Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].N[C:3]1[S:4][C:5]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][C:6]=2[N:7]=1.N([O-])=O.[Na+]>O>[Cl:1][C:3]1[S:4][C:5]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: N#Cc1ccc2nc(N)sc2c1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc2nc(Cl)sc2c1
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-aminobenzonitrile (23.6 g, 0.2 mol) and ammonium rhodanate (30.4 g, 0.4 mol) was added glacial acetic acid (600 mL) and the resulting solution was cooled to 13.5° C. on an ice-bath. A mixture of bromine and glacial acetic acid was added drop-wise and slowly. The resulting mixture was stirred for 1 hour at 13.5° C. and filtered. The filter cake was washed with glacial acetic (6×100 mL) and placed in hot water (1000 mL) with stirring. The mixture was filtered and pH of the filtrate was adjusted to 7 with a saturated sodium carbonate solution. The precipitate was isolated and dried to give 19.5 g (56%) of 2-amino-benzothiazole-6-carbonitrile. A mixture of concentrated hydrochloric acid (113 mL) and water (52 mL) was heated at 90° C. while 2-aminobenzothiazole-6-carbonitrile (19 g, 0.108 mol) was added. The mixture was cooled to −5° C. on an ice-bath and a solution of sodium nitrite (7.72 g, 0.112 mol) in water (20 mL) was added drop-wise, keeping the temperature below than 0° C. When addition was complete the mixture was stirred for 0.5 hour and a solution of CuCl2 (16 g) in water (108 mL) was added drop-wise. When addition was complete the mixture was stirred for 10 min, and the ice-bath was removed. Stirring was continued for 2 h and the mixture was cooled to room temperature. The mixture was filtered and the solid was washed to neutrality with water and dried. This afforded 12.8 g (61%) of 2-chlorobenzothiazole-6-carbonitrile. 1H-NMR δ 8.14 (s, 1H), 8.03 (d, 1H), 7.75 (d, 1H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]1([S:12]([CH2:15][CH2:16][CH2:17][C:18]2[N:22]([CH2:23][CH2:24][CH2:25][CH3:26])[N:21]=[C:20]([C:27]([NH2:29])=O)[CH:19]=2)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[NH4+]>>[C:6]1([S:12]([CH2:15][CH2:16][CH2:17][C:18]2[N:22]([CH2:23][CH2:24][CH2:25][CH3:26])[N:21]=[C:20]([C:27]#[N:29])[CH:19]=2)(=[O:13])=[O:14])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCCCn1nc(C(N)=O)cc1CCCS(=O)(=O)c1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCn1nc(C#N)cc1CCCS(=O)(=O)c1ccccc1
Temperature: 90 °C
Yield: 86.5 %

Procedure:
Phosphorus oxychloride (25 mL) was added to 5-(3-benzenesulfonylpropyl)-1-butyl-1H-pyrazole-3-carboxamide (10.4 g, 30.0 mmol) and heated to 90° C. for 2.5 hours. The reaction mixture was then cooled to ambient temperature and poured into ice water cooled by an ice bath. Additional ice was added to the reaction mixture and the pH of the mixture was adjusted to 8-9 by addition of 30% saturated aqueous ammonium hydroxide. The mixture was extracted with ethyl acetate and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford 8.60 g of 5-(3-benzenesulfonylpropyl)-1-butyl-1H-pyrazole-3-carbonitrile.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][O:33][Si:34]([CH:41]([CH3:43])[CH3:42])([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36])[CH2:27][CH2:26]3)=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C.O>[CH:41]([Si:34]([CH:35]([CH3:37])[CH3:36])([CH:38]([CH3:40])[CH3:39])[O:33][CH2:32][CH2:31][N:28]1[CH2:27][CH2:26][N:25]([C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:30][CH2:29]1)([CH3:42])[CH3:43]
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: CC(C)[Si](OCCN1CCN(c2nnc3ccc(F)cn23)CC1)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[Si](OCCN1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68 %

