Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)=[O:5])C.[OH-].[Na+].Cl>C(O)C.O>[Cl:16][C:15]1[C:14]2[C:9](=[CH:10][C:11]([O:19][CH3:20])=[C:12]([O:17][CH3:18])[CH:13]=2)[N:8]=[CH:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnc2cc(OC)c(OC)cc2c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc2ncc(C(=O)O)c(Cl)c2cc1OC
Yield: 116.4 %

Procedure:
4-chloro-6,7-dimethoxy-3-quinolinecarboxylic ethyl ester (ex RSL) (50 g) was suspended in ethanol (400 ml) and aqueous 2M sodium hydroxide (400 ml) was added with stirring, stirred for 24 hours. The reaction mixture was diluted with water (400 ml), cooled in an ice/water bath and brought to pH4 by carefully addition of concentrated hydrochloric acid. The resulting solid was filtered off, washed with water and dried in a vacuum oven at 50° C. To give 4-chloro-6,7-dimethoxy-3-quinolinecarboxylic acid (52.7 g, 98.7%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Br:9])[CH:3]=1.[CH:10]1([Mg]Br)[CH2:12][CH2:11]1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:9][C:4]1[CH:3]=[C:2]([CH:10]2[CH2:12][CH2:11]2)[CH:7]=[C:6]([Cl:8])[CH:5]=1
Reactant: Clc1cc(Br)cc(Br)c1
Reactant: Br[Mg]C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1cc(Br)cc(C2CC2)c1
Temperature: 70 °C
Yield: 63.5 %

Procedure:
To a solution of 1,3-dibromo-5-chlorobenzene (500 mg, 1.85 mmol) in THF (1 ml) was added cyclopropylmagnesium bromide (3698 μl, 0.5M solution in THF, 1.85 mmol) in a sealed tube and the reaction mixture was degassed with argon for 5 min before tetrakis(triphenylphosphine)palladium (0) (107 mg, 0.09 mmol) was added. The resulting solution was heated to 70° C. overnight, cooled to RT and then quenched with sat. NH4Cl solution and extracted with pentane. The organic phases were combined, washed with water and brine, dried over MgSO4 and filtered through a short pad of silica gel to give the desired product (272 mg, 64%) which did not require further purification. 1H NMR (CDCl3, 300 MHz): 7.28 (aptt, J=2.0 Hz, 1H), 7.08 (aptt, J=1.5 Hz, 1H), 6.97 (aptt, J=1.5 Hz, 1H), 1.83 (m, 1H), 1.04-0.97 (m, 2H), 0.72-0.67 (m, 2H).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12](Cl)=[N:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][CH:16]=2)=[CH:7][C:6]=1[O:24]C(=O)C)(=O)C.O.[SH2:29].[Na]>CO>[OH:24][C:6]1[CH:7]=[C:8]([C:11]2[C:12](=[S:29])[NH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:15][CH:16]=2)[CH:9]=[CH:10][C:5]=1[OH:4]
Reactant: CC(=O)Oc1ccc(-c2cnc(-c3ccccc3)nc2Cl)cc1OC(C)=O
Reactant: S
Agent: [Na]
Solvent: CO
Solvent: O
Product: Oc1ccc(-c2cnc(-c3ccccc3)[nH]c2=S)cc1O
Yield: 77.4 %

Procedure:
4-(4-Chloro-2-phenyl-5-pyrimidinyl)-o-phenylene diacetate (6.0 g) (15.7 mmol) are suspended in 200 ml of methanol. 10 g of sodium hydrogen sulphide hydrate are added at 50° C. while stirring. After a further 4 hours at 60° C. the mixture is filtered and the filtrate is concentrated. The residue is dissolved in about 150 ml of water and the solution is brought to pH 5 with 1N aqueous hydrochloric acid. The precipitated product is filtered off under suction, washed with water, dried at room temperature and crystallized from ethanol. There are obtained 3.6 g of 5-(3,4-dihydroxyphenyl)-2-phenyl-4(3H)-pyrimidinethione as yellow crystals of m.p. 220° C.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-])=O)[CH:10]=2)[N:5]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH:4]=1)#[N:2].[Cl-].[NH4+].O>C(O)C.[Fe]>[NH2:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]([CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:17][CH2:16]1)[CH:4]=[C:3]2[C:1]#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(C#N)c3cc([N+](=O)[O-])ccc32)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(C#N)c3cc(N)ccc32)CC1
Temperature: 85 °C
Yield: 21.4 %

