Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].C(=O)([O-])[O-].[Cs+].[Cs+].I[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(CC(=O)C(C)(C)C)(=O)C(C)(C)C>CN1CCCC1=O.[Cu]Cl.COC(C)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Ic1ccccc1
Reactant: COC(=O)CCc1ccc(O)c(Br)c1
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Solvent: COC(C)(C)C
Product: COC(=O)CCc1ccc(Oc2ccccc2)c(Br)c1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
A solution of Intermediate 5 (3.08 g) in anhydrous N-methylpyrrolidone (9.5 ml, WAKO) was successively added with cesium carbonate (3.58 g, WAKO), iodobenzene (1.4 ml, TCI), dipivaloylmethane (0.12 ml, TCI) and copper(I) chloride (275 mg, WAKO), and stirred 120° C. for 16 hours under argon gas atmosphere. The reaction mixture was added with t-butyl methyl ether (25 ml), and insoluble solids were removed by filtration. The filtrate was washed successively with 2 N aqueous hydrochloric acid and saturated brine and dried, and then the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (hexane:ethyl acetate=1:10) to obtain the title compound (Compound No. A-31, 1.00 g).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][S:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:11])=[O:10])=[O:7])=[CH:4][C:3]=1[N:19]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[Cl:29])[CH3:20].C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38].O>C(Cl)(Cl)Cl>[C:37]([NH:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][S:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:11])=[O:10])=[O:7])=[CH:4][C:3]=1[N:19]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[Cl:29])[CH3:20])(=[O:39])[CH3:38]
Reactant: CC(=O)Cl
Reactant: CCCCCS(=O)(=O)NC(=O)c1ccc(N)c(N(C)Cc2ccc(Cl)cc2Cl)c1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCS(=O)(=O)NC(=O)c1ccc(NC(C)=O)c(N(C)Cc2ccc(Cl)cc2Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-amino-3-((N-methyl)-2,4-dichlorobenzylamino)-(N-(n-pentanesulfonyl))benzamide was dissolved in chloroform, and triethylamine and acetyl chloride were added to the solution. The reaction mixture was stirred at room temperature for 30 minutes. The reaction solution was mixed with water and separated into aqueous and organic layers. The organic layer was washed with water and concentrated. The resulting residue was crystallized from ether. The crystals were filtrated and dried to yield 4-(acetylamino)-3-((N-methyl)-2,4-dichlorobenzylamino)-(N-(n-pentanesulfonyl))benzamide (33).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([C:15](=[O:21])[CH2:16][CH2:17][O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15]([OH:21])[CH2:16][CH2:17][O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCOc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc(F)c1)c1ccc2c(c1)OCCC2O
Temperature: 0 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
To a solution of 7-(3-Fluoro-benzenesulfonyl)-chroman-4-one (3.31 g, 10.81 mmol) in THF (100 ml) was added NaBH4 (0.49 g, 12.9 mmol) at 0° C. The mixture was stirred at 0° C. for 3 hours. The reaction mixture was partitioned between water and EtOAc. The EtOAc layer was washed with brine, dried with MgSO4, filtered and concentrated. The residue was purified with flash chromatography to give 2.0 g of 7-(3-Fluorobenzene-sulfonyl)-chroman-4-ol, as a white foam. MS: 599.2 (2M−OH)+.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([S:33][C:34]3[CH:39]=[CH:38][C:37]([Br:40])=[CH:36][CH:35]=3)[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:22]([S:33]([C:34]3[CH:35]=[CH:36][C:37]([Br:40])=[CH:38][CH:39]=3)=[O:9])[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(-c2nc(Sc3ccc(Br)cc3)[nH]c2-c2ccc(OC)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(-c2nc(S(=O)c3ccc(Br)cc3)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.3 %

