Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])(C)(C)C.[Cl:31][C:32]1[CH:33]=[C:34]([CH2:38][CH2:39][NH2:40])[CH:35]=[CH:36][CH:37]=1>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:40][CH2:39][CH2:38][C:34]3[CH:35]=[CH:36][CH:37]=[C:32]([Cl:31])[CH:33]=3)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Reactant: NCCc1cccc(Cl)c1
Product: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCCc3cccc(Cl)c3)n2)c1

Procedure:
Intermediate 4 was coupled to 2-(3-Chloro-phenyl)-ethylamine following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 474. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.30 ppm) δ 8.85 (m, 1H) 8.15 (m, 4H) 7.6 (m, 6H) 4.45 (s, 2H) 3.95 (m, 2H) 3.4 (m, 2H) 3.18 (m, 4H) 3.0 (m, 2H) 2.9 (s, 3H) 1.75 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:18]([OH:20])=[O:19])[S:17][C:13]=2[N:12]2[C:21]([CH3:24])=[N:22][N:23]=[C:11]2[CH2:10][N:9]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:31](I)[CH3:32]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:18]([O:20][CH2:31][CH3:32])=[O:19])[S:17][C:13]=2[N:12]2[C:21]([CH3:24])=[N:22][N:23]=[C:11]2[CH2:10][N:9]=1
Reactant: CCI
Reactant: Cc1nnc2n1-c1sc(C(=O)O)cc1C(c1ccccc1Cl)=NC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(s1)-n1c(C)nnc1CN=C2c1ccccc1Cl
Reaction time: 8 h

Procedure:
The obtained (4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepin-2-yl)carboxylic acid was dissolved in dimethylformamide. Potassium carbonate and ethyl iodide were added, and the mixture was stirred overnight to give ethyl (4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepin-2-yl)carboxylate.
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[NH2:5][C@@H:6]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O>O1CCOCC1>[NH2:5][C@@H:6]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)[C:7]([O:9][C:2]([CH3:3])([CH3:1])[CH3:4])=[O:8]
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Liquid isobutylene (45 ml) was slowly added to a mixture of (2S)-2-amino-3-(4-nitrophenyl)propionic acid (7.2 g), 1,4-dioxane (45 ml) and concentrated sulphuric acid (4.5 ml) in a pressure bottle. The vessel was sealed and the reaction mixture was agitated at ambient temperature for 24 hours and then carefully opened. The excess of isobutylene was allowed to evaporate. The reaction mixture was poured into an ice-cold mixture of ethyl acetate (250 ml) and 0.25M NaOH(aq) (300-400 ml). The pH of the two-phase system was adjusted to between 9 and 10, and the ethyl acetate layer was separated. The aqueous layer was re-extracted with ethyl acetate (200 ml) and the combined organic extracts were washed with water, dried (MgSO4) and evaporated to give t-butyl (2S)-2-amino-3-(4-nitrophenyl)propionate (6.9 g) as a brown oil which was used without further purification.
Reaction SMILES: C(N(CC)CC)C.[SH:8][C:9]1[S:10][CH2:11][CH2:12][N:13]=1.[CH2:14]([O:16][C:17](=[O:27])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1Br)[CH3:15]>C1COCC1>[CH2:14]([O:16][C:17](=[O:27])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:8][C:9]1[S:10][CH2:11][CH2:12][N:13]=1)[CH3:15]
Reactant: CCOC(=O)CCc1ccccc1Br
Reactant: SC1=NCCS1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CCc1ccccc1SC1=NCCS1

