Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][CH:3]=1.CCN(S(F)(F)[F:16])CC>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][F:16])[N:7]=1
Reactant: OCc1cccc(Br)n1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: FCc1cccc(Br)n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
A solution of (6-bromopyridin-2-yl)methanol (5 g, 27 mmol) in dry DCM (60 mL) was added dropwise at −78° C. to a cooled solution of DAST (13 g, 80 mmol) in dry DCM (50 mL). The reaction mixture was stirred 1 h at −78° C. then 1 h at room temperature. To complete the reaction, an additional 5 mL of DAST were slowly added at −60° C. and the reaction mixture was kept overnight at room temperature. The reaction was quenched with water and the organic layer extracted with DCM, dried over MgSO4 and evaporated. Purification over silicagel chromatography (prepacked 85 g silicagel column, Cyclohexane/AcOEt: 90/10 as eluent) to afford 4.50 g of 2-bromo-6-(fluoromethyl)pyridine
Reaction SMILES: C([O:3][C:4](=[O:33])[CH:5]([C:10]1[CH:15]=[C:14]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[C:12]([Cl:32])[CH:11]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[Li+].[OH-]>CO.C1COCC1.O>[Cl:32][C:12]1[CH:11]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([OH:33])=[O:3])[CH:15]=[C:14]([O:16][CH2:17][C:18]([F:20])([F:21])[F:19])[C:13]=1[C:22]1[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=1
Reactant: CCOC(=O)C(CC(C)C)c1cc(Cl)c(-c2ccc(C(F)(F)F)cc2)c(OCC(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CC(C(=O)O)c1cc(Cl)c(-c2ccc(C(F)(F)F)cc2)c(OCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 24.7 %

Procedure:
Ethyl-2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-4-methylpentanoate (0.35 g, 0.733 mmol) was dissolved in 25 mL of MeOH/THF/H2O (10:10:5, vvl), LiOH (0.176 g, 7.33 mmol) was added. The reaction mixture was stirred for 5 h at room temperature and concentrated under reduced pressure. Water (10 mL) was added and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over Na2SO4, filtered and evaporated under reduced pressure. Purification by column chromatography over silica gel (DCM/MeOH, 95:5) gave the compound 2-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)-4-methylpentanoic acid (0.085 g) as a white solid. 1H NMR (500 MHz, CDCl3): δ 7.69 (d, 2H), 7.41 (d, 2H), 7.20 (s, 1H), 6.86 (s, 1H), 4.23 (q, 2H), 3.71 (t, 1H), 2.01 (m, 1H), 1.73 (m, 1H), 1.58 (m, 1H), 0.98 (d, 6H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[F:9][C:10]1[C:22]([F:23])=[C:21]([F:24])[C:20]([F:25])=[C:19]([F:26])[C:11]=1[O:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.Cl[CH2:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[O:43][CH3:44])[CH2:33][CH2:32]1>CN(C)C=O.O>[CH3:44][O:43][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[N:34]1[CH2:33][CH2:32][N:31]([CH2:30][CH2:29][CH2:28][N:16]2[CH2:17][CH2:18][CH:13]([O:12][C:11]3[C:19]([F:26])=[C:20]([F:25])[C:21]([F:24])=[C:22]([F:23])[C:10]=3[F:9])[CH2:14][CH2:15]2)[CH2:36][CH2:35]1
Reactant: COc1ccccc1N1CCN(CCCCl)CC1
Reactant: Fc1c(F)c(F)c(OC2CCNCC2)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(CCCN2CCC(Oc3c(F)c(F)c(F)c(F)c3F)CC2)CC1
Temperature: 75 °C
Reaction time: 7 h
Yield: 51.4 %

Procedure:
A mixture of 10 g of potassium carbonate, 0.18 g of potassium iodide, 4.0 g of 4-(2,3,4,5,6-pentafluorophenoxy)piperidine and 50 ml of dimethylformamide was treated with a solution of 4.56 g of 1-(3-chloropropyl)-4-(2-methoxyphenyl)piperazine in 25 ml dimethylformamide and stirred for seven hours at 75° C. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water followed by a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering, evaporation afforded a residue which was purified by means of high pressure liquid chromatography (silica gel; elution with 7.5% methanol/dichloromethane). Evaporation of the appropriate fractions afforded 3.84 g of 1-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl}-4-(2,3,4,5,6-pentafluorophenoxy)piperidine as an oil. The oil was dissolved in isopropanol and acidified to pH 1 with etheral hydrogen chloride to precipitate the corresponding dihydrochloride salt. Recrystallization from isopropanol afforded 3.34 g (44.6%) of 1-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl}-4-(2,3,4,5,6-pentaflurophenoxy)piperidine hydrochloride, m.p. 261°-263° C.
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][NH2:9].[CH3:11][C:12]([CH3:19])([CH3:18])[C:13](=O)[CH2:14][C:15]#[N:16].CCN(CC)CC>C1(C)C=CC=CC=1>[C:12]([C:13]1[CH:14]=[C:15]([NH2:16])[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:10])[N:9]=1)([CH3:19])([CH3:18])[CH3:11]
Reactant: Cc1ccccc1NN
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccccc1-n1nc(C(C)(C)C)cc1N
Reaction time: 0.25 h

