Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8](O)(=O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(Cl)(=O)OCC.[CH3:38][N:39]([CH3:50])[CH2:40][CH2:41][NH:42][C:43]1[C:44]([NH2:49])=[CH:45][CH:46]=[CH:47][CH:48]=1>C(Cl)(Cl)Cl>[CH2:9]([C:8]1[N:42]([CH2:41][CH2:40][N:39]([CH3:50])[CH3:38])[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[N:49]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CN(C)CCNc1ccccc1N
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCCCCc1nc2ccccc2n1CCN(C)C
Reaction time: 1.5 h
Yield: 65.8 %

Procedure:
Triethylamine (2.25 ml) was added to a suspension containing n-docosanoic acid (4.930 g) in chloroform (50 ml), and then ethyl chlorocarbonate (1.52 ml) was added thereto while being cooled with ice. After being stirred for 1.5 hours, a solution containing N-[2-(dimethylamino)ethyl]-1,2-benzenediamine (2.593 g) in chloroform (13 ml). After being stirred for 2.5 hours while being cooled with ice, the reaction mixture was diluted with chloroform, washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. Concentrated hydrochloric acid (12.1 ml) was added to a solution containing the residue (8.644 g) in ethanol (87 ml). After being stirred for 2.5 hours at 90° C., the reaction mixture was concentrated. The residue, with ethyl acetate added thereto, was washed with 1N sodium hydroxide aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue (6.90 g) was purified by silica gel column chromatography (silica gel 150 g, chloroform:methanol=60:1-30:1), thereby yielding the entitled compound (4.604 g) as pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:12]O>S(=O)(=O)(O)O>[OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cccc(O)c1

Procedure:
10 g of 3-hydroxyphenylacetic acid are dissolved in 60 ml of methanol and 2.5 ml of sulphuric acid. The solution is heated at reflux for two hours. It is brought back to ambient temperature and the methanol is evaporated. The residue is taken up in a saturated K2CO3 solution. Extraction is carried out with AcOEt. The organic phase is dried over MgSO4, filtered and evaporated to dryness. 11.1 g of oil are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([Li])CCC.[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[C:18]2=[O:25]>CCOCC.CCCCCC.C1COCC1>[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[C:18]2([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[F:8])[OH:25]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: Fc1ccccc1F
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1Nc2ccc(Cl)cc2C1(O)c1cccc(F)c1F
Temperature: -10 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
A solution of 5.6 g of 1,2-difluorobenzene in 50 ml of ether is cooled to −10° C, 31 ml of a 1.6 M solution of n-butyllithium in hexane are added drop wise and the mixture is stirred at −10° C. for 2 hours. The reaction mixture is cooled to −50° C., a solution of 4 g of 5-chloro-1H-indole-2,3-dione in 40 ml of THF is added and the resulting mixture is stirred for 12 hours, while allowing the temperature to return to RT. The reaction mixture is poured into a concentrated HCl/ice/water mixture, the resulting mixture is extracted with EtOAc, the organic phase is washed with 1N NaOH solution, with water and dried over Na2SO4, and the solvent is evaporated off under vacuum. 2.8 g of the expected product are obtained after crystallization from iso-ether; m.p.=248° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]([NH2:17])[S:15][CH:16]=2)=[CH:8][CH:7]=1.[N:18]1([C:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[S:26][N:25]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(N(C(C)C)CC)(C)C.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CC(CC(C)C)=O>[S:26]1[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:24]([N:18]2[CH2:19][CH2:20][N:21]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]3[CH:11]=[CH:10][C:9]([C:12]4[N:13]=[C:14]([NH2:17])[S:15][CH:16]=4)=[CH:8][CH:7]=3)[CH2:22][CH2:23]2)=[N:25]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: Nc1nc(-c2ccc(CCCCCl)cc2)cs1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(-c2ccc(CCCCN3CCN(c4nsc5ccccc45)CC3)cc2)cs1

