Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:14])[CH2:10][C:11](=[O:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:15]Br.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([NH:8][C:9](=[O:14])[CH2:10][C:11](=[O:13])[CH2:12][Br:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)CC(=O)NCc1ccccc1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CBr)CC(=O)NCc1ccccc1
Temperature: 22.5 °C
Yield: 80.9 %

Procedure:
To a solution of N-benzyl-3-oxobutanamide (compound A 100 g, 522.9 mmol) in dichloromethane (500 ml) at 0-5° C. was added dropwise a solution of bromine (25.55 ml, 575.2 mmol) over 6 h. The reaction mixture was warmed up to 20-25° C. and stirred for 2 hours (bromine colour disappeared). An aqueous solution (600 mL) of sodium bicarbonate (65.9 g, 784.44 mmol) was added to the mixture. The organic layer was separated, washed with brine (200 mL), and then evaporated to dryness to give N-benzyl-4-bromo-3-oxobutanamide (114.25 g, quantitative) and was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[O:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[N:3]=1.[OH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:13]2[O:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[C:5]([C:11]#[N:12])=[C:6]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:7]=1
Reactant: Cc1ccc(-c2nc(N)nc(S(C)=O)c2C#N)o1
Reactant: OCc1ccccn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Cc1ccc(-c2nc(N)nc(OCc3ccccn3)c2C#N)o1

Procedure:
From 2-amino-4-methanesulfinyl-6-(5-methyl-furan-2-yl)-pyrimidine-5-carbonitrile, 2-(hydroxymethyl)pyridine and DBU in DME. ES-MS m/e (%): 308 (M+H+, 100).
Reaction SMILES: [C:1](#[N:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][C:12]1[NH:16][N:15]=[C:14]([NH2:17])[CH:13]=1.[O:18]1[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]1>>[O:18]1[CH2:23][CH2:22][CH:21]([NH:24][C:3]2[CH:2]=[C:1]([NH:17][C:14]3[CH:13]=[C:12]([CH3:11])[NH:16][N:15]=3)[N:10]=[C:1]([CH:2]=[CH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[N:10]=2)[CH2:20][CH2:19]1
Reactant: NC1CCOCC1
Reactant: N#CC=Cc1ccccc1
Reactant: Cc1cc(N)n[nH]1
Product: Cc1cc(Nc2cc(NC3CCOCC3)nc(C=Cc3ccccc3)n2)n[nH]1

Procedure:
Example 99 was synthesized via Scheme 6 according to the general scheme provided above with the appropriate starting materials cinnamonitrile, 5-methyl-1H-pyrazole-3-amine, and tetrahydro-2H-pyran-4-amine. Structure of the target was confirmed by 1H-NMR. The 1H-NMR is attached.
Reaction SMILES: C([O:4][C:5]([C:7]1([CH2:13][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])CC.CC([O-])(C)C.[K+].O.OS(O)(=O)=O>C1COCC1>[CH2:17]([CH:14]([CH2:15][CH3:16])[CH2:13][C:7]1([C:5]([OH:6])=[O:4])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)[CH3:18]
Reactant: CCCOC(=O)C1(CC(CC)CC)CCCCC1
Agent: CC(C)(C)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCC(CC)CC1(C(=O)O)CCCCC1
Temperature: 54 °C
Reaction time: 20 h
Yield: 99 %

Procedure:
1-(2-Ethyl-butyl)-cyclohexanecarboxylic acid n-propyl ester (2.3 g, 9.04 mmol) was added dropwise under stirring to a solution of KOtBu (4.058 g, 36.2 mmol) in THF (17 mL) containing a small amount of water (244 mg, 13.6 mmol). The mixture was stirred 20 h at 54° C., cooled to room temperature, slowly poured onto a mixture of ice and 4N H2SO4 and extracted with DCM (2×150 mL) after adjusting to pH 1. The organic phases were washed with diluted aq. NaCl (100 mL), combined, dried over sodium sulfate and concentrated to afford 1.901 g (99%) 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid, purity 96% (GC area).
Reaction SMILES: [Si:1]([O:8][CH:9]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:31]#[N:32])[CH:29]=2)[O:24][C:11]2([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCN(CC)CC.Cl.[OH:41][NH2:42]>CCO>[NH2:32][C:31](=[N:42][OH:41])[C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)[CH2:10][CH:9]2[O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(O[Si](C)(C)C(C)(C)C)c1cc(C#N)ccc1O2
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(O[Si](C)(C)C(C)(C)C)c1cc(C(N)=NO)ccc1O2