Procedure:
A solution of 2.164 g of 3-chloroperbenzoic acid (80%) in 150 ml of dichloromethane is added dropwise to a solution of 4.67 g of 4,5-bis(4-methoxyphenyl)-2-(4-bromophenylthio)imidazole in 100 ml of dichloromethane. The reaction mixture is agitated for 3 hours at room temperature, the solution is washed with sodium bicarbonate solution, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue is chromatographed on 150 g of silica gel with acetone/hexane, yielding 4.36 g of 4,5-bis(4-methoxyphenyl)-2-(4-bromophenylsulfinyl)imidazole as an amorphous foam.
Reaction SMILES: [Cl-].[C:2]1([N+:8]2[C:13]([Cl:14])=[C:12]([Cl:15])[C:11]([NH2:16])=[CH:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17]C(N)=O.[OH-].[Na+]>>[Cl-:14].[C:2]1([N+:8]2[C:13]([NH2:17])=[C:12]([Cl:15])[C:11]([NH2:16])=[CH:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cn[n+](-c2ccccc2)c(Cl)c1Cl
Reactant: NC(N)=O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Product: Nc1cn[n+](-c2ccccc2)c(N)c1Cl
Yield: 82.5 %

Procedure:
15 parts of 1-phenyl-4-amino-5,6-dichloropyridazinium chloride is slowly introduced into a melt of 50 parts of urea (temperature about 130°C). After fifteen minutes the melt is cooled and 150 parts of a 10% by weight caustic soda solution is added. A crystalline substance separates out (melting point 180° to 181°C after having been recrystallized from acetonitrile) which is dissolved in 50 parts of concentrated hydrochloric acid. The hydrochloric acid solution is evaporated and the oil which remains is caused to crystallize with a mixture of butyl acetate and alcohol. 11.5 parts (82.5% of theory) of 1-phenyl-4-amino-5-chloro-6-aminopyridazinium chloride is obtained; C10H10N4Cl2. The substance melts at above 300°C. The chlorine number is 27.9% (calculated 27.65%). The perchlorate melts at 160° to 163°C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[N:11]([C:26]([CH2:29][CH3:30])=[CH:27][CH:28]=3)[N:12]=[C:13]([CH2:20][C:21]([O:23]CC)=[O:22])[C:14]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:5][CH:4]=1)#[N:2].O1CCCC1.[OH-].[K+]>C(O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:10]3[N:11]([C:26]([CH2:29][CH3:30])=[CH:27][CH:28]=3)[N:12]=[C:13]([CH2:20][C:21]([OH:23])=[O:22])[C:14]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)Cc1nn2c(CC)ccc2c(-c2ccc(C#N)cc2)c1C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1c(CC(=O)O)nn2c(CC)ccc2c1-c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 25 h
Yield: 93.4 %

Procedure:
To a solution of ethyl 4-(4-cyanophenyl)-2-(2-ethoxy-2-oxoethyl)-7-ethylpyrrolo[1,2-b]pyridazine-3-carboxylate (77.9 mg) in ethanol (0.5 mL)-tetrahydrofuran (0.5 mL) was added 1N potassium hydroxide. The resulting solution was stirred for 25 hours at room temperature. The mixture was stirred for futher 1 hour after adding 1N potassium hydroxide (0.04 mL). The reaction was quenched by adding 1N hydrochloric acid (0.23 mL). The volatile was evaporated off, and the resulting residue was partitioned between ethyl acetate (10 mL) and 1N hydrochloric acid (6 mL). The organic layer was washed with brine, dried, and evaporated to give [4-(4-cyanophenyl)-3-(ethoxycarbonyl)-7-ethylpyrrolo[1,2-b]pyridazin-2-yl]acetic acid as an yellow solid (67.7 mg, 93.4%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[OH:16])[CH:8]=[CH:9][C:10]([OH:12])=[O:11])[CH:2]=[CH2:3].[C:17](OC(=O)C)(=[O:19])[CH3:18]>[OH-].[Na+]>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[O:16][C:17](=[O:19])[CH3:18])[CH:8]=[CH:9][C:10]([OH:12])=[O:11])[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(C=CC(=O)O)ccc1O
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Product: C=CCOc1cc(C=CC(=O)O)ccc1OC(C)=O
Temperature: 0 °C

