Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:20]3[C:21]([CH3:27])=[N:22][C:23]([CH3:26])=[CH:24][CH:25]=3)([C:14]3[N:18]([CH3:19])[N:17]=[N:16][CH:15]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:28][CH3:29])[C:3]=1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=1.[H-].[Na+].[C:43](OC(=O)C)(=[O:45])[CH3:44]>CN(C=O)C>[C:43]([O:13][C:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([O:28][CH3:29])[C:3]([CH2:30][C:31]1[CH:32]=[CH:33][C:34]([C:37]([F:40])([F:38])[F:39])=[CH:35][CH:36]=1)=[C:2]2[Cl:1])([C:20]1[C:21]([CH3:27])=[N:22][C:23]([CH3:26])=[CH:24][CH:25]=1)[C:14]1[N:18]([CH3:19])[N:17]=[N:16][CH:15]=1)(=[O:45])[CH3:44]
Reactant: CC(=O)OC(C)=O
Reactant: COc1nc2ccc(C(O)(c3ccc(C)nc3C)c3cnnn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nc2ccc(C(OC(C)=O)(c3ccc(C)nc3C)c3cnnn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reaction time: 0.33 h

Procedure:
To a solution of (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanol (544 mg, 0.960 mmol, Example 77B) in 20 mL of dry DMF at room temperature was added NaH (75 mg, 1.9 mmol, 60% in mineral oil). After stirring for 20 min, acetic anhydride (0.18 mL, 1.9 mmol) was added. The mixture was stirred for one hour and some suspension formed. After the mixture was quenched with a few drops of water, the suspension was filtered off and the filtrate was concentrated in vacuo. The residue was partitioned between dichloromethane and saturated NaHCO3 (aq). The extracts were dried (Na2SO4), filtered, and concentrated to give the title compound as a semi-solid.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:17])[N:9]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]2[NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:8]1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=1[Cl:36])=[O:6].[I-].[Na+].[NH:39]1[CH:43]=[CH:42][CH:41]=[N:40]1.C(OCC)(=O)C>CN(C=O)C.O>[Cl:36][C:30]1[CH:31]=[C:32]([Cl:35])[CH:33]=[CH:34][C:29]=1[CH:8]1[CH:7]([C:5]([NH:4][CH2:3][CH2:2][N:39]2[CH:43]=[CH:42][CH:41]=[N:40]2)=[O:6])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:17])[N:9]1[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[NH:24][S:25]([CH3:28])(=[O:27])=[O:26]
Reactant: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NCCCl)C1c1ccc(Cl)cc1Cl
Reactant: c1cn[nH]c1
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NCCn2cccn2)C1c1ccc(Cl)cc1Cl
Temperature: 100 °C
Reaction time: 24 h
Yield: 29.1 %

Procedure:
To a solution of 573 mg of (3RS,4RS)—N-(2-chloroethyl)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in 10 ml of DMF were added 150 mg of sodium iodide and 340 mg of 1H-pyrazole, followed by stirring at 100° C. for 24 hours. Ethyl acetate and water were added thereto to carry out a liquid separation operation, and the organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain a colorless crystal. The crystal was recrystallized from ethanol to obtain 176 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-[2-(1H-pyrazol-1-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless powdered crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]([CH2:21][C:22]1[CH:27]=[C:26]([O:28][CH2:29][CH3:30])[CH:25]=[C:24]([O:31][CH:32]([CH3:34])[CH3:33])[C:23]=1[F:35])[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1)[CH:6]=[CH:5]2.BrC1C=CC2C(=C(Cl)C=CC=2)N=1>>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:4]2[C:3]=1[N:8]=[C:7]([N:12]([CH2:21][C:22]1[CH:27]=[C:26]([O:28][CH2:29][CH3:30])[CH:25]=[C:24]([O:31][CH:32]([CH3:33])[CH3:34])[C:23]=1[F:35])[C:13]1[CH:14]=[CH:15][C:16]([C:17]#[N:18])=[CH:19][CH:20]=1)[CH:6]=[CH:5]2
Reactant: CCOc1cc(CN(c2ccc(C#N)cc2)c2ccc3cc(Cl)ccc3n2)c(F)c(OC(C)C)c1
Agent: Clc1cccc2ccc(Br)nc12
Product: CCOc1cc(CN(c2ccc(C#N)cc2)c2ccc3cccc(Cl)c3n2)c(F)c(OC(C)C)c1

