Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1)=[O:6].[CH3:19]COCC>>[I:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:18])([CH3:17])[C:14]([O:16][CH3:19])=[O:15])=[CH:9][CH:8]=1)=[O:6]
Reactant: CCOCC
Reactant: CC(C)(C(=O)O)c1ccc(C(=O)CCCI)cc1
Product: COC(=O)C(C)(C)c1ccc(C(=O)CCCI)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of 12.6 g of 4-(4iodo-1-oxobutyl)-α,α-dimethylphenylacetic acid, prepared in accordance with Example 3, in 100 mL of Et2O cooled in an ice bath, was added 40 mL of ethereal CH2N2. The mixture was stirred at 0° C. for few minutes, then let stand for 2 hr. A few drops of ACOH were added to decompose excess CH2N2, then the mixture was filtered and stripped to afford 12.6 g (96%) of methyl 4-(4iodo-1-oxobutyl)-α,α-dimethylphenylacetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:17]([CH3:26])=[N:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2.[CH:27]([N-:30][CH:31]([CH3:33])[CH3:32])([CH3:29])[CH3:28].[Li+].C1C(=O)N(Br)C(=O)C1.O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:17]([CH2:26][N:30]([CH:31]([CH3:33])[CH3:32])[CH:27]([CH3:29])[CH3:28])=[N:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2
Reactant: CC(C)[N-]C(C)C
Reactant: COc1cc2nccc(Oc3cc4ccccc4nc3C)c2cc1OC
Agent: O=C1CCC(=O)N1Br
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3cc4ccccc4nc3CN(C(C)C)C(C)C)c2cc1OC
Reaction time: 0.17 h
Yield: 16 %

Procedure:
6,7-Dimethoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline (compound 276) (108 mg) was dissolved in tetrahydrofuran (5 ml) to prepare a solution. A lithiumdiisopropylamide/1.8 M heptane-tetrahydrofuran-ethylbenzene solution (0.3 ml) was added to the solution at −78° C., and the mixture was stirred for 10 min. N-Bromosuccimide (180 mg) was added to the reaction solution, and the mixture was stirred at room temperature for 5 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (23 mg, yield 16%).
Reaction SMILES: [Br:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][C:5]([NH2:6])=[C:4]([F:11])[CH:3]=1.[C:12]1(=O)[O:17][C:15](=[O:16])[C:14]2[CH2:18][CH2:19][CH2:20][CH2:21][C:13]1=2.O>C(O)(=O)C>[Br:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][C:5]([N:6]2[C:15](=[O:16])[C:14]3[CH2:18][CH2:19][CH2:20][CH2:21][C:13]=3[C:12]2=[O:17])=[C:4]([F:11])[CH:3]=1
Reactant: COc1cc(N)c(F)cc1Br
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Br
Temperature: 25 °C
Yield: 33.9 %

Procedure:
4-Bromo-2-fluoro-5-methoxyaniline (1.1 g) and 3,4,5,6-tetrahydrophthalic anhydride (0.8 g) were dissolved in acetic acid (5 ml) and refluxed for 3 hours. The resultant mixture was allowed to cool to room temperature and poured into water, followed by extraction with ether. The ether extract was washed with water, dried over anhydrous sodium sulfate and subjected to filtration. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography to obtain 0.6 g of N-(4-bromo-2-fluoro-5-methoxyphenyl)-3,4,5,6-tetrahydrophthalimide (Compound No. 12).
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].I[C:19]1[CH:20]=[C:21]([CH2:28][OH:29])[CH:22]=[C:23]([O:26][CH3:27])[C:24]=1[OH:25].C(OCC)(=O)C>C(Cl)Cl>[OH:15][C:10]1[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]2[O:4][C:3]([C:1]#[C:2][C:19]3[CH:20]=[C:21]([CH2:28][OH:29])[CH:22]=[C:23]([O:26][CH3:27])[C:24]=3[OH:25])([CH3:17])[CH2:8][CH2:7][C:6]=2[C:9]=1[CH3:16]
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: COc1cc(CO)cc(I)c1O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc(CO)cc(C#CC2(C)CCc3c(C)c(O)c(C)c(C)c3O2)c1O

