Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=[O:32])[CH2:5][N:6]([CH2:17][CH2:18][CH2:19][N:20]([CH2:22][C:23]1[CH:31]=[CH:30][C:26]2[O:27][CH2:28][O:29][C:25]=2[CH:24]=1)[CH3:21])[C:7]1[S:11][N:10]=[C:9]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[N:8]=1)C.[NH3:33]>>[O:27]1[C:26]2[CH:30]=[CH:31][C:23]([CH2:22][N:20]([CH3:21])[CH2:19][CH2:18][CH2:17][N:6]([C:7]3[S:11][N:10]=[C:9]([N:12]4[CH:16]=[CH:15][N:14]=[CH:13]4)[N:8]=3)[CH2:5][C:4]([NH2:33])=[O:32])=[CH:24][C:25]=2[O:29][CH2:28]1
Reactant: CCOC(=O)CN(CCCN(C)Cc1ccc2c(c1)OCO2)c1nc(-n2ccnc2)ns1
Reactant: N
Product: CN(CCCN(CC(N)=O)c1nc(-n2ccnc2)ns1)Cc1ccc2c(c1)OCO2

Procedure:
2-[[3-(Benzo[1,3]dioxol-5-ylmethyl-methyl-amino)-propyl]-(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-amino]-acetamide was prepared following the procedures described in the preparation of Example 56 using [[3-(benzo[1,3]dioxol-5-ylmethyl-methyl-amino)-propyl]-(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-amino]-acetic acid ethyl ester and NH3. [M+H]+ 429.87; 1H NMR (400 MHz, d6-DMSO) δ 8.24 (s, 1H), 7.68 (s, 1H), 7.54 (br s, 1H), 7.18 (br s, 1H), 7.06 (s, 1H), 6.86-6.70 (m, 3H), 5.98 (s, 2H), 3.45-3.35 (m, 4H), 3.31 (s, 2H), 2.36 (m, 2H), 2.10 (s, 3H), 1.72 (m, 2H).
Reaction SMILES: [OH2:1].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([CH2:27][CH2:28][C@H:29]([OH:35])[C:30]([CH3:34])([CH3:33])[C:31]#[N:32])(C(C)(C)C)(C)C>O1CCCC1>[OH:1][CH2:27][CH2:28][C@H:29]([OH:35])[C:30]([CH3:34])([CH3:33])[C:31]#[N:32]
Reactant: CC(C)(C#N)[C@@H](O)CC[Si](C)(C)C(C)(C)C
Reactant: O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C#N)[C@@H](O)CCO
Temperature: 25 °C
Reaction time: 16 h

Procedure:
12.18 g (46.61 mmol) of tetrabutylammonium fluoride hydrate is added to a solution that consists of 3 g (11.65 mmol) of 5-tert-butyldimethylsilyl-2,2-dimethyl-3(S)hydroxy-pentane-nitrile of the title compound of Example 8b, dissolved in 40 ml of tetrahydrofuran, and it is stirred for 16 hours at room temperature. Then, it is evaporated to the dry state in a vacuum. The residue is purified by RP-18 chromatography (mobile solvent: acetonitrile/water gradient).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([CH3:11])[CH:4]=1.BrBr.[CH3:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[CH:18]=1)=O>O1CCCC1>[Br:23][C:19]1[CH:18]=[C:17]([C:15]([C:3]2[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([CH3:11])[CH:4]=2)=[CH2:14])[CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)c1cccc(Br)c1
Reactant: COc1ccc(Br)cc1C
Agent: BrBr
Agent: [Mg]
Solvent: C1CCOC1
Product: C=C(c1cccc(Br)c1)c1ccc(OC)c(C)c1
Temperature: 40 °C
Reaction time: 2 h
Yield: 55.5 %

