Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH2:13][CH2:12][NH:11][CH2:10][C:9]=3[C:5]=2[C:4]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)=[CH:3][CH:2]=1.[Cl:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34](Cl)=[O:35].C(N(CC)CC)C>ClCCCl>[Cl:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34]([N:11]1[CH2:12][CH2:13][C:8]2[NH:7][C:6]3[N:1]=[CH:2][CH:3]=[C:4]([NH:14][C:15]4[CH:16]=[CH:17][C:18]([NH:21][C:22](=[O:29])[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=5)=[CH:19][CH:20]=4)[C:5]=3[C:9]=2[CH2:10]1)=[O:35]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: O=C(Nc1ccc(Nc2ccnc3[nH]c4c(c23)CNCC4)cc1)c1ccccc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Nc2ccnc3[nH]c4c(c23)CN(C(=O)c2cccc(Cl)c2)CC4)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.8 %

Procedure:
N-[4-(6,7,8,9-Tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrol-4-ylamino)-phenyl]-benzamide (40 mg, 0.1 mmol), 3-chlorobenzoyl chloride (22 mg, 0.13 mmol), and triethylamine (0.04 mL, 0.31 mmol) were dissolved in 1,2-dichloroethane (2.0 mL), and stirred overnight at room temperature. The reaction mixture was added directly to a Biotage column. The crude product was purified via Biotage eluting with CH2Cl2/MeOH (9/1, v/v) to provide 12 (26 mg, 48% yield) as a brown solid. LC-MS (M+H=522, obsd.=522).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:11]1([S:17](Cl)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:19])=[O:18]
Reactant: Brc1cccc2[nH]ccc12
Reactant: O=S(=O)(Cl)c1ccccc1
Product: O=S(=O)(c1ccccc1)n1ccc2c(Br)cccc21

Procedure:
4-Bromo-1-(benzenesulfonyl)-1H-indole was prepared from 4-bromoindole and phenylsulfonyl chloride according to Method 4 to afford 3.1 g (91%) of a light purple solid: 1HNMR (CDCl3) δ 7.94 (d, J=8 Hz, 1H), 7.89-7.84 (m, 2H), 7.62 (d, 4 Hz, 1H), 7.57-7.51 (m, 1H), 7.46-7.37 (m, 3H), 7.19-7.13 (m, 1H), 6.72 (dd, J=1, 4 Hz, 1H); MS (ESI) 419.9+421.9 (M+H)+; Purity (HPLC) >95%.
Reaction SMILES: O[CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]2[O:17][CH2:18][O:19][C:13]=2[CH:12]=1.C(N(CC)CC)C.CS([Cl:31])(=O)=O.C(=O)([O-])O.[Na+]>ClCCl>[Cl:31][C@@H:6]1[CH2:7][CH2:8][CH2:2][CH2:3][N:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]3[O:17][CH2:18][O:19][C:13]=3[CH:12]=2)[CH2:5]1
Reactant: CS(=O)(=O)Cl
Reactant: OC[C@H]1CCCCN1CCc1ccc2c(c1)OCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cl[C@@H]1CCCCN(CCc2ccc3c(c2)OCO3)C1
Reaction time: 14 h