Procedure:
To a 100 ml round-bottomed flask equipped with condenser and N2 inlet were added 1.22 g (3.52 mmol) (4-(4-(4-chlorobutyl)phenyl)-2-aminothiazole, 0.90 g (3.52 mmol) 3-piperazinyl-benzisothiazole, 1.84 ml (10.57 mmol) diisopropylethylamine, 0.75 g (7.04 mmol) sodium carbonate, 2 mg sodium iodide, and 35 ml methylisobutylketone. The reaction mixture was refluxed 6 days, cooled, and evaporated. The residue was chromatographed on silica gel using methylene chloride/ethyl acetate as eluent, and the product fractions dissolved in methylene chloride/methanol and precipitated by addition of methylene chloride saturated with HCl. The precipitate was filtered and dried to give a solid, 242 mg (13%), m.p. 258-261° C. NMR (DMSO-d6): 1.6-1.8 (m, 4H), 2.7 (t, 2H), 3.2-3.6 (m, 8H), 4.1 (m, 2H), 7.20 (s, 1H), 7.3-8.2 (m, 8H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[Cl:36][C:37]1[CH:50]=[CH:49][C:40]([O:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[NH2:48])=[CH:39][CH:38]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[NH:48][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[O:41][C:40]2[CH:49]=[CH:50][C:37]([Cl:36])=[CH:38][CH:39]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: Nc1ccccc1Oc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccccc2Oc2ccc(Cl)cc2)CC1
Reaction time: 0.5 h
Yield: 54.8 %

Procedure:
A solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (AMR01030, 417 mg, 1.82 mmol) in dry DCM (8 mL) was stirred under nitrogen, and 4-dimethylaminopyridine (DMPA, 40 mg, 0.327 mmol), (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 1.05 g, 5.46 mmol) and triethylamine (0.25 mL) were added. The resulting mixture was stirred for 30 min under nitrogen and 2-(4-chloro-phenoxy)-phenylamine (AMR01029, 400 mg, 1.82 mmol) in dry DCM (4 mL) was added. After stirring at room temperature for 24 h, the mixture was diluted with DCM, washed with HCl 1M (3×25 mL), water, saturated NaHCO3 (2×25 mL) and brine. The organic layer was dried (MgSO4), filtered and evaporated. Flash chromatography on silica gel of the crude product using hexane/EtOAc 8:2 as eluent gave starting material (104 mg). Further elution using hexane/EtOAc 7:3 gave 4-[2-(4-chlorophenoxy)-phenylcarbamoyl]piperidine-1-carboxylic acid tert-butyl ester (430 mg, 55%) as a white solid, mp 97-99° C. Rf: 0.22 (hexane/EtOAc 7:3) LC/MS (APCI) tr=3.83 min, m/z 431.23 (33), 429.21 (M−−H, 100). 1H NMR (270 MHz, CDCl3) δ 1.44 (9H, s, 3CH3), 1.68 (2H, m, CH2), 1.83 (2H, m, CH2), 2.36 (1H, tt, J=11.4, 3.7 Hz), 2.75 (4H, br t, 2CH2), 4.11 (4H, m, 2CH2), 6.81 (1H, dd, J=8.2, 1.5 Hz, ArH), 6.93 (2H, AA′BB′, ArH), 7.01 (1H, td, ArH), 7.12 (1H, td, ArH), 7.31 (2H, AA′BB′, ArH), 7.68 (1H, br s, NH) and 8.40 (1H, dd, J=6.9, 1.5 Hz, ArH).
Reaction SMILES: Cl.[O:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.[C:11]1(/[CH:20]=[CH:21]\[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=[CH:15][C:14]([C:17](O)=[O:18])=[CH:13][CH:12]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[C:11]1(/[CH:20]=[CH:21]\[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:12]=[CH:13][C:14]([C:17]([N:7]2[CH2:8][CH2:9][C:10]3[O:2][CH:3]=[CH:4][C:5]=3[CH2:6]2)=[O:18])=[CH:15][CH:16]=1
Reactant: O=C(O)c1ccc(/C=C\c2ccccc2)cc1
Reactant: c1cc2c(o1)CCNC2
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(c1ccc(/C=C\c2ccccc2)cc1)N1CCc2occc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[3,2-c]pyridine hydrochloride, 0.269 g (1.2 mmol) of (Z)-4-stilbenecarboxylic acid and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.24 g (1.5 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1) to yield the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[N:23]([S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])[C:16]4[N:17]=[CH:18][CH:19]=[C:20]([CH:21]=O)[C:15]=4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:34][CH3:35].Cl.[NH2:37][OH:38]>N1C=CC=CC=1.O.ClCCl>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[N:23]([S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])[C:16]4[N:17]=[CH:18][CH:19]=[C:20]([CH:21]=[N:37][OH:38])[C:15]=4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:34][CH3:35]
Reactant: NO
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(C=O)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: COc1cc2c(nc1OC)c(-c1cc3c(C=NO)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Temperature: 50 °C

