Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[OH:11][CH2:12][C:13](=O)[CH3:14]>[Pd].CO>[OH:11][CH2:12][CH:13]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([F:10])=[C:8]([F:9])[C:2]=1[F:1])[CH3:14]
Reactant: CC(=O)CO
Reactant: Nc1ccc(F)c(F)c1F
Agent: [Pd]
Solvent: CO
Product: CC(CO)Nc1ccc(F)c(F)c1F
Reaction time: 1 h

Procedure:
2,3,4-Trifluoroaniline was reductively alkylated in the presence of hydroxyacetone using a palladium on carbon catalyst. 30 g of a 5% Pd/C catalyst (57.3% H2 0)) was slurried in 200 ml of absolute methanol. The mixture was allowed to settle and 90-95% of the liquid was decanted. The process was then repeated three times. 2,3,4-trifluoroaniline (118 g, 0.8 mole) of was charged into a glass autoclave liner containing the catalyst. Hydroxyacetone (80 g, 1.08 mole) was then added and the mixture was purged with nitrogen. Hydrogenation was initiated at 65° C. and continued to a maximum temperature of 107° C. Hydrogen uptake continued for one hour at a pressure of between 430 and 450 psi at which time 75% of the alkylated product (3) was obtained with the remainder being unreacted 2,3,4-trifluoroaniline and hydroxyacetone.
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[N:22]=[C:21]2[C:29]([F:32])([F:31])[F:30])=[CH:13][CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].[OH-].[Na+]>CCO.O>[CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[N:22]=[C:21]2[C:29]([F:30])([F:31])[F:32])=[CH:15][CH:16]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(OCCn2c(C(F)(F)F)nc3ccccc32)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(Cc1ccc(OCCn2c(C(F)(F)F)nc3ccccc32)cc1)C(=O)O
Yield: 79.1 %

Procedure:
To a stirred solution of ethyl 2-ethoxy-3-(4-{2-[2-(trifluoromethyl)-1H-benzimidazol-1-yl]ethoxy}phenyl)propanoate (238.5 mg, 0.5 mmol) in EtOH (5 ml) was added NaOH (2 ml, 2M aq. Solution, 2 mmol) in water (2 ml) at 0° C. at once. The reaction mixture was stirred at RT until all the ester disappeared (TLC). EtOH was removed in vacuo and the residue was dissolved in water. The solution was acidified to pH4 using 3N HCl and the precipitated acid was extracted with EtOAc to give the product as white solid (167 mg, 77.3%).
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:10]2)=[CH:6][CH:5]=1)([O-])=O.C(OCC)(=O)C>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:10]2)=[CH:24][CH:25]=1
Reactant: CCOC(=O)Cc1nn(Cc2ccc([N+](=O)[O-])cc2)c2ccccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)Cc1nn(Cc2ccc(N)cc2)c2ccccc12

Procedure:
Ethyl 2-[1-(4-nitrobenzyl)-1H-indazol-3-yl]acetate (340 mg, 1.0 mmol) was dissolved in methanol (20 mL). 10% Pd/C(20 mg) was added, and reacted under hydrogen atmosphere for half an hour. TLC (petroleum ether:ethyl acetate=2:1) indicated that starting material disappeared. It was filtered to remove solid, rotate evaporated to dryness to remove the solvent, and the resulting solid was used for the next step directly.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH:20]=[C:19]([O:21][CH2:22][C@@H:23]([NH:25][C:26](=O)[O:27]C(C)(C)C)[CH3:24])[CH:18]=[CH:17][C:15]=4[N:16]=3)=[CH:8][C:7]=2[F:33])[CH2:3][CH2:2]1.C[Si]([N:38]=C=O)(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH:20]=[C:19]([O:21][CH2:22][C@@H:23]([NH:25][C:26]([NH2:38])=[O:27])[CH3:24])[CH:18]=[CH:17][C:15]=4[N:16]=3)=[CH:8][C:7]=2[F:33])[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)N=C=O
Reactant: C[C@@H](COc1ccc2nc(-c3ccc(OCC4CC4)c(F)c3)oc2c1)NC(=O)OC(C)(C)C
Product: C[C@@H](COc1ccc2nc(-c3ccc(OCC4CC4)c(F)c3)oc2c1)NC(N)=O