Procedure:
(R)-2-Hydroxymethyl-1-(3,4-methylenedioxyphenethyl)piperidine (370 mg) was dissolved in 10 ml of dichloromethane. Triethylamine (184 mg, 1.82 mmol) and methanesulfonyl chloride (208 mg, 1.82 mmol) were added to the obtained solution under stirring under cooling on ice. They were stirred under cooling on ice for 1 hour and then at room temperature for 14 hours. The reaction liquid was distributed in dichloromethane and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain (R)-3-chloro-1-(3,4-methylenedioxyphenethyl) homopiperidine in the form of a light yellow oil (375 mg, 95%).
Reaction SMILES: [CH:1]1([C:4]([N:6]2[C:15]3[C:10](=[C:11]([OH:21])[C:12]([N:16]4[N:20]=[CH:19][CH:18]=[N:17]4)=[CH:13][CH:14]=3)[CH2:9][CH2:8][C@@H:7]2[CH3:22])=[O:5])[CH2:3][CH2:2]1.Br[CH:24]1[CH2:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH:24]1([O:21][C:11]2[C:12]([N:16]3[N:17]=[CH:18][CH:19]=[N:20]3)=[CH:13][CH:14]=[C:15]3[C:10]=2[CH2:9][CH2:8][C@H:7]([CH3:22])[N:6]3[C:4]([CH:1]2[CH2:2][CH2:3]2)=[O:5])[CH2:27][CH2:26][CH2:25]1
Reactant: BrC1CCC1
Reactant: C[C@H]1CCc2c(ccc(-n3nccn3)c2O)N1C(=O)C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: C[C@H]1CCc2c(ccc(-n3nccn3)c2OC2CCC2)N1C(=O)C1CC1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A mixture of (S)-cyclopropyl(5-hydroxy-2-methyl-6-(2H-1,2,3-triazol-2-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone (0.055 g, 0.18 mmol), bromocyclobutane (0.050 g, 0.37 mmol), and cesium carbonate (0.150 g, 0.46 mmol) in acetonitrile (5 mL) stirred for 18 h at 80° C. The reaction mixture was cooled to room temperature and filtered, and the filtrate was concentrated under vacuum. The residue was purified by preparative-HPLC with the following conditions (Waters 1): Column, XBridge Prep C18 OBD Column, 5 um, 19×150 mm; mobile phase, water (0.03% aqueous ammonia) and acetonitrile (16% to 34% acetonitrile in 10 min, flow rate: 20 mL/min); Detector: UV 220&254 nm. This afforded (S)-(5-cyclobutoxy-2-methyl-6-(2H-1,2,3-triazol-2-yl)-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone (0.030 g, 45%) as a white solid. 1H NMR (300 MHz, CD3OD) δ ppm 0.67-0.75 (m, 1H), 0.85-0.95 (m, 2H), 1.11-1.17 (m, 4H), 1.22-1.55 (m, 3H), 1.74-2.01 (m, 5H), 2.31-2.46 (m, 2H), 2.95-3.07 (m, 1H), 3.88-3.94 (m, 1H), 4.72-4.82 (m, 1H), 7.28 (d, J=8.40 Hz, 1H), 7.37 (d, J=8.40 Hz, 1H), 7.99 (s, 2H). MS (ESI, pos. ion) m/z 353 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:7][N:6]=[C:5]([OH:8])[CH:4]=1.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.C(N(CC)CC)C>ClCCl>[OH:1][CH2:2][C:3]1[NH:7][N:6]=[C:5]([O:8][S:15]([C:12]2[CH:13]=[CH:14][C:9]([CH3:19])=[CH:10][CH:11]=2)(=[O:17])=[O:16])[CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCc1cc(O)n[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Oc2cc(CO)[nH]n2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.2 %

Procedure:
To a stirred suspension of 5-hydroxymethyl-1H-pyrazol-3-ol (J. Heterocycl. Chem., 1979, 16, 505-508) (1.0245 g, 8.98 mmol) in anhydrous dichloromethane (50 ml), under nitrogen, was added p-toluenesulfonyl chloride (1.8825 g, 9.87 mmol), then dropwise over 5 min, anhydrous triethylamine (1.50 ml, 10.8 mmol). The mixture was stirred at room temperature for 16.5 h under nitrogen, then washed with brine (50 ml). The aqueous layer was further extracted with dichloromethane, and the combined organic extracts were dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 5-7% MeOH/CH2Cl2) to afford 1.3067 g (54%) of the title compound as a pale green solid; 1H NMR (360 MHz, d6-DMSO) δ2.42 (3H, s), 4.38 (2H, d, J=5.7 Hz), 5.32 (1H, t, J=5.7 Hz), 5.82 (1H, d, J=2.2 Hz), 7.47 (2H, d, J=8.3 Hz, 7.77 (2H, d, J=8.3 Hz), 12.55 (1H, s).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]([CH3:19])[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].[C:20]([N:22]=[C:23](SC)[S:24][CH3:25])#[N:21]>CO>[C:20]([N:22]=[C:23]([S:24][CH3:25])[NH:9][CH:10]([CH3:19])[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12])#[N:21]
Reactant: CC(N)C(=O)c1ccccc1
Reactant: CSC(=NC#N)SC
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CSC(=NC#N)NC(C)C(=O)c1ccccc1
Yield: 80.2 %

