Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:16]=[CH:15][C:8]([CH:9]=[CH:10][C:11](OC)=[O:12])=[CH:7][C:6]=1[N+:17]([O-:19])=[O:18].CO.O>C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:16]=[CH:15][C:8]([CH:9]=[CH:10][CH2:11][OH:12])=[CH:7][C:6]=1[N+:17]([O-:19])=[O:18]
Reactant: COCOc1ccc(C=CC(=O)OC)cc1[N+](=O)[O-]
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: COCOc1ccc(C=CCO)cc1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
Under a current of argon, a solution of 710 mg of methyl 4-methoxymethoxy-3-nitrocinnamate in 6 ml of toluene and 4.4 ml of diisobutyl aluminum hydride (1.5M toluene solution) added thereto at -78° C. were stirred for 30 minutes. The produced reaction solution was combined with methanol at -78° C. to effect decomposition of excess diisobutyl aluminum hydride and then the resultant mixture and water added thereto at 0° C. were stirred for a while. Subsequently, the mixture was filtered with sellaite and wased with ethyl acetate and the filtrate was extracted from ethyl acetate. The consequently separated organic layer was washed with saturated saline solution and then with anhydrous sodium sulfate and concentrated under a vacuum. The resultant concentrate was subjected to silica gel column chromatography. From the hexane-ethyl acetate (1:1 V/V) eluate, 560 mg of 4-methoxymethoxy-3-nitrocinnamyl alcohol was obtained in the form of a yellow oily substance. The yield was 88%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2([CH:16]([F:18])[F:17])[NH:13][C:12](=O)[CH:11]([CH3:15])[O:10][CH2:9]2)[CH:7]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2([CH:16]([F:18])[F:17])[NH:13][C:12](=[S:21])[CH:11]([CH3:15])[O:10][CH2:9]2)[CH:7]=1
Reactant: CC1OCC(c2cc(Br)ccc2F)(C(F)F)NC1=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: CC1OCC(c2cc(Br)ccc2F)(C(F)F)NC1=S
Temperature: 80 °C
Yield: 102 %

Procedure:
To a solution of 5-(5-bromo-2-fluoro-phenyl)-5-difluoromethyl-2-methyl-morpholin-3-one (659 mg, 1.949 mmol) in 6.6 mL pyridine was added phosphorus pentasulfide (433 mg, 1.949 mmol) and the mixture was heated to 80° C. for 120 minutes. The reaction mixture was cooled to room temperature and partitioned between 0.1 N NaOH and EtOAc. The layers were separated, washed with brine and EtOAc. The combined organic layers were dried over MgSO4.H2O and evaporated to give 704 mg of the title compound as a diastereomeric mixture.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10](F)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])#[N:2].[Br:14][C:15]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:16]=1[CH:17]=[O:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:14][C:15]1[CH:22]=[CH:21][C:20]([O:23][C:10]2[CH:11]=[CH:12][C:3]([C:1]#[N:2])=[C:4]([CH:9]=2)[C:5]([O:7][CH3:8])=[O:6])=[CH:19][C:16]=1[CH:17]=[O:18]
Reactant: O=Cc1cc(O)ccc1Br
Reactant: COC(=O)c1cc(F)ccc1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(Oc2ccc(Br)c(C=O)c2)ccc1C#N
Temperature: 80 °C
Reaction time: 8 h
Yield: 59.4 %

Procedure:
A mixture of methyl 2-cyano-5-fluorobenzoate (4.48 g, 25.0 mmol), 2-bromo-5-hydroxybenzaldehyde (5.03 g, 25.0 mmol), and potassium carbonate (4.14 g, 30.0 mmol) in N,N-dimethylformamide (50 mL) was stirred at 80° C. overnight. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (chloroform) to give methyl 5-(4-bromo-3-formylphenoxy)-2-cyanobenzoate (5.35 g, 71%).
Reaction SMILES: CS([O-])(=O)=O.C[S:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([C:16]1[CH:17]=[NH+:18][CH:19]=[CH:20][CH:21]=1)=O)(=O)=[O:8].C(N(CC)C(C)C)(C)C.C(O)(=S)C.O>O1CCCC1>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:14]2[S@:7](=[O:8])[CH2:10][CH2:11][CH2:12][CH:13]=2)[CH:17]=1
Reactant: CS(=O)(=O)CCCCC(=O)c1ccc[nH+]c1
Agent: CC(O)=S
Agent: CS(=O)(=O)[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=[S@@]1CCCC=C1c1cccnc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.7 %

