Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:9]1([O:15][C:16]2[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[CH:16]1([O:15][C:9]2[CH:14]=[CH:13][C:12]([C:2]3[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=3)=[CH:11][CH:10]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Nc1ncccc1Br
Reactant: OB(O)c1ccc(OC2CCCCC2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Nc1ncccc1-c1ccc(OC2CCCCC2)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 92.5 %

Procedure:
n-Butyllithium (1.6 M in hexane) (136 mL) was dropwised to a mixture of 1-bromo-4-(cyclohexyloxy)benzene (46.3 g) and THF (dry) (500 mL) at −78° C. and the mixture was stirred at the same temperature under nitrogen for 40 min. Triisopropyl borate (51.2 g) was dropwised to the mixture at −78° C. for 15 min and the mixture was stirred at the same temperature for 5 min. Then the mixture was warmed up to room temperature and stirred for additional 30 min. The mixture was poured into 1N NaOH aq. (250 mL) and water (750 mL) and the mixture was further stirred for 30 min. The organic layer was separated and the aqueous phase was washed with Et2O (300 mL×2) and acidified by 6N HCl aq. The mixture was extracted with EtOAc, dried over anhydrous sodium sulfate and concentrated in vacuo to give 4-(cyclohexyloxy)phenylboronic acid (29.5 g) as a white powder. Tetrakis(triphenylphosphine)palladium(0) (0.656 g) was added to a suspension of 3-bromopyridin-2-amine (9.83 g), 4-(cyclohexyloxy)phenylboronic acid (15.0 g) and sodium carbonate (12.0 g) in DME (325 mL) and water (65.0 mL) and the mixture was stirred at 100° C. under nitrogen for 3 hr and at 90° C. for 12 hr. Volatiles were removed in vacuo with silica-gel. The silica-supported mixture was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (14.1 g) as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.C(OP([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]P(OCC)(OCC)=O)=[CH:27][C:26]=1[SiH2:40][C:41]([CH3:50])([CH3:49])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])(OCC)=O)C.[C:51](O[K])([CH3:54])([CH3:53])[CH3:52].S(=O)(=O)(O)O>O1CCCC1.C(OCC)(=O)C.O>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]=[C:52]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:51]3[CH:54]=[CH:15][C:2]([Br:1])=[CH:3][CH:53]=3)=[CH:27][C:26]=2[SiH2:40][C:41]([CH3:49])([CH3:50])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccc(Br)cc1
Reactant: CC(C)(C)O[K]
Reactant: CCCCCCCC(C)(C)[SiH2]c1cc(CP(=O)(OCC)OCC)ccc1CP(=O)(OCC)OCC
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCC(C)(C)[SiH2]c1cc(C=C(c2ccccc2)c2ccc(Br)cc2)ccc1C=C(c1ccccc1)c1ccc(Br)cc1
Reaction time: 3.5 h

Procedure:
Under an inert atmosphere, 4-bromobenzophenone (1.306 g, 5 mmol), and 1,4-bis(diethylphosphonomethyl)-2-dimethyloctylsilyl benzene (1.125 g, 2.05 mmol) were dissolved in tetrahydrofuran (15 g). At room temperature, tetrahydrofuran (5.46 g) solution of tert-butoxy potassium (0.690 g, 6.15 mmol) was added dropwise for 5 minutes, and successively stirred for 3.5 hours. The reaction mixture was charged into water (100 ml) and neutralized with 5% sulfuric acid. After neutralization, ethyl acetate (200 ml) was added and the organic layer was partitioned. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resultant raw product was purified by silica gel chromatography to give the desired product. (Yield: 1.29 g, 83%)
Reaction SMILES: [CH2:1]1[CH2:6][NH:5][CH2:4][C:3]2[C:7](=[O:15])[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:2]1=2.C(N(CC)CC)C.Cl.Cl[CH2:25][CH2:26][N:27]1[CH2:33][CH:32]2[CH2:34][CH2:35][CH:29]([CH2:30][CH2:31]2)[CH2:28]1>>[CH:32]12[CH2:34][CH2:35][CH:29]([CH2:30][CH2:31]1)[CH2:28][N:27]([CH2:26][CH2:25][N:5]1[CH2:6][CH2:1][C:2]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[O:8][C:7](=[O:15])[C:3]=3[CH2:4]1)[CH2:33]2
Reactant: O=c1oc2ccccc2c2c1CNCC2
Reactant: ClCCN1CC2CCC(CC2)C1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=c1oc2ccccc2c2c1CN(CCN1CC3CCC(CC3)C1)CC2
Yield: 64.8 %