Procedure:
To a solution of Intermediate A (102 mg, 0.63 mmol) in DMF (1.5 mL) was added NaH (60% dispersion in oil, 68 mg, 1.71 mmol). The mixture was stirred at RT for 5 min, then a solution of Intermediate 94b (240 mg, 0.57 mmol) in DMF (1.5 mL) was added and the mixture stirred at 60° C. for 1.25 h. The cooled mixture was diluted with water and extracted with DCM (4×25 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-10% (2M NH3 in MeOH) in DCM, to give the title compound as a pale brown gum (219 mg, 68%). LCMS (Method 3): Rt 2.65 min, m/z 565 [MH+].
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][N:5]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=1)[C:6](=[O:11])[C:7]([F:10])([F:9])[F:8]>CC(O)C.[Pd]>[NH2:19][C:15]1[CH:14]=[C:13]([CH2:12][N:5]([CH2:4][CH2:3][N:2]([CH3:22])[CH3:1])[C:6](=[O:11])[C:7]([F:8])([F:9])[F:10])[CH:18]=[CH:17][CH:16]=1
Reactant: CN(C)CCN(Cc1cccc([N+](=O)[O-])c1)C(=O)C(F)(F)F
Agent: [Pd]
Solvent: CC(C)O
Product: CN(C)CCN(Cc1cccc(N)c1)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 17 h
Yield: 62 %

Procedure:
To a solution of N-[2-(dimethylamino)ethyl]-2,2,2-trifluoro-N-[(3-nitrophenyl)methyl]acetamide (204 mg, 0.64 mmol) in i-PrOH was added 10% Pd/C (20 mg, 0.02 mmol). A balloon charged with H2 was installed, and the reaction was stirred at rt under a hydrogen atmosphere. After 17 h, the reaction mixture was filtered through celite and adsorbed onto silica gel. The crude product was purified by column chromatography to generate the title compound in 62% yield. 1H NMR (400 MHz, CDCl3) δ 7.10 (t, J=7.9 Hz, 1H), 6.69-6.70 (m, 2H), 6.58 (d, J=7.9 Hz, 1H), 3.76 (s, 2H), 2.75 (t, J=6.0 Hz, 2H), 2.49 (t, J=6.0 Hz, 2H), 2.24 (s, 6H). ES-LC/MS m/z=290 [M+H]+.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[Cl:5][C:6]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:7]=1[CH:8]=[C:9]1[NH:13][C:12](=[O:14])[CH:11]=[C:10]1[OH:15]>C(O)(=O)C>[Cl:5][C:6]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:7]=1[CH:8]=[C:9]1[NH:13][C:12](=[O:14])[C:11](=[N:1][OH:3])[C:10]1=[O:15]
Reactant: O=C1C=C(O)C(=Cc2cccc(Cl)c2Cl)N1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NC(=Cc2cccc(Cl)c2Cl)C(=O)C1=NO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An aqueous solution of 1.1 mmol (0.075 g) sodium nitrite was added dropwise to an ice-cooled solution of 2 mmol 5-(2,3-dichlorobenzylidene)-4-hydroxy-1,5-dihydropyrrol-2-one (prepared in accordance with H. Poschenrieder et al (Arch. Pharm. Pharm. Med. Chem. 1998, 331, 389-394) and H.-D. Stachel et al (J. Heterocycl. Chem. 1980, vol. 17, pp. 1195-1199) and Liebigs Ann. Chem. 1985, pp. 1692-1696)) in 5 ml glacial acetic acid, while stirring. The resulting solution was then stirred at room temperature for 30 minutes and concentrated in vacuo. The residue is purified by recrystallization from ethanol. The yield of 5-(2,4-dichlorobenzylidene)-pyrrolidine-2,3,4-trione 3-oxime was 55%, with a melting point of 180° C.
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[CH2:6][NH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([O:17]CC1C=CC=CC=1)[N:12]=[CH:11]2>CO.[Pd]>[N:4]1[NH:3][N:2]=[N:1][C:5]=1[CH2:6][NH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([OH:17])[N:12]=[CH:11]2
Reactant: c1ccc(COn2ncc3cc(NCc4nn[nH]n4)ccc32)cc1
Agent: [Pd]
Solvent: CO
Product: On1ncc2cc(NCc3nn[nH]n3)ccc21
Reaction time: 8 h