Procedure:
Triethylamine (1 ml) was added to a solution of 2-aminopropiophenone hydrochloride (0.93 g) and dimethyl cyanodithioimidocarbonate (0.73 g) in methanol (3 ml), and the mixture was refluxed for 15 minutes and evaporated under reduced pressure. The residue was dissolved in chloroform and the solution was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue was dissolved in a small amount of ethyl acetate and diluted with diisopropyl ether. The resultant precipitates were collected by filtration, washed with diisopropyl ether and dried to give 2-(3-cyano-2-methyl-1-isothioureido)propiophenone (0.99 g).
Reaction SMILES: Br[N:2]1[C:11]2[NH:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH2:3]1.[CH3:12][N:13](C=O)C>C1(C)C=CC=CC=1.[C-]#N.[Zn+2].[C-]#N.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>[C:12]([N:2]1[C:11]2[NH:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH2:3]1)#[N:13]
Reactant: BrN1CC=CC2=C1NCCC2
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: N#CN1CC=CC2=C1NCCC2
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 0.8914 g (4.18 mmol) 33 in 20 mL DMF was added 0.2949 g (2.51 mmol) zinc cyanide and 0.4825 g (0.42 mmol) tetrakis(triphenylphosphine)palladium(0). After 17 h at 100° C., the reaction mixture was cooled to room temperature, diluted with 120 mL toluene and washed 60 mL 2N NH40H. The aqueous layer was extracted with 60 mL toluene. The combined organic layers were washed with 60 mL brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (50×80 mm silica gel, 5% (10% NH4OH:MeOH):CH2Cl2) yielded 0.7609 g of 34 and triphenylphosphine oxide. This material was partitioned between 50 mL ethyl ether and 50 mL 1M HCl. The aqueous layer was brought to pH 12 with 50% aqueous NaOH and extracted with 3×100 mL CH2Cl2. The combined CH2Cl2 layers were washed with 100 mL brine, dried over Na2SO4, filtered and concentrated in vacuo to give 34. 1H NMR (CDCl3, 400 MHz) δ 8.276 (s, 1H, ArH); 8.037 (s, 1H, ArH); 3.487-3.452 (m, 2H, CH2); 2.729 (t, 2H, J=6.22 Hz, CH2); 2.001-1.942 (m, 2H, CH2); MS (Electrospray): n/z 159.9 (M+H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]1[CH2:24][C:23]2[CH:22]=[C:21]([OH:25])[CH:20]=[CH:19][C:18]=2[C@@H:17]2[C@@H:8]1[C@H:9]1[C@@:13]([CH2:15][C@@H:16]2[F:26])([CH3:14])[C@@H:12]([OH:27])[CH2:11][CH2:10]1.[I-:28].[Na+].O>C(C(C)=O)C>[F:26][C@H:16]1[CH2:15][C@@:13]2([CH3:14])[C@@H:9]([CH2:10][CH2:11][C@@H:12]2[OH:27])[C@H:8]2[C@H:17]1[C:18]1[CH:19]=[CH:20][C:21]([OH:25])=[CH:22][C:23]=1[CH2:24][C@H:7]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][I:28]
Reactant: [I-]
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCl)[C@H]3[C@@H]1CC[C@@H]2O
Agent: [Na+]
Solvent: O
Solvent: CCC(C)=O
Product: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCI)[C@H]3[C@@H]1CC[C@@H]2O
Temperature: 90 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
4.29 g of 7α-(5-chloropentyl)-11β-fluor-estra-1,3,5(10)-triene-3,17β-diol is dissolved in 60 ml of ethylmethylketone, mixed with 4.91 g of sodium iodide and stirred overnight at 90° C. For working-up, the reaction mixture is cooled to room temperature, stirred into water, extracted 3 times with ethyl acetate, washed with thiosulfate solution, dried on magnesium sulfate and concentrated by evaporation in a vacuum. 5.16 g of 11β-fluor-7α-(5-iodopentyl)-estra-1,3,5(10)-triene-3,17β-diol is obtained as a crude product, which is used without further purification in the next stage.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[O:21][C:8]2([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH2:7][NH:6][CH2:5]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][C:30](=[O:32])[CH3:31]>C(#N)C.ClCCl>[CH3:1][O:2][CH2:3][CH:4]1[CH2:5][N:6]([CH2:29][C:30](=[O:32])[CH3:31])[CH2:7][C:8]2([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:10][CH2:9]2)[O:21]1
Reactant: COCC1CNCC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Reactant: CC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: COCC1CN(CC(C)=O)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1

