Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].C(N(CC)CC)C.Cl[CH2:19][C:20](Cl)=[O:21].[H-].[Na+]>C1COCC1>[Br:8][C:6]1[C:5]([CH3:9])=[CH:4][C:3]2[O:10][CH2:19][C:20](=[O:21])[NH:1][C:2]=2[CH:7]=1
Reactant: Cc1cc(O)c(N)cc1Br
Reactant: O=C(Cl)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc2c(cc1Br)NC(=O)CO2
Yield: 72.7 %

Procedure:
Prepared following the procedure for Intermediate 6 using 2-amino-4-bromo-5-methylphenol (4.73 g, 23.4 mmol), triethylamine (3.6 mL, 25.8 mmol) and chloroacetyl chloride (1.8 mL, 23.4 mmol) in THF (120 mL) followed by sodium hydride (1.9 g of a 60% suspension in oil, 49.2 mmol) to give the title compound (4.12 g, 73%) as a beige solid. δH (DMSO-d6) 2.23 (3H, s), 4.57 (2H, s), 6.97 (1H, s), 7.04 (1H, s), 10.72 (1H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:15])[CH2:12][CH2:13][CH3:14])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:15])[CH2:12][CH2:13][CH3:14])[CH:7]=[CH:8][CH:9]=1
Reactant: CCCC(=O)Nc1cccc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCC(=O)Nc1cccc(N)c1

Procedure:
A solution of N-(3-nitrophenyl)butyramide (8.60 g, 41.3 mmol) in MeOH (207 mL) was divided between two 500 mL flasks with stir bars. Each flask was flushed well with nitrogen, then 5% palladium on carbon (4.40 g, 2.065 mmol) was added, half to each flask. A 3-way adapter with a large hydrogen-filled balloon was attached to each flask, and the reactions were evacuated and back-filled with hydrogen five times, while stirring vigorously. The reactions were then stirred for 16 h, then filtered through a funnel packed with Celite. The filter cake was washed with MeOH, and the filtrate was concentrated, redissolved with DCM, then purified by column chromatography (EtOAc/hexanes gradient) to yield a white solid after precipitating from hexanes (5.87 g, 80%). LRMS (ESI+) (M+H): 179.18.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[CH:22][C:23]([CH3:27])=[C:24]([CH:26]=2)[NH2:25])[CH2:11][CH2:10]1.[C:28](Cl)(=[O:30])[CH3:29].CCN(CC)CC>C(Cl)Cl.O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[CH:22][C:23]([CH3:27])=[C:24]([NH:25][C:28](=[O:30])[CH3:29])[CH:26]=2)[CH2:13][CH2:14]1
Reactant: Cc1ccc(OCCCCN2CCN(c3cccc(Cl)c3Cl)CC2)cc1N
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(=O)Nc1cc(OCCCCN2CCN(c3cccc(Cl)c3Cl)CC2)ccc1C
Temperature: 25 °C
Yield: 34.5 %

Procedure:
A mixture of intermediate 63 (120 mg, 0.29 mmol), acetyl chloride (35 mg, 0.44 mmol) and Et3N (54 mg, 0.54 mmol) was dissolved in DCM and the solution was stirred at rt. The solution was diluted with water and extracted with DCM. The combined organic layers were washed with saturated aq NaHCO3, brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with DCM/MeOH=100:1-30:1) to give N-(5-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-methylphenyl)acetamide (compound 43) (45 mg, 35%) as a yellow solid. 1H NMR (300 MHz, CDCl3): δ 7.56 (s, 1H), 7.18-7.13 (m, 2H), 7.07-6.88 (m, 3H), 6.62 (d, J=8.1 Hz, 1H), 3.99 (br, 2H), 3.26 (br, 4H), 2.92-2.75 (br, 6H), 2.21 (s, 3H), 2.19 (s, 3H), 1.86 (br, 6H). HPLC: 99%, RT 2.464 min. MS (ESI) m/z 449.8 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[C:4]([F:16])=[CH:5][N:6]=[C:7]2[C:12]=1[N:11]=[C:10]([O:13][CH3:14])[CH:9]=[C:8]2F)=[CH2:2].[NH:17]1[CH2:21][CH2:20][C@H:19]([CH2:22][NH:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]3[O:29][CH2:30][C:31](=[O:35])N[C:33]=3[N:34]=2)[CH2:18]1>>[O:35]1[C:27]2[CH:26]=[C:25]([CH2:24][NH:23][CH2:22][C@@H:19]3[CH2:20][CH2:21][N:17]([CH2:2][CH2:1][C:3]4[C:12]5[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[N:11]=5)[N:6]=[CH:5][C:4]=4[F:16])[CH2:18]3)[N:34]=[CH:33][C:28]=2[O:29][CH2:30][CH2:31]1