Procedure:
tert-butyl 4-(3-cyano-5-nitro-1H-indol-1-yl)piperidine-1-carboxylate (1.02 g, 2.75 mmol), Iron (0.923 g, 16.52 mmol), and ammonium chloride (1.031 g, 19.28 mmol) were suspended in a mixture of Ethanol (10 mL)/Water (10 mL). The reaction mixture was heated in oil bath at 85° C. for 20 min. The reaction mixture was filtered through Celite, and then washed with water, MeOH and EtOAc. The combined filtrates were concentrated to almost dryness, and then mixed with aq. NaHCO3 and EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and evaporated to dryness to give tert-butyl 4-(5-amino-3-cyano-1H-indol-1-yl)piperidine-1-carboxylate (200 mg).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([C:16]1[C:17]([CH:49]=[O:50])=[C:18]([N:22]3[CH:26]=[C:25]([C:27]#[N:28])[C:24]([NH:29][C:30]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[N:23]3)[CH:19]=[CH:20][CH:21]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C(Cl)Cl.CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([C:16]1[C:17]([CH2:49][OH:50])=[C:18]([N:22]3[CH:26]=[C:25]([C:27]#[N:28])[C:24]([NH:29][C:30]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[N:23]3)[CH:19]=[CH:20][CH:21]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2c(=O)n(-c3cccc(-n4cc(C#N)c(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)c3C=O)ncc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)c1ccc2c(=O)n(-c3cccc(-n4cc(C#N)c(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)c3CO)ncc2c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 76.1 %

Procedure:
To a solution of 1-[3-(6-tert-Butyl-1-oxo-1H-phthalazin-2-yl)-2-formyl-phenyl]-3-(trityl-amino)-1H-pyrazole-4-carbonitril (632 mg, 0.965 mmol) in methylene chloride (20 mL) and methanol (10 mL), at 0° C. was added sodium borohydride (37 mg, 0.965 mmol). The resulting turbid reaction mixture was stirred at 0° C. for 5 minutes and then allowed to stir at room temperature for 10 minutes. The reaction was then judged to be complete by TLC. The volatiles removed in vacuo and the crude product was bound to silica gel and purified over a 40 g silica gel cartridge eluting the column with a 20-50% EtOAc/hexanes gradient to give 1-[3-(6-tert-Butyl-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-3-(trityl-amino)-1H-pyrazole-4-carbonitrile (482 mg, 76%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[CH:6][N:5]=[C:4]2[N:11]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[CH:13][C:3]=12.[CH2:22]([N:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)C(C)C)(C)C>O>[CH2:22]([N:29]1[CH2:34][CH2:33][CH:32]([NH:35][C:2]2[C:7]([C:8]([NH2:10])=[O:9])=[CH:6][N:5]=[C:4]3[N:11]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[CH:13][C:3]=23)[CH2:31][CH2:30]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)c(C(N)=O)cnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c(NC3CCN(Cc4ccccc4)CC3)c(C(N)=O)cnc21
Temperature: 25 °C
Yield: 80.7 %

Procedure:
4-Chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (456 mg, 1.40 mmol) was stirred with 1-benzyl-4-aminopiperidine (900 mg, 4.73 mmol) and N,N-diisopropylethylamine (250 μL, 1.44 mmol) at 140° C. for 3 hours. The reaction mixture was allowed to cool to room temperature and, after addition of water, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform→ethyl acetate/methanol=1/0→5/1 (v/v)) to give the title compound as a colorless solid (542 mg, yield 81%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[NH3:18]>>[NH2:18][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: N
Reactant: CCOC(=O)c1cnc2cc(F)ccc2c1Cl
Product: CCOC(=O)c1cnc2cc(F)ccc2c1N

