Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH:17]3[CH2:22][CH2:21][N:20](C#N)[CH2:19][CH2:18]3)=[N:9]2)=[CH:4][CH:3]=1.OS(O)(=O)=O.[OH-].[Na+]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: N#CN1CCC(c2nn(-c3ccc(F)cc3)c3ccccc23)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Fc1ccc(-n2nc(C3CCNCC3)c3ccccc32)cc1
Yield: 75.6 %

Procedure:
A stirred mixture of 4-[1-(4-fluorophenyl)-1H-indazol-3-yl]piperidine-1-carbonitrile of Example 102 (30 g, 0.094 moles) and 25% H2SO4 (225 ml) was refluxed for 20 hours. The mixture was cooled, poured into H2O, and basified with a 25% NaOH solution. The product was extracted (dichloromethane), dried (MgSO4), and concentrated to yield 21 g (76%) of 1-(4-fluorophenyl)-3-(4-piperidinyl)-1H-indazole as an oil. To a stirred suspension of the indazole (3.5 g, 0.012 moles) and triethylamine (3.3 ml, 0.012 moles) in toluene (50 ml) was added methyl chloroformate (1.0 ml 0.013 moles). The mixture was stirred for 17 hours at ambient temperature and was then poured into H2O. The product was extracted (ethyl acetate), dried (MgSO4), and concentrated to yield 4.6 g of an oil. The product was purified on the HPLC (silica gel:ethyl acetate-hexane, 1:2) which produced 3.0 g (72%) of 4-[1-(4-fluorophenyl)-1H-indazol-3-yl]piperidine-1-carboxylic acid methyl ester, m.p. 95°-97° C.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26](=[O:42])[C:27]3[CH:32]=[CH:31][C:30]([CH2:33][NH:34]C(OC(C)(C)C)=O)=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][C@H:9]1[OH:43])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O>[CH2:1]([C@H:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26](=[O:42])[C:27]3[CH:28]=[CH:29][C:30]([CH2:33][NH2:34])=[CH:31][CH:32]=3)=[CH:21][CH:20]=2)(=[O:17])=[O:18])[CH2:10][C@H:9]1[OH:43])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)Oc2ccc(S(=O)(=O)CCN3CC[C@H](Cc4ccccc4)[C@H](O)C3)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: NCc1ccc(C(=O)Oc2ccc(S(=O)(=O)CCN3CC[C@H](Cc4ccccc4)[C@H](O)C3)cc2)cc1
Yield: 67 %

Procedure:
A solution of 200 mg 4-(tert-butoxycarbonylamino-methyl)-benzoic acid (3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenyl ester in 3.8 ml TFA was stirred for 1 hour at 0° C. The solvent was removed under reduced pressure and the crude product was diluted in diethylether and 3 drops of a saturated HCl-solution in diethylether were added. Filtration yielded 120 mg (0.22 mmol, 67%) 4-aminomethyl-benzoic acid (3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenyl ester; hydrochloride(1:2) as colorless crystalls.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[OH:6][C:7]1[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=1[O:9][CH2:10][CH:11]1[NH:15][CH2:14][CH2:13][S:12]1>ClCCCl>[Cl:1][CH2:2][C:3]([N:15]1[CH2:14][CH2:13][S:12][CH:11]1[CH2:10][O:9][C:8]1[CH:16]=[CH:17][CH:18]=[CH:19][C:7]=1[OH:6])=[O:4]
Reactant: O=C(Cl)CCl
Reactant: Oc1ccccc1OCC1NCCS1
Solvent: ClCCCl
Product: O=C(CCl)N1CCSC1COc1ccccc1O
Temperature: -30 °C

