Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][S:8][CH:9]2[NH:12][C:11](=[O:13])[CH2:10]2)=[CH:5][CH:4]=1.Br[CH2:17][C:18]([O:20][CH3:21])=[O:19]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][CH:9]2[N:12]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:11](=[O:13])[CH2:10]2)=[CH:14][CH:15]=1
Reactant: COC(=O)CBr
Reactant: COc1ccc(CSC2CC(=O)N2)cc1
Product: COC(=O)CN1C(=O)CC1SCc1ccc(OC)cc1

Procedure:
Treatment of 4-(4-methoxybenzylthio)-azetidin-2-one (7 g) with methyl bromoacetate (5.3 g) under the conditions described for Example 29a gave the title compound as a colourless solid, m.p. 45-46° C., (5.9 g, 64%)
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7]([N:10]2[C:14]([C:15]3[C:16]([F:21])=[N:17][CH:18]=[CH:19][CH:20]=3)=[C:13]([F:22])[C:12]([CH2:23][N:24](C)[C:25](=O)OC(C)(C)C)=[CH:11]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.C(OCC)(=O)C.[ClH:39]>C(OCC)(=O)C.CC(O)C>[ClH:39].[Br:1][C:2]1[S:6][C:5]([S:7]([N:10]2[C:14]([C:15]3[C:16]([F:21])=[N:17][CH:18]=[CH:19][CH:20]=3)=[C:13]([F:22])[C:12]([CH2:23][NH:24][CH3:25])=[CH:11]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2ccc(Br)s2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CNCc1cn(S(=O)(=O)c2ccc(Br)s2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 55 %

Procedure:
To a solution of tert-butyl {[1-[(5-bromo-2-thienyl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (248 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethyl acetate-ethanol to give the title compound as a white solid (yield 121 mg, 55%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([NH:18][C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])([C:13]([F:17])([F:16])[CH:14]=C)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:29]=[O+][O-].[BH4-].[Na+].C(=O)(O)[O-].[Na+].[Cl-].[Na+]>C(Cl)(Cl)Cl.CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([NH:18][C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])([C:13]([F:17])([F:16])[CH2:14][OH:29])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=[O+][O-]
Reactant: C=CC(F)(F)C1(NC(=O)OCc2ccccc2)CCN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)(C(F)(F)CO)C1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A solution of an optically-active compound of 3-benzyloxycarbonylamino-3-(1,1-difluoroallyl)pyrrolidine-1-carboxylic acid tert-butyl ester (15.5 g) in chloroform/methanol (154 ml/154 ml) cooled to −78° C. was flowed ozone air for 30 minutes. To the reaction mixture was added sodium borohydride (4.14 g) in small batches, and then the mixture was warmed to 0° C. and stirred at the same temperature for additional 4 hours. To the mixture were added saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, and the mixture was extracted with chloroform. The separated aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1). The fractions which could not be separated and isolated were concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: n-hexane/chloroform/ethyl acetate=5/4/1) again. The purified fractions were combined and concentrated under reduced pressure to give the titled compound (12.8 g).
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH2:4].C=O.N.F.F.F[Si](F)(F)F.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:1][C:2]1[CH:16]=[N:15][CH:20]=[CH:4][CH:3]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C=CC=C
Agent: C=O
Agent: F
Agent: F[Si](F)(F)F
Solvent: c1ccncc1
Product: Cc1cccnc1
Temperature: 320 °C
Reaction time: 0 h