Procedure:
A solution of o-tolyl-hydrazine hydrochloride (0.3 mmol) in 0.5 mL of toluene with 4,4-dimethyl-3-oxopentanenitrile (375 mg, 3 mmol, 10 equiv) and Et3N (84 μL, 0.6 mmol, 2 equiv) is stirred at 110° C. overnight. The solvent is evaporated and the residue taken up in EtOAC and washed with saturated NaHCO3 and brine. The organic layer is then concentrated and the residue diluted in 1 mL of ethanol and 1 mL of 1M HCl. The mixture was left at rt for 15 min and then it was concentrated. 5-tert-Butyl-2-o-tolyl-2H-pyrazol-3-ylamine is used crude in the preparation of Example 34.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])=[CH:16][CH:15]=3)=[O:13])[CH:10]=2)[NH:5][C:4]1=[O:31].[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1>C1COCC1>[N:39]1([C:36]2[CH:35]=[CH:34][C:33]([NH:32][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]5[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]6[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=6)=[O:22])=[CH:16][CH:15]=5)=[O:13])[CH:10]=4)[NH:5][C:4]3=[O:31])=[CH:38][CH:37]=2)[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: CCn1nc(C)cc1C(=O)Nc1ccc(C(=O)c2ccc3c(c2)C(=CO)C(=O)N3)cc1
Solvent: C1CCOC1
Product: CCn1nc(C)cc1C(=O)Nc1ccc(C(=O)c2ccc3c(c2)C(=CNc2ccc(N4CCOCC4)cc2)C(=O)N3)cc1
Temperature: 65 °C
Reaction time: 24 h
Yield: 49.4 %

Procedure:
A small screw cap test tube was charged with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-5-carbonyl)-phenyl]-amide (prepared below, 70 mg, 0.168 mmol) and THF (2 mL). To the resulting solution was added N-(4-aminophenyl)morpholine (32.9 mg, 0.184 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 49% (48 mg, 0.083 mmol) of the title compound.
Reaction SMILES: [I-].[CH2:2]([O:9][C:10]([NH:12][CH:13]([C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Br:28])[C:23]=1[CH3:29])=[O:20])[CH2:14][CH2:15][S+](C)C)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.CCOC(C)=O>[Br:28][C:24]1[C:23]([CH3:29])=[C:22]([N:21]2[CH2:15][CH2:14][CH:13]([NH:12][C:10](=[O:11])[O:9][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:19]2=[O:20])[CH:27]=[CH:26][CH:25]=1
Reactant: Cc1c(Br)cccc1NC(=O)C(CC[S+](C)C)NC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1c(Br)cccc1N1CCC(NC(=O)OCc2ccccc2)C1=O
Reaction time: 4.5 h
Yield: 93.8 %

