Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C:3]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:2]1.[CH2:22]([C@@H:29]1[CH2:31][O:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[OH:30][C@H:29]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:31][N:1]1[CH2:6][CH2:5][CH2:4][C:3]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:2]1
Reactant: c1ccc(C[C@@H]2CO2)cc1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCCNC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCCN(C[C@H](O)Cc3ccccc3)C1)O2

Procedure:
Compound 195 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,3′-piperidine]-5,6-dione, (2R)-2-benzyloxirane and conditions outlined in procedure Y. M.p.=65-67° C., 400 MHz 1H NMR (CDCl3) δ: 8.04-8.03 (br d, J=7.82 Hz, 1H), 7.73-7.60 (m, 2H), 7.49-7.44 (m, 1H), 7.31-7.18 (m, 5H), 3.95-3.91 (m, 1H), 3.18-2.91 (m, 3H), 2.78-2.53 (m, 5H), 2.45-2.33 (m, 2H), 2.03-1.70 (m, 4H); LCMS: 436 [M+H].
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20]C)=[O:18])=[C:15]([O:22][CH2:23][CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:14]([C:33]3[CH:37]=[CH:36][O:35][CH:34]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:38]1C=CC(C2C(OC)=C(C(CS(C3C=CC=CC=3OC)(=O)=O)=CC=2)C(OC)=O)=[CH:39]1.C(OC(NCCBr)=O)(C)(C)C>>[C:29]([O:28][C:26]([NH:25][CH2:24][CH2:23][O:22][C:15]1[C:14]([C:33]2[CH:37]=[CH:36][O:35][CH:34]=2)=[CH:13][CH:12]=[C:11]([CH2:10][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[O:38][CH3:39])(=[O:8])=[O:9])[C:16]=1[C:17]([O:19][CH3:20])=[O:18])=[O:27])([CH3:30])([CH3:32])[CH3:31]
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1OCCNC(=O)OC(C)(C)C
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2OC)ccc(-c2ccoc2)c1OC
Agent: CC(C)(C)OC(=O)NCCBr
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2OC)ccc(-c2ccoc2)c1OCCNC(=O)OC(C)(C)C

Procedure:
Prepared by proceeding in a similar manner to Intermediate 10, starting from methyl 3-(furan-3-yl)-2-hydroxy-6-(2-methoxybenzenesulphonylmethyl)benzoate (Intermediate 39) and 2-[N-(t-butoxycarbonyl)amino]ethyl bromide.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[N:9]=[C:10]([C:17]3[CH:18]=[C:19]([C:23]4[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=4)[CH:20]=[N:21][CH:22]=3)[C:11]3[CH:16]=[CH:15][NH:14][C:12]=3[N:13]=2)[CH:5]=[CH:4][CH:3]=1.Cl.[CH3:32][NH2:33].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:32][NH:33][CH2:27][C:26]1[CH:29]=[CH:30][C:23]([C:19]2[CH:20]=[N:21][CH:22]=[C:17]([C:10]3[C:11]4[CH:16]=[CH:15][NH:14][C:12]=4[N:13]=[C:8]([C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=4)[N:9]=3)[CH:18]=2)=[CH:24][CH:25]=1
Reactant: CN
Reactant: Cc1cccc(-c2nc(-c3cncc(-c4ccc(C=O)cc4)c3)c3cc[nH]c3n2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CNCc1ccc(-c2cncc(-c3nc(-c4cccc(C)n4)nc4[nH]ccc34)c2)cc1
Reaction time: 0.08 h

