Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[N:10]=[C:9]2[N:11]([CH2:17][C:18]([N:20]3[C@H:25]([C:26](=[O:37])[NH:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=4[F:36])[CH2:24][C@@H:23]4[C@H:21]3[CH2:22]4)=[O:19])[CH:12]=[C:13]([C:14](=[O:16])[CH3:15])[C:8]2=[CH:7][CH:6]=1)=[O:4].[Li+].[OH-].Cl>C1COCC1.O>[C:14]([C:13]1[C:8]2[C:9](=[N:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=2)[N:11]([CH2:17][C:18]([N:20]2[C@H:25]([C:26](=[O:37])[NH:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=3[F:36])[CH2:24][C@@H:23]3[C@H:21]2[CH2:22]3)=[O:19])[CH:12]=1)(=[O:16])[CH3:15]
Reactant: COC(=O)c1ccc2c(C(C)=O)cn(CC(=O)N3[C@@H]4C[C@@H]4C[C@H]3C(=O)NCc3cccc(Cl)c3F)c2n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1cn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2nc(C(=O)O)ccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-acetyl-1-{2-[(1R,3S,5R)-3-(3-chloro-2-fluoro-benzylcarbamoyl)-2-aza-bicyclo[3.1.0]hex-2-yl]-2-oxo-ethyl}-1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid methyl ester (Example 689, 70 mg, 0.133 mmol) in THF (3 mL) and water (0.3 mL) was added a 2N aqueous LiOH solution (0.664 mL, 1.33 mmol). The reaction mixture was stirred at 25° C. for 16 h, then a 1N HCl aqueous solution was added to acidify the reaction mixture to pH=2 to 3. The resulting aqueous suspension was filtered, the solid was washed with water and then dried in vacuo. The crude solid was purified by preparative HPLC (Waters Sunfire C18-OBD, 5 μm, 30×100 mm, flow: 40 mL/min, eluent: 20% to 100% CH3CN in H2O in 20 min, 100% CH3CN 2 min, CH3CN and H2O containing 0.1% TFA). The pure fractions were combined, CH3CN was evaporated under reduced pressure and the resulting aqueous solution was lyophilized to give the title compound as a white solid. MS: 513 [M+H]+, 535 [M+Na]+; tR (HPLC conditions k): 3.14 min.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH2:19][C:20]1[CH:42]=[CH:41][C:23]([C:24]([N:26]2[CH2:32][C:31]3[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=3[CH2:29][C:28]3[CH:37]=[CH:38][CH:39]=[CH:40][C:27]2=3)=[O:25])=[CH:22][CH:21]=1>O>[CH:37]1[C:28]2[CH2:29][C:30]3[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=3[CH2:32][N:26]([C:24]([C:23]3[CH:22]=[CH:21][C:20]([NH:19][C:4](=[O:5])[C:3]4[CH:7]=[CH:8][CH:9]=[C:10]([Cl:11])[C:2]=4[Cl:1])=[CH:42][CH:41]=3)=[O:25])[C:27]=2[CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Cl)c1cccc(Cl)c1Cl
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)c1cccc(Cl)c1Cl
Reaction time: 2 h
Yield: 65.7 %

Procedure:
A mixture of 301.6 mg of 2,3-dichlorobenzoyl chloride and 145 mg of triethylamine is stirred while 314 mg of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz-[b,e]azepine is added. Stirring is continued for 2 hours. Water is added and the organic layer washed with 1N HCl, water, 1M NaHCO3 and water then dried over Na2SO4. The organic layer is passed through a pad of hydrous magnesium silicate and hexane added to the filtrate at the boil to give 0.32 g of the desired product as a crystalline solid, m.p. 225°-230° C.
