Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][C:5]([CH3:36])([CH2:34]C)[CH2:6][C:7]1[N:8]=[C:9]([C:18](=[O:33])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][N:27]=3)=[CH:22][CH:21]=2)[N:10]([S:12]([N:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH:11]=1>O1CCCC1>[CH3:34][C:5]([CH3:4])([CH3:36])[CH2:6][C:7]1[N:8]=[C:9]([C:18]([OH:33])([CH3:1])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][N:27]=3)=[CH:22][CH:21]=2)[N:10]([S:12]([N:15]([CH3:16])[CH3:17])(=[O:14])=[O:13])[CH:11]=1
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(=O)Cc2ccc(-c3ccc(F)cn3)cc2)n1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(C)(O)Cc1ccc(-c2ccc(F)cn2)cc1
Temperature: 25 °C

Procedure:
Methylmagnesium bromide (3 M in diethyl ether) (6.1 mL, 18.42 mmol) was added to a −78° C. solution of 4-(2,2-dimethylbutyl)-2-{[4-(5-fluoropyridin-2-yl)phenyl]acetyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide (4.22 g, 9.21 mmol) in tetrahydrofuran (50 mL). After warming slowly to ambient temperature, the reaction was quenched with saturated aqueous ammonium chloride and extracted with methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-60% ethyl acetate/hexane afforded 4-(2,2-dimethylpropyl)-2-{2-[4-(5-fluoropyridin-2-yl)phenyl]-1-hydroxy-1-methylethyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][N:25]=[CH:26]2)=[CH:21][C:20]=1F>CN(C)C(=O)C>[C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([O:14][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][C:19]=2[Cl:18])[CH:26]=[N:25][CH:24]=[CH:23]3)[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Reactant: Fc1cc2ccncc2cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Oc2cc3ccncc3cc2Cl)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
450 mg (0.21 mmol) trans-(4-Hydroxy-cyclohexyl)-carbamic acid tert-butyl ester were dissolved in 25 ml N,N-dimethyl acetamide. Under an argon atmosphere, 101 mg (4.2 mmol) sodium hydride were added and the mixture was stirred at room temperature. After 30 minutes, 250 mg (0.14 mmol) 7-chloro-6-fluoro-isoquinoline (6) were added and the solution was heated to 80° C. After 4 h, the solvent was removed under reduced pressure. The residue was taken up in H2O and extracted three times with ethyl acetate. The combined organic layers were dried over MgSO4 and evaporated. The crude product was purified by preparative HPLC, which delivered 18 mg of the title compound. Rt=1.38 min (Method #1). Detected mass: 377.2/379.3 (M+H+).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15]3)[CH2:10]2)[N:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:25][C:2]([F:1])([F:24])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][NH:14][CH2:15]3)[CH2:10]2)[N:4]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2CN(c3nccc(C(F)(F)F)n3)[C@H]2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1ccnc(N2C[C@@H]3CCNC[C@@H]32)n1
Reaction time: 3 h

Procedure:
To (1R,6S)-tert-butyl 8-(4-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[4.2.0]octane-3-carboxylate (185 mg, 0.5 mmol) in DCM (3 mL) was added TFA (3 mL). After 3 h, the reaction was concentrated, neutralized with 5% Na2CO3 (aq) and extracted with DCM (3×). The combined organics were dried (Na2SO4) and concentrated to give the title compound that was used without further purification. MS (ESI) mass calcd. For C11H13F3N4, 258.2; m/z found 259.1 [M+H]+
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:25]([O:27][C:28]([C:30]1[N:31]=[C:32](Br)[S:33][CH:34]=1)=[O:29])[CH3:26]>CC#N>[CH2:25]([O:27][C:28]([C:30]1[N:31]=[C:32]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([CH2:11][NH:10][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:18])[CH2:13]2)[S:33][CH:34]=1)=[O:29])[CH3:26]
Reactant: O=C(NCC1CCCNC1)OCc1ccccc1
Reactant: CCOC(=O)c1csc(Br)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1csc(N2CCCC(CNC(=O)OCc3ccccc3)C2)n1