Procedure:
115.5 g (0.525 mol) of 3-allyloxy-4-hydroxy-cinnamic acid are dissolved in 530 ml of 2 N sodium hydroxide solution, 800 g of ice are added and 107 g (1.05 mols) of acetic anhydride are introduced dropwise over the course of quarter of an hour at 0°-5° C., whilst stirring. The crystals which have precipitated are then filtered off, suction-dried and recrystallised from chloroform. 3-Allyloxy-4-acetoxy-cinnamic acid of melting point 154°-155° C. is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15](S(C)(=O)=O)[N:14]=2)=[CH:4][CH:3]=1.[CH3:23][NH2:24]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:24][CH3:23])[N:14]=2)=[CH:4][CH:3]=1
Reactant: CN
Reactant: CS(=O)(=O)c1nccc(-c2cc[nH]c2-c2ccc(F)cc2)n1
Product: CNc1nccc(-c2cc[nH]c2-c2ccc(F)cc2)n1

Procedure:
In a similar manner to that described in Example 42(iii) above, 2-(4-fluorophenyl)-3-(2-methanesulfonylpyrimidin-4-yl)-1H-pyrrole [prepared as described in step 1(ii) above] was reacted with methylamine to afford the title compound (quantitative yield) as a pale brown amorphous solid.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]([C:7]1[CH:16]=[CH:15][C:10]2[S:11][C:12]([CH3:14])=[CH:13][C:9]=2[CH:8]=1)=[O:6].C([O-])(=O)C.[Na+]>C(Cl)(Cl)Cl>[CH3:3][O:4][C:5]([C:7]1[CH:16]=[CH:15][C:10]2[S:11][C:12]([CH3:14])=[C:13]([Br:1])[C:9]=2[CH:8]=1)=[O:6]
Reactant: BrBr
Reactant: COC(=O)c1ccc2sc(C)cc2c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc2sc(C)c(Br)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.3 %

Procedure:
Bromine (2.08 g) was added dropwise to a stirred mixture of 2-methylbenzo[b]thiophene-5-carboxylic acid methyl ester (2.40 g) and anhydrous sodium acetate (2.40 g) in chloroform (50 ml). The mixture was stirred for 2 hours at room temperature and then washed with water, sodium bicarbonate solution and dried (NaSO4). Evaporation of the chloroform gave a solid which was crystallised from methanol/water to give 3-bromo-2-methylbenzo[b]thiophene-5-carboxylic acid methyl ester (2.00 g), m.p. 84°-85°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[CH:21]=[CH2:22]>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([O:9][CH2:22][CH:21]=[CH2:20])=[O:8]
Reactant: C=CCBr
Reactant: Nc1ccc([N+](=O)[O-])c(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1cc(N)ccc1[N+](=O)[O-]
Yield: 70.9 %

Procedure:
5-Amino-2-nitrobenzoic acid (4 g, 22 mM) was dissolved in DMF (40 ml) and anhydrous potassium carbonate (3.64 g, 26.4 mM) added while stirring. Allyl bromide (3.86 g, 26.4 mM) was added and the mixture stirred at ambient temperature overnight. The solvent was removed by evaporation and the residue taken up in acetonitrile. The organic layer was washed with water, dried (MgSO4) evaporated and purified by silica chromatography with acetonitrile/petroleum ether (40/60) to give allyl 5-amino-2-nitrobenzoate as a yellow solid (3.46 g, 71%).
Reaction SMILES: [I-:1].[Na+].Cl[CH2:4][C:5]1[N:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[O:8][C:9]=1[CH3:10]>CC(C)=O>[I:1][CH2:4][C:5]1[N:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[O:8][C:9]=1[CH3:10]
Reactant: [I-]
Reactant: COc1ccc(-c2nc(CCl)c(C)o2)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(-c2nc(CI)c(C)o2)cc1