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Br[CH2:39][C:40]([N:42]1[C:47]([CH3:49])([CH3:48])[CH2:46][CH2:45][CH2:44][C:43]1([CH3:51])[CH3:50])=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:39][CH2:40][N:42]2[C:47]([CH3:49])([CH3:48])[CH2:46][CH2:45][CH2:44][C:43]2([CH3:51])[CH3:50])=[CH:34][CH:35]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CC1(C)CCCC(C)(C)N1C(=O)CBr
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN2C(C)(C)CCCC2(C)C)cc1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 30.2 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-bromo-1-(2,2,6,6-tetramethylpiperidin-1-yl)ethanone (26 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (8.6 mg) was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([CH2:7][NH:8][C:9](=[O:25])[C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[N:12][C:11]=2[O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[CH:5][CH:4]=1)#[N:2].[N-:28]=[N+:29]=[N-:30].[Na+].Cl.C(N(CC)CC)C>CN1CCCC1=O.ClCCl>[F:16][C:14]1[CH:13]=[N:12][C:11]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[C:10]([CH:15]=1)[C:9]([NH:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([C:1]2[N:28]=[N:29][NH:30][N:2]=2)=[CH:27][CH:26]=1)=[O:25]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(CNC(=O)c2cc(F)cnc2Oc2ccc(F)cc2)cc1
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCc1ccc(-c2nn[nH]n2)cc1)c1cc(F)cnc1Oc1ccc(F)cc1
Temperature: 150 °C
Yield: 51 %

Procedure:
To a solution of N-(4-cyanobenzyl)-5-fluoro-2-(4-fluorophenoxy)nicotinamide (step 1, 220 mg, 0.60 mmol) in 1-methyl-pyrrolidin-2-one (5 mL) were added sodium azide (117 mg, 1.8 mmol) and triethylamine hydrochloride (248 mg, 1.8 mmol) at room temperature. This mixture was heated at 150° C. for 18 h. The reaction mixture was diluted with dichloromethane (100 mL), and the solution was washed with saturated sodium dihydrogenphosphate solution (50 mL). The organic phase was dried (sodium sulfate) and concentrated. The residue was purified by flash column chromatography on silica gel (50 g) eluting with dichloromethane/methanol/acetic acid (100/5/0.5) to give off white solids. The solids were triturated with ethyl acetate to afford 125 mg (50%) of the title compound as white solids: 1H-NMR (DMSO-d6) δ 9.18 (1H, t, J=5.8 Hz), 8.14 (1H, d, J=2.8 Hz), 7.99 (1H, dd, J=8.2, 2.8 Hz), 7.90 (2H, d, J=8.2 Hz), 7.51 (2H, d, J=8.2 Hz), 7.22–7.15 (4H, m), 4.56 (2H, d, J=5.8 Hz); MS (ESI) m/z 409 (M+H)+, 407 (M−H)−.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][N:22]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH:14]2[CH2:15][CH2:16][N:17]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][N:22]=3)[CH2:18][CH2:19]2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1nccc2ccccc12
Reactant: CC(C)(C)c1ccc(S(=O)(=O)C2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(S(=O)(=O)C2CCN(c3nccc4ccccc34)CC2)cc1
Yield: 18.5 %

Procedure:
Using the procedure from Example 7A, 4-[(4-tert-butylphenyl)sulfonyl]piperidine (150 mg, 0.53 mmol) was reacted with 1-chloroisoquinoline (183 mg, 1.06 mmol), DIEA (0.37 ml, 2.12) and 1,4-dioxane (0.2 ml) at 185° C. to afford the title compound (40 mg), a white solid, in 18% yield.
