Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].COC[O:5][C:6]1[CH:7]=[C:8]([CH2:12][CH2:13][C:14]2[CH:29]=[CH:28][CH:27]=[CH:26][C:15]=2[O:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[CH:9]=[CH:10][CH:11]=1>O1CCOCC1>[ClH:1].[OH:5][C:6]1[CH:7]=[C:8]([CH2:12][CH2:13][C:14]2[CH:29]=[CH:28][CH:27]=[CH:26][C:15]=2[O:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[CH:9]=[CH:10][CH:11]=1
Reactant: COCOc1cccc(CCc2ccccc2OCCC2CCN(C)CC2)c1
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCC(CCOc2ccccc2CCc2cccc(O)c2)CC1
Reaction time: 1 h
Yield: 42 %

Procedure:
2.3 ml of a 4N solution of hydrogen chloride in dioxane were added to a solution of 710 mg of 4-(2-{2-[2-(3-methoxymethoxyphenyl)ethyl]phenoxy}ethyl)-1-methylpiperidine [prepared as described in step (a) above] in 2.3 ml of dioxane, and the resulting mixture was allowed to stand at room temperature for 1 hour, after which it was concentrated by evaporation under reduced pressure. The resulting residue was dissolved in a small amount of methylene chloride, and ethyl acetate was added to the solution thus obtained, which was then allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo, to give 294 mg (yield 42%) of the title compound as a crystalline powder, melting at 130°-132° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].F[C:35]1[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[C:37]([CH3:43])[CH:36]=1>>[C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]2[CH:17]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:19]=[C:20]([O:22][C:35]3[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[C:37]([CH3:43])[CH:36]=3)[CH:21]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(O)cc(Oc3ccc(C#N)cc3)c2)CC1
Reactant: Cc1cc(F)ccc1C#N
Product: Cc1cc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)NC3CCC(NC(=O)OC(C)(C)C)CC3)c2)ccc1C#N
Yield: 71.3 %

Procedure:
Following the procedure of Example 69(b) {4-[3-(4-cyanophenoxy)-5-hydroxy-benzoylamino]cyclohexyl}carbamic acid tert-butyl ester 0.85 g (1.88 mmol) and 4-fluoro-2-methyl-benzonitrile (0.508 g, 3.76 mmol) were used to afford 0.76 g of the required product. 1H NMR (DMSO-d6): δ 1.20 (4H, m), 1.4 (9H, s), 1.8 (4H, m), 2.45 (3H, s), 3.15 (1H, m), 3.7 (1H, m), 6.72 (1H, d), 7.02 (1H, d), 7.2 (4H, m), 7.5 (2H, s), 7.8 (1H, d), 7.88 (2H, d), 8.34 (1H, d).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[C:5]([C:15](=[O:17])[CH3:16])[CH:4]=1.Cl.Cl[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]Cl.C(N(C(C)C)CC)(C)C.[OH-].[K+]>O.C1(C)C=CC=CC=1>[CH3:14][O:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([C:15](=[O:17])[CH3:16])[CH:4]=[C:3]2[N:2]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1
Reactant: COc1ccc2cc(C(C)=O)cc(N)c2c1
Reactant: ClCCNCCCl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc2cc(C(C)=O)cc(N3CCNCC3)c2c1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
1-(4-amino-6-methoxynaphthalen-2-yl)ethanone hydrochloride (3) (3.0 g) and bis(2-chloroethyl)amine hydrochloride (2.54 g) were charged in a flask and to them was added toluene (100 ml) and diisopropylethylamine (6.5 ml). The reaction was heated to 120° C. and allowed to stir overnight. Upon completion, 5 N aqueous potassium hydroxide (50 ml) and water (100 ml) were added and the reaction was allowed to stir for 2 hours at room temperature. The liquids were decanted and to them was added concentrated hydrochloric acid until the aqueous was made acidic. 1-(6-methoxy-4-(piperazin-1-yl)naphthalen-2-yl)ethanone (106) was an orange-brown solid that was filtered and used with no further purification (3.5 g) LCMS (m/z): 285 [M+H].
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:12][CH3:13])[CH:10]=2)[C:5]([CH3:15])([CH3:14])[C:4](=[O:16])[C:3]=1[C:17](OCC)=[O:18].Cl.[C:23]([O:27][C:28](=[O:31])[CH2:29][NH2:30])([CH3:26])([CH3:25])[CH3:24].CCN(C(C)C)C(C)C.O>O1CCOCC1>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:12][CH3:13])[CH:10]=2)[C:5]([CH3:14])([CH3:15])[C:4](=[O:16])[C:3]=1[C:17]([NH:30][CH2:29][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:31])=[O:18]
Reactant: CCOC(=O)C1=C(O)c2cc(SC)ccc2C(C)(C)C1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ccc2c(c1)C(O)=C(C(=O)NCC(=O)OC(C)(C)C)C(=O)C2(C)C
Temperature: 120 °C
Reaction time: 3 h
Yield: 86.7 %

