Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:17]=[CH:16][C:6]([CH2:7][CH2:8][NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])=[CH:5][CH:4]=1)#[N:2].C1C=CC=CC=1.[CH:24]([NH:26][NH2:27])=O>CCO.N1C=CC=CC=1>[N:26]1[N:27]=[C:1]([C:3]2[CH:4]=[CH:5][C:6]([CH2:7][CH2:8][NH:9][C:10](=[O:15])[C:11]([F:12])([F:13])[F:14])=[CH:16][CH:17]=2)[NH:2][CH:24]=1
Reactant: N#Cc1ccc(CCNC(=O)C(F)(F)F)cc1
Reactant: NNC=O
Solvent: CCO
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C(NCCc1ccc(-c2nnc[nH]2)cc1)C(F)(F)F
Temperature: 25 °C

Procedure:
(N-(4-cyanophenethyl)-2,2,2-trifluoroacetamide (0.61 g, 2.52 mmol) was azeotroped with benzene and was dissolved in 10 mL of anhydrous EtOH. To this solution dry HCl was bubbled though for 90 min at 0 C. The solvent was evaporated to dryness under high vacuum to give a yellow solid. This yellow solid and formohydrazide (151 mg, 2.52 mmol) was dissolved in 10 mL of dry pyridine and the resulting solution was refluxed for 2 h. After cooling to RT, pyridine was evaporated and the residue was treated with 5% HCl, extracted with EtOAc, dried over Na2SO4, filtered, and evaporated to dryness. Flash chomatography (SiO2, EtOAc/DCM=1:1 to Dcm/MeOH=10:1) afforded N-(4-(4H-1,2,4-triazol-3-yl)phenethyl)-2,2,2-trifluoroacetamide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]([OH:12])=[C:10]([O:13]C)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.B(Br)(Br)Br>ClCCl.CO>[Cl:1][C:2]1[C:11]([OH:12])=[C:10]([OH:13])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:16][CH2:17]1
Reactant: COc1cc2c(c(Cl)c1O)c(=O)c(C(=O)O)cn2C1CC1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: O=C(O)c1cn(C2CC2)c2cc(O)c(O)c(Cl)c2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.4 %

Procedure:
To a solution of 5-chloro-1-cyclopropyl-6-hydroxy-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (8.5 g, 27.4 mmol) in Dichloromethane (DCM) (100 mL) was added BBr3 (6.49 mL, 68.6 mmol) at −78° C. The mixture was allowed to warm up to rt. and stirred at rt overnight. LCMS indicated completion of the reaction. The mixture was diluted with MeOH and concentrated to dryness. This procedure was repeated several times to afford 5-chloro-1-cyclopropyl-6,7-dihydroxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (7.8 g, 26.4 mmol, 96% yield) as yellow solid. LCMS: [M+H]+: 296.1.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:9])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CC(C)=O.C(OCC)(=O)C>[CH2:16]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[C:3]=1[F:9])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cccc(Br)c1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: Fc1c(Br)cccc1OCc1ccccc1
Reaction time: 0.08 h
Yield: 105.7 %

Procedure:
To a solution of 3-bromo-2-fluorophenol (1.8 g, 9.42 mmol) in acetone (25 ml) was added sodium carbonate (2.55 g, 20 mmol) and the mixture was stirred for 5 min. Benzylbromide (1.2 ml, 10.3 mmol) was added and the reaction mixture was heated at reflux for 20 h. Water (50 ml) and ethyl acetate (50 ml) was added and the phases were separated. The aqueous phase was extracted with ethyl acetate (2×50 ml) and the combined organic phases was dried (MgSO4) and evaporated under reduced pressure to give an oil. The residue was purified by flash column chromatography (isooctane/ethyl acetate, 5:1) to give the title compound (2.8 g). MS m/z (rel. intensity, 70 eV) 282 (M+, 2), 280 (M+, 2), 163 (2), 161 (2), 91 (bp).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][N:8]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[CH:18]=1.ClC1C=CC2N=CCN=C(C3C=CC=CC=3)C=2C=1.C(O)(=O)C.[SH:41][CH2:42][CH2:43][OH:44]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH:10]([S:41][CH2:42][CH2:43][OH:44])[CH2:9][N:8]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[CH:18]=1
Reactant: Clc1ccc2c(c1)C(c1ccccc1)=NCCN2
Reactant: OCCS
Agent: Clc1ccc2c(c1)C(c1ccccc1)=NCC=N2
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: OCCSC1CN=C(c2ccccc2)c2cc(Cl)ccc2N1