Reaction SMILES: [Sn].[CH3:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]2[CH2:12][CH2:13][CH2:14][C:15](=[O:16])[C:4]=12.[Br-:17].[Br-].[Br-].C[N+](C)(C)C1C=CC=CC=1.C[N+](C1C=CC=CC=1)(C)C.C[N+](C1C=CC=CC=1)(C)C>C(Cl)Cl>[Br:17][CH:14]1[CH2:13][CH2:12][N:5]2[C:6]3[C:11]([C:3]([CH3:2])=[C:4]2[C:15]1=[O:16])=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: Cc1c2n(c3ccccc13)CCCC2=O
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Agent: [Sn]
Solvent: ClCCl
Product: Cc1c2n(c3ccccc13)CCC(Br)C2=O
Temperature: 10 °C
Reaction time: 30 h
Yield: 86.8 %

Procedure:
The reaction was performed in the dark (the flask wrapped in a tin-foil), and with the provision for maintaining a nitrogen atmosphere. To a solution of 10-methyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-one (described in Example 7, 49.75 g) in methylene chloride (250 mL) was added a solution of trimethylphenylammonium tribromide (94 g) in methylene chloride (1200 mL) as fast as possible (over 2 min); the inside temperature was maintained at 10° C. The reaction mixture was stirred at room temperature for 30 hr, evaporated in vacuo, and the solid residue was partitioned between water (600 mL) and benzene-diethyl ether 1:1 (800 mL, v/v). The separated organic layer was dried (MgSO4), filtered, and the filtrate was evaporated. The crude product was dissolved in chloroform (55 mL), and diethyl ether (600 mL) was added at once, whereby a voluminous, dark-green material precipitated. It was quickly removed by filtration (without suction), and the filtrate was chilled to 0° C. The crystals which formed were collected by filtration; 38 g, mp 126°-128° C. This material was recrystallized from chloroform-diethyl ether (1:8, v/v) to give 35 g of the title compound, mp 131°-133° C.; IR (CHCl3) 1665-1660, and 1535 cm-1 ; UV max (MeOH) 246 and 327 nm, (ε16000) and (18200) respectively; NMR (CDCl3) δ 2.67 (br s, 3H), overlapping with 2.65 (m, 2H), 4.29 (dd, J1 =7.5 Hz, J2 =4.5 Hz, 2H), 4.67 (t, J=4 Hz, 1H), 7.25-7.7 (m, 4H); Anal. Calcd for C13H12BrNO: C, 56.12% H, 4.35% N, 5.03% and Found: C, 56.20% H, 4.32% N, 5.05%.
Reaction SMILES: [C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH3:12])=[CH:8][C:7]([CH2:13][CH2:14][CH:15]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH3:12])=[CH:8][C:7]([CH2:13][CH2:14][CH2:15][N:27]2[CH2:26][CH2:25][N:24]([C:21]3[CH:20]=[CH:19][C:18]([Cl:17])=[CH:23][CH:22]=3)[CH2:29][CH2:28]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCc1cc(CCC=O)nn1C(C)(C)C
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3ccc(Cl)cc3)CC2)nn1C(C)(C)C

Procedure:
62 mg (63%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-propyl-1H-pyrazol-3-yl)propanal (50 mg, 0.225 mmol), 1-(4-chlorophenyl)piperazine (0.034 mg, 0.225 mmol), DIPEA (0.060 mL, 0338 mmol) and NaBH(OAc)3 (143 mg, 0.675 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:16])[CH:5]=[C:6]([Cl:15])[C:7]=1[O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11].C(=O)([O-])[O-].[K+].[K+].[Cl:23][C:24]([Cl:28])=[CH:25][CH2:26]Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:16][CH2:26][CH:25]=[C:24]([Cl:28])[Cl:23])[CH:5]=[C:6]([Cl:15])[C:7]=1[O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11]
Reactant: ClCC=C(Cl)Cl
Reactant: Oc1cc(Cl)c(OC(F)(F)C(F)F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)C(F)(F)Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 75.5 %

Procedure:
To a mixture of 600 mg of 3,5-dichloro-4-(1,1,2,2-tetrafluoroethoxy)phenol, 330 mg of potassium carbonate and 10 ml of N,N-dimethylformamide was added dropwise a solution of 340 mg of 1,1,3-trichloro-1-propene dissolved in 3 ml of N,N-dimethylformamide, while stirring at room temperature. After stirring continued at room temperature for 5 hours, the reaction mixture was poured into ice-water, and extracted twice with 40 ml of diethyl ether. The combined ether layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 630 mg of 3,5-dichloro-4-(1,1,2,2-tetrafluoroethoxy)-1-(3,3-dichloro-2-propenyloxy)benzene (82% yield), nD24.6 1.5067.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])=[CH:6][CH:7]=1
Reactant: C1CCNC1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Product: Cc1ccc(-c2oncc2C(=O)N2CCCC2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and pyrrolidine (4.3 mg, 0.060 mmol) as described in synthetic method A and thereafter purified by preparative HPLC method A to give a solid (7.1 mg). MS (pos) m/z 257.2 (M+H).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH2:17][C:18]([O:20]CC)=[O:19])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[OH-].[K+]>O>[C:1]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH2:17][C:18]([OH:20])=[O:19])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC=Cc1cccc(C(=O)c2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CC=Cc1cccc(C(=O)c2ccccc2)c1
Yield: 66.7 %

Procedure:
A mixture of 275 mg of ethyl 4-(m-benzoyl-phenyl)-3-butenoate, 2.75 ml of ethanol, 0.275 ml of ethanol, 0.275 ml of water and 0.08 ml of 12.5N potassium hydroxide was refluxed for 30 minutes and then was evaporated to dryness. The residue was dissolved in 10 ml of water and the solution was treated with activated carbon, and filtered. 3 ml of N hydrochloric acid were added thereto and the mixture was extracted with methylene chloride. The organic phase was washed with water, dried over sodium sulfate, treated with activated carbon, filtered and evaporated to dryness under reduced pressure to obtain 166 mg of 4-(m-benzoyl-phenyl)-3-butenoic acid in the form of a yellow oil soluble in chloroform and ethanol and insoluble in water.
Reaction SMILES: Cl[C:2]1(Cl)[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[C:3]1=[O:10]>C(O)(=O)C.C(OCC)C.[Zn]>[CH:9]12[CH2:2][C:3](=[O:10])[CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8]2
Reactant: O=C1C2CCCCC2C1(Cl)Cl
Agent: [Zn]
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=C1CC2CCCCC12
Temperature: 25 °C
Yield: 86.5 %

Procedure:
(1RS,6SR)-8,8-dichlorobicyclo[4.2.0]octan-7-one (preparation 18) (8.60 g, 44.6 mmol) was heated to reflux in acetic acid (100 ml) with zinc dust (29.0 g, 446 mmol). After 4 hrs the mixture was cooled to room temperature, diluted with diethyl ether (200 ml) and washed with 2N NaOH (2×100 ml) and then with saturated aqueous NaHCO3 (4×100 ml). The ether phase was collected, dried (MgSO4) and the solvent was removed under reduced pressure to give 4.79 g of the title compound as a clear oil.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[C:19]([C:21]3[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=4)[N:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:30][C:27]([F:28])([F:29])[C:25]1[CH:24]=[C:23]([C:31]2[CH:32]=[CH:33][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:36]=2)[N:22]=[C:21]([C:19]2[CH:18]=[CH:17][N:16]=[C:15]([C:11]3[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=3)[CH:20]=2)[N:26]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 85.7 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-3-{4-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonamide (example 156) (0.4 g, 0.69 mmol) in dichloromethane (5 mL) was added TFA (5 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane and dried to yield the title compound as an off-white solid (0.31 g, 90%). MS (ISN) 523.7 [(M−H)−]; mp 237° C.