Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][C@@H:12]([C:14]3[O:18][NH:17][C:16](=[O:19])[CH:15]=3)[CH2:11][CH2:10][N:9]2C(OC)=O)=[CH:4][CH:3]=1.Br>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][C@@H:12]([C:14]3[O:18][NH:17][C:16](=[O:19])[CH:15]=3)[CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(Cl)cc1
Agent: Br
Product: O=c1cc([C@H]2CCN[C@@H](c3ccc(Cl)cc3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
(2R,4S)-Methyl 2-(4-chlorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.447 g, 1.33 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 10.46 mL, 59.73 mmol) and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2R,4S)-2-(4-chlorophenyl)piperidin-4-yl)isoxazol-3(2H)-one (233 mg, 63%). 1H NMR (600 MHz, dmso) δ 1.32 (q, 1H), 1.44 (dq, 1H), 1.82-1.88 (m, 1H), 1.90-1.97 (m, 1H), 2.71 (dt, 1H), 2.80-2.88 (m, 1H), 3.06-3.12 (m, 1H), 3.63 (dd, 1H), 5.70 (s, 1H), 7.31-7.35 (m, 2H), 7.35-7.40 (m, 2H). HRMS Calculated for [C14H15ClN2O2+H]+: 279.0900. Found: 279.0905
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CS([C:11]1[N:12]=[C:13]([O:30][CH:31]2[CH2:34][O:33][CH2:32]2)[C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([O:27][CH3:28])=[C:22]([CH3:29])[CH:21]=3)[O:17][C:15]=2[N:16]=1)(=O)=O.[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[OH:42]>CN(C=O)C>[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[O:42][C:11]1[N:12]=[C:13]([O:30][CH:31]2[CH2:34][O:33][CH2:32]2)[C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([O:27][CH3:28])=[C:22]([CH3:29])[CH:21]=3)[O:17][C:15]=2[N:16]=1
Reactant: Oc1ccccc1F
Reactant: COc1c(C)cc(-c2nc3c(OC4COC4)nc(S(C)(=O)=O)nc3o2)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1c(C)cc(-c2nc3c(OC4COC4)nc(Oc4ccccc4F)nc3o2)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 143.8 %

Procedure:
410 mg of potassium carbonate and 547 mg of 5-methanesulfonyl-2-(4-methoxy-3,5-dimethyl-phenyl)-7-(oxetan-3-yloxy)-oxazolo[5,4-d]pyrimidine were added to a solution of 49 mg of 2-fluorophenol in 8 ml of DMF. The mixture was stirred at room temperature for 2 h. After filtration, the solvent was distilled off in vacuo, and the product was isolated by silica gel chromatography (heptane/ethyl acetate gradient) to yield 275 mg of the title compound.
Reaction SMILES: [OH:1][C@H:2]1[CH2:37][C@@H:36]2[C@:23]([CH3:40])([CH2:24][CH2:25][C@H:26]3[C@H:35]2[CH2:34][CH:33]=[C:32]2[C@:27]3([CH3:39])[CH2:28][CH2:29][C@H:30]([OH:38])[CH2:31]2)[C@H:3]1[C@H:4]([CH3:22])[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:21])[CH2:9][N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20].C([O-])(=O)C.[Na+]>O.C(O)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[O:1]=[C:2]1[CH2:37][C@@H:36]2[C@:23]([CH3:40])([CH2:24][CH2:25][C@H:26]3[C@H:35]2[CH2:34][CH:33]=[C:32]2[C@:27]3([CH3:39])[CH2:28][CH2:29][C@H:30]([OH:38])[CH2:31]2)[C@H:3]1[C@H:4]([CH3:22])[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:21])[CH2:9][N:10]1[C:11](=[O:20])[C:12]2=[CH:19][CH:18]=[CH:17][CH:16]=[C:13]2[C:14]1=[O:15]
Reactant: C[C@H](CCC[C@@H](C)[C@H]1[C@@H](O)C[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)CN1C(=O)c2ccccc2C1=O
Agent: [Cr+6]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: C[C@H](CCC[C@@H](C)[C@H]1C(=O)C[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 86 %