Procedure:
Prepared by the method described for Example 1 from 1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c]pyridin-5-one (1.5 g, 0.007 moles), triethylamine (2.2 ml, 0.016 moles), and 3-(2-chloroethyl)-3-azabicyclo[3.2.2]nonane hydrochloride (1.7 g, 0.0076 moles). Recrystallization from ethanol gave the product (1.6 g) as the monohydrochloride, 5:1 hydrate, mp 267° C. (dec).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)=[N:8][CH:7]=[C:6]2[C:26](O)=[O:27].O1CCCC1>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)=[N:8][CH:7]=[C:6]2[CH2:26][OH:27]
Reactant: COc1ccc(Cc2ncc(C(=O)O)c3cc(OC)c(OC)cc23)cc1OC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cc2ncc(CO)c3cc(OC)c(OC)cc23)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.8 %

Procedure:
A slurry of 25.2 g of 6,7-dimethoxy-1-[(3,4-dimethoxyphenyl)methyl]-4-isoquinolinecarboxylic acid and 100 of dry tetrahydrofuran was stirred at 15° in an inert atmosphere while cautiously adding 200 ml of 1 molar borane/tetrahydrofuran complex. After stirring for 2 hours at room temperature, the initial solids had dissolved and were replaced by a second precipitate. The mixture was cautiously treated with 200 ml of water and the tetrahydrofuran was removed in vacuo at 40°. The chilled reaction mixture was then filtered, washed with water, and the damp stable borane complex was added portionwise with stirring to 200 ml of 2 N hydrochloric acid previously heated to 70°-80°. The resulting solution was heated an additional 15 minutes on the steam bath and was then chilled extracted with 100 ml of diethyl ether. The aqueous layer was added dropwise to 250 ml of cold 2 N sodium hydroxide with stirring. The resulting solids were removed by filtration, washed well with water, and dried to give 20.6 g of crude 6,7-dimethoxy-1[(3,4-dimethoxyphenyl)methyl]-4-isoquinoline methanol, mp 146°-148°. Recrystallization from methylene chloride/ethyl acetate gave 19.2 g of purified 6,7-dimethoxy-1-(3,4-dimethoxyphenyl)methyl]-4-isoquinoline methanol, mp 141°-143°.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:11]1[C:12]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH:18]=[CH:17][C:13]=2[N:14]=[CH:15][N:16]=1>O1CCOCC1>[O:7]([C:11]1[C:12]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH:18]=[CH:17][C:13]=2[N:14]=[CH:15][N:16]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: Fc1ccc(-c2ccc3ncnc(Cl)c3n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Fc1ccc(-c2ccc3ncnc(Oc4ccccc4)c3n2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.5 %

Procedure:
To a solution of phenol (94 mg, 1 mmol) in dioxane (5 ml) was added sodium hydride (40 mg of a 60% dispersion in mineral oil, 1.0 mmol). The mixture was stirred at room temperature for 10 minutes. Then, 4-chloro-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidine (52 mg, 0.2 mmol) was added to this solution. The resulting mixture was stirred at room temperature for another 30 minutes. After concentration under reduced pressure, the residue was purified by silica gel flash chromatography, the mobile phase being a mixture of methanol and dichloromethane, in a volume ratio of 1:60, yielding the title compound (60 mg, yield 95%) as a white solid which was characterised by its mass spectrum as follows: MS (m/z): 318 ([M+H]+, 100).
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][C@@H:19]([C:24]([O:26]C)=[O:25])[CH2:20][CH2:21][CH2:22][CH3:23])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.[OH-].[Li+].[ClH:35]>C1COCC1.CO>[ClH:35].[F:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][C@H:19]([C:24]([OH:26])=[O:25])[CH2:20][CH2:21][CH2:22][CH3:23])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CCCC[C@@H](NC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cccn12)C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCC[C@H](NC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cccn12)C(=O)O
Temperature: 45 °C
Reaction time: 2 h