Procedure:
To a solution of N-((2H-tetrazol-5-yl)methyl)-1-(benzyloxy)-1H-indazol-5-amine (43 mg, 0.14 mmol) in dry MeOH (10 mL) was added 10% Pd on charcoal (5 mg). The reaction was stirred under hydrogen atmosphere overnight, and then the solution was filtered over filter paper. Solvent was removed using a rotatory evaporator to provide the desired product, 76, (32 mg, 0.14 mmol) as a pale green solid in quantitative yield. 1H NMR (500 MHz, DMSO) δ 7.95 (s, 1H), 7.72 (s, 1H), 7.60 (d, J=8.5 Hz, 1H), 7.02 (dd, J=1.5, 8.5 Hz, H), 5.35 (s, 2H). 13C NMR (125 MHz, DMSO) δ 155.90, 140.24, 134.21, 129.74, 127.39, 123.31, 120.85, 110.81, 60.94. MS (ESI, CH3OH): [C9H9N7O] m/z 232.1 ([M+H]+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C@H:13]([C@@H:29]2[O:33]C(C)(C)[O:31][C:30]2=O)[C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)=[O:15])=[CH:6][CH:5]=1)[CH3:2].[NH2:37][OH:38].CC#N>CC(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][C@@H:13]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)=[O:15])[C@H:29]([OH:33])[C:30]([NH:37][OH:38])=[O:31])=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(CCC[C@@H](C(=O)N2CCN(c3ccc(F)cc3)CC2)[C@@H]2OC(C)(C)OC2=O)cc1
Reactant: NO
Solvent: CC(C)O
Solvent: CC#N
Product: CCOc1ccc(CCC[C@@H](C(=O)N2CCN(c3ccc(F)cc3)CC2)[C@H](O)C(=O)NO)cc1
Reaction time: 0.75 h
Yield: 66 %

Procedure:
To a solution of (5S)-5-((1R)-4-(4-ethoxyphenyl)-1-{[4-(4-fluorophenyl)-1-piperazinyl]carbonyl}butyl)-2,2-dimethyl-1,3-dioxolan-4-one (120 mg; 0.24 mmol; 1.0 eq.) in iPrOH (1 mL) was added an aq. solution of hydroxylamine (50%, 71 μl; 1.2 mmol; 5.0 eq.) and the reaction mixture was stirred for 45 min. CH3CN (4 mL) was then added and the resulting mixture was purified by chromatography by reverse-phase preparative HPLC (gradient from 25% to 45% of CH3CN containing 0.1% TFA, in water containing 0.1% TFA). The collected fractions were lyophilized to give the title compound (19) as a white solid (75 mg, 66%). 1H NMR (CDCl3, 300 MHz) δ 7.1-6.99 (m, 6H), 6.80 (d, J=8.2 Hz, 2H), 4.26 (m, 1H), 4.06 (m, 1H), 3.96 (t, 2H, J=6.8 Hz), 3.80 (m, 1H), 3.63 (m, 2H), 3.40 (m, 1H), 3.23-3.00 (m, 4H), 2.58 (m, 2H), 1.85-1.52 (m, 4H), 1.38 (t, J=6.9 Hz, 3H). M−(ESI): 472.1; M+(ESI): 474.6. HPLC: Rt: 3.2 min (HPLC purity: 93.7%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:27][C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)=[N:5][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11](CC3C=CC(OC)=CC=3)[N:10]=2)=[N:7][CH:8]=1.FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O.[OH-].[Na+]>ClCCCl>[NH:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]([C:6]2[N:5]=[C:4]([NH:27][C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[C:3]([O:2][CH3:1])=[CH:8][N:7]=2)=[N:10]1
Reactant: COc1ccc(Cn2nc(-c3ncc(OC)c(Nc4ccncc4)n3)c3ccccc32)cc1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cnc(-c2n[nH]c3ccccc23)nc1Nc1ccncc1
Reaction time: 72 h

