Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:44]=[CH:43][C:13]2[N:14]([CH2:35][CH2:36][CH2:37][CH2:38][O:39][C:40](=[O:42])[CH3:41])[C:15]([CH2:17][N:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21](=[O:28])[N:20]([CH2:29][C:30]([F:33])([F:32])[F:31])[C:19]3=[O:34])=[N:16][C:12]=2[CH:11]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.Cl.O1CCOCC1>ClCCl>[NH2:8][CH2:9][C:10]1[CH:44]=[CH:43][C:13]2[N:14]([CH2:35][CH2:36][CH2:37][CH2:38][O:39][C:40](=[O:42])[CH3:41])[C:15]([CH2:17][N:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21](=[O:28])[N:20]([CH2:29][C:30]([F:33])([F:31])[F:32])[C:19]3=[O:34])=[N:16][C:12]=2[CH:11]=1
Reactant: CC(=O)OCCCCn1c(Cn2c(=O)n(CC(F)(F)F)c(=O)c3ccccc32)nc2cc(CNC(=O)OC(C)(C)C)ccc21
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(=O)OCCCCn1c(Cn2c(=O)n(CC(F)(F)F)c(=O)c3ccccc32)nc2cc(CN)ccc21

Procedure:
A solution of acetic acid 4-{5-(tert-butoxycarbonylamino-methyl)-2-[2,4-dioxo-3-(2,2,2-trifluoro-ethyl)-3,4-dihydro-2H-quinazolin-1-ylmethyl]-benzoimidazol-1-yl}-butyl ester (98 mg, 0.16 mmol) and TFA (244 μL, 3.17 mmol) in dichloromethane (3 mL) was stirred for 4 hrs at room temperature. The volatiles were removed in vacuo and the residue dissolved in dichloromethane. A solution of 4N HCl in dioxane (0.4 mL, 10 equiv.) was added, followed by concentration. The residue was triturated from diethyl ether and filtered to give acetic acid 4-{5-aminomethyl-2-[2,4-dioxo-3-(2,2,2-trifluoro-ethyl)-3,4-dihydro-2H-quinazolin-1-ylmethyl]-benzoimidazol-1-yl }-butyl ester; HCl salt (53 mg, 60%) as a white solid:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][C:14]2[CH:18]=[C:19]([S:22]([NH:25][C:26]3[S:30][N:29]=[CH:28][N:27]=3)(=[O:24])=[O:23])[CH:20]=[CH:21][C:13]1=2.[N:31]1[CH:36]=[C:35](B(O)O)[CH:34]=[N:33][CH:32]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[N:31]1[CH:36]=[C:35]([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=2[N:12]2[CH2:17][CH2:16][O:15][C:14]3[CH:18]=[C:19]([S:22]([NH:25][C:26]4[S:30][N:29]=[CH:28][N:27]=4)(=[O:24])=[O:23])[CH:20]=[CH:21][C:13]2=3)[CH:34]=[N:33][CH:32]=1
Reactant: O=S(=O)(Nc1ncns1)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1Br
Reactant: OB(O)c1cncnc1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=S(=O)(Nc1ncns1)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1-c1cncnc1
Temperature: 100 °C
Yield: 40.1 %

