Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[S:2]([N:5]=C=O)(=[O:4])=[O:3].[CH2:8]([N:15]1[CH2:20][CH2:19][C:18]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=2)([CH2:21][NH2:22])[CH2:17][CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1.C(O)=O>[CH2:8]([N:15]1[CH2:20][CH2:19][C:18]([CH2:21][NH:22][S:2]([NH2:5])(=[O:4])=[O:3])([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=2)[CH2:17][CH2:16]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1cccc(NC2(CN)CCN(Cc3ccccc3)CC2)c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: O=CO
Solvent: C1CCOC1
Product: Cc1cccc(NC2(CNS(N)(=O)=O)CCN(Cc3ccccc3)CC2)c1
Reaction time: 8 h

Procedure:
To a cold (5° C.) solution of chlorosulfonyl isocyanate in THF, anhydrous formic acid is added (Journal of Organic Chemistry, vol 54, page 5825,(1989)). The resultant mixture is stirred until gas evolution ceased, and treated with a solution of 1-benzyl-4-(3-methylphenylamino)-4-aminomethylpiperidine in THF. The mixture is stirred at room temp. overnight to provide the title compound.
Reaction SMILES: [CH3:1][C@H:2]1[C@@:11]2([CH3:27])[C@H:12]([O:22][C:23]([CH2:25][OH:26])=[O:24])[CH2:13][C@:14]([CH:20]=[CH2:21])([CH3:19])[C@@H:15]([OH:18])[C@H:16]([CH3:17])[C@:5]3([C@@H:10]2[C:8](=[O:9])[CH2:7][CH2:6]3)[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37].O>ClCCl>[CH3:1][C@H:2]1[C@:11]2([CH3:27])[C@@H:12]([O:22][C:23]([CH2:25][O:26][S:36]([CH3:35])(=[O:38])=[O:37])=[O:24])[CH2:13][C@@:14]([CH:20]=[CH2:21])([CH3:19])[C@H:15]([OH:18])[C@@H:16]([CH3:17])[C@@:5]3([C@@H:10]2[C:8](=[O:9])[CH2:7][CH2:6]3)[CH2:4][CH2:3]1
Reactant: C=C[C@]1(C)C[C@@H](OC(=O)CO)[C@]2(C)[C@H](C)CC[C@]3(CCC(=O)[C@@H]32)[C@@H](C)[C@@H]1O
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C[C@@]1(C)C[C@H](OC(=O)COS(C)(=O)=O)[C@@]2(C)[C@H](C)CC[C@@]3(CCC(=O)[C@@H]32)[C@H](C)[C@H]1O
Temperature: 17.5 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
Pleuromutilin (69.95 g at 90% purity) and triethylamine (26 mL, 18.33 g) in dichloromethane (0.55 L) were cooled to −10° C. Methane sulphonyl chloride (14.5 mL, 20.87 g) in dichloromethane (0.12 L) was added over 0.5 h at −5 to −10° C. After 0.5 h the mixture was warmed to 15-20° C. and water (0.25 L) added. The phases were separated and the aqueous phase was further extracted with dichoromethane (0.06 L). The combined dichloromethane solution was concentrated by distillation collecting 0.5 L. The distillation was continued by slowly adding propan-2-ol (0.3 L) and collecting a further 0.3 L to reach a solution temperature of 78° C. n-Heptane (0.29 L) was added slowly whilst maintaining the temperature between 75-80° C. The solution became turbid with the product crystallizing. The mixture was cooled to 0° C. and stirred for 1 h. The product was filtered off, washed with chilled 2:1 n-heptane/propan-2-ol (0.075 L) and dried under vacuum to give the title compound (75.33g, 95.6%).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH2:48][CH:49]2[CH2:51][CH2:50]2)[N:20]([C:39]2[CH:40]=[CH:41][C:42]3[O:46][CH2:45][CH2:44][C:43]=3[CH:47]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH2:48][CH:49]2[CH2:50][CH2:51]2)[N:20]([C:39]2[CH:40]=[CH:41][C:42]3[O:46][CH2:45][CH2:44][C:43]=3[CH:47]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCCc1nc(CC2CC2)n(-c2ccc3c(c2)CCO3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(CC2CC2)n(-c2ccc3c(c2)CCO3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
A mixture of hydroxylammonium chloride (1.0 g), sodium hydrogen carbonate (1.5 g) and dimethyl sulfoxide (6 mL) was stirred at 50° C. for 30 min, 4′-{[4-butyl-2-(cyclopropylmethyl)-1-(2,3-dihydro-1-benzofuran-5-yl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.59 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (6 mL), N,N′-carbonyldiimidazole (0.37 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.34 mL) were added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography and recrystallized from dichloromethane and diisopropyl ether to give the title compound (0.54 g, 82%) as a colorless solid.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:17][C:18]1[S:32][C:21]2[N:22]([CH:29]([CH3:31])[CH3:30])[C:23](=[O:28])[N:24]([CH3:27])[C:25](=[O:26])[C:20]=2[CH:19]=1.O>CN(C)C=O>[N:1]1([CH2:17][C:18]2[S:32][C:21]3[N:22]([CH:29]([CH3:30])[CH3:31])[C:23](=[O:28])[N:24]([CH3:27])[C:25](=[O:26])[C:20]=3[CH:19]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: CC(C)n1c(=O)n(C)c(=O)c2cc(CCl)sc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1c(=O)n(C)c(=O)c2cc(Cn3cnc4ccccc43)sc21
Reaction time: 48 h
Yield: 55.1 %