Procedure:
To a suspension of 4-{5-[2-(6-methyl-pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyridin-3-yl}-benzaldehyde (Intermediate 58) (1 eq, 0.243 mmol, 100 mg) and methylamine hydrochloride (Sigma-Aldrich, St. Louis, USA) (1 eq, 0.243 mmol, 16.7 mg) in DCM (1 ml) is added AcOH (1.1 eq, 0.267 mmol, 15.3 ul). The solution is stirred for 5 min, then NaBH(OAc)3 (1.05 eq, 0.255 mmol, 57 mg) is added. After stirring the resulting mixture at r.t. for 1.5 h the solvents are removed in vacuo. The residue is taken up in aqueous NaHCO3 solution and extracted with DCM. The organic layer is washed with brine, dried over MgSO4, and filtered. The solvents are removed in vacuo and purification of the residue by reversed phase HPLC is yielding the title compound; [M+H]+=407; 1H-NMR (400 MHz, CDCl3): δ 12.52 (s, 1H), 9.43 (s, 1H), 8.95 (s, 1H), 8.73 (s, 1H), 8.66 (d, 1H), 7.83 (t, 1H), 7.64 (d, 2H), 7.49-7.46 (m, 3H), 7.32 (d, 1H), 6.88 (d, 1H), 3.86 (s, 2H), 2.75 (s, 3H), 2.56 (s, 3H).
Reaction SMILES: C(O[N:4]=[CH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[C:15]1[CH:16]=[C:17]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[O:22])[CH:18]=[CH:19][CH:20]=1)C.[NH2:31][NH:32][C:33](=O)[CH2:34][N:35]([CH3:37])[CH3:36].C[O-].[Na+].Cl>CO.C(OCC)(=O)C>[CH3:36][N:35]([CH2:34][C:33]1[N:4]=[C:5]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][N:10]=[C:9]3[C:15]2[CH:16]=[C:17]([C:21]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)=[O:22])[CH:18]=[CH:19][CH:20]=2)[NH:31][N:32]=1)[CH3:37]
Reactant: CN(C)CC(=O)NN
Reactant: CCON=Cc1ccc2[nH]nc(-c3cccc(C(=O)Nc4ccc(F)cc4)c3)c2c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(C)Cc1n[nH]c(-c2ccc3[nH]nc(-c4cccc(C(=O)Nc5ccc(F)cc5)c4)c3c2)n1
Yield: 50 %

Procedure:
Prepared according to the procedure of Example 367 C using (3-[5-(ethoxyiminomethyl)(1H-indazol-3-yl)]phenyl)-N-(4-fluorophenyl)carboxamide.2HCl (1.50 g, 3.15 mmol), N-amino-2-(dimethylamino) acetamide (1.2 g, 10.33 mmol) and sodium methoxide (1.8 mL of a 25% w/w in methanol) in anhydrous methanol (20.0 mL) with a reaction time of 1.5 days. Purification by flash chromatography on silica gel using 50% methanol in ethyl acetate afforded a solid which was dissolved in anhydrous methanol and treated with anhydrous hydrogen chloride gas for 10 min at 0° C. After stirring at ambient temperature for 5 min anhydrous ethyl acetate was added to precipitate the desired product which was collected on a sintered glass funnel, washed with methanol and ethyl acetate and dried under vacuum to give the title compound (267 mg, 50% yield) as a light yellow solid 1H NMR (DMSO-d6) δ 13.5 (br s, 1H), 10.5 (s, 1H), 8.5 (s, 1H), 8.2 (br d, 1H), 8.1 (d, 1H), 8.0 (d, 1H), 7.84 (dd, 2H), 7.75-7.6 (m, 2H), 7.2 (t, 2H), 3.6 (bs, 2H), 2.2 (s, 6H), ES-MS (m/z) 456 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([C:9]([NH2:11])=[NH:10])=[CH:7][N:6]=[C:5]([O:12][CH3:13])[CH:4]=1.C(=O)(O)[O-].[K+].Br[CH2:20][C:21]([C:23]1[N:24]([CH:29]([CH3:31])[CH3:30])[N:25]=[C:26]([CH3:28])[N:27]=1)=O>C1COCC1.O>[Cl:2][C:3]1[C:8]([C:9]2[NH:11][CH:20]=[C:21]([C:23]3[N:24]([CH:29]([CH3:31])[CH3:30])[N:25]=[C:26]([CH3:28])[N:27]=3)[N:10]=2)=[CH:7][N:6]=[C:5]([O:12][CH3:13])[CH:4]=1
Reactant: COc1cc(Cl)c(C(=N)N)cn1
Reactant: Cc1nc(C(=O)CBr)n(C(C)C)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(Cl)c(-c2nc(-c3nc(C)nn3C(C)C)c[nH]2)cn1
Yield: 96.5 %