Procedure:
Prepared as in Example 1a from ethyl 4-chloro-7-fluoroquinoline-3-carboxylate (Example 9b) and ammonia as an off white solid (99%). MS 235 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22])[C:15]([OH:17])=O.[N:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:27][CH:26]=1.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:15]([N:35]2[CH2:36][CH2:37][N:32]([CH2:31][C:28]3[CH:27]=[CH:26][N:25]=[CH:30][CH:29]=3)[CH2:33][CH2:34]2)=[O:17])[CH:18]=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22]
Reactant: c1cc(CN2CCNCC2)ccn1
Reactant: COc1cc(C(=O)O)cc(OCCc2ccc(Cl)cc2Cl)c1OC
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCN(Cc3ccncc3)CC2)cc(OCCc2ccc(Cl)cc2Cl)c1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.100 g (0.269 mmol) of 3-[2-(2,4-Dichlorophenyl)-ethoxy]-4,5-dimethoxy-benzoic acid was dissolved in 2 ml of DMF and treated with 0.124 g (1.08 mmol) of N-NEM and 0.0477 g (0.27 mmol) of 1-Pyridin-4-ylmethyl-piperazine and 0.088 g (0.269 mmol) of TOTU. The solution was stirred for 16 h at RT. The solvent was removed under reduced pressure, the residue was taken-up in ethyl acetate and the solution was washed twice with saturated aqueous sodium bicarbonate and once with saturated aqueous sodium chloride. The organic phase was dried with magnesium sulphate, filtered and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with a gradient of 0-17% MeOH in DCM.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[CH:12]=[CH:11][O:10][CH:9]=1.[OH:13][C:14]([CH3:47])([CH3:46])[CH2:15][C@@:16]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:21][C:20](=[O:22])[N:19]([C@H:23]([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=2)[CH3:24])[CH2:18][CH2:17]1>CN(C)C=O>[O:10]1[CH:11]=[CH:12][C:8]([C:28]2[CH:27]=[CH:26][C:25]([C@@H:23]([N:19]3[CH2:18][CH2:17][C@:16]([CH2:15][C:14]([OH:13])([CH3:46])[CH3:47])([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[O:21][C:20]3=[O:22])[CH3:24])=[CH:30][CH:29]=2)=[CH:9]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Brc1ccoc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](c1ccc(-c2ccoc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 90 °C
Reaction time: 2 h

Procedure:
2 M aqueous Na2CO3 solution (0.70 mL) was added to a solution of 3-bromo-furan (75 μL) and (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one (0.33 g) in dimethylformamide (3 mL). The resulting mixture was sparged with argon for 10 min, before [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II) dichloromethane complex (16 mg) was added. The mixture was heated to 90° C. and stirred at this temperature for 2 h. After cooling to ambient temperature, water was added, and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated. The residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 80:20->0:100) to afford the title compound.
Reaction SMILES: C([NH:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[C@@H:19]1[O:24][C@H:23]([C:25]([OH:27])=[O:26])[C@@H:22]([NH:28][C:29](=[O:43])[C@H:30]([CH3:42])[NH:31][C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[C@H:20]1[OH:21])(=O)C1C=CC=CC=1.C(N)CCC>>[NH2:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[C@@H:19]1[O:24][C@H:23]([C:25]([OH:27])=[O:26])[C@@H:22]([NH:28][C:29](=[O:43])[C@H:30]([CH3:42])[NH:31][C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[C@H:20]1[OH:21]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1C(=O)O
Solvent: CCCCN
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@@H]1C(=O)O
Yield: 82.4 %

Procedure:
1-(6-Amino-9H-purin-9-yl)-3-(N-benzyloxycarbonyl-L-alanylamino)-1,3-dideoxy-β-D-ribofuranuronic acid (190 mg) was prepared by reacting 1-(6-benzoylamino-9H-purin-9-yl)-3-(N-benzyloxycarbonyl-L-alanylamino)-1,3-dideoxy-β-D-ribofuranuronic acid (280 mg) prepared in Example 13 with n-butylamine (1.5 ml) according to a similar manner to that of Example 23, mp. 151°-156° C. (dec.).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14])([O-:3])=[O:2].OS(O)(=O)=O.O.[OH-].[Na+].[CH3:28]O>>[CH3:28][O:14][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=1[NH:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: CO
Reactant: O=C(O)c1ccccc1Nc1ccccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)c1ccccc1Nc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 80 %

