Azzindani/Open_Reaction_Data huggingface dataset:
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: CS(=O)(=O)Cl
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
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
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 dichloromethane (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 (75.33 g, 95.6%).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([Cl:30])=[C:14]([NH:16][C:17](=[O:29])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[N+:26]([O-])=O)[CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C(O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.[Fe]>[C:1]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([Cl:30])=[C:14]([NH:16][C:17](=[O:29])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[NH2:26])[CH:15]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)Nc2cc(NC(=O)c3ccccc3)ccc2Cl)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(C(=O)Nc2cc(NC(=O)c3ccccc3)ccc2Cl)c(N)c1
Temperature: 25 °C
Yield: 46 %

Procedure:
Iron powder (2.79 g) was added to a stirred suspension of N-(5-benzamido-2-chlorophenyl)-4-methoxy-2-nitrobenzamide (2.13 g) in a mixture of ethanol (100 ml), water (20 ml) and acetic acid (4 ml). The mixture was stirred and heated to reflux for 6 hours. The mixture was cooled to ambient temperature. Water (50 ml) was added and the resultant mixture was basified by the addition of sodium carbonate. The mixture was filtered and the filtrate was evaporated. The residue was triturated under water. The resultant solid was isolated and dried under vacuum at 40° C. There was thus obtained the title compound (0.911 g);
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Br:10])[CH2:5]O.S(Cl)([Cl:13])=O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Br:10])[CH2:5][Cl:13]
Reactant: OCc1ccc(Br)c(Br)c1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: ClCc1ccc(Br)c(Br)c1

Procedure:
3,4-Dibromobenzoic acid (28 g, described by Miller, J.C.S. 61, 1033 (1892)) was suspended with stirring in toluene (150 ml) at 50° C. Sodium dihydrobis(2-methoxyethoxy)aluminate (70% w/v, in toluene, 52 ml) was added over 30 minutes at 50° C. The mixture was heated on a steam bath for 1 hour, cooled to 20° C. and hydrolysed by the addition of hydrochloric acid (6N; 150 ml) with cooling. The mixture was separated and the aqueous phase was extracted with diethyl ether (100 ml). The combined organic extracts were washed with saturated sodium bicarbonate solution and water, dried over sodium sulphate, filtered and evaporated to give 3,4-dibromobenzyl alcohol (19 g) as a light red oil. The unpurified alcohol was dissolved in chloroform (60 ml) and the solution was heated at reflux. Thionyl chloride (20 ml) was added in portions over 10 minutes and the solution was heated at reflux for 1 hour. The reaction mixture was evaporated to give a light oily residue, which was repeatedly diluted with chloroform (3×50 ml) and the combined chloroformic solutions evaporated. The residue was dissolved in diethyl ether, washed with saturated sodium bicarbonate solution, dried over sodium sulphate, filtered and evaporated. 3,4-Dibromobenzyl chloride (20 g) was obtained as a clear mobile oil of sufficient purity for further reaction.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]2[NH:14][CH:13]=[C:12]([C:15]([OH:17])=O)[CH:11]=2)=[N:2]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[Cl:40][C:41]1[CH:48]=[CH:47][C:44]([CH2:45][NH2:46])=[CH:43][CH:42]=1>CN(C=O)C>[Cl:40][C:41]1[CH:48]=[CH:47][C:44]([CH2:45][NH:46][C:15]([C:12]2[CH:11]=[C:10]([C:3]3[C:4]4[C:5](=[N:6][CH:7]=[CH:8][CH:9]=4)[NH:1][N:2]=3)[NH:14][CH:13]=2)=[O:17])=[CH:43][CH:42]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: O=C(O)c1c[nH]c(-c2n[nH]c3ncccc23)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)c1c[nH]c(-c2n[nH]c3ncccc23)c1

Procedure:
A mixture of 5-(1H-pyrazolo[3,4-b]pyridin-3-yl)-1H-pyrrole-3-carboxylic acid (50 mg, 0.22 mmol), HOBt (74 mg, 2.5 eq.). EDAC•HCl (105 mg, 2.5 eq.), 4-chlorobenzylamine (4 eq.) and TEA (0.5 mL) in DMF (1 mL) was heated at 40° C. overnight. The reaction was concentrated and the residue was purified on a silica gel column to give the titled compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH2:6][C:5](=[O:7])[N:4]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=2[Cl:16])[N:3]=1.N1C=CC=CC=1.[N+](C1C=CC=CC=1)([O-])=O.[C:32](Cl)(=[O:35])[CH:33]=[CH2:34]>O1CCCC1.O>[Cl:14][C:13]1[CH:12]=[C:11]([Cl:15])[CH:10]=[C:9]([Cl:16])[C:8]=1[N:4]1[C:5](=[O:7])[CH2:6][C:2]([NH:1][C:32](=[O:35])[CH:33]=[CH2:34])=[N:3]1
Reactant: C=CC(=O)Cl
Reactant: NC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1
Solvent: O
Solvent: c1ccncc1
Solvent: O=[N+]([O-])c1ccccc1
Product: C=CC(=O)NC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1
Reaction time: 2 h
Yield: 32 %