Procedure:
Tetrahydrofuran (5 mL) was added to magnesium turnings (330 mg, 13.56 mmol) in a dried apparatus consisting of 250 mL 3-necked flask, addition funnel and reflux condenser. Then 5 mL of a solution of 4-bromo-2-methylanisole (2.5 g, 12.43 mmol) in tetrahydrofuran (15 mL) was added, followed by a drop of bromine. The exothermic reaction started instantaneously, and the 4-bromo-2-methylanisole solution was added at such a rate to maintain gentle reflux of the reaction mixture (25 min). After complete addition, the light-brown hazy Grignard solution was stirred for another 2 h at 40° C. The mixture was then cooled to 0° C. and a solution of 3-bromoacetophenone (1.42 mL, 11.3 mmol) in tetrahydrofuran (15 mL) was added dropwise over 30 min. After the addition was complete, the mixture was stirred overnight, followed by cooling in an ice bath and careful quenching with 0.5 N cold HCl. After further dilution with ethyl acetate (100 mL) and water (100 mL), the layers were separated and the aqueous layer extracted once more with ethyl acetate (50 mL). The organic layer was dried (magnesium sulfate), filtered and evaporated under reduced pressure. The residual material (tertiary alcohol) was dissolved in a mixture of acetic acid/sulfuric acid (4 mL of acetic acid, 0.12 mL of sulfuric acid) and the reaction mixture was stirred for 3 h at room temperature; then it was examined by LC-MS which showed the complete formation of desired product. The solution was quenched with ice and dichloromethane (20 mL) was added. The two phases formed and were separated. The organic layer was washed with a saturated solution of sodium bicarbonate and brine. It was then dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. Crude was purified by flash chromatography eluting with cyclohexane. 1.9 g of desired product was obtained as colorless oil (Yield: 55%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[SH:10])([O-:3])=[O:2].[C:11]([O:14][C@@H:15]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:18][S:17][C@@H:16]1Br)(=[O:13])[CH3:12]>[O-2].[Zn+2]>[C:11]([O:14][C@@H:15]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:18][S:17][C@H:16]1[S:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:13])[CH3:12]
Reactant: O=[N+]([O-])c1ccccc1S
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Agent: [O-2]
Agent: [Zn+2]
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](Sc2ccccc2[N+](=O)[O-])SC[C@H]1OC(C)=O
Yield: 58.5 %

Procedure:
If the procedure described in Preparation IV is followed starting from 6.1 g (39.3.10-3 mol) of 2-nitrobenzenethiol, 15.40 g (43.3.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide and 3.68 g (45.2.10-3 mol) of zinc oxide (ZnO), 9.87 g (yield: 58%) of the expected product are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[C:7]([C:17]#[C:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[N:6][CH:5]=1>[Pd].C(O)C>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[C:7]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[N:6][CH:5]=1
Reactant: COC(=O)c1cnc(C#Cc2ccccn2)c(-c2ccc(Cl)cc2)c1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1cnc(CCc2ccccn2)c(-c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 59 %