Procedure:
This compound was obtained by reacting rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol with 3-iodo-4-hydroxy-5-methoxybenzenemethanol [P. Claus et al. Monatsh. Chem. 103, 1178 (1972)]under the conditions described in Example 1. The product was isolated by chromatography over silica gel using 30 % (V/V) of ethyl acetate in methylene chloride. Crystallization from ether/ hexane yielded colorless crystals with m.p. 160°-163°.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[C:10]([OH:12])[C:9]([C:13]23[CH2:22][CH:17]4[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]4)[CH2:14]2)[CH2:20]3)=[CH:8][C:5]=1[CH:6]=[O:7].I[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>CN(C=O)C>[CH2:24]([O:3][C:4]1[CH:11]=[C:10]([O:12][CH2:10][CH2:11][CH2:4][CH2:5][CH2:8][CH3:9])[C:9]([C:13]23[CH2:14][CH:15]4[CH2:21][CH:19]([CH2:18][CH:17]([CH2:16]4)[CH2:22]2)[CH2:20]3)=[CH:8][C:5]=1[CH:6]=[O:7])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCI
Reactant: O=Cc1cc(C23CC4CC(CC(C4)C2)C3)c(O)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCOc1cc(OCCCCCC)c(C23CC4CC(CC(C4)C2)C3)cc1C=O
Reaction time: 4 h

Procedure:
1.3 g (35.2 mmol) of sodium hydride (80% in oil) and 50 ml of DMF were introduced into a three-necked flask under a stream of nitrogen. A solution of 4.8 g (17.6 mmol) of 2,4-dihydroxy-5-(1-adamantyl)-benzaldehyde dissolved in 70 ml of DMF was added dropwise and stirring was carried out at room temperature until gas evolution has ceased. 6.5 ml (35.2 mmol) of 1-iodohexane were then added dropwise and stirring was carried out at room temperature for four hours.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[H-].[Na+].[Cl:13][C:14]([Cl:18])([Cl:17])[C:15]#[N:16]>C(OCC)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][O:8][C:15](=[NH:16])[C:14]([Cl:18])([Cl:17])[Cl:13])=[CH:5][CH:4]=1
Reactant: COc1ccc(CO)cc1
Reactant: N#CC(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: COc1ccc(COC(=N)C(Cl)(Cl)Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
Add a solution of 4-methoxybenzyl alcohol (31 mL, 250 mmol) in diethyl ether (250 ml) to sodium hydride (1.0 g, 25 mmol, 60% suspension in mineral oil) in diethyl ether (250 ml). Stir 30 min. Cool in ice bath and add trichloroacetonitrile (25 mL, 250 mmol) and let slowly warm to room temperature. Concentrate and dissolve in petroleum ether containing 0.3% methanol (330 mL) and filter through a filtering agent and concentrate to give the title compound (67 g, 95%).
Reaction SMILES: OC(C1N=C(CCC)NC=1C(OCC)=O)C.[C:17]([C:20]1[N:21]=[C:22]([CH2:30][CH2:31][CH2:32][CH3:33])[NH:23][C:24]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26])(=[O:19])[CH3:18]>>[CH2:30]([C:22]1[NH:23][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:20]([CH:17]([OH:19])[CH3:18])[N:21]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCCc1nc(C(C)=O)c(C(=O)OCC)[nH]1
Agent: CCCc1nc(C(C)O)c(C(=O)OCC)[nH]1
Product: CCCCc1nc(C(C)O)c(C(=O)OCC)[nH]1
Yield: 85.2 %

Procedure:
Following a procedure similar to that described in Preparation 23(iii), but using 0.64 g of ethyl 4-acetyl-2-butylimidazole-5-carboxylate [prepared as described in step (ii) above]. 0.55 g of the title compound was obtained as crystals, melting at 149° C.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3].[Cl:10][C:11]1[N:20]=[C:19]2[C:14]([CH:15]=[CH:16][C:17]([N:21]3[CH:25]([O:26][C:27](OC4C=CC=CC=4)=[O:28])[C:24]4[S:36][CH2:37][CH2:38][O:39][C:23]=4[C:22]3=[O:40])=[N:18]2)=[CH:13][CH:12]=1.C(OC(C)C)(C)C>C(#N)C>[CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:27]([O:26][CH:25]2[N:21]([C:17]3[CH:16]=[CH:15][C:14]4[C:19](=[N:20][C:11]([Cl:10])=[CH:12][CH:13]=4)[N:18]=3)[C:22](=[O:40])[C:23]3[O:39][CH2:38][CH2:37][S:36][C:24]2=3)=[O:28])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: O=C(Oc1ccccc1)OC1C2=C(OCCS2)C(=O)N1c1ccc2ccc(Cl)nc2n1
Reactant: C=CCN1CCNCC1
Solvent: CC#N
Solvent: CC(C)OC(C)C
Product: C=CCN1CCN(C(=O)OC2C3=C(OCCS3)C(=O)N2c2ccc3ccc(Cl)nc3n2)CC1
Reaction time: 29 h
Yield: 63.5 %

