Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].S(OC)(O[CH3:20])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:20][O:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: CC(C)=CCOc1ccc(C=O)c(O)c1
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(OCC=C(C)C)ccc1C=O

Procedure:
10.6 g (206 mmol) of 2-hydroxy4-(3-methylbut-2-enyloxy)benzaldehyde and 5.4 ml of dimethyl sulfate were dissolved in 102 ml of distilled acetone, the solution was added 25.5 g of potassium carbonate, and the resulting mixture was refluxed for 5 hours. The mixture was filtered and the filtrate concentrated in vacuo to give 8.3 g of an yellow oil from which 5.4 g of 2-methoxy4-(3-methylbut-2enyloxy)benzaldehyde was isolated by column chromatography over silica gel 60 (Merck 0.063-0.200 mm, 400 g) using petroleum ether-ethyl acetate (9:1, 1000 ml), (4:1, 500 ml) as eluents.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([S:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=3)=[CH:20][CH:19]=2)=[C:12]2[C:7]=1[CH2:8][CH2:9][CH2:10][O:11]2.[K+].[Br-]>>[F:33][C:30]([F:31])([F:32])[C:27]1[CH:28]=[CH:29][C:24]([C:21]2[CH:20]=[CH:19][C:18]([CH2:17][S:16][C:13]3[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:34])=[O:2])=[C:7]4[C:12]=3[O:11][CH2:10][CH2:9][CH2:8]4)=[CH:23][CH:22]=2)=[N:25][CH:26]=1
Reactant: COC(=O)COc1ccc(SCc2ccc(-c3ccc(C(F)(F)F)cn3)cc2)c2c1CCCO2
Agent: [Br-]
Agent: [K+]
Product: O=C(O)COc1ccc(SCc2ccc(-c3ccc(C(F)(F)F)cn3)cc2)c2c1CCCO2

Procedure:
The title compound was prepared in the manner analogous to Example 1 using 86A. mp 178-179° C.; IR (KBr) cm−1: 3034, 2577, 1707, 1604, 1332, 1111; 400 MHz 1H NMR (DMSO-d6): δ 12.95 (br(s), 1H), 8.97 (s, 1H), 7.99-8.24 (m, 4H), 7.33-7.40 (m, 2H), 6.95 (d, 2H, J=8.5 Hz), 6.26 (d, 2H, J=8.6 Hz), 4.57 (s, 2H), 4.11 (t, 2H, J=4.9 Hz), 4.04 (s, 2H), 2.56 (t, 2H, J=6.5 Hz), 1.84 (pentet, 2H); MS m/z 476 (M+1). Anal. Calc'd for C24H20F3NO4S: C, 60.63; H, 4.24; N, 2.95. found: C, 60.31; H, 4.24; N, 3.02.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10](=[C:13]1[CH2:17][CH2:16][CH2:15][O:14]1)[C:11]#[N:12].O.[NH2:19][NH2:20]>C(O)C>[NH2:12][C:11]1[C:10]([C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[C:13]([CH2:17][CH2:16][CH2:15][OH:14])[NH:19][N:20]=1
Reactant: N#CC(=C1CCCO1)c1nc2ccccc2s1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Nc1n[nH]c(CCCO)c1-c1nc2ccccc2s1
Yield: 59.1 %

Procedure:
The benzothiazol-2-yl-(dihydrofuran-2-ylidene)-acetonitrile (90 mg, 0.37 mmol) prepared above and hydrazine hydrate (25 mg, 0.5 mmol) were refluxed in ethanol (15 mL) for 10 hours. The solvent was evaporated and the resulting residue was triturated with dichloromethane. The solid was isolated by filtration and was then washed with dichloromethane and methanol to yield 60 mg (67%) of the title compound as a cream coloured solid. MS (m/z, ES+): 275.1 (M+1, 100). 1H NMR (300 MHz, ppm, DMSO-d6): δ (ppm), 11.5-12.2 (br s, 1H), 8.00 (d, 1H), 7.86 (d, 1H), 7.77 (t, 2H), 7.29 (t, 1H), 7.00-5.20 (br m, 2H), 4.55 (s, 1H), 3.52 (q, 2H), 2.83 (br s, 2H), 1.84 (q, 2H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([OH:13])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].C(N(CC)CC)C>ClCCl>[Si:16]([O:13][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[N:4]=[C:3]([C:2]([F:1])([F:14])[F:15])[CH:12]=[CH:11]2)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cccc2ccc(C(F)(F)F)nc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cccc2ccc(C(F)(F)F)nc12
Yield: 101.3 %