Procedure:
According to the procedure for Intermediate 90.2, Intermediate 91.1 (100 mg, 0.412 mmol) afforded 165 mg of Intermediate 91.2 as an off-white solid.
Reaction SMILES: C1(N2C(S[CH2:13][N:14]3[C:24](=[O:25])[C:23]4[C:18](=[C:19]([O:32][CH3:33])[C:20](CCC)=[CH:21][C:22]=4[O:26][CH2:27][CH3:28])[S:15]3(=[O:17])=[O:16])=NN=N2)C=CC=CC=1.BrC[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:13]([N:14]1[C:24](=[O:25])[C:23]2[C:18](=[C:19]([O:32][CH2:33][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH:20]=[CH:21][C:22]=2[O:26][CH2:27][CH3:28])[S:15]1(=[O:16])=[O:17])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCCc1cc(OCC)c2c(c1OC)S(=O)(=O)N(CSc1nnnn1-c1ccccc1)C2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOc1ccc(OCC(=O)OC(C)(C)C)c2c1C(=O)N(Cc1ccccc1)S2(=O)=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
A mixture of 2-benzyl-4-ethoxy-7-hydroxysaccharin (part B of Example 50, 0.5 g), t-butyl bromoacetate (0.3 g, 0.25 mL), potassium carbonate (0.30 g) and methyl ethyl ketone (about 10 mL) was heated at 70°-80° C. for about one hour, let cool and poured into ice-water (400 mL). The mixture was stirred overnight and the solid was collected affording 2-benzyl-4-ethoxy-7-(t-butoxycarbonylmethoxy)saccharin, 0.58 g, 86% yield.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[Na+]>CO>[C:10]1([S:9][CH2:8][CH:7]=[CH:6][CH:5]=[CH:4][C:3]([OH:16])=[O:2])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)C=CC=CCSc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C=CC=CCSc1ccccc1
Temperature: 20 °C
Yield: 93.9 %

Procedure:
To a solution of 6-phenylsulfanyl-hexa-2,4-dienoic acid methyl ester (0.34 g, 1.45 mmol) in methanol (5 mL) were added aqueous sodium hydroxide (1M, 5 mL, 5 mmol) and distilled water (20 mL). The stirred mixture was heated at reflux for 1 hour, allowed to cool to 20° C., and then concentrated under reduced pressure to about 10 mL. The aqueous solution was washed with diethyl ether (50 mL) and then poured onto a mixture of ethyl acetate (50 mL) and hydrochloric acid (2M, 10 mL) at 0° C. The mixture was shaken, the organic layer was separated and washed successively with saturated aqueous sodium hydrogen carbonate (25 mL), distilled water (25 mL), and brine (25 mL), then dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give a pale yellow solid that was recrystallised from diethyl ether/hexanes to give the title compound (0.30 g, 93%) as a white solid, mp 108-110° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5](=[CH:11][NH:12][C:13]1[N:14]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[N:15]=[CH:16][CH:17]=1)[C:6]([O:8]CC)=O)[CH3:2]>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5]1[C:6]([OH:8])=[C:17]2[CH:16]=[N:15][N:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:13]2=[N:12][CH:11]=1)=[O:27])[CH3:2]
Reactant: CCOC(=O)C(=CNc1ccnn1Cc1ccc(OC)cc1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2c(cnn2Cc2ccc(OC)cc2)c1O
Temperature: 240 °C
Reaction time: 5 h
Yield: 65.2 %

Procedure:
2-{([2-(4-Methoxybenzyl)-2H-pyrazol-3-ylamino]methylene}malonic acid diethyl ester (7.0 g) was dissolved in diphenyl ether (about 21 mL), the resulting mixture was stirred at 240° C. for 5 hours. The reaction solution was purified by silica-gel column chromatography (dichloromethane/methanol=100/0 to 100/1) to give 4-hydroxy-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (4.0 g, yield: 65%) as a light-yellow powder.
Reaction SMILES: [CH3:1][C@:2]12[C:9]([CH3:11])([CH3:10])[C@:6]([NH:12]C(=O)C)([CH2:7][CH2:8]1)[CH2:5][O:4][CH2:3]2.N1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.C(O)C(O)C>C1COCC1>[CH3:1][C@:2]12[C:9]([CH3:11])([CH3:10])[C@:6]([NH2:12])([CH2:7][CH2:8]1)[CH2:5][O:4][CH2:3]2
Reactant: CC(=O)N[C@@]12CC[C@@](C)(COC1)C2(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CC(O)CO
Product: CC1(C)[C@@]2(C)CC[C@]1(N)COC2
Temperature: 25 °C

