Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[CH2:2]([NH:4][C:5](=[O:16])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:15])[C@H:12]([CH3:14])[NH2:13])[CH3:3].[OH-].[Na+].[CH:19]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>ClCCl>[CH2:2]([NH:4][C:5](=[O:16])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:15])[C@H:12]([CH3:14])[NH:13][C:25]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:26])[CH3:3]
Reactant: O=C(Cl)C1CCCCC1
Reactant: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)N
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)C1CCCCC1
Reaction time: 1 h
Yield: 60 %

Procedure:
1.25 g (0.00425 mol) of L-alanyl-L-proline ethylamide hydrobromide were suspended in 20 ml of dichloromethane and to the suspension were added 17.84 ml (0.00892 mol) of 0.5-N sodium hydroxide solution followed by 0.62 ml (1.1 equivalents) of cyclohexane carboxylic acid chloride. The mixture was stirred vigorously for 1 hour. The solution was diluted with 80 ml of dichloromethane, the organic layer was separated, washed with 60 ml of brine, dried over magnesium sulphate and evaporated to give a solid. Recrystallisation from ethyl acetate yielded 0.83 g (60%) of N-cyclohexylcarbonyl-L-alanyl-L-proline ethylamide of melting point 190.5°-191.5° C.; [α]D20 =-116.0° (c=1.055% in methanol).
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([OH:8])[C@@H:6]([C:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[O:5][C:3]1=[O:4].[H][H]>C(O)C>[OH:1][C@H:2]1[C@H:7]([OH:8])[C@H:6](/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[O:5][C:3]1=[O:4]
Reactant: [H][H]
Reactant: CCCCCCC#C[C@H]1OC(=O)[C@@H](O)[C@@H]1O
Solvent: CCO
Product: CCCCCC/C=C\[C@@H]1OC(=O)[C@@H](O)[C@@H]1O
Yield: 94 %

Procedure:
1.02 g (4.51 mmol) of the compound (25) obtained in step e' were dissolved in 20 ml of ethanol, 40 mg of 5 wt % Pd--CaCO3 /Pb (Lindlar catalyst) were added thereto, and the resultant solution was strongly stirred in a hydrogen atmosphere. The solid product in the reaction solution was filtered with Celite, and the solvent was distilled at a reduced pressure, thereby obtaining a white crystal. This crystal was recrystallized from a dichloromethane/hexane solution mixture to obtain 967 mg (4.24 mmol) of a white fibrous compound (26) (yield:94%). The physical data of the resultant compound (26) were as follows:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH2:9])[CH:4]=1)[CH3:2].C1C(=O)N([I:17])C(=O)C1>>[CH2:1]([C:3]1[C:8]([I:17])=[CH:7][N:6]=[C:5]([NH2:9])[CH:4]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1I
Reactant: CCc1ccnc(N)c1
Product: CCc1cc(N)ncc1I

Procedure:
The title compound is synthesized according to general procedure GP1 starting from 5.0 g (41 mmol) 4-ethyl-pyridin-2-ylamine and 9.2 g (41 mmol) NIS. Yield after precipitation from the reaction mixture and isolation of additional product from the mother liquid by chromatography using silica gel: 10.3 g (100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]#[C:13][C:14]([OH:16])=O.[NH2:17][C:18]1[CH:33]=[CH:32][C:21]([O:22][CH2:23][CH2:24][N:25]2[CH2:29][CH2:28][CH2:27][C@H:26]2[CH2:30][OH:31])=[C:20]([O:34][CH3:35])[CH:19]=1>ClCCl.CO>[OH:31][CH2:30][C@@H:26]1[CH2:27][CH2:28][CH2:29][N:25]1[CH2:24][CH2:23][O:22][C:21]1[CH:32]=[CH:33][C:18]([NH:17][C:14](=[O:16])[C:13]#[C:12][C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=2[Cl:1])=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: O=C(O)C#Cc1ccc(C(F)(F)F)cc1Cl
Reactant: COc1cc(N)ccc1OCCN1CCC[C@H]1CO
Solvent: CO
Solvent: ClCCl
Product: COc1cc(NC(=O)C#Cc2ccc(C(F)(F)F)cc2Cl)ccc1OCCN1CCC[C@H]1CO