Procedure:
A solution of 2-trifluoromethylquinolin-8-ol (11.5 g), tert-butyldimethylsilyl chloride (8.9 g) and triethylamine (6.5 g) in dichloromethane (60 ml) was stirred overnight at room temperature. The reaction mixture was washed with water (2×50 ml), dried over sodium sulfate, filtered and the solvent removed in vacuo to give the product (17.9 g) as a white solid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:23])[N:9]([CH:16]2[CH2:21][CH2:20][CH:19]([CH3:22])[CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:4][CH:3]=1.[C:24]([O:28][CH3:29])(=[O:27])[CH2:25][SH:26]>>[CH3:29][O:28][C:24](=[O:27])[CH2:25][S:26][C:2]1[S:6][C:5]([NH:7][C:8]([N:9]([CH:16]2[CH2:21][CH2:20][CH:19]([CH3:22])[CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:23])=[N:4][CH:3]=1
Reactant: COC(=O)CS
Reactant: CC1CCC(N(C(=O)Nc2ncc(Br)s2)C2CCOCC2)CC1
Product: COC(=O)CSc1cnc(NC(=O)N(C2CCOCC2)C2CCC(C)CC2)s1

Procedure:
Prepared as described in general procedure (D) using 3-(5-bromo-thiazol-2-yl)-1-(4-methylcyclohexyl)-1-(tetrahydro-pyran-4-yl)-urea (Example 203) and methyl thioglycolate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].[N+:13]([O-:16])([OH:15])=[O:14].[N:17]#[C:18][NH2:19]>C(O)C>[N+:13]([O-:16])([OH:15])=[O:14].[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:18]([NH2:19])=[NH:17])=[CH:7][CH:6]=1)[CH3:2]
Reactant: N#CN
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CCO
Solvent: O=[N+]([O-])O
Product: CCOC(=O)c1ccc(NC(=N)N)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4-aminobenzoic acid ethyl ester (20 g, 0.121 mol), nitric acid (7.26 g, 0.121 mol), cyanamide (50%, 14 ml 0.182 mol) were mixed under reflux with ethanol (50 ml). After 24 hr, the mixture was cooled to RT, and then washed with ethanol to give the titled compound as crystalline solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[N+:12]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][C:2]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:12]([O-:14])=[O:13])[CH:20]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: COC(=O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2cccc([N+](=O)[O-])c2)cc1
Temperature: 85 °C
Yield: 16.6 %

Procedure:
To a stirred mixture of methyl 4-bromobenzoate (1.00 g) and 3-nitrophenylboronic acid (800 mg) in dioxane (20 mL) was added tetrakis(triphenylphosphine)palladium(0) (165 mg) and solid sodium carbonate (710 mg). The mixture was heated at 85° C. overnight, cooled to room temperature and partitioned between dichloromethane (100 mL) and 2 M aqueous sodium carbonate (50 mL) containing concentrated ammonium hydroxide (5 mL). The aqueous layer was further extracted twice with dichioromethane. The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was absorbed onto silica and chromatographed on silica gel eluting with 6:94 ethyl acetate in hexane to provide the title compound (198 mg) as a white solid
Reaction SMILES: [N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][C:2]=12.Br[C:14]1[CH:15]=[C:16]([N:20]([CH3:22])[CH3:21])[CH:17]=[CH:18][CH:19]=1>>[N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([C:14]3[CH:15]=[C:16]([N:20]([CH3:22])[CH3:21])[CH:17]=[CH:18][CH:19]=3)[CH:8]=[CH:9][C:2]=12
Reactant: CN(C)c1cccc(Br)c1
Reactant: OB(O)c1ccc2nonc2c1
Product: CN(C)c1cccc(-c2ccc3nonc3c2)c1