Procedure:
890 mg of methyl N-({8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridin-3-yl}carbonyl)-D-norleucinate Example 19 (2 mmol, 1 equivalent) were dissolved in 16 ml of THF/methanol (1:1), 10 ml of 1 N aqueous lithium hydroxide solution (10 mmol, 5 equivalents) were added and the mixture was stirred at 45° C. for 2 h. With ice cooling, the mixture was then adjusted to pH 5-6 using 6 N aqueous hydrochloric acid, and the organic solvent was removed under reduced pressure. A little water was added to the residue, and the mixture was extracted repeatedly with dichloromethane/methanol=100:5. The combined organic phases were dried over magnesium sulphate, filtered and concentrated. The residue obtained was dried under high vacuum. This gave 844 mg (95% of theory; purity: 98%) of the title compound.
Reaction SMILES: [N:1]1([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][C:29]3[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=3)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)C[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl.Cl.NC1CCN(CCN2CCC([OH:54])CC2)CC1>>[OH:54][CH:4]1[CH2:3][CH2:2][N:1]([CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][C:29]3[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=3)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:14][CH2:15]2)[CH2:6][CH2:5]1
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Reactant: Cc1cccc(Oc2cccc3[nH]c(C(=O)NC4CCN(CCN5CCCCCC5)CC4)cc23)c1
Agent: Cl
Product: Cc1cccc(Oc2cccc3[nH]c(C(=O)NC4CCN(CCN5CCC(O)CC5)CC4)cc23)c1

Procedure:
This compound is synthesized analogously to Example 1 from 4-m-tolyloxy-1H-indole-2-carboxylic acid 133 (see example 112) and amine 21.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[S:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Br.BrC1[C:26](=O)[CH:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])[CH2:24][CH2:23][CH2:22]1.C([N:38]([CH2:42][CH3:43])C(C)C)(C)C>C(O)C>[CH2:42]([N:38]1[CH2:26][CH:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])[C:24]2[N:18]=[C:16]([NH:15][C:5]3[CH:6]=[CH:7][C:8]([N:9]4[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]4)=[C:3]([O:2][CH3:1])[CH:4]=3)[S:17][C:23]=2[CH2:22]1)[C:43]1[CH:5]=[CH:4][CH:3]=[CH:8][CH:7]=1
Reactant: O=C1C(Br)CCCC1c1ccccc1Cl
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Reactant: CCN(C(C)C)C(C)C
Agent: Br
Solvent: CCO
Product: COc1cc(Nc2nc3c(s2)CN(Cc2ccccc2)CC3c2ccccc2Cl)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 5.8 %

Procedure:
A suspension of [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (100 mg, 0.38 mmol) and of crude 6-bromo-2-(2-chloro-phenyl)-cyclohexanone hydrobromide (163 mg, 0.36 mmol) in ethanol (5 mL) was heated to reflux under an atmosphere of nitrogen for 2 days. N,N-diisopropyl ethyl amine (49 mg, 0.38 mmol) was added and the reaction was heated to reflux over night. After cooling to room temperature the solvent was evaporated under reduced pressure and the residue was treated with dichloromethane/methanol/concentrated aqueous NH4OH solution (9:1:0.1 v/v/v). The precipitate was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by reversed preparative HPLC using acetonitril/water (0.1% formic acid) to yield the title compound (6 mg, 3%) as a yellow solid. MS ISP (m/e): 541.9/543.9 (100/35) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.60 (s, 1H), 7.37 (m, 2H), 7.26 (m, 5H), 7.09-7.18 (m, 4H), 6.82 (s, 1H), 6.66 (d, 1H), 4.70 (m, 1H), 3.74 (m, 3H), 3.60 (s, 3H), 3.19 (dd, 1H), 2.81 (dd, 1H), 2.28 (s, 2H).
Reaction SMILES: [Cl:1][CH:2]([O:6][N:7]=[CH:8][C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([OH:5])=[O:4].CO.[CH3:18]S(O)(=O)=O>ClCCCl>[Cl:1][CH:2]([O:6][N:7]=[CH:8][C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5][CH3:18])=[O:4]
Reactant: CS(=O)(=O)O
Reactant: O=C(O)C(Cl)ON=Cc1ccccc1Cl
Solvent: ClCCCl
Solvent: CO
Product: COC(=O)C(Cl)ON=Cc1ccccc1Cl