Procedure:
Chloroacetylchloride (2.5 ml) is added to a stirred solution of 2-[(o-hydroxyphenoxy)methyl]thiazolidine (6 g) in 1,2-dichloroethane (80 ml) and triethilamine (4.3 ml) cooled at -30° C. After the usual work-up 3-α-chloroacetyl-2-[(o-hydroxyphenoxy)methyl]thiazolidine (5.7 g, from Et2O, m.p. 89°-91° C.) is obtained. A stirred solution of the latter compound in 1,2-dichloroethane (50 ml) is heated with solid potassium thioacetate (4 g). After 2 hours, the mixture is washed with water to give, after the usual work-up, 3-acetylthio-acetyl-2-[(o-hydroxyphenoxy)methyl]thiazolidine (6.4 g, from EtOH) m.p. 97°-99° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([O:14][C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29](O)=[O:30])[N:20]2[C:19]1=[O:32])=[O:16])([CH3:13])([CH3:12])[CH3:11].[S:33]1[CH:37]=[CH:36][N:35]=[C:34]1[NH2:38].ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C=O)C>[O:32]=[C:19]1[C@@H:18]([NH:17][C:15](=[O:16])[O:14][C:10]([CH3:11])([CH3:12])[CH3:13])[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29](=[O:30])[NH:38][C:34]3[S:33][CH:37]=[CH:36][N:35]=3)[N:20]12
Reactant: Nc1nccs1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCS[C@H]2CCC[C@@H](C(=O)O)N2C1=O
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CCS[C@H]2CCC[C@@H](C(=O)Nc3nccs3)N2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.2 %

Procedure:
DIPEA (0.036 mL, 0.21 mmol) was added to a cold (0° C.) mixture of (4S,7S,10aS)-4-(tert-butoxycarbonylamino)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylic acid (55 mg, 0.16 mmol), thiazol-2-amine (19.2 mg, 0.192 mmol) and 1-hydroxy-7-azabenzotriazole (26.1 mg, 0.192 mmol) in DMF (0.6 mL). Then EDC (36.7 mg, 0.192 mmol) was added. The reaction was stirred at rt for 8 hr. The crude mixture was purified by RP prep-HPLC (Method B) to give tert-butyl (4S,7S,10aS)-5-oxo-7-(thiazol-2-ylcarbamoyl)octahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamate (35 mg, 0.082 mmol, 51% yield) as a white solid. Anal. Calcd. for C18H26N4O4S2 m/z 426.5. found: 427.1 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.45 (s, 1H), 6.98 (s, 1H), 5.96 (m, 1H), 5.37 (br s, 1H), 5.28 (br s, 1H), 3.35 (m, 2H), 2.94 (m, 2H), 2.36 (m, 1H), 2.45 (m, 1H), 2.05 (m, 2H), 1.53-1.50 (m, 4H), 1.50 (s, 9H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([C@H:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)=O.CO>C1COCC1>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C@H:9]1[CH2:13][CH2:12][NH:11][CH2:10]1
Reactant: C[C@H]1CCCN1C(=O)[C@H]1CCNC1
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H]1CCCN1C[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 118.9 %

Procedure:
To a solution of (2S,3S)-(2-Methyl-pyrrolidin-1-yl)-pyrrolidin-3-yl-methanone (2.3 mmol, as obtained above) in dry THF (6 mL) was added drop-wise 2 M solution of BH3SMe2 in THF (2M in THF, 5 mL, 10 mmol, 4 equiv.). The mixture was refluxed for 2 h. The solution was cooled to rt, 5 mL of methanol was added and stirred for 2 h at r.t. The solvent was evaporated to dryness to obtain 0.46 g of the title product as a semi-solid. LC/MS showed the molecular ion peak of the title compound at 169 (M+H) with a retention time of 1.742 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].C(O)C.Cl.[NH2:16][OH:17]>O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[N:16][OH:17])([O-:3])=[O:2]
Reactant: NO
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cccc(C=NO)c1

