Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N+:15]([O-:17])[CH3:16])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.[CH2:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:9][N:10]3[CH:14]=[N:13][CH:12]=[N:11]3)[CH2:35][CH:34]([CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH3:18])[O:17][N:15]2[CH3:16])=[CH:4][CH:3]=1
Reactant: C[N+]([O-])=C(Cn1cncn1)c1ccc(Cl)cc1
Reactant: C=CCCCCCCCCCCCCCCCC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCC1CC(Cn2cncn2)(c2ccc(Cl)cc2)N(C)O1
Temperature: 25 °C

Procedure:
A solution of 32.8 g (0.131 mol) of 1-(4-chlorophenyl)-N-methyl-2-(1H-1,2,4-triazol-1-yl)ethanimine N-oxide (1: R=4-Cl) [prepared by reacting 2-(1H-1,2,4-triazol-1-yl)-4'-chloroacetophenone (35.38 g, 0.160 mol) with N-methylhydroxylamine hydrochloride (20.0 g, 0.240 mol) and NaHCO3 (20.12 g, 0.240 mol) in 500 ml ethanol] and 62.8 ml (0.196 mol) of 1-octadecene (2: n=15) in 400 ml toluene is refluxed for 48 hours under a nitrogen atmosphere. Upon cooling to room temperature the solvent is removed under reduced pressure. The residual dark solid is collected and washed sequentially with acetonitrile and ether. Crystallization from ethyl acetate gave 9.0 g (14%) of isomer A (3: R=4-Cl, n=15), melting at 100°-102° C.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=[O:18])[CH2:8]1.N1C=CC=CC=1.S(Cl)([Cl:28])(=O)=O>C(OCC)(=O)C>[Cl:1][C:2]1[CH:6]=[C:5]([Cl:28])[S:4][C:3]=1[CH:7]1[CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=[O:18])[CH2:8]1
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1ccnc2c1C(=O)CC(c1sccc1Cl)C2
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccnc2c1C(=O)CC(c1sc(Cl)cc1Cl)C2
Reaction time: 3 h
Yield: 67.3 %

Procedure:
To a solution of 7-(3-chlorothiophen-2-yl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.74 g) in ethyl acetate (10 ml) were added pyridine (0.21 g) and sulfuryl chloride (1.1 g) at room temperature, and the mixture was stirred at the same temperature for 3 hours. To the reaction solution was added ethyl acetate, and the mixture was washed with sodium hydrogen carbonate solution, water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (EtOAc/hexane) to give 7-(3,5-dichlorothiophen-2-yl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.56 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:22])[CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].[CH3:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][NH2:27]>O1CCCC1>[CH2:20]([O:19][C:17]([CH2:16][CH2:15][C:14]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:27][CH2:26][C:25]1[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=1[CH3:23])=[CH:10][CH:9]=[CH:8][C:7]=2[O:12][CH3:13])=[O:22])=[O:18])[CH3:21]
Reactant: CCOC(=O)CCC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: Cc1ccccc1CN
Solvent: C1CCOC1
Product: CCOC(=O)CCC(=O)c1cnc2c(OC)cccc2c1NCc1ccccc1C
Temperature: 60 °C
Reaction time: 16 h

