Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[OH:2]/[N:3]=[C:4](/[C:10]1[N:11]=[C:12]([NH:15][C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:13][CH:14]=1)\[C:5]([O:7]CC)=[O:6].[OH-].[Na+].O.Cl>O1CCOCC1>[OH:2]/[N:3]=[C:4](/[C:10]1[N:11]=[C:12]([NH:15][C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[S:13][CH:14]=1)\[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 12 h
Yield: 96.6 %

Procedure:
Ethyl (Z)-2-hydroxyimino-2-(2-tritylaminothiazol-4-yl)acetate hydrochloride (5 g) as a suspension in dioxane (50ml) was treated at room temperature with 1M aqueous sodium hydroxide (23 ml). After stirring for 12 h, water (50 ml) was added. The pH was adjusted to 1-2 with dilute hydrochloric acid. The resulting precipitate was filtered off, washed with water and dried over P2O5 to give the title compound (4.2 g) as a white solid; δH ((CD3)2SO) 6.73 (1H, s), 7.30 (15H, s).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[NH2:12][CH2:13][C:14]([NH2:16])=[O:15].C(N(CC)CC)C>C(#N)C>[N+:8]([C:7]1[C:2]([NH:12][CH2:13][C:14]([NH2:16])=[O:15])=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: NCC(N)=O
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: NC(=O)CNc1ncccc1[N+](=O)[O-]

Procedure:
A mixture of 2-chloro-3-nitropyridine (1.0 g, 0.0063 mole), glycinamide hydrochloride (3.11 g, 0.028 mole), triethylamine (3.1 g, 0.031 mole) in 35 ml of acetonitrile was heated at reflux for 161/2 hrs. The yellow precipitate was filtered off. The precipitate was slurried and filtered successively with water, absolute alcohol and acetone. The yellow solid was dried under high vacuum at room temperature to give 0.9 g (73.2%), of title compound, m.p. 250°-51° C. with decomposition.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH:12]1([CH2:15][NH2:16])[CH2:14][CH2:13]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH:12]1([CH2:15][N:16]2[C:1](=[O:11])[C:2]3=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]3[C:4]2=[O:6])[CH2:14][CH2:13]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCC1CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1CC1CC1
Temperature: 140 °C
Reaction time: 16 h

Procedure:
N-Cyclopropylmethylphthalimide is prepared as described in Example 2, starting with 4 g of phthalic anhydride, 2.3 cm3 of cyclopropylmethylamine and a catalytic amount of para-toluenesulfonic acid in 40 cm3 of toluene. The reaction mixture is heated at a temperature in the region of 140° C. for 2 hours and is then cooled to a temperature in the region of 20° C. and stirred for 16 hours. The reaction mixture is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is taken up in dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The organic phase is separated out after settling of the phases, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 4.3 g of N-cyclopropylmethylphthalimide are thus obtained in the form of a cottony white solid (Rf=0.46, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (40/60 by volume)).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:19]([N:20]4[CH2:24][CH2:23][CH2:22][C@@H:21]4[CH2:25][O:26][CH3:27])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:28]([O:30]C)=[O:29])[CH:16]=4)[N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[Na+]>CO.O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:19]([N:20]4[CH2:24][CH2:23][CH2:22][C@@H:21]4[CH2:25][O:26][CH3:27])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:28]([OH:30])=[O:29])[CH:16]=4)[N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: COC[C@H]1CCCN1c1nc2cc(C(=O)OC)ccc2nc1-c1ccc2[nH]ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC[C@H]1CCCN1c1nc2cc(C(=O)O)ccc2nc1-c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.4 %

