Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].C(=O)=O.CC(C)=O.[H-].[Na+].[CH3:21][N:22]([CH2:29][CH2:30][O:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1>O1CCCC1>[CH3:21][N:22]([CH2:29][CH2:30][O:31][C:32]1[CH:33]=[CH:34][C:35](/[CH:36]=[CH:5]/[C:3]([O:2][CH3:1])=[O:4])=[CH:38][CH:39]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: CN(CCOc1ccc(C=O)cc1)c1ccccn1
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: COC(=O)/C=C/c1ccc(OCCN(C)c2ccccn2)cc1
Reaction time: 0.17 h

Procedure:
A solution of trimethyl phosphonoacetate (5.5 mL) in dry tetrahydrofuran (25 mL) was added slowly to a cooled (cardice-acetone bath) suspension of sodium hydride (60% dispersion in oil, 1.34 g) in tetrahydrofuran (100 mL) under a nitrogen atmosphere such that the temperature of the reaction mixture remained between 0° C. and 10° C. during the addition. The resultant slurry was then cooled in an ice bath and stirred for 10 minutes prior to the addition of a solution of 4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzaldehyde (8.3 g) (Eur. Patent. Appl., Publication No. 0306228) in tetrahydrofuran (100 mL). The mixture was stirred at room temperature for 20 hrs, then quenched with brine (10 mL) and concentrated in vacuo. The residue was suspended in brine (500 mL) and extracted with dichloromethane (3×300 mL), and the combined organic layers washed with water (1 L) and brine (1 L), dried (MgSO4) and evaporated. The residue was chromatographed on silica gel with 1% methanol in dichloromethane as eluent to afford the title compound, mp 93°-5° C. (dichloromethane-hexane).
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:44]([CH2:45][CH2:46][CH3:47])[N:43]=[N:42][CH:41]=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+]>C(Cl)Cl>[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:44]([CH2:45][CH2:46][CH3:47])[N:43]=[N:42][CH:41]=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: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cnnn4CCC)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cnnn4CCC)cc2)CCN3CC(C)C)cc1
Reaction time: 0.25 h
Yield: 63.3 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-propyl-1,2,3-triazol-5-yl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.54 g) was dissolved in methylene chloride (16.2 ml), and a solution of m-chloroperbenzoic acid (209 mg) in methylene chloride (10.8 ml) was added dropwise to the solution at −78° C. The mixture was stirred for 15 minutes, and an aqueous solution of saturated sodium thiosulfate was added to the mixture. The mixture was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-propyl-1,2,3-triazol-5-yl)methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 278) (0.35 g).
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]1[CH:16]=[N:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[N:8]=1.C(O)(C(F)(F)F)=O>ClCCl>[CH3:18][O:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH2:6])[CH:16]=[N:15]2
Reactant: COc1ccc(CNc2cnc3cc(OC)ccc3n2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2nc(N)cnc2c1
Yield: 99.4 %

Procedure:
N-(2,4-Dimethoxybenzyl)-6-methoxyquinoxalin-2-amine (2.8 g, 8.61 mmol) was stirred in TFA (10 mL, 130 mmol) and dichloromethane (10 mL) at ambient temperature for 30 min. The solvents were removed in vacuo. Saturated aq. sodium hydrogen carbonate (200 mL) was added to the red residue, which then precipitated a yellow solid. The mixture was extracted extensively with dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford 6-methoxyquinoxalin-2-amine (1.50 g, 8.56 mmol, 99% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.27 (1H, s), 7.54-7.58 (1H, m), 7.25-7.29 (2H, m), 4.71 (2H, br. s.), 3.90 (3H, s). MS (LC/MS) R.T.=0.86; [M+H]+=176.23.
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=1[N+:16]([O-])=O)[CH:2]([CH3:4])[CH3:3].[H][H]>[Pd].CO>[CH2:1]([O:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[NH2:16])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)COC(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)COC(=O)c1ccc(N)cc1N
Yield: 81.6 %

Procedure:
A 500 ml Parr Shaker was charged with 80.0 g of isobutyl-2,4-dinitrobenzoate, 200 ml methanol, and 3.0 g of a 5% palladium on carbon/50% water catalyst. The mixture was hydrogenated at 50 psi hydrogen pressure while maintaining the temperature below 50° C. Hydrogen uptake cease after 4 hrs. The mixture was cooled, filtered and the methanol removed under reduced pressure. The remaining solid was washed with toluene, filtered and dried to give 50.7 g of isobutyl-2,4-diaminobenzoate, a light tan solid, mp 89° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=2[N+:17]([O-])=O)[CH2:3][CH2:2]1>C1COCC1.CO.[Pd]>[NH2:17][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:8]=1[NH:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)[C:12]([OH:14])=[O:13]
Reactant: O=C(O)c1ccc(NC2CCOCC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cc(C(=O)O)ccc1NC1CCOCC1
Reaction time: 3 h
Yield: 100.2 %

