Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:17])[C:6]([C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:10]=1[F:16])=[N+]=[N-])[CH:2]=[CH2:3]>C(Cl)Cl.CCCCCCCC([O-])=O.CCCCCCCC([O-])=O.CCCCCCCC([O-])=O.CCCCCCCC([O-])=O.[Rh+2].[Rh+2]>[Br:15][C:13]1[CH:12]=[CH:11][C:10]([F:16])=[C:9]([C:6]23[CH2:3][CH:2]2[CH2:1][O:4][C:5]3=[O:17])[CH:14]=1
Reactant: C=CCOC(=O)C(=[N+]=[N-])c1cc(Br)ccc1F
Agent: [Rh+2]
Agent: CCCCCCCC(=O)[O-]
Solvent: ClCCl
Product: O=C1OCC2CC12c1cc(Br)ccc1F
Temperature: 23 °C
Yield: 84.8 %

Procedure:
To a solution of commercially available rhodium(II) octanoate dimer (Rh2(C7H16CO2)4) ([CAS No. 73482-96-9], 160 mg, 1 mol %) in DCM (60 ml) at 45° C. was added a solution of (5-bromo-2-fluoro-phenyl)-diazo-acetic acid allyl ester (intermediate B4A) (6.0 g, 20 mmol) in DCM (2×20 ml) via syringe pump within 16 h. Continued refluxing for 1 h, cooled to 23° C., washed with 1 M aqueous hydrochloric acid (HCl) and sat. aqueous sodium hydrogencarbonate solution (NaHCO3-sol.), dried organic layer over sodium sulfate. Removal of the solvent in vacuum left a green solid, which was purified by silica gel column chromatography with n-heptane/ethyl acetate to give the title compound as a light green solid (4.6 g, 85%) [cf. Adv. Synth. Catal. 2001, 343, 299, for an enantioselective version of this reaction].
Reaction SMILES: [ClH:1].Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:15][N:14]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12][N:11]2CC=C)=[CH:6][CH:5]=1.[OH-].[Na+]>[Ru](Cl)(Cl)Cl.C1(C)C=CC=CC=1>[ClH:3].[ClH:1].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C@H:10]2[NH:11][CH2:12][CH2:13][N:14]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:15]2)=[CH:8][CH:9]=1
Reactant: C=CCN1CCN(Cc2ccccc2)C[C@H]1c1ccc(Cl)cc1
Agent: Cl[Ru](Cl)Cl
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Clc1ccc([C@@H]2CN(Cc3ccccc3)CCN2)cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 87 %

Procedure:
Mixed were (R)-2-(4-Chlorophenyl)-4-(phenylmethyl)-1-(2-propenyl)hexahydropyrazine dihydrochloride (104 mg, 0.25 mmol) produced in Example 18 and ruthenium chloride (3 mg, 0.04 mmol). The mixture was stirred at 100° C. for 24 hours. To the mixture, 30 wt % aqueous solution of sodium hydroxide (85 mg, 2.5 equivalents) and toluene (2 mL) were added. The formed insolubles were separated by filtration, and washed with distilled water (2 mL) and toluene (2 mL). After the organic layer and aqueous layer of the filtrate were separated, the organic layer was washed twice with distilled water (4 mL). The obtained organic layer was concentrated and dried under vacuum, to obtain 68 mg of the crude product of the title compound as pale brown oil (yield: 87%, chemical purity: 93.5 area %, optical purity: 98.1% e.e.). The retention time in the chemical purity analysis method was 3.1 min.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([OH:19])=O.CN(C)CCCN=C=NCC.Cl.[C:32]([CH2:34][C@@H:35]1[CH2:43][C@@H:42]2[C@@H:38]([CH2:39][NH:40][CH2:41]2)[C@@:37]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[O:51][CH3:52])([OH:44])[CH2:36]1)#[N:33]>ClCCl.O.OC1C2N=NNC=2C=CC=1>[C:32]([CH2:34][C@@H:35]1[CH2:43][C@@H:42]2[C@@H:38]([CH2:39][N:40]([C:17](=[O:19])[CH2:16][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][CH3:8])[CH2:41]2)[C@@:37]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[O:51][CH3:52])([OH:44])[CH2:36]1)#[N:33]
Reactant: COc1ccccc1[C@]1(O)C[C@H](CC#N)C[C@H]2CNC[C@H]21
Reactant: COc1ccccc1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1CC(=O)N1C[C@@H]2C[C@@H](CC#N)C[C@@](O)(c3ccccc3OC)[C@@H]2C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 32.5 %

Procedure:
1.82 cm3 of triethylamine, 2.0 g of 2-methoxy-phenylacetic acid, 25 mg of hydroxybenzotriazole hydrate and 2.54 g of 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide are added to a solution of 3.96 g of (3aS,4S,6S,7aR)-6-cyanomethyl-4-(2-methoxyphenyl)-perhydroisoindol-4-ol hydrochloride in 60 cm3 of dichloromethane. The reaction mixture is stirred at room temperature for 20 hours, washed with 50 cm3 of water, dried over magnesium sulphate and concentrated to dryness under reduced pressure. The residue is chromatographed on a silica gel column (particle size 0.06-0.20 mm, diameter 3.6 cm, height 30 cm) under a pressure of 0.5 bar of nitrogen with ethyl acetate, collecting fractions of 100 cm3. Fractions 6 to 16 are concentrated to dryness under reduced pressure (2.7 kPa), the residue is recrystallized from ethyl acetate and then from ethanol, and the crystals are filtered, washed with a little ethanol and ethyl ether, drained and then dried under reduced pressure (2.7 kPa). 1.7 g of (3aS, 4S, 6S, 7aR)-6-cyanomethyl-4-(2-methoxyphenyl)-2-[(2-methoxyphenyl) acetyl]-perhydroisoindol-4-ol are obtained in the form of white crystals. M.p.K =160° C.
Reaction SMILES: ClC1C=C(C=CC=1CF)C=O.FC1C=C(C=C(F)C=1F)C=O.[CH2:23]([O:25][C:26](=[O:64])[CH:27]([C:32]1[CH:33]=[C:34]([C:54]2[CH:59]=[CH:58][C:57]([C:60]([F:63])([F:62])[F:61])=[CH:56][CH:55]=2)[CH:35]=[C:36]([CH2:38][N:39]([CH2:45][C:46]2[CH:51]=[CH:50][C:49]([Cl:52])=[C:48]([F:53])[CH:47]=2)[CH2:40][CH2:41][CH:42]([CH3:44])[CH3:43])[CH:37]=1)CC(C)C)[CH3:24]>>[CH2:23]([O:25][C:26](=[O:64])[CH2:27][C:32]1[CH:33]=[C:34]([C:54]2[CH:55]=[CH:56][C:57]([C:60]([F:62])([F:63])[F:61])=[CH:58][CH:59]=2)[CH:35]=[C:36]([CH2:38][N:39]([CH2:45][C:46]2[CH:51]=[CH:50][C:49]([Cl:52])=[C:48]([F:53])[CH:47]=2)[CH2:40][CH2:41][CH:42]([CH3:44])[CH3:43])[CH:37]=1)[CH3:24]
Reactant: CCOC(=O)C(CC(C)C)c1cc(CN(CCC(C)C)Cc2ccc(Cl)c(F)c2)cc(-c2ccc(C(F)(F)F)cc2)c1
Agent: O=Cc1cc(F)c(F)c(F)c1
Agent: O=Cc1ccc(CF)c(Cl)c1
Product: CCOC(=O)Cc1cc(CN(CCC(C)C)Cc2ccc(Cl)c(F)c2)cc(-c2ccc(C(F)(F)F)cc2)c1

Procedure:
Using the procedure described for Example 54, except substituting compound 57c for compound 54c and 3-chloro-4-fluoromethylbenzaldehyde for 3,4,5-trifluorobenzaldehyde, compound 57c was converted to 2-(5-{[(4-chloro-3-fluoro-benzyl)-(3-methyl-butyl)-amino]-methyl}-4′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid ethyl ester as a milky glass.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]2[C:31]([CH3:32])=[CH:30][C:29]([OH:33])=[CH:28][C:27]=2[CH3:34])=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Cl[CH2:36][C:37]1[CH:41]=[CH:40][N:39]([CH3:42])[N:38]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:34][C:27]1[CH:28]=[C:29]([O:33][CH2:36][C:37]2[CH:41]=[CH:40][N:39]([CH3:42])[N:38]=2)[CH:30]=[C:31]([CH3:32])[C:26]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: Cn1ccc(CCl)n1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(O)cc5C)ccc(F)c43)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCc6ccn(C)n6)cc5C)ccc(F)c43)ccc21
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Methyl 2-((S)-6-((R)-7-fluoro-4-(4-hydroxy-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (Intermediate 28-29) (46.3 mg) and 3-(chloromethyl)-1-methyl-1H-pyrazole (39.2 mg) were suspended in dimethylformamide (1.8 mL) and potassium carbonate (62 mg) was added. The reaction mixture was shaken for 24 h at 60° C. and than directly chromatographed by HPLC on reversed phase. The product fractions are collected and lyophilized to give the title compound. Yield: 44.5 mg; LC (method 23): tR=2.09 min; Mass spectrum (ESI+): m/z=557 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[CH:10]([C:12]([CH3:14])=O)=[CH2:11].[OH-].[Na+]>[Cl-].[Zn+2].[Cl-].C(O)C>[CH3:14][C:12]1[C:7]2[C:5](=[CH:4][C:3]([Cl:2])=[CH:9][CH:8]=2)[N:6]=[CH:11][CH:10]=1
Reactant: Nc1cccc(Cl)c1
Reactant: C=CC(C)=O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccnc2cc(Cl)ccc12
Temperature: 60 °C

Procedure:
32.8 g. (0.2 mol) 3-chloroaniline hydrochloride, 81 g. ferric trichloride hexahydrate (0.3 mol), 3.0 g. redried anhydrous zinc chloride and 150 mL 95% ethanol were added into a 500 mL 3-neck flask equipped with a reflux condenser, a magnetic stirrer with heating, a thermometer and a constant-pressure dropping funnel, and the mixture was stirred and heated to 60° C. 12.6 g. (0.18 mol) methyl vinyl ketone was added slowly through the constant-pressure dropping funnel while maintaining the temperature at 60-70° C., followed by raising the temperature to reflux for 2 hours. After cooling, the mixed solution was added with 25% aqueous sodium hydroxide until alkaline. The solvent was then distilled off under reduced pressure until dry. The resulting solids were removed and repeatedly extracted with anhydrous ethyl ether. The extracts were collected, dried over anhydrous potassium carbonate and filtered. After removing the solvent, the residue was purified in a silica column using hexane/ethyl acetate (3:1) as the mobile phase to afford 11.38 g. of product.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.CN(C)C=O.[H-].[Na+].F[C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=1>O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=2)=[CH:4][CH:3]=1
Reactant: OCc1ccc(Br)cc1
Reactant: Cc1ccnc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccnc(OCc2ccc(Br)cc2)c1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 58.8 %

Procedure:
To a mixture of 4-bromobenzyl alcohol (4.54 g, 24.3 mmol) and N,N-dimethylformamide (50.0 mL) were added sodium hydride (1.00 g, 25.0 mmol, 60% in oil) was added at 0° C. under nitrogen atmosphere, which was stirred for 50 minutes at room temperature. 2-Fluoro-4-methylpyridine (1.80 g, 16.2 mmol) was then added thereto at 0° C., and stirred for 2 hours and 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 separated, washed with saturated aqueous sodium chloride, and filtered. The filtrate was evaporated under a reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:15) to obtain the title compound (2.65 g, 58.8%).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[Cl:15][C:16]1[CH:17]=[C:18]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:19]=[CH:20][C:21]=1[Cl:22].[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].CO>C(OCC)(=O)C>[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:26]3[CH2:25][CH2:24][N:23]([C:18]4[CH:19]=[CH:20][C:21]([Cl:22])=[C:16]([Cl:15])[CH:17]=4)[CH2:28][CH2:27]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCN(c2ccc(Cl)c(Cl)c2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 1-(3,4-dichlorophenyl)piperazine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 87% overall yield. FDMS m/e=419 (M+ of free base). α[D]589 =-7.76 (c=0.82, methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](S(C1C=CC=CC=1)(=O)=O)[C:6]([S:20]([N:23]1[CH2:28][CH2:27][NH:26][CH:25]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:24]1)(=[O:22])=[O:21])=[CH:5]2>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([S:20]([N:23]1[CH2:28][CH2:27][NH:26][CH:25]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:24]1)(=[O:22])=[O:21])=[CH:5]2
Reactant: CC(C)CC1CN(S(=O)(=O)c2cc3cc(Cl)ccc3n2S(=O)(=O)c2ccccc2)CCN1
Solvent: C1COCCO1
Product: CC(C)CC1CN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CCN1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
To a solution of 1-[(5-chloro-1-phenylsulfonylindol-2-yl)sulfonyl]-3-(2-methylpropyl)piperazine (2.57 g) in a mixture of 1,4-dioxane and distilled water (100-10 ml) was added a 1N aqueous solution (10.4 ml) of sodium hydroxide. The resulting mixture was stirred at 80° C. for 3 days. After saturated ammonium chloride was added to terminate the reaction, distilled water and ethyl acetate were added. The water layer was extracted three times. The organic layers were combined, dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was subjected to chromatography on a silica gel column (methanol:methylene chloride=1:50), whereby the title compound (0.93 g) was obtained as a brown oil.