Procedure:
2-(2-Nitro-phenylamino)-benzoic acid (560 mg, 2.2 mmol) is dissolved in methanol (10 mL) and concentrated H2SO4 (0.16 mL, 98%) is added into it. The mixture is then refluxed for 60 hr. After it is cooled down to room temperature, 100 mL of water is added and the pH of this solution is adjusted to pH 7 by adding 1.0 M NaOH aqueous solution. An orange solid is formed and it is filtered and rinsed with more water. Air drying of this orange solid affords 470 mg (80%) of 2-(2-Nitro-phenylamino)-benzoic acid methyl ester.
Reaction SMILES: B([O-])=O.[Na+].[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[CH:13]([S:27][CH2:28][CH3:29])[CH:14]([N:22]1[CH:26]=[N:25][CH:24]=[N:23]1)[C:15](=[O:21])[C:16]([CH3:20])([CH3:19])[CH2:17][F:18].[Cl-].[Ca+2].[Cl-].CC(C)=O>O.C(O)(C)C>[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[CH:13]([S:27][CH2:28][CH3:29])[CH:14]([N:22]1[CH:26]=[N:25][CH:24]=[N:23]1)[CH:15]([OH:21])[C:16]([CH3:19])([CH3:20])[CH2:17][F:18]
Reactant: CCSC(c1ccc(Cl)cc1Cl)C(C(=O)C(C)(C)CF)n1cncn1
Agent: O=B[O-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CC(C)O
Solvent: O
Solvent: CC(C)=O
Product: CCSC(c1ccc(Cl)cc1Cl)C(C(O)C(C)(C)CF)n1cncn1
Temperature: 0 °C
Reaction time: 18 h
Yield: 60.7 %

Procedure:
A solution of 0.42 g (11 millimols) of sodium boranate in 20 ml of water was added dropwise, with stirring, to a suspension of 6.4 g (15.8 millimols) of 1-(2,4-dichlorophenyl)-4,4-dimethyl-1-ethylthio-5-fluoro-2-(1,2,4-triazol-1-yl)-pentan-3-one (see Example 5) and 1.2 g (10.8 millimols) of calcium chloride in 150 ml of isopropanol. The mixture was stirred for 18 hours at 0° C. and 20 ml of acetone were then added dropwise. This mixture was evaporated in vacuo and the residue was decomposed with dilute acetic acid. The organic base was dissolved in methylene chloride and the solution was washed with water, dried over sodium sulphate, filtered and evaporated down in vacuo. The oil which remained was stirred with diisopropyl ether. 3.9 g (60% of theory) of 1-(2,4-dichlorophenyl)-4,4-dimethyl-1-ethylthio-5-fluoro-2-(1,2,4-triazol-1-yl)-pentan-3-ol, of melting point 182° C., were obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]([O:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[CH:15]=[O:16])[CH2:5][CH3:6].[CH2:18](O)[CH2:19][OH:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:17])[CH:4]([O:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[CH:15]1[O:20][CH2:19][CH2:18][O:16]1)[CH2:5][CH3:6]
Reactant: OCCO
Reactant: CCC(Oc1ccc(Cl)cc1C=O)C(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCC(Oc1ccc(Cl)cc1C1OCCO1)C(=O)OC
Reaction time: 3 h
Yield: 68.2 %

Procedure:
A mixture of 2-(4-chloro-2-formyl-phenoxy)-butyric acid methyl ester (50 g, 0.195 mol), ethylene glycol (89 mL, 1.56 mol) and p-toluenesulfonic acid (2.8 g, 16.5 mmol) in toluene (400 mL) was refluxed with a Dean-Stark trap attached to remove the water. After 3 h, the reaction was cooled and washed with water, saturated NaHCO3 and water, dried over anhydrous Na2SO4 and concentrated to give the title compound as a light yellow oil (40 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=2)=[CH:4][CH:3]=1.Br>CCOCC.C(O)C.[Pt]=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(C2=CCCCC2)cc1
Agent: O=[Pt]
Agent: Br
Solvent: CCOCC
Solvent: CCO
Product: Brc1ccc(C2CCCCC2)cc1

