Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-:1].[CH2:2]([O:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH:14]([C@H:17]2[CH2:21][CH2:20][CH2:19][N:18]2[C:22]2[C:31]([CH2:32]O)=[CH:30][C:29]3[C:24](=[CH:25][C:26]([F:35])=[C:27]([F:34])[CH:28]=3)[N:23]=2)[CH2:13][CH2:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:2]([O:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH:14]([C@H:17]2[CH2:21][CH2:20][CH2:19][N:18]2[C:22]2[C:31]([CH2:32][Cl:1])=[CH:30][C:29]3[C:24](=[CH:25][C:26]([F:35])=[C:27]([F:34])[CH:28]=3)[N:23]=2)[CH2:13][CH2:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: [Cl-]
Reactant: OCc1cc2cc(F)c(F)cc2nc1N1CCC[C@@H]1C1CCC(COCc2ccccc2)CC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cc2cc(CCl)c(N3CCC[C@@H]3C3CCC(COCc4ccccc4)CC3)nc2cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methaneslufonyl chloride (1.52 mL, 20 mmol) is added dropwise to a mixture of (2-{(R)-2-[4-(benzyloxymethyl)cyclohexyl]pyrrolidin-1-yl}-6,7-difluoroquinolin-3-yl)methanol (7.03 g, 15 mmol) and N,N-diisopropylethylamine (DIPEA, 3.41 mL, 15 mmol) in toluene (75 mL) at 0° C. The reaction mixture is stirred at ambient temperature for 1 hour. To the mixture, water and ethyl acetate are added, and the organic layer is washed with sat. NaHCO3 aq, brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is dissolved with toluene and concentrated in vacuo to give crude 2-{(R)-2-[4-(benzyloxymethyl)cyclohexyl]pyrrolidin-1-yl}-3-(chloromethyl)-6,7-difluoroquinoline. To a mixture of N-[3,5-bis(trifluoromethyl)benzyl]-N-(2-methyl-2H-tetrazol-5-yl)amine (5.88 g, 18 mmol) in DMF (60 mL) is added potassium tert-butoxide (2.03 g, 18 mmol) at 0° C., and the resulting mixture is stirred for 30 min at the same temperature. A crude 2-{(R)-2-[4-(benzyloxymethyl)cyclohexyl]pyrrolidin-1-yl}-3-(chloromethyl)-6,7-difluoroquinoline dissolved in DMF (30 mL) is added dropwise to the mixture at 0° C., and the resulting mixture is stirred for 1 hour at the same temperature. Potassium tert-butoxide (1.70 g, 14 mmol) is added to the reaction mixture, and the mixture is stirred another 1 hour at room temperature. After adding water, the mixture is extracted with ethyl acetate. The combined organic layer is washed with brine, dried over magnesium sulfate, filtrated, and concentrated. The resulting mixture is purified by silica gel column chromatography to give trans-N-(2-{(R)-2-[4-(2-benzyloxymethyl)cyclohexyl]pyrrolidin-1-yl}-6,7-difluoroquinolin-3-ylmethyl)-N-[3,5-bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-yl)amine as a yellow amorphous solid.
Reaction SMILES: Cl.[CH3:2][NH:3][C:4]1[CH:46]=[CH:45][C:7]([O:8][CH2:9][C:10]([NH:12][C@H:13]([C:18]([NH:20][C@@H:21]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C@H:22]([OH:37])[C:23]([N:25]2[CH2:36][CH2:35][CH2:34][C@H:26]2[C:27]([NH:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:24])=[O:19])[CH2:14][C:15](=[O:17])[NH2:16])=[O:11])=[CH:6][CH:5]=1.[N+:47]([C:50]1[CH:59]=[CH:58][C:53]([O:54][C:55](Cl)=[O:56])=[CH:52][CH:51]=1)([O-:49])=[O:48]>>[N+:47]([C:50]1[CH:59]=[CH:58][C:53]([O:54][C:55]([N:3]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]([NH:12][C@H:13]([C:18]([NH:20][C@@H:21]([CH2:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C@H:22]([OH:37])[C:23]([N:25]3[CH2:36][CH2:35][CH2:34][C@H:26]3[C:27]([NH:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:24])=[O:19])[CH2:14][C:15](=[O:17])[NH2:16])=[O:11])=[CH:45][CH:46]=2)[CH3:2])=[O:56])=[CH:52][CH:51]=1)([O-:49])=[O:48]
Reactant: CNc1ccc(OCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc2ccccc2)[C@H](O)C(=O)N2CCC[C@H]2C(=O)NC(C)(C)C)cc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: CN(C(=O)Oc1ccc([N+](=O)[O-])cc1)c1ccc(OCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc2ccccc2)[C@H](O)C(=O)N2CCC[C@H]2C(=O)NC(C)(C)C)cc1
Yield: 20.2 %

