Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:4][C:5]1[CH:29]=[CH:28][C:8]([CH2:9][NH:10][C:11]2[C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[NH:13][N:12]=2)=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+]>O>[NH2:4][C:5]1[CH:29]=[CH:28][C:8]([CH2:9][NH:10][C:11]2[C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[NH:13][N:12]=2)=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc(CNc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(CNc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Temperature: 100 °C

Procedure:
A mixture of 0.11 g (0.27 mmol) of 3-(4-acetylamino-benzylamino)-4-(3-chlorophenylamino)-1H-pyrazolo[3,4-d]pyrimidine (Example 57), 3 ml of water and 1.5 ml of 30% sodium hydroxide solution is heated at 100° C. for 4 hours. After cooling to RT, the reaction mixture is extracted with ethyl acetate and the extract is washed with brine, dried over sodium sulfate and concentrated by evaporation in vacuo. The residue is purified by flash chromatography on silica gel having a particle size of 0.04-0.06 mm using methylene chloride/methanol mixtures (50:1 and 20:1). The product-containing fractions are concentrated by evaporation and the residue is recrystallized from ethyl acetate/hexane, yielding the title compound; m.p. 170-171° C.; EI-MS: (M)+ =365.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].C([N-]C(C)C)(C)C.[Li+].[Cl:22][CH2:23][CH2:24][CH2:25]I>O1CCCC1>[Cl:22][CH2:23][CH2:24][CH2:25][C:3]1([C:1]#[N:2])[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: ClCCCI
Reactant: CCOC(=O)N1CCC(C#N)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(C#N)(CCCCl)CC1
Temperature: -10 °C
Yield: 64.6 %

Procedure:
To a solution of ethyl 4-cyano-1-piperidinecarboxylate (6.0 g) in tetrahydrofuran (120 ml) at -70° C., under nitrogen, was added a solution of lithium diisopropylamide (4.6 g) in tetrahydrofuran (21.5 ml), dropwise, with stirring. The reaction was allowed to warm to -10° C. and after 30 min was recooled to -70° C. A solution of 1-chloro-3-iodopropane (7.4 g) in tetrahydrofuran (20 ml) was added to the mixture over 30 min. The reaction mixture was quenched with water and allowed to warm to ambient temperature. The mixture was extracted with ethyl acetate. The extracts were washed with water, saturated sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was flash chromatographed (silica), eluting with 2:1 heptane/ethyl acetate. The appropriate fractions were collected and concentrated to afford 5.5 g (64%) of product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH3:27])[N:22]=[C:23]([CH2:24][CH2:25][CH3:26])[N:16]2[N:15]=1)[CH3:2].FC(F)(F)C(O)=O.[CH3:35][N:36]1[O:40][NH+:39]([O-:41])[CH:38]=[C:37]1[C:42]([N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)=[O:43].C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:47]2[CH2:46][CH2:45][N:44]([C:42]([C:37]3[N:36]([CH3:35])[O:40][NH+:39]([O-:41])[CH:38]=3)=[O:43])[CH2:49][CH2:48]2)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH3:27])[N:22]=[C:23]([CH2:24][CH2:25][CH3:26])[N:16]2[N:15]=1)[CH3:2]
Reactant: CN1O[NH+]([O-])C=C1C(=O)N1CCNCC1
Reactant: CCCc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nn12
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(C(=O)C5=C[NH+]([O-])ON5C)CC4)ccc3OCC)nn12
Temperature: 0 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
410 mg (1.0 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride are dissolved in 10 ml of dichloromethane and cooled to 0° C. 590 mg (2.00 mmol) of 1-(5-methyl-4-furoxanecarbonyl)-piperazine trifluoroacetate and 400 mg of triethylamine are added, and the reaction mixture is stirred at room temperature overnight. The mixture is diluted with dichloromethane, the organic phase is washed with ammonium chloride solution, 1M hydrochloric acid and water and dried over sodium sulphate and the solvent is removed under reduced pressure. Crystallization from ether gives 448 mg (74%) of a colourless solid.
Reaction SMILES: Cl[CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1=O.[NH2:8][C:9]([NH2:11])=[S:10]>O1CCOCC1>[S:10]1[C:3]2[CH2:4][CH2:5][CH2:6][C:2]=2[N:8]=[C:9]1[NH2:11]
Reactant: O=C1CCCC1Cl
Reactant: NC(N)=S
Solvent: C1COCCO1
Product: Nc1nc2c(s1)CCC2
Temperature: 25 °C
Yield: 106.9 %

