Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][N:11]1[CH2:18][CH:17]2[O:19][CH:13]([CH2:14][N:15]([CH2:20][C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=3)[CH2:16]2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29]([S:32](Cl)(=[O:34])=[O:33])([CH3:31])[CH3:30]>C(Cl)Cl>[CH2:1]([N:8]([CH2:9][CH2:10][N:11]1[CH2:12][CH:13]2[O:19][CH:17]([CH2:16][N:15]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]#[N:26])=[CH:27][CH:28]=3)[CH2:14]2)[CH2:18]1)[S:32]([CH:29]([CH3:31])[CH3:30])(=[O:34])=[O:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: N#Cc1ccc(CN2CC3CN(CCNCc4ccccc4)CC(C2)O3)cc1
Solvent: ClCCl
Product: CC(C)S(=O)(=O)N(CCN1CC2CN(Cc3ccc(C#N)cc3)CC(C1)O2)Cc1ccccc1
Reaction time: 0.25 h
Yield: 43.6 %

Procedure:
4-[7-(2-Benzylamino-ethyl)-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-ylmethyl]-benzonitrile (0.5 g, 1.33 mmol, from step (iii) above) was taken in 30 ml of DCM/10% aq. NaHCO3 (1:1) and stirred for 15 min. Isopropane sulfonyl chloride (0.28 g, 1.99 mmol) was added and stirring continued at RT for 1.5 h. The organic layer was separated, washed with brine and dried over sodium sulfate. Solvent evaporation under reduced pressure followed by purification over silica gel using 10% ethyl acetate in petroleum ether as eluent afforded the desired product (280 mg) as white solid. This was further purified by prep HPLC (0.1% TFA in acetonitrile), evaporated under reduced pressure, and the residue was partitioned between sat NaHCO3 and DCM. The organic layer was washed with brine and dried over sodium sulfate. Solvent evaporation under reduced pressure afforded the title compound (140 mg) as an off-white solid.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[C:10]1([SH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>[Cu]>[Cl:9][C:5]1[CH:6]=[C:7]([F:8])[C:2]([S:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:3][CH:4]=1
Reactant: Sc1ccccc1
Reactant: Fc1cc(Cl)cnc1F
Agent: [Cu]
Product: Fc1cc(Cl)cnc1Sc1ccccc1
Temperature: 185 °C
Reaction time: 1.5 h

Procedure:
Starting from 93 g (0.508 mol) of 2,3-difluoro-5-chloropyridine, 58.8 g (0.5276 mol) of 98.7% pure thiophenol and 3.2 mg (0.01 mol %) of copper powder which were stirred in a pressure apparatus at 185° C. for 1.5 h and worked up by the method of Example 1, 121.5 g (99.9% of theory) of the title compound were obtained as a colorless oil. 1H-NMR (ppm, d6DMSO) 8.35 (s/1H), 8.05 (d/1H), 7.4-7.6 (m/5H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:7]=1[Br:13]>>[CH3:5][C:6]1[C:11]([N+:1]([O-:4])=[O:2])=[CH:10][CH:9]=[C:8]([CH3:12])[C:7]=1[Br:13]
Reactant: Cc1cccc(C)c1Br
Reactant: O=[N+]([O-])O
Product: Cc1ccc([N+](=O)[O-])c(C)c1Br
Temperature: 80 °C

Procedure:
Fuming nitric acid (83.3 mL) (>90%) was added slowly to a solution of 2,6-dimethyl bromobenzene (27.9 g, 150 mmol) in acetric acid (167 mL) and cooled in an ice-bath (above f.p). The mix was allowed to come to rt and later heated at 80° C. for 2 h. (HPLC showed no SM). Reaction mixture was cooled and poured into ice-water with stirring. The resulting yellow solid was filtered, washed with ice-water and dried to give 28.7 g of an yellow solid which was used as such in the next step.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:12])[CH2:10][CH3:11].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:13]([O:8][C:6]1[CH:5]=[CH:4][C:3]([C:9](=[O:12])[CH2:10][CH3:11])=[C:2]([OH:1])[CH:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCC(=O)c1ccc(O)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(=O)c1ccc(OCc2ccccc2)cc1O
Yield: 60.9 %