Procedure:
Following a procedure similar to that described in Example 30, but using 500 mg (0.76 mmol) of 1-{(2S,3S)-3-[N2 -(p-methylaminophenoxy)acetyl-L-asparaginyl]amino-2-hydroxy-4-phenylbutyryl}-N-t-butyl-L-prolinamide hydrochloride (prepared as described in Example 20) and 236 mg (1.13 mmol) of 4-nitrophenoxycarbonyl chloride, 121 mg of the title compound were obtained as a colorless powder, melting at 116°-119° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22]CC)=[O:21])=[CH:15][CH:14]=1.CO.C1COCC1.O[Li].O>O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:17][CH:18]=1
Reactant: CCOC(=O)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.8 %

Procedure:
To a solution of ethyl 2-(4-(quinolin-2-ylmethoxy)phenyl)acetate (25 g, 0.07 mol) in 1:1 (MeOH: THF) (400 mL) were added LiOH.H2O (6.3 g, 0.38 mol) and water (50 mL). The mixture was then stirred at RT for 1 h. The reaction mixture was then concentrated in vacuo. The residue was then acidified with aqueous HCl (1N) and extracted with EtOAc (2×300 mL). The combined organic layers were washed with water, dried over Na2SO4 and concentrated in vacuo to afford 2-(4-(quinolin-2-ylmethoxy)phenyl)acetic acid (9.0 g, 40%) as a solid.
Reaction SMILES: Br[C:2]1[C:3]([Cl:18])=[C:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[CH2:19]1[C:23]2([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:22][CH2:21][N:20]1[C:29](=[O:31])[CH3:30].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:29]([N:20]1[CH2:21][CH2:22][C:23]2([CH2:28][CH2:27][N:26]([C:2]3[C:3]([Cl:18])=[C:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=3)[CH2:25][CH2:24]2)[CH2:19]1)(=[O:31])[CH3:30]
Reactant: CC(=O)N1CCC2(CCNCC2)C1
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(Br)c1Cl
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(=O)N1CCC2(CCN(c3cc(C#N)cc(NC(=O)OC(C)(C)C)c3Cl)CC2)C1
Temperature: 105 °C
Yield: 50.5 %

Procedure:
A mixture of tert-butyl (3-bromo-2-chloro-5-cyanophenyl)carbamate (291 mg, 0.878 mmol), 1-(2,8-diazaspiro[4.5]decan-2-yl)ethanone (160 mg, 0.878 mmol), Pd2dba3 (80 mg, 0.088 mmol), BINAP (164 mg, 0.263 mmol), and Cs2CO3 (858 mg, 2.63 mmol) in Dioxane (15 mL) was evacuated and filled with nitrogen 3× and heated at 105° C. overnight. The reaction mixture was filtered through a plug of celite and the filtrate was concentrated. The crude product was purified by flash chromatography on silica gel using an automated ISCO system (40 g column, eluting with 10% to 100% EtOAc in Hexane) gave tert-butyl (3-(2-acetyl-2,8-diazaspiro[4.5]decan-8-yl)-2-chloro-5-cyanophenyl)carbamate (192 mg)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]([OH:12])[C:6]3[C:13](=O)[O:14][CH:15](O)[C:5]=3[C:4]=2[C:3]=1[Cl:18].O.[NH2:20][NH2:21].C(OCC)(=O)C>CS(C)=O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]([OH:12])[C:6]3[C:13](=[O:14])[NH:20][N:21]=[CH:15][C:5]=3[C:4]=2[C:3]=1[Cl:18]
Reactant: O=C1OC(O)c2c1c(O)nc1ccc(Cl)c(Cl)c21
Reactant: NN
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=c1[nH]ncc2c1c(O)nc1ccc(Cl)c(Cl)c12
Temperature: 25 °C
Reaction time: 50 h