Procedure:
To a solution of 3-nitrobenzaldehyde (5.0 g; 33.1 mmol) in abs. ethanol (40 ml) was added hydroxylamine, hydrochloride (3.45 g; 49.6 mmol) and the resulting suspension was heated to reflux overnight. The cooled mixture was poured into water (100 ml) and the product was filtered off and dried. Yield: 4.5 g (82%).
Reaction SMILES: C(S[C:4]1[S:5][C:6](=[CH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([OH:30])([CH3:29])[CH3:28])=[CH:23][C:22]=2[C:31]([F:34])([F:33])[F:32])[N:15]=[CH:14]3)[C:7](=[O:9])[N:8]=1)C.[CH3:35][C@@H:36]1[CH2:41][NH:40][CH2:39][C@H:38]([CH3:42])[NH:37]1>>[CH3:35][C@H:36]1[NH:37][C@@H:38]([CH3:42])[CH2:39][N:40]([C:4]2[S:5][C:6](=[CH:10][C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[N:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([OH:30])([CH3:28])[CH3:29])=[CH:23][C:22]=3[C:31]([F:32])([F:33])[F:34])[N:15]=[CH:14]4)[C:7](=[O:9])[N:8]=2)[CH2:41]1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(C)(C)O)cc3C(F)(F)F)c2)S1
Reactant: C[C@@H]1CNC[C@H](C)N1
Product: C[C@@H]1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(C)(C)O)cc4C(F)(F)F)c3)S2)C[C@H](C)N1

Procedure:
2-((3R,5S)-3,5-Dimethylpiperazin-1-yl)-5-({1-[4-(1-hydroxy-1-methylethyl)-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazol-4(5H)-one was prepared from 2-Ethylsulfanyl-5-{1-[4-(1-hydroxy-1-methyl-ethyl)-2-trifluoromethyl-benzyl]-1H-indazol-5-ylmethylene}-thiazol-4-one and (2R,6S) 2,6-Dimethyl-piperazine following General Procedure C.
Reaction SMILES: Cl.Cl.[CH:3]1([NH:6][C:7]([C:9]2[C:17]3[CH:16]=[C:15]([C:18]4[C:23]([Cl:24])=[CH:22][N:21]=[C:20]([NH:25][CH2:26][CH2:27][CH2:28][C:29]5([CH2:35][CH3:36])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)[N:19]=4)[S:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[O:8])CC1.CNC(C1C2C=C(C3C([Cl:56])=CN=C(Cl)N=3)SC=2C=CC=1)=O.C(OC(N1CCC(CCCN)(CC)CC1)=O)(C)(C)C>>[ClH:24].[ClH:56].[CH3:3][NH:6][C:7]([C:9]1[C:17]2[CH:16]=[C:15]([C:18]3[C:23]([Cl:24])=[CH:22][N:21]=[C:20]([NH:25][CH2:26][CH2:27][CH2:28][C:29]4([CH2:35][CH3:36])[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]4)[N:19]=3)[S:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: CNC(=O)c1cccc2sc(-c3nc(Cl)ncc3Cl)cc12
Reactant: CCC1(CCCNc2ncc(Cl)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CCNCC1
Agent: CCC1(CCCN)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Product: CCC1(CCCNc2ncc(Cl)c(-c3cc4c(C(=O)NC)cccc4s3)n2)CCNCC1

Procedure:
Using the method of 2-{5-chloro-2-[3-(4-ethylpiperidin-4-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide di-hydrochloride, the title compound is synthesized from 2-(2,5-dichloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid methylamide and 4-(3-aminopropyl)-4-ethylpiperidine-1-carboxylic acid tert-butyl ester and isolated as a solid. ES+(m/z) 472 (35Cl) and 474 (37Cl) [M(free base)+H].
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][C@H:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CS(C)=O>[F:1][C:2]1[C:3]([N:25]2[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]2)=[C:4]2[O:9][CH2:8][C@H:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23
Reactant: CN1CCNCC1
Reactant: C[C@H]1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Solvent: CS(C)=O
Product: C[C@H]1COc2c(N3CCN(C)CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Temperature: 135 °C
Reaction time: 1 h
Yield: 51.9 %

Procedure:
(S)-(−)-9,10-Difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid (21 mg) and N-methylpiperazine (30 mg) were dissolved in anhydrous dimethyl sulfoxide (3 ml) and stirred at 130 to 140° C. for 1 hour. After evaporating the solvent, ethanol (2 ml) was added to the residue. The solid thus precipitated was collected by filtration and washed successively with a small amount of ethanol and ether. 14 mg of the obtained powder was subjected to silica gel column chromatography with the use of 5 g of silica gel and eluted with a lower layer solution of chloroform-methanol-water (7:3:1) to thereby give (S)-(−)-9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid. The above-described filtration mother liquor was fractioned and subjected to thin layer chromatography (silica gel, 20×20 cm, 0.5 mm), thereby purifying by developing with a lower layer solution of chloroform-methanol-water (15:3:1). The products were combined to thereby give 14 mg of crystals of the target compound. Melting point: 220 to 228° C. (decomposition).
Reaction SMILES: [C@H:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[Cl:12][C:13]1[CH:18]=[N:17][CH:16]=[C:15](Cl)[N:14]=1>>[Cl:12][C:13]1[N:14]=[C:15]([NH:11][C@H:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)[CH:16]=[N:17][CH:18]=1
Reactant: Clc1cncc(Cl)n1
Reactant: N[C@@H]1CCCc2ccccc21
Product: Clc1cncc(N[C@@H]2CCCc3ccccc32)n1
Yield: 73.7 %