Procedure:
13.4 g of 5-methoxy-2-[1-(4-methoxybenzyl)-1H-indazol-3-yl]-N-(pyridin-4-yl)-pyrimidin-4-amine (1-5-1, 30.6 mmol, 1 eq.) was suspended in 121 ml of 1,2-dichloroethan. First 71 ml of trifluoroacetic acid (918 mmol, 30 eq.) were added dropwise, followed by 27 ml of trifluoromethanesulfonic acid (306 mmol, 10 eq.). The reaction mixture was stirred for three days under nitrogen atmosphere. The mixture was cooled with an ice bath to +3° C., upon which 2M aq. sodium hydroxide solution was added until pH=12. The resulting brown suspension was stirred for 18 hours at room temperature and then the precipitate was filtered off and dried under vacuo at 70° C. to yield 9.74 g (27.7 mmol, 90.3%) of the analytically pure target compound as a light brown solid.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([C:11](O)([CH3:13])[CH3:12])[C:6]([CH3:10])=[N:7][C:8]=1[CH3:9].C(Cl)[Cl:16]>>[Cl:16][CH2:2][C:3]1[C:8]([CH3:9])=[N:7][C:6]([CH3:10])=[C:5]([C:11]([CH3:13])=[CH2:12])[CH:4]=1
Reactant: ClCCl
Reactant: Cc1nc(C)c(C(C)(C)O)cc1CO
Product: C=C(C)c1cc(CCl)c(C)nc1C
Reaction time: 11 h

Procedure:
To a stirring solution of 2-(5-(hydroxymethyl)-2,6-dimethylpyridin-3-yl)propan-2-ol in 10 mL of CH2Cl2 was added 1.5 mL of SO2Cl2. After 11 h at r.t., the solution was concentrated and CH2Cl2 and 10 mL of sat. NaHCO3 solution were added, and the layers were separated. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (20% Et2O/hexanes) provided 96.5 mg of the desired 3-(chloromethyl)-2,6-dimethyl-5-(prop-1-en-2-yl)pyridine as a mixture.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH:7]=1)=[O:5])[CH3:2].Br[CH2:19][C:20]1[C:21]([Cl:26])=[N:22][CH:23]=[CH:24][CH:25]=1>>[CH2:1]([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:19][C:20]3[C:21]([Cl:26])=[N:22][CH:23]=[CH:24][CH:25]=3)=[CH:15][CH:16]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: Clc1ncccc1CBr
Reactant: CCOC(=O)c1cc(-c2ccc(O)cc2)no1
Product: CCOC(=O)c1cc(-c2ccc(OCc3cccnc3Cl)cc2)no1

Procedure:
3-(4-Hydroxy-phenyl)-isoxazole-5-carboxylic acid ethyl ester (which may be prepared as described in Preparation of Intermediate 1) and 3-bromomethyl-2-chloro-pyridine (which may be prepared as described in Selby, T. P. and Winters, M. P. U.S. Pat. No. 5,739,326 Column 19) were reacted using conditions similar to those described for Preparation of Intermediate 24 to give 3-[4-(2-chloro-pyridin-3-ylmethoxy)-phenyl]-isoxazole-5-carboxylic acid ethyl ester.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=O)[CH2:7][C:8]([CH3:10])=O)C.S(O)(O)(=O)=O.[CH3:17][S:18][C:19](=[NH:21])[NH2:20].C(O)(=O)C>O>[CH3:17][S:18][C:19]1[N:21]=[C:6]([OH:5])[CH:7]=[C:8]([CH3:10])[N:20]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CSc1nc(C)cc(O)n1
Yield: 188.7 %