Procedure:
Starting from 5-benzo[1,2,5]oxadiazoleboronic acid and (3-bromo-phenyl)-dimethyl-amine. Orange-yellow powder. MS(ES+): 240 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:17][C@H:16]3[N:12]([CH2:13][CH2:14][CH2:15]3)[C:11]([CH3:19])([CH3:18])[CH2:10]2)[C:5]([F:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:42]=[CH:41][C:25]([O:26][C@H:27]2[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][C@@H:28]2[F:40])=[C:24]([Cl:43])[CH:23]=1.CC1C=CC(S(O)(=O)=O)=CC=1.Cl>CC(O)C.O1CCOCC1>[Cl:43][C:24]1[CH:23]=[C:22]([NH:21][C:2]2[N:7]=[C:6]([NH:8][C@@H:9]3[CH2:17][C@H:16]4[N:12]([CH2:13][CH2:14][CH2:15]4)[C:11]([CH3:19])([CH3:18])[CH2:10]3)[C:5]([F:20])=[CH:4][N:3]=2)[CH:42]=[CH:41][C:25]=1[O:26][C@H:27]1[CH2:32][CH2:31][NH:30][CH2:29][C@@H:28]1[F:40]
Reactant: CC1(C)C[C@H](Nc2nc(Cl)ncc2F)C[C@@H]2CCCN21
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc(N)cc2Cl)[C@@H](F)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CC1(C)C[C@H](Nc2nc(Nc3ccc(O[C@H]4CCNC[C@@H]4F)c(Cl)c3)ncc2F)C[C@@H]2CCCN21
Temperature: 100 °C
Yield: 50 %

Procedure:
A mixture of (7R,8aS)-N-(2-chloro-5-fluoropyrimidin-4-yl)-5,5-dimethyloctahydroindolizin-7-amine (0.2 g, 1.0 eq, 0.6 mmol), tert-butyl (3S,4S)-4-(4-amino-2-chlorophenoxy)-3-fluoropiperidine-1-carboxylate (0.2 g, 1.0 eq, 0.64 mmol) and PTSA (0.1 g, 0.9 eq, 0.6 mmol) was taken in iPrOH (10 mL) and heated at 100° C. for over night. After 18 hours of heating, reaction mixture was cooled to room temperature and PTSA (1.0 eq) was added to complete the deprotection of the Boc group. Then the reaction mixture was heated at 100° C. for 3 hours while stifling and cooled to room temperature. The volatiles were removed under vacuum to leave a crude solid. 4N HCl in dioxane (5 mL) was added to the crude mixture to ensure complete dprotection of the Boc group and the mixture was concentrated to dryness. Work-up and purification conditions used were the same as in Example 89 above for Compound 119, and gave the product as a solid in 50% yield.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH:15]([CH3:19])[CH2:14]2)[C:9]([F:20])=[C:8]2[C:3]=1[C:4](=[O:27])[C:5]([C:24]([OH:26])=[O:25])=[CH:6][N:7]2[CH:21]1[CH2:23][CH2:22]1.S(=O)(=O)(O)O.[CH2:33](O)[CH3:34]>>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH:15]([CH3:19])[CH2:14]2)[C:9]([F:20])=[C:8]2[C:3]=1[C:4](=[O:27])[C:5]([C:24]([O:26][CH2:33][CH3:34])=[O:25])=[CH:6][N:7]2[CH:21]1[CH2:23][CH2:22]1
Reactant: CC1CN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CCN1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(N3CCNC(C)C3)c(F)c(N)c2c1=O