Procedure:
Together with 37.7 g of sodium iodide, 19.9 g of 4-chloromethyl-2-(4-methoxy-phenyl)-5-methyl-oxazole are, in 300 ml of acetone, heated at the boil under reflux for 2 hours. After cooling of the reaction mixture, the solvent was removed under reduced pressure and the residue dissolved in 300 ml of methyl tert-butyl ether, the mixture is washed three times with saturated Na2S2O3 solution and dried over MgSO4, and the solvent is then removed under reduced pressure. This gives 49.8 g of 4-Iodomethyl-2-(4-methoxyphenyl)-5-methyloxazole as a light-brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:24])=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([CH:22]=[O:23])=[C:15]3[N:14]=2)[CH:7]=1.Br[CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([CH:22]=[O:23])=[C:15]3[N:14]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: O=Cc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3O)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCOc1ccc(F)cc1[C@H]1CCCN1c1ccn2ncc(C=O)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
A mixture of (R)-5-(2-(5-fluoro-2-hydroxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (159 mg, 0.487 mmol), tert-butyl 2-bromoethylcarbamate (131 mg, 0.585 mmol), potassium carbonate (202 mg, 1.46 mmol) and DMF (1 mL) was combined in a sealed vessel and stirred at ambient temperature overnight and then at 60° C. for 3 hours. After diluting with DCM (20 mL), the reaction was filtered through Celite®, concentrated and purified by reverse-phase column chromatography, eluting with 0-70% acetonitrile/H2O to provide (R)-tert-butyl 2-(4-fluoro-2-(1-(3-formylpyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)phenoxy)ethylcarbamate (198 mg, 86.6% yield) as yellowish solid. MS (apci) m/z=370.4 (M+H-Boc).
Reaction SMILES: [S:1]([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)([O-:4])(=[O:3])=[O:2].N1C(C)=CC=CC=1C.[O:20]([Si:28](C(C)(C)C)(C)C)S(C(F)(F)F)(=O)=O>C(Cl)Cl.O>[S:1]([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)([O:4][O:20][SiH3:28])(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: O
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OO[SiH3])cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 140 mg of the primary tosylate 26, 0.10 ml of 2,6-lutidine and 0.10 ml of t-butyldimethylsilyl triflate in 8 ml of methylene chloride was stirred at 0° C. for 1 hour. A few drops of water were added and the mixture concentrated under vacuum. The residue was diluted with diethyl ether and the solution filtered thru silica gel. The filtrate was concentrated under vacuum and chromatography of the residue over silica gel (6 hexanes: 1 EtOAc) provided the title compound.
Reaction SMILES: C(O)(=O)C(O)=O.[CH3:7][O:8][C:9]1[C:26]([O:27][CH3:28])=[CH:25][C:12]2[CH:13]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][NH:15][CH2:16][CH2:17][C:11]=2[CH:10]=1.Cl.[Br:30]N1C(=O)CCC1=O>CO>[Br:30][C:22]1[CH:23]=[CH:24][C:19]([O:18][CH:13]2[C:12]3[CH:25]=[C:26]([O:27][CH3:28])[C:9]([O:8][CH3:7])=[CH:10][C:11]=3[CH2:17][CH2:16][NH:15][CH2:14]2)=[CH:20][CH:21]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc2c(cc1OC)C(Oc1ccccc1)CNCC2
Agent: Cl
Agent: O=C(O)C(=O)O
Solvent: CO
Product: COc1cc2c(cc1OC)C(Oc1ccc(Br)cc1)CNCC2
Temperature: 25 °C
Yield: 28.8 %