Procedure:
Palladium on carbon (10% w/w, 30 mg) was added to a solution of 5-(4-Chloro-phenyl)-6-pyridin-2-ylethynyl-nicotinic acid methyl ester (0.83 mmol) in ethanol (10 ml). The reaction mixture was stirred at room temperature under an atmosphere of hydrogen for 20 hours. The reaction vessel was purged with nitrogen and catalyst was removed by filtration. The reaction mixture was concentrated in vacuo to give 5-(4-Chloro-phenyl)-6-(2-pyridin-2-yl-ethyl)-nicotinic acid methyl ester (59% yield).
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[N:3]1[C:14](=[O:23])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN(C)CCN(C)C.CN1CCCC1=O.[Br:39][C:40]1[CH:47]=[CH:46][C:43]([CH:44]=[O:45])=[C:42]([F:48])[CH:41]=1>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:16]([CH:15]([CH:44]([C:43]1[CH:46]=[CH:47][C:40]([Br:39])=[CH:41][C:42]=1[F:48])[OH:45])[C:14]([N:3]1[CH:2]([CH3:1])[CH:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[O:5][C:4]1=[O:13])=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1C(=O)CCc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CN(C)CCN(C)C
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CC1C(c2ccccc2)OC(=O)N1C(=O)C(Cc1ccccc1)C(O)c1ccc(Br)cc1F
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
To a solution of (4R, 5S)-4-methyl-5-phenyl-3-(3-phenyl-propionyl)-oxazolidin-2-one (1.50 g, 4.8 mmol) in dichloromethane (23 mL) at −70° C. was added titanium tetrachloride (0.6 mL, 5.3 mmol) giving a yellow-orange solution which was stirred for 15 minutes at −70° C. N,N,N′,N′-Tetramethylethylenediamine(2.2 mL, 15 mmol) was added over 10 minutes giving a dark red reaction mixture which was stirred for 70 minutes at −78° C. 1-Methyl-2-pyrrolidinone (0.90 mL, 9.7 mmol) was added dropwise, and the reaction mixture was stirred for 30 minutes at −70° C. A solution of 4-bromo-2-fluoro-benzaldehyde (0.990 g, 4.9 mmol) in dichloromethane (5 mL) was added dropwise while maintaining a reaction temperature of less than or equal to −68° C. The reaction mixture was stirred at −70° C. for 60 minutes and then allowed to warm to 0 C. over 90 minutes, at which point it was quenched with 15 mL of saturated aqueous ammonium chloride and 1.2 g. of Celite®. This mixture was stirred overnight at room temperature and filtered. The phases were separated and the organic phase was washed three times with water and once with brine, dried over magnesium sulfate, and concentrated under vacuum to 2.76 g of an oil containing the title compound and 1.2 equivalents of 1 -methyl-2-pyrrolidinone: 1H NMR (400 MHz, CDCl3) 67 7.48 (t, J=8.1 Hz, 1 H), 7.09-7.34 (m, 1 2H), 5.35 (d, J=7.3 Hz, 1 H), 5.32 (d, J=4.9 Hz, 1 H), 4.89-4.92 (m, 1 H), 4.51-4.55 (m, 1 H), 3.65 (bs, 1 H), 3.35 (dd, J=7.1, 7.1 Hz, 2H), 3.03-3.06 (m, 2 H), 2.81 (s, 3H), 2.34 (dd, J=8.1, 8.1 Hz, 2H), 1.95-2.03 (m, 2H), 0.40 (d, J=6.6 Hz, 3 H).
Reaction SMILES: [C:1]1([CH:7]([CH3:11])[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:12][C@H:13]([C:15]([N:17]1[C:23](=[O:24])[CH:22]([CH3:25])[C:21]2[CH:26]=[CH:27][CH:28]=[CH:29][C:20]=2[C:19]2[C:30]([NH2:34])=[CH:31][CH:32]=[CH:33][C:18]1=2)=[O:16])[CH3:14]>>[C:1]1([CH:7]([CH3:11])[C:8]([NH:12][C@H:13]([C:15]([N:17]2[C:23](=[O:24])[CH:22]([CH3:25])[C:21]3[CH:26]=[CH:27][CH:28]=[CH:29][C:20]=3[C:19]3[C:30]([NH2:34])=[CH:31][CH:32]=[CH:33][C:18]2=3)=[O:16])[CH3:14])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C(=O)O)c1ccccc1
Reactant: CC1C(=O)N(C(=O)[C@H](C)N)c2cccc(N)c2-c2ccccc21
Product: CC(C(=O)N[C@@H](C)C(=O)N1C(=O)C(C)c2ccccc2-c2c(N)cccc21)c1ccccc1

Procedure:
Following General Procedure C-P above using 2-phenylpropionic acid and 5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, as described in Example 7-B, the title compound was prepared. The molecular weight as determined by mass spectrometry (FD) was: 442 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:39])([F:38])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[C@:40]12([CH2:50][S:51]([OH:54])(=[O:53])=[O:52])[C:47]([CH3:49])([CH3:48])[CH:44]([CH2:45][CH2:46]1)[CH2:43][C:41]2=[O:42]>CC(OC)(C)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:38])([F:39])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[C:40]12([CH2:50][S:51]([O-:54])(=[O:52])=[O:53])[C:47]([CH3:49])([CH3:48])[CH:44]([CH2:45][CH2:46]1)[CH2:43][C:41]2=[O:42]
Reactant: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Agent: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc(C(F)(F)F)c2)cn1
Solvent: COC(C)(C)C
Product: CC1(C)C2CCC1(CS(=O)(=O)[O-])C(=O)C2
Temperature: 5 °C
Reaction time: 8 h