Procedure:
In a flame-dried, three-necked round-bottomed reaction flask equipped with reflux condenser, magnetic stirring bar and rubber septum, there was placed 1.0 g (0.0031 mole) of 4-chloro-3-(3-ethoxycarbonylpropionyl)-8-methoxyquinoline (the product of Preparation C) dissolved in 10 mL of dry tetrahydrofuran. Stirring was commenced and 0.8 mL (750 mg, 0.0062 mole) of 2-methylbenzylamine (available from the Aldrich Chemical Company, Inc. of Milwaukee, Wis.), was added over a two-minute period at room temperature (ca. 20° C.). The well-stirred reaction mixture was then heated to 60° C. and thereafter kept at that temperature for a period of approximately 16 hours (i.e., overnight). Upon completion of this step, the resulting reaction mixture was then filtered to remove 2-methylbenzylamine hydrochloride that had precipitated from the mixture and the filtrate was subsequently evaporated to near dryness while under reduced pressure to afford a crude solid product as the residue. The latter material was then purified by means of column chromatography over silica gel, using a 1% solution of diethylamine in ethyl acetate as the eluant. In this manner, there was ultimately obtained a 43 mg (3%) yield of pure 3-(3-ethoxycarbonylpropionyl)-8-methoxy-4-(2-methylbenzylamino)quinoline as the free base compound (isolated as a 0.25 hydrate), m.p. 152°-155° C. The pure product was further characterized by means of mass spectrum (MS) analysis and nuclear magnetic resonance (NMR) data, in addition to elemental analysis.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([O:10]C)=O.[NH2:12][CH2:13][C:14]12[CH2:21][CH2:20][CH2:19][N:18]1[CH2:17][CH2:16][CH2:15]2.Cl>>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([NH:12][CH2:13][C:14]12[CH2:21][CH2:20][CH2:19][N:18]1[CH2:17][CH2:16][CH2:15]2)=[O:10]
Reactant: COC(=O)CN1CCCC1=O
Reactant: NCC12CCCN1CCC2
Agent: Cl
Product: O=C(CN1CCCC1=O)NCC12CCCN1CCC2
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A mixture consisting of 14.1 g (89.6 mmol) of methyl 2-oxo-1-pyrrolidineacetate and 11.4 g (81.4 mmol) of 7a-(aminomethyl)pyrrolizidine was heated and stirred for 6 hours at 80° C. under argon atmospher. After cooling, the reaction mixture was then solved with 1.0N-hydrochloric acid and extracted 3 times with dichloromethane. An aqueous layer was rendered alkaline by the addition of sodium hydroxide solution and extracted 3 times with dichloromethane followed by drying over anhydrous magnesium sulfate. After removal of the drying agent through filtration, the solvent was evaporated under reduced pressure to obtain a yellowish oil as a free base of the desired compound. The free base was converted to terephthalate by usual manner. Yield: 32.0 g (91.1%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[C:17]1[N:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[N:18]=1>N1C=CC=CC=1>[CH3:24][C:19]1[CH:20]=[C:21]([CH3:23])[N:22]=[C:17]([N:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[CH2:11][CH2:12]2)[N:18]=1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: Cc1cc(C)nc(Cl)n1
Solvent: c1ccncc1
Product: Cc1cc(C)nc(N2CCN(c3ccc([N+](=O)[O-])cc3)CC2)n1
Yield: 24.1 %