Procedure:
2-Chlorocyclopentanone (9.01 g, 74.4 mmol) was added slowly to a 95° C. stirred mixture of thiourea (5.77 g, 75.0 mmol) in 1,4-dioxane (150 mL). After full addition, the temperature was maintained for an hour then the mixture was cooled to room temperature. It was then filtered and washed with 1,4-dioxane and diethyl ether, and dried under air suction to afford 11.15 g white solid. This was partitioned between diethyl ether and saturated aqueous sodium carbonate. The ether layer was washed with brine, dried with Na2SO4, and solvent removed by rotoevaporation to afford 9.8 g beige solid. (Modified procedure from US Patent application 64 699, 2008, Florjancic, A. S.; et al).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24][CH3:25])[N:12]2[CH2:15][CH:16]2[CH2:21][CH2:20]N(CC)CC2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].C(OC1NC(N)=C2C(N=1)=NC(OC)=N2)CCC.[CH2:44]([N:46]1[CH2:51][CH2:50]C(C(C)CO)[CH2:48][CH2:47]1)[CH3:45]>>[CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24][CH3:25])[N:12]2[CH2:15][CH2:16][CH2:21][CH:20]2[CH2:48][CH2:47][N:46]([CH2:51][CH3:50])[CH2:44][CH2:45]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCN1CCC(C(C)CO)CC1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCN(CC)CC3)c2n1
Agent: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Product: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCN(CC)CC3)c2n1

Procedure:
Prepared similarly to Intermediate 19 from 2-(butyloxy)-8-(methyloxy)-1H-purin-6-amine and 2-(1-ethyl-4-piperidinyl)-1-propanol.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[CH:14][N:13]=2)[C:6](=[O:10])[N:7]([CH3:9])[N:8]=1.[O:24]1[CH2:27][C:26](=O)[CH2:25]1.[BH3-]C#N.[Na+].O>CO.[Cl-].[Zn+2].[Cl-]>[Cl:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([CH:26]4[CH2:27][O:24][CH2:25]4)[CH2:20][CH2:19]3)=[CH:14][N:13]=2)[C:6](=[O:10])[N:7]([CH3:9])[N:8]=1
Reactant: O=C1COC1
Reactant: Cn1nc(Cl)cc(Nc2ccc(N3CCNCC3)cn2)c1=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: Cn1nc(Cl)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Reaction time: 3.5 h
Yield: 47.8 %

Procedure:
A mixture of 328b (1.2 g, 3.5 mmol), oxetan-3-one (0.5 g, 7.0 mmol), NaBH3CN (0.44 g, 7.0 mmol) and zinc chloride (0.93 g, 7.0 mmol) in methanol (125 ml) was stirred at 50 degree for 3.5 hours. The mixture was added to water and extracted with methylene chloride. The organic layers were combined and concentrated under reduced pressure. The residue was purified by column chromatography eluting with 25:1 methylene chloride/methanol to give 328c (0.63 g, 50%). MS: [M+H]+ 377.
Reaction SMILES: [C-:1]#[N:2].[Na+].CS([C:8]1[N:13]=[C:12]([CH2:14][CH2:15][CH3:16])[CH:11]=[C:10]([Sn:17]([CH3:20])([CH3:19])[CH3:18])[N:9]=1)(=O)=O>CS(C)=O>[CH2:14]([C:12]1[CH:11]=[C:10]([Sn:17]([CH3:20])([CH3:19])[CH3:18])[N:9]=[C:8]([C:1]#[N:2])[N:13]=1)[CH2:15][CH3:16]
Reactant: [C-]#N
Reactant: CCCc1cc([Sn](C)(C)C)nc(S(C)(=O)=O)n1
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCc1cc([Sn](C)(C)C)nc(C#N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.9 %