Procedure:
In a procedure analogous to Example 1, reaction of (1R)-1,2,3,4-tetrahydronaphthalen-1-amine (441 mg, 3.0 mmol) and 2,6-dichloropyrazine (0.4055 g, 2.72 mmol) furnished the product (521 mg, 74%).
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH2:16])=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5])C.[H-].[Na+].[N-:19]=[C:20]=[O:21].[N-]=C=S>CN(C=O)C.O>[NH:16]1[C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[C:4](=[O:5])[NH:19][C:20]1=[O:21]
Reactant: [N-]=C=O
Reactant: CCOC(=O)c1cnc2ccccc2c1N
Agent: [H-]
Agent: [N-]=C=S
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c(=O)c2cnc3ccccc3c2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of a 4-amino-quinoline-3-carboxylic acid ethyl ester derivative (0.50 mmol) in 10 mL anhydrous DMF is added sodium hydride (4 eq., 2.0 mmol) and stirred at room temperature for 30 min. To this solution an isocyanate or isothiocyanate (1.5-4 eq. 2.0 mmol) is added. The resulting reaction mixture is stirred for 18 h at room temperature or at 100° C. After completion of the reaction, the mixture is poured into water (20 mL) and extracted with ethyl acetate (2×25 mL). The organic extracts are combined, washed with water (2×25 mL), brine (2×25 mL), dried over Na2SO4 and concentrated in vacuo to give the crude product. The residue is then purified by silica gel chromatography using dichloromethane-ethyl acetate to provide desired 1H-pyrimido[5,4-c]quinoline-2,4-dione or thio-ketone derivative.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:39])=[C:5]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]2C(=O)C3=CC=CC=C3C2=O)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])[C:7]=1[C:8]([O:10][CH3:11])=[O:9].O.NN>>[CH3:1][C:2]1[NH:3][C:4]([CH3:39])=[C:5]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][NH2:28])=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCN2C(=O)c3ccccc3C2=O)C1c1ccccc1[N+](=O)[O-]
Agent: NN
Solvent: O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCN)C1c1ccccc1[N+](=O)[O-]
Yield: 77.8 %