Procedure:
Prepared analogously to Example 2.3.f. from (2-chloro-4-trifluoromethylphenyl)propynoic acid and {(S)-1-[2-(4-amino-2-methoxyphenoxy)ethyl]pyrrolidin-2-yl}methanol. Yield: 140 mg (58.9% of theory); melting point: decomposition at 300° C.; C24H24ClF3N2O4 (M=496.91); calc.: molecular ion peak (M+H)+: 497/499; found: molecular ion peak (M+H)+: 497/499; Rf value: 0.2 (silica gel, dichloromethane/methanol (9:1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.I[CH3:10]>C(Cl)(Cl)Cl.C(=O)([O-])[O-].[Ag+2]>[CH3:10][O:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccnc(O)c1
Reactant: CI
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Product: COc1cc(C)ccn1
Reaction time: 48 h
Yield: 70.6 %

Procedure:
To a stirred solution of 2-hydroxy-4-methylpyridine (10 g, 92 mmol) in chloroform (350 mL) was added at room temperature silver carbonate (34.2 g, 124 mmol) and iodomethane (130 g, 920 mmol). The reaction mixture was stirred in the dark for 48 h, and then filtered through Celite and washed with ether. The filtrate was concentrated below 20° C., and the residue was purified by chromatography with pentane/ether (5:1) to afford 2-methoxy-4-methylpyridine as a colorless oil (8.0 g, 71%). 1H NMR (CDCl3) δ 8.02 (d, 1H, J=5.4 Hz), 6.69 (d, 1H, J=5.4 Hz), 6.55 (s, 1H), 3.91 (s, 3H), 2.28 (s, 3H); 13C NMR (CDCl3) δ 164.40, 149.72, 146.31, 118.21, 110.88, 53.17, 20.81. MS m/z (%): 123 (M+, 76), 122 (100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:22][CH2:23][CH2:24][OH:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)(=[O:11])=[O:10])=[C:4]([CH2:26][C:27]2[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=2[F:34])[CH:3]=1.I([O-])(=O)(=O)=[O:36].[Na+].O>C(#N)C.[Ru](Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)(=[O:11])=[O:10])[CH2:22][CH2:23][C:24]([OH:36])=[O:25])=[C:4]([CH2:26][C:27]2[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=2[F:34])[CH:3]=1
Reactant: COc1ccc(S(=O)(=O)N(CCCO)c2ccc(Cl)cc2Cc2c(F)cccc2F)cc1OC
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(S(=O)(=O)N(CCC(=O)O)c2ccc(Cl)cc2Cc2c(F)cccc2F)cc1OC
Reaction time: 10 h
Yield: 115.8 %

Procedure:
To 2.63 g of N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N-(3-hydroxypropyl)-3,4-dimethoxybenzenesulfonamide (Example 37) dissolved in 35 ml of acetonitrile are added, at room temperature, 0.069 g of ruthenium trichloride, 1.65 g of sodium periodate and 2.7 ml of water. The mixture is left for 10 hours at room temperature. The reaction medium is filtered through talc and then concentrated. The residue is taken up in dichloromethane and washed with 1M hydrochloric acid solution. The organic phase is dried over anhydrous sodium sulfate and concentrated to give 3.13 g of the expected product.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]([OH:9])=[C:7]([CH2:10][OH:11])[CH:6]=[C:5]([CH3:12])[CH:4]=1.[OH-].[Na+].S(OC)(O[CH3:19])(=O)=O>O>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH3:12])[CH:6]=[C:7]([CH2:10][OH:11])[C:8]=1[O:9][CH3:19]
Reactant: Cc1cc(CO)c(O)c(CO)c1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1c(CO)cc(C)cc1CO
Reaction time: 8 h

