Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:6]=[CH:7][C:8](=[O:24])[C:9](=[CH:14][NH:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=2[CH3:23])[C:10]([O:12]C)=[O:11])[CH2:5][CH2:4][CH2:3][CH:2]=1.ClC1C(=O)C(Cl)=C(Cl)C(=O)C=1Cl.C(O)(=O)C>CN(C)C=O.O1CCOCC1>[C:1]1([C:6]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=3[CH3:23])[CH:14]=[C:9]([C:8](=[O:24])[CH:7]=2)[C:10]([OH:12])=[O:11])[CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: COC(=O)C(=CNc1ccc(O)cc1C)C(=O)C=CC1=CCCC1
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Cc1cc(O)ccc1-n1cc(C(=O)O)c(=O)cc1C1=CCCC1
Temperature: 25 °C
Yield: 195.3 %

Procedure:
In 5 ml of N,N-dimethylformamide was dissolved 0.7 g of methyl 5-(cyclopenten-1-yl)-2-(4-hydroxy-2-methylphenylaminomethylene)-3-oxo-4-pentenoate, and they were reacted at 140° C. for 2 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the residue was purified by a column chromatography (Wako Silica Gel C-200; eluent: chloroform) to obtain an oily substance. This oily substance was dissolved in 10 ml of dioxane, and 0.5 g of 2,3,5,6-tetrachloro-p-benzoquinone was added thereto. They were reacted at 80° C. for 30 minutes. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration, and washed with 5 ml of dioxane. These crystals were dissolved in a mixture of 5 ml of methanol and 5 ml of a 1N aqueous sodium hydroxide solution, the resulting mixture was subjected to reaction at room temperature for 30 minutes. The reaction mixture was adjusted to a pH of 5.5 with acetic acid and the precipitated crystals were collected by filtration, washed with water, and dried to obtain 1.3 g of 6-(cyclopenten-1-yl)-1-(4-hydroxy-2-methylphenyl)-4-oxo-1,4-dihydronicotinic acid having a melting point of 211°-213° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([Cl:15])[CH:14]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[NH2:11].[H-].[Na+].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Br>CN(C=O)C.CCOC(C)=O>[Cl:15][C:13]1[CH:12]=[C:4]([CH:3]=[C:2]([Cl:1])[CH:14]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[NH:11][CH2:23][C:22]1[CH:25]=[CH:26][CH:27]=[C:20]([O:19][CH3:18])[CH:21]=1
Reactant: COc1cccc(CBr)c1
Reactant: Nc1nccn1Cc1cc(Cl)cc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cccc(CNc2nccn2Cc2cc(Cl)cc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 5 %

Procedure:
1-(3,5-Dichloro-benzyl)-1H-imidazol-2-ylamine (see Example 12) was dissolved in anhydrous DMF and NaH was added to the solution under H2. The reaction mixture was stirred at room temperature for 10 min and 3-methoxybenzylbromide was added. The reaction mixture was stirred at 65° C. for 5 h. The reaction mixture was then diluted with EtOAc and washed with water (×5). The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel preparative TLC using CH2Cl2:MeOH 95:5 to afford the title compound (7 mg, 5%); LCMS m/z 362 [C18H17Cl2N3O+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]2[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=2[C:6]2[C:7](=[O:20])[NH:8][C:9]([NH:13]C(=O)C(C)(C)C)=[N:10][C:11]=2[CH:12]=1.[C:25](O)(=[O:27])C>C[O-].[Na+]>[NH2:13][C:9]1[NH:8][C:7](=[O:20])[C:6]2[C:5]3[CH:21]=[CH:22][CH:23]=[CH:24][C:4]=3[C:3]([CH2:2][O:27][CH3:25])=[CH:12][C:11]=2[N:10]=1
Reactant: CC(=O)O
Reactant: CC(C)(C)C(=O)Nc1nc2cc(CBr)c3ccccc3c2c(=O)[nH]1
Agent: C[O-]
Agent: [Na+]
Product: COCc1cc2nc(N)[nH]c(=O)c2c2ccccc12