Procedure:
1-(4-Nitrophenyl)-piperazine (2.18 g, 10.6 mmol) was added to 2-chloro-4,6-dimethyl-pyrimidine (1.5 g, 10.6 mmol) in pyridine (10 mL) and the mixture was heated at reflux for 7 h. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. The organic phase was separated, washed with water and brine, dried over anhydrous sodium sulfate and concentrated to afford 4,6-dimethyl-2-[4-(4-nitro-phenyl)-piperazin-1-yl]-pyrimidine (0.8 g, 24%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([O:23]C2C(F)=C(F)C(F)=C(F)C=2F)=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[Cl:35][C:36]1[C:37]([O:46][CH2:47][CH:48]2[CH2:52][CH2:51][CH2:50][NH:49]2)=[N:38][CH:39]=[C:40]([C:42]([O:44][CH3:45])=[O:43])[CH:41]=1>CN(C=O)C.CCOC(C)=O>[Cl:35][C:36]1[C:37]([O:46][CH2:47][CH:48]2[CH2:52][CH2:51][CH2:50][N:49]2[C:21](=[O:23])[CH2:20][C:5]2[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:38][CH:39]=[C:40]([C:42]([O:44][CH3:45])=[O:43])[CH:41]=1
Reactant: COC(=O)c1cnc(OCC2CCCN2)c(Cl)c1
Reactant: COc1cc(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1NC(=O)Nc1ccccc1C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(OCC2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The mixture of pentafluorophenyl 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetate (317.0 mg, 0.660 mmol), methyl 3chloro-2-[(2-pyrrolidinyl)methoxy]pyridine-5-carboxylate (172.0 mg, 0.635 mmol), Et3 N (105 ul, 0.756 mmol) in DMF (2.0 mL) was stirred for 1 hr at room temp. The mixture was diluted with EtOAc, washed with brine, and dried over Na2SO4. The solvent was removed under a reduced pressure to afford methyl 3chloro-2-[[1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methoxy]pyridine-5-carboxylate as a brownish oil. To a stirred solution of this compound in THF (6.0 mL) and H2O (2.0. mL) was added LiOH (45.3 mg, 1.89 mmol), and the reaction mixture was stirred for 5 hr at room temp. The mixture was diluted with n-hexane and extracted with 1N-NaOH. The aqueous layer was acidified by the addition of 1 N HCl and extracted with CHCl3. The extract was washed with brine, dried over Na2SO4. The solvent was removed under a reduced pressure and the obtained crude solid was recrystallized from n-hexane-EtOAc-EtOH to afford 242.2 mg (70%/0) 47 as an orange crystalline powder. mp 122–125; IR (KBr) 3354, 1709, 1593, 1535, 1454, 1257 cm−1; 1H-NMR (400 MHz, DMSO-d6) δ 1.67–2.03 (m, 4H), 2.50 (s, 3H), 3.33–3.42 (m, 1H), 3.52 (m, 2H), 3.58 (d, J=4.4 Hz, 1H), 3.83 (s, 3H), 4.27–4.31 (m, 2H), 4.42–4.47 (m, 1H), 6.73 (d, J=7.8 Hz, 1H), 6.87–6.95 (m, 3H), 7.11–7.17 (m, 2H), 7.79 (d, J=8.3 Hz, 1H), 7.99 (d, J=8.3 Hz, 1H), 8.14 (dd, J=2.0, 8.8 Hz, 1H), 8.46 (s, 1H), 8.56 (s, 1H), 8.69 (d, J=2.0 Hz, 1H), 13.06 (br s, 1H); MS (FAB) m/z 553 (M++1); Anal. Calcd for C28H29ClN4O6: C, 60.81; H, 5.29; N, 10.31. Found: C, 60.98; H, 5.50; N, 9.46.
Reaction SMILES: Cl[S:2]([C:5]1[S:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)(=[O:4])=[O:3].[NH2:20][C:21]1[O:25][N:24]=[C:23]([CH3:26])[C:22]=1[Br:27]>>[Br:27][C:22]1[C:23]([CH3:26])=[N:24][O:25][C:21]=1[NH:20][S:2]([C:5]1[S:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)(=[O:4])=[O:3]
Reactant: COC(=O)c1ccc(-c2ccc(S(=O)(=O)Cl)s2)cc1
Reactant: Cc1noc(N)c1Br
Product: COC(=O)c1ccc(-c2ccc(S(=O)(=O)Nc3onc(C)c3Br)s2)cc1
Yield: 41.2 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-methoxycarbonylphenyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 2 from 2-chlorosulfonyl-5-(4-methoxycarbonylphenyl)thiophene (646 mg, 2.04 mmol) and 5-amino-4-bromo-3-methylisoxazole (361 mg, 2.04 mmol). Purification by column chromatography using 10% MeOH/CHCl3 gave 384 mg of N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-methoxycarbonylphenyl)thiophene-2-sulfonamide as a brown oil (41% yield).
Reaction SMILES: [CH3:1][C:2]1[O:7][CH2:6][CH2:5][CH2:4][C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[Se](=O)=[O:14]>C(O)(=O)C>[CH:1]([C:2]1[O:7][CH2:6][CH2:5][CH2:4][C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:14]
Reactant: CCOC(=O)C1=C(C)OCCC1
Reactant: O=[Se]=O
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(C=O)OCCC1
Temperature: 25 °C
Yield: 26.3 %