Procedure:
A microwave vial was charged with INTERMEDIATE D (0.100 g, 0.192 mmol), pyrimidin-5-ylboronic acid (Small Molecules, Inc., Hoboken, N.J., 0.036 g, 0.288 mmol), tetrakis(triphenylphosphine)palladium(0) (0.022 g, 0.019 mmol), and K2CO3 (0.133 g, 0.959 mmol). The solids were diluted with dioxane (1.279 mL) and water (0.639 mL), and the reaction was heated under microwave irradiation at 100° C. for 30 minutes. The reaction mixture was diluted with water, and washed with ether (the ether layer was extracted once more with water). The combined aqueous layers were acidified with 1.0N HCl, and then washed with DCM (×2). The combined organics were dried using a phase separator and concentrated. After concentration, the material was purified by reverse-phase preparative HPLC (Column: Phenomenex 150×30 mm, 5 micron, C18 column; 0.1% TFA in CH3CN/H2O, gradient 25% to 90% over 20 min) to provide 4-(2-(pyrimidin-5-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.040 g, 0.077 mmol) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.45 (m, J=13.00 Hz, 1H) 3.76 (m, J=11.20 Hz, 1 H) 4.06-4.15 (m, 1 H) 4.31 (m, J=10.50 Hz, 1 H) 6.38 (d, J=8.22 Hz, 1 H) 6.98-7.00 (m, 1 H) 7.01-7.03 (m, 1 H) 7.73 (d, J=8.41 Hz, 1H) 7.94 (dd, J=8.56, 2.01 Hz, 1 H) 7.99 (m, J=1.70 Hz, 1 H) 8.26 (s, 1 H) 8.90 (s, 2 H) 9.07 (s, 1 H). m/z (ESI) 520.8 (M+H)+.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][S:7][CH2:6][C@@H:5]([C:15]([OH:17])=[O:16])[NH:4][C:3]1=[O:18].[CH2:19](O)[CH3:20]>>[CH2:1]=[C:2]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][S:7][CH2:6][C@@H:5]([C:15]([O:17][CH2:19][CH3:20])=[O:16])[NH:4][C:3]1=[O:18]
Reactant: CCO
Reactant: C=C1CCCCCCCSC[C@@H](C(=O)O)NC1=O
Product: C=C1CCCCCCCSC[C@@H](C(=O)OCC)NC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(3R)-6-Methylidene-5-oxo-1-thia-4-azacyclotridecane-3-carboxylic acid (0.16 g), 0.62 mmol) is dissolved in ethanol (5 ml) and hydrogen chloride gas is bubbled through the solution for 5 minutes. The solution is stirred overnight at room temperature and the solvent is evaporated to give ethyl (3R)-6-methylidene-5-oxo-1-thia-4-azacyclotridecane-3-carboxylate, m.p. 146°-147° C.
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:12])[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([CH2:18]C(O)=O)([C:15]([OH:17])=[O:16])=[O:14].[OH-].[K+].Cl>O>[C:1]1([CH2:7][C:8]([OH:12])([C:9]([OH:11])=[O:10])[CH2:18][C:13](=[O:14])[C:15]([OH:17])=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CC(=O)C(=O)O
Reactant: O=C(O)C(=O)Cc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C(=O)CC(O)(Cc1ccccc1)C(=O)O

Procedure:
5.0 g (30.5 mmol) of phenylpyruvic acid and 12.1 g (91.4 mmol) of oxaloacetic acid are added to 25 ml of water preliminarily dissolving 13.8 g of potassium hydroxide (purity of 85%) therein, for reaction at ambient temperature for 72 hours. Using the conc. hydrochloric acid, the reaction solution is adjusted to pH 2.2, for extraction into ethyl acetate. The organic layer is rinsed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated to obtain the residue. The residue is recrystallized in ethyl acetate and toluene to obtain PHOG of 2.8 g (11.3 mmoL) in crystal.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.C(N(CC)CC)C.[Cl:14][CH2:15][C:16](Cl)=[O:17]>C1C=CC=CC=1>[Cl:14][CH2:15][C:16]([N:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1)=[O:17]
Reactant: C1=CCNCC1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C(CCl)N1CC=CCC1
Reaction time: 0.25 h

Procedure:
A solution of 1,2,5,6-tetrahydropyridine (41.5 grams; 0.5 mol) and triethylamine (50 grams) in benzene (1 l.) was placed into a 2 l. glass reaction flask equipped with a mechanical stirrer, reflux condenser and addition funnel. Chloroacetyl chloride (56.5 grams; 0.5 mol) was slowly added, with stirring, over a period of about 15 minutes. After the addition was completed stirring was continued for an additional period of about 15 minutes. After this time the reaction mixture was cooled and filtered to remove the triethylamine hydrochloride which had formed. The remaining benzene solution was stripped of solvent to yield a dark colored oil. The oil was then distilled under reduced pressure, to yield 1-(α-chloroacetyl)-1,2,5,6-tetrahydropyridine as a pale yellow oil having a boiling point of 88° to 91° C. at 0.35 mm Hg. pressure, an index of refraction of 1.5224 at 25° C. and having the following elemental analysis as calculated for C7H10ClNO.
Reaction SMILES: N.[CH3:2][C:3]1[CH2:8][CH2:7][CH2:6][C:5]([CH3:10])([CH3:9])[C:4]=1[C:11](=[O:16])[CH2:12][C:13](N)=[CH2:14].[Na].[Cl-].[NH4+]>C(O)(C)(C)C.O1CCCC1>[CH3:2][C:3]1[CH2:8][CH2:7][CH2:6][C:5]([CH3:9])([CH3:10])[C:4]=1[C:11](=[O:16])[CH:12]=[CH:13][CH3:14]
Reactant: C=C(N)CC(=O)C1=C(C)CCCC1(C)C
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CC=CC(=O)C1=C(C)CCCC1(C)C
Yield: 19 %