Procedure:
To a suspension of 18.2 g of tert-butyl 4-{[tert-butyl(dimethyl)silyl]oxy}-6-cyano-spiro[chroman-2,4′-piperidine]-1′-carboxylate in EtOH was added 16.3 mL of Et3N and 8.12 g of hydroxyamine hydrochloride at rt, and the reaction mixture was stirred at 85° C. for 1d. The resultant solution was cooled to rt, and concentrated in reduced pressure. To the residue was added H2O, the resultant white solid was filtered, washed with H2O, and dried in vacuo to give a crude product, which was used in the next step without further purification.
Reaction SMILES: [H-].[Na+].[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:24])[O:22][CH3:23])=[C:16]([CH3:25])[CH:15]=1.[Cl:26][CH:27]([CH3:31])[C:28](Cl)=[O:29].O>CN(C)C=O>[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]([C:21]([O:22][CH3:23])=[O:24])[C:28](=[O:29])[CH:27]([Cl:26])[CH3:31])=[C:16]([CH3:25])[CH:15]=1
Reactant: CC(Cl)C(=O)Cl
Reactant: COC(=O)Nc1ccc(OCc2nc3ccccc3s2)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)N(C(=O)C(C)Cl)c1ccc(OCc2nc3ccccc3s2)cc1C
Reaction time: 0.25 h
Yield: 54 %

Procedure:
18 mg of sodium hydride (as a 60% w/w dispersion in mineral oil) were added to a solution of 100 mg of methyl N-[4-(benzothiazol-2-ylmethoxy)-2-methylphenyl]carbamate (prepared as described in Example 22 above) in 4 ml of dimethylformamide cooled in an ice-water bath. The resulting mixture was stirred for 15 minutes at the same temperature, after which 0.059 mi of 2-chloropropionyl chloride were added. The temperature of the resulting mixture was elevated to room temperature and the mixture was stirred for 3 hours. At the end of this time, water was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The resulting extract was washed consecutively with water and a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure. The resulting.; residue was purified by preparative thin layer chromatography using a 1:1 by volume mixture of hexane and ethyl acetate to give 70 mg (yield 54%) of the title compound as an oil.
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][S:7]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:13][CH:12]=1)(=[O:9])=[O:8].C([Li])CCC.[CH3:35][C:36]([CH3:38])=[O:37].FC(F)(F)C(O)=O>C1COCC1.CCCCCC>[OH:37][C:36]([CH3:38])([CH3:35])[CH:10]([C:11]1[CH:12]=[CH:13][C:14]([CH2:17][N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)=[CH:15][CH:16]=1)[S:7]([NH2:6])(=[O:8])=[O:9]
Reactant: COc1ccc(CNS(=O)(=O)Cc2ccc(CN3CCOCC3)cc2)c(OC)c1
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(O)C(c1ccc(CN2CCOCC2)cc1)S(N)(=O)=O
Reaction time: 0.08 h

Procedure:
Under inert gas, 0.410 g of N-(2,4-dimethoxybenzyl)-C-(4-morpholin-4-ylmethylphenyl)methanesulfonamide was initially charged in 5 ml of THF and then, at −78° C., 1.34 ml of a 1.6 N butyllithium solution in hexane were added dropwise. The reaction mixture was stirred for 5 minutes and then 0.29 ml of acetone was added dropwise. The mixture was stirred at constant temperature for 5 minutes, 0.22 ml of trifluoroacetic acid were added and the mixture was allowed to come to room temperature. The solvent was removed under reduced pressure. The residue was dissolved in 10 ml of dichloromethane, and 2 ml of trifluoroacetic acid were added. After stirring at room temperature for 16 h, 20 ml of 1M HCl were added and the aqueous phase was removed and concentrated. This gave the crude product with a molecular weight of 364.9 g/mol (C15H25N2O4S), which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[NH:31][C:20]3[C:21](=[O:30])[N:22]([CH3:29])[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=4[C:19]=3[N:18]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:32])[NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[N:31]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:20]3[C:21](=[O:30])[N:22]([CH3:29])[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=4[C:19]=3[N:18]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: Cn1c(=O)c2[nH]c(C3CCCC(NC(=O)OCc4ccccc4)C3)nc2c2ccccc21
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(nc(C3CCCC(NC(=O)OCc4ccccc4)C3)n2Cc2ccccc2)c2ccccc21
Yield: 70 %