Procedure:
Sodium cyanide (0.63 g, 12.9 mmol) was added at room temperature to 2-methanesulfonyl-4-propyl-6-trimethylstannanyl-pyrimidine (2.34 g, 6.5 mmol) in DMSO (23 mL). The mixture was stirred at room temperature for 2 hours, then partitioned between ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was chromatographed over silica gel (eluent: Cyclohexane/Ethyl acetate 9/1) to give 4-propyl-6-trimethylstannanyl-pyrimidine-2-carbonitrile (1.53 g, 76%) as an off white solid (mp=62° C.).
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[CH3:25][C:26]1[CH:30]=[C:29]([N:31]2[CH2:35][CH2:34][N:33]([CH2:36][C:37](=[O:44])[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]2=[O:45])[S:28][C:27]=1[C:46]([OH:48])=O.[NH2:49][CH2:50][C:51]1[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=1>>[CH3:25][C:26]1[CH:30]=[C:29]([N:31]2[CH2:35][CH2:34][N:33]([CH2:36][C:37](=[O:44])[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]2=[O:45])[S:28][C:27]=1[C:46]([NH:49][CH2:50][C:51]1[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=1)=[O:48]
Reactant: NCc1cccnc1
Reactant: Cc1cc(N2CCN(CC(=O)c3ccccc3)C2=O)sc1C(=O)O
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1cc(N2CCN(CC(=O)c3ccccc3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 61 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 3-methyl-5-(2-oxo-3-(2-oxo-2-phenylethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a cream solid in 61% yield: mp 174-176° C.: 1H NMR (300 MHz, CDCl3) δ 8.58 (s, 1H), 8.48 (d, J=4.4 Hz, 1H), 7.97-7.92 (m, 2H), 7.67 (d, J=7.8 Hz, 1H), 7.64-7.57 (m, 1H), 7.51-7.44 (m, 2H), 7.23 (dd, J=7.8, 4.4 Hz, 1H), 6.24 (t, J=5.7 Hz, 1H), 6.11 (s, 1H), 4.72 (s, 2H), 4.56 (d, J=5.7 Hz, 2H), 3.93-3.85 (m, 2H), 3.75-3.67 (m, 2H), 2.48 (s, 3H): 13C NMR (75 MHz, CDCl3) δ 193.8, 163.5, 156.2, 149.2, 148.7, 142.4, 141.6, 135.5, 134.6, 134.2, 134.0, 128.9, 127.9, 123.5, 112.6, 50.0, 43.0, 42.7, 41.1, 16.1: MS (ES+) m/z 435.4 (M+1).
Reaction SMILES: [F:1][CH:2]([F:17])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1.[N+](C1C=CC(C(O)C(N(C)C)CO)=CC=1)([O-])=O>C(O)C>[F:1][CH:2]([F:17])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C@H:10]([CH:14]([CH3:15])[CH3:16])[C:11]([OH:13])=[O:12])=[CH:8][CH:9]=1
Reactant: CC(C)C(C(=O)O)c1ccc(OC(F)F)cc1
Agent: CN(C)C(CO)C(O)c1ccc([N+](=O)[O-])cc1
Solvent: CCO
Product: CC(C)[C@H](C(=O)O)c1ccc(OC(F)F)cc1
Temperature: 25 °C
Yield: 42.5 %

