Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23](O)[CH:24]=2)[CH:19]=[CH:18][CH:17]=1.N1C=CC=CC=1>ClCCl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:23]1[CH:24]=[C:25]2[C:20]([CH:19]=[CH:18][CH:17]=[N:16]2)=[CH:21][CH:22]=1)(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Oc1ccc2cccnc2c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Oc1ccc2cccnc2c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
Trifluoromethanesulfonic anhydride (1.40 mL, 8.32 mmol) was added dropwise via a syringe to a solution of quinolin-7-ol (930 mg, 6.41 mmol), and pyridine (1.05 mL, 13.0 mmol) in anhydrous dichloromethane (50 mL) at 0° C. After addition the ice bath was removed and the reaction was allowed to warm to room temperature and stirred overnight. The reaction was concentrated and purified via flash chromatography using an Analogix SF25-40 g column and eluant of ethyl acetate in heptane (0-40%) to afford the title compound as an orange-white solid (1.54 g, 86.7%). LC-MS m/z 278.4 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.42-7.57 (m, 2H) 7.95 (d, J=8.98 Hz, 1H) 8.05 (d, J=2.54 Hz, 1H) 8.20-8.29 (m, 1H) 8.97-9.06 (m, 1H).
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]([NH:22][C:23](=O)[CH2:24][CH2:25][CH3:26])[CH2:9][CH2:10][O:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)(=O)[CH2:2]CC.[CH2:28](Cl)[CH3:29]>>[CH2:1]([O:6][CH2:7][CH:8]([N:22]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:28][CH3:29])[CH2:9][CH2:10][O:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)[CH3:2]
Reactant: CCCC(=O)NC(CCOc1cccc2ccccc12)COC(=O)CCC
Reactant: CCCl
Product: CCCCN(CC)C(CCOc1cccc2ccccc12)COCC

Procedure:
2-(butanoylamino)-4-(1-naphthyloxy)butanol butyrate, described in Example 5, with ethyl chloride, followed by reduction, gives 1-ethoxy-N-butyl-N-ethyl-4-(1-naphthyloxy)-2-butanamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([NH2:16])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:17][O:18][C:19]1[CH:30]=[CH:29][C:22]2[N:23]=[C:24]([C:26](N)=[O:27])[S:25][C:21]=2[CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([NH:16][C:26]([C:24]3[S:25][C:21]4[CH:20]=[C:19]([O:18][CH3:17])[CH:30]=[CH:29][C:22]=4[N:23]=3)=[O:27])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc2nc(C(N)=O)sc2c1
Reactant: Cc1c(N)nnn1Cc1ccc(Cl)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2nc(C(=O)Nc3nnn(Cc4ccc(Cl)c(Cl)c4)c3C)sc2c1
Temperature: 45 °C
Reaction time: 48 h

Procedure:
A mixture of 1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-amine (Intermediate 19) (0.1 g, 0.39 mmol), 6-(methyloxy)-1,3-benzothiazole-2-carboxamide (81 mg, 1 eq), HATU (0.192 g, 1.3 eq) and DIPEA (0.12 mL, 1.3 eq) in DMF (5 mL) was stirred at 45° C. for 48 hours. The solvent was evaporated and the residue was washed with water and extracted with DCM. The organic phase was dried over sodium sulphate, filtered and concentrated. The residue was purified by flash chromatography eluting with DCM/MeOH (99/1) to give after recrystallisation from acetonitrile the title compound as pink pale crystals (110 mg, 65%). HRMS calculated for C19H15Cl2N5O2S (M+H)+448.0402, found: 448.0406, Rt: 3.08 min. MP: 176° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][C:15](=[O:17])[CH3:16])[CH:13]=1)[C:8](O)=[O:9])(=[O:3])[CH3:2].S(Cl)([Cl:20])=O>C(Cl)Cl>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][C:15](=[O:17])[CH3:16])[CH:13]=1)[C:8]([Cl:20])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(OC(C)=O)cc(C(=O)O)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(=O)Oc1cc(OC(C)=O)cc(C(=O)Cl)c1
Yield: 98.2 %