Procedure:
A suspension of 4-chloro-6-methoxy-nicotinamidine hydrochloride (18.4 mmol) and potassium bicarbonate (7.37 g, 73.6 mmol) in THF (42 mL) and water (8.5 mL) was heated to reflux and treated with a solution of 2-bromo-1-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-ethanone (4.53 g, 18.4 mmol) in THF (14 mL) added dropwise. The reaction mixture was heated at reflux for 18 h before removal of volatile solvent in vacuo. The resultant suspension was filtered and the residue washed with water then dried to give the title compound as a brown solid (5.91 g, 97%). LCMS: RT=2.68 min, [M+H]+=333/335. 1H NMR 400 MHz (CDCl3) δ: 10.41 (1 H, s), 9.02 (1 H, s), 7.81 (1 H, s), 6.87 (1H, s), 5.91 (1 H, m), 4.00 (3 H, s), 2.41 (3 H, s), 1.55 (6 H, d, J=6.71 Hz).
Reaction SMILES: [C:1]([OH:15])(=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[CH:19][C:18]=1O.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[C:1]([O:15][C:18]1[CH:19]=[C:20]([Cl:24])[C:21]([Cl:23])=[CH:22][C:17]=1[Cl:16])(=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCCC(=O)O
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCCCCCCC(=O)Oc1cc(Cl)c(Cl)cc1Cl
Yield: 95.9 %

Procedure:
A solution of n-tridecanoic acid (Sigma Chemical Co.) (12.5 g), 2,4,5-trichlorophenol (11.5 g), and N,N'-dicyclohexylcarbodiimide (12.0 g) in methylene chloride (650 ml) is stirred at room temperature for 16 hours. The reaction mixture is then filtered and dried in vacuo to give 2,4,5-trichlorophenyl n-tridecanoate (22 g). The material is purified by column chromatography over silica gel (Woelm) using toluene as the eluent. Fractions are monitored by TLC using a shortware UV light for detection. Fractions containing the purified product are pooled and concentrated in vacuo to dryness.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].[F:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[C:14](F)[CH:13]=1.O>CN(C)C=O>[F:11][C:12]1[CH:13]=[C:14]([CH:15]=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=1)[O:8][CH:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CN1CCC(O)CC1
Reactant: O=[N+]([O-])c1cc(F)cc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCC(Oc2cc(F)cc([N+](=O)[O-])c2)CC1
Temperature: 65 °C
Reaction time: 0.67 h
Yield: 34.5 %

Procedure:
Dissolve 1-methyl-piperidin-4-ol (3.62 g, 31.43 mmol) in N,N-dimethylformamide (20 mL) and add 95% sodium hydride (0.83 g, 33.0 mmol) at ambient temperature. After 40 min., add 1,3-difluoro-5-nitro-benzene (5.0 g, 31.43 mmol), stir and heat at 65° C. After 2 hr., cool to ambient temperature and pour slowly into water (100 mL). Extract the reaction mixture with ethyl acetate (3×150 mL), wash the combined organic layers with aqueous NaCl solution (100 mL), dry over sodium sulfate, filter and concentrate. Purify the residue by silica gel flash chromatography eluting with 10% (2M NH3/methanol)/methylene dichloride to obtain of the title compound (2.76 g, 35%). 1H NMR (CDCl3): 7.6 (s, 1H), 7.5 (d, 1H), 7.0 (d, 1H), 4.4 (m, 1H), 2.7 (m, 2H), 2.4 (m, 5H), 2.0 (m, 2H), 1.9 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].[C:19](Cl)(=[O:23])[O:20][CH2:21][CH3:22]>O.CC(C)=O>[CH2:21]([O:20][C:19]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2)=[O:23])[CH3:22]
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc2c(c1)CCC(=O)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)Nc1ccc2c(c1)CCC(=O)N2