Procedure:
A solution of chromium trioxide (0.04 g, 0.4 mmoles) in water (0.15 ml) and acetic acid (0.3 ml) was added dropwise to a solution of (25R)-16β-hydroxy-26-phthalimidocholesterol (4) (0.26 g, 0.49 mmoles), and sodium acetate (1.00 g, 12.19 mmoles) in acetic acid (35 ml), and stirred for 18 hours at room temperature. The excess reagent was then destroyed with methanol (15 ml), and solvent was evaporated under reduced pressure. The resulting residue was diluted with water, and extracted with methylene chloride. The organic layer was washed with 5% K2CO3 and water, dried over sodium sulfate, and evaporated under reduced pressure to yield 0.23 g (89%) of (25R)-16-oxo-26-phthalimidocholesterol (5). The product was recrystallized from acetone and was found to have a melting point of 178°-180° C. Elemental and structural 1H-NMR) analyses of the product are described below.
Reaction SMILES: [N:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7])=[N+:2]=[N-:3].[C:12](O)(=[O:15])[C:13]#[CH:14].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:12]([O:7][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N:1]=[N+:2]=[N-:3])(=[O:15])[C:13]#[CH:14]
Reactant: [N-]=[N+]=Nc1ccccc1CO
Reactant: C#CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C#CC(=O)OCc1ccccc1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 51 %

Procedure:
To a solution of 2-azidobenzyl alcohol (15.66 g, 105.1 mol) in 200 mL of methylene chloride was added propiolic acid (7.1 mL, 115.6 immol), dicyclohexylcarbodiimide (20.0 g, 110.3 mnmol) and 4-dimethylaminopyridine (1.93 g, 15.8 mmol). The resulting mixture was allowed to stir at ambient temperature for 18 h. The mixture was filtered, concentrated and the residue was purified by flash chromatography (elution with 1:1 hexanes/ethyl acetate) to afford 10.7 g (51%) of the title compound. 1H NMR (CDCl3) δ7.40 (m, 2H), 7.17 (m, 2H), 5.20 (s, 2H), 2.92 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([NH2:13])[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:15]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([NH:13][S:20]([C:16]3[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=3)(=[O:22])=[O:21])[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: COc1cc(N)c2ncccc2c1
Product: COc1cc(NS(=O)(=O)c2cccnc2)c2ncccc2c1
Yield: 38.3 %

Procedure:
In a similar fashion using route 14 general procedure 26, 6-methoxyquinolin-8-amine (Intermediate 23) (50 mg, 0.29 mmol), pyridine-3-sulfonyl chloride (Intermediate 17) (76 mg, 0.43 mmol) gave the title compound (35 mg, 39%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O)=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:31][CH2:32][CH2:33][C:34]1([CH2:40][CH2:41][N:42]2[CH2:47][CH2:46][CH:45]([N:48]([C:56]3[CH:61]=[CH:60][C:59]([CH3:62])=[CH:58][CH:57]=3)[C:49]([C:51]3[O:52][CH:53]=[CH:54][CH:55]=3)=[O:50])[CH2:44][CH2:43]2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>ClCCCl.C(Cl)(Cl)Cl>[O:7]=[C:5]1[C:4]2[C:3](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:1][N:31]1[CH2:32][CH2:33][C:34]1([CH2:40][CH2:41][N:42]2[CH2:47][CH2:46][CH:45]([N:48]([C:56]3[CH:57]=[CH:58][C:59]([CH3:62])=[CH:60][CH:61]=3)[C:49]([C:51]3[O:52][CH:53]=[CH:54][CH:55]=3)=[O:50])[CH2:44][CH2:43]2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: COC(=O)c1ccccc1C=O
Reactant: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CCN)CCCCC3)CC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CCN4Cc5ccccc5C4=O)CCCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
After adding methyl 2-formylbenzoate (254 mg, 1.55 mmol), acetic acid (89 μL, 1.55 mmol) and sodium triacetoxyborohydride (265 mg, 1.25 mmol) to a solution of N-[1-[2-[1-(2-aminoethyl)cyclohexyl]ethyl]piperidin-4-yl]-N-(p-tolyl)-2-furancarboxamide (226 mg, 0.52 mmol) in 1,2-dichloroethane (3 mL), the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with chloroform and washed with saturated aqueous sodium hydrogencarbonate and saturated brine in that order. The organic layer was dried (anhydrous sodium sulfate) and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (10 g NH Silica Chromatorex DM2035, hexane:ethyl acetate=7:3-1:1) to obtain the title compound as a colorless oil (194 mg, 0.26 mmol) (67% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[N:14][O:15][C:16]=2[CH:17]=[O:18])=[N:6][CH:5]=1.[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(OCC)(=O)C>CO>[CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)=[N:14][O:15][C:16]=2[CH2:17][OH:18])=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2C=O)nc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)nc1
Yield: 103.4 %

