Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[CH3:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:11]=1[C:19]([F:22])([F:21])[F:20].O>CN(C)C=O>[CH3:5][N:4]([CH3:6])/[CH:3]=[CH:9]/[C:10]1[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:12][CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17]
Reactant: Cc1c([N+](=O)[O-])cccc1C(F)(F)F
Reactant: COC(OC)N(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)/C=C/c1c([N+](=O)[O-])cccc1C(F)(F)F
Temperature: 110 °C

Procedure:
3.5 ml of DMF-DMA (N,N-dimethylformamide-dimethyl acetal) are added to a solution of 1 g of 2-methyl-3-nitrobenzotrifluoride in 6 ml of N,N-dimethylformamide. The reaction medium is heated at 110° C. until the starting material has disappeared, then poured into water and extracted with ethyl acetate. The organic phases are washed successively with a 10% sodium bicarbonate solution, a 10% ammonium chloride solution and a saturated sodium chloride solution, dried over magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure so as to give 1.2 g of dimethyl[(E)-2-(2-nitro-6-trifluoromethylphenyl)vinyl]amine in the form of an oil which is used in the next step.
Reaction SMILES: [CH:1]1([N:4]([CH3:23])[C:5]2[C:6]3[C:18]4[CH2:19][CH2:20][CH2:21][CH2:22][C:17]=4[S:16][C:7]=3[N:8]=[C:9]([CH2:11][CH2:12][C:13](O)=[O:14])[N:10]=2)[CH2:3][CH2:2]1.C[CH2:25][N:26]=[C:27]=NCCCN(C)C.Cl.C(N(CC)CC)C.CNC>C1COCC1>[CH:1]1([N:4]([CH3:23])[C:5]2[C:6]3[C:18]4[CH2:19][CH2:20][CH2:21][CH2:22][C:17]=4[S:16][C:7]=3[N:8]=[C:9]([CH2:11][CH2:12][C:13]([N:26]([CH3:27])[CH3:25])=[O:14])[N:10]=2)[CH2:3][CH2:2]1
Reactant: CCN=C=NCCCN(C)C
Reactant: CN(c1nc(CCC(=O)O)nc2sc3c(c12)CCCC3)C1CC1
Agent: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)C(=O)CCc1nc(N(C)C2CC2)c2c3c(sc2n1)CCCC3
Reaction time: 0.25 h
Yield: 23.2 %

Procedure:
To a mixture of 3-[4-(cyclopropyl-methyl-amino)-5,6,7,8-tetrahydro-[1]benzothiopheno[2,3-d]pyrimidin-2-yl]-propionic acid (0.2 g, 0.0006 mol) and EDC HCl (0.116 g, 0.0006 mol) in THF (10 ml) was added triethyl amine (0.122 g, 0.0012 mol), and the resulting mixture was stirred at R.T for 15 min. The dimethyl amine (0.0027 g, 0.0006 mol) in THF was added dropwise to the reaction mixture and stirring at R.T was continued for another 4 hrs. The solvent was removed; the reaction mixture was diluted with water and extracted with ethyl acetate (3×10 ml). The combined organic layers were dried over Na2SO4, concentrated. The crude material was subjected to column purification on 60-120 silica using ethyl acetate (50%) in hexane to give 0.05 g (51%) of the desired product as off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm=0.43 (m, 2H), 0.69 (m, 2H), 1.75 (m, 2H), 1.89 (m, 2H), 2.85 (m, 7H), 2.94 (s, 3H), 3.0 (s, 3H), 3.05 (s, 3H), 3.20 (t, 2H). LC-MS: [M+H]=359.3.
Reaction SMILES: Cl.[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([NH2:11])[CH2:7][CH2:6]1)(=[O:4])[CH3:3].[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C>ClCCl>[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:20]([NH:19][C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)=[O:21])[CH2:7][CH2:6]1)(=[O:4])[CH3:3]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CC(=O)N1CCC(N)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC(NC(=O)Nc2ccc(F)cc2)CC1
Reaction time: 3 h