Procedure:
Using tert-butyl ((2S)-1-((2-(4-(cyclopropylmethoxy)-3-fluorophenyl)-1,3-benzoxazol-6-yl)oxy)propan-2-yl)carbamate and trimethylsilyl isocyanate, and in the same manner as in Example 10, the title compound was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:27][O:28][CH2:29]Cl>CN(C)C=O.ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:27][O:28][CH3:29])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1
Reactant: COCCl
Reactant: N#Cc1cc(O)cc(-c2nc(-c3ccccn3)no2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCOc1cc(C#N)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 70 °C
Yield: 54 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (30 mg, 0.11 mmol), potassium carbonate (31 mg, 0.23 mmol) and chloromethyl methyl ether (26 μL, 0.34 mmol) in N,N-dimethylformamide (1 mL) was heated in a sealed vial at 70° C. for 2 hour. The reaction was cooled, diluted with dichloromethane, washed with water (3×) and saturated brine, filtered and concentrated. Silica gel chromatography using 20–30% hexanes/ethyl acetate afforded 1 g mg (54%) of 3-(2-Pyridyl)-5-(3-cyano-5-(methoxymethoxy)phenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3), δ (ppm): 8.86 (d, 1H), 8.24 (d, 1H), 8.22 (s, 1H), 8.15 (s, 1H), 7.91 (t, 1H), 7.56 (s, 1H), 7.49 (m, 1H), 5.31 (s, 2H), 3.52 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:12]2[Br:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:25][CH2:26][CH2:27][O:28][C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:25][CH2:26][CH2:27][O:28][C:29]1[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=[CH:31][CH:30]=1)[C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:12]2[Br:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCCCOc1cccc2ccccc12
Reactant: CCOC(=O)c1[nH]c2ccc(OCc3ccccc3)cc2c1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Br)c2cc(OCc3ccccc3)ccc2n1CCCOc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 135A (500 mg) and 1-(3-bromopropoxy)naphthalene (354 mg) in N,N-dimethylformamide (10 ml) was added Cs2CO3 (871 mg). The reaction was stirred at room temperature overnight, diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography, eluting with 0%-50% dichloromethane in hexane, to provide the desired product.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][CH:18]=[O:19])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[H-].[Na+].[CH3:22]N(C)C=O>>[CH3:22][N:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2]([CH3:1])=[N:3][N:4]=3)[N:7]=2)[CH:12]=1)[CH:18]=[O:19]
Reactant: Cc1nnc2ccc(-c3cccc(NC=O)c3)nn12
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: Cc1nnc2ccc(-c3cccc(N(C)C=O)c3)nn12

Procedure:
A mixture of 2.5 g of N-[3-(3-methyl-1,2,4-triazolo-[4,3-b]-pyridazin-6-yl)phenyl]formamide, 0.56 g of sodium hydride (50% in oil) and 250 ml of dimethylformamide were reacted as described in example 2, giving 1.72 g of the desired product as a white powder, mp 207°-210° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[N:2]1.[Cl:9][C:10]1[CH:11]=[C:12]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]1[CH:17]([NH2:23])[CH2:16][CH2:15][CH2:14][C:13]2=1>>[Cl:9][C:10]1[CH:11]=[C:12]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]1[CH:17]([NH:23][C:6]([C:3]3[CH:4]=[CH:5][NH:1][N:2]=3)=[O:8])[CH2:16][CH2:15][CH2:14][C:13]2=1
Reactant: NC1CCCc2c1[nH]c1ccc(Cl)cc21
Reactant: O=C(O)c1cc[nH]n1
Product: O=C(NC1CCCc2c1[nH]c1ccc(Cl)cc21)c1cc[nH]n1