Procedure:
6-Amino-3,4-dihydrocarbostyril (60 g) is added to a solution of potassium carbonate (128 g) in water (300 ml) and acetone (300 ml), and thereto is added dropwise ethyl chlorocarbonate (46 ml) with stirring under ice-cooling. After the addition, the mixture is further reacted at the same temperature for 30 minutes. After the reaction, the reaction mixture is poured into water, and the resulting precipitate is separated by filtration, washed with water and further with diethyl ether. After drying, the crystal thus obtained is purified by silica gel column chromatography (solvent; chloroform:methanol=100:1) and then recrystallized from ethanol to give 6-ethoxycarbonylamino-3,4-dihydrocarbostyril (68.5 g), as colorless prisms, m.p. 193°-194° C.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[CH3:27][N:28]([CH3:38])[CH2:29][CH2:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1.[OH-].[Na+]>CN(C=O)C.CO>[CH3:38][N:28]([CH3:27])[CH2:29][CH2:30][C:31]1[CH:37]=[CH:36][C:34]([NH:35]/[C:16](=[C:6]2\[C:5](=[O:26])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:33][CH:32]=1
Reactant: CN(C)CCc1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CN(C)CCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-(2-dimethylamino-ethyl)-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [C:1]([OH:18])(=[O:17])[C:2]1[C:3](=[CH:7][C:8](=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14])[C:9]([OH:11])=[O:10])[C:4]([OH:6])=[O:5].[H][H]>[Rh].O>[CH:8]1([C:9]([OH:11])=[O:10])[CH2:7][CH:3]([C:4]([OH:6])=[O:5])[CH:2]([C:1]([OH:18])=[O:17])[CH2:16][CH:12]1[C:13]([OH:15])=[O:14]
Reactant: [H][H]
Reactant: O=C(O)c1cc(C(=O)O)c(C(=O)O)cc1C(=O)O
Agent: [Rh]
Solvent: O
Product: O=C(O)C1CC(C(=O)O)C(C(=O)O)CC1C(=O)O
Temperature: 50 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
22.08 kg (86.88 mol) of pyromellitic acid, 8 kg of a catalyst containing rhodium supported on activated carbon (produced by N.E. Chemcat Corporation) and 80 kg of water were charged in a reactor made of Hastelloy (HC22) having a capacity of 200 L, and the interior of the reactor was replaced by nitrogen gas under stirring. The interior of the reactor was then replaced by hydrogen gas, and the temperature was increased to 50° C. under a hydrogen pressure in the reactor of 3.3 MPa. The reaction was performed for 2 hours while maintaining the hydrogen pressure to 3.3 MPa. The hydrogen gas in the reactor was replaced by nitrogen gas, the reaction liquid was taken out from the autoclave, and the reaction liquid was filtered in a hot state to separate the catalyst. The filtrate was concentrated by evaporating water under reduced pressure with a rotary evaporator to deposit crystals. The crystals thus deposited were separated by solid-liquid separation at room temperature and dried to provide 19.24 kg (73.94 mol, yield: 85.1%) of 1,2,4,5-cyclohexanetetracarboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:15])([CH3:14])[C:7](=[O:13])[N:8]2[CH2:11][CH3:12])=[CH:4][CH:3]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[CH2:11]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:16](=[O:18])[CH3:17])[CH:10]=2)[C:6]([CH3:14])([CH3:15])[C:7]1=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: CCN1C(=O)C(C)(C)c2ccc(N)cc21
Product: CCN1C(=O)C(C)(C)c2ccc(NC(C)=O)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
A solution of 6-amino-1-ethyl-3,3-dimethyl-1,3-dihydro-indol-2-one (5.05 g, 24.72 mmol) in acetic anhydride (80 ml) was stirred at room temperature for 4 h. The mixture was poured onto ice water (150 ml), allowed to warm to room temperature and was stirred again for 2 h. After extraction with ethyl acetate (3×100 ml), the combined organic layers were washed with sat. NaHCO3-solution (3×100 ml), brine (100 ml) and dried over sodium sulfate. After removal of the solvent the crude product was purified by column chromatography on silica gel (ethyl acetate/n-heptane 1:1) yielding 5.6 g (91%) N-(1-ethyl-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-acetamide as light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=O.[CH2:14]([NH2:16])[CH3:15].C([BH3-])#N.[Na+].C(O)(=O)C>CO>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH2:4][NH:16][CH2:14][CH3:15]
Reactant: CCN
Reactant: O=Cc1cc(C(F)(F)F)ccc1Br
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCNCc1cc(C(F)(F)F)ccc1Br
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To 2-bromo-5-(trifluoromethyl)benzaldehyde (7.5 g, 29.6 mmol) in MeOH (80 mL) was added ethylamine (2M in MeOH; 30 mL, 60 mmol), sodium cyanoborohydride (3.7 g, 58.9 mmol), and acetic acid (1.7 mL, 26.2 mmol), and the reaction was stirred at room temperature for 4 days. The mixture was quenched with saturated aqueous NaHCO3 and extracted with CH2Cl2, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The crude material was purified by silica gel chromatography (0-4% MeOH in CH2Cl2) to give (2-bromo-5-trifluoromethyl-benzyl)-ethyl-amine.
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]2[N:23]=[C:24]([NH:27][C:28](=[O:30])[CH3:29])[S:25][CH:26]=2)=[CH:16][C:15]=1[F:31])=[O:11])[NH:2]C(OC(C)(C)C)=O.O1CCOCC1.[ClH:38]>ClCCl>[ClH:38].[NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]2[N:23]=[C:24]([NH:27][C:28](=[O:30])[CH3:29])[S:25][CH:26]=2)=[CH:16][C:15]=1[F:31])=[O:11])[NH2:2]
Reactant: CC(=O)Nc1nc(CCc2ccc(COC(=O)NNC(=O)OC(C)(C)C)c(F)c2)cs1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(=O)Nc1nc(CCc2ccc(COC(=O)NN)c(F)c2)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}-2-fluorobenzyl tert-butyl hydrazine-1,2-dicarboxylate (147.0 mg, 0.325 mmol) in anhydrous dichloromethane (2 ml) was added 4M hydrogen chloride dioxane solution (2 ml). After stirring at room temperature for 2 hr, and the mixture was concentrated under reduced pressure. Ethyl acetate was added to the concentrated residue, and the mixture was concentrated again under reduced pressure. This operation was performed 3 times to remove hydrogen chloride gas azeotropically. The residue was suspended in a mixture of ethanol (2 ml) and ethyl acetate (8 ml) and filtered. The filtered product was washed twice with ethyl acetate, and dried under reduced pressure to give 4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}-2-fluorobenzyl hydrazinecarboxylate hydrochloride (129.1 mg, quantitative) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:15]([CH3:16])=[C:14]([F:17])[C:13]([F:18])=[CH:12][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH2:19]([O:21][CH:22](OCC)OCC)[CH3:20].C(OC(=O)C)(=O)C>>[Cl:1][C:2]1[C:15]([CH3:16])=[C:14]([F:17])[C:13]([F:18])=[CH:12][C:3]=1[C:4]([C:6](=[CH:22][O:21][CH2:19][CH3:20])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)c(C)c1Cl
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(C)c1Cl
Temperature: 150 °C

