Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[C:4](/[CH:6]=[C:7](/[C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=2[F:27])=[C:13]([CH2:15][CH:16]=[O:17])[CH:14]=1)\[CH3:8])=[O:5])[CH3:2].CC(=C)C.C1C[O:37]CC1.[O-]Cl=O.[Na+].Cl>CC(O)(C)C.O>[CH2:28]([N:3]([CH2:1][CH3:2])[C:4](/[CH:6]=[C:7](/[C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[C:21]([F:27])=[CH:22][CH:23]=[CH:24][C:25]=2[F:26])=[C:13]([CH2:15][C:16]([OH:37])=[O:17])[CH:14]=1)\[CH3:8])=[O:5])[CH3:29]
Reactant: C1CCOC1
Reactant: CCN(CC)C(=O)/C=C(\C)c1ccc(OCc2c(F)cccc2F)c(CC=O)c1
Agent: C=C(C)C
Agent: Cl
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCN(CC)C(=O)/C=C(\C)c1ccc(OCc2c(F)cccc2F)c(CC(=O)O)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (E)-[5-(2-diethylcarbamoyl-1-methylvinyl)-2-(2,6-difluorobenzyloxy)-phenyl]-acetaldehyde (4.38 g, 10.92 mmol) and 2 M isobutylene in THF (36.6 mL, 73.2 mmol) in tBuOH (70 mL) is added a solution of NaClO2 (1.58 g, 17.48 mmol) and NaH2PO4.H2O (1.96 g, 14.2 mmol) in H2O (25 mL), and the mixture is stirred at room temperature for 1.5 hours. The mixture is then acidified to pH 3 with 1 N HCl, and then extracted with ether (3×150 mL). The combined organic layers are then extracted with 1 N NaOH (3×150 mL), and the combined aqueous layers are acidified to pH 3 with conc. HCl, and then extracted with EtOAc(3×10). The combined organic phase is washed with water (1×50 mL) and brine (1×50 mL), dried over MgSO4, and concentrated in vacuo. Recrystallization from MeOH/EtOAc yields (E)-[5-(2-diethylcarbamoyl-1-methyl-vinyl)-2-(2,6-difluorobenzyloxy)-phenyl]-acetic acid; m.p.=167°-168°.
Reaction SMILES: NO.C[N:4](C)[CH:5]=[CH:6][C:7]([C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][N:13]1[C:23](=[O:24])[CH2:22][NH:21][C:20](=[O:25])[CH:19]=[C:14]12)=[O:8]>CO>[O:8]1[C:7]([C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[CH2:11][CH2:12][N:13]2[C:23](=[O:24])[CH2:22][NH:21][C:20](=[O:25])[CH:19]=[C:14]23)=[CH:6][CH:5]=[N:4]1
Reactant: CN(C)C=CC(=O)c1cccc2c1CCN1C(=O)CNC(=O)C=C21
Agent: NO
Solvent: CO
Product: O=C1C=C2c3cccc(-c4ccno4)c3CCN2C(=O)CN1
Yield: 62.2 %

Procedure:
100-3. NH2OH*HCl (51 mg, 0.74 mmol) was added to a mixture of (E)-9-(3-(dimethylamino)acryloyl)-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (160 mg, 0.49 mmol) in MeOH (5 mL) and the solution was heated to reflux for 1 h. The mixture was then concentrated in vacuo and the crude product was purified by flash chromatography (SiO2, DCM/MeOH 99:1 to 90:10) to afford the title compound (90 mg) as a beige solid. UPLC-MS: MS 296.1 (M+H+). UPLC rt 0.65 nm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:18]([OH:20])=[O:19])=[C:11]([CH2:13][O:14][CH2:15][O:16][CH3:17])[N:12]=2)=[CH:4][CH:3]=1.[CH3:21][Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1.CO.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:18]([O:20][CH3:21])=[O:19])=[C:11]([CH2:13][O:14][CH2:15][O:16][CH3:17])[N:12]=2)=[CH:4][CH:3]=1
Reactant: COCOCc1nc(-c2ccc(Cl)cc2)oc1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CO
Product: COCOCc1nc(-c2ccc(Cl)cc2)oc1C(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
138 mg (0.52 mmol) of the compound from Example 42A are dissolved in 3 ml toluene and 2.5 ml of methanol. 0.4 ml (0.79 mmol) of a 2 M solution of trimethylsilyldiazomethane in hexane is then added dropwise. The mixture is stirred at RT for 10 min and the solvent is then removed on a rotary evaporator. The residue is used without further purification in the subsequent reaction.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=O)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.B>C1COCC1>[CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=c1c2ccccc2sc2ccccc12
Agent: B
Solvent: C1CCOC1
Product: c1ccc2c(c1)Cc1ccccc1S2
Temperature: 0 °C