Procedure:
6-[3-(4-Fluoro-phenyl)-5-formyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (2.50 g, 7.02 mmol) and sodium borohydride (553 mg, 14.0 mmol) in methanol (125 mL) were stirred for 2 h at room temperature. Addition of 10% aqueous citric acid (200 mL) and extraction with ethyl acetate yielded 6-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (2.60 g, quant.) as white solid. MS: m/e=359.2 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)[CH2:8][CH2:7]1)=[O:4].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:23]([N:2]([CH3:1])[C:3]([NH:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)[CH2:8][CH2:7]1)=[O:4])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CNC(=O)NC1CCN(Cc2ccc3ccccc3c2)CC1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CN(C(=O)NC1CCN(Cc2ccc3ccccc3c2)CC1)C(=O)c1ccccc1

Procedure:
1-Methyl-3-[1-(naphth-2-ylmethyl)piperid-4-yl]urea (1.4 g.) (prepared by reacting 4-amino-1-(naphth-2-ylmethyl)piperidine with methyl isocyanate) in toluene (30 cm3) was acylated using benzoyl chloride (0.92 g) in presence of pyridine (0.6 g) to give the title compound: m.p. of HCl, hemihydrate salt=164°-166° C.
Reaction SMILES: [I:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:13]1([CH3:19])[CH:18]=CC=C[CH:14]=1>C(OCC)(=O)C>[C:13]([O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([I:1])[C:3]([CH3:12])=[CH:4][C:5]=1[CH3:11])([CH3:19])([CH3:18])[CH3:14]
Reactant: Cc1ccccc1
Reactant: Cc1cc(C)c(C(=O)O)cc1I
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(C(=O)OC(C)(C)C)cc1I
Temperature: 80 °C
Reaction time: 2 h

Procedure:
5-Iodo-2,4-dimethylbenzoic acid (4.5 g, 16.3 mmol) obtained in Step 1 above was placed in a reaction vessel, and then anhydrous toluene (10 ml) and N,N-dimethylformamide/di-tert-butyl acetal (25 ml) were added thereto. The resulting mixture was stirred at 80° C. for 2 hours. The reaction solution was diluted with ethyl acetate (300 ml), and washed three times with a saturated aqueous sodium bicarbonate solution (100 ml), twice with water (100 ml), and once with a saturated aqueous sodium chloride solution (100 ml). The washed ethyl acetate solution was dried over anhydrous sodium sulfate (50 g). After filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (developing solvent: n-hexane:ethyl acetate=10:1) to yield 5-iodo-2,4-dimethylbenzoic acid tert-butyl ester (3.8 g) as a white solid material.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].Br[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1>>[S:7]1[CH:8]=[CH:9][CH:10]=[C:6]1[C:3]#[C:2][CH2:1][OH:4]
Reactant: Brc1cccs1
Reactant: C#CCO
Product: OCC#Cc1cccs1

Procedure:
In a manner described in Example 18 above, propargyl alcohol was reacted with 2-bromothiophene to give the title compound as a brown oil which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:14](OCC)[O:15]CC)=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])=[O:4].C(O)=O>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:14]=[O:15])=[CH:8][C:9]=1[C:10]([F:11])([F:12])[F:13])=[O:4]
Reactant: CCOC(OCC)c1cc(C(F)(F)F)c(C(=O)OC)s1
Solvent: O=CO
Solvent: C1COCCO1
Product: COC(=O)c1sc(C=O)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 98.8 %