Procedure:
To a solution of 2,6-bis(hydroxymethyl)-p-cresol (1) (250 g, 1.48 mol), NaOH pellet (90 g, 2.25 mol) in water (2 L), dimethyl sulfate (105 g, 0.84 mol) was added slowly while stirring. The temperature of the reaction mixture was maintained below 40° C. during dimethyl sulfate addition. Copious white precipitate formed upon standing overnight, the white product (150 g) was collected by filtration as the first crop. Dimethyl sulfate (31 g, 0.25 mol) was added to the mother liquor, and the mixture was stirred at room temperature for 5 days. During this time the volume of the mother liquor was reduced to half of its original volume and 70 g of product was collected as the second crop by filtration. Total yield, 220 g (81%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[C@H:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Br:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21](F)[CH:20]=1>CN(C)C=O>[CH2:1]([N:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([Br:18])[CH:20]=2)[C@H:10]([CH3:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1CN(Cc2ccccc2)CC[C@@H]1O
Reactant: Fc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H]1CN(Cc2ccccc2)CC[C@@H]1Oc1cccc(Br)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Dissolve 1-benzyl-cis-3-methyl-piperidin-4-ol (preparation 6, 3.84 g, 18.73 mmol) in dry N,N-dimethylformamide (100 mL), treat with 60% sodium hydride (1.05 g, 26.22 mmol), heat and stir at 80° C. After 1 hr., add-1-bromo-3-fluoro-benzene (2.51 mL, 22.45 mmol), stir and heat at 110° C. After 16 hr., cool to ambient temperature. Partition between water (100 mL) and ethyl acetate (100 mL), wash the aqueous layer with ethyl acetate (2×100 mL), combine the organic layers, wash with water (5×100 mL) and aqueous NaCl solution (100 mL). Dry the organic layer over sodium sulfate, filter and concentrate. Purify the residue by silica gel flash chromatography eluting with 2% (2M NH3/methanol)/methylene dichloride to obtain the title compound as a mixture of enantiomers (1.69 g, 24%). 1H NMR (CDCl3): 7.3 (m, 5H), 7.1 (m, 3H), 6.8 (m, 1H), 4.3 (m, 1H), 3.5 (d, 2H), 2.5 (m, 2H), 2.4 (m, 2H), 2.0 (m, 2H), 1.8 (m, 1H), 1.0 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@H:20]([NH2:24])[CH2:19]4)[C:14]([F:25])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:26][N:27]([CH2:35][CH:36]=O)[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31].C(N(C(C)C)CC)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.CCO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][CH2:36][CH2:35][N:27]([CH3:26])[C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH2:19]4)[C:14]([F:25])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CN(CC=O)C(=O)OC(C)(C)C
Reactant: N[C@@H]1CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCN[C@@H]1CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1)C(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 12 h

Procedure:
In a flask containing (1S,3R)—N1-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yl)cyclohexane-1,3-diamine, 47a, (0.14 g, 0.39 mmol) in THF/EtOH was added tert-butyl N-methyl-N-(2-oxoethyl)carbamate (0.10 g, 0.58 mmol) and diisopropylethylamine (0.13 mL, 0.77 mmol). The solution was heated at 70° C. for 30 min. Sodium triacetoxyborohydride (0.08 g, 0.39 mmol) was added. The solution was stirred at room temperature for 12 hrs. The solution was filtered and the solvent evaporated under reduced pressure. The resulting residue was purified by HPLC using 5-70% MeOH/H2O with 6 mM HCl to provide the desired product.
Reaction SMILES: C([BH3-])#N.[Na+].[C:5]1(=O)[CH2:9][CH2:8][CH2:7][CH2:6]1.Cl.[C:12]([O:16][C:17](=[O:20])[CH2:18][NH2:19])([CH3:15])([CH3:14])[CH3:13].CO>OP(O)(O)=O.O>[C:12]([O:16][C:17](=[O:20])[CH2:18][NH:19][CH:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C1CCCC1
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Agent: O=P(O)(O)O
Agent: [BH3-]C#N
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)CNC1CCCC1
Reaction time: 4 h
Yield: 90.4 %