Reactant: C=Cc1c(F)cnc2c(F)cc(OC)nc12
Reactant: O=C1COc2ccc(CNC[C@H]3CCNC3)nc2N1
Product: COc1ccc2ncc(F)c(CCN3CC[C@@H](CNCc4cc5c(cn4)OCCO5)C3)c2n1

Procedure:
Prepared essentially according to the procedure for Example 22, except substituting 8-ethenyl-7-fluoro-2-(methyloxy)-1,5-naphthyridine (143 mg, 0.70 mmole) for 8-ethenyl-4,7-difluoro-2-(methyloxy)-1,5-naphthyridine, and substituting 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (115 mg, 0.70 mmole) for 6-({[(3S)-3-pyrrolidinylmethyl]amino}methyl)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one, the title compound was prepared as an orange hygroscopic solid: LC/MS (ES) m/e 454 (M+H)+; 1H NMR (DMSO, 400 MHz) δ 9.8 (bs, 1H), 8.85 (s, 1H), 8.4 (d, J=5.6 Hz, 1H), 8.33 (d, J=9.1 Hz, 1H), 7.51 (d, J=11.6 Hz, 1H), 7.29 (d, J=9.1 Hz, 1H), 4.5 (m, 3H), 4.25 (s, 2H), 4.1 (s, 3H), 3.8 (m, 1H), 3.7 (m, 2H), 3.6 (m, 2H), 3.5 (m, 2H), 3.25 (m, 2H), 3.1 (s, 2H), 2.85 (m, 2H), 2.25 (m, 1H), 1.8 (m, 1H), 1.3 (s, 1H), 0.8 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:49](=[O:57])[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[OH:56])[C:5]([OH:48])=[C:6]([CH:47]=1)[C:7]([C:9]1[C:10]([OH:46])=[C:11]([CH:43]=[CH:44][CH:45]=1)[C:12]([O:14][CH2:15][C:16]1[CH2:17][S:18][C@@H:19]2[CH:30]([NH:31][C:32](=[O:41])[CH2:33][O:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29](=[O:42])[N:20]2[C:21]=1[C:22]([O:24]C(C)(C)C)=[O:23])=[O:13])=[O:8].ClC1C=C(CC2C=CC=CC=2O)C(O)=C(C=1)CC1C(O)=C(C=CC=1)C(OCC1CS[C@@H]2C(NC(=O)COC3C=CC=CC=3)C(=O)N2C=1C(O)=O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:49](=[O:57])[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[OH:56])[C:5]([OH:48])=[C:6]([CH:47]=1)[C:7]([C:9]1[C:10]([OH:46])=[C:11]([CH:43]=[CH:44][CH:45]=1)[C:12]([O:14][CH2:15][C:16]1[CH2:17][S:18][C@@H:19]2[CH:30]([NH:31][C:32](=[O:41])[CH2:33][O:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29](=[O:42])[N:20]2[C:21]=1[C:22]([OH:24])=[O:23])=[O:13])=[O:8]
Reactant: CC(C)(C)OC(=O)C1=C(COC(=O)c2cccc(C(=O)c3cc(Cl)cc(C(=O)c4ccccc4O)c3O)c2O)CS[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N12
Agent: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)O)=C(COC(=O)c3cccc(Cc4cc(Cl)cc(Cc5ccccc5O)c4O)c3O)CS[C@H]12
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)O)=C(COC(=O)c3cccc(C(=O)c4cc(Cl)cc(C(=O)c5ccccc5O)c4O)c3O)CS[C@H]12
Yield: 94.2 %

Procedure:
Compound 20 (3.21 g, 4.23 mmol) was prepared from 18 (3.66 g, 4.49 mmol) in 94% yield by the method used for the preparation of 19. For 20: mp 180-182° C.; 1H NMR (DMSO-d6 /D2O) d 3.69, 3.81 (AB, Jgem =19 Hz, 2H, CH2S), 4.61 (s, 2H, OCH2CO), 4.93, 5.20 (AB, Jgem =14 Hz, 2H, CH2O), 5.20 (d, J=5.0 Hz, 1H, HC(6)), 5.77 (d, J=5.0 Hz, 1H, HC(7)), 6.96-7.53 (m, 14H, 4×ArH); IR (nujol): 3270-3400 (OH, NH, CO2H)), 1788 (β-lactam), 1725 (ester), 1680 (amide), 1620-1635 (C=O) cm-1. Anal. (C37H27N2O12SCl) C, H, N, S, Cl.