Procedure:
A mixture of 5.0 g of 2',4'-dihydroxypropiophenone, 5.4 g of benzyl bromide, 6.2 g of potassium carbonate and 50 ml of acetone was refluxed for 7 hours. After cooling, the solid was separated by filtration. The filtrate was concentrated, and the residue was separated by column chromatography to give 4.7 g of 4'-benzyloxy-2'-hydroxypropiophenone as a white solid (yield 61%, melting point 111.5°-112.5° C.). Then, a mixture of 4.5 g of this solid, 3.5 g of ethyl bromoacetate, 6.1 g of potassium carbonate and 45 ml of acetone was refluxed for 7.5 hours. After cooling, the solid was separated by filtration. The filtrate was concentrated, and the residue was purified by column chromatography to give 5.8 g of ethyl 3-benzyloxy-6-propionylphenoxyacetate as white crystals (yield 97%, melting point 81.5° to 82.0° C.). This ester (5.5 g) was dissolved in a solution composed of 1.3 g of potassium hydroxide and 55 ml of methanol, and the solution was stirred at room temperature for 2 hours to hydrolyze the ester. The hydrolysis product was worked up in a customary manner to give 3.9 g (yield 77%) of 3-benzyloxy-6-propionylphenoxyacetic acid as a pale yellowish orange solid. Then, 9.3 g of sodium acetate and 39 ml of acetic anhydride were added to this solid, and the mixture was heated at 155° C. for 30 minutes. The solvent was evaporated, and the residue was purified by column chromatography to give 2.8 g (yield 95%, melting point 69.5°-70.5° C.) of 6-benzyloxy-3-ethylbenzofuran as a white solid. Palladium (5%)-carbon (0.27 g) and 27 ml of acetic acid were added to 2.7 g of the resulting benzofuran, and the mixture was stirred at room temperature for 3 hours in an atmosphere of nitrogen. The catalyst was separated by filtration, and the filtrate was concentrated and then purified by column chromatography to give 1.7 g (yield 90%) of the desired product as a pale orange liquid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[NH:7][CH:8]=1.C(N(CC)CC)C.Cl[CH2:18][N:19]([CH:26]=[O:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[CH:26]([N:19]([CH2:18][N:5]1[CH:4]=[C:3]([Cl:2])[CH:8]=[N:7][C:6]1=[O:9])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:27]
Reactant: O=CN(CCl)c1ccccc1
Reactant: O=c1ncc(Cl)c[nH]1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=CN(Cn1cc(Cl)cnc1=O)c1ccccc1
Temperature: 40 °C
Reaction time: 18 h

Procedure:
5-Chloropyrimidin-2-one hydrochloride (3.0 mmol) and triethylamine (6 mmol) were stirred together in CH2Cl2 (50 ml) for 15 minutes before a solution of N-chloromethylformanilide (see Prepartion 12) (3 mmol) in CH2Cl2 was added. The mixture was stirred at 40° C. for 18 hours before the solvent was distilled off. The residue was washed with water and ether. Yield: 0.79 g (50%), m. p. 200° C. (EtOH). 1H NMR (DMSO-d6, δ): 5.68 (s, CH2), 7.32 (Ph), 8.05-8.65 (CHO, H-4 and H-6). IR (KBr, cm-1): 1660 (CO), 1680 (CO). MS (70 eV, m/e (% rel. int.)): 263 (M+, 1), 143 (7), 134 (41), 116 (6), 107 (6), 106 (100), 105 (57), 104 (10), 79 (10), 78 (7), 77 (41), 52 (11), 51 (20).
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[O:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=1)=[O:9])([CH3:6])[CH3:5].[OH-].[Na+]>CO>[F:30][C:28]1[CH:29]=[C:24]([CH:25]=[C:26]([F:31])[CH:27]=1)[O:23][CH2:22][CH2:21][O:20][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]=[CH:19][C:10]=1[C:8]([NH:7][C:4]([CH3:5])([CH3:6])[C:3]([OH:32])=[O:2])=[O:9]
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1OCCOc1cc(F)cc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(NC(=O)c1ccc2ccccc2c1OCCOc1cc(F)cc(F)c1)C(=O)O