Procedure:
A mixture of 12.4 gm. (0.050 mole) of 2,6-dichlorobenzylideneaminooxyacetic acid, 4.8 gm. (0.150 mole) of methanol and about 0.8 gm. of methanesulfonic acid in 15 ml. of 1,2-dichloroethane was refluxed for 15-16 hours. The cooled reaction mixture was then washed with cold, aqueous sodium bicarbonate, followed by a cold water wash. The organic phase was then concentrated under reduced pressure and at a mixture bath temperature of about 60° C. The resulting oil solidified on cooling. There were obtained 12.5 gm. (96%) of product melting at 58°-65° C. Purification by high vacuum distillation yielded material which, when allowed to crystallize, melted at 60°-62° C. (uncorrected).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)=[O:5].[CH2:16](O)[CH2:17][OH:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[CH:15][C:6]=1[C:4]1([CH2:3][CH2:2][Cl:1])[O:18][CH2:17][CH2:16][O:5]1
Reactant: OCCO
Reactant: O=C(CCCl)c1ccc2ccccc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: ClCCC1(c2ccc3ccccc3c2)OCCO1

Procedure:
A solution of 1.36 g of 2-chloroethyl-2-naphthyl ketone, 6.05 g ethylene glycol and a crystal of p-toluenesulfonic acid monohydrate in 50 ml of toluene is heated for 8 hours under reflux through a Dean-Stark trap. After cooling, the mixture is neutralized by pouring into excess aqueous potassium carbonate, extracted with 200 ml ether and the organic phase washed, dried (MgSO4), and evaporated to yield 2-(2-naphthyl)-2-(2-chloroethyl)-1,3-dioxolane. Without further purification the crude ketal (1.36 g.) is heated with 1.77 g of imidazole in 2 ml of acetonitrile at 85° overnight. The resulting mixture is evaporated to dryness, treated with water and the product extracted with ether. The extracts are washed well with water, dried (MgSO4), evaporated and the residue chromatographed on silica gel eluting with 5% methanol/dichloromethane to give 0.78 g of 1-[3,3-ethylenedioxy-3-(2-naphthyl)-n-propyl]imidazole.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:13])[C:10](C#N)=[C:6]2[N:5]=[C:4]([CH3:14])[C:3]=1[CH2:15][CH2:16]Cl.C(=O)([O-])[O-].[K+].[K+].[C:24]([NH2:28])([CH3:27])([CH3:26])[CH3:25]>CN(C)C=O>[C:24]([N:28]1[C:2]2[N:7]3[N:8]=[C:9]([C:13]4[CH:16]=[CH:15][CH:3]=[CH:4][CH:14]=4)[CH:10]=[C:6]3[N:5]=[C:4]([CH3:14])[C:3]=2[CH2:15][CH2:16]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: Cc1nc2c(C#N)c(C)nn2c(Cl)c1CCCl
Reactant: CC(C)(C)N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc2cc(-c3ccccc3)nn2c2c1CCN2C(C)(C)C
Yield: 70.1 %