Procedure:
4-((Tetrahydropyran-4-yl)amino)-3-nitrobenzoic acid (see Working Example 4-1) (202 g, 0.76 mol) was dissolved in a solvent mixture of THF (2.2 L) and methanol (1.5 L), Pd/C (5%, wet, 20 g) was added, and hydrogenation was carried out under 5 atm. Hydrogen absorption stopped at 3 h, and after the system was purged with argon the catalyst was removed by filtration, and the filtrate was concentrated at reduced pressure to yield the title compound (180 g, quant.) as a dark gray solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[CH:5]=[C:4]([N:11]([CH3:13])[CH3:12])[N:3]=1.[Br:14]Br.[OH-].[Na+]>C(O)(=O)C.O>[Br:14][C:5]1[C:6]([CH3:10])=[C:7]([C:8]#[N:9])[C:2]([Cl:1])=[N:3][C:4]=1[N:11]([CH3:12])[CH3:13]
Reactant: BrBr
Reactant: Cc1cc(N(C)C)nc(Cl)c1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(Br)c(N(C)C)nc(Cl)c1C#N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98.9 %

Procedure:
To a suspension of 2-chloro-3-cyano-6-(N,N-dimethylamino)-4-methylpyridine (0.98 g) in acetic acid (10 mL) was added bromine (0.9 g) in acetic acid (1 mL). The reaction mixture was stirred at room temperature for 20 minutes and then warmed to 60° C. for 5 minutes. After cooling to room temperature the mixture was poured into a solution of sodium hydroxide (8 g) in water (100 mL). The mixture was extracted with chloroform (3×30 mL). The combined organic phase was washed, dried, and evaporated to give 1.36 g of the title compound, suitable for use in the next reaction.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH3:14].[C:15]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[C:16]1([C:15](=[N:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:11])([F:12])[F:13])[C:3]=2[CH3:14])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1c(N)ccc(C#N)c1C(F)(F)F
Reactant: O=C(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1c(N=C(c2ccccc2)c2ccccc2)ccc(C#N)c1C(F)(F)F
Yield: 79.1 %

Procedure:
To a stirred solution of 4-amino-3-methyl-2-(trifluoromethyl)benzonitrile (3.59 g, 17.9 mmol) in toluene (80 mL) was added benzophenone (3.59 g, 19.7 mmol) followed by PTSA monohydrate (0.035 g, 0.18 mmol). The reaction flask was fitted with a Dean-Stark trap and heated at reflux for 7 d. The reaction was concentrated and purified by SiO2 chromatography (5% EtOAc in hexanes) to afford 4-[(diphenylmethylidene)amino]-3-methyl-2-(trifluoromethyl)benzonitrile (5.16 g, 79%) as a yellow solid: 1H NMR (400 MHz, DMSO-d6): δ 7.71-7.01 (m, 10H), 7.65 (d, J=8.4 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 2.30 (s, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.Cl[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=2)[CH:20]=[CH:19][CH:18]=1>>[CH3:28][O:27][C:24]1[CH:25]=[C:26]2[C:21]([CH:20]=[CH:19][CH:18]=[C:17]2[CH2:16][N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]=[C:6]2[C:4]([OH:3])=[O:5])=[CH:22][CH:23]=1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: COc1ccc2cccc(CCl)c2c1
Product: COc1ccc2cccc(Cn3c(C(=O)O)cc4ccccc43)c2c1

Procedure:
Using general procedure B, 1H-indole-2-carboxylic acid ethyl ester was coupled with 1-chloromethyl-7-methoxy-naphthalene (Lit. 12) and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 330.1 ([M−H]−).
Reaction SMILES: [Cl:1][CH2:2][CH:3](OC)OC.[CH3:8][C:9]([SH:16])([CH2:11][C:12]([CH3:15])([SH:14])[CH3:13])[CH3:10].C1(C)C(S(O)(=O)=O)=CC=CC=1>>[Cl:1][CH2:2][CH:3]1[S:16][C:9]([CH3:10])([CH3:8])[CH2:11][C:12]([CH3:15])([CH3:13])[S:14]1
Reactant: COC(CCl)OC
Reactant: CC(C)(S)CC(C)(C)S
Agent: Cc1ccccc1S(=O)(=O)O
Product: CC1(C)CC(C)(C)SC(CCl)S1
Temperature: 25 °C