Reaction SMILES: I[C:2]1[C:12]2[O:11][CH2:10][CH2:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[F:18][C:19]([F:24])([F:23])C(O)=O.[Na]>CN1CCCC1=O.[Cu]I>[F:18][C:19]([F:24])([F:23])[C:2]1[C:12]2[O:11][CH2:10][CH2:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CCOC(=O)C1=Cc2cccc(I)c2OCC1
Agent: [Cu]I
Agent: [Na]
Solvent: CN1CCCC1=O
Product: CCOC(=O)C1=Cc2cccc(C(F)(F)F)c2OCC1
Temperature: 160 °C
Reaction time: 6 h

Procedure:
A mixture of ethyl 2,3-dihydro-9-iodo-1-benzoxepin-4-carboxylate (1.00 g), trifluoroacetic acid, sodium salt (1.58 g), and copper(I) iodide (1.11 g) in 1-methyl-2-pyrrolidinone (10 ml) was stirred at 160° C. under nitrogen atmosphere for 6 hours and partitioned between ethyl acetate and 1N hydrochloric acid. The aqueous layer was extracted twice with ethyl acetate. The combined organic layer was washed successively with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel using a mixture of n-hexane and ethyl acetate (4:1) to give ethyl 2,3-dihydro-9-trifluoromethyl-1-benzoxepin-4-carboxylate (0.93 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([OH:11])=O)[CH:7]=1.NN.C1CN([P+](O[N:45]2[N:53]=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12]([NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)(=[O:24])=[O:25])=[C:6]([CH2:8][C:9]([NH:45][NH2:53])=[O:11])[CH:7]=1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)O)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: NN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NNC(=O)Cc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.1 %

Procedure:
To a stirred solution of 2-(5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetic acid (23.6 mg, 0.066 mmol) and hydrazine (6.3 uL, 0.13 mmol) in 1 mL of DMF were added PyBOP (69 mg, 0.13 mmol) and triethylamine (31 uL, 0.22 mmol). The reaction mixture was stirred at room temperature for 1 hour. The crude mixture was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give the title compound as a white solid (5.0 mg, yield 16%). MS calcd for (C15H17BN4O5S): 376.1. MS found (ESI negative): (M−H)−=375.1. 1H NMR (DMSO-d6) δ (ppm): 10.4 (bs, 1H), 9.74 (s, 1H), 9.11 (bs, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.36 (s, 1H), 7.17 (d, J=8.0 Hz, 1H), 7.06 (d, J=8.0 Hz, 1H), 6.34 (m, 2H), 5.89 (bs, 2H), 4.81 (s, 2H), 3.76 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([CH2:36][C:37]([F:44])([F:43])[C:38](OCC)=[O:39])=[C:32]([C:45]([F:48])([F:47])[F:46])[CH:31]=3)=[O:28])=[C:22]([F:49])[CH:21]=2)[CH:7]=[N:8][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].CC(=O)OCC>C1COCC1>[F:44][C:37]([F:43])([CH2:38][OH:39])[CH2:36][C:33]1[CH:34]=[CH:35][C:30]([NH:29][C:27](=[O:28])[CH2:26][C:23]2[CH:24]=[CH:25][C:20]([C:6]3[CH:7]=[N:8][C:9]([O:10][CH2:11][C:12]4[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=4)=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)=[CH:21][C:22]=2[F:49])=[CH:31][C:32]=1[C:45]([F:46])([F:47])[F:48]