Procedure:
A mixture of 16.11 g of Compound (VI) [R2 =H, R3 =H], 38 g of anhydrous potassium carbonate, 5.85 g of tert-butylamine, and 140 ml of dimethylformamide was heated at 50°-60° C. in a water bath for 2 days while stirring. The reaction mixture was cooled and filtered. The filtrate was evaporated under reduced pressure. The residue was dissolved in 150 ml of chloroform. The chloroform layer was washed with water and evaporated under reduced pressure to obtain 15.72 g of an oily substance. The oily substance was purified using silica gel chromatography, followed by recrystallizing in a mixed solvent of benzene-isopropylether-hexane to produce 8-tert-butyl-6,7-dihydro-5-methyl-8H-pyrrolo[3,2-e]pyrazolo[1,5-a]pyrimidine [R1 =C(CH3)3, R2 =H, R3 =H in formula (I)] (Compound 11 of this invention) as light yellow plate crystals having a melting point of 147°-149° C. at a yield of 70.1%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C:19]([C:22]1[CH:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH3:35])[CH:25]=[CH:26][CH:27]=1)(O)[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:14]([C:15]([CH3:17])([CH3:16])[CH3:18])=[CH:13][CH:12]=[CH:11][C:10]=1[C:19]([C:22]1[CH:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH3:35])[CH:25]=[CH:26][CH:27]=1)=[CH2:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1-c1cccc(C(C)(O)c2cccc(C(C)(C)C)c2OCc2ccccc2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=C(c1cccc(-c2ccccc2OC)c1)c1cccc(C(C)(C)C)c1OCc1ccccc1