Procedure:
To a solution of 1 g of [2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde in 50 cm3 of pyridine, at a temperature in the region of 20° C., is added 0.46 g of hydroxylamine hydrochloride. The reaction medium is heated at 50° C. for 24 hours. The reaction medium is concentrated under reduced pressure. The residue obtained is taken up in 20 cm3 of water and 50 cm3 of dichloromethane. After separation of the phases by settling, the organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure. 0.510 g of [2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-carbaldehyde oxime is obtained with the following characteristics:
Reaction SMILES: C([N:4]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[O:26][C:27]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([NH2:37])[C:28]=3[C:29](=[O:31])[CH:30]=2)=[CH:21][CH:20]=1)[CH2:5][CH2:6][CH2:7][N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18])(=O)C.Cl.[OH-].[Na+].O>O1CCOCC1>[NH2:37][C:32]1[C:28]2[C:29](=[O:31])[CH:30]=[C:25]([C:22]3[CH:21]=[CH:20][C:19]([NH:4][CH2:5][CH2:6][CH2:7][N:8]4[C:12](=[O:13])[C:11]5=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]5[C:9]4=[O:18])=[CH:24][CH:23]=3)[O:26][C:27]=2[CH:35]=[CH:34][C:33]=1[F:36]
Reactant: CC(=O)N(CCCN1C(=O)c2ccccc2C1=O)c1ccc(-c2cc(=O)c3c(N)c(F)ccc3o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Nc1c(F)ccc2oc(-c3ccc(NCCCN4C(=O)c5ccccc5C4=O)cc3)cc(=O)c12
Yield: 87 %

Procedure:
6.0 g of Compound 14 was dissolved in 90 ml of dioxane, 60 ml of concentrated hydrochloric acid was added and the mixture was heated at reflux for 5 hours. The reaction solution was cooled on ice and adjusted to pH 7.5 by addition of a 10N aqueous solution of sodium hydroxide thereto, water was further added, and the precipitated crystals were collected by filtration to give 4.78 g (87%) of Compound 15.
Reaction SMILES: C(O)(=O)C(O)=O.[N+:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[CH2:13][CH2:14][NH2:15])([O-:9])=[O:8].[Br:19][C:20]1[CH:21]=[C:22]([CH2:29][C:30](Cl)=[O:31])[CH:23]=[C:24]([Br:28])[C:25]=1[O:26][CH3:27]>C(Cl)Cl.[OH-].[Na+]>[Br:19][C:20]1[CH:21]=[C:22]([CH2:29][C:30]([NH:15][CH2:14][CH2:13][C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([N+:7]([O-:9])=[O:8])[CH:11]=2)=[O:31])[CH:23]=[C:24]([Br:28])[C:25]=1[O:26][CH3:27]
Reactant: COc1c(Br)cc(CC(=O)Cl)cc1Br
Reactant: NCCc1cccc([N+](=O)[O-])c1
Agent: O=C(O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1c(Br)cc(CC(=O)NCCc2cccc([N+](=O)[O-])c2)cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 3-nitro-phenethylamine oxalate (1.792 g, 0.007 mol) in methylene chloride (45 mL), 1 N NaOH (45 mL) was added. It was stirred at room temperature to get a clear solution. A solution of 3,5-dibromo-4-methoxyphenyl acetyl chloride (0.0072 mol) in methylene chloride was added. Stirring was continued overnight and the completion of the reaction was monitored by thin layer chromatography. The reaction mixture was washed with 1N HCl and 1N NaOH, extracted with methylene chloride. The combined extracts were dried over anhydrous sodium sulfate and concentrated. The solid obtained was crystallized from ethyl acetate-hexanes mixture. Yield 2.159 g, 65%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:60][CH2:61][C:62]1[CH:63]=[CH:64][C:65]2[C:69]([CH3:71])([CH3:70])[O:68][B:67]([OH:72])[C:66]=2[CH:73]=1>CC#N>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:25])([F:26])[F:27])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:60][CH2:61][C:62]4[CH:63]=[CH:64][C:65]5[C:69]([CH3:71])([CH3:70])[O:68][B:67]([OH:72])[C:66]=5[CH:73]=4)=[O:20])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC1(C)OB(O)c2cc(CN)ccc21
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCc1ccc2c(c1)B(O)OC2(C)C
Reaction time: 0.17 h
Yield: 21.4 %