Procedure:
To a suspension of 1-acetyl-4-aminopiperidine hydrochloride (536 mg) in dichloromethane (5 ml) were added 4-fluorophenyl isocyanate (375 μl) and diisopropylethylamine (575 μl ) at ambient temperature. After stirring for 3 hours, the reaction mixture was diluted with dichloromethane. An organic phase was separated and an aqueous phase was extracted with dichloromethane. A combined organic phase was dried over magnesium sulfate and the solvents were removed under reduced pressure. After crystallization from diisopropyl ether and n-hexane, N-(1-acetylpiperidin-4-yl)-N′-(4-fluorophenyl)urea (448 mg) was obtained.
Reaction SMILES: C(=O)([O-])O.[K+].Br[CH2:7][C:8]1[O:9][C:10](=[O:14])[O:11][C:12]=1[CH3:13].[C:15]1([S:21]([NH:24][C:25]2[CH:26]=[C:27]([C@@H:31]([OH:51])[CH2:32][NH:33][C:34]([CH3:50])([CH3:49])[CH2:35][CH2:36][N:37]3[C:45]4[C:40](=[CH:41][C:42]([C:46]([OH:48])=[O:47])=[CH:43][CH:44]=4)[CH:39]=[CH:38]3)[CH:28]=[CH:29][CH:30]=2)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C>[C:15]1([S:21]([NH:24][C:25]2[CH:26]=[C:27]([C@@H:31]([OH:51])[CH2:32][NH:33][C:34]([CH3:49])([CH3:50])[CH2:35][CH2:36][N:37]3[C:45]4[C:40](=[CH:41][C:42]([C:46]([O:48][CH2:7][C:8]5[O:9][C:10](=[O:14])[O:11][C:12]=5[CH3:13])=[O:47])=[CH:43][CH:44]=4)[CH:39]=[CH:38]3)[CH:28]=[CH:29][CH:30]=2)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(CCn1ccc2cc(C(=O)O)ccc21)NC[C@H](O)c1cccc(NS(=O)(=O)c2ccccc2)c1
Reactant: Cc1oc(=O)oc1CBr
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1oc(=O)oc1COC(=O)c1ccc2c(ccn2CCC(C)(C)NC[C@H](O)c2cccc(NS(=O)(=O)c3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Potassium hydrogen carbonate (331 mg, 3.30 mmol) and 4-bromomethyl-5-methyl-[1,3]dioxol-2-one (Chem. Pharm. Bull. 1984, vol. 32 (6), page 2241-2248) (505 mg, 2.36 mmol) are added to a solution of 1-{3-[(R)-2-[3-(phenylsulphonylamino)-phenyl]-2-hydroxy-ethylamino]-3-methyl-butyl}-1H-indole-5-carboxylic acid-hydrotrifluoroacetate (Example 6; 1.0 g, 1.57 mmol) in 10 ml DMF. Then the reaction mixture is stirred for 18 hours at RT. Then the solid is filtered off and the filtrate is freed from the solvent in vacuo. The residue is chromatographed on silica gel (DCM/methanol/ammonia=100:0:0→90:10:0.1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C=O)C>[CH2:13]([NH:20][C:4]1[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=[C:2]([Cl:1])[N:3]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCc1ccccc1
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Solvent: CN(C)C=O
Solvent: O
Product: Cc1csc2c(NCc3ccccc3)nc(Cl)nc12
Reaction time: 3 h
Yield: 92.4 %

Procedure:
In 3 ml of DMF was dissolved 300 mg (1.4 mmol) of 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine, and after 220 mg (2.1 mmol) of benzylamine was added to the resulting solution, the mixture was stirred for 3 hours. Water was added to the reaction mixture, and crystals thus precipitated were filtered to give 375 mg (yield: 94.5%) of the title compound.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([NH2:6])[CH2:4]O.[OH-].[Na+].[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.O>COC(C)(C)C>[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15]([N:6]2[CH2:4][C@H:3]2[CH2:2][CH3:1])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC(N)CO
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: O
Product: CC[C@@H]1CN1S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C