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:13])[CH2:4][CH2:5][C:6]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)=[O:7].[OH-].[Na+].[BH4-].[Na+]>CO.O>[CH3:13][N:3]([CH3:2])[CH2:4][CH2:5][CH:6]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[OH:7]
Reactant: CN(C)CCC(=O)c1cccs1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN(C)CCC(O)c1cccs1
Temperature: 25 °C
Yield: 90 %

Procedure:
To a solution of 3-dimethylamino-1-(2-thienyl)-1-propanone hydrochloride (70.0 g, 0.34 mol) in 840 ml of methanol and 420 ml of water at about 0° C. was added 5N sodium hydroxide until the solution was slightly basic. To the resulting solution was added sodium borohydride (12.9 g., 0.34 mol) in portions. The mixture was allowed to warm to room temperature overnight. The methanol was removed in vacuo and the remaining solution was diluted with water. The solution was extracted with diethyl ether, and the solution was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo to provide 56.7 g of colorless crystals. Recrystallization of the crystals from hexanes gave 49.24 g (78%) of the title compound as colorless crystals mp=72° C.-74° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([SH:12])[CH:9]=[CH:8][C:7]=2[NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:3][CH2:2]1.[Cl:18][C:19]1[CH:20]=[N+:21]([O-:56])[CH:22]=[C:23]([Cl:55])[C:24]=1[CH2:25][C@@H:26]([C:40]1[CH:45]=[CH:44][C:43]([O:46][CH:47]([F:49])[F:48])=[C:42]([O:50][CH2:51][CH:52]2[CH2:54][CH2:53]2)[CH:41]=1)[O:27][C:28](OC1C=CC([N+]([O-])=O)=CC=1)=[O:29]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:55][C:23]1[CH:22]=[N+:21]([O-:56])[CH:20]=[C:19]([Cl:18])[C:24]=1[CH2:25][C@@H:26]([C:40]1[CH:45]=[CH:44][C:43]([O:46][CH:47]([F:49])[F:48])=[C:42]([O:50][CH2:51][CH:52]2[CH2:54][CH2:53]2)[CH:41]=1)[O:27][C:28]([S:12][C:10]1[CH:9]=[CH:8][C:7]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[CH:11]=1)=[O:29]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: CS(=O)(=O)Nc1ccc(S)cc1OCC1CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(SC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OCC1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N-(2-(cyclopropylmethoxy)-4-mercaptophenyl)-methanesulfonamide (0.112 g, 0.410 mmol), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((4-nitrophenoxy)-carbonyloxy)ethyl)pyridine 1-oxide (prepared with an analogous procedure to that described in Scheme 3, Step 1) (0.200 g, 0.342 mmol), and DMAP (0.021 g, 0.171 mmol) in DCM (8 ml) was stirred at RT overnight. The mixture was diluted with DCM and washed several times with diluted aqueous K2CO3. The organic layer was dried over Na2SO4 and the solvent was removed. The crude was purified by filtration on silica gel cartridge (DCM:EtOAc=80:20) affording the desired compound as a pale yellow amorphous solid. The product was further purified by flash chromatography on silica gel cartridge (petroleum ether:EtOAc=50:50 to 35:65) and by preparative LC/MS affording (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((3-(cyclopropylmethoxy)-4-(methylsulfonamido)phenylthio)carbonyloxy)ethyl)pyridine 1-oxide as an off-white amorphous solid (0.060 g, 0.083 mmol, 24.40% yield, MS/ESI+ 719.23 [MH]+, [αD]=−64.64, c=0.47 in DCM).