Procedure:
A solution of 3-(5-methanesulphonyl-pentanoyl)pyridinium methanesulphonate (35.3 g) in tetrahydrofuran (200 ml) is treated with N,N-diisopropylethylamine (39 ml) and the resulting solution is stirred for 10 minutes. It is then treated with thioacetic acid (8.25 ml), dropwise, and the mixture is stirred at ambient temperature for 17 hours. It is then treated with water (200 ml), the mixture is stirred for 5 minutes, and the product is then extracted into toluene (150 ml;75 ml). The combined organic solution is washed with aqueous sodium chloride solution (250 ml), dried over magnesium sulphate and filtered. The filtrate is extracted with hydrochloric acid (1N;2×125 ml). The acid solution is then stirred at reflux for 2 hours, cooled to room temperature and washed with toluene (50 ml). The aqueous layer is stirred with charcoal (0.5 g) and filtered. This filtrate is stirred with dichloromethane (75 ml) and it is then treated with aqueous sodium hydroxide solution until the pH is between 10 and 11. The organic layer is separated and the aqueous fraction is extracted with dichloromethane (75 ml). The combined organic solution is dried over magnesium sulphate and filtered. The filtrate is added to a solution of diethyl L-tartrate (45.34 g) in dichloromethane (176ml), followed by a solution of titanium isopropoxide (16.36 ml) in dichloromethane (24 ml), and the solution is cooled to between -19° C. and -21°C. under an atmosphere of nitrogen. It is then treated with a solution of cumene hydroperoxide (24.42 ml) in dichloromethane (22 ml) is added during 20 minutes keeping the mixture between -19° C. and -21° C., then the mixture is stirred at this temperature for 7 hours. It is then treated with dilute hydrochloric acid (1N;250 ml) and the mixture is warmed to room temperature with stirring. The aqueous fraction is separated and washed with dichloromethane (125 ml), then treated with tartaric acid (7.5 g) and toluene (156 ml). The pH is adjusted to 10 by treatment with aqueous sodium hydroxide solution and the toluene fraction is removed. The aqueous fraction is extracted with dichloromethane (5×156 ml), adjusting the pH to 10 for each extraction. The combined dichloromethane and toluene solutions are washed with an aqueous solution of sodium disulphite saturated with sodium chloride, then dried over magnesium sulphate, filtered and concentrated under reduced pressure, to give crude (R)-6-(3-pyridyl)-3,4-dihydro-2H-thiopyran 1-oxide (12.48 g) in the form of a yellow oil.
Reaction SMILES: C1COCC1.[Br-].[C:7]1([CH2:13][CH2:14][CH2:15][CH2:16][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:36]([N:43]1[CH2:48][CH2:47][C:46](=O)[CH2:45][CH2:44]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.Cl>C1(C)C=CC=CC=1>[CH2:36]([N:43]1[CH2:48][CH2:47][C:46](=[CH:16][CH2:15][CH2:14][CH2:13][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:45][CH2:44]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: c1ccc(CCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C(CCCc1ccccc1)=C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 58.7 %

Procedure:
A 0.62M solution of potassium bis(trimethylsilyl)aride in THF (180 mL, 112 mmol) in toluene (250 mL) was added to a mixture of (4-phenylbut-1-yl)triphenylphosphonium bromide from Step B (53 g) in toluene (250 mL) in an ice bath over 15 min with stirring under nitrogen. After stirring for a further 15 min, a solution of 1-benzyl4-piperidone (16.9 g) in toluene (100 mL) was added over 30 min with stirring. The reaction mixture was allowed to warm to rt over 15 h. The reaction mixture was then poured into cold 1N HCl (400 mL) and the layers were separated. The organic layer was extracted with two more portions of 1N HCl. The combined cloudy HCl solution and an oil layer in between were washed with toluene (200 mL) before the aqueous layer was basified by the addition of potassium hydroxide (30 g). The aqueous layer was extracted with ether (3×150 mL) and the combined organic layers were washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by FC (10-15% ethyl acetate in hexanes having 4% (v/v) TEA) to give the title compound (16 g) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:16]([N+:20]#[C-:21])[CH2:17][CH2:18][CH3:19].[OH:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=O>Cl(O)(=O)(=O)=O>[CH2:9]([O:8][C:7]1[C:2]2[N:3]([C:21]([NH:20][CH2:16][CH2:17][CH2:18][CH3:19])=[C:26]([C:25]3[CH:24]=[C:23]([OH:22])[CH:30]=[CH:29][CH:28]=3)[N:1]=2)[CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: [C-]#[N+]CCCC
Reactant: O=Cc1cccc(O)c1
Reactant: Nc1ncccc1OCc1ccccc1
Agent: [O-][Cl+3]([O-])([O-])O
Product: CCCCNc1c(-c2cccc(O)c2)nc2c(OCc3ccccc3)cccn12