Procedure:
Sodium cyanoborohydride(1.9 g) was added portionwise to a stirred mixture of cyclopentanone(2.1 g), glycine tert-butyl ester hydrochloride(5.0 g), water(12 ml) and methanol(25 ml) during 15 min at water-bath temperature. The resulting mixture was stirred for 4 hr, diluted with 20% H3PO4 (40 ml) and water(20 ml), and extracted with ether(80 ml). The aqueous layer was made alkaline(pH 10) with 20% NaOH and extracted with CHCl3 (50 ml). The extract was dried(Na2SO4) and concentrated in vacuo to give an oily residue, which was purified by silica gel column chromatography(ethyl acetate:hexane=3:1) to yield N-cyclopentylglycine tert-butyl ester(4.5 g) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9](O)[CH3:10])[CH:5]=[N:6][C:7]=1[Cl:8].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>ClC1C=CC=CC=1>[Cl:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([CH:9]=[CH2:10])=[CH:5][N:6]=1
Reactant: CC(O)c1cnc(Cl)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Clc1ccccc1
Product: C=Cc1cnc(Cl)c(Cl)c1
Temperature: 4 °C
Yield: 63 %

Procedure:
To a solution of the 1-(5,6-dichloro-pyridin-3-yl)-ethanol 15 (311 g. 1.62 mole) in chlorobenzene (3 L) was added p-toluene sulfonic acid (431 g, 2.5 mole) and the reaction mixture was heated at reflux with concomitant removal of water. When the reaction was complete the mixture was concentrated to about 500 mL, diluted with 2 L water, and extracted with 3×1 L ethyl acetate. The organic layer was dried (Na2SO4), concentrated under reduced pressure with low heat, dissolved in 500 mL methylene chloride, and applied to the top of 2 Kg silica column. The purified vinyl pyridine was eluted with a slight gradient of ethyl acetate in hexane, 0% to 10%. 178.55 g, 100% pure 2,3-dichloro-5-vinylpyridine was collected as a clear oil which solidified upon cooling to 4° C. 63% yield. 1H NMR (400 MHz, CDCl3) δ 8.27 (m, 1H), 7.80 (dd, J=12, 18 Hz, 1H), 6.62 (d, J=18 Hz, 1H), 5.46 (d, J=12 Hz, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]#[N:26])[CH:23]=3)[N:18]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)[N:17]=2)[CH:13]=[CH:14][CH:15]=1.[OH-:33].[Na+].OO>CCO>[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([NH2:26])=[O:33])[CH:23]=3)[N:18]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)[N:17]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: N#Cc1ccc2c(c1)c(-c1cccc(OCCC3CCCCN3)c1)nn2C1CCCCO1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1ccc2c(c1)c(-c1cccc(OCCC3CCCCN3)c1)nn2C1CCCCO1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
3-[3-(2-Piperidylethoxy)phenyl]-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (0.67 g, 1.6 mmol) was dissolved in 2 mL EtOH and the solution was cooled to 0° C. Aqueous 6 N NaOH solution (1.04 mL, 0.25 g, 6.2 mmol) and aqueous 30% H2O2 (0.7 mL, 0.21 g, 6.2 mmol) were added to the reaction mixture. The reaction mixture was warmed to room temperature and stirred for 1.5 h. The reaction was quenched by addition of 6 N HCl. The resultant solution was neutralized by addition of saturated aqueous solution of sodium bicarbonate. The solution was extracted with EtOAc, the organic layer was washed with water, brine, dried (Na2SO4) and filtered. The filtrate was concentrated to 0.61 g (87%) of the title compound obtained as a yellow solid. ES-MS (m/z) 449 [M+H]+.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[NH2:20][C@H:21]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:22][OH:23].CCN(C(C)C)C(C)C>>[OH:23][CH2:22][C@H:21]([NH:20][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1)[CH2:24][CH:25]([CH3:27])[CH3:26]
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: CC(C)C[C@@H](N)CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H](CO)NC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, (R)-2-amino-4-methyl-pentan-1-ol and DIEA to give 2-((R)-1-hydroxymethyl-3-methyl-butylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 356 (MH+).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][C@H:14]([CH2:16][CH2:17][CH3:18])[NH:13][C:12]2=[O:19])=[CH:7][CH:6]=1.Cl[CH2:21][C:22]([NH:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=1)=[O:23]>CN(C=O)C>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:15][C@H:14]([CH2:16][CH2:17][CH3:18])[N:13]([CH2:21][C:22]([NH:24][C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:28]=[CH:27][N:26]=3)=[O:23])[C:12]2=[O:19])=[CH:9][CH:10]=1
Reactant: CCC[C@H]1CN(c2ccc(OC)cc2)C(=O)N1
Reactant: O=C(CCl)Nc1cc(C(F)(F)F)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC[C@H]1CN(c2ccc(OC)cc2)C(=O)N1CC(=O)Nc1cc(C(F)(F)F)ccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 31.9 %