Procedure:
A 250 ml three-necked flask with magnetic stirrer, thermometer and condenser was charged with 15.4 g (64.7 mmol) of 3,5-diacetoxybenzoic acid, 10 ml of thionyl chloride and 80 ml of CH2Cl2. The mixture was refluxed for 3-5 hours. Then the solvent and remaining thionyl chloride were distilled off. Fresh CH2Cl2 was added and distilled off again. The crude solid was dissolved in 120 ml toluene, and the solution was filtered. Evaporated the solvent out and dried the product at room temperature under 1 mbar. 16.3 g of 3,5-diacetoxybenzoyl chloride were obtained as a white solid. The yield was 98.2%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:27]([C:29]2[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=2[C:31]([OH:33])=O)=[O:28])[CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][CH:13]([N:16]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][O:18][C:17]2=[O:26])[CH2:12][CH2:11]1)([O-:3])=[O:2].C(N1C=CN=C1)([N:40]1C=CN=C1)=O.N>ClCCl>[N+:1]([C:4]1[CH:5]=[C:6]([C:27]([C:29]2[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=2[C:31]([NH2:40])=[O:33])=[O:28])[CH:7]=[CH:8][C:9]=1[N:10]1[CH2:11][CH2:12][CH:13]([N:16]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][O:18][C:17]2=[O:26])[CH2:14][CH2:15]1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c([N+](=O)[O-])c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: ClCCl
Product: NC(=O)c1ccccc1C(=O)c1ccc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
A solution of the product from example 1 (0.9 g) and carbonyldiimidazole (1.1 equiv.) in dichloromethane (4 ml) was stirred at room temperature for 1 h, poured onto aqueous ammonia and stirred for a further 1 h. The mixture was extracted with ethyl acetate, the organics washed with water, dried and evaporated under reduced pressure. Purification was by chromatography eluting with 2.5% methanol/dichloromethane. Yield 0.01 g as a solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]1[O:13][C:14]([CH3:33])=[C:15]([CH3:32])[C:16]=1[C:17]([C:19]1[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[C:22]([OH:28])=[C:21]([CH:29]([CH3:31])[CH3:30])[CH:20]=1)=[O:18].Cl[S:35]([C:38]1[CH:46]=[CH:45][C:41]([C:42]([OH:44])=[O:43])=[C:40]([OH:47])[CH:39]=1)(=[O:37])=[O:36]>>[CH3:32][C:15]1[C:16]([C:17]([C:19]2[CH:20]=[C:21]([CH:29]([CH3:31])[CH3:30])[C:22]([O:28][S:35]([C:38]3[CH:46]=[CH:45][C:41]([C:42]([OH:44])=[O:43])=[C:40]([OH:47])[CH:39]=3)(=[O:37])=[O:36])=[C:23]([CH:25]([CH3:26])[CH3:27])[CH:24]=2)=[O:18])=[C:12]([CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[O:13][C:14]=1[CH3:33]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: Cc1oc(Cc2ccc3ccccc3c2)c(C(=O)c2cc(C(C)C)c(O)c(C(C)C)c2)c1C
Product: Cc1oc(Cc2ccc3ccccc3c2)c(C(=O)c2cc(C(C)C)c(OS(=O)(=O)c3ccc(C(=O)O)c(O)c3)c(C(C)C)c2)c1C
Yield: 55 %

Procedure:
The title compound was prepared according to the procedure in Example 4 using (2-naphthalen-2-ylmethyl-4,5-dimethyl-furan-3-yl)-(3,5-diisopropyl-4-hydroxy-phenyl)-methanone (0.300 g, 0.681 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.209 g, 0.885 mmol). Purification on Dynamax C18 (80% CH3CN/H2O) gave 0.240 g (55%) of the title compound as a yellow solid, mp 130-135° C. 1H NMR (DMSO-d6) δ 1.03 (d, 12H), 1.83 (s, 3H), 2.20 (s, 3H), 3.09 (septet, 2H), 4.01 (s, 2H), 7.18 (d, 1H), 7.43-7.48 (m, 5H), 7.51 (s, 2H), 7.77-7.79 (m, 2H), 7.82-7.86 (m, 1H), 8.05 (d, 1H). IR (KBr) 3400, 2950, 1700, 1375 and 1190 cm−1. mass spectrum (−ESI) m/z 639 (M−H). Anal. Calcd. for C37H36O8S: C, 69.36; H, 5.66; N, 0.00. Found: C, 69.04; H, 5.77; N, 0.04.
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)([CH3:5])[CH2:3][OH:4].[H-].[Na+].Cl[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[O:23][CH3:24]>CN(C=O)C.CCOC(C)=O>[CH3:24][O:23][C:15]1[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:14]=1[O:4][CH2:3][C:2]([N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)([CH3:5])[CH3:1]
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Reactant: CC(C)(CO)N1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc([N+](=O)[O-])ccc1OCC(C)(C)N1CCCC1
Temperature: 25 °C
Yield: 12.3 %