Procedure:
Thioxanthen-9-one, 28 (14.0 g, 66.0 mmol) was dissolved in THF (186 mL). While under argon, the solution was treated dropwise with 1.0M borane in THF (50 mL, 50.0 mmol) and refluxed (3 hrs). The reaction mixture was cooled, poured into ice (300 g) and extracted with ethyl acetate (3×350 mL). The extracts were combined, washed with brine (1×), dried over Na2SO4, filtered and concentrated to dryness in vacuo. Treatment of the resulting oil with methanol gave the title compound as a white solid.
Reaction SMILES: C(O[C:5]1[C:6](=[O:18])[C:7](=[O:17])[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(C)C.[CH3:19][CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:21][NH2:22]>C(O)C>[CH3:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([C:8]2[C:7](=[O:17])[C:6](=[O:18])[C:5]=2[NH:22][CH2:21][CH:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:19])=[CH:14][CH:13]=1
Reactant: CC(CN)c1ccccc1
Reactant: COc1ccc(-c2c(OC(C)C)c(=O)c2=O)cc1
Solvent: CCO
Product: COc1ccc(-c2c(NCC(C)c3ccccc3)c(=O)c2=O)cc1
Yield: 66.4 %

Procedure:
In a manner similar to Example 1, Step 2; 3-isopropoxy-4-(4-methoxy-phenyl)-cyclobut-3-ene-1,2-dione (0.150 g, 0.609 mmol) and 2-methyl-2-phenyl-ethylamine (0.165 g, 1.22 mmol) in ethanol (2 mL) were converted to the title compound (0.130 g, 66%) m.p.: 215.4-216.2° C.; 1H NMR (DMSO-d6) δ9.07(br t,1H), 7.95(ABq,2H), 7.30-7.18(m,5H), 7.08(ABq,2H), 3.90-3.72(m,2H), 3.82(s,3H), 3.09,(m,1H), 1.26(d,3H); IR(KBr) 3160, 2960, 1775, 1730, 1560, 1430, 1300, 1250, 1170, 1100, 1020, 840 cm−1; MS (m/z) 322 [M+H+].
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=1[F:10]>[Cu].O>[F:8][C:7]1[CH:2]=[C:3]([F:10])[CH:4]=[C:5]([F:9])[CH:6]=1
Reactant: Fc1cc(F)c(Cl)c(F)c1
Agent: [Cu]
Solvent: O
Product: Fc1cc(F)cc(F)c1
Temperature: 300 °C
Reaction time: 28 h
Yield: 73 %