Procedure:
To a solution of methyl 2-(1H-indol-5-yl)-3-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]quinoxaline-6-carboxylate (200 mg, 0.48 mmol) in methanol (35.0 mL) and water (1.0 mL) was added sodium hydroxide (76.9 mg, 1.92 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (30.0 mL), adjusted pH to 4 with HCl (3N) to give the precipitate, which was collected by filtration to afford 2-(1H-indol-5-yl)-3-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]quinoxaline-6-carboxylic acid (80 mg, 41%).
Reaction SMILES: [C:1]1([C:7]2([OH:12])[CH:10]3[CH2:11][CH:8]2[CH2:9]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13](Cl)(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([O:12][C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]2[CH2:9][CH:10]1[CH2:11]2)(=[O:15])[CH3:14]
Reactant: CC(=O)Cl
Reactant: OC1(c2ccccc2)C2CC1C2
Solvent: c1ccncc1
Product: CC(=O)OC1(c2ccccc2)C2CC1C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
To a stirring solution of 2.7 g (16.8 mmol) of 2-phenylbicyclo[1.1.1]pentan-2-ol in pyridine (15 mL) at 0° C. was added dropwise acetyl chloride (1.5 mL, 21.0 mmol) in a nitrogen atmosphere. The reaction mixture was stirred for 0.5 h at 0° C. and for 1 h at room temperature. The solution was poured onto ice and extracted with 50 mL of diethyl ether twice. The combined diethyl ether solution was washed with saturated aqueous sodium bicarbonate solution and with saturated aqueous copper sulfate solution. After drying over anhydrous magnesium sulfate, the solution was concentrated and the crude product was purified by column chromatography (0-5% ethyl acetate in petroleum ether) to give the desired product (2.7 g, 13.4 mmol, yield: 80%). 1H NMR (400 MHz, CDCl3) δ ppm 7.47-7.26 (m, 5H), 3.31 (s, 2H), 2.43 (dd, J1=10.4 Hz, J2=2.8 Hz, 1H), 1.95 (s, 3H), 1.80 (d, J=2.8 Hz, 1H), 1.66 (d, J=3.2 Hz, 1H), 1.49 (dd, J1=10.4, J2=3.2 Hz, 1H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[CH:13][C:14](=O)[NH:15][N:16]=1)(=[O:3])[CH3:2].P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:14]1[N:15]=[N:16][C:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:1](=[O:3])[CH3:2])=[CH:12][CH:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)Oc1ccccc1-c1ccc(=O)[nH]n1
Product: CC(=O)Oc1ccccc1-c1ccc(Cl)nn1
Reaction time: 8 h

Procedure:
A mixture of 6-(2-acetoxyphenyl)-3(2H)pyridazinone (22.4g) and phosphoryl chloride (90 ml) was stirred and warmed at 55°-60° for 40 minutes. The phosphoryl chloride was removed under reduced pressure at 50° and the residual oil was poured on to ice (200 g). The mixture was allowed to stand overnight at 5° and was filtered to give 3-chloro-6-(2-acetoxyphenyl)pyridazine (23.1 g m.p. 131°-133.5°. A sample recrystallised from ethanol had m.p. 137°-138°.
Reaction SMILES: F[C:2]1[C:7](F)=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]([CH2:32][CH2:33][S:34]([CH3:37])(=[O:36])=[O:35])C(=O)C2C=C(C(F)(F)F)N=C(C(F)(F)F)C=2)=[C:4](OC)[CH:3]=1.[CH3:40]C1C=CC=CC=1B(O)O>C(Cl)Cl.CO>[CH3:37][S:34]([CH2:33][CH2:32][NH:15][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:9]=1[C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=1[CH3:40])(=[O:35])=[O:36]
Reactant: Cc1ccccc1B(O)O
Reactant: COc1cc(F)c(F)cc1-c1ccncc1N(CCS(C)(=O)=O)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CO
Product: Cc1ccccc1-c1ccncc1NCCS(C)(=O)=O