Procedure:
N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-1H-pyrazole-3-carboxamide was prepared from 1H-pyrazole-3-carboxylic acid and 6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-amine in a similar manner as described above to give a white solid (16% yield). 1H-NMR (CD3OD-d4): δ 7.70 (d, 1H), 7.37 (d, 1H), 7.22 (d, 1H), 6.99 (dd, 1H), 6.81 (d, 1H), 5.37 (m, 1H), 2.70 (m, 2H), 2.19 (m, 1H), 2.00 (m, 3H); MS m/z 313 (M−1).
Reaction SMILES: [CH2:1]1[C:4]2([CH2:7][NH:6][CH2:5]2)[CH2:3][N:2]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Br[C:16]1[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[N:20][CH:21]=1.CS(C)=O>O>[C:11]([O:10][C:8]([N:2]1[CH2:3][C:4]2([CH2:7][N:6]([C:16]3[CH:21]=[N:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)[CH2:5]2)[CH2:1]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CC2(CNC2)C1
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC2(C1)CN(c1ccc([N+](=O)[O-])nc1)C2
Temperature: 90 °C
Reaction time: 40 h

Procedure:
In a 25 mL pear-shaped flask, tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (2.81 g, 14.2 mmol), 5-bromo-2-nitropyridine (2.88 g, 14.2 mmol), and TEA (1.58 g, 2.17 ml, 15.6 mmol) were combined with DMSO (12 ml) to give a light yellow solution. The reaction mixture was heated to 90° C. and stirred for 40 h. Cooled to 25° C. and the reaction mixture was diluted with 50 mL H2O and extracted with EtOAc (3×50 mL). The organic layers were combined, washed with sat NaCl (1×50 mL), dried over Na2SO4 and concentrated in vacuo. The purple oil was used crude in the subsequent reduction. (M+H)+=321 m/e.
Reaction SMILES: C([C@@H]1[O:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)(O)[C@@:7]([CH2:20][CH3:21])([CH3:19])[O:6]1)(C)(C)C.[OH2:22].C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH2:34]>>[OH:6][C@:7]([CH3:19])([CH2:20][CH3:21])[C:8]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:18])(=[O:34])=[O:22])=[CH:13][CH:12]=1)=[O:9]
Reactant: CC[C@]1(C)O[C@H](C(C)(C)C)OC1(O)c1ccc(SC)cc1
Reactant: O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC[C@@](C)(O)C(=O)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of the dioxolanol from Step 3 (46.2 g) in water (50 mL) with p-toluenesulfonic acid mono hydrate (1.3 g) was refluxed for 1 hour. The reaction was allowed to cool to r.t. and extract twice with EtOAc (200+150 mL). To this solution was added t-BuOH (175 mL) and Aliquat® 336. This solution was cooled to 10° C. and then a solution of OXONE® (130 g) in water (800 mL) was added over 30 min. The resulting mixture was stirred at r.t. for 20 h. The reaction mixture was neutralized by carefull and portionwise addition of aqueous saturated NaHCO3 and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give a yellow syrup. 1H NMR(CD3COCD3): δ0.90 (3H, t), 1.49 (3H, s), 1.81 (1 H, m), 1.95 (1H, s, OH), 1.99 (1H, m), 3.17 (3H, s), 8.02 (2H, d), 8.32 (2H, d).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[NH2:11].C(N(CC)CC)C.[Cl:19][CH2:20][CH2:21][N:22]=[C:23]=[O:24]>C(Cl)Cl>[Cl:19][CH2:20][CH2:21][NH:22][C:23]([NH:11][CH:6]1[C:7]2[C:3](=[C:2]([F:1])[CH:10]=[CH:9][CH:8]=2)[CH2:4][CH2:5]1)=[O:24]
Reactant: NC1CCc2c(F)cccc21
Reactant: O=C=NCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCl)NC1CCc2c(F)cccc21
Reaction time: 3 h
Yield: 33.9 %