Procedure:
Dissolve 50 g of 2-(4-difluoromethoxyphenyl)-3-methylbutyric acid in 150 g of ethyl alcohol and to this solution is added 0.24 mole of resolving agent 1-(4-nitrophenyl)-2-dimethylamino-1,3-propanediol. Heat the solution with stirring under reflux for 1.5 hours, then cool, filter, and transfer the resulting solids to 73 g of 10% hydrochloric acid. Heat the mixture with stirring at 30° C. for 2 hours and then allow the mixture to cool to room temperature. The resulting mixture is extracted with benzene 2-3 times, and the solvent benzene is then removed by distillation to give 21.25 g (yield: 42.5%) of (S)-2-(4-difluoromethoxyphenyl)-3-methylbutyric acid.
Reaction SMILES: [ClH:1].[F:2][C@@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:5]2([CH3:6])[C:4]1=[O:27])[C@:17]1([CH3:18])[C:12]2(O[CH:13]2[C:14](=[O:23])[CH:15]=[C:16]1[CH3:22])[C:11](=[CH2:25])[C@H:10]3[CH3:26].O>C(O)(=O)C>[F:2][C@@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:5]2([CH3:6])[C:4]1=[O:27])[C@:17]1([CH3:18])[C:12](=[C:13]([Cl:1])[C:14](=[O:23])[CH:15]=[C:16]1[CH3:22])[C:11](=[CH2:25])[C@H:10]3[CH3:26]
Reactant: Cl
Reactant: C=C1[C@@H](C)[C@H]2[C@@H]3C[C@@H](F)C(=O)[C@@]3(C)CC[C@@H]2[C@@]2(C)C(C)=CC(=O)C3OC132
Solvent: O
Solvent: CC(=O)O
Product: C=C1C2=C(Cl)C(=O)C=C(C)[C@]2(C)[C@H]2CC[C@]3(C)C(=O)[C@H](F)C[C@H]3[C@@H]2[C@@H]1C

Procedure:
Gaseous hydrogen chloride is introduced for about 30 min into a solution of 16α-fluoro-4,5-epoxy-1,7α-dimethyl-6-methylenandrost-1-ene-3,17-dione (359 mg) in glacial acetic acid (5 ml). Thereupon water is added, the precipitate filtered off, washed with diethylether and chromatographed on silica gel to yield pure 16α-fluoro-4-chloro-1,7α-dimethyl-6-methylenandrosta-1,4-diene-3,17-dione (264 mg). Found: C 70.05, H 6.89, Cl 9.32, F 4.99. C22H26ClFO2 requires: C 70.11, H 6.95, Cl 9.41, F 5.04.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][S:15]([O-:18])(=O)=[O:16].[K+].P(Cl)(Cl)(Cl)(Cl)[Cl:21]>ClCCl>[Cl:21][S:15]([CH2:14][CH2:13][CH2:12][N:3]1[C:2](=[O:1])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]1=[O:11])(=[O:18])=[O:16]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C1c2ccccc2C(=O)N1CCCS(=O)(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1CCCS(=O)(=O)Cl
Reaction time: 8 h
Yield: 34.8 %

Procedure:
Adapting a procedure according to Shue et al., Bioorg. Med. Chem. 1996, 6, 1709-1714, a 250 mL round-bottomed flask equipped with a magnetic stirring bar and a reflux condenser was charged under an atmosphere of nitrogen with 5.4 g (20 mmol) of potassium 3-(1,3-dioxobenzo[c]azolin-2-yl)propanesulfonic acid (10a), 150 mL of anhydrous dichloromethane (DCM), and 4.6 g (22 mmol) of phosphorus pentachloride (PCl5). The reaction mixture was heated to reflux. After reacting overnight, the reaction mixture was quenched with water and the phases were separated. The aqueous phase was extracted with dichloromethane (DCM). The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate (MgSO4), filtered, and the solvents removed under reduced pressure using a rotary evaporator. After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:2) as eluent to provide 2.0 g (35% yield) of the title compound (10) as a off-white to beige solid. 1H NMR (400 MHz, CDCl3): δ=2.42-2.49 (m, 2H), 3.75-3.79 (m, 2H), 3.91 (t, J=6.4 Hz, 2H), 7.75-7.77 (m, 2H), 7.87-7.89 (m, 2H) ppm. MS (ESI) m/z 287.99 (M+H)+.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[N:12]=[C:11]([C:13]([O:15]C)=[O:14])[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>C(O)C.O>[N:1]1([CH2:6][C:7]2[N:12]=[C:11]([C:13]([OH:15])=[O:14])[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cccc(CN2CCCC2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cccc(CN2CCCC2)n1
Temperature: 75 °C
Reaction time: 16 h
Yield: 80.1 %