Procedure:
To a mixture of liquid ammonia (250 ml), anhydrous tetrahydrofuran (15 ml), tert-butanol (0.358 g) and 1.002 g (4.84 millimoles) of 2,6,6-trimethyl-1-[3-amino-but-3-enoyl]-cyclohex-1-ene, kept under stirring, there was added sodium metal until the solution acquired a steady blue colour. The reaction mixture was stirred for 15 more minutes and solid ammonium chloride was added thereto until complete discolouration and the ammonia was then evaporated under a stream of argon. After having added to the mixture 25 ml of ether and 75 ml of a concentrated ammonium chloride solution in water, the mixture was extracted with two fractions of 200 ml of ether and 100 ml of chloroform, respectively. The combined organic extracts were dried over anhydrous sodium sulphate, concentrated under reduced pressure and the thus obtained residue (1.038 g) was dissolved in 10 ml of toluene. The said solution was then refluxed overnight, then concentrated under reduced pressure. The thus obtained residue was subjected to a fractional distillation to yield 0.177 g of 2,6,6-trimethyl-1-[but-2-enoyl]-cyclohex-1-ene. The analytical data of the obtained product were identical with those of a pure sample prepared by one of the known methods (cf. Swiss Pat. No. 505,773).
Reaction SMILES: [Mg].[B:2]([O:7]C)(OC)[O:3]C.Br[C:10]([C:12]([F:15])([F:14])[F:13])=[CH2:11].Cl>O1CCCC1.O.C(OCC)C>[F:13][C:12]([F:15])([F:14])[C:10]([B:2]([OH:7])[OH:3])=[CH2:11]
Reactant: COB(OC)OC
Reactant: C=C(Br)C(F)(F)F
Agent: Cl
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=C(B(O)O)C(F)(F)F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To magnesium turnings (5.83 g, 0.24 mol) in tetrahydrofuran (400 ml) was added dropwise trimethyl borate (68.13 ml, 0.6 mol). The reaction mixture was cooled to 0° C. and 2-bromo-3,3,3-trifluoropropene (20.75 ml, 0.2 mol) was added dropwise. The reaction mixture was then allowed to warm to room temperature and stirred under nitrogen overnight. The reaction mixture was again cooled to 0° C. and hydrochloric acid (5M, 200 ml) was added dropwise, ensuring that the temperature of the solution remained below 10° C. The reaction mixture was then stirred under nitrogen for 48 h. To the reaction mixture was added diethyl ether (100 ml) and water (200 ml) to give two phases. The aqueous layer was separated and extracted with diethyl ether (100 ml). The combined organic phases were washed with water (100 ml), dried (MgSO4) and concentrated in vacuo. To the residue was added cyclohexane (50 ml), resulting in precipitate formation. The precipitate was isolated by decanting the solution, washed with cyclohexane, and dried in vacuo to give Preparation 59 (2.62 g, 0.02 mol) as a white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:7]=[CH:6][S:5][C:4]=1[NH:8][C:9](=[O:15])OC(C)(C)C)=O.C(OCC)(=O)[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].N1CCCCC1>CCO>[O:15]=[C:9]1[NH:8][C:4]2[S:5][CH:6]=[CH:7][C:3]=2[CH:1]=[C:17]1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)(C)OC(=O)Nc1sccc1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)c1cc2ccsc2[nH]c1=O