Procedure:
Prepared by a method analogous to that of Example 1(b) from 27.0 g (51 mmol) of 1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(2-nitrophenyl)-5-(4-phthalimidobutoxy)carbonyl-pyridine and 7.4 ml (152 mmol) of hydrazine hydrate. 16.0 g (78%) of an orange yellow oil obtained after chromatographic purification on silica gel with dichloromethane/methanol (95:5) as solvent.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH:4]1[O:8][C:7](C)(C)[O:6][C:5]1=[O:11].CC1C=CC(S(O)(=O)=O)=CC=1.O.CO>C1(C)C=CC=CC=1>[CH3:7][O:6][C:5](=[O:11])[CH:4]([OH:8])[CH2:3][CH2:2][Br:1]
Reactant: CC1(C)OC(=O)C(CCBr)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C(O)CCBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To a solution of 5-(2-bromo-ethyl)-2,2-dimethyl-[1,3]dioxolan-4-one (synthesized as instructed in Tetrahedron Letters, 1997, 38, 28, 4935) (93 mg, 0.416 mmol) in toluene (0.5 mL) were added p-TsOH.H2O (8 mg, 0.0415 mmol) and methanol (0.5 mL), followed stirring overnight at room temperature. The solution was concentrated in a vacuum, diluted with dichloromethane and washed with an aqueous saturated sodium bicarbonate solution. The organic layer thus formed was dried over sodium sulfate and filtered. The filtrate was concentrated to produce 68 mg of the compound as an oil. 1H NMR (300 MHz, CDCl3) δ 1.98 (1H, m), 2.34 (1H, m), 2.96 (1H, d), 3.56 (2H, m), 3.82 (3H, s), 4.37 (1H, pentet).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[NH:24][C:25]([NH:27][CH:28]1[CH2:30][CH2:29]1)=[O:26])[O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[C:13]([C:16]([OH:18])=O)[CH:14]=2)[N:9]=[CH:8][CH:7]=1.Cl.C(N=C=N[CH2:37][CH2:38][CH2:39][N:40](C)C)C.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.C1(N)CC1>CN(C)C=O.O.C(OCC)(=O)C>[CH:39]1([NH:40][C:16]([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][C:12]=2[O:19][CH3:20])[N:9]=[CH:8][CH:7]=[C:6]3[O:5][C:4]2[CH:21]=[CH:22][C:23]([NH:24][C:25]([NH:27][CH:28]3[CH2:29][CH2:30]3)=[O:26])=[C:2]([Cl:1])[CH:3]=2)=[O:18])[CH2:37][CH2:38]1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)c2cc1C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NC1CC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)c2cc1C(=O)NC1CC1
Yield: 43 %

Procedure:
After dissolving 4-(3-chloro-4-(((cyclopropylamino) carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylic acid (86 mg, 0.20 mmol) in dimethylformamide (2 ml), there were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (77 mg, 0.40 mmol), 1-hydroxy-1H-benzotriazole monohydrate (61 mg, 0.40 mmol), triethylamine (0.112 ml, 0.80 mmol) and cyclopropylamine (0.055 ml) while stirring on ice, and the mixture was stirred overnight at room temperature. The reaction solution was distributed between ethyl acetate and water, and the organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was suspended in ethyl acetate and diluted with hexane, and the crystals were filtered out and blow-dried to obtain the title compound (40.0 mg, 0.086 mmol, 42.6%) as white crystals.
Reaction SMILES: [CH:1]([C:4]1[N:8]2[N:9]=[C:10]([CH:13]=[N:14][CH3:15])[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1)([CH3:3])[CH3:2].[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[CH:24]([N+:35]#[C-:36])S(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[C:24]1[N:35]=[CH:36][N:14]([CH3:15])[C:13]=1[C:10]1[CH:11]=[CH:12][C:7]2[N:8]([C:4]([CH:1]([CH3:2])[CH3:3])=[N:5][N:6]=2)[N:9]=1
Reactant: [C-]#[N+]C(c1ccc(F)cc1F)S(=O)(=O)c1ccc(C)cc1
Reactant: CN=Cc1ccc2nnc(C(C)C)n2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1nnc2ccc(-c3c(-c4ccc(F)cc4F)ncn3C)nn12
Temperature: 60 °C
Yield: 23.1 %