Procedure:
7-chloro-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine (10 g) was oxidized to 7-chloro-5-phenyl-3H-1,4-benzodiazepine as described in Example 1 with the addition of 0.1 ml of acetic acid. The crude oxidation product was taken up in THF (60 ml), treated with 2-mercaptoethanol (10 ml ) and heated under reflux overnight. The resulting solution was concentrated under reduced pressure until the product began to crystallize and then diluted with 100 ml of ether. The product was collected and washed with ether to give the above-named product as colorless crystals, mp 135°-140° (dec).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH3:9].Br[CH2:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15]>>[CH3:15][C:14]([CH3:17])([CH3:16])[C:13]([C:12]1[S:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]=1[CH3:9])=[O:18]
Reactant: CC(=O)c1ccccc1S
Reactant: CC(C)(C)C(=O)CBr
Product: Cc1c(C(=O)C(C)(C)C)sc2ccccc12

Procedure:
The title compound was prepared from 1-(2-mercaptophenyl)ethanone and 1-bromopinacolone using the procedure in Step B Examples 36˜49. 1H NMR (CDCl3, 500 MHz) 7.82˜7.88 (m, 2H), 7.44˜7.50 (m, 2H), 2.60 (s, 3H), 1.41 (s, 9H). LC-MS: 4.06 min. (m/Z=233.4, 191).
Reaction SMILES: [C:1]([C:3](=[CH:13]OCC)[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:5])#[N:2].Cl.[NH:18]([C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([O:25][CH3:26])=[O:24])[NH2:19].CCN(C(C)C)C(C)C.CCOCC>C(O)C>[NH2:2][C:1]1[N:18]([C:20]2[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=2)[C:23]([O:25][CH3:26])=[O:24])[N:19]=[CH:13][C:3]=1[C:4](=[O:5])[NH:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CCOC=C(C#N)C(=O)NC1CCCCC1
Reactant: COC(=O)c1cccc(NN)c1
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc(-n2ncc(C(=O)NC3CCCCC3)c2N)c1
Temperature: 70 °C
Yield: 47.4 %

