Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:16][CH2:17][C:18](=[O:20])[NH2:19])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[CH2:26](I)[CH3:27]>O>[CH2:26]([O:14][C:13](=[O:15])[CH:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[CH2:16][CH2:17][C:18](=[O:20])[NH2:19])[CH3:27]
Reactant: NC(=O)CCC(NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(CCC(N)=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.9 %

Procedure:
A mixture of acid (1) (64 g, 0.228 mol), dimeththylformamide (210 ml) and sodium bicarbonate (111 g, 1.32 mol, 5.8 equiv.) was stirred at room temperature for 30 min. Ethyl iodide (34 ml, 66.3 g, 0.425 mol, 1.86 equiv.) was added and stirring was continued overnight under nitrogen. The reaction mixture was slowly diluted with water to 1 L and stirred for 40 min. The solid was collected by filtration, washed well with water and partitioned between ethyl acetate (8 L) and water (3 L). Phases were separated and the aqueous phase was extracted with ethyl acetate (2.5 L). The combined organic extracts were washed with water (1 L), dried over sodium sulfate, stripped and dried in a vacuum oven (50° C.) to produce (2) (47 g, 66.7%).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:5]=1[CH:6]([OH:10])[C:7]([OH:9])=[O:8])([O-:3])=[O:2].[CH2:18](O)[C:19]([CH3:22])([CH3:21])[CH3:20]>OS(O)(=O)=O>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:5]=1[CH:6]([OH:10])[C:7]([O:9][CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:8])([O-:3])=[O:2]
Reactant: CC(C)(C)CO
Reactant: O=C(O)C(O)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: CC(C)(C)COC(=O)C(O)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]

Procedure:
2,6-dinitromandelic acid (4.00 g, 16.5 mmol) was added to an excess of neopentyl alcohol (20.0 g, 227 mmol) melted in a round bottom flask. To this solution was added 5 drops of H2SO4 and it was heated to reflux for 3 hours. The excess neopentyl alcohol was removed under reduced pressure, and the residue was purified by column chromatography over silica gel (60-200 mesh) using methylene chloride/hexane (1:1) as the eluant. The yield after two recrystallizations from CHCl3 /petroleum ether was 3.8 g (74%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=O)[CH2:9][N:8]=[C:7]([C:13]3[NH:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:18]=1.O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[S:21])[CH2:9][N:8]=[C:7]([C:13]3[NH:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:18]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1CN=C(c2ccc[nH]2)c2cc(Cl)ccc2N1
Solvent: O
Solvent: C1CCOC1
Product: S=C1CN=C(c2ccc[nH]2)c2cc(Cl)ccc2N1
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 159.6 %

Procedure:
10 g (38.5 mmol) of 7-chloro-1,3-dihydro-5-(1H-pyrrol-2-yl)-1,4-benzodiazepin-2-one were dissolved in anhydrous THF (400 ml) in a 1 litre round-bottom 3-neck flask equipped with a mechanical stirrer. The flask was then placed in the water bath of an ultrasonic apparatus. To the stirred reaction solution was added P4S10 (10 g; 22.5 mmol) and the reaction mixture was irradiated with ultrasound. The temperature was maintained at about 40° C. throughout the reaction. After 2.5 hours, an additional portion of P4S10 (10 g; 22.5 mmol) was added to the mixture and the reaction was continued for an additional 2 hours. The heterogeneous mixture was cooled to ambient temperature and filtered. After washing the solid by-product with several portions of CH2CL2, the filtrates were combined and approximately 80% of the solvent was removed in vacuo. The residual solution was basified with saturated sodium bicarbonate solution until a pH of about 8 was reached. The product which precipitated out was filtered. The filtrate was then extracted with CH2Cl2, followed by concentration in vacuo. The solids were combined and recrystallized in THF/Petroleum ether to give 9.9 g (94% yield) of 7-chloro-1,3-dihydro-5-(1H-pyrrol-2yl)-1,4-benzodiazepin-2-thione as a pale yellow powder having the following characteristics: m.p. 258°-260° C. dec.; IR (KBr) 3450, 3165 cm-1. Anal. Calcd. for C13H10C1N3S: C 56.62; H 3.66; N 15.24. Found: C 56.50; H 3.59; N 15.12.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[K+]>O.C1(C)C=CC=CC=1>[CH2:11]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[C:2]1[CH3:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cc2ccccc2[nH]1
Reactant: ClCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc2ccccc2n1Cc1ccccc1
Temperature: 25 °C
Yield: 9.4 %

