Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].C[O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[O:8][C:7]=1[CH2:21][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=O.[CH3:41][CH:42]([CH3:45])[CH:43]=O>>[CH2:21]([C:7]1[O:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:10][C:6]=1[CH2:4][OH:3])[CH2:41][CH:42]([CH3:45])[CH3:43]
Reactant: CC(C)C=O
Reactant: COC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)oc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: CC(C)CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1CO

Procedure:
Prepared from intermediate 62 and 2-methylpropanal
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12](=O)[CH2:13][O:14][CH3:15])=[C:7]([CH:11]=1)[C:8](O)=[O:9].O.[NH2:18][NH2:19]>>[CH3:1][O:2][C:3]1[CH:11]=[C:7]2[C:6]([C:12]([CH2:13][O:14][CH3:15])=[N:18][NH:19][C:8]2=[O:9])=[CH:5][CH:4]=1
Reactant: NN
Reactant: COCC(=O)c1ccc(OC)cc1C(=O)O
Solvent: O
Product: COCc1n[nH]c(=O)c2cc(OC)ccc12

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting unpurified 5-methoxy-2-(methoxyacetyl)benzoic acid with hydrazine hydrate.
Reaction SMILES: [OH:1][C@H:2]([CH3:11])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C=O)C.CCOCC>[Si:17]([O:1][C@H:2]([CH3:11])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)CCCC[C@@H](C)O
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)CCCC[C@@H](C)O[Si](C)(C)C(C)(C)C
Yield: 71.3 %

Procedure:
A solution of alcohol 25 (2.53 g, 15.89 mmol), imidazole (1.9 g, 27.9 mmol), and tert-butyldimethylsilyl chloride (2.4 g, 15.89 mmol) in DMF (32 mL) was stirred at 23° C. After 16 h the reaction was diluted with Et2O and then washed with 1N HCl, saturated aqueous NaHCO3 and brine. The organic portion was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 9:1 hex/EtOAc) afforded 3.11 g (71%) of silyl ether 26 (see scheme 4).
Reaction SMILES: [C:1]1([C@H:7]([OH:26])[CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18]C(OC(C)(C)C)=O)=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28]>C(Cl)Cl>[F:30][C:29]([F:32])([F:31])[C:27]([OH:33])=[O:28].[C:1]1([C@H:7]([OH:26])[CH2:8][NH:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][NH2:18])=[CH:14][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(NC[C@@H](O)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCc1ccc(NC[C@@H](O)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of N-(2-phenyl-2-(S)-hydroxyethyl)-4-(N-Boc-2-aminoethyl)-aniline (2.5 g, 7.0 mmole) in CH2Cl2 (15 mL) was cooled in an ice bath under stream of nitrogen and TFA (15 mL) was slowly added. The reaction mixture was stirred for 2 h at 0° C. and then concentrated in vacuo. The crude product was dissolved in 20% MeCN/H2O and purified by preparative reversed phase HPLC (5 to 2% MeCN/H2O over 50 min; 254 nm; 20 mL/min.), to give N-(2-phenyl-2-(S)-hydroxyethyl)-4-(2-aminoethyl)aniline trifluoroacetate salt 31 as a colorless oil. 1H-NMR (CD3OD, 299.96 MHz): δ (ppm); 7.45-7.25 (m, 9H), 4.9 (dd, 1H), 3.55-3.45 (m, 2H), 3.21-3.15 (t, 2H), 3.05-2.95 (t, 2H) ESMS (C16H20N2O1): calcd. 256.4, obsd. 257.1 [M+H]+, 280.2 [M+Na]+.