Procedure:
To a stirred, cold (0° C.) solution of 7.0 grams (0.046 mole) of 4-fluoroindanylamine (known compound) and 5.7 grams (0.056 mole) of triethylamine in 100 mL of methylene chloride was added 5.4 grams (0.051 mole) of 2-chloroethyl isocyanate. The cold reaction mixture was stirred for three hours at which time it was filtered. The filter cake was rinsed with methylene chloride. The filtrates were combined and concentrated under reduced pressure to a residue. The residue was triturated with hexanes and the mixture filtered. The filter cake was dried under reduced pressure to yield 4.0 grams of [(2-chloroethyl)amino]-N-(4-fluoroindanyl)carboxamide. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:36])[C@H:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:22][C:21]=1[Cl:35])[CH2:16][CH:17]=C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C[O:40]CC1.C(O)(C)(C)C.I([O-])(=O)(=O)=O.[Na+]>[Os](=O)(=O)(=O)=O.O>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:36])[C@H:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:22][C:21]=1[Cl:35])[CH2:16][CH:17]=[O:40])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: C=CC[C@@H](Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Product: O=CC[C@@H](Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Yield: 48 %

Procedure:
Treat a mixture of (R)-4-benzyl-3-[(S)-2-(4-benzyloxy-2,6-dichloro-benzyl)-pent-4-enoyl]-oxazolidin-2-one (0.96 g, 1.8 mmol), THF (21 mL) and water (7 mL) with 2.5% osmium tetroxide in t-butanol (46 mg, 0.18 mmol). Add sodium periodate (1.17 g, 5.5 mmol) and stir the reaction 4 hr at room temperature. Quench the reaction with water and extract with ethyl acetate. Wash the organic phase with aqueous 1N sodium thiosulfate then brine. Dry the organic layer over magnesium sulfate, filter, and concentrate under vacuum. Purify the crude material by silica gel chromatography using hexanes:ethyl acetate to elute the pure product. Concentrate the fractions containing product under vacuum to afford 0.46 g (48%) of desired product. MS (m/z): 526 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[C:13](O)=[O:14])=[CH:5][CH:4]=1.B.C1COCC1>C1COCC1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][OH:14])=[CH:5][CH:4]=1
Reactant: COc1ccc2cccc(C(=O)O)c2c1
Agent: B
Solvent: C1CCOC1
Product: COc1ccc2cccc(CO)c2c1
Temperature: -2 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
To 1 equivalent of 7-methoxy-1-naphthoic acid (100 g) in THF (3.8 ml/g) there are slowly added 2.5 equivalents of 1M BH3-THF (1.235 liters). During the addition, the temperature of the reaction mixture is maintained at 5° C. (+/−2° C.) and then the mixture is left at ambient temperature for 3 hours. After evaporation under reduced pressure, the residue is taken up in dichloromethane and washed with water. The organic phase is dried over MgSO4 and then the solvents are evaporated off under reduced pressure to yield the title compound in the form of a light-brown solid in a yield of 91%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH3:27])[C:8]2[O:14][C:13]3[C:15]([Cl:23])=[CH:16][C:17]([NH:19][CH2:20][CH2:21][Cl:22])=[CH:18][C:12]=3[CH2:11][S:10](=[O:25])(=[O:24])[C:9]=2[CH:26]=1)=[O:4].[Cl:28][CH2:29][C:30](Cl)=[O:31]>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH3:27])[C:8]2[O:14][C:13]3[C:15]([Cl:23])=[CH:16][C:17]([N:19]([C:30](=[O:31])[CH2:29][Cl:28])[CH2:20][CH2:21][Cl:22])=[CH:18][C:12]=3[CH2:11][S:10](=[O:24])(=[O:25])[C:9]=2[CH:26]=1)=[O:4]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCCl)cc(Cl)c1O2
Reactant: O=C(Cl)CCl
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N(CCCl)C(=O)CCl)cc(Cl)c1O2
Temperature: 90 °C
Reaction time: 1 h