Procedure:
A mixture of 13.11 g (0.1 mole) of 2-methylindole, 13.92 g (0.11 mole) of benzyl chloride, 33 g (0.5 mole) of 85% KOH, 14 mL of H2O, 2.5 g (2.5 mmoles) of PEG-1000, and 100 mL of toluene was stirred and heated at 60° for 23 hours. After cooling to room temperature, 100 mL of H2O was added. The layers were separated. The aqueous layer was extracted with 100 mL of toluene. The combined toluene phases were washed 2N HCl (2×50 mL), H2O (2×50 mL), and 50 mL of brine and dried over MgSO4. Evaporation of the solvent left 26.98 g of dark brown oil. The oil was chromatographed on a 1100 g column of silica gel. The column was eluted with 25% CH2Cl2 -Skellysolve B and 200 mL fractions were collected. The fractions were assayed by silica gel tlc (1×4") (25% CH2Cl2 -Skellysolve B). Fractions 20-22 were combined giving 2.08 g (9%) of 1-benzyl-2-methylindole as a yellow oil which solidified.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@@H:10]([OH:29])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[C:18]=1[O:27][CH3:28])[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C=CN=C1.[C:42]([Si:46]([CH3:49])([CH3:48])Cl)([CH3:45])([CH3:44])[CH3:43]>CN(C=O)C>[C:1]([NH:8][C@@H:9]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@@H:10]([O:29][Si:46]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:49])[CH3:48])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[C:18]=1[O:27][CH3:28])[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(C[C@H](C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)c(OC)c1OC
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1ccc(C[C@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)c(OC)c1OC
Reaction time: 2.5 h

Procedure:
A solution of 1.308 g (2.597 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(2,3,4-trimethoxyphenyl)methyl]hexanoic acid, 1.443 g (20.776 mmol) of imidazole and 1.816 g (11.686 mmol) of tert-butyldimethylchlorosilane in 13 ml of abs. DMF is stirred at RT for 17 h under argon. After that, the reaction mixture is poured onto ice-water and this mixture is extracted with ethyl acetate. The organic phase is washed with cold 10% citric acid solution and saline. The combined aqueous phases are reextracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and evaporated on a RE at approximately 30° C. The resulting product is dissolved in 34.51 ml of methanol and 11.82 ml of THF, and this solution is treated, at RT, with 2.08 g of potassium carbonate in 11.82 ml of water. After it has been stirred for 2.5 h, the reaction mixture is concentrated down, at approximately 30° C., to half its volume and treated with ethyl acetate and 10% citric acid solution (cold), and the phases are separated. The organic phase is washed a further two times with (cold) saline. The combined aqueous phases are reextracted with ethyl acetate. The combined organic phases are dried over Na2SO4 and concentrated. The residue is purified by chromatography on silica gel (hexane:ethyl acetate, 1:1, and then 1:1.5), and the title compound is obtained. TLC Rf (J)=0.02. FAB-MS (M+H)+ =618 IR(KBr) inter alia: 1712, 1495, 1366, 1101 and 836 cm-1. 1H-NMR(CD3OD) inter alia: 7.30-7.10 (m, 5H); 6.84 and 6.67 (each d, each 1H); 6.23 and 5.55 (each d, in all 1H from NH); 3.86, 3.81 and 3.80 (each s, each 3H); 1.31 and 1.20 (each s, in all 9H from Boc); 0.93 (s, 9H); 0.14 and 0.11 (each s, each 3H).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([OH:6])[CH2:3]1.C(=O)([O-])O.[Na+].C1COCC1.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[C:18]1([C:17]([N:2]2[CH2:5][CH:4]([OH:6])[CH2:3]2)=[O:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OC1CNC1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(c1ccccc1)N1CC(O)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 78.1 %