Reactant: CCOC(=O)C(F)(F)Cc1ccc(NC(=O)Cc2ccc(-c3cnc(OCc4ccc(OC)cc4)c(OCC)c3)cc2F)cc1C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOc1cc(-c2ccc(CC(=O)Nc3ccc(CC(F)(F)CO)c(C(F)(F)F)c3)c(F)c2)cnc1OCc1ccc(OC)cc1
Reaction time: 1 h
Yield: 71.7 %

Procedure:
To a mixture of ethyl 3-(4-(2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamido)-2-(trifluoromethyl)phenyl)-2,2-difluoropropanoate (100 mg, 0.145 mmol) in THF (5 mL) was added LAH (5.50 mg, 0.145 mmol) at 0° C. The mixture was stirred for 1 h. LCMS and TLC (PE/EA=1:1, Rf=0.2) showed the reaction was finished. The reaction was quenched by water (0.3 mL). The mixture was filtered, and the filtrate was concentrated to give N-(4-(2,2-difluoro-3-hydroxypropyl)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (80 mg, 0.104 mmol, 71.6% yield): 1H NMR (400 MHz, CD3OD-d4) δ 8.01 (s, 1H), 7.94 (d, J=2.0 Hz, 1H), 7.77 (d, J=8.6 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.47-7.27 (m, 6H), 6.90 (d, J=8.8 Hz, 2H), 5.35 (s, 2H), 4.22-4.11 (m, 2H), 3.82-3.75 (m, 3H), 3.67 (t, J=13.0 Hz, 2H), 3.47-3.37 (m, 2H), 3.37-3.34 (m, 2H), 1.41 (t, J=7.1 Hz, 3H). ES-LCMS m/z 649 (M+H).
Reaction SMILES: [CH3:1][C:2]([N+:23]([O-])=O)([CH3:22])[CH:3]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1)=O.[C:26](O)(=[O:28])[CH3:27].C(OC(=O)C)(=O)C>[Zn].N1C=CC=CC=1>[CH3:1][C:2]1([CH3:22])[N:23]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:26](=[O:28])[CH3:27])=[CH:9][CH:8]=2)[CH2:4][CH:3]1[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C(CC(=O)c1ccc([N+](=O)[O-])cc1)c1ccncc1)[N+](=O)[O-]
Reactant: CC(=O)O
Agent: [Zn]
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(C2=NC(C)(C)C(c3ccncc3)C2)cc1
Reaction time: 1 h

Procedure:
18 G. of zinc powder are added to a solution of 18.0 g. of 4-methyl-4,4'-dinitro-3-(4-pyridyl)-valerophenone in 500 ml. of glacial acetic acid while stirring. After one hour, an additional 18 g. of zinc powder are added and the reaction mixture is left to react overnight. Then the reaction mixture is filtered, the filter residue is washed with dilute acetic acid and the filtrate evaporated under reduced pressure. The resulting residue is treated with dilute ammonia solution and extracted with ethyl acetate. The extract is dried over sodium sulfate and evaporated under reduced pressure to obtain a residue, which is then treated with a mixture of 70 ml. of acetic anhydride and 35 ml. of pyridine. After 1 hour, the crystals which precipitate are filtered off and washed with ethyl acetate to yield 4'-[5,5-dimethyl-4-(4-pyridyl)-1-pyrrolin-2-yl]-acetanilide, which is recrystallized from methanol to give a product with a melting point of 227°-228° C.