Procedure:
1-Allylpiperazine (6.3 g.) is added to a suspension of 6-(7-chloro-1,8-naphthyridin-2-yl)-7-oxo-5-phenoxycarbonyloxy-2,3,6,7-tetrahydro-5H-1,4-oxathiino[2,3-c]pyrrole (4.56 g.) in acetonitrile (25 cc.). The temperature of the reaction mixture rises to about 25° C. After 29 hours, diisopropyl ether (50 cc.) is added and the insoluble product is filtered off and washed with diisopropyl ether (2 × 15 cc.). After drying, 5-(4-allylpiperazine-1-yl)carbonyloxy-6-(7-chloro-1,8-naphthyridin-2-yl)-7-oxo-2,3,6,7-tetrahydro-5H-1,4-oxathiino[2,3-c]pyrrole (3.1 g.), melting at 254° C., is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4](I)[CH:3]=1.C([Li])CCC.CCCCCC.[CH2:21]([O:24][CH2:25][C:26](N(OC)C)=[O:27])[CH:22]=[CH2:23]>O1CCCC1>[CH2:21]([O:24][CH2:25][C:26]([C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[F:8])=[O:27])[CH:22]=[CH2:23]
Reactant: C=CCOCC(=O)N(C)OC
Reactant: Fc1ccc(Br)cc1I
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CCOCC(=O)c1cc(Br)ccc1F
Temperature: -72 °C
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
To a stirred −72° C. solution of 4-bromo-1-fluoro-2-iodobenzene (130.4 g, 433.5 mmol) in tetrahydrofuran (722 mL) is added 2.5 M butyl lithium in hexane (173.4 mL, 433.5 mmol) under a nitrogen atmosphere over 40 min. The reaction is stirred for 30 minutes at −72° C. and 2-(allyloxy)-N-methoxy-N-methylacetamide (57.5 g, 361.2 mmol) in tetrahydrofuran (115 mL) is added dropwise for 35 minutes. After 45 min at −72° C., the cooling bath is removed and mixture is warmed to 25° C. The reaction is quenched with saturated aqueous NH4Cl (500 mL), diluted with water (300 mL) and extracted three times with ethyl acetate. Organics are combined, dried over magnesium sulfate, filtered, and the solvent is removed under reduced pressure. The residue is purified by silica gel chromatography using a linear gradient of 5% to 10% ethyl acetate in hexanes to give the title compound (63 g, 64%). ES/MS m/e (79Br/81Br) 273/275 (M+1).
Reaction SMILES: C(O)(=O)CC(O)=O.[CH:8]1[C:13](/[CH:14]=[CH:15]/[C:16]([OH:18])=[O:17])=[CH:12][CH:11]=[C:10]([OH:19])[CH:9]=1.[CH2:20](Br)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>>[CH2:31]([O:19][C:10]1[CH:11]=[CH:12][C:13]([CH:14]=[CH:15][C:16]([OH:18])=[O:17])=[CH:8][CH:9]=1)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20]
Reactant: O=C(O)/C=C/c1ccc(O)cc1
Reactant: CCCCCCCCCCCCBr
Agent: O=C(O)CC(=O)O
Product: CCCCCCCCCCCCOc1ccc(C=CC(=O)O)cc1

Procedure:
4-Dodecyloxycinnamic acid is prepared by generally known processes by condensation of a 4-alkoxybenzaldehyde with malonic acid or by reaction of coumaric acid with dodecyl bromide. The colourless crystals have a melting point of 158-159° C. The corresponding acid chloride is obtained therefrom virtually quantitatively by reaction with oxalyl chloride in benzene (18 hours, room temperature).
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH2:19]([C:26]1[CH:27]=[C:28]([NH2:31])[NH:29][N:30]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH2:19]([C:26]1[CH:27]=[C:28]([NH:31][CH:8]=[C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[NH:29][N:30]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C1Nc2ccccc2/C1=C/O
Reactant: Nc1cc(Cc2ccccc2)n[nH]1
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C1=CNc1cc(Cc2ccccc2)n[nH]1