Procedure:
To a stirred solution of piperidin-3-ylmethyl-carbamic acid benzyl ester (43 mg, 0.17 mmol) in CH3CN (5 mL), at RT under N2, K2CO3 (26 mg, 0.19 mmol) and 2-bromo-thiazole-4-carboxylic acid ethyl ester (41 mg, 0.17 mmol) were added. The resulting mixture was heated at reflux for 29 h. The solvent was evaporated in vacuo. The residue was treated with a saturated solution of NH4Cl (aq) (10 mL) and extracted with EtOAc (10 mL). The organic layer was separated, dried over Na2SO4, filtered and the solvent evaporated in vacuo. The residue was purified by flash chromatography on silica gel (1:2, EtOAc:hexane) to yield the title compound as a colorless oil. MS m/z: 404.2 (M+H). Calc'd. for C20H25N3O4S-403.50.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([OH:18])[C:12]=2[C:13]([O:15]CC)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCOCCOCCOCCOCCOCC1.[OH-].[K+]>C(O)C.O>[C:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([OH:18])[C:12]=2[C:13]([OH:15])=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1c(O)cccc1-c1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1c(O)cccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 3.3 grams (0.014 mole) of ethyl 6-phenylsalicylate in 30 mL of ethanol was added a catalytic amount of 1,4,7,10,13,16-hexaoxacyclooctadecane. This was followed by the addition of a solution of 2.0 grams (0.030 mole) of 85% potassium hydroxide in 15 mL of water. Upon completion of addition, the reaction mixture was warmed to reflux where it was stirred for 4 hours. The reaction mixture was allowed to cool to ambient temperature where it stood for about 18 hours. After this time the reaction mixture was again warmed to reflux where it stirred for 4 hours. Thin layer chromatographic analysis of the reaction mixture indicated the reaction had not gone to completion. An additional 0.3 gram of 85% potassium hydroxide was added to the reaction mixture and the heating at reflux was continued for another 3 hours. After this time the reaction mixture was cooled, and volatile materials were removed under reduced pressure. The aqueous concentrate was washed with two portions of diethyl ether. The combined ether washes were backwashed with water. The water washes and the aqueous concentrate were combined, and the combination was acidified to pH 1 with concentrated hydrochloric acid. The mixture was extracted with three portions of ethyl acetate. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was dissolved in hot ethanol, and the solution was treated with decolorizing carbon. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to a residue. The residue was recrystallized from diethyl ether and hexane to yield 6-phenylsalicylic acid, m.p. 143°-146°. The filtrate from the recrystallization was concentrated under reduced pressure to a residual solid. The residue was combined with the 6-phenylsalicylic acid, m.p. 143°-146° C., yielding 2.8 grams of this material.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][C:12](=[O:14])[CH3:13])[C:6]=2[C:5](=[O:15])[NH:4][C:3]1=[O:16].Cl[CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:25])([CH3:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:25][C:22]([CH3:24])([CH3:23])[CH2:21][CH2:20][CH2:19][CH2:18][N:4]1[C:5](=[O:15])[C:6]2[N:7]([CH2:11][C:12](=[O:14])[CH3:13])[CH:8]=[N:9][C:10]=2[N:2]([CH3:1])[C:3]1=[O:16]
Reactant: CC(C)(O)CCCCCl
Reactant: CC(=O)Cn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Cn1cnc2c1c(=O)n(CCCCC(C)(C)O)c(=O)n2C