Procedure:
Sodium hydride (60%, 27 mg) was added to a solution of (4S)-1-(4-methoxyphenyl)-4-propylimidazolidin-2-one (32 mg) in DMF (1.5 mL), and the mixture was stirred at room temperature for 15 min. To the mixture was added 2-chloro-N-[4-(trifluoromethyl)pyridin-2-yl]acetamide (39 mg), and the resulting mixture was stirred for 15 hr. Thereafter, the reaction mixture was subjected to filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC, and further the resulting solid was washed with isopropyl ether to afford 2-[(55)-3-(4-methoxyphenyl)-2-oxo-5-propylimidazolidin-1-yl]-N-[4-(trifluoromethyl)pyridin-2-yl]acetamide (19 mg).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([OH:9])[CH:4]=1.Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1)[CH3:18]
Reactant: CCOC(=O)CBr
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cccc(C(F)(F)F)c1
Reaction time: 18 h
Yield: 80.8 %

Procedure:
A mixture of 100 g (0.618 mole) of α,α,α-trifluoro-m-cresol, 106 g (0.632 mole) of ethyl bromoacetate, 87.5 g (0.632 mole) of potassium carbonate, and 1500 ml of acetone is stirred at reflux for 4 hours, and at room temperature for 18 hours. The mixture is filtered, evaporated under vacuum on a rotarary evaporator at 45° C. and at 85° C. (0.1 mm) to remove excess ethyl bromoacetate. The reaction mixture is taken up in 500 ml of ether, washed three times with 100 ml each of 0.1 M potassium carbonate, once with 100 ml of water, 100 ml of 0.01 M hydrochloric acid, and 100 ml of water. It is then dried with magnesium sulfate, filtered and evaporated, giving 142 g of the crude product. This is fractionally distilled at 73°-75° C. (0.1 mm) to give 124 g of the purified subject product as a colorless liquid.
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[S:11]([NH:14][CH:15]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:16][C:17](O)=[O:18])(=[O:13])=[O:12].[NH2:26][CH:27]1[C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([C:36]#[N:37])[C:30]=2[CH2:29][CH2:28]1>>[C:36]([C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:30]=1[CH2:29][CH2:28][CH:27]2[NH:26][C:17](=[O:18])[CH2:16][CH:15]([NH:14][S:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)(=[O:12])=[O:13])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)#[N:37]
Reactant: N#Cc1cccc2c1CCC2N
Reactant: O=C(O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Product: N#Cc1cccc2c1CCC2NC(=O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1