Procedure:
2-cyano-N-cyclohexyl-3-ethoxy-prop-2-enamide (Intermediate #17) (605 mg, 2.73 mmol) and methyl 3-hydrazinylbenzoate hydrochloride (552 mg, 2.73 mmol) were suspended in ethanol (20 mL). DIPEA (352 mg, 2.73 mmol) was added and the mixture heated to 70° C. for 1 h. The reaction mixture was cooled to ambient and concentrated to a small volume. Water (50 mL) was added and the resulting solid recovered by filtration, redissolved in ethyl acetate (50 mL), dried (MgSO4) and evaporated to give a brown solid which was slurried with ether and recovered by filtration to give the title compound as light brown solid (443 mg, 47%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Br:22])=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C:6]=2[C:18]([NH:20][CH3:21])=[O:19].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl.N1C=CC=CC=1.O>[Br:22][C:3]1[C:2]([NH:1][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:10][C:9]2[C:5](=[C:6]([C:18]([NH:20][CH3:21])=[O:19])[N:7]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[N:8]=2)[CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: CNC(=O)c1c2cc(Br)c(N)cc2nn1-c1ccc(F)cc1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CNC(=O)c1c2cc(Br)c(NS(C)(=O)=O)cc2nn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
To a degassed solution of 6-amino-5-bromo-2-(4-fluorophenyl)-N-methyl-2H-indazole-3-carboxamide (0.75 g, 2.1 mmol) in DCM/Pyridine (10 mL/3 mL) was added MsCl (1.2 g, 10.5 mmol) under N2 at 0° C. for 30 min. The reaction was stirred at 25° C. for 8 hours. The reaction mixture was diluted with water, extracted with EtOAc and washed with brine, and then dried over Na2SO4. After concentration, the residue was purified by column chromatography (PE:EA=2:1) to give crude 5-bromo-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)-2H-indazole-3-carboxamide (0.65 g, yield: 78%). 1H-NMR (CDCl3, 400 MHz) δ 8.30 (s, 1H), 8.03 (s, 1H), 7.56˜7.60 (m, 2H), 7.20˜7.25 (m, 2H), 6.97 (s, 1H), 5.73 (s, 1H), 3.08 (s, 3H), 2.99 (d, J=4.8 Hz, 3H). MS (M+H)+: 441/443.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.N1C=CC=CC=1.Cl[C:49]([O:51][C:52]1[CH:57]=[CH:56][C:55]([N+:58]([O-:60])=[O:59])=[CH:54][CH:53]=1)=[O:50]>ClCCl>[C:49](=[O:50])([O:51][C:52]1[CH:53]=[CH:54][C:55]([N+:58]([O-:60])=[O:59])=[CH:56][CH:57]=1)[O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][C@H:16]([NH:25][C:26]([O:27][C@@H:28]2[C@H:35]3[C@H:31]([O:32][CH2:33][CH2:34]3)[O:30][CH2:29]2)=[O:36])[C@H:15]([OH:37])[CH2:14][N:13]([S:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)(=[O:12])=[O:11])[CH2:38][CH:39]([CH3:41])[CH3:40])=[CH:19][CH:20]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-(4-hydroxybenzyl)propylcarbamate (0.5 g, 0.84 mmol) in dichloromethane (4 mL) at 0° C. was added pyridine (0.16 mL, 0.158 g, 2.0 mmol) and 4-nitrophenyl chloroformate (0.22 g, 1.09 mmol) and the mixture was stirred at ambient temperature for 1 h. Dichloromethane was added and the mixture was washed with 15% citric acid/water (2×), saturated sodium bicarbonate/water, dried (sodium sulfate), evaporated, and purified by chromatography (silica gel, dichloromethane/methanol, 49:1) to provide the title compound as a solid foam (0.5 g, 79% yield). 1H NMR (DMSO-d6): δ 0.78 (3H, d), 0.82 (3H, d), 1.16 (1H, dd), 1.3-1.4 (1H, m), 1.9-2.0 (1H, m), 2.42 (1H, t), 2.65-2.80 (3H, m), 3.0 (2H, dd), 3.3-3.4 (1H, m), 3.5-3.6 (4H, m), 3.7 (1H, t), 3.8 (1H, dd), 4.8 (1H, dt), 5.1 (1H, d), 5.5 (1H, d), 6.18 (2H, s), 7.05 (1H, d), 7.2-7.4 (7H, m), 7.7 (2H, d), 8.35 (2H, d)
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](Cl)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:21])(=O)C.[CH3:22][NH:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1.[OH-].[Na+]>C1COCC1.CO>[C:28]([C:27]1[CH:30]=[CH:31][C:24]([N:23]([C:13](=[C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[NH:4][C:5]2=[O:21])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH3:22])=[CH:25][CH:26]=1)#[N:29]
Reactant: CNc1ccc(C#N)cc1
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2ccccc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C(=C1C(=O)Nc2ccccc21)c1ccccc1)c1ccc(C#N)cc1