Procedure:
22.2 g (0.1 mol) of the xanthine from stage (a) are reacted with 16.6 g (0.11 mol) of 1-chloro-5-hydroxy-5-methylhexane (Example 1a) and 15.2 g (0.11 mol) of potassium carbonate in 500 ml of dimethylformamide and the mixture is worked up, under the experimental conditions described in Example 2. The reaction product is purified by column chromatography and finally recrystallized from diisopropyl ether, with the addition of ethyl acetate, at the boiling point.
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:6]1[N:7]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=1)[CH3:5])[CH3:2].[NH2:22][C@@H:23]([CH3:40])[CH2:24][N:25]1[CH:29]=[CH:28][C:27]([C:30]2[CH:37]=[C:36]([F:38])[C:33]([C:34]#[N:35])=[C:32]([Cl:39])[CH:31]=2)=[N:26]1>>[Cl:39][C:32]1[CH:31]=[C:30]([C:27]2[CH:28]=[CH:29][N:25]([CH2:24][C@@H:23]([NH:22][C:11]([C:9]3[N:10]=[C:6]([CH:4]([O:3][CH2:1][CH3:2])[CH3:5])[N:7]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:8]=3)=[O:13])[CH3:40])[N:26]=2)[CH:37]=[C:36]([F:38])[C:33]=1[C:34]#[N:35]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: CCOC(C)c1nc(C(=O)O)cn1COCC[Si](C)(C)C
Product: CCOC(C)c1nc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)cn1COCC[Si](C)(C)C

Procedure:
The title compound was prepared using the procedure described in Example 32(e) starting from 2-(1-ethoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylic acid (1.27 mmol, 400 mg) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (1.27 mmol, 350 mg). The product was purified by flash-chromatography. Yield 230 mg. LC-MS: [M+1]=575.28.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([C@H:42]2[CH2:47][CH2:46][C@@H:45]([N:48]3[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]3)[CH2:44][CH2:43]2)=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2>>[CH3:29][O:28][C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][C:13]=1[NH:12][C:4]1[N:3]=[C:2]([NH:30][C:31]2[CH:32]=[CH:33][C:34]([C@H:42]3[CH2:47][CH2:46][C@@H:45]([N:48]4[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]4)[CH2:44][CH2:43]3)=[C:35]3[C:39]=2[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]3)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=1)[CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: CN1CCN([C@H]2CC[C@@H](c3ccc(N)c4c3CN(C)C4=O)CC2)CC1
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@@H](N5CCN(C)CC5)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
This compound was prepared in a manner analogous to Example 87 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and 7-amino-2-methyl-4-[cis-4-(4-methylpiperazin-1-yl)cyclohexyl]-2,3-dihydro-1H-isoindol-1-one.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][N:13]([CH3:22])[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1>C(Cl)Cl>[CH3:12][N:13]([CH3:22])[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N+:19][O-:6])=[CH:16][CH:15]=1
Reactant: CN(C)c1ccc(C#N)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CN(C)c1ccc(C#[N+][O-])cc1