Procedure:
A solution of ethyl 4-hydroxy-1,1-dimethyl-6-(methylthio)-2-oxo-naphthalen-3-carboxylate (0.800 g, 2.61 mmol), glycine tert-butyl ester hydrochloride (0.525 g, 3.13 mmol) and DIPEA (0.910 mL, 5.22 mmol in 1,4-dioxane (25 mL) in a 75 mL sealed vessel, was stirred at 120° C. for 3 hours. Deionized water (75 mL) was added, and the resulting mixture was extracted with EtOAc (2×50 mL). The combined organic layers were then washed with brine (50 mL). The organic layer was dried over MgSO4, concentrated, and dried in vacuo to give 1.44 g crude product which was purified by flash column chromatography (silica, 0-50% DCM in hexane) to give the title compound (0.886 g). MS m/e=336 (M+H-tBu)+.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]2[NH:8][C:9](=O)[C:10]3[C:11](=[CH:13][S:14][CH:15]=3)[NH:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].B.Cl>O1CCCC1>[N+:1]([C:4]1[CH:18]=[CH:17][C:7]2[NH:8][CH2:9][C:10]3[C:11](=[CH:13][S:14][CH:15]=3)[NH:12][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1Nc2ccc([N+](=O)[O-])cc2Nc2cscc21
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(c1)Nc1cscc1CN2

Procedure:
An 8 g. portion of 4,9-dihydro-6-nitro-10H-thieno [3,4-b][1,5]benzodiazepin-10-one in 155 ml. of tetrahydrofuran is stirred, under nitrogen, with cooling in an ice bath. To this is added slowly with stirring 155 ml. of 1M borane in tetrahydrofuran over a period of 15 minutes. The reaction mixture is then stirred at room temperature for one hour and then heated under reflux with stirring for 5 hours. The mixture is stirred at room temperature for 48 hours. The mixture is stirred and cooled in an ice bath while 45 ml. of 6N hydrochloric acid is added dropwise. The tetrahydrofuran is distilled off on a steam bath and the acidic residue is treated portionwise, with swirling in ice with 35 g. of sodium hydroxide pellets. The reaction mixture is extracted with benzene. The benzene extracts are concentrated, and the residue is repeatedly triturated with ether and filtered. The ether filtrate produces red crystals which are collected, washed with ether and dried. This solid is heated in 60 ml. of benzene to solution, filtered, and the filtrate is concentrated to 30 ml. and cooled. The solid is collected, washed with benzene and hexane and dried giving the desired product, mp. 184°-186° C.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].Cl.[CH2:6]([N:13]1[C@H:17]([CH2:18]Cl)[CH2:16][CH2:15][C@@H:14]1[CH2:20]Cl)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Na+].[I-].C([O-])(O)=O.[Na+]>C(#N)C>[CH2:6]([N:13]1[CH:17]2[CH2:16][CH2:15][CH:14]1[CH2:20][N:4]([CH2:1][CH:2]=[CH2:3])[CH2:18]2)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C=CCN
Reactant: ClC[C@@H]1CC[C@H](CCl)N1Cc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CC#N
Product: C=CCN1CC2CCC(C1)N2Cc1ccccc1
Yield: 98.7 %

Procedure:
Allylamine (9.5 mL, 0.13 mol) was added to a suspension of cis-1-benzyl-2,5-bis(chloromethyl)pyrrolidine hydrochloride (37.5 g, 0.13 mol, from step (e) above), NaI (47.6 g, 0.32 mol) and NaHCO3 (106.7 g, 1.27 mol) in acetonitrile (1.8 L). The reaction was heated at reflux for 8 h, filtered, and the filtrate concentrated in vacuo. The residue was partitioned between ethyl acetate and ice cold 1 N NaOH. The ethyl acetate layer was separated, dried (Na2SO4), filtered and concentrated in vacuo to afford 31.1 g of an oil. The oil was chromatographed on a column of silica (75 mm×220 mm) eluting with a mixture of chloroform, methanol and conc. NH4OH (240:9:1). Fractions (100 mL each) 5–10 were combined and concentrated in vacuo to afford 22.2 g (72%) of the sub-title compound.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])[C:3]1=[O:27].[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:35]=[C:36]=[O:37]>O1CCCC1>[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH:35][C:36]([NH:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])[C:3]1=[O:27])=[O:37]
Reactant: CCN(CC)C(=O)CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reactant: O=C=Nc1ccccc1Cl
Solvent: C1CCOC1
Product: CCN(CC)C(=O)CN1C(=O)C(NC(=O)Nc2ccccc2Cl)N=C(c2ccccc2)c2ccccc21
Reaction time: 8 h