Procedure:
Prepared analogously to Example 2 from 1-acetyl-3-(1-chloro-1-phenyl-methylidene)-2-indolinone and 4-methylamino-benzonitrile in THF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: C([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([Br:30])[C:22]([N:23]3[CH2:28][CH2:27][CH2:26][CH:25]([CH3:29])[CH2:24]3)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:31])C1C=CC=CC=1.FC(F)(F)C([O-])=O.FC(F)(F)C([O-])=O.FC(F)(F)C([O-])=O.[B+3].O.CO>C(O)(C(F)(F)F)=O>[Br:30][C:21]1[C:22]([N:23]2[CH2:28][CH2:27][CH2:26][CH:25]([CH3:29])[CH2:24]2)=[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:16]2=[C:17]([CH:20]=1)[C:18](=[O:19])[N:9]([OH:8])[C:10]3=[O:31]
Reactant: CC1CCCN(c2c(Br)cc3c4c(cccc24)C(=O)N(OCc2ccccc2)C3=O)C1
Agent: O=C([O-])C(F)(F)F
Agent: [B+3]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CO
Product: CC1CCCN(c2c(Br)cc3c4c(cccc24)C(=O)N(O)C3=O)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
To a solution of 2-benzyloxy-5-bromo-6-(3-methyl-piperidin-1-yl)-benzo[de]isoquinoline-1,3-dione (0.24 g, 0.50 mmol, from Example U1) in TFA (8.0 mL) at 0° C. was added a 1.0 M solution of boron tris(trifluoroacetate) in TFA (5 mL). The reaction was stirred at 0° C. for 2 hours, then poured into a solution of water/methanol (1:1), and extracted with chloroform. The organic layer was dried over MgSO4, filtered, and the solvent removed under vacuum to give 0.19 g of the title compound as the TFA salt, mp>250° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1)([CH3:3])[CH3:2].[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]C>C1COCC1>[Br-:18].[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N+:13]1[CH:17]=[CH:16][N:15]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:14]=1)([CH3:2])[CH3:3]
Reactant: CC(C)c1cccc(C(C)C)c1-n1ccnc1
Reactant: CCCCCCCBr
Solvent: C1CCOC1
Product: CCCCCCn1cc[n+](-c2c(C(C)C)cccc2C(C)C)c1
Product: [Br-]

Procedure:
According to the general synthesis procedure 4.4 mmol (1.00 g) 1-(2,6-diisopropylphenyl)imidazole and 5.3 mmol (0.940 g, 0.83 ml) 1-bromoheptane are dissolved in 5 ml THF and heated for 20 h to 110° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[CH3:2].[CH2:16]([Mg]Cl)[CH3:17].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]([CH2:16][CH3:17])[CH:7]=1)[CH3:2]
Reactant: CC[Mg]Cl
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc([N+](=O)[O-])c(CC)c1
Reaction time: 0.5 h