Procedure:
R-(-)-2-amino-1-butanol (99.96 g, 105 mL) and tert-butyl methyl ether (TBME) (277 g, 366 mL) are combined under a nitrogen atmosphere. This mixture is stirred for several minutes and 10 N aqueous sodium hydroxide (449 mL) is added over a period of about 10 minutes. The reaction mixture is cooled to below 10° C. and a solution of p-toluene sulfonyl chloride (TsCl) (464 g) in TBME (711 g) is added over a period of about 50 minutes, maintaining the temperature of the reaction mixture at or below 32° C. After the addition is complete, the mixture is stirred for about 30 minutes at 40° C., and water (900 mL) is added while cooling the mixture to 25° C. The layers are separated and the organic layer washed sequentially with water (150 g) and 25% aqueous sodium chloride solution (300 g). Toluene (450 g) is added to the organic layer, and the mixture distilled under reduced pressure, maintaining the temperature of the mixture at or below 45° C., until the water content of the mixture is below about 0.1%. The resulting solution is used, without further treatment, for the preparation described in Example 2.
Reaction SMILES: [N:1]1[CH2:2][CH2:3][N:4]2[C:8]3[CH:9]=[CH:10][C:11]([NH:13][CH:14]=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][C:7]=3[S:6][C:5]=12.[H-].[Na+].[Br:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>CN(C)P(=O)(N(C)C)N(C)C>[Br-:28].[CH2:19]([O:18][C:16]([C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:14][N:13]([CH2:11][CH2:12][CH2:7][CH2:8][CH2:9][CH3:10])[C:11]1[CH:10]=[CH:9][C:8]2[N:4]3[CH2:3][CH2:2][N+:1]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[C:5]3[S:6][C:7]=2[CH:12]=1)=[O:17])[CH3:20]
Reactant: CCOC(=O)C(=CNc1ccc2c(c1)SC1=NCCN12)C(=O)OCC
Reactant: CCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCN(C=C(C(=O)OCC)C(=O)OCC)c1ccc2c(c1)SC1=[N+](CCCCCC)CCN12
Product: [Br-]
Temperature: 50 °C

Procedure:
To a stirred mixture of 10 parts of diethyl 2-[(2,3-dihydroimidazo[2,1-b]benzothiazol-7-ylamino)methylene]propanedioate, 1.1 parts of sodium hydride dispersion 76.8% and 100 parts of hexamethylphosphoric triamide are added 13.2 parts of 1-bromohexane. The whole is stirred over weekend at 50° C. The reaction mixture is poured onto methylbenzene. The latter is washed three times with water, dried, filtered and evaporated. The residue solidifies on triturating in 1,1'-oxybisethane. The product is filtered off and crystallized from 4-methyl-2-pentanone, yielding 4.5 parts of 7-{[2,2-bis(ethoxycarbonyl)ethenyl]hexylamino}-1-hexyl-2,3-dihydroimidazo[2,1-b]benzothiazolium bromide; mp. 162° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C1(C)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(O[C:42](=[O:48])[O:43][C:44](Cl)(Cl)Cl)Cl.[CH3:50][O:51][C:52]1[CH:62]=[CH:61][C:55]([O:56][CH2:57][CH2:58]CO)=[CH:54][CH:53]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:42](=[O:48])[O:43][CH2:44][CH2:58][CH2:57][O:56][C:55]1[CH:61]=[CH:62][C:52]([O:51][CH3:50])=[CH:53][CH:54]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: COc1ccc(OCCCO)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1ccc(OCCCOC(=O)Nc2ccc(Oc3ncnc4cc(OC)c(OC)cc34)cc2Cl)cc1
Temperature: 25 °C
Yield: 48 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (87 mg) was added to toluene/triethylamine=10/1 (9 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (117 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-(4-methoxyphenoxy)-1-propanol (72 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (68 mg, yield 45%).
Reaction SMILES: [CH3:1][O:2]C1C=CC=CC=1CC#N.ClCCCl.[C:16]1([C:22]2([CH2:26][C:27](=[O:31])[C:28]([OH:30])=[O:29])[CH2:25][CH2:24]C2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C>[CH3:1][O:2][C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:22]1([CH2:26][C:27](=[O:31])[C:28]([OH:30])=[O:29])[CH2:25][CH2:24]1
Reactant: O=C(O)C(=O)CC1(c2ccccc2)CCC1
Reactant: COc1ccccc1CC#N
Solvent: ClCCCl
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COc1ccccc1C1(CC(=O)C(=O)O)CC1