Procedure:
A solution of 120 g of sodium hydroxide (3 moles) in 250 ml of water was added dropwise at room temperature to a mixture of 195 g (1.5 moles) of acetoacetic acid ethyl ester, 210 g (0.76 mole) of S-methylisothiourea sulfate and 300 ml of water and the batch was allowed to react for a further 18 hours at room temperature. The reaction mixture was then acidified with acetic acid and the product which had crystallized out was filtered off and rinsed thoroughly with water. 224 g (96% of theory) of 2-methylmercapto-4-hydroxy-6-methyl-pyrimidine were obtained in the form of a colorless powder of melting point 219°C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6].[CH3:25][O:26][C:27]1[C:32](B(O)O)=[CH:31][CH:30]=[CH:29][N:28]=1>>[OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:18]([C:32]4[C:27]([O:26][CH3:25])=[N:28][CH:29]=[CH:30][CH:31]=4)=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6]
Reactant: CC(C)N(CCO)C(=O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Reactant: COc1ncccc1B(O)O
Product: COc1ncccc1-c1ccc2c(c1)-c1nc(C(=O)N(CCO)C(C)C)sc1CCO2
Yield: 7.2 %

Procedure:
Following the procedure for 277, 9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (2-hydroxy-ethyl)-isopropyl-amide (52.2 mg, 0.127 mmol) and 2-methoxypyridin-3-ylboronic acid (23.3 mg, 0.152 mmol) were reacted to give 299 (4.0 mg, 7% yield, M+1 440.1).
Reaction SMILES: CC(O)=O.[O:5]1[CH2:10][CH2:9][CH:8]([CH:11]=O)[CH2:7][CH2:6]1.[NH2:13][C:14]1[CH:15]=[C:16]([C@H:20]([OH:24])[CH2:21][C:22]#[N:23])[CH:17]=[CH:18][CH:19]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[OH:24][C@@H:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([NH:13][CH2:11][CH:8]2[CH2:7][CH2:6][O:5][CH2:10][CH2:9]2)[CH:15]=1)[CH2:21][C:22]#[N:23]
Reactant: O=CC1CCOCC1
Reactant: N#CC[C@@H](O)c1cccc(N)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: N#CC[C@@H](O)c1cccc(NCC2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
CH3COOH (1 mL) was added to a solution of tetrahydro-2H-pyran-4-carbaldehyde (0.7 g, 6.12 mmol) and (R)-3-(3-aminophenyl)-3-hydroxypropanenitrile (1.0 g, 6.12 mmol) in CH2Cl2 (20 mL) at 0° C. followed by the addition of Na(OAc)3BH (3.89 g, 18.34 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with NaHCO3 (50 mL), extracted with EtOAc (200 mL), organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (50% EtOAc: hexanes) gave (R)-3-hydroxy-3-(3-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)propanenitrile as a pale yellow liquid. Yield (1.0 g, 63%); 1H NMR (400 MHz, DMSO-d6) δ 7.02 (t, J=8.0 Hz, 1H), 6.62 (s, 1H), 6.51 (d, J=7.2 Hz, 1H), 6.47 (d, J=7.6 Hz, 1H), 5.77 (d, J=4.4 Hz, 1H), 5.68 (t, J=5.2 Hz, 1H), 4.73 (dd, J=10.8, 4.8 Hz, 1H), 3.85 (dd, J=10.8, 2.8 Hz, 2H), 3.26 (t, J=11.2 Hz, 2H), 2.89 (t, J=6.0 Hz, 2H), 2.82 (dd, J=16.8, 4.8 Hz, 1H), 2.73 (dd, J=16.8, 6.8 Hz, 1H), 1.81-1.75 (m, 1H), 1.66 (d, J=12.8 Hz, 2H), 1.23-1.19 (m, 2H).
Reaction SMILES: Cl.C([N:9]([C@@H:13]1[C@@:20]2([CH3:24])[C:21]([CH3:23])([CH3:22])[C@H:17]([CH2:18][CH2:19]2)[CH2:16][N:15]2[C:25](=[O:41])[C:26]([OH:40])=[C:27]([C:29](=[O:39])[NH:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[N:28]=[C:14]12)C(=O)O)C1C=CC=CC=1.[CH3:42][N:43]([CH3:49])[C:44](=[O:48])[C:45]([OH:47])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:38][C:35]1[CH:34]=[CH:33][C:32]([CH2:31][NH:30][C:29]([C:27]2[N:28]=[C:14]3[C@H:13]([NH:9][C:45](=[O:47])[C:44]([N:43]([CH3:49])[CH3:42])=[O:48])[C@@:20]4([CH3:24])[C:21]([CH3:23])([CH3:22])[C@H:17]([CH2:18][CH2:19]4)[CH2:16][N:15]3[C:25](=[O:41])[C:26]=2[OH:40])=[O:39])=[CH:37][CH:36]=1
Reactant: CN(C)C(=O)C(=O)O
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)[C@@H](N(Cc1ccccc1)C(=O)O)c1nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n1C2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)C(=O)N[C@H]1c2nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n2C[C@H]2CC[C@]1(C)C2(C)C
Yield: 72.8 %