Reaction SMILES: [OH-].[Na+].[NH:3]1[CH2:8][CH2:7][C:6](=[C:9]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH:16]=[CH:15][C:14]3[S:13][C:12]([CH2:23][CH2:24][C:25]([O:27]CC)=[O:26])=[CH:11][C:10]2=3)[CH2:5][CH2:4]1>C(O)C>[NH:3]1[CH2:4][CH2:5][C:6](=[C:9]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH:16]=[CH:15][C:14]3[S:13][C:12]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:11][C:10]2=3)[CH2:7][CH2:8]1
Reactant: CCOC(=O)CCc1cc2c(s1)C=Cc1ccccc1C2=C1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCc1cc2c(s1)C=Cc1ccccc1C2=C1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
A 2 mol/L aqueous sodium hydroxide solution (10 mL, equivalent to 20 mmol of sodium hydroxide) was added to an ethanol (30 mL) solution of the compound obtained in Example 36 (2.0 g, 5.3 mmol), and the mixture was stirred at room temperature for 2 hours. The solvents were distilled off, water was then added to the residue, and the mixture was adjusted to a pH of 7 with a diluted hydrochloric acid. The precipitated crystals were separated by filtration and dried, to give 1.1 g (59%) of the captioned compound.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][CH:5]([O:8][CH3:9])[CH2:6][NH2:7].Cl[C:11]([O:13][CH2:14][CH3:15])=[O:12]>O.C1(C)C=CC=CC=1>[CH3:3][O:4][CH:5]([O:8][CH3:9])[CH2:6][NH:7][C:11](=[O:12])[O:13][CH2:14][CH3:15]
Reactant: CCOC(=O)Cl
Reactant: COC(CN)OC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)NCC(OC)OC
Temperature: 0 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
A solution of NaOH (578.4 g, 14.46 mol) in H2O (2 L) was added to a solution of 2,2-dimethoxyethanamine (800 g, 7.6 mol) in toluene (2 L) and the resulting mixture was cooled to 0° C. using an ice bath. Ethyl chloroformate (825 g, 7.6 mol) was added dropwise while keeping the temperature near 10° C. The mixture was then stirred at r.t. overnight. The phases were then separated and the aqueous solution was saturated with solid NaCl. This solution was then extracted with toluene (1.25 L×3). The combined organic solutions were dried (Na2SO4) and concentrated in vacuo to give the title compound (1.123 kg, 83%) as colorless oil; 1H NMR: (CDCl3) 1.17 (3H, t), 3.14 (2H, s), 3.32 (6H, s), 4.02-4.07 (2H, m), 4.30 (1H, t).
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][OH:14])=[N:11][CH:12]=1.[H-].[Na+].[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1F)[CH:21]=[O:22]>O>[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:14][CH2:13][C:10]1[CH:9]=[CH:8][C:7]([F:6])=[CH:12][N:11]=1)[CH:21]=[O:22]
Reactant: OCc1ccc(F)cn1
Reactant: O=Cc1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCc2ccc(F)cn2)c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 42.2 %

Procedure:
To an N,N-dimethylformamide (20.0 mL) solution of (5-fluoro-pyridin-2-yl)-methanol (760 mg, 5.98 mmol) described in Manufacturing Example 41-1-1 was added sodium hydride (239 mg, 5.98 mmol, 60% in oil) under nitrogen atmosphere at 0° C., which was stirred for 10 minutes at room temperature. 3,4-Difluorobenzaldehyde (935 mg, 6.58 mmol) was then added at room temperature, and stirred for 30 minutes at room temperature. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:3) to obtain the title compound (629 mg, 42.2%).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[C:27](O)(=[O:31])[C:28]#[C:29][CH3:30]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:27](=[O:31])[C:28]#[C:29][CH3:30])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: CC#CC(=O)O
Agent: Cl