Procedure:
Corresponding to J. Org. Chem. 40 (1975) 3497, 16.7 g of 2-methoxyphenylacetonitrile, 158 ml of lithium triisopropyl-amide (2 mol solution) and 46.7 ml of 1,2-dichloroethane in 96 ml of tetrahydrofuran and 58.6 ml of hexamethylphosphoric acid triamide are reacted with one another. 5.6 g of 1-(2-methoxy-phenyl)-cyclopropyl-carbonitrile, boiling point 104-115° C./0.1 mbar, which was also reacted as described for 3-(1-phenyl-cyclobutyl)-2-oxo-propionic acid, is obtained. 3-[1-(2-Methoxyphenyl)-cyclopropyl]-2-oxo-propionic acid is thus obtained as an oil.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[C:8]([C:21]([O:23]CC)=[O:22])=[CH:7]2>O.C(O)C>[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[C:8]([C:21]([OH:23])=[O:22])=[CH:7]2
Reactant: CCOC(=O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1

Procedure:
An aqueous solution of sodium hydroxide, prepared from 1.15 g (28.92 mmol) of sodium hydroxide pellets in 50 ml of water, is added to a solution of 7.6 g (24.10 mmol) of ethyl 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylate (WO 2006/024776) in 241 ml of ethanol. The mixture is heated for two hours and then concentrated under reduced pressure. The resulting solid is taken up in 200 ml of water. The solution is washed with twice 100 ml of ethyl ether, acidified by successive additions of small amounts of concentrated hydrochloric acid, and then extracted with 200 ml of ethyl acetate. The organic phase is finally washed twice with 100 ml of water and once with 50 ml of a saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. After drying at 50° C. under reduced pressure, 6.4 g of the expected product are obtained in the form of a solid, which will be used as it is in the next step.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[O:8][C:9]([C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10].[Cl:18]N1C(=O)CCC1=O>CN(C=O)C>[ClH:18].[NH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[O:8][C:9]([C:11]2[C:16]([C:17]=1[Cl:1])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10]
Reactant: NCCCOc1cc2ccccc2c(=O)o1
Reactant: O=C1CCC(=O)N1Cl
Agent: Cl
Solvent: CN(C)C=O
Product: NCCCOc1oc(=O)c2ccccc2c1Cl
Yield: 6.2 %

Procedure:
0.13 g of 3-(3-aminopropoxy)isocoumarin hydrochloride (0.5 mmole) was chlorinated with 0.007 g of N-chlorosuccinimide (0.5 mmole) in 5 ml of DMF at r.t. overnight. The reaction mixture was purified by silica gel column chromatography (methylene chloride:methanol=5:1) and crystallized from MeOH-ether to give 0.009 g of 3-(3-aminopropoxy)-4-chloro-isocoumarin hydrochloride (yield, 60%). The NMR spectrum of this compound is similar to 3-(3-aminopropoxy)isocoumarin without the peak at δ6.2 ppm; m.p. 160°-163° C.; mass spectrum, m/e=254 (M+ -Cl). Anal. Calc. for C12H13N1O3Cl2.1/4H2O: C, 48.88; H, 4.61; N, 4.75; Cl, 24.06. Found: C, 48.85; H, 4.54; N, 4.74; Cl, 24.02.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]1)[CH3:2].Cl[C:18]1[N:23]=[CH:22][C:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:20][N:19]=1.CCN(CC)CC>CS(C)=O.O>[CH2:1]([O:3][C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:18]2[N:19]=[CH:20][C:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][N:23]=2)[CH2:8]1)[CH3:2]
Reactant: CCOC(=O)c1cnc(Cl)nc1
Reactant: CCOc1ccccc1O[C@@H]1CCCNC1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc(N2CCC[C@@H](Oc3ccccc3OCC)C2)nc1
Temperature: 100 °C
Yield: 94.4 %