Procedure:
To a solution of step 3 intermediate (0.165 g, 0.78 mmol) in 3 mL of dry THF and pyridine (0.37 mL, 47 mmol) maintained at 0° C., oxalyl chloride was added with stirring. After 30 minutes propylene glycol (0.46 mL, 63 mmol) was added to the above reaction mixture and reaction warmed to room temperature. Reaction mixture was concentrated after adding ethyl alcohol. The residue was partitioned between 1N HCl and tert-butyl ether. Aqueous layer was separated and basified with 4N NaOH and extracted with ethyl acetate. Ethyl acetate layer was separated, dried and concentrated. Crude material was carried to next step without further purification. m/z (M+1): 170.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:14]([N:15]([CH3:25])[C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:26]([N:29]1[CH2:34][CH2:33][CH:32]([C:35](O)=[O:36])[CH2:31][CH2:30]1)(=[O:28])[CH3:27]>>[C:26]([N:29]1[CH2:30][CH2:31][CH:32]([C:35]([N:11]2[CH2:12][CH2:13][C@@H:14]([N:15]([CH3:25])[C:16](=[O:24])[C:17]3[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=3)[C@H:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:10]2)=[O:36])[CH2:33][CH2:34]1)(=[O:28])[CH3:27]
Reactant: CC(=O)N1CCC(C(=O)O)CC1
Reactant: Cc1ccc(C(=O)N(C)[C@@H]2CCNC[C@H]2c2ccc(Cl)c(Cl)c2)cc1
Product: CC(=O)N1CCC(C(=O)N2CC[C@@H](N(C)C(=O)c3ccc(C)cc3)[C@H](c3ccc(Cl)c(Cl)c3)C2)CC1

Procedure:
Using the compound obtained in Example 23 and 1-acetylpiperidine-4-carboxylic acid, and by the reaction and purification in the same manner as in Example 3, the title compound was obtained.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=[C:9]([NH2:17])[C:8]=1[O:18][CH:19]([CH3:21])[CH3:20].N1C=CC=CC=1>ClCCl>[NH2:6][C:7]1[C:8]([O:18][CH:19]([CH3:21])[CH3:20])=[C:9]([NH:17][S:2]([CH3:1])(=[O:4])=[O:3])[CH:10]=[C:11]([C:13]([CH3:16])([CH3:14])[CH3:15])[CH:12]=1
Reactant: CC(C)Oc1c(N)cc(C(C)(C)C)cc1N
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)Oc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At ambient temperature 0.20 ml methanesulphonic acid chloride are added dropwise to a solution of 0.48 g 1,3-diamino-5-tert-butyl-2-isopropoxy-benzene and 0.35 ml of pyridine in 5 ml dichloromethane. The solution is stirred for 2 h at ambient temperature and then evaporated down. The residue is chromatographed on silica gel with cyclohexane/ethyl acetate (90:10→40:60) as eluant.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([S:13]([F:18])([F:17])([F:16])([F:15])[F:14])[CH:12]=1)[C:6](OC)=[O:7].Cl.[CH3:20][NH:21][O:22][CH3:23].C([Mg]Br)(C)C>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([S:13]([F:16])([F:18])([F:17])([F:14])[F:15])[CH:12]=1)[C:6]([N:21]([O:22][CH3:23])[CH3:20])=[O:7]
Reactant: CNOC
Reactant: COC(=O)c1cc(OC)cc(S(F)(F)(F)(F)F)c1
Agent: CC(C)[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc(C(=O)N(C)OC)cc(S(F)(F)(F)(F)F)c1
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 64.8 %