Procedure:
A solution of tert-butyl 3-formyl-2-thienylcarbamate (11-3, 1.90, 8.36 mmol, 1 equiv), diethyl malonate (2.54 mL, 16.7 mmol, 2.00 equiv), and piperidine (0.413 mL, 4.18 mmol, 0.500 equiv) in EtOH (100 mL) was heated at reflux for 6 h. The reaction mixture was concentrated, and the residue was purified by flash column chromatography (EtOAc, initally, then 10% MeOH in EtOAc) to give ethyl 6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carboxylate (10-4). 1H NMR (400 MHz, CDCl3) δ 11.57 (brs, 1H), 8.60 (s, 1H), 7.33 (d, 1H, J=6.0 Hz), 7.21 (d, 1H, J=6.0 Hz), 4.49 (q, 2H, J=7.1 Hz), 1.46 (t, 3H, J=7.1 Hz).
Reaction SMILES: [Br:1][C:2]([Br:5])(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([C@@H:29]1[CH2:34][O:33][C@@H:32]([C:35]2[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=2)[O:31][CH2:30]1)[CH2:26][CH2:27][CH3:28].CCCCCC>C(Cl)Cl>[Br:1][C:2]([Br:5])=[CH:39][C:38]1[CH:37]=[CH:36][C:35]([C@H:32]2[O:31][CH2:30][C@H:29]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:34][O:33]2)=[CH:42][CH:41]=1
Reactant: BrC(Br)(Br)Br
Reactant: CCCC[C@H]1CO[C@H](c2ccc(C=O)cc2)OC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CCCC[C@H]1CO[C@H](c2ccc(C=C(Br)Br)cc2)OC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of 13.6 g of tetrabromomethane in 150 ml of methylene chloride was placed at 0° C. in a sulphonation flask under argon gasification and treated within 10 minutes with a solution of 21.51 g of triphenylphosphine in 40 ml of methylene chloride. After completion of the addition, the clear orange solution was stirred at 0° C. for a further 5 minutes and then a solution of 5.08 g of p-(trans-5-butyl-1,3-dioxan-2-yl)benzaldehyde in 30 ml of methylene chloride was added dropwise within 5 minutes. The mixture was subsequently stirred at 0° C. for a further 30 minutes, then the flask content was poured into 800 ml of hexane and the separated precipitate was filtered off (rinsing with hexane). The concentrated filtrate was digested with 400 ml of hexane, left to stand at 0° C. for 15 hours, filtered (rinsing with hexane) and the filtrate was concentrated. Low-pressure chromatography (0.5 bar) of the residue (8.2 g) on silica gel with hexane followed by petroleum ether/ethyl acetate/triethylamine (97:3:0.5) gave 3.23 g of trans-2-[p-(2,2-dibromovinyl)phenyl]-5-butyl-1,3-dioxane as colourless crystals (purity 95.1%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([CH:26]=O)[CH2:22][CH2:21]1)=[O:19].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:16][O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([CH2:26][N:13]2[CH2:12][CH2:11][CH:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:15][CH2:14]2)[CH2:22][CH2:21]1)=[O:19]
Reactant: COC(=O)N1CCC(C=O)CC1
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)N1CCC(CN2CCC(CNC(=O)OC(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.5 %

Procedure:
To a solution of 4-tert-butoxycarbonylaminomethylpiperidine (3.62 g, 16.9 mmol) in dichloromethane (100 mL) was added 4-formylpiperidine-1-carboxylic acid methyl ester (2.89 g, 16.9 mmol) and acetic acid (0.96 mL). The mixture was stirred at room temperature for 10 min prior to the addition of sodium triacetoxyborohydride (5.4 g, 25.5 mmol). The final mixture was stirred at room temperature for 1 h. The reaction was terminated by adding saturated sodium bicarbonate solution (50 mL). The mixture was extracted with dichloromethane (100 mL), and the organic layer was dried over MgSO4. Evaporation of the organic solution afforded a pale yellow oily residue. It was purified by flash silica column chromatography (CH2Cl2 to 5% MeOH/CH2Cl2), yielding the title intermediate (4.4 g). (m/z): [M+H]+ calcd for C19H35N3O4 370.27. found 370.5.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[CH2:17][C@H:16]2[C@H:12]([CH2:13][C:14](=[O:18])[O:15]2)[C@H:11]1/[CH:19]=[C:20](/[Br:30])\[C@H:21](O)[C@@H:22]([CH3:28])[CH2:23][C:24]#[C:25][CH2:26][CH3:27])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([OH:34])(C)C.O.C(O[C@@H]1C[C@H]2[C@H](CC(=O)O2)[C@H]1/C=C(/Br)\C(=O)[C@@H](C)CC#CCC)(=O)C1C=CC=CC=1>CC(C)=O>[C:1]([O:9][C@@H:10]1[CH2:17][C@H:16]2[C@H:12]([CH2:13][C:14](=[O:18])[O:15]2)[C@H:11]1[C:19](=[O:34])/[C:20](/[Br:30])=[CH:21]/[C@@H:22]([CH3:28])[CH2:23][C:24]#[C:25][CH2:26][CH3:27])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC#CC[C@H](C)[C@@H](O)/C(Br)=C\[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Reactant: CC(C)O
Agent: CCC#CC[C@H](C)C(=O)/C(Br)=C\[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Solvent: CC(C)=O
Solvent: O
Product: CCC#CC[C@H](C)/C=C(\Br)C(=O)[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Temperature: -30 °C
Reaction time: 0.17 h
Yield: 26 %