Procedure:
A solution of N-(6-(bromomethyl)-1,2-dihydro-1-oxobenzo[f]quinazolin-- 3-yl)pivalamide (0.28 g, 0.72 mmole) in 0.3 M sodium methoxide (25 ml) was stirred and heated at 650 C under a nitrogen atmosphere for 4 hours. After cooling, the mixure was acidified to pH 6 with glacial acetic acid, and then all solvent was removed under reduced pressure. The residue was triturated with water (20 ml), then filtered, washid with water and acetone, and dried to give 3-amino-6-(methoxymethyl)- benzo[f]quinazolin-1(2H)-one as an off-white solid. (0.12 9, 58%) 1H NMR(DMSO-d61 200 MHz) d 3.39(s, 3H, OCH3); 4.85(s, 2H, CH2); 6.54(br s, 2H, NH2); 7.33(s, 1H, Ar); 7.44(dt, J=6.9, 1.4 Hz, 1H, Ar); 7.59(dt, J=6.9, 1.4 Hz, 1H, Ar); 7.96(dd, J=8.2, 1.0 Hz, 1H, Ar); 9.69(d, J=8 Hz, 1H, Ar); 11.11(br s, 1H, NH); 11.91(br s, <1H, pyr-NH+). Anal. Calculated for C1-4H13N3 02.1/2HOAc.1/10H2O: C, 62.75; H, 5.34; N, 14.64. Found C, 62.74; H, 5.31; N, 14.64.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([NH:17][C:18]([CH2:24][CH3:25])([CH2:22][CH3:23])[C:19](O)=[O:20])=[O:16])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.C[Si](C)(C)[O:28][CH2:29][CH2:30][NH2:31]>>[CH2:24]([C:18]([NH:17][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[N:8]=1)=[O:16])([C:19](=[O:20])[NH:31][CH2:30][CH2:29][OH:28])[CH2:22][CH3:23])[CH3:25]
Reactant: C[Si](C)(C)OCCN
Reactant: CCC(CC)(NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)C(=O)O
Product: CCC(CC)(NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)C(=O)NCCO

Procedure:
The title compound was synthesized in analogy to Example 1, using 2-(5-cyclopropyl-6-(cyclopropylmethoxy)picolinamido)-2-ethylbutanoic acid (Example 274 a) and 2-(trimethylsilyloxy)ethanamine (CAN 5804-92-2)-as starting materials. MS (EI): m/e=390.5 [M+H]+.
Reaction SMILES: [CH:1]([O:3][C:4]1[C:5]([C:15]#[C:16][C@@:17]([O:35]CC2C=CC=CC=2)([CH3:34])[CH2:18][CH2:19][CH2:20][C@H:21]([CH3:33])[CH2:22][CH2:23][CH2:24][C@H:25]([CH3:32])[CH2:26][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])=C2CCN(C)C2=[N:8][C:9]=1[CH3:10])=[O:2].[CH3:43]C(C[AlH]CC(C)C)C.[CH2:52]([N:54]([CH2:57][CH3:58])[CH2:55][CH3:56])C.C(OC(=O)C)(=O)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:3][C:4]1[C:5]([CH2:15][CH2:16][C@@:17]([OH:35])([CH3:34])[CH2:18][CH2:19][CH2:20][C@H:21]([CH3:33])[CH2:22][CH2:23][CH2:24][C@H:25]([CH3:32])[CH2:26][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[C:56]2[CH2:58][CH2:57][N:54]([CH3:52])[C:55]2=[N:8][C:9]=1[CH3:10])(=[O:2])[CH3:43]
Reactant: Cc1nc2c(c(C#C[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)OCc3ccccc3)c1OC=O)CCN2C
Reactant: CCN(CC)CC
Reactant: CC(C)C[AlH]CC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1c(C)nc2c(c1CC[C@](C)(O)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)CCN2C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 25 mg of formate ester 33 in 2 mL of CH2Cl2 was added 220 μL (1M in toluene, 5 eq) of DIBAL-H at −78° C. The reaction mixture was stirred at the same temperature for 1.5 h then 300 μL of triethylamine and 150 μL of acetic anhydride and catalytic amount of DMAP was added. The resulting reaction mixture was allowed to warm to room temperature and stirred for 24 h. The reaction was quenched with 2 mL of aqueous saturated ammonium chloride and extracted with three portions of 5-mL of ethyl acetate. The combined organic layer was washed with brine, dried (Na2SO4) and concentrated under diminished pressure. The residue was purified by flash chromatography on a silica gel column (20×1.7 cm). Elution with 6:100 EtOAc-hexanes gave the product 34 as yellowish oil: yield 20 mg, (78%); Silica gel TLC Rf 0.48 (1:4 EtOAc-hexanes); 1H NMR (C6H6): δ 0.87-0.93 (m, 12H), 1.02-1.99 (m, 25H), 1.52 (s, 3H), 1.95 (s, 3H), 2.37 (s, 3H), 2.49 (t, J=8.0 Hz, 2H), 2.67 (s, 3H), 4.76 (dd, J=11.6, 55.2 Hz, 2H), 7.06-7.20 (m, 3H), and 7.44 (d, J=7.6 Hz, 2H); HRMS (ESI+) calculated for C38H56N2O3 (M+H+) 589.4364. found 589.4383.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([NH2:17])=[N:13][NH:14]3)=[CH:10][CH:9]=2)[CH:5]=[C:4](SC)[N:3]=1.OO.O1CCOCC1.[NH:28]1[CH2:33][CH2:32][S:31][CH2:30][CH2:29]1>FC(F)(F)C(O)=O.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([NH2:17])=[N:13][NH:14]3)=[CH:10][CH:9]=2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][S:31][CH2:30][CH2:29]2)[N:3]=1
Reactant: C1CSCCN1
Reactant: CSc1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Agent: OO
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCSCC2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 39.6 %