Procedure:
1.4 ml of triethylamine are added dropwise to a solution of 1.8 g of 2-mercapto-1,3-thiazoline and 2.6 g of 2-bromo-hydrocinnamic acid ethyl ester in 15 ml of THF and the whole is stirred under reflux for 6 hours. The reaction mixture is filtered, the filtrate is concentrated by evaporation and the residue is partitioned between ethyl acetate and water. The organic phase is washed with water, dried, concentrated by evaporation and purified by chromatography on silica gel with eluant R. Rf (W)=0.67.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].[CH3:9][C:10]1([CH3:26])[C:14]([CH3:16])([CH3:15])[O:13][B:12]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][NH2:25])=[CH:19][CH:18]=2)[O:11]1.C1CCN2C(=NCCC2)CC1.Cl>ClCCl>[CH3:15][C:14]1([CH3:16])[C:10]([CH3:9])([CH3:26])[O:11][B:12]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][NH:25][S:5]([CH2:4][CH2:3][CH2:2][Cl:1])(=[O:7])=[O:6])=[CH:19][CH:18]=2)[O:13]1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CC1(C)OB(c2ccc(CCN)cc2)OC1(C)C
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC1(C)OB(c2ccc(CCNS(=O)(=O)CCCCl)cc2)OC1(C)C
Temperature: 23 °C
Reaction time: 2 h
Yield: 66.1 %

Procedure:
Add 3-chloropropanesulfonyl chloride (0.285 g, 1.6 mmol) to a suspension of 2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ethylamine (0.383 g, 1.3 mmol) in dichloromethane (10 mL) at 0° C. Then slowly add DBU (0.457 g, 3.0 mmol) and allow the mixture to warm up to 23° C. Stir 2 h at 23° C. and add more dichloromethane and 1M HCl. Separate layers and wash organic phase with more HCl (×2). Back-extract aqueous phase with dichloromethane (×2). Combine organic phases and wash them with brine, dry over sodium sulfate, concentrate over Celite® and purify by flash chromatography (silica gel), eluting with hexanes-ethyl acetate 3:1 to give 0.333 g of the desired compound as a thick oil. Mass spectrum ESI positive (m/z): 388 (M+1), 410 (M+23).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C1COCC1.C([O-])(O)=O.[Na+].[Cl:45][CH2:46][C:47](Cl)=[O:48]>CCOC(C)=O>[Cl:45][CH2:46][C:47]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1)=[O:48]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(N)c4)nc4ccccc34)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(NC(=O)CCl)c4)nc4ccccc34)ccc21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (1.0 g, 2.21 mmol) in EtOAc:THF:sat'd NaHCO3 (110 mL: 30 mL: 50 mL) was added 2-chloroacetyl chloride (1 mL, 12.6 mmol) and stirred at RT for 2.5 hr. The reaction mixture was stirred at RT for 1.5 h. Another addition of 2-chloroacetyl chloride (0.5 mL) was added and continued to stir for 2 h. Concentrated in vacuo to remove volatiles and residue was washed with 5% citric acid (2×50 mL), water (2×100 mL), and sat'd NaCl (1×50 mL). The organic layer was dried under Na2SO4 and concentrated in vacuo to give the desired product tert-butyl 5-(2-(3-(2-chloroacetamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate. (1.02 g, 87%)
Reaction SMILES: C([SiH](CC)CC)C.FC(F)(F)C(O)=O.ClC(Cl)C.[C:19]1([N:25](COCC[Si](C)(C)C)[S:26]([C:29]2[C:34]([CH:35]=O)=[CH:33][CH:32]=[CH:31][N:30]=2)(=[O:28])=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH3:45][O:46][C:47](=[O:60])[CH2:48][N:49]1[C:57]2[C:52](=[CH:53][C:54]([F:58])=[CH:55][CH:56]=2)[CH:51]=[C:50]1[CH3:59]>>[CH3:45][O:46][C:47](=[O:60])[CH2:48][N:49]1[C:57]2[C:52](=[CH:53][C:54]([F:58])=[CH:55][CH:56]=2)[C:51]([CH2:35][C:34]2[C:29]([S:26](=[O:27])(=[O:28])[NH:25][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[N:30][CH:31]=[CH:32][CH:33]=2)=[C:50]1[CH3:59]
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Reactant: C[Si](C)(C)CCOCN(c1ccccc1)S(=O)(=O)c1ncccc1C=O
Agent: CC[SiH](CC)CC
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cn1c(C)c(Cc2cccnc2S(=O)(=O)Nc2ccccc2)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.6 %