Procedure:
A solution of 5-Diethoxymethyl-3-trifluoromethyl-thiophene-2-carboxylic acid methyl ester (2.72 g, 8.71 mmol) in dioxane (20 ml) was cooled to 0° C. (ice bath). 88% formic acid (25 ml) was added in one portion and the mixture was stirred at 0° C. for 5 min and then at rt for 60 min The reaction mixture was quenched by pouring into EtOAc. The organic layer was washed with water, dried over Na2SO4 and concentrated under reduced pressure to afford the desired product (2.05 g, 99% yield).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH2:4][CH2:3]1.Br[C:18]1[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[N:22][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[N:22][CH:23]=2)[CH2:4][CH2:3]1
Reactant: CN1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN1CC=C(c2ccc([N+](=O)[O-])nc2)CC1
Temperature: 100 °C

Procedure:
To a round-bottomed flask equipped with a stirring bar, 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (1.50 g, 6.72 mmol), 5-bromo-2-nitropyridine (1.64 g, 8.07 mmol), Pd(PPh3)4 (388 mg, 0.336 mmol), Na2CO3 aqueous solution (1.0 N, 20.2 mL, 20.2 mmol), dioxane (60.6 mL) were added. The reaction mixture was heated at 100° C. for 10 hrs. CH2Cl2 (200 mL) was added to the resulting mixture was washed with water (30 mL×3). CH2Cl2(200 mL) was added and the resulting mixture was washed with water (30 mL×3), brine (30 mL×1), dried over MgSO4, filtered, and removed solvent in vacuo. Silica gel column chromatography (MeOH:DCM=5:95) gave 5-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-nitropyridine (130a) as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[N:8]2[CH2:9][C@H:10](C3C=C([N+]([O-])=O)C=CC=3C([O-])=O)[CH2:11][C@H:7]2[CH2:6][N:5]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=2)[CH2:4][CH2:3]1.C(=O)([O-])[O-:35].[K+].[K+].C(OCC)(=O)C.CO>CO>[OH:35][C@@H:10]1[CH2:9][N:8]2[C:2](=[O:1])[CH2:3][CH2:4][N:5]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][N:25]=3)[CH2:6][C@@H:7]2[CH2:11]1
Reactant: O=C([O-])[O-]
Reactant: O=C([O-])c1ccc([N+](=O)[O-])cc1[C@@H]1C[C@H]2CN(c3ccc(C(F)(F)F)cn3)CCC(=O)N2C1
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1CCN(c2ccc(C(F)(F)F)cn2)C[C@@H]2C[C@H](O)CN12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 142.2 %

Procedure:
To (8S,9aS)-5-oxo-2-[5-(trifluoromethyl)pyridin-2-yl]octahydro-1H-pyrrolo[1,2-a][1,4]diazepin-8-yl-4-nitrobenzoate (135 mg, 0.291 mmol, Part C) in methanol (2.5 mL) was added potassium carbonate (24 mg, 0.174 mmol). The mixture was stirred at room temperature for 1.5 hours and then concentrated. The residue was purified by chromatography on silica gel (ethyl acetate, then ethyl acetate/methanol=10:1) to give 78 mg (85% yield) of the titled compound as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.72 (m, 1H), 2.28 (m, 1 H), 2.45 (m, 1H), 2.63 (m, 1 H), 3.35 (m, 3 H), 3.44 (m, 1 H), 3.92 (m, 1H), 4.17 (m, 1H), 4.42 (m, 2H), 5.09 (br s, 1H), 7.00 (d, J=8 Hz, 1 H), 7.80 (d, J=8 Hz, 1 H), 8.43 (s, 1 H); MS (ESI) m/z 316.0 (M+H)+.
Reaction SMILES: [C:1]([OH:5])#[C:2][CH2:3][CH3:4].I[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:9][CH:8]=1.C(N(CC)CC)C>C(#N)C.[Cu]I>[OH:5][CH2:1][CH2:2][C:3]#[C:4][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:9][CH:8]=1
Reactant: COC(=O)Cc1ccc(I)cc1
Reactant: CCC#CO
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)Cc1ccc(C#CCCO)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 84.9 %