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[S:21][C:22](S(C)(=O)=O)=[N:23][N:24]=4)[CH:18]=3)[N:13]([S:29]([C:32]3[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=3)(=[O:31])=[O:30])[CH:12]=2)[CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[NH2:39][CH:40]1[CH2:45][CH2:44][CH2:43][N:42]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:41]1>O1CCOCC1>[CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[S:21][C:22]([NH:39][CH:40]5[CH2:45][CH2:44][CH2:43][N:42]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:41]5)=[N:23][N:24]=4)[CH:18]=3)[N:13]([S:29]([C:32]3[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=3)(=[O:31])=[O:30])[CH:12]=2)[CH:8]=[CH:7][CH:6]=1)([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cccc(OC(C)C)n3)c3cc(-c4nnc(S(C)(=O)=O)s4)ccc32)cc1
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cccc(OC(C)C)n3)c3cc(-c4nnc(NC5CCCN(C(=O)OC(C)(C)C)C5)s4)ccc32)cc1
Yield: 48.7 %

Procedure:
A yellow solution of 2-(3-(6-isopropoxypyridin-2-yl)-1-tosyl-1H-indol-5-yl)-5-(methylsulfonyl)-1,3,4-thiadiazole (89.3 mg, 0.115 mmol) and (±)-tert-butyl 3-aminopiperidine-1-carboxylate (Combi-Blocks, Inc., San Diego, Calif.; 0.110 mL, 0.573 mmol) in dioxane (1.0 mL) was heated in an open microwave vial at 90° C. for 3.5 d. Chromatographic purification of the resulting dry residue (silica gel, 0-100% EtOAc/Hex) furnished tert-butyl 3-(5-(3-(6-isopropoxypyridin-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-thiadiazol-2-ylamino)piperidine-1-carboxylate (38.6 mg, 0.056 mmol, 49%) as a yellow oil: MS (ESI, pos. ion) m/z: 689.2 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 8.79 (s, 1H), 8.07 (s, 2H), 7.92 (d, J=7.4 Hz, 1H), 7.82 (d, J=8.4 Hz, 4H), 7.59-7.64 (m, 2H), 7.29 (br. s., 1H), 6.61-6.65 (m, 1H), 5.55 (dt, J=12.5, 6.3 Hz, 1H), 3.69 (d, J=13.3 Hz, 2H), 3.48-3.59 (m, 1H), 3.41 (t, J=7.2 Hz, 2H), 2.36-2.39 (m, 2H), 2.35 (s, 3H), 1.55-1.57 (m, 2H), 1.46 (d, J=3.1 Hz, 6H), 1.44 (s, 9H).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16](C2CCCCO2)[N:15]=[C:14]3[C:26]2[N:31]=[C:30]([O:32][C@@H:33]3[CH2:38][CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34]3)[CH:29]=[N:28][CH:27]=2)[CH:8]=[N:7][CH:6]=1)[CH3:3].Cl>CO>[CH3:3][CH:2]([O:4][C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[C:26]2[CH:27]=[N:28][CH:29]=[C:30]([O:32][C@@H:33]3[CH2:38][CH2:37][CH2:36][NH:35][CH2:34]3)[N:31]=2)[CH:8]=[N:7][CH:6]=1)[CH3:1]
Reactant: CC(C)Oc1cncc(-c2ccc3c(c2)c(-c2cncc(O[C@@H]4CCCN(C(=O)OC(C)(C)C)C4)n2)nn3C2CCCCO2)n1
Agent: Cl
Solvent: CO
Product: CC(C)Oc1cncc(-c2ccc3[nH]nc(-c4cncc(O[C@@H]5CCCNC5)n4)c3c2)n1
Temperature: 80 °C

Procedure:
To a solution of tert-butyl (3R)-3-((6-(5-(6-(1-methylethoxy)-2-pyrazinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-2-pyrazinyl)oxy)-1-piperidinecarboxylate (0.130 g, 0.21 mmol) in MeOH (2.0 mL) was added HCl (5 M in IPA, 4.2 mL, 21.11 mmol, Acros). The mixture was heated at 80° C. for 30 min. The crude reaction was cooled to RT and concentrated to a yellow solid that was slurried with a 1/1 mixture of DCM/MeOH (2 mL) and applied to a pre-washed (5 mL MeOH) of Si-propylsulfonic acid (Silicycle, Cat# R51230B). The column was washed with MeOH (10 mL). The compound was released with 15 mL of 2 M NH3 in MeOH to afford 5-(6-(1-methylethoxy)-2-pyrazinyl)-3-(6-((3R)-3-piperidinyloxy)-2-pyrazinyl)-1H-indazole as a pink solid. MS (ESI, pos. ion) m/z: 432.2 (M+1).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([C@H:18]1[O:20][CH2:19]1)[Cl:17]>CCOCC>[Cl:17][CH2:16][C@@H:18]([OH:20])[CH2:19][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: ClC[C@@H]1CO1