Procedure:
A solution of 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid (1.65 g, 3.95 mmol) and Et3N (1.6 g, 15.8 mmol) in MeCN (35 ml) was stirred at rt for 5 min and then HATU (3 g, 7.9 mmol) was added. The mixture was stirred for 10 min prior to the addition of 6-(aminomethyl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (906 mg, 4.74 mmol). And the resulting mixture was stirred at rt overnight. It was then concentrated under vacuum, and the residue was partitioned between 1N HCl and ethyl acetate. The organic layer separated was concentrated under vacuum, and the residue was purified by column chromatography and preparative HPLC to provide the product (500 mg, yield 21%). 1H NMR (300 MHz, DMSO-d6): δ 9.05 (s, 1H), 8.92 (s, 1H), 7.82 (s, 1H), 7.61 (m, 5H), 7.40 (m, 3H), 4.49 (d, 2H), 4.37 (d, 2H), 2.39 (s, 3H), 1.44 (s, 6H) ppm; HPLC purity: 97.4% at 220 nm and 98.1% at 254 nm; MS: m/z=591.3 (M+H, ESI+).
Reaction SMILES: N1C=CC=CC=1.[O:7]=[C:8]1[N:13]([CH2:14][C:15]#[CH:16])[C:12]2[CH:17]=[C:18]([N:21]3[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[NH:23][C:22]3=O)[CH:19]=[CH:20][C:11]=2[O:10][CH2:9]1.P(Cl)(Cl)([Cl:35])=O>C1(C)C=CC=CC=1>[Cl:35][C:22]1[N:21]([C:18]2[CH:19]=[CH:20][C:11]3[O:10][CH2:9][C:8](=[O:7])[N:13]([CH2:14][C:15]#[CH:16])[C:12]=3[CH:17]=2)[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[N:23]=1
Reactant: C#CCN1C(=O)COc2ccc(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc21
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: C#CCN1C(=O)COc2ccc(-n3c(Cl)nc(C(F)(F)F)cc3=O)cc21
Temperature: 100 °C

Procedure:
16.61 g of pyridine are added at 25° C. while stirring to a suspension of 25.55 g of 3-[3,4-dihydro-3-oxo-4-(2-propynyl)-2H-1,4-benzoxazin-6-yl]-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (see Example 3) and 32.13 g of phosphorus oxychloride in 250 ml of toluene. The reaction mixture is heated to 100° C. for 6 hours, cooled to 25° C. and poured on to 500 g of ice. Subsequently, the aqueous mixture is extracted three times with 150 ml of ethyl acetate each time and the organic phase is washed neutral with water, dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The resinous product is purified by chromatography on a silica gel column with ethyl acetate/n-hexane (1:3) as the eluent. Finally, the product is recrystallized from diethyl ether/n-hexane. In this manner there is obtained 6-[2-chloro-6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]-4-(2-propynyl)-2H-1,4-benzoxazin-3(4H)-one, m.p. 143°-145° C. (see Example 78).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[N:16])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].O.Cl.[CH3:25][O:26][C:27](=[O:33])[C@H:28]([CH:30]([CH3:32])[CH3:31])[NH2:29]>C(OCC)(=O)C>[CH3:25][O:26][C:27](=[O:33])[C@H:28]([CH:30]([CH3:32])[CH3:31])[NH:29][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[N:16])=[CH:5][CH:4]=1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@@H](NCc1ccc(-c2ccccc2C#N)cc1)C(C)C
Temperature: 45 °C
Reaction time: 25 h