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-(2-methanesulfonyl-ethyl)-amine (example 158, intermediate b) and 2-methylphenylboronic acid (CAS RN 16419-60-6) and using a gradient of CH2Cl2: methanol (100:0 to 85:15) for the chromatographic purification. Brown oil (85%). MS (ESI): m/z=291.12 [M+H]+.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:26][O:27][CH2:28][C@@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1>C(Cl)Cl>[CH3:26][O:27][CH2:28][C@@H:29]1[CH2:33][CH2:32][CH2:31][N:30]1[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(C)cc(CO)c1
Reactant: COC[C@@H]1CCCN1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC[C@@H]1CCCN1Cc1cc(C)cc(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cold, stirred solution of methyl 3-(hydroxymethyl)-5-methylbenzoate (200 mg, 1.1 mmol) in methylene chloride (2.2 mL) is added triethylamine (0.304 mL, 2.2 mmol) followed by methanesulfonyl chloride (0.116 mL, 1.5 mmol). The reaction mixture is stirred for 15 min and filtered. (S)-(+)-2-(Methoxymethyl)pyrrolidine (380 mg, 3.3 mmol) is added to the filtrate, and the reaction mixture is stirred at room temperature for 5 h. The reaction mixture is diluted with methylene chloride (10 mL), washed with 1 N hydrochloric acid, and saturated sodium bicarbonate, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 15% ethyl acetate/hexanes) provides the title compound. 1H NMR (300 MHz, CDCl3) δ 7.77 (s, 1H), 7.73 (s, 1H), 7.37 (s, 1H), 4.12 (d, J=17 Hz, 1H), 3.90 (s, 3H), 3.85 (m, 2H), 3.51 (m, 2H), 3.44 (m, 2H), 3.15 (s, 1H), 2.38 (s, 3H), 1.94 (m, 3H), 1.72 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][S:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:5][C:4]=1[N+:15]([O-:17])=[O:16].[OH:18]O>C(O)(=O)C>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][S:10]([CH2:11][C:12]([OH:14])=[O:13])=[O:18])=[CH:5][C:4]=1[N+:15]([O-:17])=[O:16]
Reactant: COc1ncc(CSCC(=O)O)cc1[N+](=O)[O-]
Reactant: OO
Solvent: CC(=O)O
Product: COc1ncc(CS(=O)CC(=O)O)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
Treatment of 2-((6-methoxy-5-nitropyridin-3-yl)methylthio)acetic acid (1.0 mmol, 0.26 g) in acetic acid (30 mL) with hydrogen peroxide 35% (1.0 mmol, 0.05 mL) and the mixture was stirred at room temperature for 1.5 hr followed by 60° C. for 30 minutes. The mixture was evaporated in vacuo to yield the title compound. 1H-NMR (D2O) δ: 1.97 (s, 2H, CH2), 4.23 (d, 1H, J=14.0 Hz, CH), 4.44 (d, 1H, J=14.0 Hz, CH), 4.14 (s, 3H, OCH3), 8.43 (s, 1H, Py-H), 8.52 (s, 1H, Py-H); HR-MS (ESL) m/z: 273.0146 [M−H]−, C9H10N2O6S requires 274.0260.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][CH:13]1[CH:18]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37]COCC[Si](C)(C)C)=[CH:21][CH:20]=2)[CH2:17][CH2:16][N:15]([C:46]([O-:48])=[O:47])[CH2:14]1.Cl.C(Cl)Cl>CO>[OH:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH2:30][O:29][CH2:28][CH2:27][CH2:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([CH:18]2[CH2:17][CH2:16][N:15]([C:46]([O:48][C:2]([CH3:11])([CH3:3])[CH3:1])=[O:47])[CH2:14][CH:13]2[O:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[CH:20][CH:21]=1
Reactant: C[Si](C)(C)CCOCOc1ccccc1COCCCOc1ccc(C2CCN(C(=O)[O-])CC2OCc2ccc3ccccc3c2)cc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOCc3ccccc3O)cc2)C(OCc2ccc3ccccc3c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 160.5 %

Procedure:
A solution of 50 mg (0.069 mmol) of 3-(naphthalen-2-ylmethoxy)-4-(4-{3-[2-(2-trimethylsilanyl-ethoxymethoxy)-benzyloxy]-propoxy}-phenyl)-piperidine-1-carboxylate in 0.5 ml of methanol was cooled to 0° C. under argon and treated with 69 μl (0.138 mmol) of a 2N solution of hydrogen chloride in methanol. Subsequently, the mixture was left to warm to room temperature and was stirred for a further one hour. For the working-up, the reaction solution was treated with a 95:5 mixture of methylene chloride and methanol (extracted against 5 vol. % saturated ammonia) and evaporated to dryness under reduced pressure. For purification, the residue was chromatographed on silica gel using a 3:1 mixture of hexane and ethyl acetate as the eluent. There were obtained 33.1 mg (81% of theory) of tert-butyl (3RS,4RS)-4-{4-[3-(2-hydroxy-benzyloxy)-propoxy]-phenyl}-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; MS: 598 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C@H:16]([NH:18]C(=O)OC(C)(C)C)[CH3:17])[C:3]=1[C:26]([NH:28][C:29]1[S:30][CH:31]=[CH:32][N:33]=1)=[O:27].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:18][C@@H:16]([C:4]1[C:3]([C:26]([NH:28][C:29]2[S:30][CH:31]=[CH:32][N:33]=2)=[O:27])=[C:2]([OH:1])[C:11]2[C:6](=[C:7]([C:12]([F:13])([F:15])[F:14])[CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:17]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](N)c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1