Procedure:
To a mixture of tert-butyl 10-(methoxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate and K2CO3 (115 mg, 0.832 mmol) in acetonitrile (1.4 mL) was added 1-bromopropan-2-one (304 mg, 2.00 mmol). The reaction mixture was heated under argon in a sealed tube for 16 h. The mixture was cooled, diluted with dichloromethane and washed with water. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to provide tert-butyl 2-(methoxymethyl)-4-(2-oxopropyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate. ESI-MS m/z calc. 356.2. found 357.3 (M+1)+; Retention time: 0.98 minutes (3 min run).
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:2]12.[Cl:11][C:12]1[CH:17]=[N:16][CH:15]=[C:14](Cl)[N:13]=1.C(N(CC)CC)C>C(#N)C>[Cl:11][C:12]1[N:13]=[C:14]([N:6]2[CH2:5][CH2:4][N:3]3[CH2:7][CH2:8][CH2:9][CH2:10][CH:2]3[CH2:1]2)[CH:15]=[N:16][CH:17]=1
Reactant: Clc1cncc(Cl)n1
Reactant: C1CCN2CCNCC2C1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Clc1cncc(N2CCN3CCCCC3C2)n1

Procedure:
A solution of octahydro-2H-pyrido[1,2-a]pyrazine (4 gm, 0.029 moles), 2,6-dichloropyrazine (4.28 gm, 0.029 moles) and triethylamine (8 ml. 0.06 moles) in 75 ml of acetonitrile is heated under reflux for 4 hours. After cooling, the precipitate is filtered off and washed with a little acetonitrile. The filtrate is concentrated under reduced pressure and the resulting residue is partitioned between water and ether. The aqueous layer is made basic with potassium carbonate and extracted 3 times with 100 ml. portions of ether. The combined ether layer is washed with saline and dried over sodium sulfate. After filtering off the drying agent the clear filtrate is made acidic with dry hydrogen chloride gas. The precipitate is filtered off, washed with ether and dried. After two crystallizations from ethanol there is obtained a 4.5 gm (54 percent) yield of title compound, m.p. 298°-301° C.
Reaction SMILES: FC(F)(F)C1C=CC([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17]CC)=[O:16])[CH2:11][CH2:10]2)=NC=1.[OH-].[K+]>CO.O>[NH:9]1[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=[O:16])[CH2:11][CH2:10]1
Reactant: CCOC(=O)C1CCN(c2ccc(C(F)(F)F)cn2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1CCNCC1