Procedure:
To a solution of (R)-3-(2-ethoxyphenoxy)piperidine (45 g, 204 mmol) and ethyl 2-chloropyrimidine-5-carboxylate (41.7 g, 224 mmol) in DMSO (300 mL) was added Et3N (40 mL, 305 mmol) at 20-25° C. The reaction mixture was heated to 100° C. for 2 hours, then was cooled to 20-25° C., diluted with H2O (300 mL) and extracted with EtOAc (3 times with 300 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated to obtain ethyl (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylate (71.5 g). MS (ES+) 372.3 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[C:4]([CH3:10])[N:3]=1.[Cl:11]CCCl.S(Cl)([Cl:17])=O>CN(C=O)C>[ClH:11].[Cl:17][CH2:8][C:6]1[CH:7]=[C:2]([CH3:1])[N:3]=[C:4]([CH3:10])[CH:5]=1
Reactant: ClCCCl
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(CO)cc(C)n1
Solvent: CN(C)C=O
Product: Cc1cc(CCl)cc(C)n1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(2,6-Dimethylpyridin-4-yl)methanol (457 mg) was mixed with DCE (8 ml), and thionyl chloride (0.6 ml) and DMF (19 mg) were added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain 4-(chloromethyl)-2,6-dimethylpyridine hydrochloride (567 mg).
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[C:5](F)[CH:4]=1.C1CC(C(N)=O)[C:15](=[O:16])CC1>>[N:9]1[C:6]2[C:5](=[CH:4][CH:3]=[CH:8][CH:7]=2)[C:15](=[O:16])[N:10]=1
Reactant: NC(=O)C1CCCCC1=O
Reactant: NNc1ccc(Cl)cc1F
Agent: Cl
Product: O=C1N=Nc2ccccc21

Procedure:
The pH of the 4-chloro-2-fluorophenylhydrazine hydrochloride slurry was adjusted to 3.8-4.0 and the temperature was raised to 90°-95°. To this mixture was added an aqueous solution (preheated to 90°-95°) of 1118 parts of cyclohexanone-2-carboxamide prepared as previously described. The resulting mixture was heated for 1-2 hr at 90°-95° during which time the product precipitated from solution. The product was isolated by filtration, washed by digestion with toluene and air-dried to give 1771 parts of an indazolone, an off-white solid mp 179-182 which was 2-(4-chloro-2-fluorophenyl)-1,2,4,5,6,7-hexahydro-3H-indazol-3-one.
Reaction SMILES: [C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH:9]=[CH:10][C:11](OCC)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.O>ClCCl>[C:16]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH:9]=[CH:10][CH2:11][OH:12])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)C=CCC(c1ccccc1)c1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: ClCCl
Product: OCC=CCC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2.22 mg (7.92 mmol) of ethyl 5,5-diphenyl-2-pentenoate was dissolved in 30 ml of dichloromethane. 16.1 ml (15.1 mmol) of diisobutylaluminum hydride (0.94 mol/L: hexane solution) was added to the obtained solution under cooling with ice, and they were stirred at room temperature for 2 days. Water was added to the reaction mixture and they were stirred under cooling with ice. The precipitate thus formed was filtered through Celite. The precipitate was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by the silica gel chromatography (hexane/ethyl acetate=3/1 to 1/1) to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[C:12]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[C:16]3[NH:20][C:21](=O)[CH3:22])[N:11]=[CH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]>CO>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[C:12]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[C:16]3[NH:20][CH2:21][CH3:22])[N:11]=[CH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(=O)Nc1nccn1Cc1cn(-c2ccc(Cl)c(Cl)c2)cn1
Solvent: CO
Product: CCNc1nccn1Cc1cn(-c2ccc(Cl)c(Cl)c2)cn1
Product: Cl
Temperature: 5 °C