Procedure:
Methyl 3-methoxy-5-(pentafluorosulfanyl)benzoate (O4.007; 2.5 g) was dissolved in absolute THF (65 ml), and N,O-dimethylhydroxylamine hydrochloride (1.2 g) was added. Then the mixture was cooled to −15° C. and isopropylmagnesium bromide solution (13.59 ml, 2 M in THF) was added dropwise. After 20 min, the cooling bath was removed and the mixture was stirred at RT for 1 h. Then ammonium chloride solution was added and the aqueous phase was extracted three times with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. The crude product thus obtained still contained significant reactant, and was therefore converted and worked up again as described above. No reactant was present any longer in the residue which was then obtained. Purification was effected by means of preparative HPLC (met. A). The product-containing fractions were combined and freed of the acetonitrile, and the aqueous phase was extracted three times with EA. The combined extracts were dried over magnesium sulfate, filtered and concentrated. 1.78 g of the desired compound were obtained.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:3]=1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CN(C1C=CC=CN=1)C>ClCCl>[F:14][C:11]1[CH:10]=[CH:9][C:8]([C:4]2[C:3]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[C:2]([NH:1][C:28]([NH:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:29])[N:6]([CH3:7])[N:5]=2)=[CH:13][CH:12]=1
Reactant: O=C=Nc1ccccc1
Reactant: Cn1nc(-c2ccc(F)cc2)c(-c2ccncc2)c1N
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: Cn1nc(-c2ccc(F)cc2)c(-c2ccncc2)c1NC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.3 %

Procedure:
150 mg of 5-amino-3-(4-fluorophenyl)-1-methyl-4-(4-pyridyl)pyrazole was dissolved in 5 ml of dichloromethane. Then, 80 mg of phenyl isocyanate and 80 mg of dimethylaminopyridine were added thereto, followed by stirring at room temperature overnight. After the reaction mixture was washed with water and dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography using 20 g of silica gel and eluted with chloroform-methanol (50:1). Thus, 70 mg of the title compound was obtained and crystallized from ether.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18](=O)[C:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20]N(C)C)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[NH2:32][C:33]([NH2:35])=[NH:34].CO[Na]>CN(C=O)C.CC(=O)OCC>[C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:20][N:32]=[C:33]([NH2:35])[N:34]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N=C(N)N
Reactant: CN(C)C=C(C(=O)c1ccc(C2(NC(=O)OC(C)(C)C)CCC2)cc1)c1ccccc1
Agent: CO[Na]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc(N)ncc3-c3ccccc3)cc2)CCC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
To a solution of compound 1 (3 g, 7.2 mmol) and guanidine (2 g, 35 mmol) in DMF (15 mL) was added MeONa (1.8 g, 35 mmol) and the mixture was heated to 100° C. and stirred for 4 h. The solution was cooled to r.t. and diluted with 80 mL of EA. The organic phase was washed with 0.1N HClaq and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography to give 2.1 g of 5-1 as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]23[O:14][CH:10]2[CH2:11][CH2:12][CH2:13]3)[CH:6]=[CH:7][CH:8]=1.[CH3:15][NH2:16]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@:9]2([OH:14])[CH2:13][CH2:12][CH2:11][C@@H:10]2[NH:16][CH3:15])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C23CCCC2O3)c1
Reactant: CN
Product: CN[C@H]1CCC[C@@]1(O)c1cccc(OC)c1

Procedure:
Crude 1-(3-methoxyphenyl)cyclopentene oxide (prepared according to the method of Ger. Offen. No. 2,942,644) is treated with ethanolic methylamine solution by the method of Example 1(b) above to give the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH:8]2[CH2:9][CH:3]1[CH2:4][CH2:5][C:6]2=O.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:10])[CH:8]2[CH2:9][CH:3]1[CH2:4][CH:5]=[C:6]2[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC1(C)C2CCC(=O)C1C2
Reactant: C1CCNC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC1(C)C2CC=C(N3CCCC3)C1C2
Yield: 95 %

Procedure:
A solution of 30 g of nopinone ([α]D20 =+39.90; c=8 in ethanol), 29 of pyrrolidine and 0.4 g of p-toluenesulfonic acid in 150 ml anhydrous benzene was heated at reflux for 40 h under nitrogen atmosphere in a vessel fitted with a water separator. After evaporation of the solvent and distillation of the residue, there were obtained 39.5 g (95% yield) of 1-(6,6-dimethylnorpin-2-en-2-yl)-pyrrolidine having b.p. 117°-118° C./10 Torr.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH3:11])[CH:10]=2)[CH:7]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:2]2[CH:3]=[N:4][C:5]3[N:6]([N:8]=[C:9]([CH3:11])[CH:10]=3)[CH:7]=2)=[CH:15][CH:14]=1
Reactant: C#Cc1ccc(Cl)cc1
Reactant: Cc1cc2ncc(Br)cn2n1
Product: Cc1cc2ncc(C#Cc3ccc(Cl)cc3)cn2n1