Procedure:
A mixture of triethylsilane (3.1 mL), trifluoroacetic acid (0.88 mL) and dichloroethane (12 mL) at −15° C. was treated dropwise with a mixture of 3-formylpyridine-2-sulfonic acid phenyl[2-(trimethylsilanyl)ethoxymethyl]amide (0.55 g), (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester (0.29 g) and dichloroethane (18 mL), and the resulting mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane. The mixture was washed with saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane, cyclohexane, ethyl acetate and methanol (9:1:0:0 to 0:0:9:1 by volume) to afford the title compound (0.20 g).
Reaction SMILES: [N-]=C=O.[N-]=C=O.C1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)C=CC=CC=1.[N+:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([O-])=O.NC1C=CC=CC=1.C=O>C1C=CC=CC=1>[CH2:13]=[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]1[NH:20][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=[N+]([O-])c1ccccc1
Reactant: c1ccc(Cc2ccccc2)cc1
Agent: C=O
Agent: [N-]=C=O
Solvent: Nc1ccccc1
Solvent: c1ccccc1
Product: C=C1C=CC=CC1Nc1ccccc1

Procedure:
The invention relates to a process for preparation and distillative workup of diphenylmethane diisocyanate, referred to hereinafter as MDI for short, proceeding from a benzene-comprising feed stream, in which benzene is nitrated to nitrobenzene which is hydrogenated to aniline, aniline is reacted with formaldehyde to give methylenediphenylamine (MDA) and MDA is phosgenated to MDI. In this process, not the pure products but at first product mixtures are obtained in each process step, which are purified before further processing.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][CH2:14][CH2:15][NH2:16])(=[O:12])=[O:11])([O-:3])=[O:2].[OH:17][CH2:18][C:19]([CH3:24])([CH3:23])[C:20](O)=[O:21].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(Cl)Cl>[OH:21][CH2:20][C:19]([CH3:24])([CH3:23])[C:18]([NH:16][CH2:15][CH2:14][NH:13][S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])=[O:17]
Reactant: CC(C)(CO)C(=O)O
Reactant: NCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(CO)C(=O)NCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of N-(2-nitrobenzenesulfonyl)ethylenediamine, 3-hydroxy-2,2-dimethylpropionic acid, EDCI, HOBt, methylene chloride, and DMF was stirred at ambient temperature for 4 hours to yield 3-hydroxy-2,2-dimethyl-N-(2-{[(2-nitrophenyl)sulfonyl]amino}ethyl)propanamide. A mixture of this compound, triphenylphosphine, a toluene solution of diethyl azodicarboxylate, and THF was stirred at 0° C. for 15 hours to yield 6,6-dimethyl-1-[(2-nitrophenyl)sulfonyl]-1,4-diazepan-5-one. A mixture of this compound, 4-methylbenzenethiol, potassium carbonate, and acetonitrile was stirred at ambient temperature for 3 hours to yield 6,6-dimethyl-1,4-diazepan-5-one.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][C@H:6]([OH:8])[CH2:5][N:4]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.Cl>N1C=CC=CC=1>[C:9]([N:4]1[CH2:5][C@H:6]([O:8][S:25]([C:22]2[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=2)(=[O:27])=[O:26])[CH2:7][C@H:3]1[CH2:2][O:1][S:25]([C:22]1[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=1)(=[O:27])=[O:26])([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: O=C(OCc1ccccc1)N1C[C@@H](O)C[C@@H]1CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H](OS(=O)(=O)c3ccc(C)cc3)CN2C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82 %