Reaction SMILES: [NH:1]1[C:8]23[CH2:17][CH:4]([CH2:5][CH2:6][CH:7]2[CH2:16][CH2:15][C:14]2[C:9]3=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:3][C:2]1=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:2][NH:1][C:8]12[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:15][CH2:16][CH:7]1[CH2:6][CH2:5][CH:4]([OH:3])[CH2:17]2
Reactant: O=C1NC23CC(CCC2CCc2ccccc23)O1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNC12CC(O)CCC1CCc1ccccc12
Reaction time: 8 h
Yield: 82.7 %

Procedure:
A solution of the compound from Example 62 (1.4 g, 5.75 mmol) in 20 ml THF was added to a slurry of lithium aluminum hydride (1 g) in 30 ml THF. After stirring overnight, additional lithium aluminum hydride was added (1 g) and stirring continued 3 hours. Workup afforded the title compound as a white solid (1.1 g, 83%), mp 141°-143° C.
Reaction SMILES: [CH3:1][N:2]([C:9]([C:11]1[C:12]([CH2:20][C:21]2[N:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[N:22]=2)=[N:13][S:14][C:15]=1[Si](C)(C)C)=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(O)(=O)C.C(Cl)Cl>C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Mn+3]>[CH3:1][N:2]([C:9]([C:11]1[C:12]([CH2:20][C:21]2[N:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[N:22]=2)=[N:13][S:14][CH:15]=1)=[O:10])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1cc(OC)nc(Cc2nsc([Si](C)(C)C)c2C(=O)N(C)c2ccccc2)n1
Agent: [Mn+3]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc(OC)nc(Cc2nscc2C(=O)N(C)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 2.0 g of N-methyl 3-(4,6-dimethoxy-2-pyrimidinylmethyl)-5-trimethylsilyl-4-isothiazolecarboxanilide, 1.5 g of manganese (III) triacetate, 20 ml of acetic acid and 30 ml of methylene dichloride is stirred at RT for 48 hours. The resulting suspension is suction filtered through filter aid and the filter cake washed with water and methylene dichloride. The organic layer is separated, dried and concentrated. The concentrate is flash chromatographed through 300 ml silica gel, 230-400 mesh, using 1 l 70/30 hexane/ethyl acetate, 500 ml 50/50 hexane/ethyl acetate taking 30×50 ml fractions. Fractions 10-15 give a mixture of two components which is heated with boron trifluoride methanol complex (4 drops) in 50 ml of toluene at 80° C. for 2 hrs. The reaction mixture is washed with 30 ml of 15% sodium bicarbonate solution, dried, and concentrated. The concentrate is flash chromatographed through 300 ml silica gel, 230-400 mesh, using 1 l 60/40 hexane/ethyl acetate, 500 ml 40/60 hexane/ethyl acetate and 200 ml ethyl acetate taking 34×50 ml fractions. Fractions 20-23 give N-methyl 3-(4,6-dimethoxy-2-pyrimidinylmethyl)-4-isothiazolecarboxanilide, 0.12 g, mp 92°-93° (Table F, cpd. no. 513). Fractions 24-28 give N-methyl 3-(4,6-dimethoxy-2-pyrimidinylcarbonyl)-4-isothiazolecarboxanilide, 0.3 g, mp 140°-142° C. (Table F, cpd. no. 514).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.O[CH2:12][C@H:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=3)[CH:19]=2)[O:14]1.C(N(CC)CC)C.[NH2:40][CH2:41][C@H:42]([OH:51])[CH2:43][O:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[OH:51][C@H:42]([CH2:43][O:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:41][NH:40][CH2:12][C@H:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=3)[CH:19]=2)[O:14]1
Reactant: COC(=O)c1ccc(-c2ccc3c(c2)CC[C@H](CO)O3)cc1