Procedure:
N-{1-[1-(3,4-Dichloro-phenyl)-1H-imidazol-4-ylmethyl]-1H-imidazol-2-yl}-acetamide (0.30 g, 0.86 mmol) was treated with 1M BH3 THF complex (1.6 ml) and refluxed for 2 h. The mixture was cooled to 5° C. and MeOH (5 ml) was added slowly. After evaporation of all volatiles the residue was taken up in 2N HCl solution (3 ml) and refluxed for 20 min. The mixture was cooled and 2N NaOH solution (3 ml) was added. After extraction with AcOEt (50 ml), the organic phase was dried (Na2SO4) and evaporated to dryness. Purification by chromatography [silica, elution with gradient CH2Cl2 to 50% (CH2Cl2/MeOH/aq. NH4OH=90:10:1)] gave the free base of the title compound. After treatment with a solution of HCl in MeOH followed by addition of Et2O the title compound was isolated as an off-white crystalline material (0.062 g, 22%). Mp.>250° C. (MeOH/Et2O), MS: m/e=336 (M+H′).
Reaction SMILES: Br[CH2:2][C:3](CBr)=[O:4].[C:7]([NH:15][C@H:16]([C:20]([NH:22][C@H:23]([C:25]([NH:27][C@H:28]([C:33]([OH:35])=[O:34])[CH2:29][CH2:30][CH2:31][CH3:32])=[O:26])[CH3:24])=[O:21])[CH:17]([CH3:19])[CH3:18])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH:36][C:37]1[CH:45]=[CH:44][CH:43]=[CH:42][C:38]=1[C:39]([OH:41])=[O:40]>>[CH3:2][C:3]([O:40][C:39](=[O:41])[C:38]1[CH:42]=[CH:43][CH:44]=[CH:45][C:37]=1[OH:36])=[O:4].[C:7]([NH:15][C@H:16]([C:20]([NH:22][C@H:23]([C:25]([NH:27][C@H:28]([C:33]([OH:35])=[O:34])[CH2:29][CH2:30][CH2:31][CH3:32])=[O:26])[CH3:24])=[O:21])[CH:17]([CH3:18])[CH3:19])(=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(CBr)CBr
Reactant: O=C(O)c1ccccc1O
Agent: CCCC[C@H](NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)c1ccccc1)C(C)C)C(=O)O
Product: CC(=O)OC(=O)c1ccccc1O

Procedure:
(Electrospray MS m/z 540 [MH+ ]) from of N-benzoyl-L-valyl-L-alanyl-L-norleucine bromomethyl ketone and 2-hydroxybenzoic acid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C:19]([NH:21][CH2:22][CH:23]([OH:26])[CH2:24][CH3:25])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:11]([O:18][C:19]([NH:21][CH2:22][C:23](=[O:26])[CH2:24][CH3:25])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCC(O)CNC(=O)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCC(=O)CNC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 81.9 %

Procedure:
To methylene chloride (60 mL) at −78° C. under argon was added oxalyl chloride (37 mL of 2 M solution in methylene chloride, 74 mmol), followed by DMSO (7.8 g, 100 mmol). The mixture was stirred at −78° C. for 20 min. and to this mixture was added a solution of 1-benzyloxycarbonylamino-2-butanol (13.9 g, 61.8 mmol) in methylene chloride (40 mL). The mixture was stirred at −78° C. for 1 h and triethylamine (21 mL) was added to the mixture. It was warmed to room temperature (rt) and washed successively with 1 N hydrochloric acid and aqueous sodium bicarbonate solution. The methylene chloride solution was dried over MgSO4 and concentrated to afford 1-15 benzyloxycarbonylamino-2-butanone (11.2 g, 82%) as a solid, which was enough pure for the next reaction.
Reaction SMILES: [CH3:1][I:2].[Br:3][C:4]1[CH:5]=[C:6]([Cl:16])[CH:7]=[C:8]2[C:13]=1[NH:12][C:11](=[S:14])[NH:10][CH:9]2[CH3:15]>CC(C)=O>[IH:2].[Br:3][C:4]1[CH:5]=[C:6]([Cl:16])[CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([S:14][CH3:1])[NH:10][CH:9]2[CH3:15]
Reactant: CI
Reactant: CC1NC(=S)Nc2c(Br)cc(Cl)cc21
Solvent: CC(C)=O
Product: CSC1=Nc2c(Br)cc(Cl)cc2C(C)N1
Product: I
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.1 %

Procedure:
Methyl iodide (0.51 ml, 8.23 mmol) was added to a suspension of 8-bromo-6-chloro-4-methyl-3,4-dihydro-1H-quinazoline-2-thione (800 mg, 2.74 mmol) in acetone (8 ml). The mixture was stirred for 3 hours (r.t.), and the title compound (690 mg, 58%) was isolated from the reaction mixture by filtration.