Procedure:
To a mixture of azetidin-3-ol hydrochloride (200 mg), saturated aqueous sodium hydrogen carbonate solution (2 mL) and THF (2 mL) was added benzoylchloride (132 mg) under ice-cooling. The reaction mixture was stirred at room temperature for 3 days, water was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (130 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH2:13]([O:15][CH:16]([O:19][CH2:20][CH3:21])[CH2:17][NH2:18])[CH3:14].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:13]([O:15][CH:16]([O:19][CH2:20][CH3:21])[CH2:17][NH:18][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[C:3]=1[O:2][CH3:1])[CH3:14]
Reactant: COc1cccc(C=O)c1OC
Reactant: CCOC(CN)OCC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(CNCc1cccc(OC)c1OC)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2,3-dimethoxybenzaldehyde (2 g, 12 mmol) in MeOH (50 mL) was added aminoacetaldehyde diethyl acetal (1.49 mL, 12 mmol) and acetic acid (1.03 mL, 18 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was added to a stirred solution of sodium cyanoborohydride (829 mg, 13 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure. Then H2O and ethyl acetate were added to the reaction mixture. The organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. The crude compound was used next step without further purification.
Reaction SMILES: [CH3:1][Li].[CH3:3][C:4](=[CH:6][CH2:7][CH2:8][C:9](=[CH:11][CH:12]=[O:13])[CH3:10])[CH3:5]>O1CCCC1>[OH:13][CH:12]([CH3:1])[CH:11]=[C:9]([CH3:10])[CH2:8][CH2:7][CH:6]=[C:4]([CH3:3])[CH3:5]
Reactant: [Li]C
Reactant: CC(C)=CCCC(C)=CC=O
Solvent: C1CCOC1
Product: CC(C)=CCCC(C)=CC(C)O
Temperature: 30 °C

Procedure:
Methyl lithium in tetrahydrofuran (THF) (1.6 L, 1 M) was charged to a flame dried 3 L reaction flask equipped with a thermometer, a mechanical stirrer, condenser, and an addition funnel. Citral was added dropwise for over 2-2.5 hours. The reaction mixture was aged until the conversion rate was greater than 90%. The reaction mixture was cooled to lower than 30° C. and quenched by the slow addition of HCl (pH<5.10%). The aqueous phase was extracted three times with toluene (100 mL) and the extracts were added to the crude reaction mixture. The crude reaction mixture was then washed with saturated sodium bicarbonate (500 mL) followed by saturated salt solution and dried over anhydrous sodium sulphate. The crude reaction mixture was concentrated. The solvents were recovered via a rotary evaporator to provide 8-hydroxy-2,6-dimethyl-nona-2,6-diene.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10](=[O:13])[NH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:14]([O-])([OH:16])=[O:15].S(=O)(=O)(O)O>>[N+:14]([C:4]1[CH:3]=[CH:2][C:1]([C:7]2[N:8]=[CH:9][C:10](=[O:13])[NH:11][CH:12]=2)=[CH:6][CH:5]=1)([O-:16])=[O:15]
Reactant: O=c1cnc(-c2ccccc2)c[nH]1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=c1cnc(-c2ccc([N+](=O)[O-])cc2)c[nH]1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5-phenyl-2-(1-H)-pyrazinone (5 g) was added in portions during 30 minutes to a stirred mixture of fuming nitric acid (30 ml) and sulphuric acid (5 ml) at -5° C. The mixture was stirred in the cold for 30 minutes, and the temperature of the mixture was then allowed to rise to 10° C. The mixture was then poured into ice-water (250 ml) to give 5-(4-nitrophenyl)-2-(1H)-pyrazinone recrystallised from dimethylformamide, m.p. 336°-338° C., δ (DMSO-d6) 8.15 and 8.30 (2d, 3-and 6- protons of pyrazinone ring), 8.18 (m, phenyl); ν max (Nujol mull) 3200-2500 (NH), 1690, 1675, 1545, 1510, 1349, 860 and 750 cm-1.
Reaction SMILES: [Cl-:1].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[C:5]([O:20][CH3:21])[CH:4]=1>C1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:8]1[C:3]([OH:2])=[CH:4][C:5]([O:20][CH3:21])=[C:6]([CH:9]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:7]=1
Reactant: CCCCCC(CC(=O)OC)c1ccc(O)cc1OC
Reactant: [Cl-]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCCCCC(CC(=O)OC)c1cc(Cl)c(O)cc1OC
Temperature: 70 °C
Reaction time: 3.5 h
Yield: 88 %