Reactant: NC[C@H](O)COc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccc3c(c2)CC[C@H](CNC[C@H](O)COc2ccccc2)O3)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a solution of anhydrous DMSO (0.839 mmol, 2.5 eq.) in CH2Cl2 (4 mL) at −78° C. was added oxalyl chloride (2M in CH2Cl2, 0.536 mmol, 1.6 eq.) dropwise by syringe. The resulting mixture was stirred at −78° C. for 10 minutes before a solution of methyl 4-[(2R)-2-(hydroxymethyl)-3,4-dihydro-2H-chromen-6-yl]benzoate (Example 62, 0.335 mmol, 1.0 eq.) in CH2Cl2 (4 mL) was added very slowly by syringe. The resulting reaction mixture was stirred at −78° C. for 2 hours, at which time triethylamine (2.01 mmol, 6.0 eq.) was added. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature (about 10 minutes). To the resulting crude aldehyde was added (2S)-1-amino-3-phenoxy-2-propanol (0.67 mmol, 2.0 eq.) in a single portion followed by acetic acid (6.03 mmol, 18.0 eq.). The resulting mixture was stirred for 5 minutes before sodium triacetoxyborohydride (1.005 mmol, 3.0 eq.) was added in a single portion. The reaction mixture was stirred at room temperature for 3 hours. The triacetoxyborohydride was quenched by the addition of 1N NaOH until the pH reached 9-10. The resulting two-phase mixture was extracted with CH2Cl2. The organic extracts were dried over sodium sulfate, concentrated and purified by medium pressure column chromatography (Biotage 40S normal phase silica gel column, CH2Cl2 to CH2Cl2:MeOH=100:3). The product was obtained as a pale yellow solid in 99% yield (two steps). MH+=448.3, retention time (LC-MS)=2.46 min.
Reaction SMILES: [C:1]([CH:3]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[C:10]=1[O:23][CH3:24])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[H-].[Na+].[CH2:27](Br)[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>CN(C)C=O>[C:1]([C:3]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[C:10]=1[O:23][CH3:24])([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCCCCCBr
Reactant: CCOC(=O)C(C#N)c1cccc(Sc2ccccc2C)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCC(C#N)(C(=O)OCC)c1cccc(Sc2ccccc2C)c1OC
Yield: 100.3 %

Procedure:
A solution of ethyl 2-cyano-2-[2-methoxy-3-(o-tolylthio)phenyl]acetate (4 g) in dimethylformamide (5 ml) was added dropwise to a solution of sodium hydride (purity 65%, 450 mg) in dimethylformamide (20 ml) in 10 minutes at temperature below 10° C. with stirring. After stirring the mixture at the same temperature for 10 minutes, n-hexyl bromide (3.85 g) was added to the mixture and stirred at 50° C. for an hour. After evaporation, water was added to the residue, and the mixture was extracted with diethyl ether. The extract was washed with water, dried and evaporated under reduced pressure to give oily ethyl 2-cyano-2-[2-methoxy-3-(o-tolylthio)phenyl]octanoate (5 g).
Reaction SMILES: [C:1](OC(C1C=C(OC2C=CC(S(C)(=O)=O)=CC=2)C2CC(COC)OC=2C=1)=O)(C)(C)C.[C:31]([O:35][C:36]([C:38]1[CH:49]=[C:48]([O:50][C:51]2[CH:56]=[CH:55][C:54]([S:57]([CH:60]3[CH2:62][CH2:61]3)(=[O:59])=[O:58])=[CH:53][CH:52]=2)[C:41]2[CH2:42][C:43]([CH2:46][OH:47])([CH3:45])[O:44][C:40]=2[CH:39]=1)=[O:37])([CH3:34])([CH3:33])[CH3:32].CI>>[C:31]([O:35][C:36]([C:38]1[CH:49]=[C:48]([O:50][C:51]2[CH:52]=[CH:53][C:54]([S:57]([CH:60]3[CH2:61][CH2:62]3)(=[O:59])=[O:58])=[CH:55][CH:56]=2)[C:41]2[CH2:42][C:43]([CH2:46][O:47][CH3:1])([CH3:45])[O:44][C:40]=2[CH:39]=1)=[O:37])([CH3:32])([CH3:33])[CH3:34]
Reactant: COCC1Cc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(C(=O)OC(C)(C)C)cc2O1
Reactant: CC(C)(C)OC(=O)c1cc(Oc2ccc(S(=O)(=O)C3CC3)cc2)c2c(c1)OC(C)(CO)C2