Procedure:
4′-Bromomethyl-2-cyanobiphenyl (75 g, 0.2757 moles) was added to a mixture of potassium carbonate (95.12 g), DM water (225 ml), ethyl acetate (450 ml) and L-valine methyl ester hydrochloride (55.45 g, 0.330 moles) at 20-30° C. The reaction mixture was heated to 40-50° C. and stirred for 25 h. After completion of the reaction, the ethyl acetate layer was separated at 20-30° C., added DM water (375 ml) and adjusted the pH to 0.8-1.0 with dilute hydrochloric acid at 20-30° C. The aqueous layer was separated and extracted the product in to toluene (430 ml) by adjusting the pH to 8.0-8.5 with 20% w/w aqueous sodium carbonate solution. The toluene layer was washed with DM water (225 ml), concentrated under reduced pressure and dissolved in toluene (450 ml)
Reaction SMILES: CI.[I-].CS[C:6]([NH2:18])=[NH+:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[N:13]=[CH:14][NH:15][C:16]=1[CH3:17].[I-].S([O-])([O-])(=O)=O.S([O-])([O-])(=O)=O.CSC(N)=[NH+]CCSCC1N=CNC=1C.CSC(N)=[NH+]CCSCC1N=CNC=1C.[NH2:60][CH2:61][CH2:62][CH2:63][C:64]1[N:65]=[CH:66][NH:67][CH:68]=1>CO.O>[CH3:17][C:16]1[NH:15][CH:14]=[N:13][C:12]=1[CH2:11][S:10][CH2:9][CH2:8][NH:7][C:6]([NH:60][CH2:61][CH2:62][CH2:63][C:64]1[N:65]=[CH:66][NH:67][CH:68]=1)=[NH:18]
Reactant: NCCCc1c[nH]cn1
Reactant: CSC(N)=[NH+]CCSCc1nc[nH]c1C
Agent: O=S(=O)([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CO
Solvent: CI
Product: Cc1[nH]cnc1CSCCNC(=N)NCCCc1c[nH]cn1

Procedure:
i A solution of n-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]-thiourea (2.29 g) and methyl iodide (1.56 g) in methanol (5 ml) was kept at room temperature for 18 hours affordng S-methyl-N -[2-((5-methyl-4-imidazolyl)methylthio)ethyl] thiouronium iodide (2.3 g), m.p. 128°-131°. The iodide was converted into the corresponding sulphate by ion-exchange on an ion-exchange resin (IRA 401) in the sulphate form. ii. A solution of S-methyl-N-[2-((5-methyl-4-imidazolyl) methylthio)-ethyl] thiouronium sulphate (2.93 g) and 4-(3-aminopropyl) imidazole (1.25 g) in water (10 ml) was heated under reflux for 3 hours. Following concentration, the residue was converted to the free base with an ion-exchange resin (IRA 401) in the OH- form and then applied to a weakly acid cation exchange resin (CG 50 in the H+ form) and eluted with dilute hydrochloric acid. The eluate was concentraed to give the title compound which was isolated as the tripicrate (1.8 g) m.p. 183°-185° (from acetone-water). (Found: C, 37.8; H, 3.2; N,21.8% C14H23N7S.3 C6H3N3O7 requires: C, 38.1; H, 3.2; N,22.2%). The tripicrate was converted into the trihydrochloride salt by means of ion-exchange resin IRA 400 (Cl-). The tripcrate was converted into the free base by means of ion-exchange resin IRA 401 (OH-) and the free base was treated with oxalic acid in warm ethanol. The dioxalate crystallised on cooling and was recrystalised from aqueous etanol m.p. 125°-127°. (Found: C, 42.8; H, 5.4; N, 19.4; S, 6.3; C14H23N7S.2 C2H2O4 requires: C, 43.1; H, 5.4; N, 19.5; S, 6.4%)
Reaction SMILES: [CH:1]1([CH:7]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([NH:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:32])=[CH:27][CH:26]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21]SC)=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:42]1C=CC=C(C(OO)=O)C=1.[S:52]([O-:55])([O-])=[O:53].[Na+].[Na+]>CC(C)=O>[CH:1]1([CH:7]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([NH:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:32])=[CH:27][CH:26]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][S:52]([CH3:42])(=[O:55])=[O:53])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3ccc(OCCCSC)cc3c2C)C2CCCCC2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3ccc(OCCCS(C)(=O)=O)cc3c2C)C2CCCCC2)cc1
Reaction time: 0.25 h
Yield: 68 %

Procedure:
Ethyl 3-[({4-[(cyclohexyl{3-methyl-5-[3-(methylsulfanyl)propoxy]-1-benzofuran-2-yl}methyl)amino]phenyl}carbonyl)amino]propanoate (0.16 g) synthesized in Example A151(1) was dissolved in acetone (5 mL), metachloroperbenzoic acid (0.2 g) was added to the solution under ice-cooling, and the mixture was stirred for 15 min. To the reaction mixture was added sodium sulfite aqueous solution, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1, volume ratio) to give the title object compound (0.11 g, 68%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH:37]1(CO)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH2:26][CH:37]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[C:18]([CH3:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCC1CCCCCC1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OCC4CCCCCC4)cc3C)c2cc1OC
Yield: 86.8 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, cycloheptylmethanol (30 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (64 mg, yield 83%).