Procedure:
Step 3 A solution of racemic (3-(benzyloxycarbonylamino)-4-(3-bromo-2-methylphenylamino)-4-oxobutyl)dimethylsulfonium iodide (1.96 g, 3.30 mmol) in anhydrous DMSO (33 mL) was stirred at rt and treated with cesium carbonate (2.69 g, 8.26 mmol) in 3 portions over 25 min. After 4.5 h, the mixture was diluted with EtOAc, washed three times with water and twice with brine, dried and concentrated to provide racemic benzyl 1-(3-bromo-2-methylphenyl)-2-oxopyrrolidin-3-ylcarbamate as a tan solid (1.248 g, 94%). 1H NMR (400 MHz, chloroform-d) δ 7.52-7.58 (1H, m), 7.30-7.40 (5H, m), 7.10 (2H, d, J=5.1 Hz), 5.47 (1H, br. s.), 5.15 (2H, s), 4.39 (1H, ddd, J=10.6, 8.3, 5.2 Hz), 3.72 (1H, td, J=9.9, 6.4 Hz), 3.60 (1H, t, J=9.4 Hz), 2.27 (3H, s), 2.11-2.26 (2H, m). Mass spectrum m/z 425, 427 (M+Na)+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][Cl:37]>CN(C=O)C>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][Cl:37])=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: ClCCCCCBr
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCCCl)c2n1
Temperature: 50 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
2-(Butyloxy)-8-(methyloxy)-9H-purin-6-amine trifluoroacetate (2 g, 5.69 mmol) and potassium carbonate (1.967 g, 14.23 mmol) were suspended in DMF (20 ml) and heated to 50° C., under nitrogen for 1 hour. The mixture was cooled to room temperature, 1-bromo-5-chloropentane (0.75 ml, 5.69 mmol) was added and stirring was continued at room temperature for 18 hours. The reaction mixture was partitioned between DCM (40 ml) and water (40 ml) and the layers were separated using a hydrophobic frit. The aqueous layer was extracted again with DCM (10 ml) and the combined organics were washed with saturated lithium chloride solution, separated (hydrophobic frit) and concentrated in vacuo to give the title compound as a yellow oil (1.946 g).
Reaction SMILES: [Cl:1][C:2]1[N:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[CH:4]=[O:5].N1C=CN=C1.[C:16]1(=[O:21])[CH2:20][CH2:19][CH:18]=[CH:17]1>CO.O>[Cl:1][C:2]1[C:3]([CH:4]([OH:5])[C:17]2[C:16](=[O:21])[CH2:20][CH2:19][CH:18]=2)=[CH:6][C:7]([CH3:10])=[CH:8][N:9]=1
Reactant: O=C1C=CCC1
Reactant: Cc1cnc(Cl)c(C=O)c1
Agent: c1c[nH]cn1
Solvent: CO
Solvent: O
Product: Cc1cnc(Cl)c(C(O)C2=CCCC2=O)c1
Yield: 98 %

Procedure:
The clear solution of 2-Chloro-5-methylnicotinaldehyde (10 mmol, 1.55 g) and imidazole (10 mmol, 0.68 g) in 50 ml. of MeOH was slowly charged with 50 ml. of deionized water. To a stirred homogeneous reaction mixture was added 2-cyclopenten-1-one (10.2 mmol., 0.88 g) at room temperature and reaction progress was monitored by TLC. Upon completion of the reaction, excess MeOH was removed under reduced pressure, washed with water and extracted with CHCl3 thrice. Combined organic layers were washed with brine solution twice. The organic layer was concentrated and column chromatography of the crude product on silica gel, using 30% EtOAC in hexane as eluent, gave pure Baylis-Hillman adduct in 98% yield (2.32 g)
Reaction SMILES: [C:1]1([C:7]2([C:12]([OH:14])=O)[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:17])=O>>[C:1]1([C:7]2([C:12]([Cl:17])=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1(c2ccccc2)CCCC1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)C1(c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The carboxylic acid chlorides used in the synthesis of the parent amides were all synthesized as described below. In a 1-liter 3-neck flask, 200 gm (1.05 mole) of 1-phenylcyclopentanecarboxylic acid (ACROS ORGANICS) was added drop-wise to stirring excess of thionyl chloride (Aldrich) under nitrogen. The resulting mixture was heated at reflux for two hrs. The reaction was further stirred at room temperature overnight. The resulting brown-red solution was concentrated at reduced pressure and heat on a rotary evaporator to remove excess thionyl chloride. The reaction yielded 216 gm in of a lachrymator substance whose 1H-NMR and 13C-NMR spectra were ideal for the desired acid chloride.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[S:30][C:29]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:28][CH:27]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[S:30][C:29]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:28][CH:27]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: NS(=O)(=O)c1ccc(Br)s1
Product: NS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 7-difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (169 mg, 0.5 mmol) and commercially available 5-bromo-thiophene-2-sulfonamide (121 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (192 mg, 77%). MS (ISN) 497.0 [(M−H)−]; mp 210° C.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([NH:27][C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCc1ccccc1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Product: c1ccc(CNc2nccc(-n3cnc4ccccc43)n2)cc1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with benzylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[N:10]([C:19]1[S:20][CH:21]=[CH:22][N:23]=1)[CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][NH:14]1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:28](C)=O.[Na+].C(O)(=O)C>ClCCCl.C(OCC)(=O)C.[OH-].[Na+]>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[N:10]([C:19]1[S:20][CH:21]=[CH:22][N:23]=1)[CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][N:14]1[CH3:28]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: c1ccc2c(c1)CC(N(CCC1CCCCN1)c1nccs1)C2
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN1CCCCC1CCN(c1nccs1)C1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of compound 53 (0.53 g, 1.62 mmol) in DCE (25 mL) were added successively formaldehyde (35% solution in H2O, 0.2 mL, 2.43 mmol), Na(OAc)3BH (1.03 g, 4.86 mmol) and acetic acid (0.2 mL) at 0° C., and the solution was allowed to stir at rt for 16 hours. The reaction mixture was diluted with ethyl acetate and basified with 1N NaOH solution. The organic layer was separated and washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude material was purified by chromatography on neutral alumina eluting 1% methanol-DCM to get compound 54.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH2:4][N:5]([C:7]([C:9]1[C:18]2[C:13](=[C:14]([Br:19])[CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)=[O:8])[CH3:6].[OH-].[Na+].Cl>CO>[Br:19][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[CH:12]=[CH:11][CH:10]=[C:9]2[C:7]([N:5]([CH3:6])[CH2:4][C:3]([OH:20])=[O:2])=[O:8]
Reactant: COC(=O)CN(C)C(=O)c1cccc2c(Br)cccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(CC(=O)O)C(=O)c1cccc2c(Br)cccc12
Reaction time: 1.5 h
Yield: 91.7 %