Procedure:
2-Chloro-1,1-dimethoxyethane (0.1 mole) and 2,4-dimethyl-2,4-pentanedithiol (0.1 mole) are charged into a glass reaction vessel fitted with a mechanical stirrer, thermometer, Dean Stark trap and reflux condenser. Toluene sulfonic acid (0.1 grams) is added and the reaction mixture is heated and thiol removed. When the thiol evolution ceases, the reaction mixture is then cooled to room temperature, treated with sodium carbonate (5 grams) and filtered. Volatiles are stripped from the filtrate using a rotary evaporator to yield the desired product 2-chloromethyl-4,4,6,6-tetramethyl-1,3-dithiane as the residue.
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]([C:14]2[N:22]3[C:17]([CH2:18][O:19][CH2:20][CH2:21]3)=[N:16][CH:15]=2)[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([Li])CCC.IC>CCCCCC>[NH:1]([C:8]1[N:13]=[C:12]([C:14]2[N:22]3[C:17]([CH:18]([CH3:23])[O:19][CH2:20][CH2:21]3)=[N:16][CH:15]=2)[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [Li]CCCC
Reactant: c1ccc(Nc2nccc(-c3cnc4n3CCOC4)n2)cc1
Solvent: CCCCCC
Solvent: CI
Product: CC1OCCn2c(-c3ccnc(Nc4ccccc4)n3)cnc21
Yield: 39 %

Procedure:
By an analogous process to Example 10, 2-Anilino-4-(5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazin-3-yl)pyrimidine (Example 5; 163 mg, 0.556 mmol) was treated with n-butyllithium (0.73 ml of a 1.6M solution in hexane, 1.168 mmol) and iodomethane (36 μl, 0.583 mmol) to give the title compound (67 mg, 39%) as a pale yellow solid. NMR: 1.5 (d, 3H), 3.9 (m, 1H), 4.18 (m, 1H), 4.32 (m, 1H), 4.63 (m, 1H), 4.87 (q, 1H), 6.95 (t, 1H), 7.13 (d, 1H), 7.3 (t, 2H), 7.67 (d, 2H), 7.75 (s, 1H), 8.37 (d, 1H), 9.4 (s, 1H); m/z 308.
Reaction SMILES: [CH:1]1([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:18][NH:19][C:20]([NH2:22])=[O:21].C([O-])(=O)C.[Na+]>C(O)C.O>[CH:1]1([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[N:18][NH:19][C:20]([NH2:22])=[O:21])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NNC(N)=O
Reactant: O=Cc1ccc(OC2CCCCCC2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=O)NN=Cc1ccc(OC2CCCCCC2)cc1
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
To a solution of 4-cycloheptyloxybenzaldehyde (1.7 g) in ethanol (20 mL) was added a solution of semicarbazide hydrochloride (0.96 g) and sodium acetate (0.69 g) in water (10 mL) at room temperature. The mixture was stirred for 30 min, and the resulting solid was collected by filtration, washed with water (3×30 mL) and dried in vacuo to yield the title compound as a white solid (1.7 g; 79%), mp: 215-216° C. 1H NMR (DMSO-d6): δ 10.07 (s, 1H), 7.76 (s, 1H), 7.61 (d, J=8.4, 2H), 6.89 (d, J=8.4, 2H), 6.40 (s, 2H), 4.54 (m, 1H), 1.98-1.47 (m, 2H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:26])([CH3:25])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].C(Cl)(=O)C(Cl)=O.[C:33]1([C@H:39](O)[CH3:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.N1C=CC=CC=1>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:26])([CH3:25])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:12]([O:14][C@@H:39]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:40])=[O:13])(=[O:7])=[O:6]
Reactant: C[C@@H](O)c1ccccc1
Reactant: COc1ccc(CO[C@@H](C(=O)O)C(C)(C)COS(=O)(=O)CCCCl)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(CO[C@@H](C(=O)O[C@H](C)c2ccccc2)C(C)(C)COS(=O)(=O)CCCCl)cc1
Yield: 68.2 %