Procedure:
Benzimidazole (0.395 g) and potassium carbonate (1 g) were added to a stirred solution of 6-(chloromethyl)-3-methyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.55 g) in anhydrous dimethylformamide (5 ml) at room temperature. After 2 days, water (50 ml) was added and the mixture was extracted with ethyl acetate (2×50 ml). The organic extracts were dried over anhydrous magnesium sulfate and filtered through a silica pad which was washed with ethyl acetate. The filtrate was evaporated and the residue was purified twice by normal-phase preparative HPLC with gradient dichloromethane/ethanol elution to give the title compound (0.394 g) as a foam.
Reaction SMILES: [OH2:1].S(=O)(=O)(O)[OH:3].[CH3:7][C:8]1[C:16]([C:17]#N)=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[N:11][NH:12]2>C(O)(=O)C>[CH3:7][C:8]1[C:16]([C:17]([OH:3])=[O:1])=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[N:11][NH:12]2
Reactant: Cc1c(C#N)ccc2[nH]ncc12
Reactant: O=S(=O)(O)O
Reactant: O
Solvent: CC(=O)O
Product: Cc1c(C(=O)O)ccc2[nH]ncc12
Reaction time: 18 h
Yield: 70.1 %

Procedure:
Water (2 ml) and concentrated sulfuric acid (2 ml) were added to a acetic acid suspension (2 ml) of 4-methyl-1H-indazole-5-carbonitrile (399 mg, 2.00 mmol) at room temperature, and then the reaction was carried out for 18 hours under reflux conditions. The reaction mixture was poured onto ice (20 g) and the precipitate was collected by filtration and dried to obtain 4-methyl-1H-indazole-5-carboxylic acid (247 mg, 70.1%).
Reaction SMILES: C(=[N:8][CH:9]([P:22]([O:27][CH2:28][CH3:29])([O:24][CH2:25][CH3:26])=[O:23])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=[O:11])C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.NC(P(O)(ON(CC)CC)=O)C(OCC1C=CC(OC)=CC=1)=O>CCOCC>[NH2:8][CH:9]([P:22]([O:27][CH2:28][CH3:29])([O:24][CH2:25][CH3:26])=[O:23])[C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)=[O:11]
Reactant: CCOP(=O)(OCC)C(N=Cc1ccccc1)C(=O)OCc1ccc(OC)cc1
Agent: CCN(CC)OP(=O)(O)C(N)C(=O)OCc1ccc(OC)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: O
Product: CCOP(=O)(OCC)C(N)C(=O)OCc1ccc(OC)cc1