Procedure:
A solution of 7,8-dimethoxy-1-phenoxy-2,3,4,5-tetrahydro-3-benzazepine of Example 35 (6.5 g, 22 mmole) in 300 ml methanol was acidified to pH 1 with ethereal hydrogen chloride. After this solution was cooled with an ice bath, N-bromosuccinimide (4.2 g, 24 mmole) was added. The reaction mixture slowly warmed to ambient temperature, was evaporated, stirred with water, basified with saturated sodium carbonate and was extracted with ethyl acetate-ether. The organic extracts were washed with water, saturated sodium chloride and were dried (anhydrous MgSO4), filtered and evaporated to 8 g of an oil. This oil was converted to the maleate salt (8 g, 74%, m.p. 95°-100° C.) by the addition of ethereal maleic acid of which 4 g was recrystallized twice from isopropanol-ether to give 2.4 g (45%) of 1-(4-bromophenoxy)-7,8-dimethoxy-2,3,4,5-tetrahydro-3-benzazepine meleate, d 145°-146° C.
Reaction SMILES: Cl[CH2:2][C@@H:3]([CH3:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[F:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[O:5][CH2:4][C@H:3]([CH3:13])[CH2:2][N:28]1[CH2:29][CH2:30][CH:25]([C:21]2[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=2)[CH2:26][CH2:27]1
Reactant: C[C@H](CCl)COc1cccc(F)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(C[C@@H](C)COc3cccc(F)c3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-{[(2S)-3-chloro-2-methylpropyl]oxy}-3-fluorobenzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 413.2 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:21]=[CH:20][C:19]2[CH:18]3[CH2:22][C:11]([C:23]([N:25]4[CH2:30][CH2:29][CH:28]([C:31](OCC)=[O:32])[CH2:27][CH2:26]4)=O)([C:12]4[C:17]3=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:10]=2[CH:9]=1>O1CCCC1>[Cl:7][C:8]1[CH:21]=[CH:20][C:19]2[CH:18]3[CH2:22][C:11]([CH2:23][N:25]4[CH2:26][CH2:27][CH:28]([CH2:31][OH:32])[CH2:29][CH2:30]4)([C:12]4[C:17]3=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:10]=2[CH:9]=1
Reactant: CCOC(=O)C1CCN(C(=O)C23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
A suspension of lithium aluminum hydride (4.53 g, 119.5 mmol) in tetrahydrofuran (175 mL) was heated to reflux temperature and was treated dropwise with a solution of ethyl 1-((9RS,10RS)-2-chloro-9,10-dihydro-9,10-methanoanthracen-9-ylcarbonyl)-4-piperidine carboxylate (9.83 g, 23.9 mmol) in tetrahydrofuran (75 mL) at a rate sufficient to maintain reflux. Upon complete addition, the mixture was stirred for 1 h at reflux, then was cooled to 0° C. and quenched by sequential addition of water (4.5 mL), 10% aqueous sodium hydroxide (4.5 mL) and water (13.5 mL). The resulting milky suspension was treated with Celite, warmed to room temperature and stirred for 15 min. The solids were removed by filtration through Celite, the filter cake was washed with tetrahydrofuran/methanol (20:1, 2×200 mL), and the filtrate was evaporated. Trituration of the solid obtained with ethyl acetate/hexane (1:1, 50 mL) and evaporation of solvent afforded the title compound as a white solid (8.40 g, 23.7 mmol, 99%). 1H NMR (d6-DMSO): δ7.24 (m, 4H), 6.93 (m, 4H), 4.39 (brs, 1H, CH2OH), 4.30 (s, 1H, H--C(10)), 3.36-3.21 (m, 4H, CH2OH, CH2N), 2.96 (m, 2H, eq-H--C(2')), 2.46 (s, 2H, H--C(11)), 2.15 (m, 2H, ax-H--C(2')), 1.60 (m, 2H, eq-H--C(3')), 1.35 (m, 1H, H--C(4')), 1.10 (m, 2H, ax-H--C(3')).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][C@@H:21]([CH3:23])[C@@:20]2([CH2:24][OH:25])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[O:26][C:27](=[O:29])[CH3:28])[CH2:6]1)(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([O:4][C@H:5]1[CH2:22][C@@H:21]([CH3:23])[C@@:20]2([CH2:24][OH:25])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[O:26][C:27](=[O:29])[CH3:28])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]3[C@@]2(CO)[C@H](C)C1
Agent: [Pd]
Solvent: CO
Product: CC(=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]3[C@@]2(CO)[C@H](C)C1