Reactant: c1ccc(CNCc2ccccc2)cc1
Solvent: CCOCC
Product: O[C@H](CCl)CN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
Dibenzylamine (39.4 g, 0.20 mol) and ferric chloride (12.6 g. 0.30 mol) were added to 100 mL of ether. The mixture was stirred at 25° C. for 30 minutes, (S)-epichlorohydrin (18.6 g, 0.2 mol) was then added and stirred for at 60° C. 8 hours. Filtered and the solvent was evaporated to provide 53 g of colorless oil in 92% yield. HPLC: 99%.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:41]=[N:42][C:43]([CH3:47])=[C:44]([CH3:46])[N:45]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:41]=[N:42][C:43]([CH3:47])=[C:44]([CH3:46])[N:45]=5)=[O:57])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nnc(C)c(C)n4)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nnc(C)c(C)n4)cc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 78.1 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(5,6-dimethyl-1,2,4-triazin-3-yl)methylthio]phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.25 g) was dissolved in dichloromethane (100 ml). The solution was cooled to −78° C., and to the solution, a solution of 3-chloroperbenzoic acid (0.14 g) in dichloromethane (3 ml) was added dropwise. The mixture was stirred for 1 hour at −78° C., and to the mixture was added sodium thiosulfate solution, and the mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized from ethyl acetate-hexane, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(5,6-dimethyl-1,2,4-triazin-3-yl)methylsulfinyl]phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 37) (0.20 g) as yellow crystals.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][C:20]([F:23])([F:22])[F:21])[C:9]([CH2:24]Cl)=[CH:8]2.CN(C=O)C.[N-:31]=[N+:32]=[N-:33].[Na+]>>[N:31]([CH2:24][C:9]1[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][C:20]([F:23])([F:22])[F:21])=[N:11][C:12]2[C:7]([CH:8]=1)=[CH:6][CH:5]=[CH:4][C:3]=2[Cl:2])=[N+:32]=[N-:33]
Reactant: FC(F)(F)Oc1ccccc1-c1nc2c(Cl)cccc2cc1CCl
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1cc2cccc(Cl)c2nc1-c1ccccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring solution of 8-chloro-3-(chloromethyl)-2-(2-(trifluoromethoxy)-phenyl)quinoline hydrochloride (0.6319 g, 1.546 mmol) in DMF (7.732 mL, 1.546 mmol) was added sodium azide (0.2011 g, 3.093 mmol) at room temperature and the mixture was stirred at room temperature. After 1 h, the mixture was partitioned between EtOAc (100 mL) and H2O (100 mL). The organic layer was washed with brine (50 mL×1), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 40 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 14 min, then 50% isocratic of EtOAc for 5 min as eluent to give 3-(azidomethyl)-8-chloro-2-(2-(trifluoromethoxy)phenyl)quinoline as a colorless syrup: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.66 (1 H, s), 8.11 (1 H, dd, J=8.2, 1.2 Hz), 8.02 (1 H, dd, J=7.6, 1.4 Hz), 7.54-7.74 (5 H, m), 4.52 (2 H, br. s.); LC-MS (ESI) m/z 379.0 [M+H]+.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:7]=1[C:8]([OH:10])=[O:9].[OH-].[Na+]>O>[CH3:16][O:15][C:11]1[C:7]2[C:8](=[O:10])[O:9][C:1](=[O:2])[NH:5][C:6]=2[CH:14]=[CH:13][CH:12]=1