Procedure:
22 mg 2-({1-[2-(3,5-difluoro-phenoxy)-ethoxy]-naphthalene-2-carbonyl}-amino)-2-methyl-propionic acid methyl ester were reacted with 0.2 ml of 2 M sodium hydroxide in 1 ml methanol at 65° C. for 1 h. The organic solvents were then removed in vacuo, and the residue was acidified with 2 M hydrochloric acid and extracted with ethyl acetate twice. The combined organic layers were dried over sodium sulphate, and concentrated. After recrystallization from n-heptane 3 mg of 2-({1-[2-(3,5-difluoro-phenoxy)-ethoxy]-naphthalene-2-carbonyl}-amino)-2-methyl-propionic acid were obtained.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH2:28][CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:27])[NH:23][CH:24]([CH3:26])[CH3:25])[CH:17]=2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CCNC2C=C(C=CC=2)C(NC(C)C)=O)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:29]1([CH2:28][N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:27])[NH:23][CH:24]([CH3:25])[CH3:26])[CH:17]=2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:34])=[O:3])=[CH:8][N:9]=2)[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2cccc(C(=O)NC(C)C)c2)s1
Agent: CC(C)NC(=O)c1cccc(NCCC2CCCC2)c1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Product: CC(C)NC(=O)c1cccc(N(CC2CCCC2)C(=O)Nc2ncc(SCC(=O)O)s2)c1

Procedure:
The title compound was prepared via {2-[3-cyclopentylmethyl-3-(3-isopropylcarbamoyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using 3-(cyclopentylethyl-amino)-N-isopropyl-benzamide and (2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[C:5]([O-:7])=[O:6])([CH3:3])[CH3:2].[K+].[F:16][CH:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]=1.O>CN(C)C=O>[CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[C:5]([O:7][CH:17]([F:16])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:19]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: FC(Br)c1cccc(Oc2ccccc2)c1
Reactant: CC(C)C(C(=O)[O-])c1ccc(Cl)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C(C(=O)OC(F)c1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.4 %

Procedure:
A mixture of potassium α-isopropyl-4-chlorophenylacetate (0.91 g) and α-fluoro-3-phenoxy benzyl bromide (1.06 g) in dimethylformamide (10 ml) was stirred at ambient temperature over a period of 2 hours. The reaction mixture was poured into water and the aqueous solution was extracted with diethyl ether. The ether extract was washed with aqueous sodium carbonate solution and was then dried over anhydrous sodium sulfate. The ether was removed by distillation under reduced pressure and the residue chromatographed over silica gel to give α-fluoro-3-phenoxybenzyl α-isopropyl-4-chlorophenylacetate (0.62 g; 37%) as a colourless oil. The product was characterised by pmr spectroscopy. Chemical shift δppm (solvent CDCl3): 0.69(3H, d, J=6Hz, CH3); 1.05(3H, d of d, J=6Hz and J=2Hz, CH3); 2.34(1H, m, --CH(CH3)2); 3.29 (1H, d, J=10Hz, CH); 7.22(1H, d of d, J=56Hz and J= 2Hz, CHF) and c. 7.24(13H, m, aromatic protons).
Reaction SMILES: [As:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH2:12][S:13][CH2:14][CH2:15][C:16]([NH:18][C@H:19]([C:24]([OH:26])=[O:25])[CH2:20][C:21](O)=O)=[O:17])=[O:11])=[CH:5][CH:4]=1)=[O:2].SCCC(N[C@H](C([O-])=O)CC[C:36]([O-:38])=[O:37])=O.[Na+].[Na+].C(=O)(O)[O-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CS(C)=O>[As:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH2:12][S:13][CH2:14][CH2:15][C:16]([NH:18][C@H:19]([C:24]([OH:26])=[O:25])[CH2:20][CH2:21][C:36]([OH:38])=[O:37])=[O:17])=[O:11])=[CH:5][CH:4]=1)=[O:2]
Reactant: O=C([O-])CC[C@H](NC(=O)CCS)C(=O)[O-]
Reactant: O=[As]c1ccc(NC(=O)CSCCC(=O)N[C@@H](CC(=O)O)C(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Product: O=[As]c1ccc(NC(=O)CSCCC(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1