Procedure:
224 g (0.8 mole) of 3-amino-1-(2,4,6-trichlorophenyl)-2-pyrazolin-5-one was dissolved in 3.5 l of tetrahydrofuran to which were added 144 ml (1.76 mol) of pyridine and 12 ml of nitrobenzene. To the mixture was gradually added dropwise 160 g (1.76 mol) of acryloyl chloride while cooling with ice and the mixture was stirred for about 2 hours. After adding 1 l of water, the mixture was extracted with 1.5 l of ethyl acetate, and the extract was dried with anhydrous sodium sulfate. After distilling off the solvent at fro 20° C. to 30° C. under reduced pressure, the residual oily product was dissolved in a mixture of 500 ml of water and 500 ml of ethanol, to which was then added 50 ml of an aqueous ammonia solution at room temperature. After stirring for 30 minutes, acetic acid was added to the mixture for neutralization and the crystals thus deposited were collected by filtration. By recrystallization from acetonitrile, 83 g (32% yield) of Coupler Monomer (5) was obtained.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[CH:5]=1.O.O.[OH-].[Li+].Cl>CO>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[CH2:14][CH2:13][O:12][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[O:10][CH3:11])[C:3]([OH:23])=[O:2]
Reactant: COC(=O)c1ccc(OC)c(OCCc2ccc(Cl)cc2Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(C(=O)O)cc1OCCc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
17 g of 3-[2-(2,4-Dichlorophenyl)-ethoxy]-4-methoxy-benzoic acid methyl ester were dissolved in 200 ml of MeOH:water/3:1. 4.1 g of lithium hydroxide monohydrate was added to the solution, and the reaction was stirred at RT for 16 h then at 90° C. for 2 h. The solution was cooled to RT, then acidified with half-concentrated hydrochloric acid. The solvents were removed under reduced pressure and the residue was washed twice with warm water to remove salts. The so obtained acid was used for the subsequent reaction without further purification.
Reaction SMILES: CC1(C)[O:6][C@@H:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C@:4]2([CH:11](O)[C:12]2[CH:13]=[C:14]([O:18][Si:19]([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:15]=[CH:16][CH:17]=2)[O:3]1.C1C=CC(OC(Cl)=S)=CC=1.N(C(C)(C)C#N)=NC(C)(C)C#N.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.C1(C)C=CC=CC=1.C([SnH](CCCC)CCCC)CCC.CO.C1COCC1.N1C=CC=CC=1>[C:32]([Si:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[O:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[CH2:11][C@:4]1([OH:3])[CH2:10][CH2:9][CH2:8][CH2:7][C@H:5]1[OH:6])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC1(C)O[C@@H]2CCCC[C@]2(C(O)c2cccc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)O1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)[Si](Oc1cccc(C[C@]2(O)CCCC[C@H]2O)c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.8 %

Procedure:
To a solution of 3-[((3aR,7aR)-2,2-dimethyl-hexahydro-1,3-benzodioxol-3a-yl) hydroxymethyl]-1-(tertbutyldiphenyl-silyloxy)benzene (45 g) in CH2Cl2 (450 ml) were added phenyl chlorothionoformate (14.5 ml) and pyridine (18 ml) at 0° C. After being stirred for 12 hours at room temperature, the mixture was evaporated and the resultant was partitioned between EtOAc and water. The organic layer was washed with water, 1N-HCl solution, sat.NaHCO3 solution and then brine. The solvent was evaporated in vacuo to give an oily residue. The residue was dissolved in toluene (400 ml) to which tributyltinhydride (50 ml) and 2,2′-azobis-(isobutyronitrile)(100 mg) were added. The mixture was refluxed for 4 hours under stirring and then purified by chromatography on silica gel to give an oily compound. The oily compound was dissolved in a mixture of MeOH (200 ml) and THF (100 ml), to which p-toluenesulphonic acid (200mg) was added at room temperature. The mixture was stirred for 12 hours and evaporated. The residue was partitioned between EtOAc and water. The organic layer was washed with water, sat. NaHCO3 solution and then brine. The solvent was evaporated in vacuo to give (1R,2R)-1-[3-(tertbutyldiphenylsilyloxy)benzyl]-1,2-dihydroxycyclohexane (30 g).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][CH:8]([Cl:31])[C:9]([NH:11][C@H:12]([CH2:29][F:30])[C@@H:13]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]#[N:28])=[CH:25][CH:26]=2)=[CH:17][CH:16]=1)[OH:14])=[O:10]>O1CCCC1>[NH2:28][CH2:27][C:24]1[N:23]=[CH:22][C:21]([C:18]2[CH:17]=[CH:16][C:15]([C@@H:13]([OH:14])[C@H:12]([NH:11][C:9](=[O:10])[CH:8]([Cl:31])[Cl:7])[CH2:29][F:30])=[CH:20][CH:19]=2)=[CH:26][CH:25]=1
Reactant: N#Cc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)cn1
Temperature: -40 °C
Reaction time: 4 h
Yield: 32.7 %