Procedure:
N-((3-Isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)methylene)methanamine (0.154 g, 0.758 mmol; Preparation #AP.1.1) and 2,4-difluoro-1-(isocyano(tosyl)methyl)benzene (0.233 g, 0.758 mmol, J. W. Pharmlab) were added to a 25 mL flask in DMF (4 mL). To the mixture was added K2CO3 (0.105 g, 0.758 mmol) and the mixture was heated to about 60° C. for about 17 h. The solvent was removed in vacuo and the material was washed with saturated aqueous NaHCO3 (10 mL) and extracted with EtOAc (15 mL), dried over MgSO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (using MeOH/DCM 0-5% gradient) and then triturated with Et2O and dried in a vacuum oven overnight to afford the title compound as an off-white solid (0.062 g, 23%): LC/MS (Table 1, Method g) Rt=2.03 min; MS m/z: 355.2 (M+1)+.
Reaction SMILES: I[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]2[N:18]3[CH:19]=[CH:20][C:21]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:3]=1.O1C=C[CH:30]=[C:29]1P(C1OC=CC=1)C1OC=CC=1.C([Sn](CCCC)(CCCC)C=C)CCC>CN1C(=O)CCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:13][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([C:14]1[N:18]3[CH:19]=[CH:20][C:21]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:22][C:17]3=[N:16][CH:15]=1)[CH:3]=[C:2]2[CH:29]=[CH2:30]
Reactant: COCCOc1ccn2c(-c3cc(I)c4cccc(OC)c4n3)cnc2c1
Reactant: c1coc(P(c2ccco2)c2ccco2)c1
Agent: [Pd]
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN1CCCC1=O
Product: C=Cc1cc(-c2cnc3cc(OCCOC)ccn23)nc2c(OC)cccc12
Temperature: 80 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To 4-iodo-8-methoxy-2-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)quinoline (898 mg, 1.89 mmol) in NMP (10 mL) was added Pd2dba3 (87 mg, 0.09 mmol), trifuran-2-ylphosphine (88 mg, 0.37 mmol) and tributyl(vinyl)stannane (659 mg, 2.1 mmol). The reaction flask was purged with N2 and the reaction was stirred at 80° C. for 2 hours. The crude mixture was diluted with EtOAc (30 mL) then washed with H2O, dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography (EtOAc/Hexane 8:1) affording the desired product (80%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[NH:10][C:11](=[O:19])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:28][O:29][C:30]1[C:31](=O)[C:32](=[O:36])[C:33]=1[O:34]C>>[CH3:28][O:29][C:30]1[C:33](=[O:34])[C:32](=[O:36])[C:31]=1[NH:2][C:3]1[CH:4]=[C:5]([CH:9]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[NH:10][C:11](=[O:19])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc(C(NC(=O)c2cccc(F)c2)c2cccc(N)c2)cc1
Reactant: COc1c(OC)c(=O)c1=O
Agent: Cl
Product: COc1ccc(C(NC(=O)c2cccc(F)c2)c2cccc(Nc3c(OC)c(=O)c3=O)c2)cc1
Yield: 98.1 %

Procedure:
In a similar manner to that described in Example (46e) N-[(3-aminophenyl)-(4-methoxyphenyl)methyl]-3-fluorobenzamide hydrochloride (244 mg) [prepared as described in step (b) above] and 3,4-dimethoxy-3-cyclobutene-1,2-dione (107 mg) were reacted, to afford the title compound (285 mg) as a white solid.
Reaction SMILES: [Si]([O:18][CH:19]1[C:28]2[C:23](=[N:24][C:25]([CH:29]([O:32][CH3:33])[O:30][CH3:31])=[CH:26][CH:27]=2)[N:22]([C:34]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][N:38]=2)=[O:35])[CH2:21][CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:43]([C:40]1[CH:41]=[CH:42][C:37]([NH:36][C:34]([N:22]2[C:23]3[C:28](=[CH:27][CH:26]=[C:25]([CH:29]([O:32][CH3:33])[O:30][CH3:31])[N:24]=3)[CH:19]([OH:18])[CH2:20][CH2:21]2)=[O:35])=[N:38][CH:39]=1)#[N:44]
Reactant: COC(OC)c1ccc2c(n1)N(C(=O)Nc1ccc(C#N)cn1)CCC2O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(OC)c1ccc2c(n1)N(C(=O)Nc1ccc(C#N)cn1)CCC2O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (racemic) 4-((tert-butyldiphenylsilyl)oxy)-N-(5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 37Y, 30 mg, 0.049 mmol) in THF (0.3 ml) was treated with TBAF (1 M in THF, 0.054 ml, 0.054 mmol) and stirred at room temperature for 2 h. The reaction mixture was partitioned between DCM and sat. aq. NaHCO3. The aq. layer was extracted with DCM (2×). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum. The crude material was purified by normal phase chromatography (4 g silica gel cartridge, heptanes/EtOAc 100:0 to 10:90) to give the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 13.93 (s, 1H), 8.76-8.81 (m, 1H), 8.19-8.27 (m, 2H), 7.95 (d, 1H), 7.26 (d, 1H), 5.71 (d, 1H), 5.39 (s, 1H), 4.67-4.75 (m, 1H), 3.96-4.01 (m, 2H), 3.38 (d, 6H), 2.01-2.10 (m, 1H), 1.79-1.90 (m, 1H).