Procedure:
Equimolar amounts of 3-amino-N,N-diethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-1-acetamide and 2-chlorophenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 173°-175° C.
Reaction SMILES: [Mg].[CH3:2]I.[C:4]([N:8]1[C:13](=[O:14])[C:12](Cl)=[C:11]([Cl:16])[CH:10]=[N:9]1)([CH3:7])([CH3:6])[CH3:5].Cl>O1CCCC1.C1(C)C=CC=CC=1>[C:4]([N:8]1[C:13](=[O:14])[C:12]([CH3:2])=[C:11]([Cl:16])[CH:10]=[N:9]1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)n1ncc(Cl)c(Cl)c1=O
Reactant: CI
Agent: Cl
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1c(Cl)cnn(C(C)(C)C)c1=O
Temperature: 0 °C

Procedure:
To a solution of 6.0 g (0.25 mol) of magnesium in 50 ml of dry tetrahydrofuran was added dropwise under stream of nitrogen 35.5 g (0.25 mol) of methyl iodide to prepare a Grignard reagent. After dropwise addition of the methyl iodide, 1000 ml of dry toluene was added thereto. The resulting solution was heated at 60° to 70° C. and additional methyl iodide was added thereto until the magnesium completely disappeared. The Grignard reagent was cooled to room temperature and then added dropwise over 20 minutes with a solution of 22.1 g (0.1 mol) of 2-t-butyl-4,5-dichloro-3(2H)-pyridazinone in 200 ml of dry toluene. After dropwise addition, the resulting mixture was subjected to reaction at room temperature for 1.5 hours. The reaction liquid was poured into a solution of 100 ml of concentrated hydrochloric acid in 900 ml of ice water to effect extraction. The resulting organic layer was washed with 500 ml of a 10% sodium hydroxide solution and then with 500 ml of water, and then dried over anhydrous sodium sulfate. Solvent was distilled off therefrom under reduced pressure to give 17.2 g of a crude product. The crude product was subjected to distillation (boiling point: 60° to 62° C./0.22 mmHg) and then to column chromatography [on silica gel; eluting with hexane-acetone (15:1)] for separation and purification to obtain 4.5 g of 2-t-butyl-5-chloro-4-methyl-3(2H)-pyridazinone.
Reaction SMILES: [BrH:1].[CH3:2][O:3][C@@H:4]1[CH2:9][CH2:8][CH2:7][NH:6][C@H:5]1[CH2:10][C:11](=[O:13])[CH3:12].Br>>[BrH:1].[Br:1][CH2:12][C:11](=[O:13])[CH2:10][C@H:5]1[C@H:4]([O:3][CH3:2])[CH2:9][CH2:8][CH2:7][NH:6]1
Reactant: CO[C@@H]1CCCN[C@H]1CC(C)=O
Agent: Br
Product: CO[C@@H]1CCCN[C@H]1CC(=O)CBr