Reactant: COc1cccc(N)c1C(=O)O
Reactant: O=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cccc2[nH]c(=O)oc(=O)c12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 65.8 %

Procedure:
Phosgene (4.72 ml, 8.97 mmol; 20% in toluene) was added dropwise to a solution of 2-amino-6-methoxybenzoic acid (1 g, 5.98 mmol) in 2N aqueous sodium hydroxide (6.28 ml, 12.56 mmol) and water (15 ml) cooled to 0° C. over a period of 15 minutes, maintaining the temperature at 0-5° C. The resulting suspension was stirred at 0° C. for 15 minutes. The precipitate was collected by filtration, washed with water, followed by a small amount of acetonitrile and ether and dried under vacuum at 40° C. to afford 5-methoxy-1H-3,1-benzoxazine-2,4-dione (0.760 g, 65.8%) as a beige solid. 40% aqueous methylamine (1.57 ml, 18.1 mmol) was added to a stirred suspension of 5-methoxy-1H-3,1-benzoxazine-2,4-dione (700 mg, 3.62 mmol;) in water (5 ml). The resulting solution was stirred at room temperature for 36 hours. The mixture was diluted with EtOAc, washed sequentially with saturated aqueous sodium carbonate, water and brine. The organic layer was dried over MgSO4 and evaporated to afford 2-amino-6-methoxy-N-methylbenzamide (457 mg, 70.0%) as a white solid. 1H NMR spectrum (500 MHz, DMSO): 2.73 (d, 3H), 3.73 (s, 3H), 5.79 (bs, 2H), 6.19 (d, 1H), 6.30 (d, 1H), 6.99 (dd, 1H), 7.98 (q, 1H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10].C(=O)=O.C([Li])CCC.[F:28][C:29]([F:39])([F:38])[C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]Br>O1CCCC1>[F:19][C:2]([F:18])([F:1])[C:3]1[CH:4]=[C:5]([CH:6]([P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[CH2:33][C:32]2[CH:35]=[CH:36][CH:37]=[C:30]([C:29]([F:28])([F:38])[F:39])[CH:31]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: CCOP(=O)(Cc1cccc(C(F)(F)F)c1)OCC
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(Cc1cccc(C(F)(F)F)c1)c1cccc(C(F)(F)F)c1
Reaction time: 0.25 h

Procedure:
A solution of O,O-diethyl 3-trifluoromethylbenzylphosphonate (20.0 g, 67.5 mmol) in tetrahydrofuran (90 mL) was cooled to -70° C. (dry ice bath), under N2, and a solution of butyllithium (1.6M, in hexanes, 46.4 mL, 74.3 mmol) in 90 mL of dry tetrahydrofuran cooled to -70° C. (dry ice) was added. After 15 minutes, a solution of 3-trifluoromethylbenzylbromide (10.3 mL, 67.5 mmol)in tetrahydrofuran (90 mL) was added. The green reaction mixture turned yellow and was brought to room temperature and allowed to stir for 4 hours. The mixture was then quenched with H2O (200 mL), and extracted with ether (2×200 mL). The combined ether extracts were dried (MgSO4), filtered, and concentrated to dryness to give a yellow oil, 32.3 g. The crude product was chromatographed on a silica gel column. Elution with ethyl acetate/hexane (1:1) afforded analytically pure product as a pale yellow oil, 24.1 g (78.4 %). 300 MHz 1H NMR (CDCl3): δ, 3.16-4.20 (m,7H, PCH, PhCH2, 2(OCH2). MS: 455 (M+1).