Procedure:
An autoclave was charged with 66.8 g of 2-chloro-1,3,5-trifluorobenzene, 5 g of water and 65 g of copper powder, and the content was heated at 300° C. with high speed stirring for 28 hours. After the reaction, the content was distilled off, and the fraction distilled at 74° to 77° C. was collected and dried over sodium sulfate to obtain 1,3,5-trifluorobenzene in an amount of 38.5 g (yield 73%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([OH:19])([C:14]#[C:15][CH:16]1[CH2:18][CH2:17]1)[C:10]([F:13])([F:12])[F:11].[C:20](N1C=CN=C1)(N1C=CN=C1)=[O:21]>C1COCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:20](=[O:21])[O:19][C:9]([C:14]#[C:15][CH:16]3[CH2:18][CH2:17]3)([C:10]([F:13])([F:11])[F:12])[C:3]=2[CH:4]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(Cl)cc1C(O)(C#CC1CC1)C(F)(F)F
Solvent: C1CCOC1
Product: O=C1Nc2ccc(Cl)cc2C(C#CC2CC2)(C(F)(F)F)O1
Yield: 100.4 %

Procedure:
A solution of 2-(2-amino-5-chlorophenyl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol (15.00 g, 0.0518 mol) and 41.98 g (0.259 mol) of 1,1'-carbonyldiimidazole in 250 mL of dry THF was stirred under argon at 55° C. for 24 hours. The solvent was removed on a rotary evaporator and the residue was partitioned between 500 mL of ethyl acetate and 400 mL of water. The layers were separated and the aqueous phase was extracted once more with ethyl acetate. The combined ethyl acetate extracts were washed with 2×200 mL of 2% aqueous HCl, saturated aqueous NaHCO3, and brine. Drying over MgSO4, filtration, and removal of the solvent in vacuo provided 16.42 g of the title compound as a solid. Recrystallization from ethyl acetate-hexane afforded 12.97 g of analytically pure (±)6-chloro-4-cyclo-propylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as a white crystals. mp: 178°-180° C. 1H-NMR (CDCl3): 0.85 (m, 2H), 0.94 (m, 2H), 1.40 (m, 1H), 6.81 (d, J=8.5 Hz, 1H), 7.37 (dd, J=2.5, 8.5 Hz, 1H), 7.49 (d, J=2.5 Hz, 1H), 8.87 (br s, 1H).
Reaction SMILES: C(O)C.C1(C)C=CC=CC=1.[CH2:11]([C@H:14]1[CH2:19][CH2:18][C@H:17]([CH2:20][CH2:21][CH:22]2[CH2:27][CH2:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:24][CH2:23]2)[CH2:16][CH2:15]1)[CH2:12][CH3:13]>[H][H].[Pd]>[CH2:11]([C@H:14]1[CH2:19][CH2:18][C@H:17]([CH2:20][CH2:21][C@H:22]2[CH2:27][CH2:26][C@H:25]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:24][CH2:23]2)[CH2:16][CH2:15]1)[CH2:12][CH3:13]
Reactant: CCC[C@H]1CC[C@H](CCC2CC=C(c3ccccc3)CC2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccccc3)CC2)CC1