Procedure:
The said known procedure comprises reacting trans 1-(3-methoxy-2-piperidyl)-2-propanone hydrobromide with hydrobromic acid as in U.S. Pat. No. 2,775,597 to form the trans 3-bromo-1-(3-methoxy-2-piperidyl)-2-propanone hydrobromide, reacting the latter with allyl chloroformate as indicated in J. Org. Chem., Vol. 20 (1955), p. 118-142 to block the nitrogen atom of the piperidine with allyloxycarbonyl by forming 1-allyloxycarbonyl-2-(ω-bromoacetonyl)-3-methoxypiperidine, condensing the latter with 6-chloro-7-bromo-3,4-dihydro-4-quinazolinone as described in French Pat. No. 1,550,956 to obtain 7-bromo-6-chloro-3-[3-(1-allyloxycarbonyl-3-methoxy-2-piperidyl)-acetonyl]-4(3H)-quinazolinone, subjecting the latter to hydrobromic acid as taught in French Pat. No. 1,550,956 to obtain 7-bromo-6-chloro-3-[3-(3-hydroxy-2-piperidyl)-acetonyl]-4(3H)-quinazolinone hydrobromide and treating the latter with a base to form the corresponding free base which if desired may be salified with a non-toxic, pharmaceutically acceptable acid to form the desired acid addition salt.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][OH:26])[O:22][C:21]3=[O:27])=[CH:16][C:15]=2[F:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[CH3:4][C:2]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][O:26][S:37]([CH3:36])(=[O:39])=[O:38])[O:22][C:21]3=[O:27])=[CH:16][C:15]=2[F:28])[CH2:12][CH2:13]1)=[O:7])([CH3:1])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N3C[C@H](CO)OC3=O)cc2F)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N3C[C@H](COS(C)(=O)=O)OC3=O)cc2F)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of (R)-(-)-4-[4-[5-hydroxymethyl)-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperidinecarboxylic acid 1,1-dimethylethyl ester (EXAMPLE 20, Step 5, 970 mg) and triethylamine (0.50 mL) in dry methylene chloride (9.5 mL) at 0° C. under N2 is treated with methanesulfonyl chloride (0.20 mL) dropwise. The resulting mixture is stirred at 0° C. for one hour, diluted with methylene chloride (40 mL), washed with water (10 mL), saturated aqueous sodium bicarbonate (10 mL) and saline (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound, mp 163-165° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:20])[CH2:10][C:11]2[NH:15][C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[N:12]=2)=[CH:5][CH:4]=1.C[O-].[Na+].[C:24](OC)(=[O:27])[C:25]#[CH:26]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:10]2[CH:26]=[CH:25][C:24](=[O:27])[N:15]3[C:14]4[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=4[NH:12][C:11]=23)=[O:20])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)Cc2nc3c([nH]2)CCCC3)cc1
Reactant: C#CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Product: COc1ccc(C(=O)c2ccc(=O)n3c4c([nH]c23)CCCC4)cc1

Procedure:
The compound is prepared as described in example 25 with 200 mg (0.74 mmol) of 1-(4-methoxyphenyl)-2-(4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)ethanone (example LIII), 80 mg (1.48 mmol) of sodium methylate and 62 mg (0.74 mmol) methyl propiolate.
Reaction SMILES: [CH2:1]([Li])CCC.C(NC(C)C)(C)C.[C:13]([CH:18]1[CH2:22][S:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:19]1)([O:15][CH2:16][CH3:17])=[O:14].CI.Cl>CC(OC)(C)C>[C:13]([C:18]1([CH3:1])[CH2:22][S:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:19]1)([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)C1CSC(c2ccccc2)=N1
Reactant: [Li]CCCC
Agent: Cl
Solvent: COC(C)(C)C
Solvent: CC(C)NC(C)C
Solvent: CI
Product: CCOC(=O)C1(C)CSC(c2ccccc2)=N1
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
152.2 g (0.594 mol, 1.10 eq) of butyllithium solution (25% strength in heptane) were added dropwise under nitrogen in the course of 30 min to a solution of 90.8 ml (65.6 g, 0.648 mol, 1.20 eq) of diisopropylamine in 800 ml of absolute MTBE at −15° C. This solution was stirred at −15° C. for 30 min. 400 ml of the MTBE solution containing the 4-carbethoxy-2-phenyl-thiazoline were added dropwise at −15° C. in the course of 30 min and the mixture was stirred at −15° C. for 1 h, whereby a brown solution resulted. 115.0 g (50.4 ml, 0.81 mol, 1.50 eq) of methyl iodide were added and the reaction mixture was warmed to 23° C. and stirred at this temperature for a further 3 h. 300 ml of 2 M HCl were then slowly added with vigorous stirring, then the mixture was adjusted to pH 2-3 so that the temperature did not exceed 30° C. The two-phase mixture obtained thereby was stirred for a further 30 min. The organic phase was then separated off. This MTBE solution, containing 4-carbethoxy-4-methyl-2-phenylthiazoline, was employed in stage 3.
Reaction SMILES: [CH3:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)([CH3:11])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[NH2:4].Cl>C(OC(C)C)(=O)C.C(O)(C)C>[CH3:11][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)([CH3:1])[C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[NH2:4]
Reactant: CC(C)(c1ccccn1)C(N)c1ccccc1
Agent: Cl
Solvent: CC(=O)OC(C)C
Solvent: CC(C)O
Product: CC(C)(c1ccccn1)[C@@H](N)c1ccccc1