Procedure:
A solution of 16.4 g. of p-methoxybenzyl N-benzylidene-α-amino-diethylphosphonoacetate in 100 ml. of ether is added over 30 minutes with stirring to a solution of 8.25 g. of p-toluenesulfonic acid monohydrate in 150 ml. of ether. To the reaction mixture is added 60 ml. of cyclohexane and the solvent layer is separated by decantation. The residue is washed with additional 2:1 ether-cyclohexane and is again decanted. The resulting oil is dissolved in about 25 ml. of 1 M dipotassium phosphate (final pH about 7), and this solution is extracted 4 times with methylene chloride. The methylene chloride solution is then dried with magnesium sulfate, filtered and evaporated to give 12 g. of p-methoxybenzyl α-amino-diethylaminophosphonoacetate as an orange oily product. ir (neat) μ: 2.95 (NH), 5.75 (C=O), and 9.75 (P--O); nmr (CDCl3) τ: 8.73 (t, 6, J=7Hz, CH2CH3), 8.12 (s, 2, NH2), 6.18 (s, 3, ArOCH3), 6.03 (d, 1, J=21Hz, CH), 5.86 (p, 4, J=7Hz, CH2CH3), 4.80 (s, 2, ArCH2), 3.11 (d, 2, J=8Hz, arH), and 2.64 (d, 2, J=8Hz, ArH).
Reaction SMILES: [I-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li][CH2:23][CH2:24][CH2:25][CH3:26].[C:27]1(=O)[CH2:41][CH2:40]CCC[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.O>C1COCC1.C(Cl)Cl>[CH2:26]=[C:25]1[CH2:40][CH2:41][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:23][CH2:24]1
Reactant: [Li]CCCC
Reactant: O=C1CCCCCCCCCCCCCC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=C1CCCCCCCCCCCCCC1
Temperature: 0 °C
Yield: 69 %

Procedure:
To a solution of methyltriphenylphosphonium iodide (12 g, 30 mmol) in THF (200 mL) was added dropwise n-BuLi (18.5 mL, 30 mmol) at 0° C. The suspension was stirred at 0° C. until a yellow color persisted, and then cyclopentadecanone, 48, (2.21 g, 9.8 mmol) was added as a solution in THF (20 mL). The mixture was allowed to warm to room temperature and stirred overnight. Upon completion, H2O was added to quench any remaining n-BuLi and any precipitates were filtered off. The filtrate was concentrated in vacuo and the residue was redissolved in CH2Cl2, washed three times with deionized H2O. The organic layer was separated, dried over anhydrous Na2SO4, filtered, and then concentrated under reduced pressure to give a pale red oil. After column chromatography (Rf=0.9, 10% CH2Cl2/90% hexanes) 51 was isolated as a pale yellow oil (1.5 g, 69%). 1H NMR (CDCl3) δ 4.65 (s, 2H), 1.96 (t, 4H), 1.37 (m, 4H), 1.27-1.25 (m, 20H).48
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][OH:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:10](OCC)(=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(O)C>C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.C(C1C=C(O)C(C(C)(C)C)=CC=1O)(C)(C)C>[C:1]([O:6][CH2:7][CH2:8][O:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:16])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CCOC(=O)C(=O)OCC
Reactant: C=C(C)C(=O)OCCO
Agent: CC(C)(C)c1cc(O)c(C(C)(C)C)cc1O
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: CCO
Product: C=C(C)C(=O)OCCOC(=O)C(=O)OCC
Yield: 73.1 %

Procedure:
A 500 ml flask equipped with a decanter, a thermometer, a stirrer and an inlet for nitrogen gas was charged with 65.1 g (0.5 mol) of 2-hydroxyethyl methacrylate and 365.4 g (2.5 mol) of diethyl oxalate, to which 2 g (10 mmol) of dibutyltin dilaurate (catalyst) and 4 g of 2,5-di-t-butylhydroquinone (polymerization inhibitor) were added. The mixture was heated to keep it at about 120° C. for 2 hours in nitrogen atmosphere with distilling 32.5 ml (0.56 mol) of ethanol away. The reaction mixture was evaporated to remove excess diethyl oxalate and then distilled under vacuum to obtain 84.2 g (yield 73.2%) of 2-ethoxalyloxyethyl methacrylate (bp 124° C./0.4 mmHg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:18][N:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](Cl)=[O:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:20](=[O:21])[N:19]([CH3:18])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: O=S(=O)(c1ccc(O)cc1)c1ccc(Cl)cc1
Product: CN(C(=O)Oc1ccc(S(=O)(=O)c2ccc(Cl)cc2)cc1)c1ccccc1