Reaction SMILES: [N:1]1([CH2:8][C:9]2[N:14]=[C:13]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)=[CH:20][C:19]=3[C:30]3[CH:35]=[C:34]([C:36](=[O:49])[NH:37][CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([F:48])([F:47])[F:46])[CH:40]=4)[CH:33]=[CH:32][N:31]=3)=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:57](Cl)(=[O:59])[CH3:58]>ClCCl>[C:57]([N:4]1[CH2:5][CH2:6][CH2:7][N:1]([CH2:8][C:9]2[N:14]=[C:13]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]4)=[CH:20][C:19]=3[C:30]3[CH:35]=[C:34]([C:36](=[O:49])[NH:37][CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([F:47])([F:46])[F:48])[CH:40]=4)[CH:33]=[CH:32][N:31]=3)=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH2:2][CH2:3]1)(=[O:59])[CH3:58]
Reactant: CC(=O)Cl
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CN3CCCNCC3)n2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCCN(Cc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)n2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 6-((1,4-diazepan-1-yl)methyl)-N-(4-(piperidin-1-yl)-2-(4-(3-(trifluoromethyl)benzylcarbamoyl)pyridin-2-yl)phenyl)picolinamide (135 mg, 0.19 mmol, 1.00 equiv, 95%) in dichloromethane (5 mL), triethylamine (40 mg, 0.39 mmol, 2.00 equiv, 99%), and acetyl chloride (18 mg, 0.23 mmol, 1.20 equiv, 99%). The resulting solution was stirred for 3 h at room temperature. The resulting solution was diluted with 50 mL of dichloromethane. The resulting mixture was washed with 1×50 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting mixture was washed with 2×10 mL of hexane. The product was obtained as 120 mg (87%) of a yellow solid. 1H-NMR (400 MHz, DMSO-d6, ppm): δ 12.86 (s, 1H), 9.54-9.51 (t, 1H), 9.00 (s, 1H), 8.51-8.49 (d, J=6 Hz, 1H), 8.23 (s, 1H), 8.00 (s, 2H), 7.88-7.86 (d, 1H), 7.72-7.55 (m 5H), 7.33 (s, 1H), 7.14-7.11 (d, J=9 Hz, 1H), 4.63 (s, 2H), 3.91-3.88 (s, J=9 Hz, 2H), 3.52-3.50 (m, 4H), 3.21-3.19 (m, 4H), 2.78-2.63 (m, 4H), 2.01-1.98 (d, J=9 Hz, 3H), 1.79-1.55 (m, 8H). MS (ES, m/z): 714 [M+H]+.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[CH:60][C:61]([F:65])=[CH:62][CH:63]=2)[N:58]=[C:57]([C:66]2[CH:71]=[C:70]([CH3:72])[CH:69]=[CH:68][N:67]=2)[C:56]=1[CH:73]([CH3:75])[CH3:74].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH:47][C:55]3[C:64]4[C:59](=[CH:60][C:61]([F:65])=[CH:62][CH:63]=4)[N:58]=[C:57]([C:66]4[CH:71]=[C:70]([CH3:72])[CH:69]=[CH:68][N:67]=4)[C:56]=3[CH:73]([CH3:75])[CH3:74])=[CH:45][C:44]([N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1
Reactant: Cc1ccnc(-c2nc3cc(F)ccc3c(Cl)c2C(C)C)c1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1ccnc(-c2nc3cc(F)ccc3c(Nc3cc(N4CCOCC4)cnc3N3CCOCC3)c2C(C)C)c1

Procedure:
The Buchwald coupled product was prepared according to Procedure H using dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.025 g, 0.053 mmol), 2,5-dimorpholinopyridin-3-amine (0.106 g, 0.40 mmol), 4-chloro-7-fluoro-3-isopropyl-2-(4-methylpyridin-2-yl)quinoline (0.105 g, 0.33 mmol), Pd2dba3 (0.012 g, 0.013 mmol) and sodium tert-butoxide (0.080 g, 0.83 mmol) in toluene (3.3 mL) at 120° C. for 4.6 h. The crude product was purified by column chromatography on basic alumina (0 to 50% hexanes/EtOAc) to give the desired product N-(2,5-dimorpholinopyridin-3-yl)-7-fluoro-3-isopropyl-2-(4-methylpyridin-2-yl)-quinolin-4-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.58 (1H, dd, J=5.1, 0.6 Hz), 7.96 (1H, br s), 7.55-7.62 (2H, m), 7.52 (1H, m), 7.22 (1H, m), 7.13 (1H, br s), 7.07 (2H, dd, J=4.6, 1.1 Hz), 6.19 (1H, s), 3.96-3.91 (4H, m), 3.71 (4H, m), 3.50 (2H, br. s.), 3.40 (1H, m), 3.00 (1H, br s), 2.86 (4H, t, J=4.8 Hz), 2.48 (3H, s), 1.52 (3H, d, J=7.4 Hz), 1.13 (3H, d, J=7.4 Hz). Mass Spectrum (ESI) m/e=543.2 (M+1).