Procedure:
A solution of benzyl((7S,10R,11R)-2-((4-fluorobenzyl)carbamoyl)-3-hydroxy-10,12,12-trimethyl-4-oxo-6,7,8,9,10,11-hexahydro-4H-7,10-methanopyrimido[1,2-a]azocin-11-yl)carbamate hydrochloride salt (0.0367 g, 0.081 mmol), 2-(dimethylamino)-2-oxoacetic acid (9.53 mg, 0.081 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (0.031 g, 0.081 mmol) and diisopropyl-ethylamine (0.014 mL, 0.081 mmol) in DMF (3 mL) was stirred at room temperature for 24 h. After this the crude reaction mixture was purified by preparative-HPLC using methanol/water (0.1% trifluoroacetic acid) to afford the title compound (0.0301 g, 0.059 mmol, 72% yield) as a purple solid. 1H NMR (500 MHz, CDCl3) δ: 12.01 (1H, s), 8.76 (1 H, t, J=6.0 Hz), 8.21 (1 H, d, J=9.8 Hz), 7.36-7.41 (2 H, m), 6.99-7.05 (2 H, m), 5.27 (1 H, d, J=9.8 Hz), 5.18 (1 H, dd, J=15.6, 8.9 Hz), 4.50-4.63 (2 H, m), 3.65 (1 H, d, J=15.6 Hz), 3.34 (3 H, s), 2.95 (3 H, s), 2.14 (1 H, t, J=8.2 Hz), 1.83-1.94 (1 H, m), 1.47-1.52 (1 H, m), 1.41 (1 H, dd, J=9.5, 5.2 Hz), 1.36 (3 H, s), 1.06 (1 H, dd, 9.8, 4.6 Hz), 1.03 (3 H, s), 0.97 (3 H, s). LCMS (M+H) calcd for C26H33FN5O5: 514.25; found: 514.29.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)=[O:21])=[CH:16][CH:15]=1.I[CH2:35][CH3:36]>>[CH2:35]([N:22]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:28][CH:29]=1)[C:20]([C:17]1[CH:16]=[CH:15][C:14]([C:3]2[CH:4]=[C:5]([C:8]3[O:9][C:10]([CH3:13])=[N:11][N:12]=3)[CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:19][CH:18]=1)=[O:21])[CH3:36]
Reactant: CCI
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4ccc(C(F)(F)F)cc4)cc3)c2)o1
Product: CCN(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccc(-c2cc(-c3nnc(C)o3)ccc2C)cc1