Procedure:
To 6-[2-amino-6-(methylthio)-4-pyrimidinyl]-1H-indazol-3-amine (0.43 g, 1.58 mmol) in trifluoroacetic acid (TFA) (15 mL) at 0° C. was added aqueous H2O2 (0.97 mL, 9.47 mmol, 30% (w/w)) dropwise. After 10 minutes, the reaction mixture was allowed to warm to room temperature and stirred at this temperature for 30 minutes. LCMS showed a mixture of sulfoxide and sulfone. The reaction mixture was cooled to 0° C. and quenched with dimethyl sulfide (1.0 mL, 13.5 mmol, dropwise addition) to ensure no hydrogen peroxide is left. The reaction mixture was warmed to room temperature and diluted with diethyl ether (Et2O). When the oxidation converts all the starting material to the sulfone, this material precipitate out when Et2O is added. However, this time the sulfoxide species was the dominant (˜80%) as shown in the LCMS. Therefore, hexane was added to ensure complete precipitation of the sulfoxide and sulfone mixture. The material was filtered, and the solid was treated with 1,4-dioxane (10 mL) and thiomorpholine (1.21 mL, 12.6 mmol). The reaction mixture was stirred overnight at 100° C. The mixture was cooled to room temperature and poured onto water and EtOAc. The layers were separated and the aqueous layer was further extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated. The crude mixture was purified via flash chromatography on SiO2 (gradient: 99:1:0.1 CHCl3/CH3OH/NH4OH to 90:10:1 CHCl3/CH3OH/NH4OH). The fractions containing the desired product were combined and concentrated. Trituration with Et2O afforded the title compound (205 mg, 40%) as a yellow solid. LC-MS (ES) m/z=328 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 2.61 (m, 4H), 3.99 (m, 4H), 5.37 (s, 2H), 6.12 (s, 2H), 6.61 (s, 1H), 7.58 (dd, J=8.6, 1.3 Hz, 1H), 7.70 (d, J=8.6 Hz, 1H), 7.95 (s, 1H), 11.50 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([NH:25][C:21]1[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=1)=[O:9]
Reactant: Cc1ccc(OCc2ccccc2)c(C(=O)O)c1
Reactant: Nc1cccnc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1

Procedure:
A solution of 5-methyl-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 9; 400 mg, 1.65 mmol), 3-pyridinamine (311 mg, 3.30 mmol), HOBT (379 mg, 2.48 mmol) and EDC (475 mg, 2.48 mmol) in DMF (5 ml) was stirred at room temperature overnight. The reaction mixture was poured into water (20 ml), filtered and the solid was washed by water and dried to yield the title compound as a white solid. 220 mg.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C@@H:9]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]3[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=3[CH:36]=2)[CH2:8][NH:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:44]1([CH3:54])[CH:49]=[CH:48][C:47]([S:50](Cl)(=[O:52])=[O:51])=[CH:46][CH:45]=1>ClCCl.CN(C)C1C=CN=CC=1.O.Cl>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][C@H:10]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[C@@H:9]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]3[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=3[CH:36]=2)[CH2:8][N:7]1[S:50]([C:47]1[CH:48]=[CH:49][C:44]([CH3:54])=[CH:45][CH:46]=1)(=[O:52])=[O:51])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1C[C@H](c2ccc(OC)cc2)[C@@H](OCc2ccc3c(c2)N(CCCOC)CCO3)CN1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)[C@@H]1C[C@H](c2ccc(OC)cc2)[C@@H](OCc2ccc3c(c2)N(CCCOC)CCO3)CN1S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C