Procedure:
A mixture of methyl 6-(pyrrolidin-1-ylmethyl)picolinate 69 (36 g) and NaOH (40 g, 1.0 mol) in ethanol/H2O (320 mL) was stirred at 75° C. for 16 h. The pH was adjusted to 7 with 3N HCl and extracted with EtOAc. The aqueous layer was concentrated to dryness and extracted with dichloromethane/methanol (v:v=3:1), The organic layer was dried to give 70 (27 g, 55% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[CH:6]=[CH:5]2.O1CCCC1.[CH3:24][C@H:25]1[CH2:30][CH2:29][C@H:28](O)[CH2:27][CH2:26]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[CH3:18][C@@:12]1([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([O:1][C@H:28]4[CH2:29][CH2:30][C@@H:25]([CH3:24])[CH2:26][CH2:27]4)[CH:3]=3)[CH:8]=2)[CH2:16][O:15][C:14](=[O:17])[NH:13]1
Reactant: C[C@H]1CC[C@H](O)CC1
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@]1(c2ccc3cc(O[C@H]4CC[C@@H](C)CC4)ccc3c2)COC(=O)N1
Temperature: 25 °C

Procedure:
(R)-4-(6-Hydroxynaphthalen-2-yl)-4-methyl-oxazolidin-2-one (Example 4, 0.3144 g, 0.001292 mol) was dissolved in tetrahydrofuran (5.00 mL, 0.0616 mol) in a capped 40 mL vial. trans-4-Methyl-cyclohexanol (0.177 g, 0.00155 mol) and triphenylphosphine polymer-bound (1.12 g, 0.00207 mol) were added and the mixture was stirred at room temperature. Diisopropyl azodicarboxylate (0.407 mL, 0.00207 mol) was added and the mixture was stirred for 2 days at room temperature. The mixture was filtered through CELITE™, concentrated and purified by flash column chromatography (0-30% EtOAc in methylene chloride) to give 0.3059 g of the title compound (69% yield).
Reaction SMILES: [NH2:1][C:2]([CH3:19])([CH2:5][N:6]1[N:10]=[C:9]2[C:11]([Cl:18])=[C:12]([Br:17])[C:13]([Cl:16])=[C:14]([Br:15])[C:8]2=[N:7]1)[C:3]#[N:4].[F:20][C:21]([F:32])([F:31])[C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[S:27])=[CH:24][CH:23]=1>>[C:3]([C:2]([NH:1][C:26](=[S:27])[C:25]1[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:31])[F:32])=[CH:30][CH:29]=1)([CH3:19])[CH2:5][N:6]1[N:10]=[C:9]2[C:11]([Cl:18])=[C:12]([Br:17])[C:13]([Cl:16])=[C:14]([Br:15])[C:8]2=[N:7]1)#[N:4]
Reactant: CC(N)(C#N)Cn1nc2c(Cl)c(Br)c(Cl)c(Br)c2n1
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Product: CC(C#N)(Cn1nc2c(Cl)c(Br)c(Cl)c(Br)c2n1)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(4,6-dibromo-5,7-dichloro-2H-benzotriazol-2-yl)-2-methylpropionitrile, described in Example 57, and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (100 mg). MS (ES): M/Z [M+H]=630. NMR: (400 MHz, DMSO-d6): 1.75 (s, 3H), 5.45 (d, J=13.3 Hz, 1H), 5.60 (d, J=13.0 Hz, 1H), 7.82-7.92 (m, 4H) and 8.90 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −42.0 (s, 3F).
Reaction SMILES: Cl[C:2]1[CH:34]=[CH:33][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)([CH3:25])[CH3:24])[C:10]=3[OH:32])[N:8]=[C:4]2[CH:3]=1.[CH2:35]([SH:39])[CH2:36][CH2:37][CH3:38].[OH-].[K+].CN1CCCC1=O.Cl>C(OCC)(=O)C>[CH2:35]([S:39][C:2]1[CH:34]=[CH:33][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)([CH3:25])[CH3:24])[C:10]=3[OH:32])[N:8]=[C:4]2[CH:3]=1)[CH2:36][CH2:37][CH3:38]
Reactant: CC(C)(C)CC(C)(C)c1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)c2ccccc2)c1
Reactant: CCCCS
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCCCSc1ccc2nn(-c3cc(C(C)(C)CC(C)(C)C)cc(C(C)(C)c4ccccc4)c3O)nc2c1
Temperature: 170 °C
Reaction time: 5 h
Yield: 83 %