Procedure:
4-Chloro-2-(2-chloro-ethylamino)-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]-cycloheptene-8-carboxylic acid methyl ester (prepared by following the method described in example 29a or example 29b, 1.9 gm, 4.4 mmol) was added to chloroacetyl chloride (6 mL) at room temperature. Reaction mixture was then stirred at 90° C. for 1 h. Reaction mixture was cooled and diluted using ice water (100 mL). The solid separated was filtered, washed with water and dried to obtain the title compound. Yield: 1.85 g, (83%); 1H NMR (DMSO-d6, 300 MHz): δ 2.60 (s, 3H, CH3), 3.67 (t, 2H, CH2), 3.88 (s, 3H, OCH3), 3.99 (t, 2H, CH2), 4.27 (bs, 2H, CH2), 5.31 (s, 2H, CH2), 7.66 (s, 1H, Ar), 7.80 (s, 1H, Ar), 8.17 (s, 1H, Ar), 8.19 (s, 1H, Ar); MS: m/e (ES+) 505 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH3:12])[N:6]=[CH:7]2.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH2:21][N:22]=[C:23]=[O:24]>C1(C)C=CC=CC=1>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH2:21][NH:22][C:23]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH3:12])[N:6]=[CH:7]2)=[O:24]
Reactant: O=C=NCc1ccc(Cl)cc1Cl
Reactant: Cc1cc2c(N)cccc2cn1
Solvent: Cc1ccccc1
Product: Cc1cc2c(NC(=O)NCc3ccc(Cl)cc3Cl)cccc2cn1
Temperature: 25 °C

Procedure:
5-Amino-3-methylisoquinoline (390 mg, 2.47 mmol) and the product from Example 195A (0.36 mL, 2.47 mmol) were heated in toluene (10 mL) at 80° for 2.5 hours. Upon cooling to room temperature, a precipitate formed, which was collected by filtration, washed with toluene, and air-dried. Remaining impurities were removed by slurrying the solid in 9:1 CH2Cl2:CH3OH and then filtering the mixture to provide the title compound. The corresponding hydrochloride salt was formed by treatment of the free base with methanolic HCl. 1H NMR (300 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.78 (s, 1H), 8.21 (dd, 1H, J=7.4 Hz, 1.0 Hz), 7.77 (s, 1H), 7.70 (d, 1H, J=8.1 Hz), 7.64 (m, 1H), 7.44-7.52 (m, 3H), 7.14 (t, 1H, J=6.1 Hz), 4.38 (d, 2H, J=6.0 Hz), 2.65 (s, 3H); MS (ESI+) m/z 360/362 (M+H, 35Cl/37Cl).
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:8])[CH2:6][OH:7])[CH2:2][CH3:3].[H-].[Na+].Cl[CH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[N:13]1[C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[N:25][C:26]([Cl:32])=[CH:27][CH:28]=2)[N:23]=1>O1CCCC1>[Cl:32][C:26]1[N:25]=[C:24]2[C:29]([CH:30]=[CH:31][C:22]([N:13]3[C:14](=[O:21])[C:15]4[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:12]3[O:7][CH2:6][C:5]([NH:4][CH2:1][CH2:2][CH3:3])=[O:8])=[N:23]2)=[CH:28][CH:27]=1
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Reactant: CCCNC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCNC(=O)COC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Yield: 56.3 %

Procedure:
The procedure is as in Example 22, but starting with N-propylglycolamide (9.4 g) in tetrahydrofuran (375 cc), an oily suspension (50% by weight; 3.3 g) of sodium hydride and 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (15 g). After recrystallization in acetonitrile, [2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1isoindolinyloxy]-N-propylacetamide (10.5 g), m.p. 167° C., is obtained.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:23])=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14]2)C1C=CC=CC=1.C([O-])=O.[NH4+]>[C].[Pd].C(O)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:23])=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14]2
Reactant: CCOC(=O)c1cc2c(C)ccc(OCc3ccccc3)c2[nH]1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)c1cc2c(C)ccc(O)c2[nH]1
Temperature: 25 °C
Yield: 6.5 %

