Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][NH:2][C:3]([CH:5]1[CH2:7][CH2:6]1)=[NH:4].[H-].[Na+].[C:10]([O:14][C:15]([NH:17][CH2:18][CH2:19][C:20](OCC)=O)=[O:16])([CH3:13])([CH3:12])[CH3:11].O>CN(C)C=O>[CH:5]1([C:3]2[N:4]=[C:20]([CH2:19][CH2:18][NH:17][C:15](=[O:16])[O:14][C:10]([CH3:13])([CH3:12])[CH3:11])[O:1][N:2]=2)[CH2:7][CH2:6]1
Reactant: CCOC(=O)CCNC(=O)OC(C)(C)C
Reactant: N=C(NO)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCc1nc(C2CC2)no1
Temperature: 50 °C
Reaction time: 0.1 h

Procedure:
3.10 g (30.96 mmol) N-hydroxy-cyclopropanecarboxamidine are placed in 10 ml dimethylformamide and molecular sieve. 1.32 g (34.06 mmol) sodium hydride (60% in mineral oil) are added. The mixture is stirred for 0.1 hours at 50° C., then 7.40 g (34.06 mmol) ethyl 3-tert-butoxycarbonylamino-propionate in 20 ml dimethylformamide are added. The reaction mixture is stirred for 3 hours at 50° C. After cooling 15 ml of water are added, the mixture is suction filtered through Celite. The 2 phases of the filtrate are separated, the aqueous phase is extracted with ethyl acetate, the combined organic phase is evaporated down. The residue is purified by chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[N:11][C:10]2[C:9]([CH:15]=O)=[CH:8][C:7]([N+:17]([O-:19])=[O:18])=[CH:6][C:5]=2[N:4]=1.[NH2:20][CH:21]([P:23](=[O:28])([O:26][CH3:27])[O:24][CH3:25])[CH3:22].S([O-])([O-])(=O)=O.[Mg+2].C(O)(=O)C.C([O-])(=O)C.[Na+].C([BH3-])#N.[Na+].Cl>CS(C)=O>[N+:17]([C:7]1[CH:6]=[C:5]2[C:10]([N:11]=[C:12]([O:13][CH3:14])[C:3]([O:2][CH3:1])=[N:4]2)=[C:9]([CH2:15][NH:20][CH:21]([P:23](=[O:28])([O:26][CH3:27])[O:24][CH3:25])[CH3:22])[CH:8]=1)([O-:19])=[O:18]
Reactant: COP(=O)(OC)C(C)N
Reactant: COc1nc2cc([N+](=O)[O-])cc(C=O)c2nc1OC
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: COc1nc2cc([N+](=O)[O-])cc(CNC(C)P(=O)(OC)OC)c2nc1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
150 mg (0.569 mmol) of 2,3-dimethoxy-7-nitroquinoxaline-5-carbaldehyde, 90 mg (1.04 eq.) of dimethyl α-aminoethylphosphonate and 500 mg (7.3 eq.) of magnesium sulfate are dissolved in 5 ml of DMSO and stirred at room temperature for 24 hours. The reaction mixture is filtered off, the filtrate is evaporated and the residue is dissolved in 5 ml of methanol. 0.027 ml (1 eq.) of acetic acid, 78 mg (2 eq.) of sodium acetate and 36 mg (1.2 eq.) of sodium cyanoborohydride are added and the mixture is stirred at room temperature for 48 hours. The reaction mixture is treated with 1N hydrochloric acid, stirred for 30 minutes and then washed with diethyl ether. The aqueous phase is rendered basic with a 2N sodium hydroxide solution and extracted with ethyl acetate. The combined ethyl acetate phases are dried using brine and magnesium sulfate and evaporated. The title compound is obtained as a yellow resin.
Reaction SMILES: [NH2:1][C:2]([N:4]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:24]=1[C:33]([F:36])([F:35])[F:34])[CH2:5][CH2:6][C:7]1[CH:21]=[CH:20][C:10]([O:11][C:12]([CH3:19])([CH3:18])[C:13]([O:15]CC)=[O:14])=[CH:9][CH:8]=1)=[S:3].[Cl:37][C:38]1[CH:47]=[CH:46][CH:45]=[CH:44][C:39]=1[C:40](=O)[CH2:41]Br>>[F:35][C:33]([F:34])([F:36])[C:24]1[CH:25]=[C:26]([C:29]([F:32])([F:31])[F:30])[CH:27]=[CH:28][C:23]=1[CH2:22][N:4]([C:2]1[S:3][CH:41]=[C:40]([C:39]2[CH:44]=[CH:45][CH:46]=[CH:47][C:38]=2[Cl:37])[N:1]=1)[CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:11][C:12]([CH3:19])([CH3:18])[C:13]([OH:15])=[O:14])=[CH:20][CH:21]=1
Reactant: O=C(CBr)c1ccccc1Cl
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)C(N)=S)cc1
Product: CC(C)(Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c2nc(-c3ccccc3Cl)cs2)cc1)C(=O)O