Solvent: CI
Product: COCC1(C)Cc2c(Oc3ccc(S(=O)(=O)C4CC4)cc3)cc(C(=O)OC(C)(C)C)cc2O1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 201a, from 4-(4-cyclopropanesulfonyl-phenoxy)-2-hydroxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (245a) and methyl iodide. 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J=8.84 Hz, 2 H) 7.22 (s, 1 H) 7.07 (d, J=8.84 Hz, 2 H) 3.41-3.52 (m, 2 H) 3.40 (s, 3 H) 3.11 (d, J=16.67 Hz, 1 H) 2.76 (d, J=16.67 Hz, 1 H) 2.48 (td, J=7.89, 4.67 Hz, 1 H) 1.56 (s, 9 H) 1.46 (s, 3 H) 1.32-1.43 (m, 2 H) 1.00-1.12 (m, 2 H); LCMS for C25H30O7S m/z 475.20 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11]3)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:25][O:26][C:27]1[CH:51]=[C:50]([O:52][CH3:53])[CH:49]=[CH:48][C:28]=1[CH2:29][N:30]([C:43]1[S:47][N:46]=[CH:45][N:44]=1)[S:31]([C:34]1[CH:39]=[C:38]([F:40])[C:37](F)=[CH:36][C:35]=1[F:42])(=[O:33])=[O:32]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][C:37]2[C:38]([F:40])=[CH:39][C:34]([S:31]([N:30]([CH2:29][C:28]3[CH:48]=[CH:49][C:50]([O:52][CH3:53])=[CH:51][C:27]=3[O:26][CH3:25])[C:43]3[S:47][N:46]=[CH:45][N:44]=3)(=[O:32])=[O:33])=[C:35]([F:42])[CH:36]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11]3)[CH:7]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(F)cc2F)c(OC)c1
Reactant: O=C1Cc2cc(-c3cc(Cl)ccc3O)ccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(Oc3ccc(Cl)cc3-c3ccc4c(c3)CC(=O)N4)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 5-(5-chloro-2-hydroxyphenyl)indolin-2-one (0.132 g, 0.51 mmol) and potassium carbonate (0.105 g, 0.76 mmol) in dimethylsulfoxide (3 mL) was added N-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (0.239 g, 0.54 mmol). The reaction mixture was degassed with nitrogen for 10 minutes and stirred for 16 h at ambient temperature. The reaction mixture was partitioned between ethyl acetate (50 mL) and water (5 mL). The organic phase was washed with water (2 5 mL) and brine (2 5 mL), dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography, eluting with a 10-50% gradient of ethyl acetate in hexanes to afford 4-(4-chloro-2-(2-oxoindolin-5-yl)phenoxy)-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide as a colorless foam that was carried forward without further purification.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:8][Si:9]([C:12]#[C:13][Si](C)(C)C)([CH3:11])[CH3:10].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[CH3:8][Si:9]([C:12]#[C:13][C:1]([CH2:2][CH2:3][CH2:4][CH3:5])=[O:6])([CH3:11])[CH3:10]
Reactant: C[Si](C)(C)C#C[Si](C)(C)C
Reactant: CCCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCC(=O)C#C[Si](C)(C)C
Reaction time: 0.33 h
Yield: 76 %

Procedure:
To a stirred solution of 14.4 g of valeryl chloride and 20.4 g of bis-trimethylsilylacetylene in 300 ml of dry methylene chloride, cooled in an ice bath, is added powdered anhydrous aluminum chloride, portionwise, over a period of 20 minutes. The mixture is stirred for 5 minutes, then the cooling bath is removed and the mixture is stirred at room temperature for 4 hours. The mixture is poured into 500 ml of ice-water. The organic layer is separated, washed with water and brine, dried over anhydrous sodium sulfate and filtered through diatomaceous earth. The mother liquor is evaporated to dryness giving a brownish residue. This residue is Kugelrohr-distilled to give 16.56 g of colorless liquid at 45° C./0.3 mm which is essentially identical with the authentic product.