Procedure:
The procedure used was the same as for N-(3-(4-arsenosophenylcarbamoylmethylthio)-propanoyl)-L-aspartic acid, using 2.63 mL (184 μmol) of 70.0 mM BRAO in DMSO, the disulfide of disodium N-(3-mercaptopropanoyl)-L-glutamate (0.61 g), 0.5 M bicarbonate buffer, pH 9 (10.52 mL, 5.3 mmol), and 0.69 M triphenylphosphine in DMSO (1.7 mL, 1.2 mmol). In this case, DMSO (2 mL) was added to the precipitated mixture before leaving overnight. The active concentration of trivalent arsenic was found to be 15.4 mM (10.3 mL of solution).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]3[NH:17][C@H:16]([C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:14][N:10]3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25](I)[CH:24]=1>>[F:22][C:23]1[CH:24]=[C:25]([N:17]2[C:9]3=[N:8][C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:12][C:11](=[O:13])[N:10]3[CH2:14][CH2:15][C@H:16]2[C:18]([F:20])([F:21])[F:19])[CH:26]=[CH:27][CH:28]=1
Reactant: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2
Reactant: Fc1cccc(I)c1
Product: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2c1cccc(F)c1

Procedure:
The product is prepared according to the procedure described in Example 12, using 140 mg of (S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e) and 0.66 ml of 1-fluoro-3-iodobenzene. After purification by silica chromatography (gradient of 5% to 15% of the eluent CH2Cl2/MeOH/NH4OH 28% 38/17/2 in dichloromethane), 60 mg of (88)-9-(3-fluorophenyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained, the characteristics of which are the following:
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:4][CH:3]=1.I[CH2:12][C:13]1[O:17][N:16]=[C:15]([CH3:18])[N:14]=1>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][CH2:9][O:10][CH2:12][C:13]2[O:17][N:16]=[C:15]([CH3:18])[N:14]=2)[N:7]=1
Reactant: OCCc1cccc(Br)n1
Reactant: Cc1noc(CI)n1
Product: Cc1noc(COCCc2cccc(Br)n2)n1

Procedure:
The title compound was prepared as described in Example 236, Step 1 using 2-(6-bromopyridin-2-yl)ethanol (Example 235 Step 3) (50 mg, 0.25 mmol) and 5-(iodomethyl)-3-methyl-1,2,4-oxadiazole (110 mg, 0.50 mmol) as starting materials.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:17])[C:14]([OH:16])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:30]=[CH:29][C:24]2[NH:25][C:26](=[O:28])[O:27][C:23]=2[CH:22]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:17])[C:14]([NH:20][C:21]3[CH:30]=[CH:29][C:24]4[NH:25][C:26](=[O:28])[O:27][C:23]=4[CH:22]=3)=[O:16])[CH2:11][CH2:12]2)=[CH:18][CH:19]=1
Reactant: O=C(O)C(=O)N1CCC(Oc2ccc(Cl)cc2)CC1
Reactant: Nc1ccc2[nH]c(=O)oc2c1
Product: O=C(Nc1ccc2[nH]c(=O)oc2c1)C(=O)N1CCC(Oc2ccc(Cl)cc2)CC1

Procedure:
The title compound is prepared from [4-(4-chloro-phenoxy)-piperidin-1-yl]-oxo-acetic acid (Example 29d) and 6-amino-3H-benzoxazol-2-one according to the method described in Example 2. The filtered crystals are purified by column chromatography using Kieselgel 60 (Merck) as adsorbent and toluene:methanol=4:1 as eluent. Melting Point: 242-244° C. (isopropanol)
Reaction SMILES: [CH2:1]([C:3]1[N:7]=[C:6]([C:8]2[S:12][C:11]([NH2:13])=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:5][N:4]=1)[CH3:2].[CH:20]1([CH2:25][C:26](Cl)=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([CH2:25][C:26]([NH:13][C:11]2[S:12][C:8]([C:6]3[O:5][N:4]=[C:3]([CH2:1][CH3:2])[N:7]=3)=[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:10]=2)=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCc1noc(-c2sc(N)nc2-c2ccccc2)n1
Reactant: O=C(Cl)CC1CCCC1
Product: CCc1noc(-c2sc(NC(=O)CC3CCCC3)nc2-c2ccccc2)n1