Procedure:
To a liquid mixture comprising 250 ml of ethanol and 250 ml of toluene was dissolved 92 g of the (4-(2-(trans-4-n-propylcyclohexyl)ethyl)cyclohexene-1-yl)benzene mentioned above, 5 g of palladium/carbon (5%) was added as catalyst thereto, and they were subjected to a catalytic reduction in hydrogen gas atmosphere. After finishing of the reaction, the catalyst was filtered off and the solvent was distilled off under a reduced pressure to obtain a yellow oily product. This product was recrystallized from ethanol to obtain 58.5 g of (trans-4-(2-(trans-4-n-propylcyclohexyl)ethyl)cyclohexyl)benzene.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:32])=[C:6]([CH:31]=1)[O:7][CH2:8][C:9]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=2[O:26][CH3:27])=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([CH3:30])=[CH:12][C:13]([CH3:29])([CH3:28])[NH:14]2.C(N(CC)CC)C.[C:40]1([N:46]=[C:47]=[O:48])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:32])=[C:6]([CH:31]=1)[O:7][CH2:8][C:9]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:47]([NH:46][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:48])=[CH:21][C:20]=2[O:26][CH3:27])=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([CH3:30])=[CH:12][C:13]([CH3:28])([CH3:29])[NH:14]2
Reactant: O=C=Nc1ccccc1
Reactant: COc1cc(O)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)C(C)=CC(C)(C)N2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(OC(=O)Nc2ccccc2)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
5-(5-Fluoro-2-methylphenoxymethyl)-6-(4-hydroxy-2-methoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 5-1, 25.0 mg, 0.058 mmol) was dissolved in tetrahydrofuran (0.5 mL), triethylamine (19.3 μL, 0.138 mmol) and phenyl isocyanate (9.5 μL, 0.087 mmol) were added thereto, and then the mixture was stirred at room temperature for 2 hours. The reaction mixture was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (27.3 mg) as a colorless amorphous product. (Yield 86%)
Reaction SMILES: [NH2:1][C@H:2]([CH2:24][CH3:25])[C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[C:18]3[C:19]([CH3:23])([CH3:22])[CH2:20][O:21][C:17]=3[CH:16]=[CH:15][CH:14]=2)=[N:10][CH:11]=1)=[O:4].Cl[C:27](Cl)([O:29]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH3:23][C:19]1([CH3:22])[C:18]2[C:13]([O:12][C:9]3[N:10]=[CH:11][C:6]([N:5]4[C:3](=[O:4])[C@@H:2]([CH2:24][CH3:25])[NH:1][C:27]4=[O:29])=[CH:7][N:8]=3)=[CH:14][CH:15]=[CH:16][C:17]=2[O:21][CH2:20]1
Reactant: CC[C@@H](N)C(=O)Nc1cnc(Oc2cccc3c2C(C)(C)CO3)nc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC[C@H]1NC(=O)N(c2cnc(Oc3cccc4c3C(C)(C)CO4)nc2)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
To a solution of (2R)-2-amino-N-{2-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-pyrimidinyl}butanamide (Intermediate 67, 3 mg) in dry dichloromethane (0.5 ml), TEA (6.11 μL, 0.044 mmol) was added and the reaction mixture was cooled to 0° C. A solution of triphosgene (1.170 mg, 3.94 μmol) in dry dichloromethane (0.125 ml) was then added dropwise and the reaction mixture was stirred at the 0° C. for 30 minutes. The reaction was quenched with water (3 ml), and the organic phase was separated, dried over sodium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using a column Isolute (1 g) and dichloromethane/methanol from 99.5:0.5 to 9:10 as eluent to afford the title compound (0.7 mg) as a white solid.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+](N[C:23]1[NH:28][C:27](=[O:29])[C:26]([CH2:30][C:31]2[CH:36]=[CH:35][N:34]([CH3:37])[C:33](=[O:38])[CH:32]=2)=[CH:25][N:24]=1)([O-])=O.N1C=CC=CC=1>C(O)C>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:23]2[NH:28][C:27](=[O:29])[C:26]([CH2:30][C:31]3[CH:36]=[CH:35][N:34]([CH3:37])[C:33](=[O:38])[CH:32]=3)=[CH:25][N:24]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: Cn1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cc1=O
Solvent: c1ccncc1
Solvent: CCO
Product: Cn1ccc(Cc2cnc(NCCCOc3cccc(CN4CCCCC4)c3)[nH]c2=O)cc1=O

Procedure:
3-[3-(Piperidinomethyl)phenoxy]propylamine (1.12 g) and 2-nitroamino-5-(1-methyl-2-oxopyridin-4-ylmethyl)pyrimidin-4-one (1.11 g) were refluxed in ethanol (8 ml) for 20 hours. As the reaction was incomplete the ethanol was replaced by pyridine (8 ml) and the solution refluxed for a further 6 hours. The reaction mixture was evaporated under reduced pressure and the residue was subjected to medium pressure chromatography on silica gel (eluting with 10% methanol/90% chloroform) to afford the title compound. This was treated with dilute ethanolic HCl to afford material which was recrystallised from isopropanol/ether to afford 2-[3-[3-(piperidinomethyl)phenoxy]propylamino]-5-(1-methyl-2-oxopyridin-4-ylmethyl)pyrimidin-4-one dihydrochloride (0.85 g), m.p. 164°-167° C.
Reaction SMILES: CO.[CH3:3][S:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14](C(OCCC(C)(C)C)=O)[C:13]([C:27]([O-:29])=[O:28])=[CH:12]2.[Li+].[OH-]>C1COCC1>[CH3:3][S:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:27]([OH:29])=[O:28])=[CH:12]2
Reactant: CSCCCOc1ccc2c(c1)cc(C(=O)[O-])n2C(=O)OCCC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CSCCCOc1ccc2[nH]c(C(=O)O)cc2c1
Temperature: 70 °C
Yield: 79.9 %