Procedure:
According to the procedure described in example 3, step E; [3-(5-methyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]quinolin-2-yl)-cyclohexyl]-carbamic acid benzyl ester (94 mg, 0.22 mmol) in DMF (3.5 mL) was alkylated with benzyl bromide to give, after work-up and chromatography, [3-(3-benzyl-5-methyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]quinolin-2-yl)-cyclohexyl]-carbamic acid benzyl ester (80 mg, 70% yield). 1H-NMR (CDCl3): δ 8.38 (m, 1H), 7.52 (m, 1H), 7.42 (m, 1H), 7.22-7.37 (m, 9H), 7.12 (m, 1H), 5.97 (m, 1H), 5.82 (m, 1H), 5.09 (s, 2H), 3.78 (s, 3H), 3.68 (m, 1H), 2.94 (m, 1H), 2.08 (m, 1H), 1.93 (m, 1H), 1.81 (m, 2H), 1.73 (m, 1H), 1.62 (m, 2H), 1.35 (m, 2H). MS: calculated for C33H31N5O3+H 521.3; found: 521.2.
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl-].[CH3:12][O:13][CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[F:34][C:35]1[CH:53]=[CH:52][CH:51]=[C:50]([F:54])[C:36]=1[CH2:37][N:38]1[C:43]([CH3:44])=[C:42](C=O)[C:41](=[O:47])[C:40]([Br:48])=[C:39]1[CH3:49]>C1(C)C=CC=CC=1.C1COCC1>[F:54][C:50]1[CH:51]=[CH:52][CH:53]=[C:35]([F:34])[C:36]=1[CH2:37][N:38]1[C:43]([CH3:44])=[C:42]([CH:1]=[CH:14][O:13][CH3:12])[C:41](=[O:47])[C:40]([Br:48])=[C:39]1[CH3:49]
Reactant: Cc1c(Br)c(=O)c(C=O)c(C)n1Cc1c(F)cccc1F
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC=Cc1c(C)n(Cc2c(F)cccc2F)c(C)c(Br)c1=O
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
KHMDS (2.4 mmol, 4.8 mL of a 0.5 M solution in toluene) was added dropwise to a vigorously stirred suspension of (methoxymethyl)triphenylphosphonium chloride (771 mg, 2.25 mmol) in anhydrous THF (8 mL), at −78° C. under N2. The resulting orange suspension was stirred at −78° C. for 45 min. Then, a solution of 1-(2,6-difluorobenzyl)-2,6-dimethyl-3-bromo-5-formyl-4-pyridone (534 mg, 1.50 mmol) in THF (8 mL) was added dropwise and the reaction was allowed to warm slowly to room temperature. After 1 h at room temperature, the reaction was quenched with an aqueous saturated solution of NaHCO3. The organics were extracted with EtOAc (50 mL), the organic layer was separated, washed with H2O and brine, dried over MgSO4, filtered and evaporated under vacuum. The crude residue was utilized in the next step. LRMS m/z 384.0 (M+−1), 386.0 (M++1).
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH:14]=[CH:13]3)C(=O)C2=CC=CC=C12.O.NN.Cl>C(O)C>[NH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[CH:14]=[CH:13]2
Reactant: O=C1c2ccccc2C(=O)N1CCCOc1ccc2[nH]c(=O)ccc2c1
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCOc1ccc2[nH]c(=O)ccc2c1
Reaction time: 1 h
Yield: 74.5 %