Procedure:
A solution of 1β-methyl-5-androstene-3β,17β,19-triol 3,17-diacetate in methanol is hydrogenated with a 10% palladium-on-carbon catalyst at atmospheric pressure for about 8 hours. The catalyst is removed by filtration, the filtrate is concentrated to a small volume, cooled and filtered. The residue is crystallized from a solution of hexane to yield 1β-methyl-5α-androstane-3β,17β,19-triol 3,17-diacetate.
Reaction SMILES: [C:1]1([S:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:15]1[CH:19]=[CH:18][CH:17]=[CH:16]1.[F:20][P-:21]([F:26])([F:25])([F:24])([F:23])[F:22].[K+]>O>[F:20][P-:21]([F:26])([F:25])([F:24])([F:23])[F:22].[C:1]1([S+:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:16]2[S:15][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccsc1
Reactant: O=S(c1ccccc1)c1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: O
Product: c1ccc([S+](c2ccccc2)c2cccs2)cc1
Reaction time: 0.5 h
Yield: 51.2 %

Procedure:
There was added 20 ml of the PP/MSA solution to a mixture of 10.1 grams (0.05 mole) of diphenylsulfoxide and 4.2 grams (0.05 mole) of thiophene. The resulting mixture exothermed to 50° C. and became viscous and purple in color. After 0.5 hours, the blue reaction mixture was poured into 200 ml of water. A very dark colored solution was obtained. It was added to the solution, 9.2 grams (0.05 mole) of potassium hexafluorophosphate. A dark colored solid was obtained. The solid was isolated by decantation and washed several times with fresh water and thenfiltered. The solid was dissolved in dichloromethane and passed through a column of neutral alumina. A pale yellow crystalline solid was obtained upon evaporation of the solvent. It was recovered, 10.6 grams for a 51.2% yield of diphenyl (2-thiophenyl) sulfonium hexafluorophosphate having a melting point of 177°-173° C. Elemental analysis showed; Calculated: % carbon 46.30; % hydrogen 3.14; % sulfur 15.46; Found: % carbon 46.80; % hydrogen 3.12; % sulfur 15.75.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[C:27]([Cl:29])[CH:28]=1)[CH2:5][NH:6][C:7]([C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][N:12]=[C:11](S(C)(=O)=O)[N:10]=1)=[O:8].O1[CH2:35][CH2:34]OCC1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[C:27]([Cl:29])[CH:28]=1)[CH2:5][NH:6][C:7]([C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][N:12]=[C:11]([N:10]2[CH2:35][CH2:34][N:6]([CH3:5])[CH2:7][CH2:9]2)[N:10]=1)=[O:8]
Reactant: C1COCCO1
Reactant: Cc1ccccc1-c1cnc(S(C)(=O)=O)nc1C(=O)NCc1cc(Cl)cc(Cl)c1
Product: Cc1ccccc1-c1cnc(N2CCN(C)CC2)nc1C(=O)NCc1cc(Cl)cc(Cl)c1
Reaction time: 16 h
Yield: 175.9 %

Procedure:
To a solution of 0.19 g (0.435 mmol) 2-methanesulfonyl-5-o-tolyl-pyrimidine-4-carboxylic acid 3,5-dichloro-benzylamide in 5 ml dioxane 0.12 ml (1.08 mmol) 1-methylpiperazine was added. The reaction mixture was stirred for 16 hrs. After evaporation of the solvent, the residue was distributed between 5 ml CH2Cl2 and 25 ml H2O. The aqueous layer was extracted with 20 ml CH2Cl2, the combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/MeOH 9:1) to give 0.18 g (88%) 2-(4-methyl-piperazin-1-yl)-5-o-tolyl-pyrimidine-4-carboxylic acid 3,5-dichloro-benzylamide as a colorless oil, MS (ISP): 470.2, 472.2 (M+H+).