Procedure:
Similarly prepared from ethyl 2-[4-(2-{(aminocarbonothioyl)[2,4-bis(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate and 2-chlorophenacyl bromide.
Reaction SMILES: Br.[Cl:2][C:3]1[C:4]([O:24]C)=[N:5][C:6](/[C:9](/[C:16]2[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=2)=[CH:10]/[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:8]=1.O>O1CCOCC1>[Cl:2][C:3]1[C:4](=[O:24])[NH:5][C:6](/[C:9](/[C:16]2[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=2)=[CH:10]/[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:8]=1
Reactant: COc1nc(/C(=C/C2CCCC2)c2ccc(SC)cc2)ccc1Cl
Agent: Br
Solvent: C1COCCO1
Solvent: O
Product: CSc1ccc(/C(=C\C2CCCC2)c2ccc(Cl)c(=O)[nH]2)cc1
Temperature: 85 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
48% hydrobromic acid (1.5 mL) was added to a solution of 3-chloro-6-{(E)-2-cyclopentyl-1-[4-(methylsulfanyl)phenyl]ethenyl}-2-methoxypyridine (250 mg) in 1,4-dioxane (1.5 mL), and the mixture was stirred at 85° C. for one hour. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered, after which the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=9:1) to give a pale brown oil. This was powdered with a hexane/ethyl acetate solution, and filtration operation gave the title compound as a pale brown powder (230 mg, 71%).
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([C:23]([OH:25])=O)[N:18]=2)[CH2:13][CH2:12]1.Cl.Cl.[CH3:28][C:29]1([CH3:38])[CH2:34][NH:33][CH2:32][C:31]2[CH:35]=[N:36][NH:37][C:30]1=2.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:28][C:29]1([CH3:38])[CH2:34][N:33]([C:23]([C:19]2[N:18]=[C:17]([N:14]3[CH2:15][CH2:16][CH:11]([N:3]4[C:4]5[C:5](=[N:6][CH:7]=[CH:8][CH:9]=5)[NH:10][C:2]4=[O:1])[CH2:12][CH2:13]3)[CH:22]=[CH:21][N:20]=2)=[O:25])[CH2:32][C:31]2[CH:35]=[N:36][NH:37][C:30]1=2
Reactant: O=C(O)c1nccc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)n1
Reactant: CC1(C)CNCc2cn[nH]c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C)CN(C(=O)c2nccc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)n2)Cc2cn[nH]c21

Procedure:
60 mg (0.18 mmol) 4-[4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-2-carboxylic acid, 40 mg (0.18 mmol) 7,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine dihydrochloride, 0.10 (0.72 mmol) triethylamine and 62 (0.19 mmol) TBTU in 1.5 mL DMF were stirred overnight at RT. The reaction mixture was purified by HPLC. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:22][C:23]#[N:24])[C:15]=2[C:14]2[C:9]1=[CH:10][C:11]([O:25][CH3:26])=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>C1COCC1>[CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:22][CH2:23][NH2:24])[C:15]=2[C:14]2[C:9]1=[CH:10][C:11]([O:25][CH3:26])=[CH:12][CH:13]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c3c(OCC#N)cccc3n(Cc3ccccc3)c2c1
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c3c(OCCN)cccc3n(Cc3ccccc3)c2c1
Temperature: 40 °C
Yield: 57.7 %