Procedure:
To ethyl 2-chloro-4,5-difluoro-3-methylbenzoylacetate (3.9 g) are added triethoxymethane (3.1 g) and acetic anhydride (3.4 g), and the mixture is heated at 150° C. for one hour. The mixture is concentrated to give ethyl 2-(2-chloro-3-methyl-4,5-difluorobenzoyl)-3-ethoxyacrylate. To the product is added ethanol (50 ml) and thereto is added cyclopropylamine (1.1 ml) at room temperature, and the mixture is stirred for 30 minutes. Ethanol is distilled off to give ethyl 2-(2-chloro-3-methyl-4,5-difluorobenzoyl)-3-cyclopropylaminoacrylate. To the product is added anhydrous dioxane (30 ml) and thereto is added portionwise 60% sodium hydride (0.6 g). The mixture is stirred at room temperature for 30 minutes and then refluxed for one hour. The reaction mixture is poured into aquoeus saturated ammonium chloride and extracted with dichloromethane. The extract is dried over magnesium sulfate and concentrated to give ethyl 1-cyclopropyl-6,7-difluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3carboxylate (2.2 g).
Reaction SMILES: Cl.[OH:2][CH2:3][C@@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[NH2:10].[F:11][C:12]1[CH:13]=[N:14][C:15]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([S:28][CH3:29])[CH:23]=2)=[C:16]([CH:20]=1)[C:17](O)=[O:18].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(N(CC)CC)C>[F:11][C:12]1[CH:13]=[N:14][C:15]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([S:28][CH3:29])[CH:23]=2)=[C:16]([CH:20]=1)[C:17]([NH:10][C@@H:5]1[CH2:6][CH2:7][CH2:8][CH2:9][C@H:4]1[CH2:3][OH:2])=[O:18]
Reactant: N[C@@H]1CCCC[C@H]1CO
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@@H]2CCCC[C@H]2CO)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 70.9 %