Procedure:
The title compound, brown solid, MS: m/e=268.1 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-methylpyrazolo[1,5-a]pyrimidine and 1-chloro-4-ethynylbenzene.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6]=1[CH2:21]Br)=[O:4].[CH:23]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([CH3:25])[CH3:24]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6]=1[CH2:21][N:29]1[CH2:30][CH2:31][N:26]([CH:23]([CH3:25])[CH3:24])[CH2:27][CH2:28]1)=[O:4]
Reactant: CC(C)N1CCNCC1
Reactant: COC(=O)c1c(CBr)c(-c2ccccc2)nc2ccccc12
Solvent: C1CCOC1
Product: COC(=O)c1c(CN2CCN(C(C)C)CC2)c(-c2ccccc2)nc2ccccc12
Temperature: 10 °C
Reaction time: 8 h

Procedure:
7.8 g of crude 3-bromomethyl-2-phenyl-quinoline-4-carboxylic acid methyl ester (compound of Description 2) were dissolved, under nitrogen atmosphere, in 130 ml of dry THF. The solution was cooled to 10° C. and 2.8 g (21.6 mmol) of 1-isopropylpiperazine, dissolved in 20 ml of THF, were added dropwise. The reaction mixture was allowed to warm to room temperature and stirred overnight. Salts were filtered off and the filtrate was evaporated in vacuo to dryness, taken up with 2 N HCl and washed with EtOAc; the aqueous layer was basified with 10% NaOH and extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered and evaporated in vacuo to dryness to obtain a crude material which was purified by flash column chromatography on 230-400 mesh silica gel, utilising a mixture of Et2O/iPr2O 70:30 containing 0.3% ammonium hydroxide (28%). 3.8 g of the title compound were recovered as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:21][CH3:22])=[CH:5][C:6]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:11][NH:10][C:9](=[O:19])[CH2:8][C:7]=2[CH:20]=1.[H-].[Na+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[CH2:25]([N:10]1[C:9](=[O:19])[CH2:8][C:7]2[CH:20]=[C:3]([O:2][CH3:1])[C:4]([O:21][CH3:22])=[CH:5][C:6]=2[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:11]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1cc2c(cc1OC)C(c1ccccc1)=NNC(=O)C2
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)C(c1ccccc1)=NN(Cc1ccccc1)C(=O)C2
Reaction time: 2 h
Yield: 71 %

Procedure:
To a solution of 7,8-dimethoxy-1-phenyl-3,5-dihydro-4H-2,3-benzodiazepin-4-one VIaa (100 mg, 0.34 mmol) in DMF (5 ml), under an inert atmosphere, add NaH in oil (12 mg, 0.30 mmol). Then add dropwise benzyl bromide (40 μl, 0.34 mmol). After 2 hours at room temperature, evaporate the DMF. Take up the residue in CH2Cl2, wash twice with water. Dry the organic phases on Na2SO4. Purify by silica gel column chromatography (AcOEt/hexane, 4:1). Yield: 71%. M: 114–116° C. 1H-NMR (200 MHz, CDCl3): d 3.53–3.64 (m, 2H, CH2), 3.73 (s, 3H, OCH3), 4.00 (s, 3H, OCH3), 4.93–5.32 (d, 2H, NCH2Ph), 6.63 (s, 1H, Ar), 6.92 (s, 1H, Ar), 7.20–7.59 (m, 10H, Ar).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]([N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:8].ClC1C=C2C(N=CC=C2)=C2C=1C=CC=N2.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:36]1[CH:41]=[CH:40][C:39]([S:42][CH3:43])=[CH:38][CH:37]=1.[OH-].[NH4+].O>CN1CCCC1=O>[CH3:43][S:42][C:39]1[CH:40]=[CH:41][C:36]([N:3]2[CH:4]=[CH:5][S:1]/[C:2]/2=[N:6]\[C:7]([N:9]2[CH2:10][CH2:11][CH2:12][CH2:13]2)=[O:8])=[CH:37][CH:38]=1
Reactant: O=C(Nc1nccs1)N1CCCC1
Reactant: CSc1ccc(Br)cc1
Agent: Clc1cc2cccnc2c2ncccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CSc1ccc(-n2ccs/c2=N\C(=O)N2CCCC2)cc1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
In a 4 mL vial charged with a stir bar, N-1,3-thiazol-2-ylpyrrolidine-1-carboxamide (53 mg, 0.27 mmol, Example 32A) was added, followed by copper(I) trifluoromethanesulfonate benzene complex (27 mg, 0.05 mmol), 5-chloro-1,10-phenanthroline (23 mg, 0.11 mmol) and cesium carbonate (97 mg, 0.3 mmol). A loose cap with a septum was placed on the vial, and then the vial was placed under vacuum in a vacuum oven for 30 minutes. The mixture was purged with nitrogen gas a couple of times. Then (4-bromophenyl)(methyl)sulfane (61 mg, 0.3 mmol) dissolved in 1-methyl-2-pyrrolidinone (1.0 mL) was added to the solid mixture. The vial was capped and placed on a heater/stirrer and heated to 120° C. overnight. Then a 1 mL solution of concentrated ammonium hydroxide/water (1:2) was added. The reaction was filtered and concentrated to dryness. The residue was purified by reverse phase HPLC (C8, gradient 10-100% acetonitrile/water/0.1% trifluoroacetic acid).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([C@:11]([O:24][SiH3])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]([N:15]=[N+]=[N-])(C)C)(C)(C)C.O.[OH-].[Na+]>O1CCCC1>[NH2:15][CH2:12][C@H:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[OH:24]
Reactant: CC(C)(C)[C@](O[SiH3])(c1ccccc1)C(C)(C)N=[N+]=[N-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NC[C@@H](O)c1ccccc1
Reaction time: 1 h