Procedure:
To a mixture of [(9-benzyl-7-methoxy-9H-carbazol-4-yl)oxy]acetonitrile (0.9 g, 2.6 mmol) in dry THF (50 mL) is added borane-methylsulfide complex (0.75 mL, 7.9 mmol). The mixture is heated at 40° C. overnight. Methanol is slowly added to mixture until addition of methanol did not evolve gas. The solvents are removed under reduced pressure. Methanol (50 mL) is added to the residue then removed under reduced pressure. Methanol (100 mL) and concentrated hydrochloric acid (3 mL) is added to the residue. The mixture is heated at 75° C. for 2.5 h. The mixture is neutralized with saturated potassium carbonate and partitioned between water and ethyl acetate. The layers are separated and the organic layer washed twice with brine. The organic layer is dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography, silica gel (100 mL) using CH2Cl2: CH3OH (95:5) as eluent gave 0.52 g (58%) of the title compound; 1H NMR (DMSO-d6) δ2.48, 3.8, 4.12, 5.59, 6.69, 6.8, 7.14, 7.2, 8.03; Anal. Calcd for C22H22N2O2: C, 76.28; H, 6.40; N, 8.09. Found: C, 76.00; H, 6.54; N, 7.92.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8]([OH:10])=O)[N:6]=1.C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.[NH2:28][C@@H:29]1[C:57](=[O:58])[N:31]2[C:32]([C:45]([O:47][CH2:48][C:49]3[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=3)=[O:46])=[C:33]([C@@H:36]3[C:40](=[C:41]=[O:42])[CH2:39][C@H:38]([O:43][CH3:44])[O:37]3)[CH2:34][S:35][C@H:30]12>CN(C)C=O.N1C=CC=CC=1>[CH3:44][O:43][C@@H:38]1[O:37][C@H:36]([C:33]2[CH2:34][S:35][C@@H:30]3[C@H:29]([NH:28][C:8](=[O:10])/[C:7](/[C:5]4[N:6]=[C:2]([NH2:1])[S:3][CH:4]=4)=[N:11]\[O:12][CH3:13])[C:57](=[O:58])[N:31]3[C:32]=2[C:45]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)=[O:46])[C:40](=[C:41]=[O:42])[CH2:39]1
Reactant: CO/N=C(\C(=O)O)c1csc(N)n1
Reactant: COc1ccc(COC(=O)C2=C([C@H]3O[C@@H](OC)CC3=C=O)CS[C@@H]3[C@H](N)C(=O)N23)cc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C([C@H]3O[C@@H](OC)CC3=C=O)CS[C@H]12)c1csc(N)n1
Reaction time: 0.5 h
Yield: 53.6 %

Procedure:
A stirred solution of 2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetic acid (20.1 mg) and N,N-diisopropylethylamine (0.0176 ml) in dimethylformamide (0.3 ml) was cooled to -55 to -60° C. and methanesulphonyl chloride (0.0081 ml) was added. The mixture was stirred at the same temperature for 0.5 h and then a solution of 4-methoxybenzyl (6R,7R)-7-amino-3-[(2S,5R)-5-methoxy-carbonyltetrahydrofuran-2-yl]ceph-3-em-4-carboxylate (41 mg) in dimethylformamide (0.3 ml) was added followed by pyridine (0.0073 ml). The mixture was then stored at 0° C. for 1 h and then at room temperature for 0.5 h. The reaction mixture was partitioned between ethyl acetate and aqueous citric acid solution and the organic phase washed with water and brine. The solution was dried over magnesium sulphate and evaporated, and the title compound (31 mg) isolated by column chromatography of the residue (silica gel, ethyl acetate as eluent); νmax (CHCl3) 3496, 3397, 1784, 1733 and 1684 cm-1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([F:31])[CH:25]=1>>[F:31][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][C:27]=1[CH3:30])[CH2:23][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: Cc1ccc(CBr)cc1F
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: Cc1ccc(CN2CCC3(CC2)CSC2=C(O3)c3ccccc3C(=O)C2=O)cc1F