Procedure:
2.9 g (0.010 mol) of (RS)-8,9-dichloro-1,4-dihydroxy-1,3-dihydro-furo[3,4-c]quinolin-3-one were dissolved in 60 ml of dimethyl sulphoxide while gassing with argon. 0.51 g (0.010 mol) of hydrazine hydrate was added thereto and the mixture was stirred at room temperature for 50 hrs. An orange coloured solution was obtained and this was treated with 300 ml of ethyl acetate. The precipitated product was filtered off under suction, rinsed with ethyl acetate and recrystallized from dimethylformamide/ethyl acetate. Yield: 0.70 g (25%) of 9,10-dichloro-5-hydroxy-3,4-dihydro-pyridazino[4,5-c]quinolin-4-one as yellow-orange coloured crystals; m.p. ~270° C.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:8][CH2:9][CH2:10][C:11](O)=[O:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)C>[CH:1]1([O:7][C:11](=[O:12])[CH2:10][CH2:9][SH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CCS
Reactant: OC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: O=C(CCS)OC1CCCCC1
Temperature: 25 °C

Procedure:
Into a 250 ml reaction flask equipped with stirrer, thermometer, reflux condenser and heating mantle are placed 100 grams of cyclohexanol; 26 grams of 3-mercaptopropionic acid and 0.5 grams of paratoluene sulfonic acid. The reaction mass is heated to reflux and refluxed for a period of 11 hours. At the end of the 11 hour period of refluxing, the reaction mass is cooled to room temperature. 200 ml Diethylether are added to the reaction mass. The reaction mass is then washed with two 100 ml volumes of 10% aqueous sodium bicarbonate solution followed by one 100 ml volume of water. The reaction mass is dried over anhydrous sodium sulfate and the solvent is recovered on a Buchi evaporator. The reaction mass is then micro distilled on a micro distillation apparatus yielding the following fractions:
Reaction SMILES: [Na].[F:2][C:3]([F:13])([F:12])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O>[Cl-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC=CC=1.C(O)C>[C:6]1([CH2:4][CH:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([F:13])([F:12])[F:2])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(c1ccccc1)C(F)(F)F
Agent: [Cl-]
Agent: [Na]
Agent: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Product: FC(F)(F)C(Cc1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 183.1 %