Procedure:
To a solution of 1.51 g of (2S,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-2-carboxylic acid ethyl ester (from example 1a) in 25 ml of dichlormethane are added 1.97 ml of triethylamine, 3.5 mg of 4-dimethylaminopyridine and 0.57 g of 4-toluenesulfonylchloride at 0° C. The reaction mixture is allowed to warm to room temperature overnight, diluted with water and 1N hydrochloric acid and the organic phase is separated and dried over sodium sulfate. The organic phase is concentrated under reduced pressure and the residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a colourless oil. Rf=0.50 (EtOAc-heptane 1:1); Rt=5.44.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[N:16][NH:17]2)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.C(OC(=O)C=C(C1C=CC=C2C=1C(C#N)=[CH:38][NH:39]2)C1C=CC=CC=1)C>>[NH:17]1[C:18]2[C:14](=[C:13]([C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:5][C:4]([NH:39][CH3:38])=[O:3])[CH:21]=[CH:20][CH:19]=2)[CH:15]=[N:16]1
Reactant: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]ncc12
Reactant: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Product: CNC(=O)C=C(c1ccccc1)c1cccc2[nH]ncc12

Procedure:
3-(1H-Indazol-4-yl)-N-methyl-3-phenyl-acrylamide CXCII was prepared from 3-(1H-indazol-4-yl)-3-phenyl-acrylic acid ethyl ester using the procedure described for preparation of 3-(1H-Indol-7-yl)-N-methyl-3-phenyl-acrylamide XVIII (see Example 4).
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:25]=[N:26][C:27]([CH:30]=O)=[CH:28][CH:29]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.CC(O)=O.[NH2:37][CH2:38][CH2:39][CH2:40][C:41]([OH:43])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C.O>[CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:25]=[N:26][C:27]([CH2:30][N:37]6[CH2:38][CH2:39][CH2:40][C:41]6=[O:43])=[CH:28][CH:29]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: NCCCC(=O)O
Reactant: O=Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCCC5=O)nc4)sc23)c(F)c1)NC1CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 3.6 %

Procedure:
To a stirred solution of aldehyde 282 (0.5 g, 1.115 mmol) and AcOH (128 μl, 2.23 mmol) in DMF (10 mL) was added 4-aminobutyric acid (345 mg, 3.34 mmol). After 40 min, sodium triacetoxyborohydride (945 mg, 4.46 mmol) was added and the reaction was stirred at RT for 22 h. The reaction mixture was then diluted with water to form a precipitate that was collected by filtration, dried under vacuum and purified by Biotage (SNAP 50 g cartridge; 2% of ammonium hydroxide in MeOH/DCM: 0/100 to 15/85 over 20 CV) and by Gilson (Phenomenex, Luna 15 μl, C18(2) 100A, 250×50.0 mm, 15 μm; 0.05% of formic acid in both MeOH/water:30/80 to 95/5 over 60 min, flow; 30 mL/min), to afford the title compound 283 (20 mg, 0.04 mmol, 3% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.28 (s, 1H), 9.06 (d, J=2.4 Hz, 1H), 8.53 (d, J=5.6 Hz, 1H), 8.42 (bs, 1H), 8.26 (dd, J=2.4 and 8.0 Hz, 1H), 8.25 (s, 1H), 7.74 (dd, J=2.0 and 13.6 Hz, 1H), 7.41-7.34 (m, 2H), 7.24-7.20 (m, 1H), 7.08 (bs, 1H), 6.62 (d, J=5.6 Hz, 1H), 4.53 (s, 2H), 2.58-2.51 (m, 1H), 2.32 (t, J=8.0 Hz, 2H), 1.98 (quin, J=7.2 Hz, 2H), 0.65-0.60 (m, 2H), 0.45-0.40 (m, 2H). MS (m/z): 518.5 (M+H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].[O:7]=[CH:8][CH2:9][CH2:10][C:11](OCC(C)C)=O>>[O:5]=[C:4]1[CH2:3][N:2]2[C:8](=[O:7])[CH2:9][CH2:10][CH:11]2[NH:6]1
Reactant: CC(C)COC(=O)CCC=O
Reactant: NCC(N)=O
Agent: Cl
Product: O=C1CN2C(=O)CCC2N1
Yield: 22.6 %