Procedure:
Compound 146 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 4-(bromomethyl)-2-fluoro-1-methylbenzene and conditions outlined in procedure V. LCMS: 424 [M+H]; Rt=1.03 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[CH3:9][C:10]1([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[O:11]1.N12CCCN=C1CCCCC2.[Cl-].[Na+]>C(O)C>[CH3:9][C:10]1([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[C:14](=[O:15])[CH:13]=[C:12]([CH:16]=[CH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[O:11]1
Reactant: O=Cc1ccccn1
Reactant: CC1=CC(=O)C(C)(c2ccc(F)cc2)O1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: CC1(c2ccc(F)cc2)OC(C=Cc2ccccn2)=CC1=O
Temperature: 80 °C
Yield: 59.4 %

Procedure:
To a solution of 2-pyridinecarboxaldehyde (1.26 g, 10.2 mM) and 2,5-dimethyl-2-(4-fluorophenyl)-3(2H)-furanone (2.0 g, 9.8 mM) in ethanol (100 mL), was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.2 mL, 1.3 mM). The reaction solution was heated at 80° C. for 4 hours. After the reaction solution cooled to room temperature, saturated aqueous sodium chloride (400 mL) was added. The aqueous layer was extracted with diethyl ether (3×100 mL). The combined ethereal extracts were washed with saturated aqueous sodium chloride (50 mL), dried over MgSO4, filtered and concentrated to give a yellow liquid. The crude product was purified by chromatography (silica gel, pet. ether-ethyl acetate) to yield a yellow solid (1.7 g, 59% yield), m.p. 70°-72° C.
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][CH3:13])=[C:10]([Cl:14])[C:9]2[C:4](=[CH:5][C:6]([F:16])=[CH:7][C:8]=2[F:15])[N:3]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]1=[O:23]>>[Cl:14][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:16])=[CH:7][C:8]=2[F:15])[N:3]=[C:2]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C:18]2=[O:23])[C:11]=1[CH2:12][CH3:13]
Reactant: CCc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: O=C1CCCCN1
Product: CCc1c(N2CCCCC2=O)nc2cc(F)cc(F)c2c1Cl

Procedure:
Prepared according to Procedure I using 2,4-dichloro-5,7-difluoro-3-ethylquinoline (400 mg, 1.50 mmol) and piperidin-2-one to give 1-(4-chloro-3-ethyl-5,7-difluoroquinolin-2-yl)piperidin-2-one. Mass Spectrum (ESI) m/e=325.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[N:8]1[CH:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[S:19][C:7]1=[C:6]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:5]2=[O:32].F[C:34]1C=C2C(=CC=1N1CCNC(C)C1)N1C(C3C=CC(F)=CC=3)SC1=C(C(OCC)=O)C2=O.FC1C=C2C(=CC=1N1CCN(C)C(C)C1)N1C(C3C=CC(F)=CC=3)SC1=C(C(OCC)=O)C2=O.ClC1C=CC(C2N3C4C(C(=O)C(C(OCC)=O)=C3S2)=CC(F)=C(N2CCN(C)CC2)C=4)=CC=1.ClC1C=CC(C2N3C4C(C(=O)C(C(OCC)=O)=C3S2)=CC(F)=C(N2CCNCC2)C=4)=CC=1.ClC1C=CC(C2N3C4C(C(=O)C(C(OCC)=O)=C3S2)=CC(F)=C(N2CCNC(C)C2)C=4)=CC=1.ClC1C=CC(C2N3C4C(C(=O)C(C(OCC)=O)=C3S2)=CC(F)=C(N2CCN(C)C(C)C2)C=4)=CC=1.FC1C=C2C(=C(OC)C=1N1CCNCC1)N1C(C)SC1=C(C(O)=O)C2=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH2:13][CH2:14][N:15]([CH3:34])[CH2:16][CH2:17]1)[N:8]1[CH:18]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[S:19][C:7]1=[C:6]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:5]2=[O:32]
Reactant: CCOC(=O)c1c2n(c3cc(N4CCNCC4)c(F)cc3c1=O)C(c1ccc(F)cc1)S2
Reactant: CCOC(=O)c1c2n(c3cc(N4CCNC(C)C4)c(F)cc3c1=O)C(c1ccc(F)cc1)S2
Agent: CCOC(=O)c1c2n(c3cc(N4CCN(C)C(C)C4)c(F)cc3c1=O)C(c1ccc(Cl)cc1)S2
Agent: CCOC(=O)c1c2n(c3cc(N4CCN(C)C(C)C4)c(F)cc3c1=O)C(c1ccc(F)cc1)S2
Agent: CCOC(=O)c1c2n(c3cc(N4CCN(C)CC4)c(F)cc3c1=O)C(c1ccc(Cl)cc1)S2
Product: CCOC(=O)c1c2n(c3cc(N4CCN(C)CC4)c(F)cc3c1=O)C(c1ccc(F)cc1)S2