Procedure:
604 mg (4.48 mmol) of sufliryl chloride were added to a solution of 1.26 g (4.48 mmol) of methyl 3-(4-hydroxy-2-methoxyphenyl)octanoate (prepared as described in Preparation 44) in 10 ml of benzene, and the resulting mixture was stirred at 70° C. for 3.5 hours. At the end of this time, the reaction mixture was diluted with ethyl acetate, and the diluted solution was washed with an aqueous solution of sodium carbonate, with water and with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 100 g of silica gel, using a 1:2 by volume mixture of ethyl acetate and hexane as the eluent, to give the title compound as an oily substance in a 88% yield.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:32][CH2:31][NH:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([N:30]1[CH2:31][CH2:32][C@@H:28]([NH:27][C:25]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:8]4[CH:9]=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:16]=3[NH:23][C:22]=2[CH3:24])=[O:26])[CH2:29]1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: COc1ccc(-c2ncnc3c(C(=O)N[C@@H]4CCNC4)c(C)[nH]c23)c(OCC2CC2)c1
Agent: Cl
Product: COc1ccc(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(C)=O)C4)c(C)[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-6-methyl-N-[(3R)-pyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f21) and commercially acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[S:3]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]1[N:19]2[CH:20]=[CH:21][N:22]=[C:18]2[CH:17]=[CH:16][CH:15]=1)(=[O:5])=[O:4].[CH2:25]=O>C(O)(=O)C>[F:24][C:2]([F:1])([F:23])[S:3]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:13][C:14]2[N:19]3[C:20](=[CH:21][N:22]=[C:18]3[CH:17]=[CH:16][CH:15]=2)[CH2:25]1)(=[O:5])=[O:4]
Reactant: C=O
Reactant: O=S(=O)(NCCCCCNCc1cccc2nccn12)C(F)(F)F
Solvent: CC(=O)O
Product: O=S(=O)(NCCCCCN1Cc2cccc3ncc(n23)C1)C(F)(F)F
Temperature: 100 °C
Yield: 69 %