Procedure:
The title compound was prepared from 4-(4-chloro-benzenesulfonyl)-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (46%, colourless oil). HPLC-MS m/z=402.1(M+1), Rt: 4.65 min.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C:11](=[O:27])[CH2:12][C:13]1[N:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:14]=1.[CH3:28][Si]([N-][Si](C)(C)C)(C)C.[K+].CI>O1CCCC1.[Cl-].[NH4+].C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C:11](=[O:27])[CH:12]([C:13]1[N:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:14]=1)[CH3:28]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COc1cc(N2CCOCC2)nc(CC(=O)N2CCc3c(F)cccc32)n1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CI
Product: COc1cc(N2CCOCC2)nc(C(C)C(=O)N2CCc3c(F)cccc32)n1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
300 mg of 1-(4-fluoro-2,3-dihydroindol-1-yl)-2-(4-methoxy-6-morpholin-4-yl-pyrimidin-2-yl)ethanone dissolved in 10 ml of tetrahydrofuran are cooled to −78° C. using a dry ice bath. 2.65 ml of 1N potassium bis(trimethylsilyl)amide in THF are slowly added while maintaining the temperature at −75° C. After 30 minutes of stirring, 0.125 ml of methyl iodide is added and the stirring is continued for 2 h 15. The reaction mixture is diluted with 50 ml of a saturated ammonium chloride solution and 30 ml of ethyl acetate. After settling out, the organic phase is washed with 5 times 15 ml of water, dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue is purified by silica column chromatography, elution being carried out with a 99/01 mixture of dichloromethane and methanol, so as to give 215 mg of 1-(4-fluoro-2,3-dihydroindol-1-yl)-2-(4-methoxy-6-morpholin-4-ylpyrimidin-2-yl)propan-1-one in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][C@H:2]1[C:5]([O:7][CH3:8])=[O:6].Cl[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].C(N(C(C)C)CC)(C)C>ClCCl.CCOCC>[CH3:8][O:7][C:5]([C@@H:2]1[CH2:3][CH2:4][N:1]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:6]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)[C@@H]1CCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
(2S)-Methyl azetidine-2-carboxylate (2.83 g, 18.7 mmol, 1.0 eq) was dissolved in dry dichloromethane (100 mL) and cooled to about 0° C. under an argon atmosphere. After the addition of benzyl chloroformate (3.00 mL, 20.0 mmol, 1.1 eq), diisopropyl ethylamine (8.00 mL, 45.9 mmol, 2.5 eq) was added to the mixture dropwise. The reaction mixture was stirred at about 0° C. for about 30 minutes and then at about room temperature overnight. The solvent was evaporated and then the residue was dissolved in ether, washed with 1N HCl, water and brine, dried over magnesium sulfate and concentrated. Flash chromatography (in ether) gave 3.75 g (80% yield) of the product as a colorless oil. 1H NMR (CDCl3) δ 2.19-2.32 (m, 1H); 2.52-2.66 (m, 1H); 3.74 (s, 3H); 3.94-4.03 (m, 1H); 4.08-4.18 (m, 1H); 4.72 (dd, 1H, J=9.4, 6.9); 5.12 (q, 2H, J=12.9); 7.29-7.42 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH:26]1([C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=2F)[CH:32]=[O:33])[CH2:28][CH2:27]1>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([O:16][C:36]3[CH:35]=[CH:34][C:31]([CH:32]=[O:33])=[CH:30][C:29]=3[CH:26]3[CH2:27][CH2:28]3)=[CH:12][CH:11]=2)=[CH:18][CH:19]=1
Reactant: O=Cc1ccc(F)c(C2CC2)c1
Reactant: O=C(NCCc1ccc(Cl)cc1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(C2CC2)c1
Temperature: 85 °C
Reaction time: 8 h
Yield: 20.8 %

Procedure:
N-(4-Chlorophenethyl)-4-hydroxybenzamide (504 mg, 1.83 mmol) was diluted with DMSO (8 mL) and K2CO3 (379 mg, 2.74 mmol) and 3-cyclopropyl-4-fluorobenzaldehyde (300 mg, 1.83 mmol) were added. The reaction was stirred 85° C. overnight. The reaction was cooled to ambient temperature, diluted with ethyl acetate and washed with twice with 10% sodium carbonate, water and brine, and concentrated. The crude material was purified by silica gel chromatography eluting with hexanes:ethyl acetate (3:1) to provide N-(4-chlorophenethyl)-4-(2-cyclopropyl-4-formylphenoxy)benzamide (160 mg, 20.9% yield).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[NH:23]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[N:23]1([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][NH:2][CH:3]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1
Reactant: C1CNCCNC1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCCNCC1