Procedure:
5-Amino-1-cyclopropyl-6,8-difluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was suspended in absolute ethanol. Concentrated sulfuric acid was added to the suspension and the mixture was refluxed for 10 hours with stirring. After evaporation of ethanol, chloroform and a 20% aqueous sodium hydroxide solution were added to the residue, and the mixture was adjusted to pH 9. The organic layer was separated and chloroform was evaporated under reduced pressure. The resulting crystals were collected by filtration to give ethyl 5-amino-1-cyclopropyl-6,8-difluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate, m.p. 132°-134° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.I[CH2:12][CH:13]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].O>C1COCC1>[CH2:22]([CH:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:12][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCC(CI)CCCCCC
Reactant: c1ccsc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCC(CCCCCC)Cc1cccs1
Temperature: -78 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
A solution of thiophene (46.4 g, 551 mmol., 2.50 equiv.) and THF (300 mL) was cooled to −78° C. n-Butyllithium (2.5 M in hexanes, 212 mL, 528 mmol., 2.40 equiv.) was added over 1 hour. The mixture was stirred for an additional 30 minutes at −78° C. before a solution of 1-iodo-2-hexyldecane (90.0 g, 220 mmol., 1.00 equiv) in THF (200 mL) was added slowly over 1 hour. After stirring for 1 hour at −78° C., the reaction mixture was warmed to ambient temperature and stirred for 18 hours. Water (200 mL) was added and the organic material was extracted with Et2O (3×250 mL), washed with additional water, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting brown residue was purified by silica gel column chromatography (hexanes) to give a pale yellow oil (52.03 g, 77% yield). 1H NMR (500 MHz, CDCl3) δ 7.12 (dd, J=5.2, 1.2 Hz, 1H), 6.92 (m, 1H), 6.76 (dd, J=3.4, 0.9 Hz, 1H), 2.76 (d, J=6.7, 2H), 1.62 (b, 1H), 1.33-1.21 (m, 24H), 0.91-0.87 (m, 6H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([Cl:10])=[CH2:9])=[C:6]([C:11]([F:14])([F:13])[F:12])[N:5]=[C:4]([CH3:15])[N:3]=1.[NH:16]1[CH:20]=[CH:19][N:18]=[CH:17]1.O>C(#N)C>[Cl:10][C:8]([C:7]1[C:2]([N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)=[N:3][C:4]([CH3:15])=[N:5][C:6]=1[C:11]([F:14])([F:13])[F:12])=[CH2:9]
Reactant: c1c[nH]cn1
Reactant: C=C(Cl)c1c(Cl)nc(C)nc1C(F)(F)F
Solvent: CC#N
Solvent: O
Product: C=C(Cl)c1c(-n2ccnc2)nc(C)nc1C(F)(F)F
Temperature: 25 °C
Yield: 65.2 %