Procedure:
Nilotinib base (0.300 g, 0.57 mmol) was dissolved in TFE (2 mL) at 40° C. to obtain a mixture. The mixture was stirred and added to a solution of (S)-camphor-sulfonic acid (0.132 g, 0.57 mmol) in TFE (1 mL) at 40° C. The resulting clear solution was stirred for about 4 h at 40° C. and it was subsequently cooled to 5° C. The mixture was kept at 5° C. overnight and then MTBE (1.5 v/v) was added to the mixture at room temperature leading to precipitation. The precipitate was filtered and the filter cake was dried at 40° C. in a vacuum oven overnight to give Nilotinib camphorsulfonate form I.
Reaction SMILES: [C:1]([C:3](=[CH:9][NH:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[C:4]([O:6]CC)=O)#[N:2].CO.C(Cl)Cl>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[OH:6][C:4]1[C:12]2[C:11](=[CH:16][CH:15]=[CH:14][N:13]=2)[N:10]=[CH:9][C:3]=1[C:1]#[N:2]
Reactant: CCOC(=O)C(C#N)=CNc1cccnc1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: ClCCl
Product: N#Cc1cnc2cccnc2c1O
Temperature: 260 °C
Reaction time: 5 h

Procedure:
The mixture of ethyl 2-cyano-3-(pyridin-3-ylamino)acrylate (C-3) (2.0 g, 9.26 mmol, 1.0 eq) in Dowtherm A (48 mL) is stirred at 260° C. for 5 h. The mixture is cooled to RT and poured into a mixture of MeOH and DCM (v/v=1:2, 20 mL). The precipitate is filtered, rinsed with DCM, and dried in vacuo to afford the product, 4-hydroxy-1,5-naphthyridine-3-carbonitrile (C-4).
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]([CH:20]4[C:25]5=[N:26][NH:27][C:28](=[O:33])[C:29]6[CH:30]=[CH:31][CH:32]=[C:23]([C:24]=65)[NH:22][CH:21]4[C:34]4[CH:39]=[CH:38][C:37]([CH:40](OCC)[O:41]CC)=[CH:36][CH:35]=4)[CH:17]=[CH:18][CH:19]=3)=[O:13])[CH2:8][CH2:7]2)=[O:5])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+]>Cl>[CH:1]1([C:4]([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]([CH:20]4[C:25]5=[N:26][NH:27][C:28](=[O:33])[C:29]6[CH:30]=[CH:31][CH:32]=[C:23]([C:24]=65)[NH:22][CH:21]4[C:34]4[CH:39]=[CH:38][C:37]([CH:40]=[O:41])=[CH:36][CH:35]=4)[CH:17]=[CH:18][CH:19]=3)=[O:13])[CH2:10][CH2:11]2)=[O:5])[CH2:3][CH2:2]1
Reactant: CCOC(OCC)c1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2cccc(C(=O)N3CCN(C(=O)C4CC4)CC3)c2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2cccc(C(=O)N3CCN(C(=O)C4CC4)CC3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.6 %

Procedure:
A mixture of 9-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4-(diethoxymethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (290 mg, 0.48 mmol) in 3N hydrochloric acid (10 mL) was stirred at room temperature overnight. Then the mixture was neutralized with potassium carbonate. The resulting suspension was filtered to give crude. The crude product was purified by prep-HPLC to give the 4-(9-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (20 mg, yield 8%) as a light yellow solid. 1H-NMR (400 MHz, CD3OD) δ (ppm): 0.83-0.91 (m, 4H), 1.94-2.03 (m, 1H), 3.18-3.23 (m, 1H), 3.46-3.82 (m, 7H), 4.42 (d, J=7.6 Hz, 1H), 4.87 (d, J=7.4 Hz, 1H), 7.22-7.41 (m, 7H), 7.52-7.54 (d, J=8.0 Hz, 2H), 7.60 (d, 1H), 9.94 (s, 1H); LC-MS (ESI) m/z: 548 (M+1)+.
Reaction SMILES: Cl.[H-].[Na+].[CH3:4][N:5]1[CH2:18][CH2:17][C:8]2[NH:9][C:10]3[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][C:15]=3[C:7]=2[CH2:6]1.Cl[CH2:20][C:21]([N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:22]>CCCCCC.C1COCC1>[CH3:4][N:5]1[CH2:18][CH2:17][C:8]2[N:9]([CH2:20][C:21]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])[C:10]3[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][C:15]=3[C:7]=2[CH2:6]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: O=C(CCl)N1CCCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc2c(c1)c1c(n2CC(=O)N2CCCCC2)CCN(C)C1
Reaction time: 0.5 h
Yield: 30.7 %