Procedure:
Glycinamide hydrochloride (4.2 g, 38 mmol) and isobutyl 4-oxobutanoate (5 g, 31.6 mmol) were reacted together according to the procedure of example 2, to give the title compound 1 g (22.6%), m.p. 154°-157° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.[F:19][C:20]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>C1(C)C=CC=CC=1>[F:19][C:20]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[CH:26]=[CH:25][C:21]=1[C:22]([NH:1][C:2]1[C:3]([OH:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])=[O:23]
Reactant: COC(=O)c1cccc(N)c1O
Reactant: O=C(Cl)c1ccc(-c2ccccn2)cc1F
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(NC(=O)c2ccc(-c3ccccn3)cc2F)c1O
Temperature: 70 °C
Reaction time: 4 h
Yield: 45 %

Procedure:
To a solution of methyl 3-amino-2-hydroxybenzoate (1.42 g, 8.50 mmol) and pyridine (1.0 mL, 8.5 mmol) in toluene (20 ml) was added 2-fluoro-4-(pyridine-2-yl)benzoyl chloride (2.0 g, 8.50 mmol) portion wise at 0° C. and then stirred at 70° C. for 4 h. The resulting mixture was extracted with ethyl acetate (4×100 mL). The organic phase was washed with water and saturated sodium bicarbonate, dried with anhydrous sodium sulfate and evaporated under reduced pressure to obtain methyl 3-(2-fluoro-4-(pyridin-2-yl)benzamido)-2-hydroxybenzoate as a yellow solid (1.40 g, yield 45%). LC-MS (ESI) m/z: 367 (M+1)+.
Reaction SMILES: [F:1][CH:2]([F:21])[O:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][C:5]=1[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[CH:15]=1.[H-].[Na+].[CH3:24][NH:25][C:26](=O)[O:27]C1C=CC=CC=1.O>CN(C)C=O.C(OCC)(=O)C>[NH2:20][C:16]1[CH:15]=[C:14]([O:13][C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][C:4]=2[O:3][CH:2]([F:1])[F:21])[N:10]([C:26]([NH:25][CH3:24])=[O:27])[CH:9]=[CH:8]3)[CH:19]=[CH:18][N:17]=1
Reactant: CNC(=O)Oc1ccccc1
Reactant: Nc1cc(Oc2cc3cc[nH]c3cc2OC(F)F)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)n1ccc2cc(Oc3ccnc(N)c3)c(OC(F)F)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
4-((6-(Difluoromethoxy)-1H-indol-5-yl)oxy)pyridin-2-amine described in Production Example 19-6 (4.4 mg, 0.015 mmol) was dissolved in N,N-dimethylformamide (500 μL), then 50-72% oily sodium hydride (4.1 mg) was added under nitrogen atmosphere at 0° C., and the mixture was stirred at room temperature for 30 minutes. The mixture was cooled to 0° C. again and phenyl methylcarbamate described in Production Example 1-7 (16.4 mg, 0.108 mmol) was added, and the mixture was stirred at room temperature for 50 minutes. Water and ethyl acetate were added to the reaction mixture for partition. The organic layer was washed with a saturated saline solution, then dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under vacuum. The residue was dissolved in dichloromethane and the resultant was purified with NH silica gel column chromatography (n-heptane:ethyl acetate=1:1-0:1-ethyl acetate:methanol=99:1-9:1), and then the target fraction was concentrated under vacuum to obtain the title compound (4.3 mg, 82%).
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[CH:4][C:5]2[C:6]([CH:21]=1)=[N:7][C:8]1[N:9]([NH:19][CH3:20])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[CH3:23][CH:24]1[CH2:29][NH:28][CH2:27][CH2:26][NH:25]1>N1C=CC=CC=1>[F:22][C:3]1[C:2]([N:28]2[CH2:27][CH2:26][NH:25][CH:24]([CH3:23])[CH2:29]2)=[CH:21][C:6]2=[N:7][C:8]3[N:9]([NH:19][CH3:20])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=3[CH:14]=[C:5]2[CH:4]=1
Reactant: CC1CNCCN1
Reactant: CNn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Solvent: c1ccncc1
Product: CNn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCNC(C)C4)cc3nc21