Procedure:
To an ice-cold solution of 150 g (596.9 mmol) of (2R,4S)-2-hydroxymethyl-4-hydroxy-N-(carbobenzyloxy)-pyrrolidine in 0.5 l of pyridine was added 250 g (1.32 mol) of 4-toluenesulfonyl chloride in 3 portions to keep the temperature of the reaction below 15° C. for 1 hour and then warmed to room temperature. After 12 hours, an additional 125 g (656 mmol) of p-toluenesulfonyl chloride was added and the mixture was allowed to stir at room temperature for 16 additional hours. The mixture was then cooled with an ice bath and 3 l of 10% aqueous HCl solution was carefully added. The mixture was extracted with 2×250 ml of methylene chloride and dried over MgSO4. Evaporation of the solvent provided 274 g of the product as an oil (82% yield). NMR(CDCl3): 7.70 & 7.40 (m,9H, aromatic), 5.0 (m,3H), 4.43 (dd,1H), 4.12 (m,1H), 4.02 (m,H), 3.70 (m,1H), 3.88 (m,1H), 2.42 (m,6H), 2.15 (m,2H).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10](Cl)=[O:11])=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.[CH3:21][NH:22][CH3:23].O>C1COCC1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([N:22]([CH3:23])[CH3:21])=[O:11])=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1
Reactant: CNC
Reactant: O=C(Cl)c1cccc(Oc2ccc(Cl)cc2[N+](=O)[O-])c1
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cccc(Oc2ccc(Cl)cc2[N+](=O)[O-])c1
Reaction time: 16 h
Yield: 92.6 %

Procedure:
To the product from Example 168b (2.0 g, 6.4 mmol) in THF (25 mL) was added dimethylamine (0.6 g, 13.3 mmol) and the reaction stirred for 16 h. The reaction was poured into water and extracted with ethyl acetate. The organic layer washed with 5% HCL, water, brine, and dried over sodium sulfate, filtered and concentrated under vacuum giving the title compound (1.9 g, 87%).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]3[C:25]([C:26]#[N:27])=[CH:24][NH:23][C:7]=3[N:8]=[C:9]([NH:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]4)[N:10]=2)[CH2:3][CH2:2]1.C([O-])([O-])=[O:29].[K+].[K+].OO>CS(C)=O>[CH:1]1([NH:4][C:5]2[C:6]3[C:25]([C:26]([NH2:27])=[O:29])=[CH:24][NH:23][C:7]=3[N:8]=[C:9]([NH:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]4)[N:10]=2)[CH2:2][CH2:3]1
Reactant: N#Cc1c[nH]c2nc(Nc3ccc4c(c3)CCC(=O)N4)nc(NC3CC3)c12
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1c[nH]c2nc(Nc3ccc4c(c3)CCC(=O)N4)nc(NC3CC3)c12
Yield: 22.3 %

Procedure:
A solution of 4-(cyclopropylamino)-2-(2-oxo-1,2,3,4-tetrahydroquinolin-6-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (30 mg, 0.083 mmol), K2CO3 (100 mg, 0.724 mmol) and H2O2 (50% aq., 0.500 mL) in DMSO (1 mL) was heated at 100° C. for 5 min. Gas evolved violently. After cooling down, the mixture was purified by HPLC to give the titled compound (7 mg). MS 378.4 (M+H); UV 200.4, 241.8, 295.8 nm.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH3:18][C:19]1[N:24]=[C:23]([CH2:25][OH:26])[CH:22]=[CH:21][CH:20]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:26][CH2:25][C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:18])[N:24]=2)[N:3]=1
Reactant: Cc1cccc(CO)n1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Cc1cccc(COc2nc(N)nc(-c3ccco3)c2C#N)n1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, 6-methyl-2-pyridinemethanol and DBU in DME. ES-MS m/e (%): 330 (M+Na+, 10), 308 (M+H+, 100).
Reaction SMILES: C(C1N(CC2C=CC=CC=2Cl)C([C:10]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]([O:18]CC)=[O:17])[C:11]([O:13]CC)=[O:12])=CN=1)CCC.[OH-].[K+]>C(O)C.O>[CH2:21]([CH:10]([C:11]([OH:13])=[O:12])[C:16]([OH:18])=[O:17])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCCCc1ncc(C(Cc2ccccc2)(C(=O)OCC)C(=O)OCC)n1Cc1ccccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C(Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of diethyl [2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzyl-malonate [Example 8(iii)] (5.54 g, 0.0108 mol) in ethanol (75 mL) was treated all at once with a solution of potassium hydroxide (3.65 g, 0.065 mol) in water (50 mL). The resulting mixture was stirred at room temperature for 24 hours, then refluxed for 3 hours. The ethanol was evaporated, water was added to the aqueous product, and the basic solution was extracted with diethyl ether. The aqueous layer was acidified to pH 4 with hydrochloric acid and the product was extracted into ethyl acetate. The dried, concentrated product was crystallized twice from ethyl acetate to give 0.6 g of 2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzyl-malonic acid; mp 165°-166° C.(d). The filtrates from the crystallizations (4.9 g) consisted of additional malonic acid, the propanoic acid derivative and the mono ethyl ester malonate derivative. These are converted to [ 2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzylpropanoic acid by the method described previously.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C@H:12]([CH3:14])[NH:11][CH2:10][C@H:9]1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C.[C:20]([O:24][C:25](=O)[O:26]C(C)(C)C)([CH3:23])([CH3:22])[CH3:21].O>O1CCCC1>[CH2:1]([N:8]1[C@@H:9]([CH3:15])[CH2:10][N:11]([C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])[C@H:12]([CH3:14])[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: C[C@@H]1CN[C@@H](C)CN1Cc1ccccc1
Agent: CN(C)C
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1CN(Cc2ccccc2)[C@@H](C)CN1C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 60.3 %