Procedure:
7 g of the product of Example 3 were suspended in 140 ml of methylene chloride and 70 ml of trifluoroacetic acid were slowly added with the temperature falling to 15° C. Contact was maintained for 4 hours and then, after concentrating to dryness under reduced pressure, the residue was taken up in 100 ml of ether. The crystals were separated by filtration and the product was slowly added to 50 ml of a 10% aqueous solution of sodium bicarbonate. After stirring, filtration, and washing with water, the crude product was treated at reflux with 300 ml of methanol without complete solution and after cooling and concentrating to 50 ml, 2.3 g of 2-[(R) 1-aminoethyl]-4-hydroxy-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline-carboxamide melting at 265° C. and with a specific rotation of [α]D =-72°±2.5° (c=0.5% in CH3COOH) were obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@@H:5]1[CH:10]([CH3:11])[C:9](=[O:12])[CH:8]=[CH:7][CH2:6]1.[H][H]>CCOC(C)=O>[OH:1][CH2:2][CH2:3][CH2:4][C@H:5]1[CH2:6][CH2:7][CH2:8][C:9](=[O:12])[CH:10]1[CH3:11]
Reactant: [H][H]
Reactant: CC1C(=O)C=CC[C@@H]1CCCO
Solvent: CCOC(C)=O
Product: CC1C(=O)CCC[C@@H]1CCCO
Yield: 100.2 %

Procedure:
A solution of 21.8 g (0.129 mole) of the crude (5S)-5-(3-hydroxypropyl)-6-methyl-2-cyclohexene-1-one in 200 ml of EtOAc was stirred with 1.0 g 10% Pd(C) under 1 atmosphere pressure of hydrogen until a total of 2600 ml of hydrogen was consumed. The reaction mixture was then filtered through a pad of celite which was washed further with EtOAc. The combined filtrates were concentrated to give 22.0 g of the crude ketone which was chromatographed on a silica gel column (4:1, hexane/EtOAc) to give 13.5 g (50% from s-carvone) of the pure (3R)-3-(3-hydroxypropyl)-2-methycyclohexanone. B.P. 110° C./0.15 mmHg. IR (CHCl3): 1702, 3475, 3625 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:30])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12](OC)[C:11]=2[NH:19][C:20]([C:22]2[S:23][CH:24]=[C:25]([CH2:28]Cl)[C:26]=2[Cl:27])=[O:21])=[CH:4][CH:3]=1.[CH3:31][S-:32].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:30])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH:19][C:20]([C:22]2[S:23][CH:24]=[C:25]([CH2:28][S:32][CH3:31])[C:26]=2[Cl:27])=[O:21])=[CH:6][CH:7]=1
Reactant: C[S-]
Reactant: COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cc2)c1NC(=O)c1scc(CCl)c1Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSCc1csc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cc2)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.4 %