Procedure:
A methanol solution of 1-(1,1-dimethylethyl)2-ethyl 5-{[3-(methylthio)propyl]oxy}-1H-indole-1,2-dicarboxylate (0.488 g, 1.24 mmol) was treated with 1 N LiOH (4 mL). The reaction mixture turned cloudy, THF was added to redissolve the precipitate and the mixture was heated to 70° C. When no starting material remained as evident by TLC the reaction mixture was partitioned between EtOAc and water. The aqueous layer was separated and acidified with conc. HCl. The aqueous layer was extracted with EtOAc and the organic layer was evaporated to afford the title compound (0.263 g, 80%). 1H NMR (400 MHz, Acetone-d6) δ ppm 10.73 (br. s., 1H), 7.43 (d, 1H), 7.14 (d, 1H), 7.09-7.13 (m, 1H), 6.96 (dd, 1H), 4.09 (t, 2H), 2.68 (t, 2H), 2.08 (s, 3H), 2.04 (t, 2H). LCMS: m/z=264.1 (M−1).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1([F:42])[CH2:14][CH2:13][CH:12]([N:15]([C:22]2[CH:34]=[C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)[CH:32]=[CH:31][C:23]=2[C:24]([O:26]C(C)(C)C)=[O:25])[C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:11][CH2:10]1>ClCCl.C(OCC)(=O)C.C(OCC)C>[F:42][C:9]1([F:8])[CH2:14][CH2:13][CH:12]([N:15]([C:22]2[CH:34]=[C:33]([N:35]3[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]3)[CH:32]=[CH:31][C:23]=2[C:24]([OH:26])=[O:25])[C:16](=[O:21])[C:17]([F:18])([F:19])[F:20])[CH2:11][CH2:10]1
Reactant: CN1CCN(c2ccc(C(=O)OC(C)(C)C)c(N(C(=O)C(F)(F)F)C3CCC(F)(F)CC3)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN1CCN(c2ccc(C(=O)O)c(N(C(=O)C(F)(F)F)C3CCC(F)(F)CC3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
7.62 ml (99 mmol) of trifluoroacetic acid is added to 2.5 g (4.95 mmol) of tert-butyl 2-(N-(4,4-difluorocyclohexyl)-2,2,2-trifluoroacetamido)-4-(4-methylpiperazin-1-yl)benzoate dissolved in 30 ml of dichloromethane. The reaction is left under stirring at room temperature overnight. The solvent is evaporated and then the crude reaction product is redissolved in 30 ml of ethyl acetate. The solvents are evaporated, the solid formed is redissolved in ethyl ether and the solvent is evaporated again. This operation is repeated three times until a light brown solid is obtained. 2.2 g of 2-(N-(4,4-difluorocyclohexyl)-2,2,2-trifluoroacetamido)-4-(4-methylpiperazin-1-yl)benzoic acid in the form of a trifluoroacetic salt is obtained (yield=79%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([CH3:26])=[C:8]([C:16]([C:18]2[C:19]([CH3:25])=[N:20][N:21]([CH3:24])[C:22]=2[OH:23])=[O:17])[CH:9]=[CH:10][C:11]=1[S:12]([CH3:15])(=[O:14])=[O:13].C(=O)([O-])[O-].[K+].[K+].[C:33](=[O:40])([O:38][CH3:39])[O:34][CH:35](Cl)[CH3:36].O>CC(=O)CC.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:33](=[O:40])([O:38][CH3:39])[O:34][CH:35]([O:23][C:22]1[N:21]([CH3:24])[N:20]=[C:19]([CH3:25])[C:18]=1[C:16](=[O:17])[C:8]1[CH:9]=[CH:10][C:11]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[C:7]=1[CH3:26])[CH3:36]
Reactant: COCCOc1c(S(C)(=O)=O)ccc(C(=O)c2c(C)nn(C)c2O)c1C
Reactant: COC(=O)OC(C)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: O
Solvent: CCC(C)=O
Product: COCCOc1c(S(C)(=O)=O)ccc(C(=O)c2c(C)nn(C)c2OC(C)OC(=O)OC)c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52.6 %