Procedure:
4-Chloro-5-(1-chlorovinyl)-2-methyl-6-trifluoromethylpyrimidine (1.83 g) was dissolved in acetonitrile (20 ml) under stirring in room temperature. The mixture was added imidazole (1.45 g) and refluxed 3 hr and then cooled to room temperature and added water. The mixture was extracted with chloroform. The chloroform layer was washed with water and brine, respectively and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-THF) to give 5-(1-chlorovinyl)-4-imidazol-1-yl-2-methyl-6-trifluoromethyl-pyrimidine (1.34 g) as pale brown oil. 1H-NMR (δ, ppm); 2.82 (s, 3H), 5.78 (d, 1H), 6.03 (d, 1H), 7.21 (br, 1H), 7.87 (br, 1H), 8.55 (br, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[C:13]([NH:21][CH2:22][C:23]1[S:27][C:26]([S:28](Cl)(=[O:30])=[O:29])=[CH:25][CH:24]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:13]([NH:21][CH2:22][C:23]1[S:27][C:26]([S:28]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:29])=[O:30])=[CH:25][CH:24]=1)(=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(NCc1ccc(S(=O)(=O)Cl)s1)c1ccccc1
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(CNC(=O)c3ccccc3)s2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 5-[(benzoylamino)methyl]thiophene-2-sulfonyl chloride as described in the synthetic METHOD B to give a white solid (8.6 mg) with purity >70%. MS (pos) m/z 466.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:13][CH2:12][S:11][C:10]2=[NH:14])=[CH:4][N:3]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:13][CH2:12][S:11][C:10]2=[N:14][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:4][N:3]=1
Reactant: N=C1SCCN1Cc1ccc(Cl)nc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(N=C1SCCN1Cc1ccc(Cl)nc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(2-Chloro-5-pyridinylmethyl)-2-iminothiazolidine (227 mg, 1.1 mmol) and triethylamine (110 mg, 1.1 mmol) were dissolved in 10 ml of acetonitrile, into which, benzoyl chloride (141 mg, 1.0 mmol) dissolved in acetonitrile 5 ml was added under cooling with ice, and stirred at room temperature overnight. After distilling the solvent off under reduced pressure followed by extraction with ethyl acetate, the ethyl acetate layer was washed with 2N-hydrochloric acid, saturated aqueous sodium bicarbonate, and water in this order, and the ethyl acetate layer was dehydrated and dried, and then the ethyl acetate layer was distilled off, and remaining oil was purified by a silica gel column chromatography to obtain the intended substance. The crude crystal of the intended substance was washed with hexane. Yield: 160 mg (65%). Melting point: 133° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:39])([CH2:36][CH2:37][CH3:38])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:35])=[N:15][N:16]2[C:21]([O:22][CH2:23][C:24]3[C:29]([F:30])=[CH:28][CH:27]=[C:26]([O:31][CH3:32])[C:25]=3[F:33])=[CH:20][C:19]([CH3:34])=[CH:18][C:17]=12)=[O:12])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C:8]([CH3:39])([CH2:36][CH2:37][CH3:38])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:35])=[N:15][N:16]2[C:21]([O:22][CH2:23][C:24]3[C:29]([F:30])=[CH:28][CH:27]=[C:26]([O:31][CH3:32])[C:25]=3[F:33])=[CH:20][C:19]([CH3:34])=[CH:18][C:17]=12)=[O:12]
Reactant: CCCC(C)(CNC(=O)c1c(C)nn2c(OCc3c(F)ccc(OC)c3F)cc(C)cc12)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCC(C)(N)CNC(=O)c1c(C)nn2c(OCc3c(F)ccc(OC)c3F)cc(C)cc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
rac-{1-[({7-[(2,6-Difluoro-3-methoxybenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]-pyridin-3-yl}carbonyl)amino]-2-methylpentan-2-yl}carbamic acid tert-butyl ester (Example 125A) in 4 ml of dichloromethane was admixed with 3 ml of trifluoroacetic acid. The resulting solution was stirred at room temperature for 3 h. After the reaction had ended, the solvent was drawn off under reduced pressure and the residue was purified by preparative HPLC chromatography (Method 21), which gave 10 mg (11% of theory, over 2 stages) of the target compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]([CH:12]=[CH2:13])[CH2:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[NH:22])[NH2:21])[CH:15]=3)[C:8]2=[O:23])[CH2:3][CH2:2]1.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>O1CCCC1>[C:24]1([S:30]([N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[CH:11]([CH:12]=[CH2:13])[CH2:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[NH:21])[NH2:22])[CH:15]=4)[C:8]3=[O:23])[CH2:3][CH2:2]2)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: C=CC1CN(c2cccc(C(=N)N)c2)C(=O)N1C1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC1CN(c2cccc(C(=N)N)c2)C(=O)N1C1CCN(S(=O)(=O)c2ccccc2)CC1

Procedure:
In this case the title compound was prepared by sulfonylation of 1-(piperidin-4-yl)-3-(3-amidinophenyl)-5-ethenyl-2-imidazolidinone with phenylsulfonyl chloride in tetrahydrofuran with triethylamine folowed by amidine formation as described above; HRMS (M+H)+ calc. 454.191287, found 454.191418.
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][N:5]=[C:6]([C:12](=[O:14])[CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].S(Cl)([Cl:18])(=O)=O.C(O)=O>O>[Br:1][CH2:2][CH2:3][O:4][N:5]=[C:6]([C:12](=[O:14])[CH2:13][Cl:18])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C(=NOCCBr)C(C)=O
Reactant: O=S(=O)(Cl)Cl
Solvent: O=CO
Solvent: O
Product: CCOC(=O)C(=NOCCBr)C(=O)CCl
Temperature: 40 °C
Reaction time: 5.5 h
Yield: 82.2 %