Procedure:
5-Chloro-2-(2-hydroxy-3-α-cumyl-5-tert-octylphenyl)-2H-benzotriazole (38.1 g, 0.08 mol), n-butyl mercaptan (9 g, 0.10 mol), potassium hydroxide (10.1 g, 0.18 mol) and N-methylpyrrolidone (99 g, 1.0 mol) are charged to a reactor and heated to 170° C. The reaction mass is held at 170° C. with vigorous stirring for five hours. The reaction is judged as complete using thin layer chromatogrphy. The temperature is reduced to 5° C. and 100 mL of aqueous 2N hydrochloric acid are then added to the reactor. The liquid is decantedand the solids are dissolved in ethyl acetate. The organic layer is washed with aqueous 2N hydrochloric acid followed by water. The ethyl acetate is stripped off and the product is crystallized from ethanol and toluene. The tide compound is obtained as a yellow crystalline product in 83% yield. The structure is verified by 1Hnmr.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]([F:13])([F:12])[F:11])=[N:6][C:7]=1[C:8]#[N:9].S(=O)(=O)(O)[OH:15]>>[NH2:1][C:2]1[C:7]([C:8]([NH2:9])=[O:15])=[N:6][C:5]([C:10]([F:13])([F:11])[F:12])=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1nc(C(F)(F)F)ccc1N
Product: NC(=O)c1nc(C(F)(F)F)ccc1N
Temperature: 70 °C

Procedure:
7 g (0.0374 mol, 1 eq) of 5-amino-6-cyano-2-(trifluoromethyl)pyridine dissolved in 106 ml of 90% sulfuric acid was and heated at 70° C. for 3 h. The reaction mixture was cooled to RT and quenched with ice water and extracted with ethyl acetate. The organic layer was washed with brine and concentrated. The solid product obtained was washed with to get 6.8 g (89.47%) of off white solid. 1H NMR (CDCl3, 400 MHz) 5.5 (1H, bs), 7.1 (1H, d), 7.53 (1H, d), 7.80 (1H, bs). MS 206 (M+H)+.
Reaction SMILES: [F:1][CH2:2][C@H:3]1[CH2:7][N:6]([C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[C:5](=[O:16])[C@:4]1([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18].IC.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl-].[NH4+]>O1CCCC1>[F:1][CH2:2][C@H:3]1[CH2:7][N:6]([C@@H:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH3:9])[C:5](=[O:16])[C@@:4]1([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)[C@@]1(C)C(=O)N([C@H](C)c2ccccc2)C[C@@H]1CF
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)[C@]1(C)C(=O)N([C@H](C)c2ccccc2)C[C@@H]1CF
Reaction time: 0.17 h
Yield: 83.1 %