Procedure:
To a suspension of 6-(3-phthalimidopropoxy)carbostyril (300 g) in ethanol (3 liters) is added hydrazine monohydrate (46 g), and the mixture is refluxed for 8 hours. After the mixture is allowed to cool, the precipitated crystals are collected by filtration, suspended in water, and the suspension thus obtained is acidified with conc. hydrochloric acid, and stirred for one hour. The insoluble materials are removed by filtration, and the filtrate is concentrated under reduced pressure to remove the solvent. The residue is neutralized to pH 7 with a 15% aqueous sodium hydroxide solution. The precipitated crystals are collected by filtration, and washed successively with ethanol and diethyl ether, and dried to give 6-(3-aminopropoxy)carbostyril (140 g) as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([NH2:16])=[CH:15][C:9]=2[S:8][CH:7]=1)[CH3:2].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([NH:16][S:26]([CH3:25])(=[O:28])=[O:27])=[CH:15][C:9]=2[S:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)CC1=CSc2cc(N)ccc2N1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC1=CSc2cc(NS(C)(=O)=O)ccc2N1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
A solution of (7-amino-4H-benzo[1,4]thiazin-3-yl)-acetic acid ethyl ester (2.38 g, 9.51 mmol) in dichloromethane (80 mL) was cooled to 0° C. and treated with triethylamine (3.1 g, 30.4 mmol) followed by dropwise addition of methanesulfonyl chloride (1.37 g, 9.51 mmol). The reaction mixture was stirred at 0° C. for 0.5 h and allowed to warm to 25° C. The reaction mixture was concentrated in vacuo and purified by flash column chromatography (Merck silica gel 60, 40-63 μm, ethyl acetate/hexanes) to afford the desired product, (7-methanesulfonylamino-4H-benzo[1,4]thiazin-3-yl)-acetic acid ethyl ester (2.2 g, 6.7 mmol, 71%) as a light tan solid. 1H NMR (400 MHz, CDCl3) δ 1.31 (t, 3H, J=7.0 Hz), 3.00 (s, 3H), 3.43 (s, 2H), 4.19 (quartet, 2H, J=7.1 Hz), 4.73 (s, 1H), 6.28 (s, 1H), 6.85 (d, 1H, J=8.5 Hz), 6.99 (dd, 1H, J1=8.5 Hz, J2=2.4 Hz), 7.12 (d, 1H, J=2.3 Hz), 10.64 (bs, 1H). LC-MS (ESI) calcd for C13H16N2O4S [M+H+] 329.06, found 329.10 [M+H+].
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4](=[O:14])[C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1.[C:15]([O:19][C:20](=[O:29])[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH2:28])([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C.O>ClCCl>[C:15]([O:19][C:20]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][C:9](=[O:11])[C:8]1[CH:7]=[CH:6][C:5]([C:4]([O:3][CH3:2])=[O:14])=[CH:13][CH:12]=1)=[O:29])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1
Yield: 99 %

Procedure:
Under ice cooling, terephthalic acid monomethylester chloride (1.1 g, 5.0 mmol) was added to a solution of 2-aminophenylcarbamic acid t-butyl ester (Reference Compound No. 1-1, 1.1 g, 5.0 mmol) and triethylamine (30 mL) in dichloromethane (15 mL), and then the mixture was stirred at room temperature for 4 hours. Water (50 mL) was added thereto, and the whole was extracted with ethyl acetate (40 mL) twice. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The resulting solid was collected by filtration with a mixed solvent (hexane (10 mL) and ethyl acetate (5 mL)), and the whole was dried under reduced pressure to give 1.8 g of the title reference compound as a white solid. (Yield 99%)
Reaction SMILES: [CH3:1][N:2]([S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[C:8]=1[CH2:17][S:18](Cl)(=[O:20])=[O:19])(=[O:6])=[O:5])[CH3:3].[OH-].[NH4+:23]>O1CCCC1>[CH3:1][N:2]([S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[C:8]=1[CH2:17][S:18]([NH2:23])(=[O:20])=[O:19])(=[O:6])=[O:5])[CH3:3]
Reactant: [NH4+]
Reactant: COC(=O)c1cccc(S(=O)(=O)N(C)C)c1CS(=O)(=O)Cl
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)c1cccc(S(=O)(=O)N(C)C)c1CS(N)(=O)=O
Temperature: 25 °C