Procedure:
A solution of crude 27 (5 mmol) in toluene (120 mL) was treated with p-toluene sulfonic acid (0.2 g) and refluxed under a Dean-Stark trap for 2 hr. After cooling the reaction mixture was diluted with ethyl acetate (100 mL) and washed with saturated sodium bicarbonate (80 mL) and water (2×80 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was removed on a rotary evaporator. The crude product was purified by chromatography on silica (80 g) with hexane (4 L). Pure 28 (1.3 g, 58% over 2 steps) was isolated.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li].[CH3:15][C:16]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[C:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1.O>O1CCCC1.[Cl-].[Cl-].C1(C(=[Hf+2](C2C3C=CC=CC=3C3C2=CC=CC=3)C2C=CC=C2)C)C=CC=CC=1>[CH:17]1([C:16]2[CH:15]=[CH:25][CH:26]=[CH:27][C:22]=2[CH2:23][CH2:24][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH2:18][CH2:19][CH:20]=[CH:21]1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: CC(=C1C=CC=C1)c1ccccc1
Agent: CC(c1ccccc1)=[Hf+2](C1C=CC=C1)C1c2ccccc2-c2ccccc21
Agent: [Cl-]
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Product: C1=CC(c2ccccc2CCC2c3ccccc3-c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
(Phenyl(methyl)methylene)(9-fluorenyl)(cyclopentadienyl)hafnium dichloride ##STR12## A solution of 67.8 mmol of lithium-fluorene in 50 cm3 of tetrahydrofuran was added to a solution of 11.4 g (67.8 mmol) of 6-methyl-6-phenyl-fulvene in 40 cm3 of tetrahydrofuran at room temperature. After the mixture had been stirred at room temperature for 2 hours, 60 cm3 of water were added. The substance obtained after this addition was filtered off with suction, washed with diethyl ether and dried under an oil pump vacuum. 19.1 g (84.2%) of 2,2-cyclopentadienyl(9-fluorenyl)ethylbenzene were obtained (correct elemental analyses; 1H-NMR spectrum).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.CCN(CC)CC.[OH:19][CH2:20][CH:21]1[O:25][C:24](=[O:26])[NH:23][CH2:22]1>ClCCl>[S:7]([O:19][CH2:20][CH:21]1[O:25][C:24](=[O:26])[NH:23][CH2:22]1)([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: O=C1NCC(CO)O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2CNC(=O)O2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
p-Toluenesulphonyl chloride (2.74 g, 14.36 mmol) and Et3N (1.45 g, 14.36 mmol) were added to 5-hydroxymethyl-1,3-oxazolidine-2-one (1.40 g, 11.97 mmol) dispersed in 20 mL of dichloromethane and stirred overnight at room temperature under N2. After completion of the reaction (TLC), the solvent in the reaction mixture was evaporated and the residue was purified by column chromatography employing EtOAc-hexane (70:30) as eluent to afford 5-tosyloxymethyl-1,3-oxazolidine-2-one in 80% yield. m.p. 96-99° C.; [α]27D=+45.40 CHCl3); IR (KBr) 3302, 2980, 2925, 2871, 1757, 1694, 1357, 1184, 1090, 996, 965 cm1; 1HNMR (200 MHz, CDCl3) δ 2.47 (s, 3H), 3.40-3.50 (m, 1H), 3.64-3.74 (m, 1H), 4.14 (d, 2H, J=4.4 Hz), 4.71-4.82 (m, 1H), 7.35 (d, 2H, J=8.2 Hz), 7.78 (d, 2H, J=8.2 Hz); Mass (EI) 271, 207, 173, 155, 139, 91.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl.CN(C=O)C>[Br:17][C:18]1[CH:19]=[CH:20][C:21]([OH:24])=[C:22]([C:8](=[O:10])[CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:23]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: COc1ccc(Br)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cc1ccccc1)c1cc(Br)ccc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
Phenylacetic acid (1.09 g, 8.0 mmoles) was dissolved in 5 ml dichloromethane. To this mixture, oxalylchloride (1.01 g, 8.0 mmoles) and DMF (3 drops) were added at 0° C. and stirred for 30 min. The solvent was evaporated and dissolved in 5 ml dichloromethane. To this mixture, 4-bromoanisole (1 g, 5.34 mmoles) was added and cooled to 0° C. At 0° C. AlCl3 (1.06 g, 8.0 mmoles) was added and the reaction mixture was warmed to RT and stirred overnight. The reaction mixture was quenched by the addition of 2N HCl and extracted with ethyl acetate, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography to afford the title compound as white solid (1 g, 66% yield). MP: 83-86° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): δ 11.56 (s, 1H), 8.01 (d, J=2.2 Hz, 1H), 7.64 (dd, J=8.8, 2.5 Hz, 1H), 7.32 (t, 2H), 7.29 (m, 3H), 6.96 (d, J=8.8 Hz, 1H), 4.43 (s, 2H).
Reaction SMILES: C(N(CC)C1C=C2C(=CC=1)N(C(=O)C1C=CC(F)=CC=1)[C@@H](C)C[C@H]2N(C1C=CC(N(CC)CC)=CC=1)C(=O)CC)C.[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([N:49]([C@H:54]2[C:63]3[C:58](=[CH:59][CH:60]=[C:61]([N:64]4[CH2:69][CH2:68]O[CH2:66][CH2:65]4)[CH:62]=3)[N:57]([C:70](=[O:78])[C:71]3[CH:76]=[CH:75][C:74]([F:77])=[CH:73][CH:72]=3)[C@@H:56]([CH3:79])[CH2:55]2)[C:50](=[O:53])[CH2:51][CH3:52])=[CH:45][CH:44]=1.C(NCC)C.N1CCOCC1>>[Cl:42][C:43]1[CH:44]=[CH:45][C:46]([N:49]([C@H:54]2[C:63]3[C:58](=[CH:59][CH:60]=[C:61]([N:64]([CH2:65][CH3:66])[CH2:69][CH3:68])[CH:62]=3)[N:57]([C:70](=[O:78])[C:71]3[CH:72]=[CH:73][C:74]([F:77])=[CH:75][CH:76]=3)[C@@H:56]([CH3:79])[CH2:55]2)[C:50](=[O:53])[CH2:51][CH3:52])=[CH:47][CH:48]=1
Reactant: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(F)cc2)c2ccc(N3CCOCC3)cc21
Agent: CCC(=O)N(c1ccc(N(CC)CC)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(F)cc2)c2ccc(N(CC)CC)cc21
Solvent: C1COCCN1
Solvent: CCNCC
Product: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(F)cc2)c2ccc(N(CC)CC)cc21

Procedure:
(±)-Cis-N-[6-diethylamino-1-(4-fluoro-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N(4-diethylamino-phenyl)-propionamide was made in the same way as (±)-cis-N-(4-chloro-phenyl)-N-[1-(4-fluoro-benzoyl)-2-methyl-6-morpholin-4-yl-1,2,3,4-tetrahydro-quinolin-4-yl]-propionamide except diethylamine was substituted for morpholine. The reaction was non-selective and yielded (±)-cis-N-(4-chloro-phenyl)-N-[6-diethylamino-1-(4-fluoro-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-propionamide in addition to the titled compound.