Procedure:
Compound (8) was prepared according to the general synthesis instructions from 1.0 ml of 2-amino-3-benzyloxypyridine solution (0.1 M, DCM), 0.575 ml of n-butyl isocyanide solution (0.2 M, DCM), 0.500 ml of 3-hydroxybenzaldehyde solution (0.3 M, DCM), and 10 μl of perchloric acid (w=20%).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:13])=[N:4][CH:5]=[C:6]([CH:8]2[CH2:12][CH2:11][NH:10][CH2:9]2)[CH:7]=1.CCN(C(C)C)C(C)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[Br:1][C:2]1[C:3]([NH2:13])=[N:4][CH:5]=[C:6]([CH:8]2[CH2:12][CH2:11][N:10]([S:24]([CH3:23])(=[O:26])=[O:25])[CH2:9]2)[CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ncc(C2CCNC2)cc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(c2cnc(N)c(Br)c2)C1
Reaction time: 0.5 h

Procedure:
To 3-bromo-5-(pyrrolidin-3-yl)pyridin-2-amine (20 mg, 0.083 mmol) in DCM in ice bath was added DIEA (57.7 μl, 0.330 mmol) and methanesulfonyl chloride (7.08 μl, 0.091 mmol). The reaction mixture was stirred in ice bath 30 min. The reaction mixture was partitioned between DCM and water. The DCM layer was separated and washed with brine, dried over sodium sulfate, filtered and evaporated. The crude product was used for next step without purification. LCMS (m/z): 320.0/322.0 (MH+), 0.363 min.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:31]=[CH:30][C:6]([C:7]([NH:9][CH2:10][CH2:11][N:12]2[CH2:29][CH2:28][C:15]3([N:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[CH2:18][NH:17][C:16]3=[O:27])[CH2:14][CH2:13]2)=[O:8])=[C:5]([N+:32]([O-])=O)[CH:4]=1.CO.[H][H]>[Ni].O>[OH2:8].[ClH:1].[NH2:32][C:5]1[CH:4]=[C:3]([F:2])[CH:31]=[CH:30][C:6]=1[C:7]([NH:9][CH2:10][CH2:11][N:12]1[CH2:29][CH2:28][C:15]2([N:19]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[CH2:18][NH:17][C:16]2=[O:27])[CH2:14][CH2:13]1)=[O:8]
Reactant: [H][H]
Reactant: O=C(NCCN1CCC2(CC1)C(=O)NCN2c1ccc(F)cc1)c1ccc(F)cc1[N+](=O)[O-]
Agent: [Ni]
Agent: Cl
Solvent: CO
Solvent: O
Product: Nc1cc(F)ccc1C(=O)NCCN1CCC2(CC1)C(=O)NCN2c1ccc(F)cc1

Procedure:
A mixture of 8 parts of 4-fluoro-N-{2-[1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4,5]dec-8-yl]ethyl}-2-nitrobenzamide hydrochloride, 120 parts of methanol and 25 parts of water is hydrogenated at normal pressure and at room temperature with 5 parts of Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is crystallized from methanol. The product is filtered off and recrystallized from ethanol, yielding 1 part of 2-amino-4-fluoro-N-{2-[1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4,5]dec-8-yl]ethyl}benzamide hydrochloride hydrate; mp. 223.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:3]=1[C:4]#[N:5].O=[C:19]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[N:1]=[C:19]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:26]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Reactant: N#Cc1c(N)cccc1CCC1CCCCC1
Product: CCOC(=O)Cc1nc2cccc(CCC3CCCCC3)c2c(N)c1C(=O)OCC

