Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.[Cl:9][C:10]1[C:11]([C:29]2[CH:30]=[N:31][N:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=23)=[N:12][C:13]([NH:16][C:17]2[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[C:20](F)=[CH:19][C:18]=2[O:27][CH3:28])=[N:14][CH:15]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O.CO>[Cl:9][C:10]1[C:11]([C:29]2[CH:30]=[N:31][N:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=23)=[N:12][C:13]([NH:16][C:17]2[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[C:20]([N:5]3[CH2:6][CH2:7][C@H:3]([N:2]([CH3:8])[CH3:1])[CH2:4]3)=[CH:19][C:18]=2[O:27][CH3:28])=[N:14][CH:15]=1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Reactant: CN(C)[C@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CC(=O)N(C)C
Product: COc1cc(N2CC[C@H](N(C)C)C2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Temperature: 140 °C
Yield: 98.2 %

Procedure:
(3S)—N,N-Dimethylpyrrolidin-3-amine (0.092 mL, 0.72 mmol) was added to a suspension of 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 20, 250 mg, 0.60 mmol) and DIPEA (0.125 mL, 0.72 mmol) in DMA (3 mL) and the mixture was heated at 140° C. in a microwave for 0.5 h. The mixture was then diluted with CH3OH and absorbed onto an SCX column. The column was washed with CH3OH and then eluted with 1:1 7M methanolic ammonia in CH2Cl2. Appropriate fractions were concentrated and further purification by FCC, eluting with 2% 7N methanolic ammonia in CH2Cl2 gave the title compound (300 mg, 98%) as an orange foam; 1H NMR: 1.75-1.95 (1H, m), 2.09-2.30 (7H, m), 2.72-2.87 (1H, m), 3.11-3.27 (3H, m), 3.42-3.56 (1H, m), 3.90 (3H, s), 6.57 (1H, s), 7.13 (1H, t), 7.26-7.41 (1H, m), 8.09 (1H, s), 8.28-8.50 (2H, m), 8.67 (1H, s), 8.84 (1H, d), 8.95 (1H, s); m/z: ES+ MH+ 509.5.
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:21]([O:23][CH2:24][CH3:25])=[O:22])([O:14]C2CCCCO2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CCO>[C:1]1([CH2:7][C:8]([OH:14])([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(Cc1ccccc1)(OC1CCCCO1)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C(O)(Cc1ccccc1)C(=O)OCC
Reaction time: 12 h
Yield: 94.3 %

Procedure:
25 mg of pTS acid are added to a solution of ethyl 3-phenyl-2-ethoxycarbonyl-2-(2-tetrahydropyranyloxy)-propanoate (6 g) in EtOH (25 ml). After 12 hours at r.t., the solvent is evaporated under vacuum, the mixture is partitioned between water and AcOEt; the organic phase is separated, dried, concentrated to small volume. The residue is adsorbed on SiO2 (40 g); by elution with 90:10 cyclohexane:AcOEt, 4.3 g of ethyl 3-phenyl-2-hydroxy-2-ethoxycarbonyl-propanoate, oil, are obtained. I.R.: 3500, 3000, 1740, 1600 cm-1 ; HNMR (CDCl3) δ (TMS): 1.2-1.35 t, 3.35 s, 3.15 s, 4.2-4.3 q, 7.25 s.
Reaction SMILES: ClCS(O)(=O)=O.[CH2:7]([N:10]1[C:18](=[O:19])[C:17]2[C:12](=[N:13][C:14]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27]O)=[CH:23][CH:22]=3)=[N:15][CH:16]=2)[N:11]1[C:29]1[N:34]=[C:33]([N:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]2=[O:41])[CH:32]=[CH:31][CH:30]=1)[CH:8]=[CH2:9].[C:42]([NH2:46])([CH3:45])([CH3:44])[CH3:43].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(N(CC)CC)C.O1CCCC1>[CH2:7]([N:10]1[C:18](=[O:19])[C:17]2[C:12](=[N:13][C:14]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([CH2:27][NH:46][C:42]([CH3:45])([CH3:44])[CH3:43])=[CH:25][CH:26]=3)=[N:15][CH:16]=2)[N:11]1[C:29]1[N:34]=[C:33]([N:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]2=[O:41])[CH:32]=[CH:31][CH:30]=1)[CH:8]=[CH2:9]
Reactant: CC(C)(C)N
Reactant: C=CCn1c(=O)c2cnc(Nc3ccc(CO)cc3)nc2n1-c1cccc(-n2ccccc2=O)n1
Agent: O=C([O-])O
Agent: O=S(=O)(O)CCl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: C=CCn1c(=O)c2cnc(Nc3ccc(CNC(C)(C)C)cc3)nc2n1-c1cccc(-n2ccccc2=O)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Chloromethanesulfonic acid (37 μL) was added to a tetrahydrofuran solution (10 mL) of 6′-[2-allyl-6-{[4-(hydroxymethyl)phenyl]amino}-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-2H-1,2′-bipyridin-2-one (110 mg) and triethylamine (164 μL), and stirred at room temperature for 1 hour, then tert-butylamine (500 μL) was added to the reaction liquid, and stirred for 6 hours. Chloroform and aqueous sodium hydrogencarbonate solution were added to the reaction liquid, and the organic layer was separated. The organic layer was washed with saturated saline water, then dried with anhydrous magnesium sulfate, filtered, the solvent was evaporated away, and the resulting crude product was purified through basic silica gel column chromatography (hexane-ethyl acetate/ethanol (19/1) mixture) to give the entitled compound as a white solid substance (9.2 mg).
Reaction SMILES: [CH:1]([NH:3][CH2:4][C@@H:5]([C:7]([O:9]C=O)=[O:8])[OH:6])=[O:2].N1C=CC=CC=1>CO>[CH:1]([NH:3][CH2:4][C@@H:5]([C:7]([OH:9])=[O:8])[OH:6])=[O:2]
Reactant: O=CNC[C@H](O)C(=O)OC=O
Solvent: CO
Solvent: c1ccncc1
Product: O=CNC[C@H](O)C(=O)O