Procedure:
To an ice cold solution of lithium aluminum hydride (0.048 g, 1.33 mmol, 4.0 eq) in tetrahydrofuran (10 mL) to −40° C. is added a solution of 2,2-dichloro-N-((1R,2S)-1-(4-(6-cyanopyridin-3-yl)phenyl)-3-fluoro-1-hydroxypropan-2-yl)acetamide (0.13 g, 0.34 mmol) in tetrahydrofuran (5 mL) at −40° C. Further lithium aluminum hydride is added (0.012 g, 0.33 mmol) three times and reaction mixture is stirred at −40° C. for 4 hours. The reaction mixture is quenched with saturated aqueous sodium sulphate and stirred for 15 minutes followed by filtration. The filtrate is evaporated in vacuo and the crude material purified by column chromatography on silica gel using methanol/CH2Cl2 and ammonia to afford title compound (43 mg): 1H NMR (400 MHz, CDCl3) δ: 4.20-4.24 (m, 2H), 4.27-4.29 (m, 0.5H), 4.39-4.43 (m, 0.5H), 4.56-4.59 (m, 1H), 4.67-4.69 (m, 0.5H), 4.89-4.90 (m, 1H), 5.99 (d, J=4.2 Hz, 1H), 6.52 (s, 1H), 7.46-7.48 (m, 3H), 7.64-7.69 (m, 3H), 8.06-8.10 (m, 1H), 8.63 (d, J=8.76 Hz, 1H). LC-MS (m/z): [M+H]=386.10.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:19][CH2:18][NH:17][CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1.Cl[C:23]1[C:28]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:26]=[CH:25][N:24]=1.C(N(CC)C(C)C)(C)C>>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[C:11]3[CH2:19][CH2:18][N:17]([C:23]4[C:28]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:26]=[CH:25][N:24]=4)[CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccc(Nc2ncnc3c2CCNC3)cc1
Reactant: FC(F)(F)c1cccnc1Cl
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1ccc(Nc2ncnc3c2CCN(c2ncccc2C(F)(F)F)C3)cc1

Procedure:
The title compound was prepared according to the procedure given for Example 9 using N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine prepared as described in Example 1.D. (0.150 g, 0.51 mmol), 2-chloro-3-(trifluoromethyl)pyridine (0.185 g, 0.10 mmol), N,N-diisopropylethylamine (0.133 mL, 0.76 mmol) and heating the reaction mixture 6 h at 180° C. to obtain 0.130 g of a light yellow solid.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.CS(O[C@H:13]1[CH2:18][CH2:17][C@H:16]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][CH2:14]1)(=O)=O>CN(C)C=O>[N:3]1([C@@H:13]2[CH2:14][CH2:15][C@H:16]([NH:19][C:20](=[O:21])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:17][CH2:18]2)[CH:7]=[N:6][CH:5]=[N:4]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](OS(C)(=O)=O)CC1
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](n2cncn2)CC1
Reaction time: 0.08 h
Yield: 86.2 %