Procedure:
The named compound is prepared by substituting 5-benzyl-2H-pyrazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.100 gms.) is reacted with 0.231 gms. 5-benzyl-2H-pyrazol-3-ylamine by refluxing in tetrahydrofuran (2.5 mL) overnight.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[NH:8][C:7](=[O:16])[N:6]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:5]2=[O:22].C[O:24][CH:25]1[CH:29]([CH:30]=O)[CH2:28][CH:27](OC)O1>C(O)(=O)C>[CH:25]([C:29]1[CH:28]=[CH:27][N:1]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[C:12]([F:13])([F:15])[F:14])[NH:8][C:7](=[O:16])[N:6]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:5]3=[O:22])[CH:30]=1)=[O:24]
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(N)cc2c1=O
Reactant: COC1CC(C=O)C(OC)O1
Solvent: CC(=O)O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(-n3ccc(C=O)c3)cc2c1=O
Yield: 65 %

Procedure:
To a solution of 100 mg (0.296 mmol) of N-(6-amino-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide in 2 ml acetic acid is added a solution of 2,5-dimethoxy-tetrahydrofuran-3-carbaldehyde in 1 ml acetic acid and the mixture is refluxed for 3 hours. The solvent is removed by rotavapor evaporation and the brown oil is purified by reversed phase chromatography (C18) with an acetonitril-water gradient to give 80 mg (65%) of N-[6-(3-formyl-pyrrol-1-yl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl]-methanesulfonamide as a black solid. MS (ES+): m/e =417 (M+H+).
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:12]([CH2:13][C:14]([C:35](OCC)=O)([CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:26]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:11]([O:40][CH3:41])[C:10]([O:42][CH3:43])=[C:9]([O:44][CH3:45])[C:8]=1[O:46][CH3:47].C(O)(=[O:50])C.C(=O)(O)[O-].[Na+]>C1COCC1.CCCCCC>[CH3:41][O:40][C:11]1[C:10]([O:42][CH3:43])=[C:9]([O:44][CH3:45])[C:8]([O:46][CH3:47])=[C:7]2[C:12]=1[CH2:13][C:14]([CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:26]=1)([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:35]2=[O:50]
Reactant: CCOC(=O)C(CCCCOc1ccc(C(=O)OC)cc1)(Cc1c(Br)c(OC)c(OC)c(OC)c1OC)C(=O)OCC
Reactant: CC(=O)O
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C1(CCCCOc2ccc(C(=O)OC)cc2)Cc2c(OC)c(OC)c(OC)c(OC)c2C1=O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 50.2 %

Procedure:
A hexane solution of n-butyl lithium (1.68 M, 3.27 ml, 5.50 mmols) was dropwise added to a THF (30 ml) solution of ethyl 2-(6-bromo-2,3,4,5-tetramethoxybenzyl)-2-ethoxycarbonyl-6-(4-methoxycarbonylphenoxy)hexanoate (3.00 g, 4.58 mmols), under a nitrogen stream at −90° C. or lower, and stirring was continued for 15 minutes. Then, the temperature was raised to −78° C., and stirring was further continued for 15 minutes. To the reaction mixtures was added a THF (5 ml) solution of acetic acid (1.38 g, 22.9 mmols) at −70° C. or lower, which was then allowed to warm to room temperature, and a saturated aqueous sodium bicarbonate solution was added thereto, which was then extracted with diethyl ether. The organic layer waswashed with water and a saturated aqueous sodium chloride solution, and then dried. The solvent was evaporated out, and the resulting crude product was purified by recrystallization (from hexane-ethyl acetate) to obtain the entitled compound (1.22 g) as crystals.
Reaction SMILES: C(=O)/C=C/C1C=CC=CC=1.[OH:11][CH2:12][CH:13]([CH2:15][OH:16])[OH:14].C1(CCC[CH2:26][CH:27]([OH:30])[CH2:28][OH:29])C=CC=CC=1.C1(CCCCC(O)CO)CCCCC1>[Pd]>[CH2:12]([O:11][CH2:26][CH:27]([CH2:28][OH:29])[OH:30])[CH:13]([CH2:15][OH:16])[OH:14]
Reactant: OCC(O)CO
Reactant: OCC(O)CCCCc1ccccc1
Agent: [Pd]
Agent: O=C/C=C/c1ccccc1
Agent: OCC(O)CCCCC1CCCCC1
Product: OCC(O)COCC(O)CO
Temperature: 200 °C