Procedure:
A solution of 13.8 g of meta-chloroperoxybenzoic acid in 200 ml of methylene chloride was added dropwise to a solution of 11.7 g of para-dimethylaminobenzonitrile in 80 ml of methylene chloride at a temperature of from 0° C. to -5° C. over the course of two hours. When no more peroxide was detectable (negative KI test), the solvent was evaporated on a rotary evaporator. This gave 25.7 g of the meta-chlorobenzoic acid salt of para-dimethylaminobenzonitrile N-oxide. Pure para-dimethylaminobenzonitrile N-oxide was isolated by chromatography on aluminum oxide.
Reaction SMILES: [BH4-].[Na+].[Si:3]([O:10][C:11]1[CH:12]=[C:13]([O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])[C:14]2[CH2:25][S:24][CH2:23][C@@H:22]([C:26](OC)=[O:27])[NH:21][C:20](=[O:30])[C@@H:19]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:18][O:17][C:16](=[O:39])[C:15]=2[C:40]=1[CH3:41])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]>CO.CO.O1CCCC1>[Si:3]([O:10][C:11]1[CH:12]=[C:13]([O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:44])[CH3:45])[C:14]2[CH2:25][S:24][CH2:23][C@@H:22]([CH2:26][OH:27])[NH:21][C:20](=[O:30])[C@@H:19]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[CH2:18][O:17][C:16](=[O:39])[C:15]=2[C:40]=1[CH3:41])([C:6]([CH3:9])([CH3:7])[CH3:8])([CH3:4])[CH3:5]
Reactant: COC(=O)[C@@H]1CSCc2c(O[Si](C)(C)C(C)(C)C)cc(O[Si](C)(C)C(C)(C)C)c(C)c2C(=O)OC[C@H](NC(=O)OC(C)(C)C)C(=O)N1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(O[Si](C)(C)C(C)(C)C)cc(O[Si](C)(C)C(C)(C)C)c2c1C(=O)OC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](CO)CSC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a solution of 114 mg of sodium borohydride in 1.5 ml of 80% aqueous methanol, cooled to 0° C., was added within 5 minutes a solution of 214 mg of tert-butyl (4R, 7S)-12,14-bis(tert-butyldimethylsilyloxy)-1,3,4,5,6,7,8,10-octahydro-4-(methoxycarbonyl)-11-methyl-6,10-dioxo-9,2,5-benzoxathiaazacyclododecine-7-carbamate in 1.5 ml of methanol/tetrahydro-furan (1:1, v/v). The solution was stirred at 0° C. for 30 minutes, and then poured into ice-cold 0.5N hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic layer was washed with brine, and dried over sodium sulfate. The solvent was evaporated in vacuo to yield 181 mg of tert-butyl (4R, 7S)-12, 14-bis (tert-butyldimethylsilyloxy)-1,3,4,5,6,7,8, 10-octahydro-4-hydroxymethyl-11-methyl-6,10-dioxo-9,2,5-benzoxathiaazacyclododecine-7-carbamate as an amorphous solid. This material was treated with ammonium fluoride in methanol in an analogous manner to the procedure described in Example 13 to yield, after crystallization from ethyl acetate/methanol/hexane, tert-butyl (4R, 7S)-1,3,4,5,6,7,8,10 -octahydro-12,14-dihydroxy-4-hydroxymethyl-11-methyl-6,10-dioxo-9,2,5-benzoxathiaazacyclododecine-7-carbamate as a white solid.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:34]4[CH:38]=[CH:37][N:36]=[CH:35]4)=[CH:27][CH:26]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([C:25]3[CH:26]=[CH:27][C:28]([O:31][CH2:32][CH2:33][N:34]4[CH:38]=[CH:37][N:36]=[CH:35]4)=[CH:29][CH:30]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: Nc1ncnc2c1c(-c1cccc(OCc3ccccc3)c1)cn2-c1ccc(OCCn2ccnc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ncnc2c1c(-c1cccc(O)c1)cn2-c1ccc(OCCn2ccnc2)cc1

Procedure:
1.7 g of 5-(3-benzyloxyphenyl)-7-[4-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]-pyrimidine are hydrogenated in a hydrogen atmosphere at normal pressure and about 40° C. for 24 h in 40 ml of methanol in the presence of 0.4 g of 5% palladium/carbon. After filtration through Celite and chromatography on silica gel (methylene chloride/methanol containing 5% of about 5N ammonia in methanol 9:1), 5-(3-hydroxyphenyl)-7-[4-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine having an m.p. of 221°-223° C. is obtained.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16].[Cl:22][C:23]([CH2:25]Cl)=[CH2:24]>O1CCCC1>[Cl:22][C:23](=[CH2:24])[CH2:25][CH:14]([CH:15]([CH3:17])[CH3:16])[C:13]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: C=C(Cl)CCl
Reactant: CCOC(=O)CC(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C=C(Cl)CC(C(=O)OCC)C(C)C
Temperature: -4 °C
Reaction time: 0.5 h
Yield: 45.6 %