Procedure:
To a solution of butyn-1-ol (0.76 g, 0.11 mol) and methyl 4-iodophenylacetate (1.5 g, 0.0054 mol) in acetonitrile (10 mL) at 0° C., triethylamine (1.5 mL, 0.01 mol) was added, followed by the addition of bistriphenylphosphine palladium chloride (0.25 g, 0.36 mmol) and CuI (0.025 g). The reaction mixture was stirred at 0° C. under an argon atmosphere for 30 minutes and at room temperature for 3 hours. The dark colored reaction mixture was concentrated under reduced pressure, and the residue was partitioned between 5% citric acid (50 mL) and EtOAc (50 ML). The organic phase was washed with 5% citric acid (3×15 mL), water, dried (Na2SO4), filtered, and concentrated. The resulting material was purified by silica gel flash column chromatography eluting with 35% EtOAc in hexane to afford methyl 4-(4-hydroxy-1-butynyl)phenylacetate (1 g, 85%) as a dark colored liquid. FAB-MS m/z=219 (M+H), HRMS calcd. for C13H15O3 (M+H), 219.1021, found 219.1008. Calcd for C13H14O3 : C, 71.54, H 6.46; found: C, 71.04, H, 6.41.
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[C:8]([N:17]([C:22]([O:24][CH3:25])=[O:23])[C:18]([O:20][CH3:21])=[O:19])[C:7]([CH3:26])=[C:6]([Cl:27])[CH:5]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:34].[Na+]>CO.C(#N)C>[NH2:34][CH:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[C:8]([N:17]([C:22]([O:24][CH3:25])=[O:23])[C:18]([O:20][CH3:21])=[O:19])[C:7]([CH3:26])=[C:6]([Cl:27])[CH:5]=1)[CH3:2]
Reactant: [BH3-]C#N
Reactant: COC(=O)N(C(=O)OC)c1c(C)c(Cl)cc(C(C)=O)c1-c1cccc(F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: COC(=O)N(C(=O)OC)c1c(C)c(Cl)cc(C(C)N)c1-c1cccc(F)c1
Temperature: 65 °C

Procedure:
A mixture of dimethyl (6-acetyl-4-chloro-3′-fluoro-3-methylbiphenyl-2-yl)imidodicarbonate (67 mg, 0.17 mmol), ammonium acetate (131 mg, 1.70 mmol) and sodium cyanoborohydride (21 mg, 0.34 mmol) in methanol (0.6 mL) and acetonitrile (0.6 mL) was heated at 65° C. overnight in a sealed tube. The mixture was then cooled to room temperature and quenched with saturated sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The crude product was used directly in next step (67 mg, 100%). LCMS calculated for C19H21ClFN2O4 (M+H)+: m/z=395.1. found: 395.1.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[C:10]([C:15](=O)[CH3:16])[C:11]([O:13][CH3:14])=[O:12].[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[SH:27]>CN(C)C=O.C(OCC)(=O)C>[CH3:16][C:15]1[NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[S:27][CH:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:19])([F:18])[F:1])[C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C(=Cc1ccccc1C(F)(F)F)C(C)=O
Reactant: Nc1ccccc1S
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)Nc2ccccc2SC1c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 2-[[2-(trifluoromethyl)phenyl]methylene]-3-oxobutanoic acid, methyl ester (1.8 g., 6.61 mmole) in dimethylformamide (5 ml.) is treated with 2-aminothiophenol (919 mg., 6.61 mmole) at room temperature. The reaction is stirred at room temperature for about 72 hours. The reaction is then heated at 65°-70° (oil bath temperature) for 10 hours. It is cooled to room temperature and diluted with ethyl acetate (50 ml.). The solution is thoroughly washed with water, sodium bicarbonate, and brine. After drying over anhydrous magnesium sulfate, the solvent is stripped off to give a yellow solid. Recrystallization from isopropyl ether-dichloromethane gives 783 mg. of product as fluffy needles. The mother liquor is purified by flash chromatography (20% ethyl acetate in hexane) and the resulting solid is recrystallized from isopropyl ether-dichloromethane to give 153 g. of additional product. Recrystallization from isopropyl ether-dichloromethane gives an analytically pure sample of 2,5-dihydro-4-methyl-2-[2-(trifluoromethyl)phenyl]-1,5-benzothiazepine-3-carboxylic acid, methyl ester; m.p. 165°-166.5°. TLC (silica gel, hexane: ethyl acetate, 60:40) Rf =0.36.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]2[CH2:13][CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:11][CH2:10][NH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18](Cl)(=[O:21])[O:19][CH3:20].CCN(C(C)C)C(C)C.ClCCl>C(OCC)C>[CH:1]1([CH2:7][CH:8]2[CH2:13][CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:11][CH2:10][N:9]2[C:18]([O:19][CH3:20])=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C1CCNC(CC2CCCCC2)C1
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(CC2CCCCC2)C1
Reaction time: 2 h