Procedure:
Prepared from 5-(3-ethyl-[1,2,4]oxadiazol-5-yl)-4-phenyl-thiazol-2-ylamine and cyclopentyl-acetyl chloride.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:28]=[CH:27][C:8]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH:19]=[C:20]4[S:24][C:23](=[S:25])[NH:22][C:21]4=[O:26])=[CH:16][CH:17]=3)[CH:12]=[N:11]2)=[C:7]([C:29]([F:32])([F:31])[F:30])[CH:6]=1)(=[O:4])=[O:3].[CH3:33]I>>[CH3:1][S:2]([C:5]1[CH:28]=[CH:27][C:8]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH:19]=[C:20]4[S:24][C:23]([S:25][CH3:33])=[N:22][C:21]4=[O:26])=[CH:16][CH:17]=3)[CH:12]=[N:11]2)=[C:7]([C:29]([F:32])([F:31])[F:30])[CH:6]=1)(=[O:4])=[O:3]
Reactant: CI
Reactant: CS(=O)(=O)c1ccc(Cn2ncc3cc(C=C4SC(=S)NC4=O)ccc32)c(C(F)(F)F)c1
Product: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(S(C)(=O)=O)cc3C(F)(F)F)c2)S1

Procedure:
5-[1-(4-Methanesulfonyl-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one was prepared from 5-[1-(4-Methanesulfonyl-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-thioxo-thiazolidin-4-one and methyl iodide following General Procedure C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:31])=[C:4]2[N:10]=[C:9]([CH2:11][CH2:12][CH3:13])[N:8]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[S:27]([NH2:30])(=[O:29])=[O:28])=[CH:17][CH:16]=3)[C:5]2=[N:6][CH:7]=1.C1COCC1.CN(C=O)C.[C:42](Cl)(=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CO>[C:42]([NH:1][C:2]1[C:3]([CH3:31])=[C:4]2[N:10]=[C:9]([CH2:11][CH2:12][CH3:13])[N:8]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[S:27]([NH2:30])(=[O:29])=[O:28])=[CH:19][CH:20]=3)[C:5]2=[N:6][CH:7]=1)(=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CCCc1nc2c(C)c(N)cnc2n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CO
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCc1nc2c(C)c(NC(=O)c3ccccc3)cnc2n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Reaction time: 12 h

Procedure:
To a mixture of 6-amino-7-methyl-2-propyl-3-[2'-(aminosulfonyl)[1,1']-biphenyl-4-yl]methyl-3H-imidazo[4,5-b]pyridine (189 mg, 0.435 mmol) in 14:1 THF/DMF (7.5 mL) at -15° C. was added benzoyl chloride (0.045 mL, 0.392 mmol). The mixture was stirred for 12 h, then 1 mL of MeOH was added and the mixture was o concentrated. Purification (SiO2, 93:3:4 CH2Cl2/MeOH/HOAc) gave the title compound as a solid.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9](=O)[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C([N:14]([CH2:17][CH3:18])CC)C>C(O)C>[CH3:10][C:9]1[NH:14][C:17]([CH2:18][CH2:4][CH2:3][CH2:9][CH3:10])=[N:2][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)C(N)C(C)=O
Agent: Cl
Solvent: CCO
Product: CCCCCc1nc(C(=O)OCC)c(C)[nH]1
Reaction time: 72 h

Procedure:
Ethyl 2-amino-3-ketobutanoate hydrochloride (3.0 g) was added portionwise to a solution of Intermediate 157 (30 g) and triethylamine (26 ml) in ethanol (500 ml) under nitrogen. The resulting solution was left to stand at 22° for 72 h. The solvent was removed in vacuo, then the residue was dissolved in ethyl acetate (200 ml) and washed with water (200 ml). The aqueous layer was further extracted with ethyl acetate (200 ml). The combined organic extracts were dried, concentrated in vacuo and the residue purified by chromatography eluting with System A (8:2) to obtain the title Compound (3.05 g) as a pale yellow solid, m.p. 89°-90° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2].[C:30]([C:32]1[CH:46]=[CH:45][C:35]([CH2:36][O:37][CH2:38][C@@H:39]([NH:41][CH:42]([CH3:44])[CH3:43])[CH3:40])=[CH:34][CH:33]=1)#[N:31]>>[C:30]([C:32]1[CH:46]=[CH:45][C:35]([CH2:36][O:37][CH2:38][C@@H:39]([N:41]([CH:42]([CH3:43])[CH3:44])[C:21](=[O:22])[C:20]2[CH:19]=[CH:18][C:17]([C:8]3[C:7]4[CH:26]=[C:27]([O:28][CH3:29])[C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]=4[C@@H:15]4[C@@H:10]([CH2:11][CH2:12][N:13]([CH3:16])[CH2:14]4)[N:9]=3)=[CH:25][CH:24]=2)[CH3:40])=[CH:34][CH:33]=1)#[N:31]
Reactant: CC(C)N[C@@H](C)COCc1ccc(C#N)cc1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCN(C)C[C@H]21
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N(C(C)C)[C@@H](C)COCc3ccc(C#N)cc3)cc1)=N[C@@H]1CCN(C)C[C@H]21