Procedure:
A stock solution of N-formyl-(S)-isoserine was prepared by stirring 20 g (124.2 mmoles) of N,O-diformyl-(S)-isoserine in a mixture of methanol (85 ml) and pyridine (15 ml, 1.5 equiv.) at room temperature for 14-16 hrs. The completion of the reaction was judged by 1HNMR.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[C:4]#[N:5].COCCOC.[OH-].[Na+].Cl[CH:20]([F:22])[F:21]>O>[F:21][CH:20]([F:22])[O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[C:3]=1[C:4]#[N:5]
Reactant: FC(F)Cl
Reactant: N#Cc1c(O)cccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: N#Cc1c(F)cccc1OC(F)F
Temperature: 65 °C
Reaction time: 8 h

Procedure:
150 g (1.1 mol) of 2-fluoro-6-hydroxybenzonitrile were introduced into 2000 ml of ethylene glycol dimethyl ether. Then, 262.8 g (3.3 mol) of concentrated NaOH were added dropwise. The reaction mixture was heated to 65° C. and 95 g (1.1 mol) of chlorodifluoromethane were passed in. The mixture was stirred at 65° C. for one hour and at room temperature overnight. Then, the reaction mixture was stirred into 3 l of water, followed by extraction repeated three times with a total of 800 ml of methyl tert.-butyl ether. The combined organic phases were washed twice with 500 ml of water, once with 250 ml of sodium chloride solution and dried over sodium sulfate. Finally, the solvent was distilled off in vacuo. Yield: 211 g (99% of theory) of the desired product with a purity of 97% according to GC. 1H NMR (in CDCl3): δ=6.5-6.9 ppm (t, 1H, OCF2H), 7.15 ppm (m, 2H, arom. H), 7.65 ppm (m, 1H, arom. H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:21]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[S:13][C:12]=2[C:11]([C:22]2[O:23][C:24]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[CH:25][C:26](=[O:28])[CH:27]=2)=[CH:10][CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][C:8]1[C:21]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[S:13][C:12]=2[C:11]([C:22]2[O:23][C:24]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[CH:25][C:26](=[O:28])[CH:27]=2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cc(=O)cc(N3CCOCC3)o2)c2c1Cc1ccccc1S2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(-c2cc(=O)cc(N3CCOCC3)o2)c2c1Cc1ccccc1S2
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.4 %