Procedure:
N-[(5-Bromo-1-naphthalenyl)carbonyl]-N-methylglycine methyl ester (3.7 g, 11.0 mmoles, described in Example 2) was suspended in methanol (50 ml). A solution of 1N aqueous NaOH (13.2 ml) was added to the suspension. The mixture was stirred at 20°-22° C. for 1.5 hr. The mixture was neutralized with aqueous HCl and concentrated under reduced pressure to remove the methanol. The residual solution was made acidic with aqueous HCl and extracted with ethyl acetate. The extract was dried (MgSO4), filtered and evaporated to dryness. The residue was crystallized from ethanol-water to give 3.25 g of the title compound; mp 205° C.; NMR (DMSO-d6) δ 2.75 & 3.10 (2s, 3H), 2.75 & 3.10 (2s, 3H), 3.75 & 4.25 (2s, 2H), 7.3-8.3 (m, 6H); IR (Nujol*) 1745 with inflection at 1720, 1580 cm-1 ; UVλmax (EtOH) 322 nm (ε680), 316 (1,000), 299 (6,510), 289 (9.055), 279 (7,150) 226 (63,080); Anal Calcd: C, 52.19% H, 3.76% N, 4.35%; Found: C, 52.09% H, 38.4% N, 4.48%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:10]2=[O:16])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].CI.[C:21](O)(=O)C>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]([CH3:21])[C:10]2=[O:16])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2CCCCNC2=O)c1
Reactant: CC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: Cc1ccccc1
Product: COc1cccc(C2C=CC=CN(C)C2=O)c1
Temperature: 5 °C

Procedure:
Hexahydro-3-(3-methoxyphenyl)-2H-azepin-2-one (2.2 g) in dry toluene (40 ml) was added dropwise to a stirred suspension of sodium hydride (0.62 g, 0.015 mole of 50% dispension in oil, pre-washed with dry light petroleum (b.p. 40°-60°). After stirring and heating at 60° for 1 hour the reaction was cooled to 5° C. and methyl iodide (1.9 ml, 2.5 g, 0.02 mole) was added rapidly. After stirring at ambient temperature for 20 hours acetic acid and water were added. The aqueous layer was separated and washed with toluene. Toluene extracts were washed with water, dried over anhydrous magnesium sulphate and evaporated to an oil. Oil was recrystallised from ethylacetate light petroleum (b.p. 60°-80°) affording 1.95 g (83%) of hexahydro-(3-(3-methoxyphenyl)-1-methyl-2H-azepin-2-one, in several crops, m.p. 74°-5° C.
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[C:10]([Cl:11])=[C:9]([SH:12])[CH:8]=[CH:7][C:6]=1[NH:13][C:14](=[O:22])[C@:15]([OH:21])([CH3:20])[C:16]([F:19])([F:18])[F:17].[O:23]1[CH:25]([CH2:26][CH3:27])[CH2:24]1.CCOC(C)=O>C1COCC1>[OH:23][CH:25]([CH2:26][CH3:27])[CH2:24][S:12][C:9]1[CH:8]=[CH:7][C:6]([NH:13][C:14](=[O:22])[C@:15]([OH:21])([CH3:20])[C:16]([F:17])([F:18])[F:19])=[C:5]([Cl:4])[C:10]=1[Cl:11]
Reactant: C[C@@](O)(C(=O)Nc1ccc(S)c(Cl)c1Cl)C(F)(F)F
Reactant: CCC1CO1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(O)CSc1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Sodium methoxide (0.075 g) was added to a stirred solution of (R)-N-[2,3-dichloro-4-mercaptophenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Method 35) (0.44 g) in anhydrous THF (10 ml). The reaction mixture was stirred at ambient temperature for 5 minutes and 1,2-epoxybutane (0.11 ml) was added. The mixture was heated under reflux for 2 hours and allowed to cool to ambient temperature. EtOAc (150 ml) was added and the mixture washed with brine (100 ml) and dried. Volatile material was removed by evaporation and the residue was purified on a 20 g silica Mega Bond Elut column eluting with 1-40% EtOAc/isohexane to give the title compound (0.259 g) as an orange solid. NMR: 0.88 (t, 3H), 1.35-1.49 (m, 1H), 1.58 (s, 3H), 2.97-3.08 (m, 1H), 3.53-3.62 (m, 1H), 5.00 (d, 1H), 7.42 (d, 1H), 7.77 (d, 1H), 9.79 (brs, 1H); m/z: 404.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[CH:19]([C:21]1[C:22]([O:33][CH3:34])=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:25][CH:26]=1)[OH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl.[O-2].[O-2].[Mn+4]>[CH2:1]([O:8][C:9]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C:19]([C:21]1[C:22]([O:33][CH3:34])=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:25][CH:26]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(-c2ccccc2)cccc1C(O)c1cccc(C(C)(C)C)c1OCc1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1c(C(=O)c2cccc(C(C)(C)C)c2OCc2ccccc2)cccc1-c1ccccc1
Yield: 59.2 %