Procedure:
A solution of trans-2-hydroxymethyl-1-cyclohexylamine hydrochloride (130 mg, 0.78 mmol) and triethylamine (300 μl) in dimethylformamide (5 ml) was added to a solution of 5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinic acid (218 mg, 0.78 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (165 mg, 0.86 mmol) and 1-hydroxybenzotriazole (116 mg, 0.86 mmol) in dimethylformamide (4 ml) and the reaction was stirred under nitrogen at room temperature for 48 h. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate (25 ml) and water (25 ml). The organic phase was removed and washed with sat. sodium bicarbonate solution (25 ml) followed by 1M citric acid (25 ml) and brine (25 ml). The organic layer was dried over MgSO4 and the solvent was removed by reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of ethyl acetate:pentane (20:80 changing to 30:70 then 50:50, by volume) to give 5-fluoro-N-[trans-2-hydroxymethyl-cyclohexyl)-2-(3-methylsulfanyl-phenoxy)-nicotinamide (216 mg) as a colourless oil.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([S:17](/[CH:20]=[CH:21]/[CH2:22][CH2:23][C:24]3[N:29]=[CH:28][CH:27]=[CH:26][N:25]=3)(=[O:19])=[O:18])[CH2:13][CH2:12]2)=[N:9][CH:10]=1.[NH2:32][OH:33].O>C1COCC1>[OH:33][NH:32][CH:21]([CH2:20][S:17]([N:14]1[CH2:13][CH2:12][N:11]([C:8]2[CH:7]=[CH:6][C:5]([O:4][CH2:3][C:2]([F:30])([F:1])[F:31])=[CH:10][N:9]=2)[CH2:16][CH2:15]1)(=[O:19])=[O:18])[CH2:22][CH2:23][C:24]1[N:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: NO
Reactant: O=S(=O)(/C=C/CCc1ncccn1)N1CCN(c2ccc(OCC(F)(F)F)cn2)CC1
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(CC(CCc1ncccn1)NO)N1CCN(c2ccc(OCC(F)(F)F)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a stirred solution of 2-[(3E)-4-({4-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]piperazin-1-yl}sulfonyl)but-3-en-1-yl]pyrimidine (10.9 g, 23.7 mmol) in THF (200 mL) was added 50% aqueous solution of hydroxylamine (11 mL) and the reaction stirred at room temperature for 2 hours. Water (100 mL) was then added and then this was extracted with EtOAc (3×100 mL) and dried (brine, MgSO4), filtered and concentrated in vacuo to give 2-[3-(hydroxyamino)-4-({4-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]piperazin-1-yl}sulfonyl)butyl]pyrimidine as a pale yellow solid (11.1 g, 22.6 mmol, 96%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[CH:6][CH:5]=1.[N+:13]([C:16]1[CH:21]=[CH:20][C:19](Cl)=[CH:18][CH:17]=1)([O-:15])=[O:14]>CS(C)=O>[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][O:12][C:19]2[CH:20]=[CH:21][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=2)=[CH:6][CH:5]=1
Reactant: Cc1ccc(CCO)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccc(CCOc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 30 °C
Yield: 89.4 %

Procedure:
To a solution of 65% sodium hydride (1.1 g, 0.03 mole) in dimethylsulfoxide (30 ml) were added 2-(4-methylphenyl)ethyl alcohol (VIII) (2.72 g, 0.02 mole) and 4-nitrochlorobenzene (IX: X=Cl) (3.15 g, 0.02 mole). After heating to 30° C. for 5 hours with stirring, the reaction mixture was treated in the same manner as in Example 12 to obtain 4.6 g of 4-[2-(4-methylphenyl)ethoxy]nitrobenzene (VI) as white crystals (yield, 89.5%).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)=[CH:13][C:12]2=[O:24])=[CH:5][CH:4]=1.P(Br)(Br)[Br:26]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Br:26][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)=[CH:13][C:12]2=[O:24])=[CH:5][CH:4]=1
Reactant: O=c1cc(OCc2cccs2)ccn1CCc1ccc(CO)cc1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1cc(OCc2cccs2)ccn1CCc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 480 mg (1.41 mmol) 1-[2-(4-hydroxymethyl-phenyl)-ethyl]-4-(thiophen-2-ylmethoxy)-1H-pyridin-2-one (example 2.1a) in 5.0 mL of DCM is added 67 μL (0.70 mmol) phosphorus tribromide at 0° C. After warming to RT, the mixture is stirred 2 h at RT and is diluted with aqueous 5% NaHCO3-solution. The layers are separated and the aqueous phase is washed with DCM. The combined organic phase is washed with water, dried over MgSO4, filtered and the solvent is evaporated to afford the product.