Procedure:
To a solution of [4-(6-Morpholin-4-yl-4-oxo-4H-pyran-2-yl)-9H-thioxanthen-1-yl]-carbamic acid tert-butyl ester (3.25 g) in CH2Cl2 (25 ml) was added trifluoroacetic acid (5 ml). The mixture was stirred at room temperature for 18 hrs whereupon it was cooled (0° C.) and quenched by dropwise addition of saturated NaHCO3 until the pH 9 was attained. The mixture was then extracted using CH2Cl2 (3×20 mL), the combined organic extracts were then dried (MgSO4), filtered and concentrated in vacuo to give a semi-crystalline solid that was applied onto a thin silica pad and eluted with EtOAc (100%) going to EtOAc:MeOH (9:1). The eluent was concentrated in vacuo to give the title compound as a mild amber oil (1.46 g, 56.4% over three steps) m/z (LC-MS, ESP): 393 [M+H]+, R/T=3.79 mins
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[Br:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([F:26])[CH:25]=1.[Cl:27]C(Cl)(Cl)C(Cl)(Cl)Cl>O1CCCC1>[Br:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([F:26])[C:25]=1[Cl:27]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: Fc1cncc(Br)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Fc1cncc(Br)c1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of diisopropylamine (0.48 mL, 0.0034 mol) in dry tetrahydrofuran (10 mL) was added 1.6 M n-butyl lithium in hexane (2.39 mL, 0.00369 mol) drop wise under nitrogen atmosphere at −78° C. and stirred for 30 min at −78° C. To the above stirred mixture was added a solution of 3-bromo-5-fluoropyridine (0.5 g, 0.00284 mol) in dry tetrahydrofuran at −78° C. and stirred for 45 min. After 45 min, a solution of hexachloroethane in dry tetrahydrofuran was added to the above reaction mixture at −78° C. and stirred for 30 min at −78° C. The reaction mixture was slowly warmed to RT and stirred for 1 h. The reaction was quenched with saturated solution of ammonium chloride (10 mL) and extracted with diethyl ether (25 mL x 3). The combined organic layer was washed with water, saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate and evaporated. The obtained crude was purified with silica gel chromatography by hexane to afford the title compound. 1H NMR (400 MHz, CDCl3) δ: 8.58 (s, 1H), 8.43 (s, 1H). MS (M+1): 209.9.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:21][C:10]3=[CH:11][C:12]4[C:13]([CH3:20])([CH3:19])[C:14](=[O:18])[NH:15][C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:20][C:13]1([CH3:19])[C:12]2[CH:11]=[C:10]3[NH:21][C:7]([C:3]4[C:2]([NH:1][S:28]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)(=[O:30])=[O:29])=[CH:6][NH:5][N:4]=4)=[N:8][C:9]3=[CH:17][C:16]=2[NH:15][C:14]1=[O:18]
Reactant: CC1(C)C(=O)Nc2cc3nc(-c4n[nH]cc4N)[nH]c3cc21
Reactant: O=S(=O)(Cl)c1ccccc1
Product: CC1(C)C(=O)Nc2cc3nc(-c4n[nH]cc4NS(=O)(=O)c4ccccc4)[nH]c3cc21

Procedure:
N-[3-(7,7-Dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-benzenesulfonamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (150 mg, 0.53 mmol) and phenylsulfonylchloride. The title compound was obtained as white powder (66 mg).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]([OH:10])[C:7]([OH:9])=[O:8])=[CH:4][C:3]=1[O:13][CH3:14].C(N(CC)CC)C.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CC(C)=O.C(OCC)(=O)C>CC(C)=O>[OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]([OH:10])[C:7]([O:9][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:8])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: BrCc1ccccc1
Reactant: COc1cc(C(O)C(=O)O)ccc1O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COc1cc(C(O)C(=O)OCc2ccccc2)ccc1O
Reaction time: 5 h
Yield: 277.5 %