Procedure:
ethyl 6-fluoro-1-(4-fluorophenyl)-4-oxo-7-(1-piperazinyl)-4H-(1,3)thiazeto(3,2-a)quinoline-3-carboxylate; ethyl 6-fluoro-1-(4-fluorophenyl)-7-(3-methyl-1-piperazinyl)-4-oxo-4H-(1,3)thiazeto(3,2-a)quinoline-3-carboxylate; ethyl 6-fluoro-1-(4-fluorophenyl)-7-(3,4-dimethyl-1-piperazinyl)-4-oxo-4H-(1,3)thiazeto(3,2-a)quinoline-3-carboxylate; ethyl 1-(4-chlorophenyl)-6-fluoro-7-(4-methyl-1-piperazinyl)-4-oxo-4H-(1,3)thiazeto(3,2-a)quinoline-3-carboxylate; ethyl 1-(4-chlorophenyl)-6-fluoro-4-oxo-7-(1-piperazinyl)-4H-(1,3)thiazeto(3,2-a)quinoline-3-carboxylate; ethyl 1-(4-chlorophenyl)-6-fluoro-7-(3-methyl-1-piperazinyl)-4-oxo-4H-(1,3)thiazeto(3,2-a)quinoline-3-carboxylate; ethyl 1-(4-chlorophenyl)-6-fluoro-7-(3,4-dimethyl-1-piperazinyl)-4-oxo-4H-(1,3)thiazeto(3,2-a)quinoline-3-carboxylate; and 6-fluoro-8-methoxy-1-methyl-4-oxo-7 (1piperazinyl)-4H-(1,3)thiazeto(3,2-a)quinoline-3-carboxylic acid (ethyl ester, m.p. 190° C. (decompn.)).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH:13][CH2:14][C:15]3[C:16](=[O:25])[NH:17][C:18]([CH3:24])=[CH:19][C:20]=3[CH2:21][CH2:22][CH3:23])=[O:12])[CH:10]=1)[N:7]([CH3:26])[CH:6]=[C:5]2[CH:27]([CH3:29])[CH3:28].Cl.[CH3:31][N:32]([CH2:34][C:35]1[CH:36]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:38]=[CH:39][CH:40]=1)[CH3:33]>>[CH3:31][N:32]([CH2:34][C:35]1[CH:40]=[C:39]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([C:11]([NH:13][CH2:14][C:15]4[C:16](=[O:25])[NH:17][C:18]([CH3:24])=[CH:19][C:20]=4[CH2:21][CH2:22][CH3:23])=[O:12])[CH:10]=2)[N:7]([CH3:26])[CH:6]=[C:5]3[CH:27]([CH3:28])[CH3:29])[CH:38]=[CH:37][CH:36]=1)[CH3:33]
Reactant: CN(C)Cc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c(C(C)C)cn(C)c12
Agent: Cl
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2cccc(CN(C)C)c2)cc2c(C(C)C)cn(C)c12
Yield: 63 %