Procedure:
5-Hydroxy-1,3-dimethylpyrazol-4-yl 3-(2-methoxyethoxy)-2-methyl-4-(methylsulfonyl)phenyl ketone (300 mg) was dissolved in 2-butanone (10 mL), and potassium carbonate (130 mg) and tetrabutyl ammonium bromide (15 mg) were added. After stirring at room temperature for 10 minutes, 1-chloroethyl methyl carbonate (purity: 85%, 270 mg) was added at room temperature, followed by heating and refluxing for 3 hours. After completion of the reaction, the reaction solution was cooled to room temperature and poured into water and then extracted with ethyl acetate. The organic layer was washed with a 1N hydrochloric solution and a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (n-hexane:ethyl acetate=1:1) to obtain the desired product (200 mg) as slightly yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:8]=[C:9]([C:13]#[C:14][CH:15]([NH:17][OH:18])[CH3:16])[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.[O-:21][C:22]#[N:23]>>[OH:18][N:17]([CH:15]([C:14]#[C:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([O:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:20][CH:19]=2)[CH:8]=1)[CH3:16])[C:22]([NH2:23])=[O:21]
Reactant: N#C[O-]
Reactant: CC(C#Cc1cccc(Oc2ccc(F)cc2)c1)NO
Product: CC(C#Cc1cccc(Oc2ccc(F)cc2)c1)N(O)C(N)=O

Procedure:
reacting the product of step 3 with cyanate to produce N-hydroxy-N-[4-(3-(4-fluorophenoxy)phenyl)-3-butyn-2-yl]urea.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]5([C:29]#[N:30])[CH2:28][CH2:27]5)[CH:21]=4)[CH:15]=[CH:16][CH:17]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[O:32]1[CH:36]=[C:35]([C:37](O)=[O:38])[N:34]=[CH:33]1.Cl.C(N=C=NCCCN(C)C)C.[OH-].[Na+]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1.CO>[C:29]([C:26]1([C:22]2[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=2)[C:19]([NH:18][C:14]2[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=2)[O:11][C:9]2[CH:8]=[CH:7][C:5]3[N:6]=[C:2]([NH:1][C:37]([C:35]4[N:34]=[CH:33][O:32][CH:36]=4)=[O:38])[S:3][C:4]=3[CH:10]=2)=[O:31])[CH2:27][CH2:28]1)#[N:30]
Reactant: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(N)sc5c4)c3)c2)CC1
Reactant: O=C(O)c1cocn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(NC(=O)c6cocn6)sc5c4)c3)c2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 38.6 %