Product: CC#CC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (64 mg, 65%), MS (ISP) m/z=395.3 [(M+H)+], mp 195° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and but-2-ynoic acid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([NH:15][CH:16]([CH:21]([CH3:23])[CH3:22])[C:17]([O:19][CH3:20])=[O:18])=[O:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:31]1[S:32][C:33]2[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:34]=2[N:35]=1>>[F:40][C:38]1[CH:37]=[CH:36][C:34]2[N:35]=[C:31]([O:1][C:2]3[CH:7]=[CH:6][C:5]([C:8]4[CH:12]=[C:11]([C:13]([NH:15][CH:16]([CH:21]([CH3:23])[CH3:22])[C:17]([O:19][CH3:20])=[O:18])=[O:14])[O:10][N:9]=4)=[CH:4][CH:3]=3)[S:32][C:33]=2[CH:39]=1
Reactant: Fc1ccc2nc(Cl)sc2c1
Reactant: COC(=O)C(NC(=O)c1cc(-c2ccc(O)cc2)no1)C(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)C(NC(=O)c1cc(-c2ccc(Oc3nc4ccc(F)cc4s3)cc2)no1)C(C)C
Reaction time: 0.29 h

Procedure:
To methyl 2-(3-(4-hydroxyphenyl)isoxazole-5-carboxamido)-3-methylbutanoate (200 mg) in N,N′-Dimethyl formamide (4 ml), cesium carbonate (245 mg) was added and stirred for 15-20 minutes. To this 2-chloro-6-fluorobenzo[d]thiazole (141 mg) was added and the reaction mixture was stirred at RT for 18 hours. Solvent was evaporated to obtain pale brown solid, which was purified by column chromatography (silica gel, EtOAc—CHCl3) to obtain off white solid, which was crystallized using DCM-Petroleum ether to obtain the title compound as white solid. Yield: 240 mg (81%); MS (ES+): m/z 470 (M+1); 1HNMR (DMSO-d6, 300 MHz): δ 9.27 (d, 1H), 8.08 (d, 2H), 7.93 (dd, 1H), 7.8 (s, 1H), 7.74 (dd, 1H), 7.67 (d, 2H), 7.31 (m, 1H), 4.33 (m, 1H), 3.69 (s, 3H), 2.23 (m, 1H), 0.98 (d, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:44])[C@@H:12]([NH:20][C:21](=[O:43])[CH:22]([NH:32]C(OCC2C=CC=CC=2)=O)[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([CH3:31])[CH:24]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:8][CH:9]=1)=[O:4].C(O)=O>CO.[Pd]>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:44])[C@@H:12]([NH:20][C:21](=[O:43])[CH:22]([NH2:32])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([CH3:31])[CH:24]=2)[CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[S:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1csc(NC(=O)[C@H](Cc2ccccc2)NC(=O)C(NC(=O)OCc2ccccc2)c2ccc(OC)c(C)c2)n1
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: COC(=O)c1csc(NC(=O)[C@H](Cc2ccccc2)NC(=O)C(N)c2ccc(OC)c(C)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-{(S)-2-[2-benzyloxycarbonylamino-2-(4-methoxy-3-methyl-phenyl)-acetylamino]-3-phenyl-propionylamino}-thiazole-4-carboxylic acid methyl ester (1.0 g, 1.62 mmol) in methanol (40 mL) was added formic acid (4 g, 87 mmol). The solution was then degassed with nitrogen for 10 minute, followed by the addition of palladium black (1 g, 9.4 mmol). The reaction mixture was stirred at room temperature under nitrogen for 0.5 hours. The reaction mixture was filtered through a short pad of celite and the filtrate was concentrated to dryness. The residue was neutralized with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated to give crude 2-{(S)-2-[2-amino-2-(4-methoxy-3-methyl-phenyl)-acetylamino]-3-phenyl-propionylamino}-thiazole-4-carboxylic acid methyl ester as an off white foam (0.73 g, 93%).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([OH:9])[C:5]2[O:10][CH:11]=[CH:12][C:4]=2[CH2:3]1.[Br:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](F)=[CH:16][CH:15]=1>>[Br:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([O:9][CH:6]2[CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][C:4]3[CH:12]=[CH:11][O:10][C:5]2=3)=[CH:16][CH:15]=1