Procedure:
The title compound was prepared in the same manner as described for Example 2 using 5-bromo-1-methyl-3-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indole-7-carboxamide (300 mg, 0.65 mmol) and 3-(N,N-dimethylaminomethyl)phenylboronic acid pinacol ester hydrochloride (250 mg, 0.84 mmol). Obtained 210 mg of the title compound (63% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.50 (s, 1H), 8.49 (t, J=4.80 Hz, 1H), 7.82 (d, J=1.77 Hz, 1H), 7.56-7.64 (m, 2H), 7.41 (t, J=7.58 Hz, 1H), 7.31 (d, J=1.52 Hz, 1H), 7.25 (d, J=7.58 Hz, 1H), 7.11 (s, 1H), 5.91 (s, 1H), 4.38 (d, J=5.05 Hz, 2H), 3.70 (s, 3H), 3.33 (s, 2H), 3.22 (quin, J=6.76 Hz, 1H), 2.52-2.59 (m, J=6.82, 8.59 Hz, 2H), 2.26 (br. s., 6H), 2.13 (s, 3H), 1.58 (sxt, J=7.53 Hz, 2H), 1.31 (d, J=6.82 Hz, 6H), 0.94 (t, J=7.33 Hz, 3H). MS (ES) [M+H]+ 513.3.
Reaction SMILES: [C-:1]#[N:2].[Na+].[C:4]([C:8]1[O:9][CH:10]=[C:11]([CH2:13]Cl)[N:12]=1)([CH3:7])([CH3:6])[CH3:5].[OH-].[Na+]>CS(C)=O>[C:4]([C:8]1[O:9][CH:10]=[C:11]([CH2:13][C:1]#[N:2])[N:12]=1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)c1nc(CCl)co1
Reactant: [C-]#N
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)c1nc(CC#N)co1
Temperature: 65 °C
Yield: 92.6 %

Procedure:
6.2 g of sodium cyanide was weighed, 50 ml of dimethylsulfoxide was added thereto, and a dimethylsulfoxide solution of 16.9 g of 2-tert-butyl-4-chloromethyloxazole was dropwise added thereto, and heated on an oil bath at 65° C. for 1 hour with stirring. After the resulting product was cooled to room temperature, 150 ml of a dilute aqueous solution of sodium hydroxide was added thereto, and extracted with toluene. The organic layer was fully washed with water, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 14.8 g of 2-tert-butyl-4-cyanomethyloxazole.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[NH2:7][CH2:8][CH2:9][N:10]1[C:18]2[C:17]([CH3:19])=[C:16]([CH3:20])[N:15]=[C:14]([NH2:21])[C:13]=2[N:12]=[C:11]1[CH3:22]>>[NH2:21][C:14]1[C:13]2[N:12]=[C:11]([CH3:22])[N:10]([CH2:9][CH2:8][NH:7][C:3](=[O:4])[N:2]([CH3:6])[CH3:1])[C:18]=2[C:17]([CH3:19])=[C:16]([CH3:20])[N:15]=1
Reactant: Cc1nc(N)c2nc(C)n(CCN)c2c1C
Reactant: CN(C)C(=O)Cl
Product: Cc1nc(N)c2nc(C)n(CCNC(=O)N(C)C)c2c1C

Procedure:
Using the method of Examples 118-133, dimethylcarbamyl chloride was reacted with 1-(2-aminoethyl)-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The observed accurate mass was 291.1929.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:25]2[N:24]3[CH2:28][CH2:29][C:30](=O)[C:23]3=[CH:22][C:21]=2[C:20]=1[CH3:32].[NH4+].[Cl-]>CN(C=O)C>[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:25]2[N:24]3[CH2:28][CH2:29][C:30](=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:23]3=[CH:22][C:21]=2[C:20]=1[CH3:32]
Reactant: COc1ccc2c(cc3n2CCC3=O)c1C
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)C=C1CCn2c1cc1c(C)c(OC)ccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54.5 %