Procedure:
Trans-Cinnamaldehyde (13.2 g, 12.6 ml, 0.1 mol) of, glycerol (92.09 g, 73.7 ml, 1 mol) and 10% Pd/C (0.66 g, 5 wt % relative to the aldehyde) are charged to a Parr reactor, purged three times with nitrogen, heated to 200° C. with stirring and reacted at 1000 psi of hydrogen for 20 h. GC analysis shows complete consumption of the aldehyde. The mixture is filtered, the product extracted with ether (50 ml×5), and the combined ether solution is dried with sodium sulfate. The solvent is evaporated and the residue chromatographed on silica gel using hexane-ethyl acetate from 5:1 to 1:1 to give 4.6 g of the monoether (95% purity). This product is approximately a 2:1 mixture of 3-(3-phenylpropyl)-1,2-propanediol and 3-(3-cyclohexylpropyl)-1,2-propanediol. The individual components of this mixture are separated by second column chromatography and characterized by 1H and 13C NMR.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[N:10][CH:11]=1)=[O:5].[F:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:20]=1[CH2:21][Mg]Br.FC1C=C(F)C=CC=1CBr.[Mg].Cl>C1COCC1.CCOCC>[F:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:20]=1[CH2:21][C:4]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[N:10][CH:11]=1)=[O:5]
Reactant: CON(C)C(=O)c1ccc(-n2ccnc2)nc1
Reactant: Fc1ccc(C[Mg]Br)c(F)c1
Agent: Cl
Agent: Fc1ccc(CBr)c(F)c1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(Cc1ccc(F)cc1F)c1ccc(-n2ccnc2)nc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
A solution of the product from part (i) (6.5 g, 28 mmol) in THF (100 ml) was stirred under a nitrogen atmosphere at -70° C. and was treated with a solution of 2,4-difluorobenzylmagnesium bromide [from 2,4-difluorobenzyl bromide (8.1 g, 39 mmol) and magnesium (1.0 g, 42 mmol) using the method of Preparation 20(i)] in ether (100 ml). The mixture was stirred at -70° C. for 0.5 hours and was allowed to warm to room temperature before the addition of dilute hydrochloric acid (2N, 100 ml). The layers were separated and the aqueous phase was extracted with dichloromethane (100 ml). The combined organic extracts were dried (MgSO4) and evaporated under reduced pressure to yield the title compound as a pale yellow solid which was characterised by
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:31])[CH2:4][CH2:5][N:6]1[C:13](=[O:14])[C@H:12]([OH:15])[C@H:11]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[S:10][C:9]2=[CH:24][CH:25]=[CH:26][C:27]3=[CH:28][CH:29]=[CH:30][C:7]1=[C:8]23.[C:32](OC(=O)C)(=[O:34])[CH3:33]>>[C:32]([O:15][C@@H:12]1[C@H:11]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[S:10][C:9]2=[CH:24][CH:25]=[CH:26][C:27]3=[CH:28][CH:29]=[CH:30][C:7](=[C:8]23)[N:6]([CH2:5][CH2:4][N:3]([CH3:2])[CH3:31])[C:13]1=[O:14])(=[O:34])[CH3:33]
Reactant: COc1ccc([C@@H]2Sc3cccc4cccc(c34)N(CCN(C)C)C(=O)[C@@H]2O)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Product: COc1ccc([C@@H]2Sc3cccc4cccc(c34)N(CCN(C)C)C(=O)[C@@H]2OC(C)=O)cc1
Reaction time: 17 h
Yield: 90 %