Procedure:
Methyl 2-(cyclohexylmethyl)piperidine-4-carboxylate (1.79 g, 7.48 mmol), methyl carbonochloridate (1.06 g, 11.2 mmol) and DIPEA (1.93 g, 15.0 mmol) were added to dichloromethane (60 mL) at room temperature and stirred for 2 h. The reaction mixture was diluted with diethylether and washed with water. The organic phase was dried over MgSO4, filtered through Celite® and the solvent was evaporated. Crude product 2.2 g. 1H NMR (400 MHz, cdcl3) δ 0.71-0.97 (m, 2H), 1.02-1.28 (m, 5H), 1.38 (dt, 1H), 1.69 (ddd, 6H), 1.98 (ddd, 3H), 2.52-2.61 (m, 1H), 3.01-3.16 (m, 1H), 3.67 (s, 3H), 3.69 (s, 3H), 3.81-3.94 (m, 1H), 4.13-4.31 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].Cl[CH2:13][C:14]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:15]=1[O:16][CH:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[O:11][CH2:13][C:14]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:15]=1[O:16][CH:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)C(C)Oc1cc(C)ccc1CCl
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1cc(C)ccc1COc1ccc([N+](=O)[O-])c(F)c1
Yield: 97.7 %

Procedure:
By the method of Example 1, Step I, 1.71 g (0.010 mole) of 3-fluoro-4-nitrophenol and 2.85 g (0.011 mole) of methyl 2-(2-chloromethyl-5-methylphenoxy)propionate were reacted in the presence of 1.66 g (0.012 mole) of anhydrous potassium carbonate in 100 mL of N,N-dimethylformamide, yielding 3.55 g of methyl 2-[2-(3-fluoro-4-nitrophenoxymethyl)-5-methylphenoxy]propionate as a yellowish solid, m.p. 92°-94° C. The NMR and IR spectra were consistent with the proposed structure.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH2:6]1[CH:11]2[C:12]3[C:17]([C:18](=[O:19])[N:10]2[CH2:9][CH2:8][NH:7]1)=[CH:16][CH:15]=[CH:14][CH:13]=3.C(N(CC)CC)C>C1C=CC=CC=1>[Cl:1][CH2:2][C:3]([CH:6]1[CH:11]2[C:12]3[C:17]([C:18](=[O:19])[N:10]2[CH2:9][CH2:8][NH:7]1)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:4]
Reactant: O=C1c2ccccc2C2CNCCN12
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C(CCl)C1NCCN2C(=O)c3ccccc3C12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.5 %

Procedure:
A solution of chloroacetyl chloride (657 mg, 0.0058 mol) in 30 ml of benzene is added dropwise to a stirring solution of 1,2,3,4,6,10b-hexahydropyrazino[2,1-a]isoindole-6-one (described in Example 8, 1.0 g, 0.0053 mol) and triethylamine (650 mg, 0.0064 mol) in 90 ml of benzene. The reaction is stirred at room temperature for 30 min and evaporated. A mixture of chloroform and water is added and the chloroform phase is collected, washed with water, dried and evaporated to afford 2-chloroacetyl-1,2,3,4,6,10b-hexahydropyrazino[2,1-a]isoindole-6-one, (1.2 g), nmr (CDCl3) δ 3.0-3.5(m), 4.2-4.8(m) and 7.3-7.9(m).