Procedure:
2-Methyl-2-pyrrolidin-1-ylpropan-1-ol (0.3776 g, 2.0682 mmol) was taken up in anhydrous DMF (5 mL). Sodium hydride (0.083 g of a 60% dispersion, 2.0682 mmol) was added. The reaction was stirred at RT until gas evolution was complete. 1-Chloro-2-methoxy-4-nitrobenzene (0.3578 g, 2.0682 mmol) was added. The reaction was heated to 80° C. and stirred for 72 h. Cooled to RT and diluted with EtOAc, (50 mL) and washed with water (3×50 mL). Organics were dried over MgSO4, filtered and concentrated. Crude product was purified by chromatatron (100% CH2Cl2 to 95:5 CH2Cl2:MeOH) to give 0.075 g (0.2551 mmol, 12%) of the product. 1H NMR (CDCl3) δ 7.81 (d, 1H, J=8.8 Hz), 7.73 (s, 1H), 7.15 (d, 1H, J=8.8 Hz), 3.88 (s, 3H), 2.76 (s, 2H), 2.68 (bs, 4H), 1.75 (bs, 4H), 1.38 (s, 6H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:10])=[O:9])[CH2:3]1.C(Cl)CCl.[CH2:15](O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([O:10][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:9])[CH2:3]1
Reactant: OCc1ccccc1
Reactant: O=C1CCCC(C(=O)O)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C1CCCC(C(=O)OCc2ccccc2)C1
Temperature: 25 °C

Procedure:
To a solution of 3-oxocyclohexane carboxylic acid (1.5 g, 10.6 mmol) in CH2Cl2 (35 mL) were added DMAP (0.129 g, 1.06 mmol), EDC (4.05 g, 21.1 mmol), and BnOH (1.2 mL, 11.6 mmol). The reaction was maintained at ambient temperature for 1 h. The reaction was further diluted with CH2Cl2, and then washed with saturated aqueous NaHCO3, followed by brine. The organic layer was separated, dried with MgSO4, filtered, and concentrated. The resulting crude product was used in the next step without further purification. LCMS: calculated for C14H16O3 232.28, observed m/e 233.1 (M+H)+ 255.0 (M+Na) (Rt 1.74/4 min).
Reaction SMILES: [OH:1][CH:2]([CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH3:3].[CH3:16]I.[H-].[Na+]>CN(C=O)C>[CH3:16][O:1][CH:2]([CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH3:3]
Reactant: CI
Reactant: CC(O)C1CCCN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(C)C1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of tert-butyl 2-(1-hydroxyethyl)pyrrolidine-1-carboxylate (750 mg, 3.48 mmol) in DMF (12 mL) at 0° C. was added methyl iodide (0.75 mL, 11.98 mmol) followed by sodium hydride (184 mg, 7.66 mmol). The mixture was stirred for 2 hours at room temperature. The reaction was quenched with ice and diluted with diethyl ether. The organic layer was washed with water and brine, dried over sodium sulfate, and filtered and concentrated under reduced pressure to afford tert-butyl 2-(1-methoxyethyl)pyrrolidine-1-carboxylate. 1H NMR (500 MHz, CDCl3) δ 3.92-3.45 (m, 2H), 3.45-3.23 (m, 4H), 2.11-1.66 (m, 4H), 1.63 (s, 1H), 1.46 (s, 9H), 1.04 (dd, J=6.3, 30.8, 3H).
Reaction SMILES: C[C:2]([C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Cl:11])=[C:6]([F:12])[CH:5]=1)=[O:3].[PH2]([O-])=[O:14].[Na+]>>[Cl:10][C:9]1[CH:8]=[C:7]([Cl:11])[C:6]([F:12])=[CH:5][C:4]=1[C:2]([OH:3])=[O:14]
Reactant: O=[PH2][O-]
Reactant: CC(=O)c1cc(F)c(Cl)cc1Cl
Agent: [Na+]
Product: O=C(O)c1cc(F)c(Cl)cc1Cl