Procedure:
Following the same general procedure as in Example 1, a gaseous mixture of 1,3-butadiene (2.1% by volume), formaldehyde (1.7% by volume), ammonia (7.8% by volume), air 31.5% by volume), steam (33.2% by volume) and nitrogen (23.7% by volume) was passed through a fluidised bed of "Synclyst" catalyst (previously treated with fluosilicic acid in an amount corresponding to 5% by weight of the catalyst) maintained at 320° C. The contact time was 4.9 seconds and the mixture was passed over a period of 4 hours during which time 0.41 mole of 1,3-butadiene and 0.33 mole of formaldehyde were fed. 0.352 mole of unreacted butadiene was recovered corresponding to a molar conversion of 14.8%. A total of 0.027 mole of pyridine and 0.0055 mole of 3-methylpyridine were formed, corresponding to a pyridine yield of 44% of the butadiene consumed.
Reaction SMILES: Cl.[NH2:2][OH:3].[N:4]1([CH2:9][C:10]2[S:14][C:13]([C:15](=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:11]=2)[CH:8]=[CH:7][N:6]=[N:5]1>C(O)C>[N:4]1([CH2:9][C:10]2[S:14][C:13]([C:15](=[N:2][OH:3])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:11]=2)[CH:8]=[CH:7][N:6]=[N:5]1
Reactant: NO
Reactant: CCOC(=O)C(=O)c1ccc(Cn2ccnn2)s1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(=NO)c1ccc(Cn2ccnn2)s1
Reaction time: 18 h
Yield: 99.7 %

Procedure:
Hydroxylamine hydrochloride (167 mg) was added to a stirred solution of ethyl 2-[5-(1,2,3-triazol-1-ylmethyl)thien-2-yl]-2-oxoacetate (Description 55) (319 mg) in ethanol (5 ml). The mixture was stirred for 18 h then the solvent was evaporated and the residue partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried over magnesium sulphate and evaporated to give the product (336 mg). νmax (nujol) 3136, 1736cm-1. δ(CD3COCD3) 1.33-1.39 (3H, m), 4.30-4.46 (2H, m), 5.89 and 5.95 (2H, two s's), 7.07 and 7.17 (1H, two d's, J 3.81 Hz), 7.23 and 7.75 (1H, two d's, J 3.90 Hz), 8.07 and 8.08 (1H, two s's). m/z 281 (MH+)
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][NH2:21])=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7].[F:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.CC(C)CCNC(C1C(C2C=CC=CC=2C(S(C2C=CC(F)=CC=2)(=O)=O)N)=CC=CC=1)=O>>[CH3:1][CH:2]([CH3:22])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][NH:21][S:30]([C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)(=[O:32])=[O:31])=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CC(C)CCNC(=O)c1ccccc1-c1ccccc1CN
Agent: CC(C)CCNC(=O)c1ccccc1-c1ccccc1C(N)S(=O)(=O)c1ccc(F)cc1
Product: CC(C)CCNC(=O)c1ccccc1-c1ccccc1CNS(=O)(=O)c1ccc(F)cc1

Procedure:
From 0.34 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid (3-methyl-butyl)amide (precursor 5c) and 4-fluorophenylsulfonyl chloride, according to the general working procedure 122 mg of 2′-(4-fluorophenylsulfonyl-aminomethyl)biphenyl-2-carboxylic acid (3-methylbutyl)amide were obtained; m.p. 149° C. MS (ES+): m/e=455 (M+1).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][N:8]1[CH:12]=[CH:11][C:10]([NH2:13])=[N:9]1.F[C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23].[NH4+].[Cl-]>C1COCC1>[F:21][C:19]1[CH:18]=[CH:17][C:16]([N+:22]([O-:24])=[O:23])=[C:15]([NH:13][C:10]2[CH:11]=[CH:12][N:8]([CH3:7])[N:9]=2)[CH:20]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: Cn1ccc(N)n1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cn1ccc(Nc2cc(F)ccc2[N+](=O)[O-])n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 40.9 %