Procedure:
To a solution of (2R,5S)-1-benzyl-2,5-dimethylpiperazine (3.52 g, 17.2 mmol) in tetrahydrofuran (50 mL), trimethylamine (2.12 g, 20.9 mmol) and di-tert-butylcarbonate (4.56 g, 20.9 mmol) were added under ice-cold conditions, and the mixture was stirred for 15 minutes. Then, the mixture was stirred at room temperature for 5.5 hours. The reaction solution was added water, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/ethyl acetate), and the title compound (3.16 g, 60%) was obtained as a pale yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].CN(C)C=O.[H-].[Na+].I[CH2:17][CH2:18][O:19][CH:20]([CH3:22])[CH3:21]>C(OCC)(=O)C>[CH:20]([O:19][CH2:18][CH2:17][N:6]1[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]1)([CH3:22])[CH3:21]
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: CC(C)OCCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)OCCn1ccc([N+](=O)[O-])n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77 %

Procedure:
In a round bottom flask was placed 3-nitro-1H-pyrazole (prepared in example 3, 315 mg, 2.79 mmol) and dry N,N-dimethylformamide (5 mL). This solution was then treated with sodium hydride (95%, 80 mg, 3.35 mmol) and gas evolution occurred. It was then stirred another 15 min at 25° C. 2-(2-Iodo-ethoxy)-propane (896 mg, 4.18 mmol) was then added to the reaction mixture and the reaction was stirred at 25° C. for 6 h. The reaction was then diluted with ethyl acetate (10 mL) and washed with water (2×10 mL). The aqueous layers were then combined and extracted with ethyl acetate (2×10 mL). The organic layers were combined and washed with a saturated aqueous brine solution (10 mL) and then dried over sodium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (12 g column, 25% ethyl acetate/hexanes to 35% ethyl acetate/hexanes) afforded 1-(2-isopropoxy-ethyl)-3-nitro-1H-pyrazole (428 mg, 77%) as a light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([CH2:11][OH:12])[C:9]=1[Cl:10])=[O:4].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([CH2:11][O:12][S:21]([CH3:20])(=[O:23])=[O:22])[C:9]=1[Cl:10])=[O:4]
Reactant: COC(=O)c1scc(CO)c1Cl
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1scc(COS(C)(=O)=O)c1Cl
Reaction time: 6 h