Procedure:
A mixture of 2.6 g of lithium aluminum hydride in 400 ml of tetrahydrofuran was cooled in an ice-acetone bath, and a solution of 9.4 g of 2(S)-t-butyldimethyl-silyloxy-2-phenylethylazide [prepared as described in step (c) above] in 100 ml of tetrahydrofuran was added dropwise to the cooled mixture. The mixture was stirred for 1 hour, whilst ice-cooling, after which 2.6 ml of water, 2.6 ml of a 15% w/v aqueous solution of sodium hydroxide and 7.8 ml of water were added dropwise to the reaction mixture, in that order. Insoluble materials were filtered off, and the filtrate was concentrated by evaporation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 1:2 by volume mixture of ethyl acetate and ethanol as the eluent, to give the title compound as crystals, melting at 69°-70° C.
Reaction SMILES: [CH3:1][C:2]1(C)[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([NH:16][CH2:17][CH:18]([OH:25])[CH2:19][N:20]3[CH:24]=[CH:23][N:22]=[CH:21]3)([CH3:15])[CH3:14])=[CH:9][CH:8]=2)=N1.S(=O)(=O)(O)[OH:28].O>C(O)CC>[OH:25][CH:18]([CH2:19][N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)[CH2:17][NH:16][C:13]([C:10]1[CH:11]=[CH:12][C:7]([C:4]([O:5][CH2:6][CH2:2][CH3:1])=[O:28])=[CH:8][CH:9]=1)([CH3:15])[CH3:14]
Reactant: CC1(C)COC(c2ccc(C(C)(C)NCC(O)Cn3ccnc3)cc2)=N1
Reactant: O=S(=O)(O)O
Solvent: CCCO
Solvent: O
Product: CCCOC(=O)c1ccc(C(C)(C)NCC(O)Cn2ccnc2)cc1

Procedure:
A mixture of 1-{1-[4-(4,4-dimethyl-2-oxazolin-2-yl)phenyl]-1-methylethylamino}-3-(imidazol-1-yl)propan-2-ol (100 mg) and a solution of sulphuric acid in propan-1-ol (5 ml) [prepared by adding concentrated sulphuric acid (4 ml) and then water (5 ml) to propan-1-ol (50 ml) and making up to 100 ml with propan-1-ol] was heated on a steam bath for 18 hours. The mixture was evaporated under reduced pressure. The residue was basified with aqueous sodium hydroxide solution and then extracted with dichloromethane to give a residue which was purified by flash column chromatography on silica using ethyl acetate/triethylamine (9:1) with increasing amounts of ethanol to give propyl 4-{1-[2-hydroxy-3-(imidazol-1-yl)propylamino]-1-methylethyl}benzoate as an oil.