Procedure:
Namely, 2,4-dichloro-5-fluoroacetophenone is subjected to a haloform reaction in a 12% sodium hypophosphite aqueous solution to obtain 2,4-dichloro-5-fluorobenzoic acid. Then, this benzoic acid is reacted with an alcohol or with a phenol in the presence of an acid catalyst to obtain the above-mentioned fluorine-containing benzoate.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:22][CH3:23])=[C:6]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([C:19]([NH2:21])=[O:20])[CH:13]=2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:30].[Na+]>CO.C(#N)C>[NH2:30][CH:1]([C:4]1[C:5]([O:22][CH3:23])=[C:6]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([C:19]([NH2:21])=[O:20])[CH:13]=2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)[CH3:2]
Reactant: [BH3-]C#N
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1-c1ccc(F)c(C(N)=O)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: COc1c(C(C)N)cc(Cl)c(C)c1-c1ccc(F)c(C(N)=O)c1
Temperature: 65 °C

Procedure:
A mixture of 3′-acetyl-5′-chloro-4-fluoro-2′-methoxy-6′-methylbiphenyl-3-carboxamide (50 mg, 0.1 mmol), ammonium acetate (115 mg, 1.49 mmol) and sodium cyanoborohydride (19 mg, 0.30 mmol) in methanol (0.5 mL) and acetonitrile (0.5 mL) was heated at 65° C. overnight in a sealed tube. The mixture was then cooled to room temperature, quenched with saturated sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate, filtered and concentrated to dryness. The resulting crude product was used directly in next step (36 mg, 70%). LCMS calculated for C17H16ClFNO2 (M−NH2)+: m/z=320.1. found: 320.1.
Reaction SMILES: Cl[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])=[O:3].C=[O:20]>>[CH2:12]([O:11][C:9](=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:2]([OH:20])=[O:3])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)CCCCCC(=O)OCc1ccccc1
Reactant: C=O
Product: O=C(O)CCCCCC(=O)OCc1ccccc1
Temperature: 120 °C

Procedure:
Pimelic acid monobenzyl ester was prepared according to an adaptation of the method of Hassner et al, Tetrahedron Letters No. 46, 4475 (1970); it boils at 205° C. (1.5 torr). This material was converted to benzyl 6-chloroformylcaproate according to the above methods and 5.25 g of the latter compound was stirred with 0.59 g of paraformaldehyde and several mg of fused zinc chloride and heated to 120° C. in an oil bath. After the paraformaldehyde was consumed (about 11/2 hrs), the mixture was cooled, giving 5.73 g of multi-component product. Purification of 3.85 g of this crude product was achieved on a 180 g (2.9×61 cm) column of Silica Gel 60, prepared in a solvent of toluene/chloroform 9:1. The column was run at the flow rate of 1.8 ml/min. and 20 ml fractions were collected. The column was eluted first with 3 liters of toluene/chloroform 9:1, secondly with 3 liters of a 8.5:1.5 mixture of these solvents and finally with 1 liter of toluene containing 15% of chloroform and 7.5% of ethyl acetate. The various fractions were analyzed and combined where appropriate to produce 1.00 g of an oil identified as benzyl chloromethyl pimelate; ir 1765 and 1735 cm-1 ; pmr δ 7.34, 5.68, 5.11, 2.25-2.50 and 1.1-1.9 ppm.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14].[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=2[N+:13]([O-:15])=[O:14])[CH2:19][CH2:18]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(Cc2ccc(C(F)(F)F)cc2[N+](=O)[O-])CC1
Temperature: 75 °C

Procedure:
To 1-chloromethyl-2-nitro-4-trifluoromethyl-benzene (1.5 g, 6.2 mmol), N-methylpiperazine (0.83 mL, 7.5 mmol), and THF (31 mL) was added NaHCO3 (1.43 g, 17.1 mmol). The mixture was heated overnight at 75° C. in a sealed tube. The cooled reaction was filtered, concentrated, diluted with CH2Cl2, and extracted with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated to yield 1-methyl-4-(2-nitro-4-trifluoromethyl-benzyl)-piperazine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:35])[O:10][C:11]3[C:16]([C:17]=2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]4)=[CH:21][CH:20]=2)=[CH:15][CH:14]=[C:13]([OH:34])[CH:12]=3)=[CH:4][CH:3]=1.[OH-].[NH4+].[I:38]I>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9](=[O:35])[O:10][C:11]3[C:16]([C:17]=2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]4)=[CH:21][CH:20]=2)=[CH:15][CH:14]=[C:13]([OH:34])[C:12]=3[I:38])=[CH:6][CH:7]=1
Reactant: II
Reactant: O=c1oc2cc(O)ccc2c(Cc2ccc(OCCC3CCCCN3)cc2)c1-c1ccc(Cl)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: O=c1oc2c(I)c(O)ccc2c(Cc2ccc(OCCC3CCCCN3)cc2)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.1 %