Procedure:
To a solution of 2.52 g (6.91 mmol) of 5-[N-[5-(trifluoromethanesulfonamido)pentan-1-yl]aminomethyl] imidazo[1,2-a]pyridine in 8 ml of acetic acid was added 7.8 ml (103.7 mmol) of a 37% aqueous solution of formalin. The mixture was heated at 100° C. for 30 minutes. The solvent was then distilled off under reduced pressure. The residue was dissolved in 50 ml of a saturated aqueous solution of potassium carbonate. This solution was neutralized, under ice-cooling, with 1N HCl, which was extracted twice with 100 ml of chloroform. The organic layer was dried over magnesium sulfate, then the solvent was distilled off under reduced pressure. The residue was purified by silicagel column chromatography to give 1.79 g of the desired compound (69.0%, colorless liquid).
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([OH:9])=O)[CH2:5][C:4]([CH3:10])=[N:3]1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:31]=[CH:32][C:33]=1[CH3:34])[O:15][C:16]1[CH:17]=[CH:18][C:19]2[N:20]([CH:22]=[C:23]([NH:25][C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])[N:24]=2)[N:21]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:28]1([C:26]([NH:25][C:23]2[N:24]=[C:19]3[CH:18]=[CH:17][C:16]([O:15][C:14]4[CH:31]=[CH:32][C:33]([CH3:34])=[C:12]([NH:11][C:7]([CH:6]5[N:2]([CH3:1])[N:3]=[C:4]([CH3:10])[CH2:5]5)=[O:9])[CH:13]=4)=[N:21][N:20]3[CH:22]=2)=[O:27])[CH2:29][CH2:30]1
Reactant: CC1=NN(C)C(C(=O)O)C1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1=NN(C)C(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2C)C1
Yield: 71.7 %

Procedure:
In the same manner as in Example 278 and using 1,3-dimethyl-4,5-dihydro-1H-pyrazole-5-carboxylic acid (120 mg, 0.87 mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.62 mmol), O-(7-azabenzotriazol-1-yl)-N,N′,N′-tetramethyluronium hexafluorophosphate (330 mg, 0.87 mmol), N,N-diisopropylethylamine (240 mg, 1.8 mmol) and N,N-dimethylformamide (7 mL) as starting materials, the title compound (199 mg, 72%) was obtained as a white solid.
Reaction SMILES: [N:1]([N:3]1[C:8]([CH3:10])([CH3:9])[CH2:7][S:6](=[O:12])(=[O:11])[CH2:5][C:4]1([CH3:14])[CH3:13])=O>C(O)(=O)C.O.[Zn]>[NH2:1][N:3]1[C:4]([CH3:13])([CH3:14])[CH2:5][S:6](=[O:12])(=[O:11])[CH2:7][C:8]1([CH3:10])[CH3:9]
Reactant: CC1(C)CS(=O)(=O)CC(C)(C)N1N=O
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)CS(=O)(=O)CC(C)(C)N1N
Temperature: 50 °C
Reaction time: 3 h

Procedure:
22.0 g (0.1 mole) of 1-nitroso-2,2,6,6-tetramethyl-1-aza-4-thiacyclohexane-4,4-dioxide is suspended in a mixture of 150 ml of glacial acetic acid and 100 ml of water. Within 3 hours, 40 g of zinc dust is introduced in small portions, the temperature being maintained between 30° and 35° C. The reaction mixture is subsequently fully stirred for 5 hours at 50° C; the zinc sediment is filtered off hot, and the cooled filtrate rendered alkaline with sodium hydroxide solution. It is extracted with ether, the ether solution dried over sodium sulphate, and the solvent evaporated off. Crystallisation of the residue from ligroin yields 1-amino-2,2,6,6-tetramethyl-1-aza-4-thiacyclohexane-4,4-dioxide (10), M.P. 122° C.
Reaction SMILES: [F:1][CH:2]([F:31])[C:3]([CH2:18][CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30])(C(OC(C)(C)C)=O)[C:4]([O:6]C(C)(C)C)=[O:5]>FC(F)(F)C(O)=O.C(O)(=O)C>[F:31][CH:2]([F:1])[CH:3]([CH2:18][CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30])[C:4]([OH:6])=[O:5]
Reactant: CC(C)(C)OC(=O)C(CCN1C(=O)c2ccccc2C1=O)(C(=O)OC(C)(C)C)C(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: O=C(O)C(CCN1C(=O)c2ccccc2C1=O)C(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60 %