Procedure:
17.6 g (37.1mmol) of (1S,5R,6S,7R)-7-benzoyloxy-6-[(E)-(3R,4S)-2 -bromo-3-hydroxy-4-methyl-1-nonen-6-inyl]-2-oxabicyclo[3.3.0]octan-3-one (for preparation see EP0284547) is dissolved in 260 ml of acetone, cooled under an atmosphere of dry argon to -30° C. and 20 ml of a standardized Jones solution is instilled within 10 minutes. It is stirred for another 1.5 hours at -20° C., excess oxidizing agent is decomposed by adding 25 ml of isopropanol, allowed to heat to 20° C., mixed with 300 ml of water and extracted several times with a total of 600 ml of diethyl ether. The combined organic extracts are washed with water and saturated sodium chloride solution until neutral reaction, dried on magnesium sulfate and the residue obtained after filtration and removal of the solvent is purified by chromatography on about 800 ml of fine silica gel by using an n-hexane/ethyl acetate mixture. In addition to 11.3 g (23.9 mmol, 64%) of (1S,5R,6S,7R)-7-benzoyloxy-6-[(E)-(4S)-2-brom-3-oxo-4-methyl-1-nonen-6-inyl]-2-oxa-bicyclo[3.3.0]octan- 3-one, 3.59 g (7.58 mmol, 26%) of (1S,5R,6R,7R)-7-benzoyloxy-6-[(Z)-(4S)-1-oxo-2-bromo-4-methyl-non-2-en-6-inyl]-2-oxabicyclo[3.3.0]octan-3-one is isolated. The latter compound is dissolved in 45 ml of anhydrous methanol, cooled under an atmosphere of dry argon to -45° C., mixed in portions with a total of 520 mg of sodium borohydride and stirred for 30 more minutes at -45° C. Excess reducing agent is decomposed by adding 0.8 ml of acetone, allowed to heat to 20° C., mixed with water and extracted several times with diethyl ether. The combined organic extracts are washed with water and saturated sodium chloride solution until neutral reaction, dried magnesium sulfate and the residue obtained after filtration and removal of the solvent is purified by chromatography on about 200 ml of fine silica gel by using a dichloromethane/ethyl ether mixture. 1.79 g (3.76 mmol, 50%) of the nonpolar alcohol as well as 528 mg (1.11 mmol, 15%) of the polar alcohol are isolated.
Reaction SMILES: [ClH:1].[C:2]1([C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[H][H]>[C].[Pd].CO>[ClH:1].[C:2]1([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C(=C2CCNCC2)c2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: c1ccc(C(c2ccccc2)C2CCNCC2)cc1
Yield: 38.1 %

Procedure:
4-diphenylmethylenepiperidine hydrochloride (6.21 g) was added to methanol (30 ml) and the atmosphere was replaced with argon. To the mixture, 10% palladium-carbon (1.54 g) and a small amount,of concentrated hydrochloric acid were added and the atmosphere was replaced with hydrogen, followed by allowing the mixture to react at 3.5 atm at room temperature for 10.5 hours. Then 10% palladium-carbon was removed through Celite and the filtrate was concentrated. The residue was again dissolved in methanol (30 ml) and 10% palladium-carbon (10 g) and a small amount of hydrochloric acid were added. The atmosphere was replaced with hydrogen, and the mixture was allowed to react at 3.5 atm at room temperature for 21 hours. The reaction mixture was filtered through Celite and the filtrate was concentrated, followed by recrystallizing the residue from methanol/ether to obtain 2.38g of 4-diphenylmethylpiperidine hydrochloride. Yield: 38%.
Reaction SMILES: [CH2:1]([C@H:3]1[N:8]([CH2:9][C:10]([F:13])([F:12])[F:11])[C:7]2[CH:14]=[CH:15][C:16]([N+:18]([O-])=O)=[CH:17][C:6]=2[O:5][CH2:4]1)[CH3:2]>C(OCC)(=O)C.[Pd]>[NH2:18][C:16]1[CH:15]=[CH:14][C:7]2[N:8]([CH2:9][C:10]([F:13])([F:12])[F:11])[C@H:3]([CH2:1][CH3:2])[CH2:4][O:5][C:6]=2[CH:17]=1
Reactant: CC[C@@H]1COc2cc([N+](=O)[O-])ccc2N1CC(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC[C@@H]1COc2cc(N)ccc2N1CC(F)(F)F
Yield: 95.6 %