Procedure:
To a solution containing 3-(4-chlorophenyl)-7-hydroxy-4-{(4-(2-piperidylethoxy)phenyl)methyl}-2H-chromen-2-one (0.500 g.) in methanol (10 mL) was added ammonium hydroxide (3 mL) and elemental iodine (0.259 g.). The reaction mixture was allowed to stir at room temperature for 10 minutes. The solvent was removed under reduced pressure. The resulting solid was extracted with methylene chloride (3×) and water. The organic layers were combined and dried over magnesium sulfate. The magnesium sulfate was filtered, and the solvent was removed under reduced pressure to afford a yellow solid. The solid was purified via preparative HPLC (20–50% acetonitrile/water, 20 mL/min.) to afford the title compound (0.290 g., 46% yield). 1H-NMR (CDCl3) δ 7.34 (dd, 3H), 7.20 (d, 2H), 6.92 (d, 2H), 6.84 (d, 1H), 6.75 (d, 2H), 4.13 (t, 2H), 3.97 (s, 2H), 2.84 (t, 2H), 2.61 (bs, 3H), 1.643 (m, 4H), 1.46 (m, 2H), 1.24 (m, 1H). MS (m/z) 616 (M+1)+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9](F)[C:10]([F:22])=[C:11]([N:15]4[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]4)[C:12]=3[F:14])[C:7](=[O:24])[C:6]([C:25]([OH:27])=[O:26])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>N1C=CC=CC=1>[CH2:28]([NH:35][C:9]1[C:10]([F:22])=[C:11]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[C:12]([F:14])=[C:13]2[C:8]=1[C:7](=[O:24])[C:6]([C:25]([OH:27])=[O:26])=[CH:5][N:4]2[CH:1]1[CH2:2][CH2:3]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CN1CCN(c2c(F)c(F)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC1
Reactant: NCc1ccccc1
Solvent: c1ccncc1
Product: CN1CCN(c2c(F)c(NCc3ccccc3)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC1
Yield: 59.4 %

Procedure:
A mixture of 1-cyclopropyl-5,6,8-trifluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.0 g), benzylamine (420 mg), and pyridine (5 ml) was heated at 100°-110° C. for 3 hours. The reaction mixture was evaporated to dryness under reduced pressure. After addition of water to the residue, the mixture was acidified with 10% aqueous acetic acid and extracted with chloroform. The extract was dried and evaporated. The resulting crystals were recrystallized from ethanol-ether to give 5-benzylamino-1-cyclopropyl-6,8-difluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (730 mg), m.p. 132°-133° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.[C:21]1([CH2:27][CH2:28][CH2:29][Mg]Br)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[C:21]1([CH2:27][CH2:28][CH2:29][CH:17]([C:16]2[CH:19]=[CH:20][C:13]([O:12][CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)=[CH:14][CH:15]=2)[OH:18])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Br[Mg]CCCc1ccccc1
Reactant: O=Cc1ccc(OCc2ccc3ccccc3n2)cc1
Solvent: C1CCOC1
Product: OC(CCCc1ccccc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Reaction time: 0.5 h