Procedure:
A solution of 456 g (1.17 moles) of benzyl-triphenylphosphoniumchloride (G. Wittig: Chem. Ber. 87, 1318 (1954)) in 1500 ml of dry ethanol is added to a solution of 27 g (1.17 g.-atoms) of sodium in 500 ml of dry ethanol at 0°-2° C. The resulting mixture is combined with a solution of 204 g (1.17 moles) of 2,2,2-trifluoroacetophenone in 100 ml of dry ethanol, and the mixture is allowed to stand overnight. The solution is evaporated, the residue is admixed with 800 ml of petroleum ether, filtered, and the filter cake is washed. The filtrate is evaporated, and the residue is distilled in vacuo. 268 g (92.5%) of 1,2-diphenyl-3,3,3-trifluoro-propane are obtained; b.p.: 107°-109° C./0.2 mm Hg, m.p.: 58°-61° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]2[O:10][CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=2)=[CH:4][CH:3]=1.C([Li])CCC.[Cl:23][CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28]>C1COCC1>[Cl:23][CH2:24][CH2:25][CH2:26][C:27]([C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]2[O:10][CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=2)=[CH:4][CH:3]=1)=[O:28]
Reactant: O=C(Cl)CCCCl
Reactant: CC1(C)COC(C(C)(C)c2ccc(Br)cc2)=N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)COC(C(C)(C)c2ccc(C(=O)CCCCl)cc2)=N1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-bromo-α,α-dimethyl-α-(4,4-dimethyloxazolin-2-yl)toluene (10.0 g. 0.0338 mole), prepared in accordance with Example 2, in 400 mL THF is cooled to −78° C., n-butyllithium (16 mL, 0.042 mole) is added via syringe, and the mixture is stirred at −78° C. for 30 minutes. While keeping the temperature below −75° C., 4-chlorobutyryl chloride (14.4 g, 0.102 mole) in 30 mL THF is added dropwise, and the mixture is stirred at −78° C. for 30 minutes. The mixture is allowed to warm to −15° C. and is quenched with water. The product is extracted with methylene chloride, washed with saturated NaCl solution, dried over Na2SO4, and concentrated. The residue is cooled to 0° C., treated with minimal acetonitrile, and filtered, to afford 4-(4-chloro-1-oxobutyl)-α,α-dimethyl-α-(4,4-dimethyloxazolin-2-yl) toluene.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([S:15]([NH2:18])(=[O:17])=[O:16])[CH:10]=2)=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+].[C:24]([OH:27])(=[S:26])[CH3:25]>C(#N)C>[S:15]([C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][S:26][C:24](=[O:27])[CH3:25])=[CH:4][CH:5]=2)[CH:14]=[CH:13][CH:12]=1)(=[O:17])(=[O:16])[NH2:18]
Reactant: CC(O)=S
Reactant: NS(=O)(=O)c1cccc(-c2ccc(CBr)cc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)SCc1ccc(-c2cccc(S(N)(=O)=O)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4′-(bromomethyl)biphenyl-3-sulfonamide (1.28 g, 3.9 mmol) (WO 01/70753) in acetonitrile (16.4 mL) was treated with sodium bicarbonate (475 mg, 5.7 mmol) and thioacetic acid (0.34 mL, 4.7 mmol). The reaction mixture was stirred at 25° C. for 16 h. Additional sodium bicarbonate and thioacetic acid (0.4 eq. each) were added followed by acetonitrile (5 mL) and the reaction mixture was heated to 50° C. for 30 min. The reaction mixture was washed with water (10 mL) and brine (10 mL), dried with MgSO4, filtered, and concentrated to give a crude residue (quantitative) which was used in the next step without further purification. 1H NMR (500 MHz, CDCl3): δ 8.15 (dd, J=2.0, 2.0 Hz, 1H), 7.92 (ddd, J=7.8, 2.0, 1.0 Hz, 1H), 7.80 (ddd, J=7.8, 2.0, 1.0 Hz, 1H), 7.61 (dd, J=7.8, 7.8 Hz, 1H), 7.58–7.55 (m, 2H), 7.44–7.41 (m, 2H), 4.90 (br s, 2H), 4.19 (s, 2H), 2.40 (s, 3H); LCMS found for C15H15NO3S2Na (M+Na)+: m/z=344.
Reaction SMILES: C[Mg]Br.[C:4]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]2[N:21]([C:22]3[CH:31]=[CH:30][CH:29]=[C:28]4[C:23]=3[CH:24]=[CH:25][CH:26]=[N:27]4)[N:20]=[C:19]([CH3:32])[CH:18]=2)(=[O:15])=[O:14])=[CH:9][CH:8]=1)(=[O:6])[CH3:5].Cl[CH2:34]Cl.CO>C1COCC1>[OH:6][C:4]([C:7]1[CH:8]=[CH:9][C:10]([S:13]([NH:16][C:17]2[N:21]([C:22]3[CH:31]=[CH:30][CH:29]=[C:28]4[C:23]=3[CH:24]=[CH:25][CH:26]=[N:27]4)[N:20]=[C:19]([CH3:32])[CH:18]=2)(=[O:15])=[O:14])=[CH:11][CH:12]=1)([CH3:34])[CH3:5]
Reactant: ClCCl
Reactant: CC(=O)c1ccc(S(=O)(=O)Nc2cc(C)nn2-c2cccc3ncccc23)cc1
Agent: C[Mg]Br
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(NS(=O)(=O)c2ccc(C(C)(C)O)cc2)n(-c2cccc3ncccc23)n1
Temperature: -10 °C
Yield: 32 %