Procedure:
Prepared as in Example 2a from 2-amino-6-(2-cyclohexylethyl)benzonitrile (Example 113b) and diethyl 3-oxopentanedioate as an orange solid (33%). 1H NR (400 MHz, DMSO-d6) δ 0.87-0.96 (m, 2H), 1.14-1.22 (m, 7H), 1.27-1.32 (m, 4H), 1.47-1.52 (m, 2H), 1.61-1.68 (m, 4H), 1.74-1.77 (m, 2H), 3.21-3.25 (m, 2H), 4.03 (s, 2H), 4.09 (q, J=8.0 Hz, 2H), 4.27 (q, J=8.0 Hz, 2H), 7.27 (t, J=4.0 Hz, 1H), 7.57 (d, J=8.0 Hz, 2H), 7.63 (brs, 2H). MS 413 (MH+).
Reaction SMILES: CC1C(N=C=O)=CC([N:8]=[C:9]=[O:10])=CC=1.C1OC1.C1OC1CC.C(C1[C:31]([OH:32])=[C:30](C(C)(C)C)C=C(C)C=1)(C)(C)C.SCCC[Si](OC)(OC)OC.[C:49]([O:53]CCO)(=[O:52])[CH:50]=[CH2:51].[N-]=C=O>>[C:49]([OH:53])(=[O:52])[CH:50]=[CH2:51].[NH2:8][C:9]([O:32][CH2:31][CH3:30])=[O:10]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: C=CC(=O)OCCO
Reactant: Cc1ccc(N=C=O)cc1N=C=O
Agent: CCC1CO1
Agent: CO[Si](CCCS)(OC)OC
Agent: [N-]=C=O
Solvent: C1CO1
Product: C=CC(=O)O
Product: CCOC(N)=O

Procedure:
Into a reaction vessel equipped with a stirrer were charged 3.0 parts of tolylene diisocyanate, 50.5 parts of a ring-opening copolymer from ethylene oxide and butene oxide, having a number average molecular weight of 4,000, and 0.01 part of 2,6-di-t-butyl-p-cresol, as a polymerization inhibitor. The mixture was cooled with ice to a temperature of below 10° C., while stirring. When the temperature was lower than 10° C., 0.04 part of dibutyltindilaurate was added and the mixture was stirred for 2 hours while controlling the temperature at 20-30° C. Then, after the addition of 0.3 part of γ-mercaptopropyltrimethoxy silane, the mixture was stirred for a further one hour at 30-40° C., whereupon 1.2 parts of hydroxyethyl acrylate was added. The mixture was stirred for 4 hours at 50-60° C., until the amount of remaining isocyanate is 0.1% by weight or less. The liquid urethane acrylate obtained in this manner is hereinafter referred to as UA-1.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[Cl:6][C:7](=[C:11]([Cl:15])[CH:12]([Cl:14])[Cl:13])[C:8](Cl)=[O:9].Cl>>[CH2:1]([O:5][C:8](=[O:9])[C:7]([Cl:6])=[C:11]([Cl:15])[CH:12]([Cl:14])[Cl:13])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCO
Reactant: O=C(Cl)C(Cl)=C(Cl)C(Cl)Cl
Agent: Cl
Product: CCCCOC(=O)C(Cl)=C(Cl)C(Cl)Cl
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
An agitated flask is charged with 0.5 mole of n-butanol and heated under stirring to 50° C. Within 30 minutes, 60.6 g (0.25 mol) of 2,3,4,4-tetrachloro-2-butenoic acid chloride is added dropwise to the charge, and the latter is agitated for 30 minutes at 80° C. During this step the main quantity of the thus-formed hydrogen chloride is driven off in the gaseous phase. Subsequently, the reaction mixture is fractionated without neutralization over a 10 cm column under vacuum, thus obtaining 64.4 g (0.23 mol) of 2,3,4,4-tetrachloro-2-butenoic acid n-butyl ester; b.p. 95° C./0.6 mbar; nD20 --1.5050. Yield: 92% of theory.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]2[CH:22]=[CH:23][CH:24]=[C:25]([O:26][CH3:27])[C:17]2=[CH:16][CH:15]=3)[CH:11]=[C:10](Cl)[CH:9]=1)=[O:7].[CH3:30][O-:31].[Na+]>CO.C(OCC)(=O)C>[CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]2[CH:22]=[CH:23][CH:24]=[C:25]([O:26][CH3:27])[C:17]2=[CH:16][CH:15]=3)[CH:11]=[C:10]([O:31][CH3:30])[CH:9]=1)=[O:7]
Reactant: COc1cccc2c1ccc1nc3cc(Cl)cc(C(=O)NCCN(C)C)c3nc12
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)NCCN(C)C)c2nc3c(ccc4c(OC)cccc43)nc2c1