Procedure:
This compound was prepared according to General Method 4 (EXAMPLE 1) from (3R)-3-ethyl-3,4-dihydro-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine (5.6 g, 19.3 mmol) and 10% Pd/C (cat.) in 60 mL ethyl acetate to afford 4.8 g (95%) of (3R)-7-amino-3,4-dihydro-3-ethyl-4-trifluoroethyl-2H-1,4benzoxazine as a tan solid, which was carried on directly to the next step.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:15][N:16]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][C:21]([CH2:25][NH2:26])=[CH:22]2)=[N:17]1>>[CH3:15][N:16]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][C:21]([CH2:25][NH:26][S:2]([C:5]3[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=3)(=[O:4])=[O:3])=[CH:22]2)=[N:17]1
Reactant: Cn1cc2cc(CN)ccc2n1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Product: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3nn(C)cc3c2)cc1

Procedure:
The titled compound was prepared according to the procedure described in step-1 of Example 1 from methyl 4-(chlorosulfonyl)benzoate and (2-methyl-2H-indazol-5-yl)methanamine.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)([OH:3])=O.N1C=CC=CC=1.S(Cl)(Cl)=O.[CH2:25]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl.C(O)C.CO.C(Cl)(Cl)Cl>[CH2:25]([N:32]1[CH2:37][CH2:36][N:35]([C:1]([C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]3)=[O:3])[CH2:34][CH2:33]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C1CCc2cc(C(=O)O)ccc2N1
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C1CCc2cc(C(=O)N3CCN(Cc4ccccc4)CC3)ccc2N1
Reaction time: 1 h

Procedure:
1.9 Grams of 6-carboxy-3,4-dihydrocarbostyril was suspended in 200 ml of methylene chloride, then 2 ml of pyridine was added to the suspension and under stirring 1.4 g of thionyl chloride was added dropwise in keeping the inside temperature at 0°-20° C. After the addition of thionyl chloride, the reaction mixture was kept at the same temperature and stirred for 1 hour, then 1.74 g of benzylpiperazine in 10 ml of methylene chloride solution was added to the mixture. Then the reaction mixture was further stirred at a room temperature for 4 hours. The reaction mixture was washed thoroughly with an aqueous solution of potassium carbonate, then washed with water and a diluted hydrochloric acid, dried with anhydrous sodium sulfate and the solvent was removed by distillation. The residue thus obtained was treated by a silica gel column chromatography (Silica gel: Wako C-200, eluate:chloroform:methanol (volume/volume)=20:1). The objective product was recyrstallized from ethanol to obtain 325 mg of 6-(4-benzyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyril. Colorless needle-like crystals. Melting point: 198°-200° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][C:12](=[O:14])[CH3:13])=[C:5]([O:15][CH3:16])[CH:4]=1)=[O:2].[BH4-].[Na+]>CO>[OH:2][CH2:1][C:3]1[CH:4]=[C:5]([O:15][CH3:16])[C:6]([O:11][C:12](=[O:14])[CH3:13])=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(C=O)cc(OC)c1OC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(CO)cc(OC)c1OC(C)=O
Yield: 85 %

Procedure:
A solution of acetic acid 4-formyl-2,6-dimethoxy-phenyl ester (25 mmol) in MeOH (100 mL) was treated with NaBH4 (1 equiv.) at 0° C. for 15 min. After quenching with acetone and evaporating the solvent, work-up (CH2Cl2) and evaporation gave the title compound as a white solid (85% yield). Rf (in EtOAc/Hexane 1:1): 0.5. 1H-NMR (CDCl3): δ 6.66 (s, 1H), 4.68–4.70 (d, 2H), 3.85 (s, 3H), 2.36 (s, 3H), 1.74 (t, 1H).