Procedure:
To a mixture of 4.371 g (0.022 mole) of 4-hydroxy-3-methoxymandelic acid, 11 ml of triethylamine in 100 ml of acetone was added 3.13 ml (0.0265 mole) of benzyl bromide. The reaction mixture was stirred (magnetic stirring) and heated at reflux (oil bath) under a nitrogen atmosphere. After 5 minutes of heating the reaction mixture became cloudy. Thin layer chromatography (TLC) (silica gel, acetone/ethyl acetate 95:5) showed 50% of the starting material remaining after 5 hours. Additional triethylamine (2 ml) and benzyl bromide (1.5 ml) were added, and the mixture was heated at reflux for 4 hours. TLC still showed starting material present. Additional reagents were added (1.5 ml benzyl bromide and 2 ml triethylamine) and heating was continued for 14 hours. The triethylamine hydrobromide was removed by filtration, and the filter cake was washed with acetone (3×10 ml). The filtrate and washings were evaporated to give 17.6 g of a semi-solid residue. The residue was triturated with water (30 ml), and the product extracted with methylene chloride (4×15 ml) and dried (sodium sulfate). Evaporation of the solvent yielded 4.99 g of a light-brown oil which was triturated with hexanes (20 ml) to crystallize the product. The cream-colored solid was separated and washed with hexanes (3×10 ml) to give 3.351 g (53% yield) of the product. Estimated purity by TLC was 98% (hexanes/acetone 5:1).
Reaction SMILES: [CH:1](/[C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=[O:12])[CH2:7][CH2:6]1)=[CH:2]\[CH2:3][CH3:4].C1(N=C=NC2CCCCC2)CCCCC1.[CH:29](/[C@H:33]1[CH2:38][CH2:37][C@H:36](O)[CH2:35][CH2:34]1)=[CH:30]\[CH2:31][CH3:32].C(Cl)Cl>CN(C)C1C=CN=CC=1.CCCCCC>[CH:29](/[C@H:33]1[CH2:38][CH2:37][C@H:36]([O:12][C:11]([C@H:8]2[CH2:9][CH2:10][C@H:5](/[CH:1]=[CH:2]/[CH2:3][CH3:4])[CH2:6][CH2:7]2)=[O:13])[CH2:35][CH2:34]1)=[CH:30]\[CH2:31][CH3:32]
Reactant: CC/C=C/[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CC/C=C/[C@H]1CC[C@H](O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CC/C=C/[C@H]1CC[C@H](OC(=O)[C@H]2CC[C@H](/C=C/CC)CC2)CC1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A mixture of 200 mg of trans-4-(1E-butenyl)cyclohexanecarboxylic acid, 272.4 mg of dicyclohexylcarbodimide, 13.4 mg of 4-(dimethylamino)pyridine, 169.7 mg of trans-4-(1E-butenyl)cyclohexanol and 4 ml of methylene chloride was stirred at room temperature for 21 hours while gassing with argon. Subsequently, the heterogeneous reaction mixture was diluted with 10 ml of hexane and filtered (rinsing with hexane). The concentrated filtrate was taken up in 30 ml of hexane and the solution was washed in each case once with 30 ml of 5 percent hydrochloric acid, 30 ml of saturated sodium hydrogen carbonate solution and 30 ml of saturated sodium chloride solution, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.5 bar) of the colourless oil (450 mg) on silica gel with ethyl acetate/petroleum ether (vol. 1:99) gave 280 mg (80.1%) of trans-4-(1E-butenyl)cyclohexanecarboxylic acid trans-4-(1E-butenyl)cyclohexyl ester as colourless crystals. Recrystallization from 15 ml of methanol at - 20° C. gave 223 mg of ester as colourless needles with melting point (C-N) 46.3° C. and cl.p. (N-I) 58.7° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]23[CH2:17][CH2:16][CH2:15][CH:14]2[C:13](=O)[N:12]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:11](=O)[CH2:10]3)[CH:6]=[CH:7][CH:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]23[CH2:17][CH2:16][CH2:15][CH:14]2[CH2:13][N:12]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:11][CH2:10]3)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C23CCCC2C(=O)N(Cc2ccccc2)C(=O)C3)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COc1cccc(C23CCCC2CN(Cc2ccccc2)CC3)c1

Procedure:
Following the procedure set forth in Example 19, 4a-(3-methoxyphenyl)-2-benzyl-2,3,4,4a,5,6,7,7a-octahydro-1,3-dioxo-1H-2-pyrindine was reduced by reaction with lithium aluminum hydride to provide 4a-(3-methoxyphenyl)-2-benzyl-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[C:14]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=1)[NH:13][C:12]2=[O:30])C1C=CC=CC=1>FC(F)(F)C(O)=O>[OH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[C:14]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=1)[NH:13][C:12]2=[O:30]
Reactant: COc1cc2nc(-c3cccc([N+](=O)[O-])c3)[nH]c(=O)c2cc1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2nc(-c3cccc([N+](=O)[O-])c3)[nH]c(=O)c2cc1O
Temperature: 75 °C
Yield: 95.6 %