Procedure:
7-Fluoro-1-methylamino-8-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is prepared under the conditions of Example 5 but starting from 3.2 g of 8-chloro-7-fluoro-1-methylamino-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid and 4 g of 2-methylpiperazine in 40 cm3 of pyridine. The crude product obtained is taken up in 30 cm3 of water and 7 cm3 of 2 N aqueous potassium hydroxide solution. A very small amount of insoluble matter is removed by filtration through diatomaceous silica. The filtrate is washed with twice 20 cm3 of diethyl ether and the product is then precipitated by adding 3.5 cm3 of 4 N methanesulphonic acid. The precipitate obtained is drained and washed with 3 times 20 cm3 of water and 3 times 20 cm3 of ethanol 2.2 g of 7-fluoro-1-methylamino-8-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a deep yellow solid melting at 343°-345° C., solvated by 3.7% of water.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][C:6]=1[CH3:19])=O.[NH2:20][C:21]([NH2:23])=[S:22]>CCO>[CH3:19][C:6]1[CH:7]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=[C:10]([CH3:11])[C:5]=1[C:3]1[N:20]=[C:21]([NH2:23])[S:22][CH:2]=1
Reactant: NC(N)=S
Reactant: Cc1cc(Oc2ccccc2)cc(C)c1C(=O)CBr
Solvent: CCO
Product: Cc1cc(Oc2ccccc2)cc(C)c1-c1csc(N)n1
Yield: 59.1 %

Procedure:
A mixture of 2-bromo-1-(2,6-dimethyl-4-phenoxyphenyl)ethanone (5.18 g, 16.2 mmol) and thiourea (1.24 g. 16.3 mmol) in 95% EtOH (23.2 mL) was heated at reflux for 60 min. The solution was concentrated and added with water (50 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene (30 mL). The solids were filtered and dried under vacuum to give 4-(2,6-dimethyl-4-phenoxyphenyl)thiazol-2-amine (2.84 g) as yellow solids in 59% yield: 1H NMR (500 MHz, CDCl3) δ 7.33 (t, J=7.5 Hz, 2 H), 7.26 (t, J=7.5 Hz, 1 H), 7.10 (d, J=7.3, 2 H), 6.72 (s, 2 H), 6.30 (s, 1 H), 5.18 (s, 2 H), 2.14 (s, 6 H).
Reaction SMILES: [CH2:1]([C:4]1[N:5]=[N:6][N:7]([CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11])[CH:8]=1)[CH2:2][CH3:3].[I:14][CH3:15]>C(#N)C>[I-:14].[CH3:15][N+:5]1[C:4]([CH2:1][CH2:2][CH3:3])=[CH:8][N:7]([CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11])[N:6]=1
Reactant: CCCc1cn(C[Si](C)(C)C)nn1
Reactant: CI
Solvent: CC#N
Product: CCCc1cn(C[Si](C)(C)C)n[n+]1C
Product: [I-]

Procedure:
4-propyl-1-((trimethylsilyl)methyl)-1H-1,2,3-triazole and excess iodomethane were added to a vial and heated for about 19 and 5 mL ACN was added. The reaction was heated for another 2 hours. The precipitate was filtered, rinsed with ether and dried in vacuo overnight. The following 3-methyl-4-propyl-1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-3-ium iodide structure was confirmed:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=O)[C:5]2=[O:12].[OH-:13].[K+].[C:15]([OH:20])(=[O:19])[C:16]([CH3:18])=O.Cl>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6]([C:5]([OH:12])=[O:13])[CH:18]=[C:16]2[C:15]([OH:20])=[O:19]
Reactant: [OH-]
Reactant: O=C1Nc2ccc(F)cc2C1=O
Reactant: CC(=O)C(=O)O
Agent: Cl
Agent: [K+]
Product: O=C(O)c1cc(C(=O)O)c2cc(F)ccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.5 %

Procedure:
5-Fluoroisatin (9.74 g) was added to a hot solution of 33% potassium hydroxide (29.1 g in 85 ml water). Pyruvic acid (9.25 g) was added, the mixture stirred at room temperature for 1 h and boiled for 1 h. The mixture was cooled to room temperature and acidified with c.HCl. After refridgerating overnight, the precipitated material was collected by filtration and dried in vacuo at 50° C. to give the title compound (14.5 g).