Procedure:
Following Example 216, to a well stirred solution of 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid and 1,4-diazepane to give 261. MS: (ESI+)=382.1
Reaction SMILES: Cl.[OH:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:21])=[C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH:13]=2)[C:8](=[O:22])[C:7]([C:23]([OH:25])=[O:24])=[CH:6]1.[C:26](O)(=[O:28])[CH3:27].C(N(CC)CC)C>CN(C=O)C>[OH:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:21])=[C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:26](=[O:28])[CH3:27])[CH2:17][CH2:16]3)[CH:13]=2)[C:8](=[O:22])[C:7]([C:23]([OH:25])=[O:24])=[CH:6]1
Reactant: O=C(O)c1cn(CCO)c2cc(N3CCNCC3)c(F)cc2c1=O
Reactant: CC(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3CCO)CC1
Yield: 96.7 %

Procedure:
A mixture of 1-(2-hydroxyethyl)-6-fluoro-7-(1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid hydrochloride 1.50 g (4 millimole), anhydrous acetic acid 0.7 g (7 millimole), triethylamine 0.5 g (5 millimole) and DMF 5 ml was heated at 90°-100° C. for 3 hours under stirring. After cooling, the reaction mixture was evaporated under vacuum, and acidified with acetic acid. The precipitated crystals were collected by filtration, washed successively with water and ethanol and dried. 1.46 g (97%) of 1-(2-hydroxyethyl)-6-fluoro-7-(4-acetyl-1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid was obtained as yellowish powders.
Reaction SMILES: [O:1]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([C:27]45[CH2:36][CH:31]6[CH2:32][CH:33]([CH2:35][CH:29]([CH2:30]6)[CH2:28]4)[CH2:34]5)[CH:20]=3)[CH:15]=2)[CH:10]=1)[Si](C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].CCN(C(C)C)C(C)C.[C:64]1([CH3:74])[CH:69]=[CH:68][C:67]([S:70](Cl)(=[O:72])=[O:71])=[CH:66][CH:65]=1>C1COCC1.CCOC(C)=O.CN(C1C=CN=CC=1)C>[C:27]12([C:21]3[CH:20]=[C:19]([C:14]4[CH:15]=[C:16]5[C:11](=[CH:12][CH:13]=4)[CH:10]=[C:9]([O:1][S:70]([C:67]4[CH:68]=[CH:69][C:64]([CH3:74])=[CH:65][CH:66]=4)(=[O:72])=[O:71])[CH:18]=[CH:17]5)[CH:24]=[CH:23][C:22]=3[O:25][CH3:26])[CH2:36][CH:31]3[CH2:32][CH:33]([CH2:35][CH:29]([CH2:30]3)[CH2:28]1)[CH2:34]2
Reactant: COc1ccc(-c2ccc3cc(O[Si](C)(C)C(C)(C)C)ccc3c2)cc1C12CC3CC(CC(C3)C1)C2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CN(C)c1ccncc1
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2ccc3cc(OS(=O)(=O)c4ccc(C)cc4)ccc3c2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-tert-butyl-dimethylsiloxy-6-(3-adamantan-1-yl-4-methoxyphenyl)-naphthalene (14 g, 28 mmol) in THF (160 ml) was added TBAF (28 ml, 28 mmol) and the reaction stirred at RT for 5 min. The reaction mixture was diluted with EtOAc and washed with 1N HCl, brine, and dried over Na2SO4. The crude product was concentrated in vacuo and the residue was dissolved in DCM (200 ml). DMAP (0.2 equiv), DIEA (1.2 equiv) and toluene-4-sulfonyl chloride (1 equiv) were added and the reaction was stirred at RT for 30 minutes. The solvent was removed, the residue was dissolved in EtOAc, washed with 1N HCl, brine, and dried over Na2SO4. The solvent was removed and the crude product was recrystallized from acetonitrile.
Reaction SMILES: [N:1]1([CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][C:22]3([C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25]3)[CH2:21][CH2:20]2)[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7]2)[CH2:3][CH2:2]1.C(O)(=O)C>C(O)C.[Pd]>[N:1]1([CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][C:22]3([C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25]3)[CH2:21][CH2:20]2)[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7]2)[CH2:3][CH2:2]1
Reactant: C1=CC2(CCN(CCCCN3CCC4(C=Cc5ccccc54)CC3)CC2)c2ccccc21
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: c1ccc2c(c1)CCC21CCN(CCCCN2CCC3(CCc4ccccc43)CC2)CC1
Reaction time: 2 h