Procedure:
A solution of methyl magnesium bromide (1.4 M solution in 3:1 toluene/THF, 1.4 mL, 2.0 mmol) was added to a flask containing 4-acetyl-N-(3-methyl-1-(quinolin-5-yl)-1H-pyrazol-5-yl)benzenesulfonamide (0.059 g, 0.15 mmol) in THF (6 mL) at −45° C. with stirring. The reaction mixture was slowly warmed to −10° C. over 1 h and 4:1 dichloromethane/methanol was added (2 mL). The organic layer was washed with aqueous saturated ammonium chloride, dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by reverse phase HPLC(C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.020 g, 0.047 mmol, 32%). 1H NMR (400 MHz, CD3OD) δ 8.81 (d, J=4.4 Hz, 1H), 8.05 (d, J=8.8 Hz, 1H), 7.54 (t, J=8.0 Hz, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.67 (s, 1H), 7.65 (s, 1H), 7.51-7.47 (m, 3H), 7.36 (dd, J=4.4, 8.4 Hz, 1H), 5.73 (s, 1H), 2.15 (s, 3H), 1.56 (s, 6H); MS: (ES) m/z calculated for C22H23N4O3S [M+H]+ 433.2. found 433.0.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[O:10][C:11]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:13]=2)=[CH:4][CH:3]=1.Cl[CH2:27][C:28]1[N:29]=[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:31][C:32]=1[CH3:33].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:33][C:32]1[O:31][C:30]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[N:29][C:28]=1[CH2:27][O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[O:10][C:11]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: COC(=O)CCc1oc(Sc2ccc(O)cc2)nc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCc1oc(Sc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1-c1ccccc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 91.3 %

Procedure:
A mixture of methyl 3-[2-(4-hydroxyphenylthio)-4-phenyl-5-oxazolyl]propionate (450 mg), 4-chloromethyl-5-methyl-2-phenyloxazole (263 mg), potassium carbonate (351 mg) and N,N-dimethylformamide (5 ml) was stirred at 50° C. for 3 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenylthio]-4-phenyl-5-oxazolyl]propionate (609 mg, yield 91%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:4, volume ratio).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([O:21][CH3:22])[CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[C:15]2[CH3:20])=[O:8].Br.Br.[CH:25]1([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(N(CC)CC)C>C1C=CC=CC=1>[CH:25]1([N:31]2[CH2:36][CH2:35][N:34]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]3[CH:11]=[C:12]([O:21][CH3:22])[CH:13]=[C:14]4[C:19]=3[N:18]=[CH:17][CH:16]=[C:15]4[CH3:20])=[O:8])[CH2:33][CH2:32]2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COc1cc(NC(=O)CCCCCBr)c2nccc(C)c2c1
Reactant: C1CCC(N2CCNCC2)CC1
Agent: Br
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc(NC(=O)CCCCCN2CCN(C3CCCCC3)CC2)c2nccc(C)c2c1
Yield: 75.1 %

Procedure:
A mixture of 3.7 g (0.01 mole) of 6-bromo-N-(6-methoxy-4-methyl-8-quinolinyl)hexanamide, 3.4 g (0.0105 mole) of 1-cyclo-hexylpiperazine, dihydrobromide, and 4.2 ml (0.03 mole) of triethylamine in 100 ml of benzene was heated under reflux for 40 hr, allowed to cool, filtered and concentrated. The residue was chromatographed over 150 g of silica gel first with dichloromethane and then with 500 ml each of the following solutions of methanol in dichloromethane: 2%, 4%, 6%, 10% and 15%. The fractions containing the product [Rf(silica--75 ethyl acetate:25 methanol:1 triethylamine)=0.6] were concentrated to provide 3.4 g (75%) of clean material and 0.8 g (18%) which was slightly contaminated according to TLC. The contaminated material was combined with 0.8 g of the purer material and recrystallized first from 2-propanol and then from 2-propanol-water to afford 0.7 g (44% recovery) of analytical material, mp 109°-110°.
Reaction SMILES: [CH:1]([C:4]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:7]=[C:6]([CH3:19])[C:5]=1[C:20](O)=[O:21])([CH3:3])[CH3:2].[N:23]1([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH:1]([C:4]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:18])[F:17])[CH:10]=2)[N:7]=[C:6]([CH3:19])[C:5]=1[C:20]([N:31]1[CH2:32][CH2:33][CH:28]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:29][CH2:30]1)=[O:21])([CH3:3])[CH3:2]
Reactant: C1CCN(C2CCNCC2)C1
Reactant: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C(C)C)c1C(=O)O
Product: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C(C)C)c1C(=O)N1CCC(N2CCCC2)CC1
Yield: 64 %