Procedure:
To a suspension of 6-(benzyloxy)-7-methoxy-2-(3-nitrophenyl)quinazolin-4(3H)-one (3.21 g, 7.95 mmol) in trifluoroacetic acid (45 mL) was heated at 75±5° C. for 2.5 h. The volatiles were removed in vacuo and residue was taken up with sat. NaHCO3 solution. A light yellow colored solid separated out, which was collected via filtration. The solid was washed with water and dried under vacuum to give 6-hydroxy-7-methoxy-2-(3-nitrophenyl)quinazolin-4(3H)-one (2.38 g, 7.60 mmol, 96%). HPLC retention time 5.486 min.
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:22])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=3[S:13][C:12]=2[CH:21]=1)C>C(O)C>[Cl:20][C:19]1[C:14]2[S:13][C:12]3[CH:21]=[C:8]([CH2:7][C:6]([OH:22])=[O:5])[CH:9]=[CH:10][C:11]=3[C:15]=2[CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)Cc1ccc2c(c1)sc1c(Cl)cccc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1ccc2c(c1)sc1c(Cl)cccc12

Procedure:
To a 100 ml. flask, fitted with a condenser and containing a solution of 0.24 g. of potassium hydroxide in 30 ml. of ethanol was added 1.3 g. of 6-chlorodibenzothiophene-3-acetic acid ethyl ester. After the solution was refluxed for 1 hour, the solvent was removed in vacuo (steam bath, rotary evaporator), the residue dissolved in 100 ml. of water, and the aqueous solution acidified with dilute hydrochloric acid. The 6-chlorodibenzothiophene-3-acetic acid was removed by filtration, washed with water and dried at 60° in a vacuum oven overnight. The yield of 6-chlorodibenzothiophene-3-acetic acid, after crystallization from acetonitrile was 0.8 g., mp 226°-228°.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].Br[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[CH:24][CH:23]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:22]4[CH:23]=[CH:24][C:25]([N:28]5[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]5)=[CH:26][CH:27]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1cccc(-c2cccn3nc(N)nc23)c1
Reactant: CN1CCN(c2ccc(Br)cc2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2ccc(Nc3nc4c(-c5cccc(S(C)(=O)=O)c5)cccn4n3)cc2)CC1

Procedure:
[8-(3-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 8-(3-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.260 mmol) and 1-(4-bromo-phenyl)-4-methyl-piperazine (80.0 mg, 0.314 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (30.0 mg, 0.0549 mmol) as the ligand in a manner analogous to Step 2d and was isolated as a yellow foam (0.068 g, 56%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.66 (s, 1H), 8.45 (d, J=6.5 Hz, 1H), 8.38 (d, J=7.7 Hz, 1H), 7.99 (d, J=7.7 Hz, 1H), 7.73 (d, J=6.9 Hz, 1H), 7.66 (d, J=7.4 Hz, 1H), 7.50 (d, J=7.7 Hz, 1H), 7.00-6395 (m, 3H), 6.70 (s, 1H), 3.19-0.314 (m, 4H), 3.12 (s, 3H), 2.62-2.57 (m, 4H), 2.36 (s, 3H). MS=463 (MH)+.
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:15][CH2:14][C:13]([CH:16]=O)=[C:12]([Cl:18])[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[NH2:20][OH:21]>C(O)C>[CH2:2]([N:9]1[CH2:15][CH2:14][C:13]([CH:16]=[N:20][OH:21])=[C:12]([Cl:18])[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=CC1=C(Cl)CCN(Cc2ccccc2)CC1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: ON=CC1=C(Cl)CCN(Cc2ccccc2)CC1

Procedure:
Prepared by reacting 1-benzyl-4-chloro-5-formyl-2,3,6,7-tetrahydro-1H-azepine hydrochloride with hydroxylamine hydrochloride in ethanol at 30° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:10]=[CH:9][S:8][CH:7]=1.C(O)(=O)C.C1C(=O)N([Br:22])C(=O)C1>C(Cl)(Cl)Cl>[Br:22][C:7]1[S:8][CH:9]=[CH:10][C:6]=1[CH2:5][CH2:4][CH2:3][CH2:2][Br:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: BrCCCCc1ccsc1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: BrCCCCc1ccsc1Br
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 68 %