Procedure:
To a solution of N-(4-chlorophenyl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide (0.52 g, 1.1 mmol) in DMF (12 mL) was added sodium thiomethoxide (0.39 g, 5.5 mmol) and the reaction mixture stirred at ambient temperature. After 16 hours, the mixture was poured into water (100 mL) and extracted with ethyl acetate (2×80 mL). The combined organics were washed with water (2×80 mL), 1M hydrochloric acid (2×80 mL) and brine (80 mL), dried over MgSO4 and concentrated of all volatiles in vacuo. Purification of the resulting solid by flash chromatography on silica gel afforded 0.36 g (68% yield) of N-(4-chlorophenyl)-2-[((3-chloro-4-((methylthio)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide; as a pale yellow solid; NMR (DMSO-d6) 11.1 (s, 1), 10.8 (s, 1), 8.3 (d, 1), 7.9 (d, 1), 7.8 (s, 1), 7.7 (d, 2), 7.6 (dd, 1), 7.4 (d, 2), 3.7 (s, 2), 2.0 (s 3) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[N:11]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]1)=[O:5])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:3][C:4]([CH:6]1[CH2:7][NH:8][CH2:9][CH2:10][N:11]1[S:12]([C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)(=[O:13])=[O:14])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1S(=O)(=O)c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1CNCCN1S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
To a solution of 0.75 g (1.803 mmol) of the product of Example 51 in 5 mL of dichloromethane was added was added 2.0 mL of trifluoroacetic acid and the resulting mixture was stirred for 2 h at room temperature. The reaction mixture was then concentrated in vacuo and the residue was diluted with ether. The organics were washed with saturated sodium bicarbonate solution, dried over Na2SO4, filtered and concentrated in vacuo to provide 0.515 g (90%) of the amine as a colorless oil pure enough for use in the next step. Electrospray Mass Spec: 316.9 (M+H)+
Reaction SMILES: [CH2:1]([Si:4]1(Cl)[N:8]([CH3:9])[C@@H:7]([CH3:10])[C@H:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:5]1)[CH:2]=[CH2:3].C(N(CC)CC)C.[CH3:25][CH:26]([OH:28])[CH3:27]>C(Cl)Cl>[CH2:1]([Si:4]1([O:28][CH:26]([CH3:27])[CH3:25])[N:8]([CH3:9])[C@@H:7]([CH3:10])[C@H:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:5]1)[CH:2]=[CH2:3]
Reactant: C=CC[Si]1(Cl)O[C@@H](c2ccccc2)[C@H](C)N1C
Reactant: CC(C)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC[Si]1(OC(C)C)O[C@@H](c2ccccc2)[C@H](C)N1C
Reaction time: 12 h
Yield: 47.5 %

Procedure:
To a solution of (4S,5S)-2-Allyl-2-chloro-3,4-dimethyl-5-phenyl-[1,3,2]oxazasilolidine (2.08 g, 7.8 mmol) in methylene chloride (25 mL) was added triethylamine (1.2 mL, 8.6 mmol). 2-Propanol (0.6 mL, 7.8 mmol) was added slowly by syringe and the mixture was allowed to stir for 12 hours. The methylene chloride was removed by distillation and pentane (20 ml) was added to the residue. The mixture was stirred for 3 hours. The mixture was then filtered through a pad of celite. The filtrate was concentrated to afford an oil which was distilled under reduced pressure (b.p. ˜72° C., ˜0.2 mm Hg) to yield 1.08 g (48%) of (4S,5S)-2-Allyl-2-isopropoxy-3,4-dimethyl-5-phenyl-[1,3,2]oxazasilolidine as a ˜2:1 mixture of diastereomers.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][O:8][CH3:9].F[C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21]>CCO>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:6][CH2:7][O:8][CH3:9])[C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: COCCNCCOC
Solvent: CCO
Product: COCCN(CCOC)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
Bis(2-methoxyethyl)amine (Aldrich B4, 820-7; 1.6 g; 12 mmol; 3 eq.) was added to a solution of 4-fluoro-3-nitrobenzoic acid (740 mg; 4 mmol; 1 eq.) in EtOH (20 mL) and the resulting mixture was stirred at room temperature for 2 hours then at 70° C. for 20 hours. The solution was concentrated in vacuo and the residue was partitioned between NaOH 0.5M and Et2O. The aqueous layer was acidified to pH 2 with HCl 5M, extracted with ethyl acetate (3×) and the combined organic phase was dried over magnesium sulfate. After evaporation of the solvent, the residue was crystallised from ethyl acetate/n-pentane to afford the title compound (1.12 g, 94%) as a yellow solid.
Reaction SMILES: [CH:1]1([C:6]2[CH:15]=[C:14]3[C:9]([C:10](=[O:18])[CH2:11][C:12]([CH3:17])([CH3:16])[O:13]3)=[C:8]([O:19][CH3:20])[C:7]=2[CH:21]=[O:22])[CH2:5][CH2:4][CH:3]=[CH:2]1.C1(C2C=C3C(C(=O)CC(C)(C)O3)=C(OC)C=2C=O)CC=CC1.[H][H]>C(OCC)(=O)C.[Pd]>[CH:1]1([C:6]2[CH:15]=[C:14]3[C:9]([C:10](=[O:18])[CH2:11][C:12]([CH3:17])([CH3:16])[O:13]3)=[C:8]([O:19][CH3:20])[C:7]=2[CH:21]=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1c(C=O)c(C2C=CCC2)cc2c1C(=O)CC(C)(C)O2
Reactant: [H][H]
Agent: [Pd]
Agent: COc1c(C=O)c(C2CC=CC2)cc2c1C(=O)CC(C)(C)O2
Solvent: CCOC(C)=O
Product: COc1c(C=O)c(C2CCCC2)cc2c1C(=O)CC(C)(C)O2
Reaction time: 1 h