Procedure:
(S)-2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine is prepared starting from racemic 2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine using chiral SFC chromatography. This oil is dissolved in isopropyl acetate and a solution of 5-6 N HCl in isopropyl alcohol is added. The mixture is concentrated, and triturated in ether to yield the title compound as a white solid. M.p.=188° C. 1HNMR (300 MHz, CD3OD): δ 1.59 (s, 3H), 1.76 (s, 3H), 5.09 (s, 1H), 7.25-7.28 (m, 2H), 7.38-7.40 (m, 3H), 8.00 (t, J=6.6 Hz, 1H), 8.11 (d, J=6.9 Hz, 1H), 8.56 (t, J=7.8 Hz, 1H), 8.77 (d, J=5.7 Hz, 1H). MS: m/z 227.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]2[C@H:9]3[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH2:16][CH3:17])[C@@H:10]3[CH2:18][O:19][C:5]=2[C:4]=1[O:20]C.C1(PC2C=CC=CC=2)C=CC=CC=1.C([Li])CCC.[C:40]([OH:47])(=[O:46])/[CH:41]=[CH:42]/[C:43]([OH:45])=[O:44]>>[C:40]([OH:47])(=[O:46])/[CH:41]=[CH:42]/[C:43]([OH:45])=[O:44].[OH:20][C:4]1[C:5]2[O:19][CH2:18][C@@H:10]3[C@@H:9]([C:6]=2[CH:7]=[CH:8][C:3]=1[CH2:2][OH:1])[CH2:14][CH2:13][CH2:12][N:11]3[CH2:15][CH2:16][CH3:17]
Reactant: CCCN1CCC[C@@H]2c3ccc(CO)c(OC)c3OC[C@H]21
Agent: O=C(O)/C=C/C(=O)O
Agent: [Li]CCCC
Agent: c1ccc(Pc2ccccc2)cc1
Product: CCCN1CCC[C@@H]2c3ccc(CO)c(O)c3OC[C@H]21

Procedure:
Reaction of trans-8-hydroxymethyl-7-methoxy-4-propyl-1,2,3,4a,5,10b-hexahydro-4H-[1]-benzopyrano[3,4-b]pyridine with diphenylphosphine and butyllithium according to the procedure of Example 9 and subsequent treatment with fumaric acid affords trans-7-hydroxy-8-hydroxymethyl-4-propyl-1,2,3,4a,5,10b-hexahydro-4H-[1]-benzopyrano[3,4-b]pyridine fumarate, m.p. 198°-200°.
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[C:12]1[C:20]2[C:15](=[CH:16][C:17]([S:21]([N:24]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:32]=3[O:39][CH3:40])[C:25]3[S:29][N:28]=[CH:27][N:26]=3)(=[O:23])=[O:22])=[CH:18][CH:19]=2)[N:14]([CH3:41])[CH:13]=1.[N:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[CH3:40][O:39][C:32]1[CH:33]=[C:34]([O:37][CH3:38])[CH:35]=[CH:36][C:31]=1[CH2:30][N:24]([C:25]1[S:29][N:28]=[CH:27][N:26]=1)[S:21]([C:17]1[CH:16]=[C:15]2[C:20]([C:12]([C:3]3[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:9])[F:10])=[CH:7][C:2]=3[C:45]3[CH:46]=[CH:47][N:42]=[CH:43][CH:44]=3)=[CH:13][N:14]2[CH3:41])=[CH:19][CH:18]=1)(=[O:23])=[O:22]
Reactant: OB(O)c1ccncc1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4Br)cn(C)c3c2)c(OC)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4-c4ccncc4)cn(C)c3c2)c(OC)c1