Procedure:
Sodium hydride (60%, 0.034 g, 0.86 mmol) was added portionwise to a solution of 1H-1,2,4-triazole (0.064 g, 0.92 mmol) in N,N-dimethylformamide (2 mL). After stirred for 5 min, trans-4-[(tert-butoxycarbonyl)amino]cyclohexyl methanesulfonate (0.18 g, 0.61 mmol) was added. The resulting mixture was stirred at 65° C. over weekend. The cooled mixture was poured into ice-cold water, extracted with EtOAc. The organic layers were concentrated and purified on silica gel (eluting with 0 to 5% MeOH in EtOAc) to give tert-butyl [cis-4-(1H-1,2,4-triazol-1-yl)cyclohexyl]carbamate (0.14 g, 86%). LCMS calculated for C13H23N4O2 (M+H)+: m/z=267.2. Found: 267.1. This carbamate intermediate was treated with trifluoroacetic acid (0.28 mL, 3.7 mmol) in methylene chloride (1 mL) at room temperature for 1 h and then concentrated to give the desired product as TFA salt. LCMS calculated for C8H15N4 (M+H)+: m/z=167.1. Found: 167.2.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=1)=[N:7]2.[CH2:20](B(O)O)[CH:21]([CH3:23])[CH3:22].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1>[CH3:19][C:14]1[CH:13]=[C:12]([C:6]2[CH:5]=[CH:4][C:3]3[C:8](=[CH:9][CH:10]=[CH:11][C:2]=3[CH2:20][CH:21]([CH3:23])[CH3:22])[N:7]=2)[CH:17]=[C:16]([CH3:18])[CH:15]=1
Reactant: Cc1cc(C)cc(-c2ccc3c(Cl)cccc3n2)c1
Reactant: CC(C)CB(O)O
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(C)cc(-c2ccc3c(CC(C)C)cccc3n2)c1
Temperature: 25 °C
Yield: 68.8 %

Procedure:
5-Chloro-2-(3,5-dimethylphenyl)quinoline (4.3 g, 16.06 mmol), isobutylboronic acid (3.2 g, 31.4 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (0.538 g, 1.31 mmol), and potassium phosphate monohydrate (18.3 g, 79 mmol) were mixed in 114 mL of toluene. The system was degassed for 20 minutes. Pd2(dba)3 was then added and the system was refluxed overnight. After cooling to room temperature, the reaction mixture was filtered through a Celite® plug and eluted with dichloromethane. The product was further purified by a Kugelrohr distillation and then further purified by column chromatography using 5% ethyl acetate in hexanes. This was followed by another Kugelrohr distillation to give 3.2 g (72% yield) of product.
Reaction SMILES: [K].[CH:2]([NH:4][CH:5]=[O:6])=[CH2:3].Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>C1COCC1>[CH2:8]([N:4]([CH:2]=[CH2:3])[CH:5]=[O:6])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCBr
Reactant: C=CNC=O
Agent: [K]
Solvent: C1CCOC1
Product: C=CN(C=O)CCCCCCCCCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a dry 250 mL three-necked round-bottomed flask equipped with magnetic stirring bar and dropping funnel was placed 8 g (0.07 mol) of fresh N-vinylformamide potassium salt and 200 mL of anhydrous THF. 1-Bromodecane, 16.1 g (0.07 mol) was added to the reaction mixture dropwise at 10° C. over 30 minutes. When addition was complete, the reaction was allowed to stir overnight at ambient temperature. The reaction mixture was concentrated under reduced pressure to remove most of the solvent and diluted with 100 mL of water. The organic layer was extracted with diethyl ether. The combined organic layers were washed twice with water and dried over anhydrous magnesium sulfate. The product was recovered after concentration in vacuum and purification by chromatography on silica (diethyl ether/petroleum ether (v/v=2:8). Yield: 13.2 g (89%). IR (NaCl, v: cm−1):1702 (—NHC(═O)H); 1631 (C═C); 1H-NMR (CDCl3, δ: ppm): 8.43, 8.27 (2s, 1H, —C(═O)H); 7.37–7.28, 6.73–6.65 (m, 1H, H2C═CH—); 4.78–4.67 (m, 1H, HaHbC═CH—); 4.58–4.55 (d, 1H, HaHbC═CH—); 3.72–3.56 (t, 2H, —NCH2CH2—); 1.76–1.62 (m, 2H, —NCH2CH2(CH2)7CH3); 1.44–1.28 (m, 14H, —NCH2CH2(CH2)7CH3); 1.04–1.00 (t, 3H, —NCH2CH2(CH2)7CH3).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH2:24][C@@H:25]5[CH2:27][O:26]5)=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]=[CH:13][N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:28][NH:29][CH3:30]>C1COCC1.CN(C=O)C>[OH:26][C@@H:25]([CH2:27][N:29]([CH3:30])[CH3:28])[CH2:24][O:23][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([O:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][CH:2]=[CH:3]4)=[N:12][CH:13]=[N:14]2)=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: CNC
Reactant: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@@H]1CO1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@@H](O)CN(C)C
Temperature: 75 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
A mixture of (2S)-4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline (100 mg, 0.28 mmol), (prepared as described for the starting material in Example 297), and dimethylamine (0.42 ml of a 2M solution in THF, 0.84 mmol) in DMF (5 ml) was stirred at 75° C. for 3 hours under an atmosphere of nitrogen and then allowed to cool to ambient temperature. The solvents were removed in vacuo and the residue purified by trituration with methanol to give (2S)-7-(2-hydroxy-3-dimethylaminopropoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline (100 mg, 85%).
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([NH2:10])=[N:7][C:6]=1[CH3:11])[CH2:2][CH2:3][CH3:4].[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([CH3:20])[C:14]=1[S:21](Cl)(=[O:23])=[O:22]>>[CH2:1]([C:5]1[S:9][C:8]([NH:10][S:21]([C:14]2[C:15]([CH3:20])=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=2[Cl:12])(=[O:23])=[O:22])=[N:7][C:6]=1[CH3:11])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1sc(N)nc1C
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Product: CCCCc1sc(NS(=O)(=O)c2c(C)cc(Cl)cc2Cl)nc1C