Procedure:
Potassium tert-butoxide (898 mg, 8.0 mmol) was added to a stirred solution of 1-methyl-1H-pyrazol-3-ylamine (0.35 mL 4.00 mmol) in anhydrous THF (5 mL) under a nitrogen atmosphere at 0° C. After 15 min 2,4-difluoro-1-nitrobenzene (0.44 mL, 4.0 mmol) in anhydrous THF (5 mL) was added and stirring at 0° C. continued for 1 h. The reaction mixture was poured into a solution of NH4Cl (50 mL). The aqueous phase was extracted with EtOAc (×2) and the combined organic fractions washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-100% EtOAc in cyclohexane) to afford the title compound as a dark red solid (386 mg, 41%). LCMS (Method C): RT 3.29 min [M+H]+ 237.08
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:17]([O:19]CC)=[O:18])[CH:9]([C:13]([F:16])([F:15])[F:14])[O:10]2)=[CH:5][C:4]=1[CH:22]=[CH2:23].[OH-].[Li+].C(O)C.Cl>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:17]([OH:19])=[O:18])[CH:9]([C:13]([F:15])([F:16])[F:14])[O:10]2)=[CH:5][C:4]=1[CH:22]=[CH2:23]
Reactant: C=Cc1cc2c(cc1OC)OC(C(F)(F)F)C(C(=O)OCC)=C2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: C=Cc1cc2c(cc1OC)OC(C(F)(F)F)C(C(=O)O)=C2
Temperature: 80 °C
Yield: 79.6 %

Procedure:
The isolated intermediate from step 1 (150 mg, 0.46 mmol) was dissolved in 3 mL of THF. To the resulting solution was added a solution of lithium hydroxide (2.3 mmol.) in 3 mL of water. To the resulting mixture was added 3 mL of ethanol. The resulting solution was heated to 80° C. for three h. The mixture was concd in vacuo and the residue acidified to pH=1.0 with dilute aqueous hydrochloric acid. The product was extracted with ethyl acetate. The combined organic extracts were washed with brine and dried over anhydrous magnesium sulfate. The solution was concd in vacuo to afford 110 mg (52%) of the final product: 1H NMR (CDCl3/300 MHz) 7.80(s, 1H), 7.48(s, 1H), 6.98-6.88(dd, J=17.7 Hz, 11.2 Hz, 1H), 6.66(s, 1H), 5.80-5.69(m, 2H), 5.20(d, J=11.4 Hz, 1H), 3.90(s, 3H). MS (ESI+) 301.1 (M+1, 100). MS(ES−) 299.1 (M−H, 100). HRMS (ES−) m/z calcd for (C14H10F3O4) M−H: 299.0526, found 299.0500.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:38]=[CH:39][C:40]2[O:45][CH2:44][C:43](=[O:46])[N:42]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[C:41]=2[CH:52]=1>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[CH:38]=[CH:39][C:40]3[O:45][CH2:44][C:43](=[O:46])[N:42]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[C:41]=3[CH:52]=2)=[CH:9][CH:10]=1
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)cc21