Procedure:
The crude ethyl 1-[5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxylate was dissolved in 15 ml of methanol and 2.5 ml of water. 535 mg (9.54 mmol) of potassium hydroxide were added and the mixture was reacted at 40° C. for 30 min. The mixture was evaporated, the residue was dissolved in water, pH 3 was adjusted with 2N hydrochloric acid and the solid formed was filtered off and dried in vacuo to yield 471 mg (54% yield) of 1-[5-trifluoromethyl)pyridin-2-yl]piperidine-4-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH3:15][O:16][C:17]1[CH:34]=[CH:33][C:32]2[C@H:31]3[N:22]([CH2:23][C@@H:24]4[C@H:29]([CH2:30]3)[N:28]([S:35]([CH2:38][CH2:39][CH2:40]Cl)(=[O:37])=[O:36])[CH2:27][CH2:26][CH2:25]4)[CH2:21][CH2:20][C:19]=2[CH:18]=1.C(N(CC)CC)C.Cl>CN(C=O)C>[CH3:15][O:16][C:17]1[CH:34]=[CH:33][C:32]2[C@H:31]3[N:22]([CH2:23][C@@H:24]4[C@H:29]([CH2:30]3)[N:28]([S:35]([CH2:38][CH2:39][CH2:40][N:12]3[CH2:13][CH2:14][N:9]([C:4]5[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=5[O:2][CH3:1])[CH2:10][CH2:11]3)(=[O:37])=[O:36])[CH2:27][CH2:26][CH2:25]4)[CH2:21][CH2:20][C:19]=2[CH:18]=1
Reactant: COc1ccc2c(c1)CCN1C[C@H]3CCCN(S(=O)(=O)CCCCl)[C@H]3C[C@@H]21
Reactant: COc1ccccc1N1CCNCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CCN1C[C@H]3CCCN(S(=O)(=O)CCCN4CCN(c5ccccc5OC)CC4)[C@H]3C[C@@H]21
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A mixture of 1.8 g of 4-(2-methoxyphenyl)piperazine, 1.8 g of (8aR,12aS,13aS)-3-methoxy-12-(3-chloropropane-sulfonyl)-5,6,8a,9,10,11,12,12a,13,13a-decahydro-8H-isoquino[2,1-g][1,6]naphthyridine and 1 ml of triethylamine in 10 ml of DMF was stirred at 90° C. for 16 hours. The temperature was then raised to 120° C. for 8 hours and stirring continued. After cooling, the solution was acidified with 2N hydrochloric acid and then washed with ethyl acetate, the aqueous portion basified with aqueous ammonium hydroxide and extracted further with diethylether. The solvent was then dried over sodium sulfate and evaporated under reduced pressure. The residue was flash chromatographed on silica gel, eluting with ethyl acetate, to give (8aR,12aS,13aS)-3-methoxy-12-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propanesulfonyl}-5,6,8a,9,10,11,12,12a,13,13a-decahydro-8H-isoquino[2,1-g][1,6]naphthyridine, a compound of formula (I).
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:37])[CH:15]([N:20]3[C:25](=[O:26])[CH:24]=[C:23]([O:27]N4C5C=CC=CC=5N=N4)[CH:22]=[N:21]3)[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:45]1(O)[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=[CH:47][CH:46]=1>C(#N)C>[CH3:1][C:2]1([CH3:38])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:37])[CH:15]([N:20]3[C:25](=[O:26])[CH:24]=[C:23]([O:27][C:53]4[C:54]5[C:49](=[CH:48][CH:47]=[CH:46][CH:45]=5)[CH:50]=[CH:51][CH:52]=4)[CH:22]=[N:21]3)[CH2:16][CH:17]([CH3:18])[CH3:19])=[N:9]2)[CH2:4][O:3]1
Reactant: Oc1cccc2ccccc12
Reactant: CC(C)CC(C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)n1ncc(On2nnc3ccccc32)cc1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)CC(C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)n1ncc(Oc2cccc3ccccc23)cc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.9 %

Procedure:
A solution of 2-[4-(benzotriazol-1-yloxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide (0.30 g, 0.57 mmol) in acetonitrile (12 mL, 0.048M) was treated with cesium carbonate (0.37 g, 1.14 mmol) and naphthalen-1-ol (0.10 g, 0.69 mmol). The resulting reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was then concentrated in vacuo and partitioned between water (100 mL) and ethyl acetate (100 mL). The organics were washed with a saturated aqueous sodium chloride solution (50 mL), dried over magnesium sulfate, filtered, rinsed, and concentrated in vacuo. Silica gel column chromatography (AnaLogix 40 g, 25-75% ethyl acetate/hexanes) afforded 4-methyl-2-[4-(naphthalen-1-yloxy)-6-oxo-6H-pyridazin-1-yl]-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide (208.7 mg, 68%) as a light orange solid as a mixture of diastereomers.
Reaction SMILES: [CH2:1]([OH:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[CH:22].CC(C)=[O:26].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[C:1]([OH:26])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[CH:22]
Reactant: CC(C)=O
Reactant: C#CCCCCCCCCCCCCCCCCCCCCO
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: C#CCCCCCCCCCCCCCCCCCCCC(=O)O
Reaction time: 0.5 h
Yield: 83 %