Procedure:
2-Difluoromethyl-2-(2-phthalimidoethyl)-propanedioic acid, bis tert.-butyl ester prepared as in Step B (0.610 g, 1.40 mM) is dissolved in trifluoroacetic acid (8 ml) at room temperature. After stirring for 1.5 hour at room temperature, the solvent is evaporated in vacuo yielding a white solid. The crude disubstituted malonic acid is dissolved in glacial acetic acid (20 ml) and the mixture is heated at 100° C. for 15 hours. The solvent is evaporated in vacuo yielding a yellowish oil. Crystallization in ether affords the required acid as a white solid (0.240 g, yield 60%). NMR (CDCl3 +CF3CO2H) 2.00-2.43 (m, 2H); 2.57-3.40 (m, 1H); 3.90 (t, JHH =7 Hz, 2H); 6.03 (td, JHF =55 Hz, JHH =4 Hz, 1H); 7.58-7.95 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([Li])(C)(C)C.[Cl:20][C:21]1[CH:32]=[CH:31][C:24]([C:25](N(OC)C)=[O:26])=[CH:23][C:22]=1[S:33](=[O:36])(=[O:35])[NH2:34]>O1CCCC1>[Cl:20][C:21]1[CH:32]=[CH:31][C:24]([C:25](=[O:26])[C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)=[CH:23][C:22]=1[S:33]([NH2:34])(=[O:36])=[O:35]
Reactant: CON(C)C(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Reactant: CN1CCN(c2ccc(Br)cc2)CC1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(C(=O)c3ccc(Cl)c(S(N)(=O)=O)c3)cc2)CC1
Temperature: 0 °C

Procedure:
A solution of 0.275 g of 1-(4-bromo-phenyl)-4-methyl-piperazine in tetrahydrofuran (90 mL) is cooled to −78° C. and treated with 1.44 mL of tert-butyllithium (1.5 M in pentane). After 15 min at −78° C. the reaction mixture is treated with 0.1 g of 4-chloro-N-methoxy-N-methyl-3-sulfamoyl-benzamide in tetrahydrofuran (3 mL). The temperature is then increased slowly to 0° C. and after completion the reaction is quenched by addition of 2 mL of saturated aqueous ammonium chloride and extracted with diethyl ether. The organics are washed with water, dried (magnesium sulfate) and concentrated to give 0.32 g of crude product which is purified by silica gel chromatography (95:5 methylene chloride/methanol) to give 2-chloro-5-[4-(4-methyl-piperazin-1-yl)-benzoyl]-benzenesulfonamide as a tan powder. MS (m/z): 394 (M+1); Rf 0.06 (95:5 methylene chloride/methanol).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[N:4][C:3]=1[CH:26]=O.[CH:28]([NH2:31])([CH3:30])[CH3:29].Cl.C([BH3-])#N.[Na+]>CO.O>[CH3:1][C:2]1[N:6]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[N:4][C:3]=1[CH2:26][NH:31][CH:28]([CH3:30])[CH3:29]
Reactant: Cc1c(C=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)N
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1c(CNC(C)C)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
A mixture of 5-methyl-1-(triphenylmethyl)-1H-imidazole-4-carboxaldehyde (3.5 g) and isopropylamine (10 ml) in methanol (125 ml) was stirred at 20° for 1h. The resulting solution was treated with ethanolic hydrogen chloride (0.027 g/ml; 15 ml), cooled to 0° and treated with sodium cyanoborohydride (0.94 g). After stirring for 2.5 h, water (15 ml) was added and the resulting mixture was stirred at 20° for 0.5 h and treated with concentrated hydrochloric acid (6 ml). The mixture was warmed to 40°, stirred at 40° for 0.5h and concentrated in vacuo to ca. 50 ml. The concentrate was then basified (to pH9) with a saturated solution of potassium carbonate (200 ml) and extracted with ethyl acetate (3×100 ml). The organic extracts were combined, dried and evaporated to leave a gum (ca. 5 g) which was purified by FCC eluting with System A (100:8:1) to give the title compound (1.9 g) as a solid, m.p. 154°-156°. A second crop of product (0.4 g) has m.p. 150°-154°.