Procedure:
A 1 liter flask was equipped with a mechanical stirrer, reflux condenser, nitrogen inlet, addition funnel, and thermometer. The flask was charged with 200 ml of tetrahydrofuran (THF) and 31.37 g (0.300 mol) of diisopropylamine and cooled to -4° C. The n-butyllithium solution (265 ml of 1.6M, 0.424 mol) was added dropwise at -4° to -6° C. over 22 minutes. The reaction mixture was then stirred for 30 minutes at -4° C. and then 39.06 g (0.300 mol) of ethyl isovalerate added over 15 minutes. The reaction mixture was cooled to -78° C. and 44.39 g (0.400 mol) of 2,3-dichloro-1-propene added dropwise. During the addition of the halide, the temperature was maintained at -78° C. to -74° C. The reaction mixture was stirred for 2 hrs. at -78° C. to give a clear, tan colored solution. The temperature of the reaction mixture was then allowed to rise to -40° C., and stirred at -40° C. to -30° C. for 2 hours. The reaction mixture was then allowed to stand at room temperature over the weekend. The reaction mixture was quenched with 25 ml of water and then poured into 300 ml of ice water. The aqueous mixture was extracted twice with 250 ml portions of ether. The combined ether extracts were washed with saturated sodium chloride solution, dried (MgSO4), and the ether removed. The residue was vacuum distilled through a vigreux column to give 28.02 g (46% yield) of ethyl 4-chloro-2-isopropyl-4-pentenoate, bp 53°-63° C./0.70 mm.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](Cl)=[O:6].C[O:13][P:14]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17]2[CH:24]=[CH:25][CH:26]=[CH:27][C:16]=2[O:15]1>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([P:14]1(=[O:13])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17]2[CH:24]=[CH:25][CH:26]=[CH:27][C:16]=2[O:15]1)=[O:6]
Reactant: Cc1ccc(C(=O)Cl)cc1C
Reactant: COP1Oc2ccccc2-c2ccccc21
Product: Cc1ccc(C(=O)P2(=O)Oc3ccccc3-c3ccccc32)cc1C
Temperature: 100 °C

Procedure:
50.6 g (0.3 mol) of 3,4-dimethylbenzoyl chloride were warmed to 80° C. under a nitrogen atmosphere. 69 g (0.3 mol) of 6-methoxy-(6H)-dibenz[c,e][1,2]oxaphosphorin were added dropwise while stirring. Crystallization began even during the dropwise addition, and the temperature was therefore increased to 100° C.; at the same time, an additional 100 ml of toluene were added dropwise. When the dropwise addition was complete, the mixture was heated to reflux. When the reaction was complete and after crystallization, 87 g (83% of theory) of the abovementioned compound, which had a melting point of 160° to 162° C., were obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1)([O:3][CH3:4])=[O:2].[C:19](/[CH:24]=[C:25]1\[CH2:26][C:27]([CH3:33])([CH3:32])[CH2:28][C:29](O\1)=[O:30])([O:21][CH2:22][CH3:23])=[O:20]>C1(C)C=CC=CC=1>[C:19]([CH:24]=[C:25]1[N:16]([CH2:15][C:14]2[CH:13]=[CH:12][C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[C:1]([O:3][CH3:4])=[O:2])=[CH:18][CH:17]=2)[C:29](=[O:30])[CH2:28][C:27]([CH3:32])([CH3:33])[CH2:26]1)([O:21][CH2:22][CH3:23])=[O:20]
Reactant: COC(=O)c1ccccc1-c1ccc(CN)cc1
Reactant: CCOC(=O)/C=C1\CC(C)(C)CC(=O)O1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=C1CC(C)(C)CC(=O)N1Cc1ccc(-c2ccccc2C(=O)OC)cc1