Procedure:
To a solution of the aldehyde from Step I, (1.34 g) in THF at 0° was added dropwise the 3-phenylpropylmagnesium bromide (1.1 mol. equiv., from above). After 30 mins, the reaction was quenched by the addition of 25% aqueous NH4OAc solution. The mixture was then extracted with ethyl acetate (×2), the organic phase was washed with brine (×2), dried and evaporated under reduced pressure. The title compound was obtained after recrystallization from ethyl acetate/hexane, m.p. 118°-119°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[NH:18][C:13]3=[CH:14][N:15]=[CH:16][CH:17]=[C:12]3[CH:11]=2)=O)=[CH:4][CH:3]=1.[C:19]([O:23][C:24](=[O:30])[NH:25][CH2:26][CH2:27][O:28][NH2:29])([CH3:22])([CH3:21])[CH3:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:29][O:28][CH2:27][CH2:26][NH:25][C:24](=[O:30])[O:23][C:19]([CH3:21])([CH3:20])[CH3:22])[C:10]2[NH:18][C:13]3=[CH:14][N:15]=[CH:16][CH:17]=[C:12]3[CH:11]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCON
Reactant: O=C(c1ccc(Cl)cc1)c1cc2ccncc2[nH]1
Product: CC(C)(C)OC(=O)NCCON=C(c1ccc(Cl)cc1)c1cc2ccncc2[nH]1

Procedure:
tert-Butyl 2-[[[(4-chlorophenyl)(1H-pyrrolo[2,3-c]pyridin-2-yl)methylene]amino]oxy]ethylcarbamate was prepared from (4-chlorophenyl)(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (Example 103) and tert-butyl[2-(aminooxy)ethyl]carbamate following the procedure described for Example 104. Purification by Biotage chromatography (silica, 2 to 15% methanol in methylene chloride) provided tert-butyl 2-[[[(4-chlorophenyl)(1H-pyrrolo[2,3-c]pyridin-2-yl)methylene]amino]oxy]ethylcarbamate (geometry of the oxime double bond undefined).
Reaction SMILES: Cl.[CH:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[C:6]=2[CH:5]=[CH:4][N:3]=1.[C:16]([O:20][C:21]([NH:23][CH2:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([NH:23][CH2:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:30][S:12]([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:6]=2[CH:5]=[CH:4][N:3]=[CH:2]3)(=[O:14])=[O:13])=[CH:27][CH:26]=1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Reactant: CC(C)(C)OC(=O)NCc1ccc(CN)cc1
Agent: Cl
Product: CC(C)(C)OC(=O)NCc1ccc(CNS(=O)(=O)c2cccc3cnccc23)cc1
Yield: 82.7 %

Procedure:
According to Reference Example 5, Step B, a reaction was performed by using isoquinoline-5-sulfonyl chloride hydrochloride (10 g) and Intermediate 59 (8.96 g) to obtain the title compound (13.39 g).
Reaction SMILES: [F:1][CH:2]([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:16]=[CH:15][C:14]([CH:17]=[CH2:18])=[CH:13][N:12]=2)=[CH:6][CH:5]=1.[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][C:31](I)=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.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.C(Cl)(Cl)Cl.[Pd].[Pd]>[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][C:31](/[CH:18]=[CH:17]/[C:14]2[CH:15]=[N:16][C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([O:3][CH:2]([F:1])[F:19])=[CH:5][CH:6]=3)=[N:12][CH:13]=2)=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C=Cc1cnc(Nc2ccc(OC(F)F)cc2)nc1
Reactant: Ic1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: FC(F)Oc1ccc(Nc2ncc(/C=C/c3ccc(OCc4ccccc4)cc3)cn2)cc1
Temperature: 90 °C
Yield: 69.7 %

Procedure:
To a solution of N-(4-(difluoromethoxy)phenyl)-5-vinylpyrimidin-2-amine (0.102 g, 0.387 mmol) in ACN (3 mL) were added 1-(benzyloxy)-4-iodobenzene (0.1 g, 0.322 mmol), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (0.033 g, 0.032 mmol), tri-o-tolylphosphine (0.039 g, 0.129 mmol), and TEA (0.135 mL, 0.967 mmol). The reaction mixture was flushed with N2 and heated at 90° C. overnight. Solvent was evaporated, and the residue was dissolved in ethyl acetate, filtered through celite and concentrated. The crude product was purified by flash chromatography on silica gel using 30% ethyl acetate in hexanes to give (E)-5-(4-(benzyloxy)styryl)-N-(4-(difluoromethoxy)phenyl)pyrimidin-2-amine (0.1 g, 70%). 1H NMR (400 MHz, DMSO-d6) δ ppm 5.14 (s, 2H), 6.93-7.30 (m, 7H), 7.34-7.52 (m, 2H), 7.78-7.80 (m, 2H), 8.71 (s, 2H), 9.82 (s, 1H). LCMS: RT 1.18 min, (M+H)+446.6.