Procedure:
To a solution of 2-methoxycarbonyl-3-chloro-4-hydroxymethylthiophene (6 g, 29 mmol) in methylene chloride (100 mL) were added triethylamine (8.1 mL, 58 mmol) and methanesulfonyl chloride (2.5 mL, 32 mmol) at ambient temperature. After stirring for 6 hours, the reaction mixture was concentrated to afford 2-methoxycarbonyl-3-chloro-4-(methylsulfonyloxy)methylthiophene. The crude product was dissolved in DMF (150 mL) and excess potassium cyanide was added to the solution. The reaction mixture was stirred at ambient temperature for 16 hours, then poured into water, and extracted with methylene chloride. The combined extracts were dried over Na2SO4, filtered, and concentrated in vacuo to afford 2-methoxycarbonyl-3-chloro-4-cyanomethylthiophene.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9]Br.[I-].[Na+].[CH:18]([NH2:21])([CH3:20])[CH3:19]>O1CCCC1.C(Cl)Cl>[CH:18]([NH:21][CH2:9][CH2:8][CH2:7][CH2:6][O:5][CH2:4][C:3]1[CH:11]=[C:12]([Br:15])[CH:13]=[CH:14][C:2]=1[F:1])([CH3:20])[CH3:19]
Reactant: Fc1ccc(Br)cc1COCCCCBr
Reactant: CC(C)N
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)NCCCCOCc1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 4-(2-fluoro-5-bromobenzyloxy)butyl bromide (1.2 g, 3.53 mmol) in tetrahydrofuran (18 ml) was treated with sodium iodide (484 mg, 3.2 mmol). The resulting mixture was stirred at ambient temperature. After 1.5 hours, the sodium bromide was removed by filtration, and the filtrate concentrated. The residue was treated with a tetrahydrofuran solution of isopropylamine (3.01 ml, 35.3 mmol). The progress of the reaction was monitored by thin layer chromatography. The resulting mixture was stirred for about 18 hours at ambient temperature, after which time an additional 10 equivalents of isopropylamine was added to drive the reaction. The reaction mixture was diluted with methylene chloride, and washed with 25 mM phosphate buffer and brine. The organic fraction was dried over sodium sulfate and the solvents were removed in vacuo. The desired title intermediate was further purified by liquid chromatography.
Reaction SMILES: [C:1]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH:4]=[CH:3][CH:2]=1.[NH:10]([CH2:14][CH2:15][OH:16])[CH2:11][CH2:12][OH:13]>>[OH:13][CH2:12][CH2:11][N:10]([CH2:14][CH2:15][OH:16])[C:7]([C:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH:2]=1)=[O:9]
Reactant: O=C(O)C1=CC=CCC1
Reactant: OCCNCCO
Product: O=C(C1=CC=CCC1)N(CCO)CCO

Procedure:
Using the same procedures as those in Example 5 as well as 1,3-cyclohexadiene-1-carboxylic acid and diethanolamine as a starting material, there was obtained 1,3-cyclohexadiene-1-carboxylic acid N,N-bis (2-hydroxyethyl)amide.
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][CH2:6][O:7][NH2:8])[CH3:4].[N+:9]([C:12]1[CH:25]=[CH:24][C:15]([CH:16]=[C:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C:18]2=O)=[CH:14][CH:13]=1)([O-:11])=[O:10]>>[CH3:2][N:3]([CH2:5][CH2:6][O:7][N:8]=[C:18]1[CH2:19][CH2:20][CH2:21][CH2:22][C:17]1=[CH:16][C:15]1[CH:14]=[CH:13][C:12]([N+:9]([O-:11])=[O:10])=[CH:25][CH:24]=1)[CH3:4]
Reactant: O=C1CCCCC1=Cc1ccc([N+](=O)[O-])cc1
Reactant: CN(C)CCON
Agent: Cl
Product: CN(C)CCON=C1CCCCC1=Cc1ccc([N+](=O)[O-])cc1

Procedure:
On starting from 17.7 g (0.1 moles) of dimethylaminoethoxyamine hydrochloride and 23.1 g (0.1 moles) of 2-(p-nitrobenzal)-cyclohexanone, one proceeds in the way as specified in Example 32.