Procedure:
2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic acid (1.5 g, 5.8 mmol) was taken in dichloromethane (15 mL) and was cooled to 0° C. using an ice-bath; oxalyl chloride (0.61 mL, 6.9 mmol) was added drop-wise, catalytic amount (2 drop) of dimethyl formamide was added to the reaction mixture. After the addition, reaction mixture was stirred for 1 h at room temperature. Excess oxalyl chloride was distilled away under reduced pressure. To this residue, solution of Piperidine (0.68 mL, 6.9 mmol) in 4 mL DCM and DMAP (0.71 g, 5.8 mmol) was added under nitrogen at room temperature and reaction mass was stirred for 0.5 h at room temperature. The reaction mixture was quenched by ice water and extracted with Dichloromethane and purified by column chromatography to gives 0.8 g of desired compound as free base. The free base was converted into HCl salt by treatment with ethanolic HCl. Sodium hydride (0.8 g, 20 mmol) washed with hexane for removal of oil and dried under vacuum. Then sodium hydride was taken in THF. To this solution 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (2 g, 10 mmol) in THF was added drop wise at 0° C. Then reaction mixture stirred for 0.5 h. The solution of 2-chloro-1-(piperidin-1-yl)ethanone (1.9 g, 12 mmol) in THF was added drop wise in react ion mixture. Then reaction mixture stirred at RT for 2 h. Reaction monitored by TLC. After completion of reaction, reaction mixture quench with ice-water. THF was evaporated and aqueous layer was extracted with ethyl acetate. Organic layer was dried over anhydrous sodium sulphate. The crude compound was washed with hexane and diethyl ether for removal of color impurities then recrystallized by using methanol to give 1 g of desired compound then it was stirred with ethanolic HCl to give HCl salt of 2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(piperidin-1-yl)ethanone.
Reaction SMILES: [Cl-].[NH4+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C@@H:17]([OH:27])[C@@H:18]([NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH3:19])=[CH:13][C:12]=1[N+:28]([O-])=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O.C(O)C.[Zn]>[NH2:28][C:12]1[CH:13]=[C:14]([C@@H:17]([OH:27])[C@@H:18]([NH:20][C:21](=[O:26])[C:22]([F:23])([F:24])[F:25])[CH3:19])[CH:15]=[CH:16][C:11]=1[O:10][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C[C@H](NC(=O)C(F)(F)F)[C@H](O)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: C[C@H](NC(=O)C(F)(F)F)[C@H](O)c1ccc(OCc2ccccc2)c(N)c1
Temperature: 70 °C
Yield: 91.8 %

Procedure:
A solution of ammonium chloride (29 g) in water (133 mL) was added to a solution of N-[(1S,2R)-2-(4-benzyloxy-3-nitrophenyl)-2-hydroxy-1-methylethyl]-2,2,2-trifluoroacetamide (73 g) in ethanol (487 mL) at room temperature with stirring. The mixture was cooled with an ice, and then zinc powder (95 g) was added to the mixture with stirring over 10 minutes. The gray suspension was heated up to 70° C. over 15 minutes, and stirred at that temperature for 1 hr. The insoluble materials were removed by filtration, and the filtrate was concentrated in vacuo. Ethyl acetate and water were added to the residue, and the insoluble materials were removed by filtration again. The organic layer in the filtrate was separated, washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford the title compound (62 g).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][C:4](=O)[C:3]1([CH3:10])[CH3:9].Cl.[NH2:12][OH:13].C(=O)([O-])[O-].[Na+].[Na+]>CCO.O>[OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][C:4](=[N:12][OH:13])[C:3]1([CH3:10])[CH3:9]
Reactant: NO
Reactant: CC1(C)C(=O)CCCC1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1(C)C(=NO)CCCC1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 101.8 %

Procedure:
A mixture of 3-hydroxy-2,2-dimethylcyclohexanone (1.6 g, crude), hydroxylamine hydrochloride (2.98 g, 42.9 mmol) and sodium carbonate (4.54 g, 42.9 mmol) in EtOH (30 mL) and water (3 mL) was stirred at 25° C. for 6 h. After removal of EtOH, the residue was extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to afford the title compound (1.8 g, crude). MS (ESI) m/z 158.2 [M+H]+.
Reaction SMILES: O.[C:2]1([CH3:19])[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.C[O:22][C:23](=[O:30])[C@H:24]([C@H:26]([CH2:28][CH3:29])[CH3:27])[NH2:25].[Li+].[OH-]>C1COCC1.O>[C:2]1([CH3:19])[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([NH:25][C@H:24]([C:23]([OH:30])=[O:22])[C@H:26]([CH2:28][CH3:29])[CH3:27])=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CC[C@H](C)[C@H](N)C(=O)OC
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC[C@H](C)[C@H](NC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccc(C)cc1)C(=O)O