Procedure:
N-Ethyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(4-trifluoromethylbenzyl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(4-trifluoromethylbenzyl)-1,1′-biphenyl-4-carboxamide and iodoethane using method L. NMR; δH [2H6]—DMSO 7.89,(1H, d), 7.77-7.73,(3H, m), 7.60-7.46,(7H, m) 4.79-4.64,(2H, b), 3.41-3.26,(2H, b), 2.55,(3H, s), 2.32,(3H, s), 1.08,(3H, b). LCMS; retention time 3.78 min, MH+ 480.
Reaction SMILES: C([SH-:5][C:6](=[S:24])[SH-:7][C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[N+]([O-])=O)(C)(C)C.O>C(O)(=O)C>[N+:14]([C:13]1[C:8]2[S:7][C:6](=[S:24])[S:5][C:9]=2[CH:10]=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:12]=1)([O-:16])=[O:15]
Reactant: CC(C)(C)[SH-]C(=S)[SH-]c1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(C(F)(F)F)cc2sc(=S)sc12
Yield: 54.5 %

Procedure:
15 g (0.037 mole) of III was dissolved in 125 ml of glacial acetic acid and heated to 90°-100° C. for 45 minutes. The mixture was poured into 500 ml of water, extracted with three 100 ml portions of methylene chloride. The organic extract was dried (Na2SO4) and solvent removed by distillation in vac. The residual solid was recrystallized from ethanol. There was obtained 6.0 g (55% theor.) of 4-nitro-6-trifluoromethyl-1,3-benzodithiole-2-thione, m.p. 163°-165° C. Analytical: Calcd. for C8H2F3NO2S3 : C, 32.32; H, 0.67; S, 32.32. Found: C, 32.18; H, 0.74; S, 32.21. Mass Spectrum mol. wt.=297. NMR(d6DMSO); 8.63δ(1H,m); 8.73(1H,m).
Reaction SMILES: [CH:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS(O[CH2:18][CH2:19][C@@:20]1([C:42]2[CH:47]=[CH:46][C:45]([Cl:48])=[C:44]([Cl:49])[CH:43]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:41])[CH2:26][C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=2)[CH2:21]1)(=O)=O.C(#N)C>>[Cl:49][C:44]1[CH:43]=[C:42]([C@@:20]2([CH2:19][CH2:18][N:10]3[CH2:11][CH2:12][N:7]([CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:8][CH2:9]3)[CH2:24][CH2:23][N:22]([C:25](=[O:41])[CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:30]=[C:29]([C:37]([F:40])([F:38])[F:39])[CH:28]=3)[CH2:21]2)[CH:47]=[CH:46][C:45]=1[Cl:48]
Reactant: CS(=O)(=O)OCC[C@@]1(c2ccc(Cl)c(Cl)c2)CCN(C(=O)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Reactant: C1CCC(N2CCNCC2)CC1
Solvent: CC#N
Product: O=C(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@](CCN2CCN(C3CCCCC3)CC2)(c2ccc(Cl)c(Cl)c2)C1

Procedure:
In 30 ml of acetonitrile (R)-3-(2-methanesulfonyloxyethyl)-3-(3,4-dichlorophenyl)-1-[[3,5-bis(trifluoromethyl)phenyl]acetyl]pyrrolidine (3.17 g), prepared as described, supra, is mixed with an equimolar amount of 1-cyclohexylpiperazine. The reaction mixture is then heated to reflux and refluxed for about ten hours. The mixture is then concentrated under vacuum and the residue is taken up in methylene chloride and washed with a 3N solution of hydrochloric acid, followed by a wash with brine. The organic fraction is dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue precipitates from an acetone/diethyl ether mixture to give the desired title product.