Procedure:
A mixture of ethyl 2-(2-bromoethoxyimino)-3-oxobutyrate (syn isomer, 168 g.), sulfuryl chloride (87.3 g.) and formic acid (168 ml.) was stirred at 40° C. for 10 minutes and at room temperature for 5.5 hours. After adding water (1 l.) to the resultant solution, the mixture was extracted with methylene chloride. The extract was washed with water, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in turn, dried over magnesium sulfate, and then concentrated in vacuo to give ethyl 2-(2-bromoethoxyimino)-4-chloro-3-oxobutyrate (syn isomer, 156 g.), oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][N:9]=[C:10]2[C:14](=O)[O:13][C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:11]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[NH4+:23].[K+].[Br-]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:11][C:10]([C:14]([NH2:23])=[O:13])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: Cc1cccc(NN=C2N=C(c3ccccc3)OC2=O)c1
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1cccc(-n2nc(C(N)=O)nc2-c2ccccc2)c1
Yield: 63 %

Procedure:
Three grams (0.01 mole) of 4-(3-methylphenyl-hydrazono)-2-phenyl-oxazoline-5-one (R1 =3--CH3, R2 =R3 =H in the formula II) was suspended in 93 ml of methanol. To the resulting suspension, 66.2 ml of 29% solution of ammonium hydroxide (0.549 mole) was added and refluxed for 5 minutes. Methanol and ammonia were then distilled off under a reduced pressure, and the resulting crystals were filtered out and washed with water. The crystals were recrystallized from a mixed solvent of 5.8 ml of methanol and 4.5 ml of water to obtain 1.8 g of almost colorless crystal, m.p. 142°-143° C., with a yield of 63%. I.R. (KBr, cm-1, refer to FIG. 2); 3500-3240 (broad and strong), 1700, 1670, 1610, 1458, 1400, 1302, 789 and 700.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([Cl:21])[C:5]2[C:10]([CH3:11])=[CH:9][N:8]([C@@H:12]3[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]3[OH:14])[C:6]=2[N:7]=1.[H-].[Na+].[CH3:24]I>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([Cl:21])[C:5]2[C:10]([CH3:11])=[CH:9][N:8]([C@@H:12]3[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]3[O:14][CH3:24])[C:6]=2[N:7]=1
Reactant: CI
Reactant: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2nc(N)nc(Cl)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cc(C)c2c(Cl)nc(N)nc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a solution of the compound from Example 12, Step B (188 mg, 0.6 mmol) in anhydrous DMF (6 mL) was added NaH (60% in mineral oil; 26 mg, 0.66 mmol). The mixture was stirred at room temperature for 0.5 h and then cooled. MeI (45 μL) was added at 0° C. and the reaction mixture allowed to warm to 15° C. in 5 h. Then the mixture was poured into ice-water (20 mL) and extracted with CH2Cl2 (100+50 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL) and dried (Na2SO4). The evaporated residue was purified on a silica gel column with a solvent system of CH2Cl2/MeOH: 30/1. Appropriate fractions were pooled and evaporated to yield the title compound (50 mg) as a colorless glass.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[N:24][N:23]=2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:45][CH2:46][O:47][CH3:48]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:45][CH2:46][O:47][CH3:48])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[N:24][N:23]=2)=[CH:19][CH:20]=1
Reactant: COCCBr
Reactant: COc1cc2c(Oc3ccc(Nc4nnc(-c5ccccc5)c5ccccc45)cc3)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCOc1cc2nccc(Oc3ccc(Nc4nnc(-c5ccccc5)c5ccccc45)cc3)c2cc1OC
Reaction time: 0.08 h

Procedure:
6-Methoxy-4-(4-(4-phenylphthalazin-1-ylamino)phenoxy)quinolin-7-ol (45 mg, 92 μmol) and cesium carbonate (33 mg, 102 μmol) were combined in DMF (2 Ml) and stirred for 5 min. 1-Bromo-2-methoxyethane (9.6 μl, 204 μmol) was added and the mixture was stirred at RT for 12 hours. DMF was then removed under vacuum overnight. The crude material was purified by silica gel chromatography using 0 to 100% ethyl acetate in hexane to afford the titled product. MS: M+H+=545.