Procedure:
3-(4-bromobutyl)thiophene (8 g, 36.5 mmol) was dissolved in 250 ml CHCl3, and glacial acetic acid (250 ml) was added in the dark. NBS (6.5 g, 36.5 mmol) was added, and the mixture was stirred for 20 minutes at room temperature in the dark. The reaction mixture was washed with water, saturated NaHCO3, dried over magnesium sulfate and the solvent was removed under vacuum. Purification by column chromatography afforded the title compound (7.4 g, 68% yield) as a light yellow oil. 1H-NMR (ppm, CDCl3): 1.71-1.77 (2H, m), 1.85-1.89 (2H, m), 2.6 (2H, t, J=7.44 Hz), 3.43 (2H, t, J=7.32 Hz), 6.78 (1H, d, J=5.6 Hz), 7.19 (1H, d, J=5.6 Hz); 13C-NMR (ppm, CDCl3): 27.5, 29.4, 32.9, 33.9, 109.2, 125.5, 128.4, 141.8; GC-MS (m/z): 295.89.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]2[O:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)=[CH:8][CH:7]=1.[H-].[Na+].[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>O1CCCC1>[N:27]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C@@H:12]3[O:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)=[CH:8][CH:7]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(OCCCBr)cc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(OCCCN3CCCC3)cc2)C1
Temperature: 80 °C
Reaction time: 5 h
Yield: 57.9 %

Procedure:
tert-Butyl (2S)-2-(4-(3-bromopropyloxy)phenyl)morpholine-4-carboxylate (2.0 g, 5.0 mmol) was added to a solution of sodium hydride (60% in oil, 0.22 g, 5.50 mmol) and pyrrolidine (0.43 g, 6.05 mmol) in tetrahydrofuran (40 ml) at room temperature and the mixture was stirred at 80° C. for 5 hours. The mixture was partitioned between water and chloroform. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting 5-10% methanol in chloroform to furnish tert-butyl (2S)-2-(4-(3-(pyrrolidin-1-yl)propyloxy)phenyl)morpholine-4-carboxylate (1.13 g, 58%) as a colorless oil.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]([CH3:40])[CH3:39])=[CH:34][CH:33]=1)[C:22]1[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=1)=[O:20])C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[C].[Pd]>[CH3:39][N:38]([CH3:40])[C:35]1[CH:36]=[CH:37][C:32]([CH2:31][N:21]([C:22]2[CH:27]=[CH:26][C:25]([CH:28]([CH3:29])[CH3:30])=[CH:24][CH:23]=2)[C:19]([CH:14]2[C:15]3[C:10](=[C:9]([OH:8])[CH:18]=[CH:17][CH:16]=3)[CH2:11][CH2:12][CH2:13]2)=[O:20])=[CH:33][CH:34]=1
Reactant: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3c(O)cccc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.2 %

Procedure:
5-Benzyloxy-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.75 g) was dissolved in methanol (60 mL), and 10% palladium carbon (0.5 g) and ammonium formate (1.5 g) were added. The mixture was stirred at room temperature for one day. The reaction mixture was filtrated, and the filtrate was concentrated. Water was added to the residue, and the precipitated crude crystals were recrystallized from ethyl acetate to give N-[(4-dimethylaminophenyl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.5 g). melting point: 200-202° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5](Cl)[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1)=O)[CH3:2].[C:17]([NH2:20])(=[S:19])[CH3:18]>>[CH2:1]([O:3][C:4]([C:5]1[S:19][C:17]([CH3:18])=[N:20][C:6]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1)=[O:16])[CH3:2]
Reactant: CCOC(=O)C(Cl)C(=O)c1cccc(F)c1
Reactant: CC(N)=S
Product: CCOC(=O)c1sc(C)nc1-c1cccc(F)c1

Procedure:
prepared by reaction of 2-chloro-3-(3-fluoro-phenyl)-3-oxo-propionic acid ethyl ester with thioacetamide. LC-MS: tR=0.95 min; [M+H]+=266.1.