Procedure:
Following the general procedure for the preparation of carboxylic esters from carboxylic acids of Description 15, (2R)-4-[(3-chloropropyl)sulfonyloxy]-2-[(4-methoxyphenyl)methoxy]-3,3-dimethylbutanoic acid (13) (0.50 g, 1.2 mmol) dissolved in 20 mL of anhydrous dichloromethane (DCM) was reacted with 0.7 mL (1.4 mmol) of oxalyl chloride (2.0 M in DCM). After completion of the reaction, a solution of 0.28 mL of (R)-(+)-1-phenylethanol (0.40 g, 3.3 mmol) and 0.28 mL of pyridine (0.26 g, 3.3 mmol) in 10 mL of anhydrous dichloromethane was added to the acid chloride. After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) as eluent (EtOAc/Hxn=1:2) to provide 0.42 g (67% yield) of the title compound (34a) as a colorless oil. Rf=0.54 (EtOAc/Hxn=1:2). 1H NMR (400 MHz, CDCl3): δ=0.98 (s, 3H), 0.99 (s, 3H), 1.61 (d, J=6.4 Hz, 3H), 2.23-2.30 (m, 2H), 3.18-3.22 (m, 2H), 3.63-3.66 (m, 2H), 3.81-3.82 (m, 4H), 3.92 (d, J=9.2 Hz, 1H), 4.19 (d, J=9.2 Hz, 1H), 4.26 (d, J=11.2 Hz, 1H), 4.49 (d, J=11.2 Hz, 1H), 6.01 (q, J=6.4 Hz, 1H), 6.85 (d, J=8.8 Hz, 2H), 7.20 (d, J=8.4 Hz, 2H), 7.35-7.39 (m, 5H) ppm. D.e.>98% (by 1H NMR-spectroscopy, 400 MHz, CDCl3). MS (ESI) m/z 535.18 (M+Na)+. The analytical data was consistant with the proposed structure.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-])=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H][H]>CO.[Ni]>[CH2:1]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: [H][H]
Reactant: CCCCCCOc1ccccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: CCCCCCOc1ccccc1N