Procedure:
Analogously to Method D, 0.340 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)-propoxy]phenyl}piperidine-1-carboxylate and 0.193 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one are reacted. The title compound is obtained as a colourless oil. Rf=0.30 (1:1 EtOAc-heptane); Rt=5.99.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:10][C:11]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[OH:23])=[O:12])[CH2:9][CH2:8][CH2:7]1)=[O:5])C.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+].Br[CH2:33][CH2:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1>CN(C=O)C>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([O:35][CH2:34][CH2:33][O:23][C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:21]=[CH:22][C:13]=2[C:11]([NH:10][C:6]2([C:4]([OH:3])=[O:5])[CH2:7][CH2:8][CH2:9]2)=[O:12])=[CH:37][CH:38]=1
Reactant: CCOC(=O)C1(NC(=O)c2ccc3ccccc3c2O)CCC1
Reactant: Clc1ccc(OCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Product: O=C(NC1(C(=O)O)CCC1)c1ccc2ccccc2c1OCCOc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 94 mg 1-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-cyclobutanecarboxylic acid ethyl ester, 195 mg cesium carbonate and 5 mg sodium iodide in 3 ml of abs. DMF 78 mg of 4-Chlorphenyl 2-bromoethyl ether were added. The reaction mixture was stirred for 2 h at room temperature, then for 5 h at 80° C. The cooled reaction mixture was filtrated, and the filtrate was diluted with 20 ml ethyl acetate and washed twice with brine. The organic phase was concentrated in vacuo, and the resulting residue was dissolved in 2 ml methanol and 1 ml THF. After addition of 0.75 ml 2M NaOH (aq) the mixture was stirred for 1 h at 45° C. and then overnight at room temperature. The solution was neutralized with 0.75 ml 2 M hydrochloride acid, evaporated, and the resulting residue was purified by RP-HPLC to yield 42 mg 1-({1-[2-(4-chloro-phenoxy)-ethoxy]-naphthalene-2-carbonyl}-amino)-cyclobutanecarboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([OH:17])=O)[N:13]=2)=[O:7])=[CH:4][CH:3]=1.Cl.Cl.[N:22]1([C:28]2[S:29][CH2:30][CH2:31][N:32]=2)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([N:25]3[CH2:26][CH2:27][N:22]([C:28]4[S:29][CH2:30][CH2:31][N:32]=4)[CH2:23][CH2:24]3)=[O:17])[N:13]=2)=[O:7])=[CH:18][CH:19]=1
Reactant: C1CSC(N2CCNCC2)=N1
Reactant: O=C(O)Cc1csc(NC(=O)c2ccc(Cl)cc2)n1
Agent: Cl
Product: O=C(Nc1nc(CC(=O)N2CCN(C3=NCCS3)CC2)cs1)c1ccc(Cl)cc1