Procedure:
A solution of crude 10 (4.5 mmol) in dichloromethane (80 mL) was treated with manganese dioxide (85%, 6 g, 15 equiv.) and this suspension was stirred at reflux for 6 hr. The solids were filtered out and washed with ethyl acetate. The solvent was removed in a rotary evaporator and the residue was chromatographed on silica (65 g) with 2% ethyl acetate in heptane (3 L). Pure 11 (1.2 g, 59%) was isolated.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13](O)=[O:14])(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+]>C1COCC1.O>[N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH2:13][OH:14])[CH:16]=[CH:17][CH:18]=2)(=[O:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc(CO)c1)N1CCCCC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 105.6 %

Procedure:
3-(Piperidin-1-ylsulfonyl)benzoic acid (7.00 g) was dissolved in THF (70 mL), and at 0° C., N,N′-carbodiimidazole (6.32 g) was added thereto and stirred at 0° C. for 4 hours. A solution prepared by dissolving sodium borohydride (1.97 g) in water (10 mL) was dropwise added to the reaction liquid, and then stirred at 0° C. for 1 hour. Water was added thereto, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried with sodium sulfate. The drying agent was removed through filtration, and the solvent was evaporated off under reduced pressure. The residue was purified through silica gel column chromatography (ethyl acetate/hexane=from 0% to 100%, gradient) to give the entitled compound (7.01 g, 100%) as a colorless oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][C:7]=1[F:20].[CH3:21][N:22]([CH3:28])[C@@H:23]1[CH2:27][CH2:26][NH:25][CH2:24]1>>[CH3:21][N:22]([CH3:28])[C@@H:23]1[CH2:27][CH2:26][N:25]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=3)=[CH:8][C:7]=2[F:20])[CH2:24]1
Reactant: CN(C)[C@@H]1CCNC1
Reactant: N#Cc1ccc(-c2ccc(OCCCCl)c(F)c2)cc1
Product: CN(C)[C@@H]1CCN(CCCOc2ccc(-c3ccc(C#N)cc3)cc2F)C1
Yield: 60 %

Procedure:
The product from Example 167B and (3R)-N,N-dimethyl-3-pyrrolidinamine were processed as described in Example 164D to provide the title compound (60% yield). 1HNMR (300 MHz, CDCl3) δ2.00-3.00 (m, 16H), 3.20 (m, 1H), 4.20 (m, 2H), 7.10-7.75 (m, 7H); MS (ESI) m/z 368 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.CO[CH:9](OC)[N:10]([CH3:12])[CH3:11]>>[CH3:9][N:10]([CH:12]=[N:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1)[CH3:11]
Reactant: Nc1ncc[nH]1
Reactant: COC(OC)N(C)C
Product: CN(C)C=Nc1ncc[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the crude 2-aminoimidazole (18.2 g) was added dimethylformamide dimethyl acetal (145 mL) (Aldrich) and stirred at room temperature overnight. The reagent was removed in vacuo to give crude 2 (32.66 g) which was taken on to the next step (tritylation) without further purification.