Procedure:
To a solution of N-{3-[(2-amino-1,3-benzothiazol-6-yl)oxy]phenyl}-3-(1-cyanocyclopropyl)benzamide (330 mg, 774 μmol) in pyridine (10 mL) were added 1,3-oxazole-4-carboxylic acid (120 mg, 1.06 mmol), N,N-dimethylpyridine-4-amine (52.3 mg, 428 μmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (220 mg, 1.15 mmol), and the mixture was stirred at room temperature for 12 hr. To the reaction mixture were added 1,3-oxazole-4-carboxylic acid (126 mg, 1.11 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (652 mg, 3.40 mmol) and the mixture was further stirred at room temperature for 16 hr. To the reaction mixture were added methanol (10 mL) and 2N aqueous sodium hydroxide solution (5 mL) and the mixture was stirred at the same temperature for 3 hr, and the solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate (50 mL), washed with water (50 mL), 0.1N hydrochloric acid (50 mL), and saturated aqueous sodium hydrogencarbonate solution (50 mL) and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by reversed phase silica gel column chromatography (containing 0.1% trifluoroacetic acid, water/acetonitrile=95/5→5/95) and concentrated. The obtained trifluoroacetate was suspended in ethyl acetate (100 mL) and methanol (10 mL), and washed with saturated aqueous sodium hydrogencarbonate solution (50 mL) and saturated brine (50 ml), successively. The organic layer was dried over anhydrous magnesium sulfate, the insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate and diisopropyl ether to give the title compound (156 mg, 34%) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9]([N:12]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[N:23](C3CCCCO3)[N:24]=[CH:25][CH:26]=2)[C:17]=1[F:33])[CH2:13][O:14][CH3:15])(=[O:11])=[O:10].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9]([N:12]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[NH:23][N:24]=[CH:25][CH:26]=2)[C:17]=1[F:33])[CH2:13][O:14][CH3:15])(=[O:11])=[O:10]
Reactant: COCN(c1cccc(-c2ccnn2C2CCCCO2)c1F)S(=O)(=O)c1cc(F)ccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COCN(c1cccc(-c2ccn[nH]2)c1F)S(=O)(=O)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.9 %

Procedure:
To a solution of crude 2,5-difluoro-N-{2-fluoro-3-[2-(tetrahydro-pyran-2-yl)-2H-pyrazol-3-yl]-phenyl}-N-methoxymethyl-benzene-sulfonamide (1.39 g) in MeOH (20 mL), p-toluenesulfonic acid (100 mg) was added and the solution was stirred at r.t. for 1 h. The reaction mixture was then concentrated under reduced pressure, taken up with AcOEt (100 mL) and washed with sat, aq. NaHCO3 (2×50 mL) and brine (50 mL). the organic phase was dried over Na2SO4 and evaporated to dryness. The crude product was purified by chromatography on silica gel (gradient cyclohexane/AcOEt 6:4 to 1:1) to give 630 mg of 2,5-difluoro-N-[2-fluoro-3-(2H-pyrazol-3-yl)-phenyl]-N-methoxymethyl-benzene-sulfonamide as a white powder (80% yield over two steps). HPLC (254 nm): Rt: 5.86 min; 1H NMR (DMSO-d6) Shift: 13.13 (br. s., 1H), 7.93-8.02 (m, 1H), 7.83 (br. s., 1H), 7.55-7.73 (m, 2H), 7.46-7.53 (m, 1H), 7.18-7.33 (m, 2H), 6.49 (br. s., 1H), 5.10 (s, 2H), 3.36-3.42 (m, 3H); HRMS (ESI) calcd for C17H15F3N3O3S [M+H]+ 3980781. found 398.0779.
Reaction SMILES: [OH-].[Na+:2].[CH2:3]([C:5]1[N:6]=[N:7][S:8][C:9]=1[C:10]([OH:12])=[O:11])[CH3:4]>C(O)C>[CH2:3]([C:5]1[N:6]=[N:7][S:8][C:9]=1[C:10]([O-:12])=[O:11])[CH3:4].[Na+:2]
Reactant: CCc1nnsc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1nnsc1C(=O)[O-]
Reaction time: 24 h

Procedure:
To a solution of 0.13 g of sodium hydroxide in 3 ml of ethanol was added 0.5 g of 4-ethyl-1,2,3-thiadiazole-5-carboxylic acid, and the reaction was carried out at room temperature for 24 hours.