Procedure:
N-(Toluene-4-sulfonyl)-L-proline hydrate was coupled to L-isoleucine methyl ester hydrochloride using the procedure described in Method 3. The title compound was prepared via hydrolysis of the methyl ester using LiOH in THF/water.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][C:13](=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:21]>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH3:21])[C:13](=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(C(=O)OCc2ccccc2)CC1=O
Yield: 79.6 %

Procedure:
Dissolve 4-benzyloxycarbonylpiperazin-2-one (2 g, 8.6 mmol) in THF (10 mL). Add sodium hydride (236 mg, 9.4 mmol, 60% dispersion in mineral oil) in one portion and stir at room temperature for 30 min. Add iodomethane (0.8 mL, 13 mmol) and stir at room temperature overnight. Concentrate, add ethyl acetate and wash with water. Separate organic layer, wash with saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with ethyl acetate) to give the title compound as a yellow oil (1.7 g, 82%).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH:5]=[C:6]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[C:16]([C:17]3[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:20]=[C:19]([CH:26]([CH3:28])[CH3:27])[C:18]=3[O:29][CH2:30][CH3:31])[C:10]=2[CH:9]=1)[CH3:7])C.C1COCC1.[Li+].[OH-]>CO>[CH2:30]([O:29][C:18]1[C:19]([CH:26]([CH3:28])[CH3:27])=[CH:20][C:21]([CH:23]([CH3:24])[CH3:25])=[CH:22][C:17]=1[C:16]1[C:10]2[CH:9]=[C:8]([C:6]([CH3:7])=[CH:5][C:4]([OH:32])=[O:3])[S:12][C:11]=2[CH:13]=[CH:14][CH:15]=1)[CH3:31]
Reactant: CCOC(=O)C=C(C)c1cc2c(-c3cc(C(C)C)cc(C(C)C)c3OCC)cccc2s1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1c(-c2cccc3sc(C(C)=CC(=O)O)cc23)cc(C(C)C)cc1C(C)C
Temperature: 25 °C

Procedure:
A mixture of 0.450 mmol of 3-[4-(2-ethoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-enoic acid ethyl ester, 3 mL of THF, 3 mL of methanol and 1 mL of LiOH (2N aqueous) was refluxed for 2 hours. After cooling at room temperature, the mixture was acidified to pH=2 and extracted with ethyl acetate. The organic layer was dried over MgSO4 and after evaporation of the solvents, the crude acid was recrystallized from acetonitrile. 3-[4-(2-Ethoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-but-2-enoic acid was isolated as a white solid. 1H NMR (CDCl3), δ: 7.77 (dd, J=5.9, 3.6 Hz, 1H), 7.51 (s, 1H), 7.43 (m, 2H), 7.17 (d, J=2.2 Hz, 1H), 7.05 (d, J=2.3 Hz, 1H), 6.32 (s, 1H), 3.43 (dt, J=13.8, 6.9 Hz, 1H), 3.33 (m, 2H), 2.93 (dt, J=13.7, 6.9 Hz, 1H), 2.61 (s, 3H),1.29 (m, 12H), 0.85 (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][C:18]=3[S:24]([CH3:27])(=[O:26])=[O:25])=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:28][C@@H:29]1[CH2:33][CH2:32][S:31](=[O:35])(=[O:34])[NH:30]1>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:30]4[C@H:29]([CH3:28])[CH2:33][CH2:32][S:31]4(=[O:35])=[O:34])=[CH:19][C:18]=3[S:24]([CH3:27])(=[O:26])=[O:25])=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3S(C)(=O)=O)CC2)c(C)c1
Reactant: C[C@@H]1CCS(=O)(=O)N1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4[C@H](C)CCS4(=O)=O)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 57.3 %

Procedure:
Using [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](4-iodo-2-methanesulfonylphenyl)methanone (580 mg) described in Preparation Example 156 and (R)-3-methylisothiazolidine 1,1-dioxide (157 mg) described in Preparation Example 2 and by the reaction and treatment in the same manner as in Example 1, the title compound (337 mg) was obtained.