Procedure:
To a solution of ethyl (3R,4R)-4-fluoromethyl-3-methyl-2-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate (33.4 g, 114 mmol) and iodomethane (9.94 mL, 159 mmol) in tetrahydrofuran (670 mL), potassium bistrimethylsilyl amide (274 mL, 137 mmol, 0.5M solution in toluene) was added at −78° C., and the mixture was stirred at the same temperature for 10 minutes. The temperature was gradually increased in 30 minutes with stirring to −10° C., and saturated aqueous solution of ammonium chloride (700 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (700 mL×2), and the organic layer was washed with saturated aqueous solution of sodium chloride (500 mL), and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elusion by hexane:ethyl acetate, 7:1→1:1) to obtain 29.1 g (83%) of the title compound as a pale yellow oily substance.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][CH2:15][C@H:14]3[CH2:18][O:19][CH3:20])=[O:12])[S:10][C:3]=12.[CH3:21][NH:22][C:23]([C:25]1[C:29]2[CH:30]=[CH:31][C:32]([OH:34])=[CH:33][C:28]=2[O:27][C:26]=1[CH3:35])=[O:24].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:21][NH:22][C:23]([C:25]1[C:29]2[CH:30]=[CH:31][C:32]([O:34][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]([N:13]5[CH2:17][CH2:16][CH2:15][C@H:14]5[CH2:18][O:19][CH3:20])=[O:12])[S:10][C:3]=34)=[CH:33][C:28]=2[O:27][C:26]=1[CH3:35])=[O:24]
Reactant: CNC(=O)c1c(C)oc2cc(O)ccc12
Reactant: COC[C@@H]1CCCN1C(=O)c1cc2nccc(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CNC(=O)c1c(C)oc2cc(Oc3ccnc4cc(C(=O)N5CCC[C@H]5COC)sc34)ccc12

Procedure:
This material was prepared by the reaction of 7-chloro-2-[(R)-2-methoxymethylpyrrolidine-1-carbonyl]thieno[3,2-b]pyridine 2a with 6-Hydroxy-2-methyl-benzofuran-3-carboxylic acid methyl amide 12c and Cs2CO3 in a manner as previously described for example 1. 1H NMR (DMSO-d6) δ 8.57 (1H,d, J=5.3 Hz), 8.02 (1H, s),7.98 (1H, m), 7.83 (1H, d, J=8.6 Hz), 7.66 (1H, d, J=2.0 Hz), 7.25 (1H, dd, J=8.6, 2.0 Hz), 6.72 (1H, d, J=5.3 Hz), 4.31 (1H,m), 3.94–3.80 (2H, m), 3.60–3.39 (2H, m), 3.28 (3H, s), 2.82 (3H, d, J=4.6 Hz), 2.63 (3H, s), 2.06–1.85 (4H,m).
Reaction SMILES: [CH3:1][N:2]([C@@H:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:12]([CH2:21]O)[CH2:11]1)[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].Cl.[N+:24]([C:27]1[CH:46]=[CH:45][C:30]([CH2:31][O:32][C:33]([N:35]([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH2:36][CH:37]=[CH2:38])=[O:34])=[CH:29][CH:28]=1)([O-:26])=[O:25]>>[CH3:1][N:2]([C@@H:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:12]([CH2:21][N:42]2[CH2:43][CH2:44][CH:39]([N:35]([C:33]([O:32][CH2:31][C:30]3[CH:29]=[CH:28][C:27]([N+:24]([O-:26])=[O:25])=[CH:46][CH:45]=3)=[O:34])[CH2:36][CH:37]=[CH2:38])[CH2:40][CH2:41]2)[CH2:11]1)[C:3]([O:5][C:6]([CH3:9])([CH3:7])[CH3:8])=[O:4]
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCNCC1
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1C[C@H](CO)[C@@H](c2ccccc2)C1
Agent: Cl
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](N(C)C(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedures as in Example 11, Steps C and D but starting with 1-(R)-(N-(methyl)-N-(t-butoxycarbonyl)amino)-3-(S)-(hydroxymethyl)-4-(S)-phenylcyclopentane (Higher Rf isomer) from Step G (257 mg, 0.84 mmol) and using 4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidine hydrochloride, the title compound was obtained and was the same as the racemic product from Example 15, [α]D=+15.9 (MeOH, c=0.21).