Procedure:
The title compound was prepared from 5-butyl-4-methyl-1,3-thiazol-2-ylamine (METHOD I) and 2,4-dichloro-6-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a yellow solid (41 mg) with purity >90%. MS (pos) m/z 393.2, 395.2.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C@@H:11]3[CH2:13][C@H:12]3[CH:14]=O)[C:5]=2[O:4][CH2:3][CH2:2]1.[OH:16][NH2:17]>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C@@H:11]3[CH2:13][C@H:12]3[CH:14]=[N:17][OH:16])[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: O=C[C@@H]1C[C@H]1c1cccc2c1OCCO2
Product: ON=C[C@@H]1C[C@H]1c1cccc2c1OCCO2

Procedure:
(-)-(trans)-2-(2,3-Dihydro-1,4-benzodioxin-5-yl)-1-cyclopropanecarboxaldehyde was reacted with hydroxyl amine as described above to give the oxime as a mixture of isomers.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH:15]1[C:23]2[C:18](=[CH:19][C:20]([C:24]3[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=3)[CH:27]=O)=[CH:21][CH:22]=2)[CH:17]=[CH:16]1.[CH2:32]([NH:39][CH2:40][CH2:41][N:42]([CH3:44])[CH3:43])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(O)(=O)C.C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:32]([N:39]([CH2:27][C:26]1[CH:29]=[CH:30][CH:31]=[C:24]([C:20]2[CH:19]=[C:18]3[C:23](=[CH:22][CH:21]=2)[NH:15][CH:16]=[CH:17]3)[CH:25]=1)[CH2:40][CH2:41][N:42]([CH3:44])[CH3:43])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CN(C)CCNCc1ccccc1
Reactant: O=Cc1cccc(-c2ccc3[nH]ccc3c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)CCN(Cc1ccccc1)Cc1cccc(-c2ccc3[nH]ccc3c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.7 %

Procedure:
Sodium triacetoxyborohydride (480 mg, 2.3 mmol) was added to a solution of 3-(1H-indol-5-yl)-benzaldehyde (250 mg, 1.1 mmol) and N′-benzyl-N,N-dimethyl-ethane-1,2-diamine (600 mg, 3.4 mmol) and acetic acid (204 mg, 3.4 mmol) in 8 mL of tetrahydrofuran. The mixture was stirred at ambient temperature overnight, and then it was diluted with ethyl acetate, and neutralized with the careful addition of saturated sodium bicarbonate solution. The layers were separated and the organic phase was treated with polystyrene supported isocyanate resin (1.49 mmol/g, 1.7 g) for 2 h. The mixture was filtered and the filtrate was washed with 1M sodium carbonate solution. The aqueous phase was extracted into ethyl acetate, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated to leave 290 mg of the title compound. LC/MS (short method): retention time, 2.61 min; (M+H)=384.50.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH:8](=[C:2]1[CH2:3][CH2:4][CH2:5][C:6](=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:1]1=[O:7])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1CCCCC1
Product: O=C1C(=Cc2ccccc2)CCCC1=Cc1ccccc1
Reaction time: 2 h

Procedure:
(75) Cyclohexanone (10 mmol) and benzaldehyde (20 mmol) were used. The reaction stirred for 2 hours. A solid formed and was filtered. Recrystallization from ethanol yielded 2.01 g (73.4%) of bright-yellow flakes: mp 118.1-119.0° C. (lit. mp 116-117° C., Smith, et al., Can. J. Chem., 1973, 51, 1458-1470). 1H NMR (250 MHz) δ 7.83 (s, 2 H), 7.50-7.32 (m, 10 H), 2.95 (t, 4 H), 1.80 (p, 2 H); 13C NMR (62.7 MHz) 190.5, 137.1, 136.4, 136.1, 130.5, 128.8, 128.5, 28.6, 23.2 ppm.