Procedure:
To a solution of ethyl 2-(diethoxyphosphoryl)acetate (1.38 mL, 6.97 mmol) in DMF (2 mL) was added sodium hydride (60% dispersion in mineral oil) (279 mg, 6.97 mmol) at 0° C. The reaction mixture was stirred for 10 min, then 7-methoxy-8-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-one (500 mg, 2.323 mmol) in DMF (6 mL) was added. The reaction mixture was warmed to room temperature and stirred for 1 h, then heated at 60° C. for 1 h, cooled down, poured into saturated NH4Cl aqueous solution, extracted with ethyl acetate. The combined organics were washed with water, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography to give the title compound (361 mg). LCMS m/z=286.2 [M+H]+.
Reaction SMILES: B([O-])([O-])O[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][O:12][CH:13]([CH3:15])[CH3:14])=[CH:5][CH:4]=1.Br[C:19]1[CH:20]=[CH:21][C:22]2[N:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:26][C:25]([C:36]([O:38][CH3:39])=[O:37])=[CH:24][C:23]=2[CH:40]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C(OCC)(=O)C.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>[C:32]([O:31][C:29]([N:28]1[C:22]2[CH:21]=[CH:20][C:19]([C:3]3[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][O:12][CH:13]([CH3:15])[CH3:14])=[CH:5][CH:4]=3)=[CH:40][C:23]=2[CH:24]=[C:25]([C:36]([O:38][CH3:39])=[O:37])[CH2:26][CH2:27]1)=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)OCCOc1ccc(OB([O-])[O-])cc1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(C(=O)OC(C)(C)C)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: [K+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)C1=Cc2cc(-c3ccc(OCCOC(C)C)cc3)ccc2N(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
In a mixture of water ethanol toluene (1:1:10, v/v, 42.0 ml) were dissolved 4-(2-propoxy)ethoxyphenyl borate (920 mg) and methyl 7-bromo-1-(t-butoxycarbonyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1308 mg). To the solution was added potassium carbonate (1135 mg), and the mixture was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (119 mg), and the mixture was heated to reflux under argon atmosphere for 14.5 hours. The mixture was diluted with ethyl acetate, and washed with water and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified with silica gel column chromatography (50 g, hexane:ethyl acetate=9:1→3:1) to give methyl 1-(t-butoxycarbonyl)-7-[4-(2-propoxy)ethoxyphenyl]-2.3-dihydro-1H-1-benzazepine-4-carboxylate (1536 mg, 93%) as colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[O:5][C:6]1[CH:7]=[C:8]([S:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)[C:9]([NH:12][C:13]2[S:17][N:16]=[C:15]([CH:18]3[CH2:22][CH2:21][CH2:20][O:19]3)[N:14]=2)=[N:10][CH:11]=1.C[Li].C([Li])CCC.[CH:42](=[O:44])[CH3:43].[NH4+].[Cl-]>C1COCC1>[CH3:31][O:30][C:26]1[CH:25]=[C:24]([S:23][C:8]2[CH:7]=[C:6]([O:5][C:4]3[CH:3]=[C:2]([CH:42]([OH:44])[CH3:43])[CH:34]=[CH:33][CH:32]=3)[CH:11]=[N:10][C:9]=2[NH:12][C:13]2[S:17][N:16]=[C:15]([CH:18]3[CH2:22][CH2:21][CH2:20][O:19]3)[N:14]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CC=O
Reactant: COc1cccc(Sc2cc(Oc3cccc(Br)c3)cnc2Nc2nc(C3CCCO3)ns2)c1
Agent: [Cl-]
Agent: [Li]C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(Sc2cc(Oc3cccc(C(C)O)c3)cnc2Nc2nc(C3CCCO3)ns2)c1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 11.2 %

Procedure:
A 10 mL round-bottomed flask was charged with 5-(3-bromophenoxy)-3-(3-methoxyphenylthio)-N-(3-(tetrahydrofuran-2-yl)-1,2,4-thiadiazol-5-yl)pyridin-2-amine (43.3 mg, 0.077 mmol) and THF (2 mL). The reaction was cooled to −78° C. and methyllithium (0.058 mL, 0.093 mmol) was added and stirred for 5 min. Butyllithium (0.037 mL, 0.093 mmol) was added and the reaction was stirred for 5 min. Acetaldehyde (0.0086 mL, 0.16 mmol) was added and the reaction warmed to room temperature and poured into saturated aqueous NH4Cl and extracted with EtOAc. The organic layer was dried with sodium sulfate, filtered and concentrated. The residue was purified on silica gel (35 to 100% ethyl acetate in hexanes) to afford the title compound (4.5 mg, 11.1% yield). 1H NMR (CDCl3) δ 9.26 (bs, 1H), 8.25 (d, 1H), 7.63 (d, 1H), 7.33 (t, 1H), 7.21 (t, 1H), 7.14 (d, 1H), 7.05 (m, 1H), 6.90 (dd, 1H), 6.76 (m, 2H), 6.70 (m, 1H), 4.89 (q, 1H), 4.15 (t, 1H), 4.03 (m, 2H), 3:90 (m, 1H), 3.77 (s, 3H), 3.64 (m, 1H), 2.34 (q, 2H), 1.47 (d, 3H). Mass spectrum (apci) m/z=523.2 (M+H).