Procedure:
A mixture of 3.4 g of (+)-cis-2,3-dihydro-5-[2-(dimethylamino)ethyl]-3-hydroxy-2-(4-methoxyphenyl)naphtho[1,8-bc]-1,5-thiazocin-4(5H)-one hydrochloride and 60 mL of acetic anhydride was stirred under nitrogen at 100° for 17 hours. The excess of reagent was removed under reduced pressure, then to the residue ice-water was added and made basic with 10% sodium hydroxide. The resulting suspension was extracted with ether (3×75 mL) and the combined ether solutions were washed with brine and dried (magnesium sulfate). Removal of the solvent under reduced pressure gave 3.1 g (90%) of (+)-cis-3-(acetyloxy)-2,3-dihydro-5-[2-(dimethylamino)ethyl]-2-(4-methoxyphenyl)naphtho[1,8-bc]-1,5-thiazocin-4(5H)-one as an amorphous compound, [α]D25 +187.94° (C 0.47, methanol).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:16]=[CH:15][N:14]=[C:13]3[C:8]=2[C:9]2[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=2[C:11](=[O:17])[NH:12]3)=[C:4]([F:24])[CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38](O)=[O:39])[C:33]2=[O:41])=[CH:28][CH:27]=1>>[F:24][C:4]1[CH:3]=[C:2]([NH:1][C:38]([C:34]2[C:33](=[O:41])[N:32]([C:29]3[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=3)[CH:37]=[CH:36][CH:35]=2)=[O:39])[CH:23]=[CH:22][C:5]=1[O:6][C:7]1[CH:16]=[CH:15][N:14]=[C:13]2[C:8]=1[C:9]1[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=1[C:11](=[O:17])[NH:12]2
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)c4ccccc4c23)c(F)c1
Reactant: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
Product: O=C(Nc1ccc(Oc2ccnc3[nH]c(=O)c4ccccc4c23)c(F)c1)c1cccn(-c2ccc(F)cc2)c1=O
Yield: 87.4 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 181 using Compound 182 (50 mg, 0.16 mmol) and 1-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid (44 mg, 0.19 mmol) to provide 184 (75 mg, 90% yield) as a dark solid. LC-MS (M+H=537, obsd.=537).
Reaction SMILES: [BrH:1].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][NH:10][CH2:9][C@H:8]([CH3:13])[C:7]=2[CH:14]=1.C(OC(C)C)(=[O:17])C>C(#N)C.C(OCC)(=O)C>[OH2:17].[BrH:1].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][NH:10][CH2:9][C@H:8]([CH3:13])[C:7]=2[CH:14]=1.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][NH:10][CH2:9][C@H:8]([CH3:13])[C:7]=2[CH:14]=1.[BrH:1]
Reactant: CC(=O)OC(C)C
Agent: Br
Agent: C[C@H]1CNCCc2ccc(Cl)cc21
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O
Reaction time: 8 h

Procedure:
(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide salt hemihydrate was prepared by the dropwise addition of one equivalent of aqueous HBr (˜48%) to a solution of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine free base in isopropyl acetate, acetonitrile, or ethyl acetate with vigorous stirring. The product readily precipitated from the reaction in isopropyl acetate. In acetonitrile the solvent was evaporated to near dryness to obtain a solid. In ethyl acetate, seeds were added and the reaction was allowed to stir unstoppered to initiate crystallization. The reaction was then closed and stirring was continued to afford a yellow suspension. The suspension was filtered and the solid was washed with cold ethyl acetate. The resulting white solid was under nitrogen at ˜38° C., and held overnight at 25° C./75% RH. (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide salt hemihydrate had an extrapolated dehydration onset temperature by TGA of about 72.5° C.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:16])[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:9](=O)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:20][CH:19]=1.B(F)(F)F.CCOCC>O1CCCC1>[C:1]([C:5]1[C:6](=[O:16])[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:9](=[N:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:22][CH:23]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(CCC(=O)O)cc1
Reactant: CC(C)(C)C1=CC(=O)C=C(C(C)(C)C)C1=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)C1=CC(=Nc2ccc(CCC(=O)O)cc2)C=C(C(C)(C)C)C1=O
Yield: 51.4 %

Procedure:
A mixture of 5.51 g (0.25 mole) of 2,6-di-tertiary-butyl-p-benzoquinone, 4.54 g (0.027 mole) of 3-(4-aminophenyl)propionic acid, 50 ml of tetrahydrofuran and 0.25 ml of boron trifluoride etherate was heated on a steam cone under a slow stream of nitrogen for two hours. The resulting solid was triturated with hexane, collected, rinsed with hexane and recrystallized from a mixture of ethyl acetate and hexane to give 5.1 g yellow 3-[4-(2,6-di-tertiary-butylcyclohexadienon-4-ylideneamino)phenyl]propionic acid, m.p. 165°-167° C. Analysis: Calculated for C23H29NO3 : %C, 75.2; %H, 8.0; %N, 3.8; Found %C, 74.8; %H, 7.9; %N, 3.7.