Reactant: CN1CCC(O)c2occc2C1
Reactant: Fc1ccc(Br)c2ccccc12
Product: CN1CCC(Oc2ccc(Br)c3ccccc23)c2occc2C1

Procedure:
The same method as in Example 1 was conducted using 5-methyl-5,6,7,8-tetrahydro-4H-furo[3,2-c]azepin-8-ol (Reference Example 21) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 1-bromo-4-fluoronaphthalene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: C([O:4][C:5]1[CH:32]=[CH:31][CH:30]=[CH:29][C:6]=1[C:7]([NH:9][C:10]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=[CH:19][C:11]=1[C:12]([O:14]C(C)(C)C)=[O:13])=[O:8])(=O)C>FC(F)(F)C(O)=O>[OH:4][C:5]1[CH:32]=[CH:31][CH:30]=[CH:29][C:6]=1[C:7]([NH:9][C:10]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=[CH:19][C:11]=1[C:12]([OH:14])=[O:13])=[O:8]
Reactant: CC(=O)Oc1ccccc1C(=O)Nc1cc(-c2ccccc2)ccc1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1ccccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 mL of trifluoroacetic acid was added to the obtained tert-butyl 2-(2-acetoxybenzamido)-4-phenylbenzoate, and stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and 0.50 mL of methanol, 0.50 mL of tetrahydrofuran and 6.1 mg of potassium carbonate were added to the obtained residue sequentially and stirred at room temperature for 2 hours. 10% citric acid aqueous solution was added to the reaction mixture and a solid substance was separated by filtration to obtain 8.2 mg of 2-(2-hydroxybenzamido)-4-phenylbenzoic acid as white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:5]=[C:4]([NH2:16])[N:3]=1.[N:17]([O-])=[O:18].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]([N:17]=[O:18])=[C:4]([NH2:16])[N:3]=1
Reactant: O=N[O-]
Reactant: Nc1cc(OCC2CCCCC2)nc(N)n1
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1nc(N)c(N=O)c(OCC2CCCCC2)n1
Temperature: 80 °C

Procedure:
2,6-Diamino-4-cyclohexylmethoxypyrimidine (0.28 g, 1.26 mmol) was dissolved in warm glacial acetic acid solution (30%, 10 ml). The solution was heated to 80° C. and sodium nitrite solution (0.12 g, 1.72 mmol in 5 ml of H2O) was added dropwise over 1 h, until and excess of oxidant, as indicated by starch iodide paper, was observed. The reaction mixture was allowed to cool to room temperature and the violet crystals were collected by filtration, and washed well with water. The title compound was purified by recrystallisation from ethanol (0.26 g, 83%), m.p. 254° C.; (Found: C, 52.73; H, 6.59; N, 27.56% C11H17N5O2 requires C, 52.59; H, 6.77; N, 27.89%); δH (200 MHz, d6-DMSO) 1.09-1.38 (5H, m, C6H11), 1.73-2.00 (6H, 5 m, C6H11), 4.39 (2H, d, OCH2, J=6.3 Hz), 7.86 (2H, br s, NH2), 8.08 (1H, br s, NH), 10.19 (1H, br s, NH); m/z (+EI) 251 (M+, 25%), 155 (M+-C7H13 , 100) , 138 (M+-C7H13O, 72) , 81 (9).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:31]1[S:32][CH:33]=[CH:34][N:35]=1)[S:7]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1[F:30])=[N:15][CH:14]=[CH:13]2)(=[O:9])=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:30][C:21]1[CH:22]=[C:23]([C:26]([F:27])([F:29])[F:28])[CH:24]=[CH:25][C:20]=1[C:16]1[C:17]2[C:12](=[CH:11][C:10]([S:7]([NH:6][C:31]3[S:32][CH:33]=[CH:34][N:35]=3)(=[O:9])=[O:8])=[CH:19][CH:18]=2)[CH:13]=[CH:14][N:15]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4F)nccc3c2)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1nccs1)c1ccc2c(-c3ccc(C(F)(F)F)cc3F)nccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A microwave vial was charged with 1-chloro-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate OOO; 0.250 g, 0.525 mmol), (2-fluoro-4-(trifluoromethyl)phenyl)boronic acid (0.164 g, 0.788 mmol), Pd(PPh3)4 (0.061 g, 0.053 mmol), and potassium carbonate (0.363 g, 2.63 mmol). Dioxane (2.63 mL) and Water (0.875 mL) were added, the vial was flushed with argon and sealed, and heated in a microwave reactor at 90° C. for 30 minutes. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via silica gel column chromatography (12 g, gradient elution 0 to 50% EtOAc:Heptane) to afford N-(2,4-dimethoxybenzyl)-1-(2-fluoro-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (0.271 g, 0.449 mmol, 85% yield) as a white solid. N-(2,4-dimethoxybenzyl)-1-(2-fluoro-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (35 mg, 0.058 mmol) was dissolved in 1 mL of DCM and TFA (0.1 ml, 1.298 mmol) was added. The reaction was stirred for 30 minutes at room temperature. The reaction was concentrated, dissolved in methanol, and passed through an SCX ion exchange column (pre-wetted with methanol). The column was flushed several times with methanol, then the product was liberated by flushing the column several times with 2.0 M ammonia in methanol. The product-containing filtrate was concentrated to afford 1-(2-fluoro-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=12.92 (br. s., 1H), 8.77 (d, J=5.7 Hz, 1H), 8.62 (d, J=1.6 Hz, 1H), 8.24 (d, J=5.6 Hz, 1H), 7.99-7.91 (m, 2H), 7.89-7.77 (m, 3H), 7.27 (d, J=4.6 Hz, 1H), 6.87 (d, J=4.6 Hz, 1H). m/z (ESI) 454.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:20]=[C:19]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH:18]=[C:17](Br)[CH:16]=2)=[CH:9][C:8]=1[CH3:27])[CH3:2].[CH2:29]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)[C:30]#[CH:31].C(OC(=O)COC1C=CC(SC2C=C(C#CC3C=CC(CO)=CC=3)C=C(OCCC3C=CC(Cl)=CC=3)C=2)=CC=1C)C>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:16]=[C:17]([C:31]#[C:30][CH2:29][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:18]=[C:19]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH:20]=2)=[CH:9][C:8]=1[CH3:27])[CH3:2]
Reactant: CCOC(=O)COc1ccc(SCc2cc(Br)cc(OCC(C)C)c2)cc1C
Reactant: C#CCN1CCOCC1
Agent: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(CO)cc3)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Product: CCOC(=O)COc1ccc(SCc2cc(C#CCN3CCOCC3)cc(OCC(C)C)c2)cc1C

Procedure:
The title product was prepared from [4-(3-Bromo-5-isobutoxy-benzylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (300 mg; 0.64 mmol) and 4-prop-2-ynyl-morpholine (221 mg; 2.6 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 140 mg (44%). HPLC-MS: m/z: 511.9 (M)+; Rt: 2.00 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C@H:8]([C:13](=[O:17])NOC)[CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[C:1]([O:5][C:6](=[O:18])[NH:7][C@H:8]([CH:13]=[O:17])[CH2:9][CH:10]([CH3:11])[CH3:12])([CH3:2])([CH3:4])[CH3:3]
Reactant: CONC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Temperature: -3 °C
Reaction time: 0.42 h
Yield: 92.9 %

Procedure:
(S)-(1-Methoxycarbamoyl-3-methyl-butyl)-carbamic acid tert-butyl ester (2.2 g, 8.0 mmol) was dissolved in dry ether (80 mL) under nitrogen atmosphere and cooled to −3° C. in a ice-water-NaCl bath. Solid lithium aluminum hydride (0.31 mg, 8.2 mmol, Aldrich, Milwaukee, Wis.) was then added; the resulting reaction mixture was stirred at that temperature for 25 minutes at which time TLC showed no starting material left, then the reaction was quenched by addition of an aqueous NaHSO4 solution (1.9 g NaHSO4 in 60 mL of water). Two layers were separated; and aqueous layer was extracted with ether (4×100 mL). The combined ether solution was washed successively with 3N aqueous HCl solution (3×100 mL), brine (100 mL), saturated aqueous NaHCO3 solution (3×100 mL), brine (3×100 mL), and was dried over MgSO4. The solution was concentrated in vacuo affording 1.6 g of desired product as a clear oil which was used in the subsequent reaction without further purification.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]3[C:25]([C:26](=[O:29])[NH:27][CH3:28])=[C:24]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)[O:23][C:7]3=[N:8][C:9]=2[N:10]([CH2:15][CH2:16][CH2:17][C@H:18]([CH3:22])[C:19]([OH:21])=[O:20])[S:11]([CH3:14])(=[O:13])=[O:12])[CH2:3][CH2:2]1.[P:37]([O:55][CH2:56]Cl)([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38].C(#N)C.O>CN(C=O)C>[CH:1]1([C:4]2[CH:5]=[C:6]3[C:25]([C:26](=[O:29])[NH:27][CH3:28])=[C:24]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)[O:23][C:7]3=[N:8][C:9]=2[N:10]([CH2:15][CH2:16][CH2:17][C@H:18]([CH3:22])[C:19]([O:21][CH2:56][O:55][P:37]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:38])=[O:20])[S:11]([CH3:14])(=[O:13])=[O:12])[CH2:2][CH2:3]1
Reactant: O=P(OCCl)(OCc1ccccc1)OCc1ccccc1
Reactant: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(N(CCC[C@H](C)C(=O)O)S(C)(=O)=O)c(C3CC3)cc12
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: O
Product: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(N(CCC[C@H](C)C(=O)OCOP(=O)(OCc3ccccc3)OCc3ccccc3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-5-(N-(5-cyclopropyl-3-(methylcarbamoyl)-2-p-tolylfuro[2,3-b]pyridin-6-yl)methylsulfonamido)-2-methylpentanoic acid (Example 47, 50 mg, 0.090 mmol) and [dibenzyl chloromethyl phosphate (32.5 mg, 0.1 mmol) were stirred in DMF at RT LCMS-80% done at 1 hr Stirred at RT ON-95% done, trace SM and trace mono-de-benzylated side prod.(+) 714 Added 800 μL ACN and 200 μL water Purified on HPLC C18 20-100% ACN/water 1% NH4OH 40 mL/min over 10 min Conc. on vac at 30° C.—no degradation. To give (S)-((bis(benzyloxy)phosphoryl)oxy)methyl 5-(N-(5-cyclopropyl-3-(methylcarbamoyl)-2-(p-tolyl)furo[2,3-b]pyridin-6-yl)methylsulfonamido)-2-methylpentanoate
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=O)=[CH:4][CH:3]=1.[CH3:10][C:11]([S:14]([NH2:16])=[O:15])([CH3:13])[CH3:12]>ClC(Cl)C.ClCCl.O.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Br:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[N:16]/[S:14]([C:11]([CH3:13])([CH3:12])[CH3:10])=[O:15])=[CH:4][CH:3]=1
Reactant: CC(C)(C)S(N)=O
Reactant: O=Cc1ccc(Br)nc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CC(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)S(=O)/N=C/c1ccc(Br)nc1
Temperature: 110 °C
Reaction time: 0.17 h

Procedure:
A mixture of 6-bromo-pyridine-3-carbaldehyde (1.0 g, 5.38 mmol), 2-methylpropane-2-sulfinamide (715 mg, 5.90 mmol) and titanium (IV) isopropoxide (2.5 mL, 8.53 mmol) in dichloroethane (10 mL) was warmed at 110° C. in the microwave for 15 minutes. The reaction was monitored by TLC (ethyl acetate-hexanes 2:8). The mixture was diluted with dichloromethane (100 mL) and water (5 mL) was added. The mixture was stirred for 10 minutes and then dried over magnesium sulfate. The crude material was purified by silica gel chromatography eluting with a gradient of 0-20% ethyl acetate in hexanes to afford 2-methyl-propane-2-sulfinic acid 1-(6-bromo-pyridin-3-yl)-meth-(E)-ylideneamide