Procedure:
Docos-21-ynol (12 g, 0.037 mol) was dissolved in warm acetone (600 ml) treated with Jones reagent (20 ml). After stirring for 30 minutes tlc showed complete reaction so the excess Jones reagent was quenched with propane-2-ol and the volatile components removed in vacuo. The organic fractions were combined, dried (MgSO4), filtered and evaporated to leave docos-21-ynoic acid (32) as a pale green solid (10.4 g, 83%).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[NH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][C:19]([C:23]([NH2:25])=[O:24])=[CH:18][CH:17]=3)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[CH2:28]([CH:30]1[O:32][CH2:31]1)Br>CC(C)=O>[CH:19]1([CH2:23][NH:25][CH2:28][CH:30]([OH:32])[CH2:31][NH:25][C:23]([C:19]2[CH:20]=[C:21]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14]([N:11]2[CH2:10][CH2:9][CH:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:13][CH2:12]2)=[CH:22]3)=[O:24])[CH2:20][CH2:21][CH2:16][CH2:17][CH2:18]1
Reactant: NC(=O)c1ccc2[nH]c(N3CCC(Cc4ccccc4)CC3)cc2c1
Reactant: BrCC1CO1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(NCC(O)CNCC1CCCCC1)c1ccc2[nH]c(N3CCC(Cc4ccccc4)CC3)cc2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The title compound was prepared according to scheme 7. To an ice-cold solution of 1.0 g (3.0 mmol) of 4-benzylpiperidinyl indole-5-carboxamide in acetone was added 15 mmol of powdered KOH followed by 3.0 mmol of epibromohydrin and the mixture was stirred for 30 min. The mixture was filtered and the solution was evaporated. The residue was dissolved in ethyl acetate, washed with water, dried and evaporated. After purification by silica gel column chromatography 435 mg of epoxide was obtained. MS (M+ 373).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@H:11]([CH2:42][C:43]([CH3:48])([CH3:47])[C:44](O)=[O:45])[CH2:10]2)=[CH:5][CH:4]=1.[CH3:49][N:50]1[CH2:55][CH2:54][CH:53]([NH2:56])[CH2:52][CH2:51]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:33])=[O:34])[C@H:11]([CH2:42][C:43]([CH3:47])([CH3:48])[C:44]([NH:56][CH:53]3[CH2:54][CH2:55][N:50]([CH3:49])[CH2:51][CH2:52]3)=[O:45])[CH2:10]2)=[CH:7][CH:8]=1
Reactant: CN1CCC(N)CC1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CC(C)(C)C(=O)O)C[C@@H]3c3ccc(OC)cc3)cc21
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CC(C)(C)C(=O)NC4CCN(C)CC4)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
According to general procedure D, 196 mg of 3-[(2S,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-2,2-dimethyl-propionic acid (from example 65b) and 37 mg of 1-methyl-piperidin-4-ylamine are used to afford the title compound as a colourless oil. Rf=0.24 (dichloromethane-methanol 10:1); Rt=4.47.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([CH2:11][N:12]([CH3:17])[S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:6]=2[N:7]=1.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]1B(O)O>>[NH:24]1[C:32]2[C:27](=[C:28]([C:2]3[N:3]=[C:4]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[C:5]4[S:10][C:9]([CH2:11][N:12]([CH3:17])[S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:6]=4[N:7]=3)[CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25]1
Reactant: OB(O)c1cc2ccccc2[nH]1
Reactant: CN(Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)S(C)(=O)=O
Product: CN(Cc1cc2nc(-c3cccc4[nH]ccc34)nc(N3CCOCC3)c2s1)S(C)(=O)=O

Procedure:
N-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-N-methyl-methanesulfonamide was reacted with indole boronic acid in general procedure A. Purification on silica yielded 194. NMR: (400 MHz, DMSO) 2.83 (s, 3H), 3.02 (s, 3H), 3.85 (t, J=4.7, 4H), 3.99 (t, J=4.7, 4H), 4.64 (s, 2H), 7.19 (t, J=7.7, 1H), 7.43 (m, 2H), 7.51 (m, 2H), 8.12 (d, J=7.3, 1H), 11.20 (s br, 1H) MS: (ESI+)[M+H]+ 458.01
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11](Cl)=[O:12].O>C1(C)C=CC=CC=1>[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:12]
Reactant: C1CCNC1
Reactant: O=C(Cl)c1cccs1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(c1cccs1)N1CCCC1

Procedure:
Pyrrolidine (47 ml) was added to 2-thiophene carbonyl chloride (40 g) in toluene below 10°. After 11/2 hr, water was added. The product was extracted with ethyl acetate, crystallised from toluene and recrystallised from light petroleum (b.p. 60°-80°)/ethyl acetate to give white crystals (40 g) m.p. 66°-68°; TLC silica/ethyl acetate Rf 0.5.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:11][CH:12]1OC(C)OC(C)O1>>[CH3:11][CH:12]1[NH:6][C:4](=[O:5])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[O:1]1
Reactant: NC(=O)c1ccccc1O
Reactant: CC1OC(C)OC(C)O1
Product: CC1NC(=O)c2ccccc2O1

Procedure:
2-Hydroxybenzamide was transformed by Method G (using paraldehyde). M.p. 124-126° C.