Procedure:
A mixture of 9-chloro-4-methoxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide (85 mg) and a 25% solution of sodium methoxide in methanol (4 mL) was heated to reflux for 6 hours. The reaction mixture was then cooled, diluted with ethyl acetate, washed with water, dried (MgSO4) and the solvent removed in vacuo to yield a yellow solid which was purified using flash chromatography to yield the desired title compound (42 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([C:12](=[O:15])[CH2:13]Br)=[CH:4][C:3]=1[Cl:16].[C:17]1([CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([CH:12]([CH2:13][N:31]([CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[OH:15])=[CH:4][C:3]=1[Cl:16]
Reactant: c1ccc(CCOCCCCCNCc2ccccc2)cc1
Reactant: Nc1c(Cl)cc(C(=O)CBr)cc1C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1c(Cl)cc(C(O)CN(CCCCCOCCc2ccccc2)Cc2ccccc2)cc1C(F)(F)F
Reaction time: 8 h
Yield: 53.8 %

Procedure:
1-[4-Amino-3-chloro-5-(trifluoromethyl)phenyl]-2-bromoethanone (0.55 g), N-[5-(2-phenylethoxy)pentyl]benzenemethanamine (0.52 g) and N,N-diisopropylethylamine (0.25 g) were stirred in tetrahydrofuran (15 ml) at room temperature under nitrogen for 40 h. The mixture was filtered and the filtrate evaporated in vacuo. The residue was dissolved in methanol (20 ml) and sodium borohydride (0.18 g) was added portionwise to the stirred solution at 0° under nitrogen. The mixture was left to stand at room temperature under nitrogen overnight, 2N hydrochloric acid (10 ml) added and the solvent evaporated in vacuo. The residue was partitioned between 8% sodium bicarbonate (100 ml) and ethyl acetate (100 ml), the organic phase separated, dried and evaporated in vacuo to give an oil. Purification by FCC on triethylamine deactivated silica (Merck 9385) eluting with cyclohexane-ethyl acetate (9:1) gave the title compound as a colourless oil (0.5 g).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([N:14]1[CH2:19][CH2:18][C:17]3([C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][NH:21][CH2:20]3)[CH2:16][CH2:15]1)=[O:13])[CH2:8]2.[C:29]1(=[O:35])[O:34][C:32](=[O:33])[CH:31]=[CH:30]1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([N:14]1[CH2:19][CH2:18][C:17]3([C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][N:21]([C:29](=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33])[CH2:20]3)[CH2:16][CH2:15]1)=[O:13])[CH2:8]2
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)N1CCC2(CC1)CNCc1ccccc12
Reactant: O=C1C=CC(=O)O1
Product: O=C(O)/C=C/C(=O)N1Cc2ccccc2C2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)C1

Procedure:
The title compound was prepared from N-(2-adamantyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxamide and maleic anhydride following a procedure analogous to that described in Example 90. LC-MS Method 1 tR=1.7 min, m/z=478; 1H NMR (CDCl3) 1.60-2.20 (18H), 3.11 (m, 2H), 3.58 (s, 2H), 3.92 (br s, 4H), 4.39 (s, 2H), 5.00 (br s, 1H), 6.30-7.45 (6H).
Reaction SMILES: [CH2:1]([P:3]([CH2:10][CH2:11][OH:12])(=[O:9])[O:4][CH2:5][CH2:6]CC)[CH3:2].C(O)C[OH:15]>C([O-])(C([O-])=O)=O.C([O-])(C([O-])=O)=O.O=[Ti+2].[K+].[K+]>[CH2:1]([P:3]([CH2:10][CH2:11][OH:12])(=[O:9])[O:4][CH2:5][CH2:6][OH:15])[CH3:2]
Reactant: OCCO
Reactant: CCCCOP(=O)(CC)CCO
Agent: O=[Ti+2]
Agent: O=C([O-])C(=O)[O-]
Agent: [K+]
Product: CCP(=O)(CCO)OCCO
Temperature: 200 °C
Reaction time: 2 h
Yield: 86.5 %

