole). The reaction mixture was stirred for 1 h at rt, prior to addition of NaCNBH3 (0.665 g, 10.6 mmole). The final mixture was stirred for 12 h at rt, concentrated, and purified by flash silica column chromatography (2 to 5% MeOH/CH2Cl2) to give N-(2-phenyl-2-hydroxyethyl)-4-(N-Boc-2-aminoethyl)-aniline as a pale yellow oil (1.71 g, 91%): Rf=0.18 in 5% MeOH/CH2Cl2. 1H-NMR (CD3OD, 299.96 MHz): δ (ppm) 7.4-7.25 (m, 5H), 7.0-6.95 (d, 2H), 6.63-6.60 (d, 2H), 4.85-4.79 (dd, 1H), 3.3-3.21 (t, 2H), 3.2-3.15 (m, 2H), 2.64-2.5 (t, 2H), 1.42 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:13][NH2:14].[CH:15]1([N:19]2[CH2:24][CH2:23][CH:22]([O:25][C:26]3[N:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][N:27]=3)[CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16]1>>[CH:15]1([N:19]2[CH2:24][CH2:23][CH:22]([O:25][C:26]3[N:31]=[CH:30][C:29]([C:32]4[N:14]([CH3:13])[C:4](=[O:6])[C:3]5[C:2](=[C:10]([O:11][CH3:12])[CH:9]=[CH:8][CH:7]=5)[N:1]=4)=[CH:28][N:27]=3)[CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16]1
Reactant: O=Cc1cnc(OC2CCN(C3CCC3)CC2)nc1
Reactant: CN
Reactant: COc1cccc(C(=O)O)c1N
Product: COc1cccc2c(=O)n(C)c(-c3cnc(OC4CCN(C5CCC5)CC4)nc3)nc12

Procedure:
The entitled compound was obtained according to the method of Example 15 but starting from 2-amino-3-methoxybenzoic acid, methylamine and 2-[(1-cyclobutylpiperidin-4-yl)oxy]pyrimidine-5-carbaldehyde.