Procedure:
In analogy to the procedure described in Example 18], 5-isopropyl-3-methyl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carboxylic acid and 4-pyrrolidine-1-yl-piperidine gave the title compound in 64% yield as light yellow oil. MS: 449.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C:8]2[N:9]=[C:10]([OH:19])[C:11]3[CH:17]=[CH:16][C:15](F)=[N:14][C:12]=3[N:13]=2)[CH:7]=1.[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][NH2:25]>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C:8]2[N:9]=[C:10]([OH:19])[C:11]3[CH:17]=[CH:16][C:15]([NH:25][CH2:24][CH2:23][N:22]([CH3:26])[CH3:21])=[N:14][C:12]=3[N:13]=2)[CH:7]=1
Reactant: CN(C)CCN
Reactant: Oc1nc(-c2cc(Cl)ccc2F)nc2nc(F)ccc12
Solvent: CC(C)O
Product: CN(C)CCNc1ccc2c(O)nc(-c3cc(Cl)ccc3F)nc2n1

Procedure:
To a solution of 2-(5-chloro-2-fluoro-phenyl)-7-fluoro-pyrido[2,3-d]pyrimidin-4-ol (0.16 g) in iso-propanol (20 mL) was added 2-dimethylamino-ethylamine (0.051 g). The mixture was heated to reflux for 1 h and the mixture was reduced in volume to afford a precipitate that was filtered and dried. The isolated solid, 2-(5-Chloro-2-fluoro-phenyl)-7-(2-dimethylamino-ethylamino)-pyrido[2,3-d]pyrimidin-4-ol, was used without further purification.
Reaction SMILES: C([BH3-])#N.[Na+].[CH2:5]([O:12][C:13]1[CH:22]=[C:21]2[C:16]([CH2:17][CH2:18][N:19]=[C:20]2[C:23]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[S:33][CH3:34])[CH2:26][CH2:25][CH2:24]2)=[CH:15][C:14]=1[O:35][CH3:36])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(O)(=O)C.Br>CC(O)C.CO>[CH2:5]([O:12][C:13]1[CH:22]=[C:21]2[C:16]([CH2:17][CH2:18][NH:19][CH:20]2[C:23]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[S:33][CH3:34])[CH2:24][CH2:25][CH2:26]2)=[CH:15][C:14]=1[O:35][CH3:36])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COc1cc2c(cc1OCc1ccccc1)C(C1(c3ccccc3SC)CCC1)=NCC2
Agent: Br
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(C)O
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc2c(cc1OCc1ccccc1)C(C1(c3ccccc3SC)CCC1)NCC2
Temperature: 25 °C
Reaction time: 60 h

Procedure:
Sodium cyanoborohydride (0.8 g) was added to a mixture of 7-benzyloxy-6-methoxy-1-[1-(2-methylthiophenyl)cyclobutyl]-3,4-dihydroisoquinoline (2.8 g, prepared as described in Example CA32), acetic acid (20 ml) and methanol (10 ml) at 0° C. and stirred for 60 hours at ambient temperature. The mixture was poured onto water (300 ml) and extracted with dichloromethane. The organic layer was washed with aqueous ammonia solution (100 ml), then brine (100 ml), and dried over magnesium sulphate. The solvent was removed by evaporation to yield a gum. The gum was dissolved in propan-2-ol and treated with excess 48% aqueous hydrobromic acid. Evaporation of the solvent yielded a solid which was triturated with petroleum ether (b.p. 60°-80° C.), then isolated by filtration to give 7-benzyloxy-6-methoxy-1-[1-(2-methylthiophenyl)cyclobutyl]-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[CH:14]1([S:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22](Br)[CH:21]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C(O)C>[CH:14]1([S:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=3)[CH:21]=2)[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Brc1cccc(SC2CCCC2)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: FC(F)(F)c1ccc(-c2cccc(SC3CCCC3)c2)cc1
Reaction time: 2 h
Yield: 77.5 %

Procedure:
1.0 g (5.2 mmol) of 4-trifluoromethylphenyl boronic acid, 1.4 g (5.4 mmol) of 3-bromophenyl cyclopentyl sulfide, 1.6 g (15.0 mmol) of sodium carbonate and 0.8 g (0.7 mmol) of tetrakis(triphenylphosphine) palladium were added to a solvent mixture of 50 ml of toluene, 25 ml of ethanol and 25 ml of water and refluxed under heating and stirring for 2 hours. The resulting reaction mixture was poured into ice-cold water and extracted with toluene. The toluene layer was washed with water twice and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by silica gel column chromatography afforded 1.3 g of [3-(4-trifluoromethylphenyl)phenyl] cyclopentyl sulfide (yield 78.0%) as a colorless liquid (nD20 1.5732).