Procedure:
A mixture of ethyl 6-methyl-3,4-dihydro-2H-pyran-5-carboxylate (6.0 g, 35.3 mmol) and selenium dioxide (4.3 g, 38.8 mmol) was stirred in acetic acid (141 mL) 5 hours at 110° C. The reaction was then cooled to room temperature and the solids were removed by filtration. The filtrate was concentrated down and purified by silica gel chromatography with 0 to 15% ethyl acetate/heptane gradient, followed by 15% to afford the title compound (1.710 g) as an amber oil in about 90% purity. MS (ESI) [m/e, (M+H)+]=185.3. 1H NMR (400 MHz, chloroform-d) δ ppm 10.22 (s, 1H), 4.28 (q, J=7.24 Hz, 2H), 4.12-4.19 (m, 2H), 2.54 (t, J=6.57 Hz, 2H), 1.88-1.98 (m, 2H), 1.30-1.38 (m, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][C:12]([C:15]([C:17]([CH3:40])([CH3:39])[CH2:18][C:19]3[CH:38]=[CH:37][C:22]4[N:23]([CH3:36])[C:24]([CH2:26][NH:27][C:28]5[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=5)=[N:25][C:21]=4[CH:20]=3)=[O:16])([CH3:14])[CH3:13])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:41][NH:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]#[N:50])=[CH:45][CH:44]=1.[ClH:51].C(=O)([O-])[O-].[NH4+:56].[NH4+:57]>C(O)C>[ClH:51].[CH3:36][N:23]1[C:22]2[CH:37]=[CH:38][C:19]([CH2:18][C:17]([C:15]([C:12]([CH3:14])([CH3:13])[CH2:11][C:9]3[CH:8]=[CH:7][C:6]4[N:2]([CH3:1])[C:3]([CH2:41][NH:42][C:43]5[CH:48]=[CH:47][C:46]([C:49](=[NH:56])[NH2:50])=[CH:45][CH:44]=5)=[N:4][C:5]=4[CH:10]=3)=[O:16])([CH3:40])[CH3:39])=[CH:20][C:21]=2[N:25]=[C:24]1[CH2:26][NH:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[NH:57])[NH2:35])=[CH:30][CH:29]=1
Reactant: [NH4+]
Reactant: Cn1c(CNc2ccc(C#N)cc2)nc2cc(CC(C)(C)C(=O)C(C)(C)Cc3ccc4c(c3)nc(CNc3ccc(C#N)cc3)n4C)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(CC(C)(C)C(=O)C(C)(C)Cc3ccc4c(c3)nc(CNc3ccc(C(=N)N)cc3)n4C)ccc21
Yield: 59 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-tert.butyl-ketone, ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 59% of theory, C21H25N5O (363.5) EKA mass spectrum: (M+H)+ =364
Reaction SMILES: C([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[CH2:18][O:19][CH2:20][CH:21]=3)[CH:14]=2)[CH2:9]1)C1C=CC=CC=1.[H][H]>>[O:19]1[CH2:20][CH2:21][CH:17]([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[CH2:9][NH:8][CH2:16]3)[CH2:18]1
Reactant: C1=C(c2ccc3c(c2)CN(Cc2ccccc2)C3)COC1
Reactant: [H][H]
Product: c1cc2c(cc1C1CCOC1)CNC2

Procedure:
Prepared in analogy to Example A62(c) from 2-benzyl-5-(2,5-dihydro-furan-3-yl)-2,3-dihydro-1H-isoindole and hydrogen. Brown oil. MS (m/e): 190.4 ([M+H]+, 100%).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=[CH2:7])[C:4](O)=[O:5].[NH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:12]=1>S(Cl)(Cl)=O.C(OCC)C>[C:15]([C:14]1[CH:17]=[CH:18][C:11]([NH:10][C:4](=[O:5])[C:3]([C:2]([F:9])([F:8])[F:1])=[CH2:7])=[CH:12][C:13]=1[C:19]([F:20])([F:21])[F:22])#[N:16]
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Reactant: C=C(C(=O)O)C(F)(F)F
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: C=C(C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1)C(F)(F)F
Temperature: 25 °C