Procedure:
A solution of the crude sulfonyl chloride from Example 13 in 150 ml of tetrahydrofuran was cooled to 0° and treated with 7.3 ml of concentrated aqueous ammonium hydroxide. The resulting suspension was allowed to warm to room temperature. Removal of the solvent in vacuo gave an oily residue which was triturated with 300 ml water. The precipitate was collected by filtration, washed with n-butyl chloride and dried to yield 9.3 g of 2-[(N,N-dimethylamino)sulfonyl]-6-(methoxycarbonyl)phenylmethanesulfonamide as a light yellow solid, m.p. 133°-142°; IR(nujol): 3400, 3310, 1720 cm-1 ; NMR (CDCl3 /DMSO-d6): δ 2.6 (6H, s, SO2N(CH3)2), 3.8 (3H, s, CO2CH3), 5.35 (2H, s, --CH2 --), 5.3-5.9 (2H, br s, NH2), 7.4-8.3 (3H, m).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].O[CH2:8][CH2:9][CH2:10][P:11]([CH3:14])(=[O:13])[OH:12].CP(Cl)Cl.Cl>>[CH3:14][P:11]1(=[O:13])[CH2:10][CH2:9][CH2:8][O:12]1.[CH3:10][P:11]1(=[O:12])[CH2:3][CH:2]([CH3:4])[C:1](=[O:6])[O:5]1
Reactant: C=C(C)C(=O)O
Reactant: CP(=O)(O)CCCO
Agent: CP(Cl)Cl
Agent: Cl
Product: CC1CP(C)(=O)OC1=O
Product: CP1(=O)CCCO1

Procedure:
A mixture of 43 g (0.5 mole) of methacrylic acid and 69 g (0.5 mole) of 3-hydroxypropyl-methyl-phosphinic acid is added to 58.5 g (0.5 mole) of methyldichloro-phosphine at 50°-60° C., while hydrogen chloride is discharged. Subsequently heating takes place under water jet vacuum to an internal temperature of up to 150° C. The residue is distilled under reduced pressure. 35 g of 2-methyl-2-oxo-1,2-oxa-phospholane (boiling point at 1.5 mm Hg: 120°-130° C.) and 55 g of 2,4-dimethyl-2,5-dioxo-1,2-oxa-phospholane (boiling point at 0.7 mm Hg: 150°-155° C.) are obtained. The yield in 2,4-dimethyl-2,5-dioxo-1,2-oxa-phospholane represents 71% of the theoretical yield.
Reaction SMILES: [C:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[N:13]=2)[C:8](=[O:20])[C:7]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:26]N1C(C)(C)C(=O)N(Cl)C1=O>ClCCl.S(=O)(O)[O-].[Na+]>[C:1]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([Cl:26])=[C:12]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[N:13]=2)[C:8](=[O:20])[C:7]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cn(C(C)(C)C)c2nc(N3CCCC3)ccc2c1=O
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1cn(C(C)(C)C)c2nc(N3CCCC3)c(Cl)cc2c1=O

Procedure:
A solution of Example 74A (448 mg) and 1,3-dichloro-5,5-dimethylhydantoin (282 mg) in dichloromethane (15 mL) was stirred for 8 hours, diluted with 10% sodium bisulfite (30 mL), and extracted with dichloromethane. The extract was washed with water and brine (30 mL), and dried (MgSO4), filtered, and concentrated.
Reaction SMILES: [N:1]#[C:2][NH2:3].[N:4]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH:20]3[CH2:22][CH2:21]3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)=[C:5]=[S:6].Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=1)=[O:26]>>[NH2:1][C:2]1[N:3]=[C:5]([NH:4][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[CH2:14][CH2:15][N:16]([CH2:19][CH:20]4[CH2:22][CH2:21]4)[CH2:17][CH2:18]3)=[CH:11][CH:12]=2)[S:6][C:24]=1[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=1)=[O:26]
Reactant: O=C(CBr)c1cccc(F)c1
Reactant: N#CN
Reactant: S=C=Nc1ccc(N2CCN(CC3CC3)CC2)cc1
Product: Nc1nc(Nc2ccc(N3CCN(CC4CC4)CC3)cc2)sc1C(=O)c1cccc(F)c1