Procedure:
Under argon, 3.3 g (11 mmol) of the mixture of 7-cyclopent-2-en-1-yl-5-methoxy-2,2-dimethyl-4-oxochroman-6-carbaldehyde and 7-cyclopent-3-en-1-yl-5-methoxy-2,2-dimethyl-4-oxochroman-6-carbaldehyde (Example 4A/5A) are dissolved in 200 ml of ethyl acetate, 500 mg of palladium-on-carbon (10%) are added and hydrogen gas is charged at room temperature under atmospheric pressure. After one hour, the mixture is filtered through a layer of silica gel, the filter cake is washed thoroughly with ethyl acetate and the filtrate is concentrated. This gives 3.3 g (99% of theory) of the title compound.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:29])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:28])[C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:30]=[N+:31]=[N-:32].[Na+]>>[N:30]([CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[C:19]([F:29])[CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])[C:15]=2[O:14]1)=[N+:31]=[N-:32]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(-c4ccccc4C)c3O2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: Cc1ccccc1-c1cc(F)cc2c1OC(CN=[N+]=[N-])C2

Procedure:
Treatment of (±)-[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (1.48 g, 3.59 mmol) with sodium azide (0.933 g, 14.35 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.101 g, 10 wt. %) generally according to the procedure described for Example 1 provided 0.555 g (53%) of (±)-1-[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 229-234° C.; Anal. calcd. for C16H16FNOHCl.0.1H2O: C, 65.02; H, 5.87; N, 4.74. Found: C, 64.99; H, 5.83; N, 4
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])=[CH:15][CH:16]=2)[C:11]([CH:26]([OH:28])[CH3:27])=[CH:10][C:9]1([CH3:30])[CH3:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:41](Br)[CH:42]=[CH:43][CH3:44].O>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])=[CH:15][CH:16]=2)[C:11]([CH:26]([O:28][CH2:41]/[CH:42]=[CH:43]/[CH3:44])[CH3:27])=[CH:10][C:9]1([CH3:29])[CH3:30])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccccc1-c1ccc2c(c1)C(C(C)O)=CC(C)(C)N2C(=O)OC(C)(C)C
Reactant: CC=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C/C=C/COC(C)C1=CC(C)(C)N(C(=O)OC(C)(C)C)c2ccc(-c3ccccc3OC)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
A mixture of 70 mg of 4-(1-hydroxyethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylic acid tert-butyl ester in 2 mL of DMSO was treated with 0.22 mL of 1.0 M sodium bis(trimethylsilyl)amide and 29 mg of crotyl bromide at room temperature. The reaction mixture was allowed to stir at room temperature overnight. The reaction was worked up by adding water and extracted with EtOAc three times. The organic layers were combined, washed sequentially with saturated aqueous sodium bicarbonate solution, water, and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to yield 58 mg of 4-{1-[((E)-but-2-enyl)oxy]ethyl}-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylic acid tert-butyl ester as a solid.