Procedure:
2-Trifluoromethyl-acrylic acid (36.0 mmoL) in thionyl chloride (2.86 mL) was refluxed for 30 min. Excess thionyl chloride was removed in vacuo to yield a residue. 4-Amino-2-trifluoromethyl-benzonitrile (36.0 mmoL) in diethyl ether (50 mL) was added dropwise to the residue at −40° C. The reaction mixture was slowly warmed to room temperature. The reaction mixture was then partitioned between diethyl ether and water. The diethyl ether layer was washed with saturated sodium bicarbonate, then brine, dried over anhydrous Na2SO4, filtered and concentrated to yield a brown oil. The crude material (the brown oil) was then purified by column chromatography (silica gel, using ethyl acetate as eluent) to yield the title compound as yellow solid.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])(C)(C)C.Br[C:20]1[CH:25]=[C:24]([S:26]([CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:28])=[O:27])[CH:23]=[CH:22][C:21]=1[CH3:37]>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:18])=[C:10]([C:16]#[C:17][C:22]2[CH:23]=[C:24]([S:26]([CH2:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)(=[O:28])=[O:27])[CH:25]=[CH:20][C:21]=2[CH3:37])[CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)CCc2ccccc2)cc1Br
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: Cc1ccc(S(=O)(=O)CCc2ccccc2)cc1C#Cc1cc(Cl)ccc1OCC(=O)O

Procedure:
Following the general method as outlined in Example 37, starting from tert-butyl(4-chloro-2-ethynyl phenoxy)acetate (Intermediate 3) and 2-bromo-1-methyl-4-[(2-phenylethyl)sulfonyl]benzene (Intermediate 70), the title compound was obtained as a yellow solid.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[CH:6]([C:17]([OH:19])=[O:18])[CH2:5]2)[CH2:3][CH2:2]1.[C:20]([O:24][C:25]([NH:27][CH:28]1[C:32]2([CH2:34][CH2:33]2)[CH2:31][NH:30][CH2:29]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>CS(C)=O>[C:20]([O:24][C:25]([NH:27][CH:28]1[C:32]2([CH2:33][CH2:34]2)[CH2:31][N:30]([C:11]2[CH:12]=[C:13]3[C:8]([C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=2[F:15])[CH2:29]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: O=C(O)C1CN(C2CC2)c2cc(F)c(F)cc2C1=O
Reactant: CC(C)(C)OC(=O)NC1CNCC12CC2
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NC1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC12CC2
Temperature: 120 °C

Procedure:
250 mg of 1-cyclopropyl-6,7-difluoro-2,3-dihydro-4-oxoquinoline-3-carboxylic acid and 250 mg of compound 11 were added to 4 ml of dimethyl sulfoxide and the mixture was heated at 120° C. for 2 hours. After cooling, the solvent was removed under reduced pressure and the residue was crystallized by the addition of ethanol. The crystals were collected by filtration. The procedure gave 7-(7-tert-butoxycarbonylamino-5-azaspiro[2.4]heptan-5-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid as a crude product.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([O:14][CH3:15])(=[O:13])[CH2:8][CH2:9][C:10]([OH:12])=O.[C:16]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:18])[CH3:17].[Cl-].[Al+3].[Cl-].[Cl-]>CN(C)C=O.ClC(Cl)C>[C:16]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:10](=[O:12])[CH2:9][CH2:8][C:7]([O:14][CH3:15])=[O:13])=[CH:28][CH:29]=1)(=[O:18])[CH3:17]
Reactant: COC(=O)CCC(=O)O
Reactant: CC(=O)NCCCCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)CCC(=O)c1ccc(CCCCNC(C)=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.6 %