Procedure:
To 388 g (2 mol) of butyl ethyl(2-hydroxyethyl)phosphinate (produced as in Example 12) are added 155 g (2.5 mol) of ethylene glycol and 0.4 g of potassium titanyloxalate, followed by stirring at 200° C. for 2 h. Volatiles are distilled off by gradual evacuation to leave 315 g (96% of theory) of 2-hydroxyethyl ethyl(2-hydroxyethyl)phosphinate.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1>CC(C)=O.[OH-].[Na+]>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:13][S:10]([C:7]2[CH:6]=[CH:5][C:4]([NH:3][CH2:1][CH3:2])=[CH:9][CH:8]=2)(=[O:11])=[O:12])=[O:23])=[CH:17][CH:16]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CCNc1ccc(S(N)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCNc1ccc(S(=O)(=O)NC(=O)Nc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
The 4-(ethylamino)benzene-sulfonamide was dissolved in 7.8 ml of acetone with 7.9 ml of 1N sodium hydroxide added. To this mixture was added 4-chlorophenylisocyanate (1.22 g, 7.9 mmoles), dissolved in 7.8 ml of acetone. This reaction mixture was allowed to stir for 25 minutes at room temperature, then filtered, with a small amount of an acetone:water (1:1) mixture being used to rinse out the flask and wash the filtered solid. The filtrate was acidified with 1N hydrochloric acid (7.9 ml) and stirred for about an hour until the initially separated oil had changed to a solid.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26]OS(C)(=O)=O)=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[NH:32]1[CH2:36][CH2:35][CH2:34][C@H:33]1[CH2:37][OH:38].Cl.[N+](C1C=CC(OC(=O)[NH:51][C:52]2[CH:57]=[CH:56][C:55]([N:58]3[CH2:62][CH2:61][CH2:60][CH2:59]3)=[CH:54][CH:53]=2)=CC=1)([O-])=O>CS(C)=O.O>[N:58]1([C:55]2[CH:56]=[CH:57][C:52]([NH:51][C:6]([N:8]3[CH2:13][CH2:12][CH:11]([C:14]4[C:23]5[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][N:32]6[CH2:36][CH2:35][CH2:34][CH:33]6[CH2:37][OH:38])=[CH:21][CH:22]=5)[N:17]=[CH:16][N:15]=4)[CH2:10][CH2:9]3)=[O:5])=[CH:53][CH:54]=2)[CH2:59][CH2:60][CH2:61][CH2:62]1
Reactant: O=C(Nc1ccc(N2CCCC2)cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(OCCOS(C)(=O)=O)ccc23)CC1
Reactant: OC[C@@H]1CCCN1
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1ccc(N2CCCC2)cc1)N1CCC(c2ncnc3cc(OCCN4CCCC4CO)ccc23)CC1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To a solution of 4-[7-(2-methanesulfonyloxy-ethoxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid tert-butyl ester (40.6 mg, 0.09 mmol) in DMSO (0.4 mL) was added (S)-(+)-2-pyrrolidinemethanol (90.9 mg, 0.9 mmol). The mixture was stirred at 120° C. overnight and subsequently partitioned between EtOAc and water. The combined organic extracts were washed with brine, dried over Na2SO4 and evaporated. The residue was treated with 50% TFA/CH2Cl2 (8 mL) for 2 h, the solvents (TFA/CH2Cl2) were removed under reduced pressure and half of the residue was re-dissolved in CH2Cl2. DIPEA (55 μL) was added to the above solution, followed by (4-pyrrolidin-1-yl-phenyl)-carbamic acid 4-nitro-phenyl ester hydrochloride (19.6 mg, 0.054 mmol), which was prepared as described in Example 74a. The reaction mixture was stirred for 1 h, diluted with water. The organic phase was collected and the solvents were evaporated. The crude residue was purified by flash column chromatography on silica gel (15% MeOH/EtOAc as eluent) to afford a white solid (10 mg, 40.8% overall yield). 1H NMR (CD3OD) δ 9.03 (s, 1H), 8.35 (d, J=9.44 Hz, 1H), 7.40 (dd, J=9.25 and 2.54 Hz, 1H), 7.34 (d, J=2.48 Hz, 1H), 7.13 (d, J=8.87 Hz, 2H), 6.54 (d, J=8.96 Hz, 2H), 4.29-4.36 (4H), 3.92 (m, 1H), 3.60 (dd, J=10.98 and 4.81 Hz, 1H), 3.52 (dd, J=11.00 and 5.90 Hz, 1H), 3.40 (m, 1H), 3.27 (m, 1H), 3.24 (t, J=6.61 Hz, 4H), 3.15 (td, J=12.57 and 2.55 Hz, 2H), 2.88 (dt, J=13.67 and 5.50 Hz, 1H), 2.71 (m, 1H), 2.47 (m, 1H), 1.90-2.09 (9H), 1.79 (m, 2H), 1.66 (m, 1H). Calcd for C31H41N6O3 (MH+) 545.3, found 545.3.