Procedure:
In analogy to example 1.3, [2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetic acid (example 1.2) was coupled with 2-(piperazino)-2-thiazoline dihydrochloride to give 4-chloro-N-(4-{2-[4-(4,5-dihydro-thiazol-2-yl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-benzamide, using general procedure C. White solid. MS 450.0 ([M+H]+)
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].Cl/[C:6](=[N:12]/[OH:13])/[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(N(CC)CC)C.[Cl-].[Na+]>O1CCCC1>[OH:4][CH2:1][C:2]1[O:13][N:12]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:3]=1
Reactant: CCOC(=O)/C(Cl)=N\O
Reactant: C=CCO
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(CO)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
24.03 g of 2-propene-1-ol and 16.24 g of ethyl (2E)-chloro(hydroxyimino)acetate were dissolved in 100 ml of tetrahydrofuran, and 12.12 ml of triethylamine dissolved in 50 ml of tetrahydrofuran was then added dropwise at 0° C. over 30 minutes. The mixture was stirred at room temperature overnight. After aqueous saturated sodium chloride was added, the reaction mixture was separated into layers. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over aqueous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 14.22 g of ethyl 5-(hydroxymethyl)-isoxazole-3-carboxylate.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]1[C:16]2[C:15]3[C:14]([O:17][CH:18]4[CH2:23][CH2:22][CH:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]4)=[N:13][CH:12]=[N:11][C:10]=3[S:9][C:8]=2[CH2:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:39][S:40]([O:1][CH2:2][CH2:3][C@H:4]1[C:16]2[C:15]3[C:14]([O:17][CH:18]4[CH2:23][CH2:22][CH:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:30])[CH3:29])[CH2:20][CH2:19]4)=[N:13][CH:12]=[N:11][C:10]=3[S:9][C:8]=2[CH2:7][CH2:6][CH2:5]1)(=[O:42])=[O:41]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1CCC(Oc2ncnc3sc4c(c23)[C@H](CCO)CCC4)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCC(Oc2ncnc3sc4c(c23)[C@H](CCOS(C)(=O)=O)CCC4)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
To a solution of tert-butyl N-(4-[[(13S)-13-(2-hydroxyethyl)-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-3-yl]oxy]cyclohexyl)carbamate (490 mg, 1.09 mmol, 1.00 equiv) in DCM (20 mL) was added triethylamine (201 mg, 1.99 mmol, 1.80 equiv) and methanesulfonyl chloride (189 mg, 1.65 mmol, 1.50 equiv) at 0° C. The resulting solution was stirred for 2 h at room temperature and then washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:3) to provide 530 mg of tert-butyl N-(4-[[(13S)-13-[2-(methanesulfonyloxy)ethyl]-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-3-yl]oxy]cyclohexyl)carbamate as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[C:18]([CH2:20][C:21]([O:23][CH2:24][CH:25]([CH2:30][CH3:31])[CH2:26][CH2:27][CH2:28][CH3:29])=[O:22])#[N:19].N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1>[C:14]([C:11]1[CH:10]=[C:7]([CH:6]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[C:12]=1[OH:13])[CH:8]=[C:20]([C:18]#[N:19])[C:21]([O:23][CH2:24][CH:25]([CH2:30][CH3:31])[CH2:26][CH2:27][CH2:28][CH3:29])=[O:22])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: CCCCC(CC)COC(=O)CC#N
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CCCCC(CC)COC(=O)C(C#N)=Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
28.1 g of 3,5-di-tertiary-butyl-4-hydroxybenzaldehyde were dissolved in 60 ml of toluene. 21.7 g of 2-ethylhexyl cyanoacetate, 0.27 g of piperidine and 0.67 g of acetic acid were added. The mixture was heated to reflux, and about 2 g of water were removed azeotropically. The clear solution was washed, dried and concentrated.
Reaction SMILES: C([Li])CCC.BrC1[C:8]([F:17])=[C:9]([CH3:16])[C:10]([F:15])=[C:11]([F:14])[C:12]=1[F:13].CN(C=O)C1C=CC=CC=1.Cl.C([O:31][CH2:32][CH3:33])C>CCCCCC>[CH3:16][C:9]1[C:8]([F:17])=[C:33]([C:12]([F:13])=[C:11]([F:14])[C:10]=1[F:15])[CH:32]=[O:31]
Reactant: CCOCC
Reactant: Cc1c(F)c(F)c(F)c(Br)c1F
Agent: CN(C=O)c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Product: Cc1c(F)c(F)c(F)c(C=O)c1F

Procedure:
n-Butyl lithium (12.9 ml of a 1.6M solution in hexane) was added dropwise to a solution of 3-bromo-2,4,5,6-tetrafluorotoluene (5.0 g) in diethyl ether (40 ml) under an argon atmosphere whilst maintaining the mixture temperature within the range -60° to -70° C. When the addition was complete the mixture was stirred for a period of 1.5 hours at -70° C. after which a solution of N-methylformanilide (2.8 g) in diethyl ether (15 ml) was added and the resultant mixture allowed to attain the ambient temperature (ca. 25° C.). Dilute hydrochloric acid (25 ml) of a 2N solution was added to the well-stirred mixture after which the ethereal layer was separated, washed with water and dried over anhydrous magnesium sulphate. After removal of the solvent by evaporation under reduced pressure the residual oil was distilled to yield 3-methyl-2,4,5,6-tetrafluorobenzaldehyde (1.6 g) b.p. 78°-80° C./14 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:30](=[O:31])[N:29]([CH3:32])[C:12]2[N:13]([CH3:28])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20](=O)[C:21]([CH3:26])=[CH:22][N:23](C)C)=[CH:16][CH:15]=3.O.[NH2:34]N>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:30](=[O:31])[N:29]([CH3:32])[C:12]2[N:13]([CH3:28])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[NH:34][N:23]=[CH:22][C:21]=1[CH3:26])=[CH:16][CH:15]=3
Reactant: CC(=CN(C)C)C(=O)c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C
Reactant: NN
Solvent: O
Product: Cc1cn[nH]c1-c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C