Procedure:
To a solution of 1,4-Bis-spiro[ind-2-en-1,4'-piperidin-1'-yl]butane (compound 4a) (3 g) in ethanol (90 ml) were added acetic acid (5 ml) and 5% palladium on carbon (0.9 g). The mixture was hydrogenated in a Parr apparatus for 2 hours ar 3 atm. The catalyst was filtered off and the solvent evaporated. The remaining oil was dissolved in diluted aqueous NH4OH (200 ml, pH>9). The title compound 5a was extracted with ethyl acetate and worked-up as above and finally crystallized from ethyl acetate. Yield 1.6 g. Mp 113°-115° C. 1H NMR (CDCl3)δ1.55-1.65 (m,8 H), 1.95-2.10 (m,8 H), 2.15 (t,4 H), 2.45 (broad s,4 H), 2.95 (t,8 H), 7.10-7.30 (m,8 H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:9]2[CH:22]=[CH:21][C:12]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])=[O:14])=[CH:11][N:10]=2)[C:6]=1[O:7]C.[C:23]([CH2:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)#[N:24]>>[C:23]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:3]=[N:4][N:5]([C:9]3[CH:22]=[CH:21][C:12]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])=[O:14])=[CH:11][N:10]=3)[C:6]=2[OH:7])=[CH:28][CH:27]=1)#[N:24]
Reactant: N#CCc1ccc(B(O)O)cc1
Reactant: COCCCNC(=O)c1ccc(-n2ncc(Br)c2OC)nc1
Product: COCCCNC(=O)c1ccc(-n2ncc(-c3ccc(CC#N)cc3)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 212 using 6-(4-bromo-5-methoxy-1H-pyrazol-1-yl)-N-(3-methoxypropyl)nicotinamide and (4-(cyanomethyl)phenyl)boronic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.71 (quin, J=6.7 Hz, 2H) 3.18 (s, 3H) 3.21-3.30 (m, 2H) 3.33 (t, J=6.2 Hz, 2H) 3.94 (s, 2H) 7.25 (d, J=8.3 Hz, 2H) 7.86 (d, J=8.1 Hz, 2H) 8.25-8.34 (m, 2H) 8.36 (br. s., 1H) 8.62 (t, J=5.6 Hz, 1H) 8.79-8.86 (m, 1H) 12.97 (br. s., 1H). MS m/z 392 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[CH:10][N:9]([O:12]CC(O)=O)[C:8]=2[CH:17]=1)([O-:3])=[O:2].C(OC(=O)C)C.C1COCC1.[ClH:29]>O>[ClH:29].[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[CH:10][N:9]([OH:12])[C:8]=2[CH:17]=1)([O-:3])=[O:2]
Reactant: O=C(O)COn1cnc2ccc([N+](=O)[O-])cc21
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc2ncn(O)c2c1
Reaction time: 0.5 h

Procedure:
(6-Nitro-benzoimidazol-1-yloxy)-acetic acid (6) A mixture of 6-nitro-benzoimidazol-1-yloxy)-acetic acid ethyl ester (5) (250 mg, 0.94 mmol), THF (5 mL), water (1 mL) and concentrated HCl (1 mL) was heated to reflux for 2 hours. The reaction mixture was evaporated and the crude residue was purified by HPLC (21.2×250 mm Phenomenex Luna C18(2) column; flow rate=20 mL/min; linear gradient 0-100% B over 30 minutes; A Buffer=water with 0.1% TFA, B Buffer=acetonitrile with 0.1% TFA). HPLC solvents removed in vacuo to yield yellow solid. Yield 65 mg (29%).