Procedure:
A mixture of ethyl 7-benzyloxy-4-methyl-1H-indole-2-carboxylate (15.0 g, 485 mmol), ammonium formate (30.6 g, 485 mmol), 10% palladium-carbon (2.00 g) and ethanol (450 ml) was heated under reflux for 0.5 hour. The reaction mixture was cooled to room temperature, after which the insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was crystallized from ethyl acetate/toluene to obtain ethyl 7-hydroxy-4-methyl-1H- indole-2-carboxylate (6.96 g). M.p. 211°-212° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C1COCC1>[CH3:22][S:23]([O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)(=[O:25])=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 41.8 %

Procedure:
To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (5.0 g, 36 mmol) and triethyl amine (6.0 ml, 43 mmol) in 50 ml of THF at 0° C. under an atmosphere of nitrogen was added MsCl (3.4 ml, 43 mmol). The mixture was stirred at 0° C. for 3 h and quenched with aqueous sodium hydrogen carbonate (saturated, 100 mL). The mixture was extracted with ethyl acetate (3×100 mL). The combined organic fractions were washed with brine (1×100 mL), dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel Biotage 40M, eluting with EtOAc/isohexane to hexanes to afford the title compound as a colorless solid (4.2 g, 42%). 1H-NMR (500 MHz, CDCl3) δ 4.90 (s, 1H), 3.70 (m, 2H), 3.30 (m, 2H), 3.05 (s, 3H), 1.95 (m, 2H), 1.82 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]1([CH3:14])[CH2:13][O:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)C>O>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH2:14][C:11]([OH:12])([CH3:13])[CH2:10][CH2:9][O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:32][CH:33]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(O)cc2)CC1
Reactant: CC1(CCOCc2ccccc2)CO1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(O)(CCOCc1ccccc1)COc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
2-[2-(Benzyloxy)ethyl]-2-methyloxirane (2.60 g, 13.5 mmol), 4-(4-hydroxyphenyl)piperazine-1-carboxylic acid tert-butyl ester (4.14 g, 14.9 mmol), tripotassium phosphate (1.15 g, 5.4 mmol) and ethanol (26 ml) were mixed and stirred at 80 to 90° C. overnight. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→30:70) to afford the title compound as a pale yellow oil (6.16 g).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([NH:22][S@@:23]([C:25]([CH3:28])([CH3:27])[CH3:26])=[O:24])([CH2:12]/[C:13](=N/N(C)C)/[C:14]([F:17])([F:16])[F:15])[CH2:10][F:11].Cl.C1C[O:33]CC1>>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([NH:22][S@@:23]([C:25]([CH3:28])([CH3:27])[CH3:26])=[O:24])([CH2:12][C:13](=[O:33])[C:14]([F:17])([F:16])[F:15])[CH2:10][F:11]
Reactant: CN(C)/N=C(/CC(CF)(N[S@](=O)C(C)(C)C)c1cccc(F)c1F)C(F)(F)F
Reactant: C1CCOC1
Agent: Cl
Product: CC(C)(C)[S@@](=O)NC(CF)(CC(=O)C(F)(F)F)c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 26 h

Procedure:
A solution of (R)-N-((Z)-2-(2,3-difluorophenyl)-4-(2,2-dimethylhydrazono)-1,5,5,5-tetrafluoropentan-2-yl)-2-methylpropane-2-sulfinamide (9.0 g, 20.86 mmol) in THF (10 mL) was treated with hydrogen chloride, 2M aq. solution (10.43 mL, 20.86 mmol). The mixture was stirred at ambient temperature for 26 h. LCMS detected formation of desired product and trace of starting material. The reaction was quenched with saturated NaHCO3 solution and then extracted with EtOAc (2×). The organic extracts were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated and purified by silica gel column (0-50% EtOAc/hexane) to afford 5.0 g of (R)-N-(2-(2,3-difluorophenyl)-1,5,5,5-tetrafluoro-4-oxopentan-2-yl)-2-methylpropane-2-sulfinamide as light yellow solid (91% purity). MS m/z=408.0 [M+H+H2O]+. Calculated for C15H17F6NO2S: 389.4