Procedure:
Compound (i) of Example 9 (1.2 g, 0.005 mole) and compound (b) of Example 2 (1.1 g, 0.005 mole) are combined in toluene (50 mL) and refluxed for 5 hours. The toluene is removed in vacuo and the residue is chromatographed on silica gel using hexane/ethyl acetate as the mobile phase. The title compound is isolated as a colorless oil (1.2 g, 52%). Mass Spec. (DCI) m/z 436 (M+H). Analysis--calc'd for C26H29NO5 : C, 70.96; H, 6.76; N, 3.18; found: C, 70.76; H, 7.11; N, 2.77.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:11][NH2:12]>C(COC)OC>[Br:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[N:11][NH:12]2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: NN
Solvent: COCCOC
Product: Brc1ccc2cn[nH]c2c1
Yield: 85.5 %

Procedure:
A solution of 2-fluoro-4-bromobenzaldehyde (5.09 g, 25 mmol) was dissolved in glyme (25 mL) and slowly treated over 10 minutes with anhydrous hydrazine (25 mL, 0.8 mol, 32 eq.). The resulting biphasic mixture was then held at reflux overnight. The reflux condenser was replaced with a short-path distillation head and about half the solvent distilled, at which time the reaction flask showed one phase and two phases were evident in the distillate. The undistilled residue was cooled and treated with water (25 mL), forming a white precipitate. This solid was collected by filtration, washed thoroughly with water, and dried in vacuo to give 6-bromoindazole (4.21 g, 85%) as white crystals.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH:14]([CH2:15][OH:16])[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)(=[O:19])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:44](OC(=O)C)(=[O:46])[CH3:45]>ClCCl>[C:1]([O:5][C:6]([CH:8]1[CH:14]([CH2:15][O:16][C:44](=[O:46])[CH3:45])[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)(=[O:19])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(S(=O)(=O)N2CCCCC(CO)C2C(=O)OC(C)(C)C)cc1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2CCCCC(COC(C)=O)C2C(=O)OC(C)(C)C)cc1
Temperature: 0 °C

Procedure:
To a solution of 3-Hydroxymethyl-1-(4-methoxy-benzenesulfonyl)-azepane-2-carboxylic acid tert-butyl ester (0.5 g, 1.25 mmoL) in 6.3 mL dichlormethane was added triethylamine (0.19 mL, 1.38 mmoL) and dimethylaminopyridine (15 mg, 0.125 mmoL). This solution was cooled to 0° C. and acetic anhydride (0.18 ml, 1.88 mmoL) was added in at once. After 5 minutes the reaction was diluted with dichloromethane and washed sequentially with 0.5N HCl, water, and brine. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was removed under reduced pressure to yield 3-Acetoxymethyl-1-(4-methoxy-benzenesulfonyl)-azepane-2-carboxylic acid tert-butyl ester; MS: (M+H)+ =442, (M+NH4)+ =459.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([OH:20])=O)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl.[OH:22][C:23]1[C:32]([CH3:33])=[CH:31][CH:30]=[C:29]2[C:24]=1[CH2:25][CH2:26][NH:27][CH2:28]2>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([N:27]3[CH2:26][CH2:25][C:24]4[C:29](=[CH:30][CH:31]=[C:32]([CH3:33])[C:23]=4[OH:22])[CH2:28]3)=[O:20])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1nc(-c2ccc(Cl)cc2)nc2ccccc12
Reactant: Cc1ccc2c(c1O)CCNC2
Agent: Cl
Product: Cc1ccc2c(c1O)CCN(C(=O)c1nc(-c3ccc(Cl)cc3)nc3ccccc13)C2
Yield: 29 %

Procedure:
Reaction of 2-(4-chlorophenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 31 (29% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 2.22 and 2.25 (2s, 3H), 2.78 and 3.03 (2t, 2H), 3.54 and 4.17 (2t, 2H), 4.43 and 5.05 (2s, 2H), 6.27-6.75 (m, 2H), 6.85-7.03 (m, 3H), 7.45-7.63 (m, 3H), 7.90-8.01 (m, 2H), 8.08-8.12 (m, 1H), 8.52-8.59 (m, 2H); MS (ESI) m/z 430 ([M+H]+).