Procedure:
A microwave vial was charged with 3-(2-bromo-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (0.050 g, 0.075 mmol), pyridin-4-ylboronic acid (0.018 g, 0.150 mmol), potassium phosphate (0.056 g, 0.262 mmol), and Pd(AmPhos)2Cl2 (5.30 mg, 7.49 μmol). The vial was flushed with Ar, then 1,4-dioxane (0.375 ml) and water (0.125 ml) were added in sequence. The vial was sealed and microwaved at 100° C. for 30 minutes. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried with sodium sulfate, filtered and concentrated. The material was purified via column chromatography (Redi-Sep Gold (Teledyne Isco, Lincoln, Nebr.) 12-g, gradient elution 0 to 100% EtOAc/Heptane) to afford N-(2,4-dimethoxybenzyl)-1-methyl-3-(2-(pyridin-4-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide as a yellow solid. The solid was dissolved in DCM (0.5 ml) and TFA (0.5 ml, 6.49 mmol), and the resulting mixture was stirred for 15 min. The mixture was concentrated in vacuo. The residue was dissolved in acetonitrile, and passed through a PEAX ion exchange column. The column was flushed several times with acetonitrile, then the product was liberated by flushing several times with an 1M HCl solution in 15% MeOH/EtOAc. The solution was concentrated to afford 1-methyl-3-(2-(pyridin-4-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=8.55 (d, J=6.1 Hz, 2 H), 8.44 (s, 1 H), 7.97-7.90 (m, 2 H), 7.87 (s, 1 H), 7.80 (d, J=8.0 Hz, 1 H), 7.56-7.49 (m, 3 H), 7.34 (d, J=1.5 Hz, 2 H), 3.85 (s, 3 H). m/z (ESI) 516.0 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH:14]2[CH2:15][O:16]2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: ClCC1CO1
Reactant: CS(=O)(=O)c1ccc(O)cc1
Product: CS(=O)(=O)c1ccc(OCC2CO2)cc1

Procedure:
The title compound was prepared from 4-methanesulfonyl-phenol and epichlorohydrin employing the procedures as set forth in Step 1 of Example 2.
Reaction SMILES: S(=O)(=O)(O)O.C(OC[O:10][C:11]1[CH:12]=[C:13]([CH:22]=[CH:23][C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([CH2:40][CH3:41])([OH:39])[CH2:37][CH3:38])[CH:27]=[CH:28][CH:29]=2)[CH:14]=[C:15]([O:17]COCC)[CH:16]=1)C>CO.C1COCC1>[CH2:37]([C:36]([OH:39])([CH2:40][CH3:41])[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=[CH:30][C:26]1[CH:25]=[C:24]([CH:23]=[CH:22][C:13]2[CH:14]=[C:15]([OH:17])[CH:16]=[C:11]([OH:10])[CH:12]=2)[CH:29]=[CH:28][CH:27]=1)[CH3:38]
Reactant: CCOCOc1cc(C=Cc2cccc(C=CCCCCC(O)(CC)CC)c2)cc(OCOCC)c1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: C1CCOC1
Product: CCC(O)(CC)CCCCC=Cc1cccc(C=Cc2cc(O)cc(O)c2)c1

Procedure:
In a manner similar to Example 1(j), by reacting 0.3 ml of concentrated sulphuric acid in 7 ml of methanol with 700 mg (1.41 mmol) of 9-{3-[2-(3,5-bis-ethoxymethoxyphenyl)vinyl]phenyl}-3-ethylnon-8-en-3-ol in 7 ml of methanol and 7 ml of THF, after purification on a silica column (ethyl acetate 40-heptane 60), beige crystals (m=477 mg; Y=77%) are obtained. m.p.=98-102° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B1C2CCCC1CCC2.C1C=C[NH+]=CC=1.[O-:37][Cr](Cl)(=O)=O>C1COCC1.CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:21]3[CH:16]([CH2:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:37])[CH2:14]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(C=Cc3ccccc32)CC1
Reactant: O=[Cr](=O)([O-])Cl
Agent: B1C2CCCC1CCC2
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)C1CC=CC=C12
Temperature: 70 °C
Yield: 46.5 %

Procedure:
To a solution of 661 mg (2.31 mmol) of 1'-(t-butyloxycarbonyl)spiro[1H-indene-1,4'-piperidine] [prepared by the method of Chambers, et al, J. Med. Chem., 1992, 35, 2036] in 5.0 ml of THF was added 5.8 ml (1.0M THF, 2.9 mmol) of 9-BBN. The reaction mixture was heated at 70° C. until TLC analysis indicated that the starting material was consumed. The solution was concentrated and the residue was dissolved in dichloromethane. The solution was cooled to 0° C. and 4.1 g (19.2 mmol) of PCC was added slowly over 15 minutes. The reaction mixture was warmed to room temperature and then to reflux for 30 minutes. The solution was then diluted with ether and filtered through a pad of a mixture of celite and florisil. Purification by flash chromotography (silica gel, hexane/ethyl acetate, 4:1) gave 326 mg (47%) of the title compound.