Procedure:
1-(Hexyloxy)-2-nitrobenzene, 61.28 g (0.27 mol) is dissolved in 700 ml of methanol, 3 g Raney nickel is added and the mixture exposed to hydrogen gas until the required amount of hydrogen is absorbed. The methanol solution is filtered and concentrated in vacuo and the residue distilled to give 50 g of 2-(hexyloxy)benzenamine; bp 145°-148° C. at 4 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)(O)[CH3:13])[C:6]3[CH2:22][CH2:23][N:24]([CH3:26])[CH2:25][C:5]=3[C:4]=2[CH:3]=1.CCN(S(F)(F)[F:33])CC>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([F:33])([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH3:13])[C:6]3[CH2:22][CH2:23][N:24]([CH3:26])[CH2:25][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2CC(C)(O)c2ccc(F)cc2)C1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CN1CCc2c(c3cc(Cl)ccc3n2CC(C)(F)c2ccc(F)cc2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cooled stirred solution of 1-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(4-fluorophenyl)propan-2-ol (500 mg, 1.3 mmol) in DCM (50 mL) was dropwise added DAST (443 mg, 2.6 mmol) and the reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was diluted with DCM (50 mL), washed with saturated sodium bicarbonate solution (3×30 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified with reverse phase HPLC to yield 8-chloro-5-(2-fluoro-2-(4-fluorophenyl)propyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole. 1H-NMR (DMSO-d6, oxalate salt) δ (ppm): 7.50 (s, 1H), 7.40 (m, 3H), 7.18 (t, 2H), 7.05 (d, 1H), 4.60 (m, 2H), 4.25 (m, 2H), 3.05 (m, 2H), 2.85 (s, 3H), 2.70 (m, 2H), 1.65 (d, 3H). Separation by chiral HPLC provides enantiomers II-2111a-b.
Reaction SMILES: [CH3:1][C:2]#[N:3].C([O-])(C)(C)C.[K+].C[O:11][C:12]([C:14]1[CH:15]=[C:16]([CH:32]=[CH:33][CH:34]=1)[O:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1)=O>C1COCC1>[C:2]([CH2:1][C:12]([C:14]1[CH:15]=[C:16]([CH:32]=[CH:33][CH:34]=1)[O:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH2:21][CH2:20]1)=[O:11])#[N:3]
Reactant: COC(=O)c1cccc(OCC2CCN(C(=O)OC(C)(C)C)CC2)c1
Reactant: CC#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COc2cccc(C(=O)CC#N)c2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
CH3CN (0.25 mL, 4.79 mmol) was added to a cold (−78° C.) solution of t-BuO−K+ in THF (1M, 5.0 mL, 5.0 mmol) under Ar and the reaction mixture was stirred for 5 mins. Solution of tert-butyl 4-((3-(methoxycarbonyl)phenoxy)methyl)piperidine-1-carboxylate (1.01 g, 2.86 mmol) in anhydrous THF (7 mL) was added to the reaction mixture and the resulting mixture was stirred at −78° C. for 10 min, then warmed to room temperature over 30 mins. The reaction mixture was quenched with 5% aqueous NaHSO4 and extracted twice with tert-butyl methyl ether. Combined organic layers were washed with brine and concentrated under reduced pressure. Purification by flash chromatography (20%-80% EtOAc-hexanes gradient) gave tert-butyl 4-((3-(2-cyanoacetyl)phenoxy)methyl)piperidine-1-carboxylate as a white solid. Yield (0.55 g, 54%); 1H NMR (400 MHz, DMSO-d6) δ 7.39-7.51 (m, 3H), 7.23-7.28 (m, 1H), 4.73 (s, 2H), 3.84-4.00 (m, 2H), 3.90 (d, J=6.26 Hz, 2H), 2.60-2.80 (m, 2H), 1.86-1.97 (m, 1H), 1.70-1.78 (m, 2H), 1.38 (s, 9H), 1.08-1.23 (m, 2H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[N:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C)C=O>[N:25]([CH2:2][C:3]1[N:4]=[C:5]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[N:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH:7]=1)=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)c1ccc(-n2cc(CCl)nc2-c2ccc(Cl)cc2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-n2cc(CN=[N+]=[N-])nc2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
A mixture of 4-chloromethyl-2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole (Example 159, Step 1) (500 mg, 1.31 mmol) and sodium azide (256 mg, 3.94 mmol) in 5 ml of dimethylformamide was stirred overnight at room temperature. The mixture was warmed to 80° C. for one hour and then cooled. The mixture was partitioned between ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and evaporated. Chromatography of the residue over silica gel using 50% ethyl acetate in hexane as the eluent gave the title compound as a pure white crystalline solid (496 mg):mp (DSC) 186° C. Anal. Calc'd. for C17H14ClN5O2S (MW 387.85): C, 52.64; H, 3.64; N, 18.06. Found: C, 52.46; H, 3.77; N, 17.84.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:20]([OH:22])=O)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:24][O:25][C:26](=[O:33])[C@H:27]([CH2:29][CH:30]([CH3:32])[CH3:31])[NH2:28].CN(C)C=O.C1(N=C=NC2CCCCC2)CCCCC1>C(N(CC)CC)C>[CH3:24][O:25][C:26](=[O:33])[C@H:27]([CH2:29][CH:30]([CH3:32])[CH3:31])[NH:28][C:20](=[O:22])[C@@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: O=C(N[C@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 6.65 g. of Nα -benzyloxycarbonyl-D-phenylalanine (0.022 mol) and 4.38 g. (0.022 mol) of L-leucine methyl ester hydrochloride in 60 ml. of spectrograde dimethylformamide is chilled in ice and treated with 3.0 ml. of triethylamine (2.24 g.). 1-Hydroxybentriazole, 3.3 g., and dicyclohexylcarbodiimide, 5 g., are added and the reaction stirred at room temperature overnight and for 24 hours longer at room temperature. The mixture is filtered and the solvent evaporated under reduced pressure. The residue is dissolved in 200 ml. of ethyl acetate and washed with 0.1N hydrochloric acid, saturated salt solution, 5% sodium bicarbonate solution, saturated salt solution and water. The ethyl acetate solution is dried over magnesium sulfate, filtered and evaporated to a crystalline residue. The product is recrystallized twice from ethyl acetate and petroleum ether; 7.3 g.; m.p. 125°-126° C.; [α]D23 -20.3° (c 1.02, methanol).
Reaction SMILES: [BrH:1].[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[OH:12])[CH2:8][NH:7][CH2:6]2.[CH:13]([O-])=O.[Na+].C=O>C(O)=O>[BrH:1].[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[OH:12])[CH2:8][N:7]([CH3:13])[CH2:6]2
Reactant: O=C[O-]
Reactant: Oc1cc2c(cc1O)CNC2
Agent: Br
Agent: C=O
Agent: [Na+]
Solvent: O=CO
Product: CN1Cc2cc(O)c(O)cc2C1
Temperature: 80 °C
Yield: 72.3 %

Procedure:
15.39 g (66 mmol) of 5,6-dihydroxyisoindoline hydrobromide and 4.48 g (66 mmol) of sodium formate were dissolved in 100 ml of a 50% formic acid aqueous solution, and then 5.17 ml (70 mmol) of 37% formalin was added thereto. The mixture was heated at 80° C. for 4 hours. Then, the reaction solvent was distilled off under reduced pressure, and 200 ml of 23% hydrobromic acid was added to the residue. The mixture was subjected to active carbon treatment. The filtrate was again evaporated under reduced pressure to dryness, and the crystalline residue was recrystallized from water to obtain 11.74 g (yield: 72.3%) of the above identified compound.