Procedure:
N-(4-Cyano-indan-1-yl)-3-(naphthalen-2-yl-sulfonylamino)-3-phenyl-propionamide was prepared from 3-(naphthalen-2-yl-sulfonylamino)-3-phenyl-propionic acid ( ) and 1-amino-indan-4-carbonitrile (Step E), using essentially the same procedure described in Example 1, Step F, yielding a white solid. MS (ESI) m/z 496 (M+H)+.
Reaction SMILES: [C:1]1(=[O:15])[C:6]2=[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C@@H:8]3[CH2:9][O:10][C@@H:5]2[CH2:4][CH2:3][CH2:2]1.[Br-].[Al+3].[Br-].[Br-].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[C:1]1(=[O:15])[C:6]2=[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C@H:8]3[CH2:9][O:10][C@@H:5]2[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCC[C@H]2OC[C@H]3C=CC=CC3=C12
Agent: [Al+3]
Agent: [Br-]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1CCC[C@H]2OC[C@@H]3C=CC=CC3=C12

Procedure:
Reaction of a dl-cis-hexahydrodibenzopyranone prepared according to this invention with an aluminum halide such as aluminum bromide or aluminum chloride in a halogenated hydrocarbon solvent such as dichloromethane effects total epimerization to afford exclusively the corresponding dl-trans-hexahydrodibenzopyranone. As an example, dl-cis-1-hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-one, which is prepared in about 80 to about 85 percent yield in accordance with the process of this invention, can be reacted with about a 3 to 4 molar excess of aluminum chloride in dichloromethane at a temperature of about 25° C. to provide exclusively dl-trans-1-hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-one, i.e., nabilone. As noted hereinbefore, such trans-hexahydrodibenzopyranones are particularly useful in the treatment of anxiety and depression.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:32][CH2:33][CH3:34])[CH2:23][CH2:22][C:21]([C:35]([O:37]C)=[O:36])=[CH:20][C:19]=3[CH:39]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.Cl>O1CCCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:32][CH2:33][CH3:34])[CH2:23][CH2:22][C:21]([C:35]([OH:37])=[O:36])=[CH:20][C:19]=3[CH:39]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2ccccc2OCC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccccc2OCC)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 75.9 %

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-1-(2-ethoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxylate (402 mg) in a mixture of tetrahydrofuran (24 ml) and methanol (24 ml) was added 1N sodium hydroxide solution (8 ml), and the mixture was stirred at room temperature for 4 days. Then, to the mixture was added water at 0° C., and 1N hydrochloric acid was further added to make acidic (pH=4), and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, which was recrystallized from hexane ethyl acetate to give 7-(4-butoxyethoxyphenyl)-1-(2-ethoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (297 mg) as yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[O:24]1[CH:29]=[CH:28][CH2:27][CH2:26][CH2:25]1>C(Cl)Cl.C1CCCCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[N:7][N:8]2[CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][O:24]2)=[CH:4][CH:3]=1
Reactant: C1=COCCC1
Reactant: O=Cc1n[nH]c2cc(Br)ccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: C1CCCCC1
Product: O=Cc1nn(C2CCCCO2)c2cc(Br)ccc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 72.5 %

Procedure:
To a solution of 6-bromo-1H-indazole-3-carbaldehyde (13.97 g, 61.9 mmol) in DCM (150 mL) was added p-TsOH (2.36 g, 12.4 mmol) and the mixture was cooled to 0° C. 3,4-Dihydro-2H-pyran (8.47 mL, 92.8 mmol) was added dropwise to the solution and the reaction was stirred at room temperature overnight. The reaction mixture was diluted with DCM (200 mL) and washed with a solution of saturated aqueous sodium hydrogen carbonate (500 mL). The aqueous layer was re-extracted with DCM (500 mL) and the combined organic layers were washed with brine (2×1 L), dried over MgSO4 and concentrated in vacuo to yield a black oil. The crude material was refluxed in cyclohexane (20 mL) and filtered while hot. The filtrate was concentrated in vacuo and the residue was stirred in heptane for 48 hours. The resulting solid was collected by filtration to give the title compound (13.87 g) in a 73% yield.