Procedure:
45.9 g of oxalyl chloride and 5 drops of dimethylformamide were added to a dichloroethane solution (500 ml) containing 45.5 g of methyl hydrogen succinate, and the mixture was stirred at room temperature for 3 hours. Under ice cooling, a dichloroethane solution (60 ml) containing 31.3 g of [4-(acetylamino)butyl]benzene, and 91.9 g of anhydrous aluminum chloride were added thereto, and the mixture was stirred for 1 hour. The reaction mixture was poured into ice water, and the organic layer was collected by separation. After the organic layer was washed with water and dried, the solvent was removed. The resulting crude crystal was recrystallized from ethyl acetate to obtain 42.3 g of 4-[4-(acetylamino)butyl]-l-(3-methoxycarbonylpropionyl)benzene.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[CH:28](O)=[O:29]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][CH:28]=[O:29])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: O=CO
Agent: Cl
Product: O=CN[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (28 mg, 31%), MS (ISP) m/z=359.4 [(M+H)+], mp 153.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and formic acid.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:19]([O:21][CH3:22])=[O:20])[C:8]([CH3:28])=[CH:7][C:5]=2[N:6]=1.[CH3:29][N:30]1[C:38]2[C:33](=[CH:34][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:37]=2)[C:32]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=2)=[N:31]1.C([O-])([O-])=O.[K+].[K+].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.O>[C:24]([O:23][C@@H:18]([C:9]1[C:8]([CH3:28])=[CH:7][C:5]2[N:6]=[C:2]([C:35]3[CH:34]=[C:33]4[C:38](=[CH:37][CH:36]=3)[N:30]([CH3:29])[N:31]=[C:32]4[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH3:22])=[O:20])([CH3:27])([CH3:26])[CH3:25]
Reactant: Cn1nc(-c2ccccn2)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)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: C1COCCO1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(c3)c(-c3ccccn3)nn4C)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
To a vial flushed with argon was added (S)-methyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (100 mg, 0.207 mmol), 1-methyl-3-(pyridin-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (83.3 mg, 0.25 mmol), Pd(PPh3)4 (24 mg, 21 mmol), and K2CO3 (86 mg, 0.62 mmol). De-gassed dioxane (2 mL) and water (0.5 mL) were then added, and the reaction was heated to 100° C. for 1 h. After cooling to rt, the reaction was filtered over a plug of Celite, concentrated, and purified by column chromatography (gradient 0 to 40% EtOAc in hexanes) to give the product. 1H NMR (400 MHz, CDCl3) δ 9.21-9.15 (m, 1H), 8.84-8.77 (m, 1H), 8.25 (dd, J=8.8, 1.7 Hz, 1H), 8.14 (d, J=8.0 Hz, 1H), 7.88 (s, 1H), 7.78 (td, J=7.7, 1.7 Hz, 1H), 7.59-7.49 (m, 4H), 7.47 (d, J=8.9 Hz, 1H), 7.29-7.24 (m, 1H), 5.21 (s, 1H), 4.17 (s, 3H), 3.75 (s, 3H), 2.59 (s, 3H), 0.98 (s, 9H).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]1.Cl[CH2:12][C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(O)C>CN(C)C=O>[CH3:10][N:7]1[CH2:8][CH2:9][CH:4]([O:3][CH2:12][C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:5][CH2:6]1
Reactant: CN1CCC(O)CC1
Reactant: CCOC(=O)CC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)CC(=O)COC1CCN(C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
Sodium hydride (5.0 g of 50% dispersion in mineral oil) was added portionwise to a stirred solution of 4-hydroxy-1-methyl-piperidine (11.5 g) in dry dimethylformamide (80 ml). The mixture was stirred at room temperature for 1 hour and then cooled to 10° C. A solution of ethyl 4-chloroacetoacetate (8.2 g) in dry dimethylformamide (20 ml) was added dropwise with stirring and stirring was continued for a further 20 hours at room temperature. Ethanol (10 ml) was added and the solution was evaporated to dryness. The residue was partitioned between dichloromethane and dilute hydrochloric acid. The organic layer was separated, dried over sodium sulphate and evaporated to given an oil which was partitioned between acetonitrile and petrol to remove mineral oil. The acetonitrile extract was evaporated to give the title compound as an oil (10.3 g) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]2=[N:4][CH:3]=1.S(Cl)([Cl:16])=O>>[Cl:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([C:11]([Cl:16])=[O:13])=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: O=C(O)c1cc2ncc(Cl)nc2s1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc2ncc(Cl)nc2s1
Yield: 98.8 %

Procedure:
A solution of 3-chlorothieno[2,3-b]pyrazine-6-carboxylic acid 93 (0.191 mmol, 41 mg) in thionyl chloride (27.4 mmol, 2 ml, 3262 mg) was heated at 80° C. for 2 h. Reaction mixture was concentrated under reduced pressure and co-evaporated with toluene (2×) to give 3-chlorothieno[2,3-b]pyrazine-6-carbonyl chloride 94 (44 mg, 100%).