Procedure:
This compound was prepared from cyanamide, 1-(4-isothiocyanatphenyl)-4-cyclopropylmethylpiperazine (of Example 14G) and 2-bromo-1-(3-fluoro-phenyl)ethanone (Aldrich) following the procedure used in Example 24 Mass spectrum (ES) MH+=452.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[Br:14]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>S(=O)(=O)(O)O>[Br:14][C:12]1[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: O=[N+]([O-])c1ccc2ncccc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(Br)c2ncccc2c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 35.2 %

Procedure:
To a flask containing 6-nitroquinoline (4 g, 23 mmol) in sulfuric acid (20 ml) was added N-bromo-succinimide (5.31 g, 29.9 mmol). The mixture was heated to 60° C. (oil bath) for 6 hours and then stored in a freezer overnight. The crude reaction mixture was poured into a beaker containing ice (250 ml). The material was basified by adding first solid sodium bicarbonate and then a saturated solution of sodium bicarbonate (to a pH of about 10). During this procedure ethyl acetate (60 ml) was also added. The material was filtered to remove insoluble material and the filtrate transferred to a reparatory funnel. Ethyl acetate (100 ml) was added and the biphasic material shaken. The organic phase was collected and shaken with an equal volume of brine solution. The ethyl acetate phase was collected and the aqueous phases were back extracted with ethyl acetate (2×100 ml). The combined organic phase was stripped to provide a solid. The solid from the above filtration was taken up in hot ethyl acetate (60 ml). The material was cooled to ambient, dried over magnesium sulfate and filtered. The solvent was stripped and the crude solid product was combined with the material obtained from aqueous work up. This material was crystallized from hot ethyl acetate/hexane to provide the desired product as a yellow powder (2.05 g).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:11]2[C:16]([CH3:17])=[C:15]([CH3:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=3)[C:11]3[C:16]([CH3:17])=[C:15]([CH3:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: Cc1sc2nc(Cl)nc(NCc3cccc([N+](=O)[O-])c3)c2c1C
Product: Cc1sc2nc(-n3ccnc3C)nc(NCc3cccc([N+](=O)[O-])c3)c2c1C

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-5,6-dimethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-5,6-dimethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([CH:8]=1)[NH2:7].[I:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([NH:7][S:18]([C:15]2[CH:16]=[CH:17][C:12]([I:11])=[CH:13][CH:14]=2)(=[O:20])=[O:19])[CH:8]=1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: COc1ccc(Br)cc1N
Product: COc1ccc(Br)cc1NS(=O)(=O)c1ccc(I)cc1

Procedure:
The title compound was prepared from 5-bromo-2-(methyloxy)aniline and 4-iodobenzenesulfonyl chloride using a similar method to that described for Examples 82-100 (E82-E100). MS (ES−) 466/468 [M−H]−.
Reaction SMILES: [Fe:1](Cl)(Cl)Cl.N.[OH-].[Fe+3].[OH-].[OH-].[C:10]([CH2:13][C:14](=[O:16])[CH3:15])(=[O:12])[CH3:11]>O>[CH3:15]/[C:14](/[O-:16])=[CH:13]/[C:10]([CH3:11])=[O:12].[CH3:15]/[C:14](/[O-:16])=[CH:13]/[C:10]([CH3:11])=[O:12].[CH3:15]/[C:14](/[O-:16])=[CH:13]/[C:10]([CH3:11])=[O:12].[Fe+3:1]
Reactant: CC(=O)CC(C)=O
Reactant: Cl[Fe](Cl)Cl
Agent: [Fe+3]
Agent: N
Agent: [OH-]
Solvent: O
Product: CC(=O)/C=C(/C)[O-]

Procedure:
20.3 g of anhydrous iron (III) chloride (0.124 mol) was dissolved in 30 g of demineralised water with gentle warming. To this was added 45 ml of ammonia solution (SG. 0.880). The mixture was then heated on a steam bath for 30 minutes. The precipitate of iron (III) hydroxide was filtered and washed free of chloride. The moist iron (III) hydroxide and 60 g of acetylacetone (0.6 mol) were mixed together and heated for 30 minutes. Crystals of Fe(acac)3 were deposited and were recrystallised from ethanol.