Procedure:
1-Bromo-4-(1-cyclohexen-1-yl)benzene was hydrogenated in an ether ethanol solvent containing 50% HBr using a platinum oxide catalyst to give the desired product, b.p. 121°-126°C/3 mm.
Reaction SMILES: [H-].[Na+].[OH:3][C@H:4]1[C@H:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[S:10][C:9]2=[CH:20][CH:21]=[CH:22][C:23]3=[CH:24][CH:25]=[CH:26][C:7](=[C:8]23)[NH:6][C:5]1=[O:27].[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31]Cl>CS(C)=O>[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31][N:6]1[C:5](=[O:27])[C@@H:4]([OH:3])[C@H:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[S:10][C:9]2=[CH:20][CH:21]=[CH:22][C:23]3=[CH:24][CH:25]=[CH:26][C:7]1=[C:8]23
Reactant: CN(C)CCCl
Reactant: COc1ccc([C@@H]2Sc3cccc4cccc(c34)NC(=O)[C@H]2O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc([C@@H]2Sc3cccc4cccc(c34)N(CCN(C)C)C(=O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
A mixture of 0.415 g of sodium hydride (58% dispersion in mineral oil) in 50 mL dimethyl sulfoxide (dried over CaH2) was stirred under nitrogen at 70° (bath temperature) for 1 hour then allowed to cool to room temperature. To this mixture 2.8 g of (±)-trans-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)naphtho[1,8-bc]-1,5-thiazocin-4(5H)-one was added then stirred at room temperature for 30 minutes. After the dropwise addition of 1.2 g of 2-dimethylaminoethyl chloride in 10 mL dimethyl sulfoxide, the mixture was heated at 50° for 30 minutes, then poured on 50 mL of ice-water. The aqueous solution was extracted with ethyl acetate (3×40 mL). The combined extracts were washed with brine (40 mL) and dried (magnesium sulfate). Removal of the solvent gave 3.1 g (92%) of crude (±)-trans-2,3-dihydro-5[2-(dimethylamino)ethyl]-3-hydroxy-2-(4-methoxyphenyl)naphtho[1,8-bc]-1,5 -thiazocin-4(5H)-one. For analysis a sample of this compound was crystallized from ethyl acetate, mp 157°-158°.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[CH3:27][N:28]([CH3:33])[S:29](Cl)(=[O:31])=[O:30]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][S:29]([N:28]([CH3:33])[CH3:27])(=[O:31])=[O:30])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: CN(C)S(=O)(=O)Cl
Agent: Cl
Product: CN(C)S(=O)(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, light yellow solid (19 mg, 17%), MS (ISP) m/z=436.3 [(M+H)+], mp 122° C., was prepared in accordance with the general method of example 47 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and dimethylsulfamoylchloride.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]2[CH2:6][CH2:7][C:8]3[C:16]([CH3:17])=[C:15]([O:18][CH3:19])[CH:14]=[CH:13][C:9]=3[C:10](=[O:12])[CH2:11][C:4]=2[CH:3]=1.C(O)(=[O:24])C.[Se](=O)=O>ClCCl>[Br:1][C:2]1[CH:21]=[CH:20][C:5]2[CH2:6][CH2:7][C:8]3[C:16]([CH3:17])=[C:15]([O:18][CH3:19])[CH:14]=[CH:13][C:9]=3[C:10](=[O:12])[C:11](=[O:24])[C:4]=2[CH:3]=1
Reactant: COc1ccc2c(c1C)CCc1ccc(Br)cc1CC2=O
Reactant: CC(=O)O
Agent: O=[Se]=O
Solvent: ClCCl
Product: COc1ccc2c(c1C)CCc1ccc(Br)cc1C(=O)C2=O
Temperature: 150 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
A mixture of 8-bromo-2-methoxy-1-methyl-11,12-dihydro-6H-dibenzo [a,e]cycloocten-5-one 12 (1.0 g: 2.9 mmol), acetic acid and selenium dioxide (0.64 g; 5.8 mmol) was stirred at 150° C. for 2 hr, cooled to room temperature, diluted with dichloromethane and filtered through silica gel to remove the suspended solids. The filtrate was evaporated to dryness. The residue was heated in ethyl acetate and crystallized by adding hexane to give compound 13 as grey needles, 0.71 g, 68% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][NH:8][C:7]=1[CH3:11])=[O:5])[CH3:2].I[CH3:13].[H-].[Na+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][N:8]([CH3:13])[C:7]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc[nH]c1C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccn(C)c1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 42.2 %

Procedure:
To a mixture of 2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (7.1 g, 46.05 mmol), iodomethane (5.73 mL, 92.1 mmol) in DMF (50 mL) at 0° C. was added sodium hydride (NaH) (2.39 g, 59.9 mmol, 60% in mineral oil) in one portion, the mixture was stirred at 0° C. for 1 h then the mixture was poured into ice-water (300 mL), extracted with EtOAc, the organic phase was washed with diluted HCl aqueous solution, water and saturated NaCl aqueous solution respectively; the EtOAc layer was then dried over anhydrous sodium sulfate, filtered, concentrated, the residue was purified with column to give a colorless oil, the desired title compound (3.25 g); 1H NMR (200 MHz, CDCl3): δ (ppm)=6.5-6.4 (m, 2H), 4.24 (q, 2H, J=7.1 Hz), 3.52 (s, 3H), 2.49 (s, 3H), 1.33 (t, 3H, J=7.1 Hz).