Procedure:
Prepared from 4-((4aR,10bS)-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6]naphthyridin-6-yl)benzoic acid and N—[(S)-2-(4-cyano-benzyloxy)-1-methyl-ethyl]-N-isopropyl-amine as described for example 1
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].C(N(CC)CC)C.[C:20](Cl)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22]>O1CCCC1>[CH3:22][C:21]([CH3:24])([CH3:23])[C:20]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH:7]=[N:8]1)=[O:25]
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)n1ncc2cc([N+](=O)[O-])ccc21
Temperature: 0 °C
Yield: 78.4 %

Procedure:
A 4 L 3-neck round bottom flask fitted with a nitrogen inlet and mechanical stirrer was charged with a solution of 5-nitroindazole (80.0 g, 0.49 mol) in tetrahydrofuran (1 L). The mixture was cooled to 0° C. and triethylamine (85.4 mL, 0.61 mol) was added. To the mixture was added pivaloyl chloride (63.4 mL, 0.52 mol) dropwise over a period of 15 minutes. The reaction was allowed to warm to 20° C. over a period of 2 hours. The reaction was filtered and concentrated to a dark red oil. To the oil was added methylene chloride (60 mL). The resulting slurry was stirred vigorously, giving a white precipitate that was isolated by filtration. The solid was dried in a vacuum oven at 40° C. overnight to afford the title compound (95 g, 79%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([F:36])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][CH2:28][CH2:29][CH2:30]OS(C)(=O)=O.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([F:36])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:20])[CH3:21])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][CH2:28][CH2:29][CH2:30][N:41]1[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]1
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCOS(C)(=O)=O)c(F)cc(F)c3o2)cc1F
Reactant: CN1CCNCC1
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(CCCNc2c(F)cc(F)c3oc(-c4ccc(NC(=O)C(C)(C)C)c(F)c4)cc(=O)c23)CC1
Temperature: 50 °C
Reaction time: 6.6 h
Yield: 80.1 %

Procedure:
612 mg (1.16mmol) of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-(3-methanesulfonyloxypropylamino)-4H-1-benzopyran-4-one obtained in Example 129 (2) was dissolved in 30 mL of dimethylformamide under argon atmosphere, 1.30 mL (11.6 mmol) of 1-methylpiperazine was added and the mixture was stirred at 50° C. for 6.6 hours. Water was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=100:1-10:1) to give 493 mg of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-[3-(4-methylpiperazin-1-yl)propylamino]-4H-1-benzopyran-4-one (yield: 80%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Br:9])[C:3]=1[OH:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][Cl:20].CC(=O)CC>C(OCC)C>[Cl:20][CH2:19][CH2:18][O:10][C:3]1[C:2]([Br:1])=[CH:7][C:6]([F:8])=[CH:5][C:4]=1[Br:9]
Reactant: ClCCBr
Reactant: Oc1c(Br)cc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCC(C)=O
Product: Fc1cc(Br)c(OCCCl)c(Br)c1
Temperature: 25 °C
Yield: 99.1 %

Procedure:
A mixture of 2,6-dibromo-4-fluoro-phenol (55 g, 0.20 mol), potassium carbonate (60 g, 0.43 mol), 1-bromo-2-chloroethane (32.5 g, 0.23 mol) and 2-butanone (500 ml) was heated to reflux for 2 hours and allowed to cool to ambient temperature. The solids were filtered and the solvent was removed under vacuum to afford an oil. The oil was dissolved in diethyl ether (300 ml) and washed with water, dried over anhydrous magnesium sulfate, charcoalized, and filtered through silica gel to afford 65.9 g (97.2%) of product as an oil; MS EI m/e 330/332/334/336 (M+); 1H NMR (CDCl3) δ3.89 (2H, t, J=6.1 Hz), 4.23 (2H, t, J=6.1 Hz), 7.28 (2H, d, J=7.5 Hz).