Procedure:
The process is carried out as indicated in Example 40 above, using 3-(2,4-dichlorophenyl)-6-(3-dimethylamino-2-methylacryloyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one from preparation 1.13 above and hydrazine hydrate.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.C(N(CC)CC)C.[Cl:14][C:15]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=2[Br:35])=[CH:20][C:16]=1[C:17](Cl)=[O:18]>C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][C:26]=2[Br:35])=[CH:20][C:16]=1[C:17]([O:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1)=[O:18]
Reactant: OC1CCOC1
Reactant: O=C(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Br)ccc1Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OC1CCOC1)c1cc(Oc2ccc(C(F)(F)F)cc2Br)ccc1Cl
Reaction time: 8 h

Procedure:
3-Hydroxytetrahydrofuran (0.04 mole), toluene (50 ml) and triethylamine (0.04 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer and addition funnel. A solution of 2-chloro-5-(2-bromo-4-trifluoromethylphenoxy)benzoyl chloride (0.04 mole) in toluene (20 ml) is slowly added at room temperature with stirring. After the addition is completed, stirring is continued for a period of about eight hours. After this time, the reaction mixture is washed with water and dried over anhydrous magnesium sulfate. The dried solution is then stripped of solvent under reduced pressure leaving a residue. This residue is purified by silica gel chromatography using toluene and ethyl acetate/toluene mixture as the eluant to yield the desired product 3-tetrahydrofuryl 2-chloro-5-(2-bromo-4-trifluoromethylphenoxy)benzoate.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[N:5][N:6]=1.[OH-].[K+].[I-].[K+].Cl[CH:19]([F:21])[F:20]>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1>[F:20][CH:19]([F:21])[S:1][C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[N:5][N:6]=1
Reactant: FC(F)Cl
Reactant: Sc1nnc(-c2ccc(Cl)cc2)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [I-]
Solvent: O
Solvent: C1COCCO1
Product: FC(F)Sc1nnc(-c2ccc(Cl)cc2)s1
Temperature: 40 °C

Procedure:
6.9 g of 2-mercapto-5-(4'-chlorophenyl)-1,3,4-thiadiazole and 60 ml fo dioxane are added to a solution of 2.4 g of potassium hydroxide in 10 ml of water. After the addition of 0.2 g of potassium iodide and 2 crystals of tetrabutylammonium bromide, the mixture is heated to 40° C. With stirring, a weak stream of chlorodifluoromethane is then passed through the mixture for 4 hours. The reaction mixture is then subsequently concentrated by evaporation in vacuo. The residue remaining after evaporation is taken up in methylene chloride, and the resultant solution is washed in succession with water and 1n sodium hydroxide solution. The solvent is evaporated off, affording the title compound (recrystallised from isopropanol) in the form of colourless crystals with a melting point of 74°-76° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10](O)[C:9]2[C:4](=[C:5]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:10]1[C:9]2[C:4](=[C:5]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])[CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([CH3:1])[CH:11]=1
Reactant: Cc1cc(C)c(-c2cccc3c(O)cc(C)nc23)c(C)c1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(C)c(-c2cccc3c(Cl)cc(C)nc23)c(C)c1
Temperature: 130 °C
Yield: 87 %

Procedure:
A mixture of 2-methyl-8-(2,4,6-trimethyl-phenyl)-quinolin-4-ol(335 mg, 1.21 mmol) and POCl3(2.5 ml) was heated in 130° C. oil bath for 3 hours. The mixture was cooled and poured into ice-water and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to give 350 mg of crude material as a brown oil. The oil residue was purified through silica gel column chromatography using chloroform as eluent to give 316 mg (87%) of the title compound as a yellow oil. 1H NMR (CDCl3) δ 8.20(d,1H), 7.60(m,1H), 7.47(d,1H), 7.35(s,1H), 6.97(s,2H), 2.54(s,3H), 2.36(s,3H), 1.86(s,6H)ppm.