Procedure:
To a solution of 4-nitrophenylacetic acid ethyl ester (1.63 g) in tetrahydrofuran (100 mL) was dropwise added 2M ethyl magnesium chloride in tetrahydrofuran (3 mL) at −15° C. under argon atmosphere, and the mixture was stirred at the same temperature for 30 minutes. After further dropwise addition of 2M ethyl magnesium chloride in tetrahydrofuran (3 mL), the mixture was stirred at −15° C. for one hour, and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (3.0 g) was added thereto at the same temperature. The mixture was stirred overnight, and water (300 mL) was added thereto, followed by extraction with chloroform (150 mL×3). The organic layers were combined, washed with saturated brine, dried over sodium sulfate and purified by column chromatography on silica gel with hexane:ethyl acetate=10:1 to give the title compound (1.09 g).
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[N:10]=[C:9]([NH:11][CH3:12])[C:8]([N+:13]([O-:15])=[O:14])=[CH:7][CH:6]=1.O>CO>[CH3:1][O:2][C:5]1[N:10]=[C:9]([NH:11][CH3:12])[C:8]([N+:13]([O-:15])=[O:14])=[CH:7][CH:6]=1
Reactant: C[O-]
Reactant: CNc1nc(Cl)ccc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CNc1nc(OC)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
19 ml of a 28% methanolic solution of sodium methoxide were added dropwise to a solution of 6.00 g of 6-chloro-2-methylamino-3-nitropyridine (prepared as described in Preparation 66) in 120 ml of methanol at room temperature, and the resulting mixture was stirred at room temperature for 3 hours. At the end of this time, the reaction mixture was poured into water, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue was crystallized by trituration with ethanol, to give 5.34 g of the title compound, melting at 152-153° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]([NH:11][C:12]([CH3:15])(C)C)[C:8]([O-:10])=O.N1C=CC=C1C(NC1[CH:33](C(O)=O)[C:32](=[O:37])[C:31]2[C:26](=[CH:27][C:28]([Cl:38])=[CH:29][CH:30]=2)[N:25]=1)=O.C(N=C=NC(C)C)(C)C.[O:48]1CCCC1>>[Cl:38][C:28]1[CH:29]=[CH:30][C:31]2[C:32](=[O:37])[C:33]3[C:8](=[O:10])[N:7]([CH2:6][C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)[N:11]=[C:12]([OH:48])[C:15]=3[NH:25][C:26]=2[CH:27]=1
Reactant: C1CCOC1
Reactant: O=C(NC1=Nc2cc(Cl)ccc2C(=O)C1C(=O)O)c1ccc[nH]1
Reactant: CC(C)(C)NN(Cc1cccs1)C(=O)[O-]
Agent: CC(C)N=C=NC(C)C
Product: O=c1c2ccc(Cl)cc2[nH]c2c(O)nn(Cc3cccs3)c(=O)c12
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 2-(thiophen-2-ylmethyl)-t-butylcarbazate (1.0 g, 4.4 mM) and 2-pyrrolamido-3-carboxy-7-chloroquinoline-4-one (1.2 g, 3.6 mM) in tetrahydrofuran (75 mL) stirred at room temperature, was added diisopropylcarbodiimide (0.84 mL, 5.4 mM). This mixture was stirred at room temperature for 2.5 hours, then suction filtered into a second reaction flask. To the filtrate (stirred at room temperature) was added methanesulfonic acid (12 mL, 185 mM). The resulting solution was stirred 17 hours at room temperature. TLC analyses at this time indicated complete reaction. The reaction mixture was poured into ice water (200 mL). This suspension was stirred about 15 minutes and filtered. The filter cake was washed with water and ether, then vacuum dried to yield the desired compound analytically pure (1.1 g, 84%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:25])[CH2:11][N:10]([CH:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9]2)=[C:4]([F:26])[CH:3]=1.C(=O)(O)[O-].[Na+].Cl[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34]>CC(C)=O.O>[C:33]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:25])[CH2:9][N:10]([CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:11]2)=[C:4]([F:26])[CH:3]=1)([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34]
Reactant: Nc1ccc(C2(O)CN(C(c3ccccc3)c3ccccc3)C2)c(F)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(Nc1ccc(C2(O)CN(C(c3ccccc3)c3ccccc3)C2)c(F)c1)OCc1ccccc1
Reaction time: 8 h

Procedure:
To a solution of 3-(4-amino-2-fluorophenyl)-3-hydroxy-1-(1,1-diphenylmethyl)azetidine (Example 81, Step 1, 5.10 g, 14.7 mmol) in acetone (75 mL) was added a solution of sodium bicarbonate (2.52 g, 30.0 mmol) in water (40 mL) to give a creamy suspension. Benzyl chloroformate (2.57 g, 15.1 mmol) was added and stirring continued overnight. The suspension was filtered and the acetone evaporated. The residue was partitioned between ethyl acetate (200 mL) and water (50 mL). The organic layer was washed with brine (50 mL), dried over magnesium sulfate, filtered and evaporated to leave an amber foam. Chromatography over silica gel (150 g, 40-60 μM) eluting with 1-2% methanol-methylene chloride gave the title compound as a cream foam. HRMS: meas. 483.2087, theory 483.2084.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.[CH:17]1([S:23](Cl)(=[O:25])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C(Cl)Cl>[CH2:8]([NH:9][S:23]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)(=[O:25])=[O:24])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)C1CCCCC1
Reactant: NCCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(NCCc1ccccc1)C1CCCCC1
Reaction time: 0.08 h

Procedure:
To a stirred solution of 2-phenylethylamine (0.60 g, 4.97 mmol) in 45 ml CH2Cl2 at room temperature was added Et3N (0.83 ml, 5.97 mmol). The mixture was stirred for 5 min, and then cyclohexanesulfonyl chloride (1.0 g, 5.47 mmol) was added at this temperature.
Reaction SMILES: [CH:1]([NH2:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][CH2:18]Cl.C(O)CCC.C(=O)([O-])[O-].[K+].[K+]>O>[CH:1]([N:14]1[CH2:18][CH2:17][CH2:16]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: O
Product: c1ccc(C(c2ccccc2)N2CCC2)cc1

Procedure:
Step 1, heating benzhydrylamine and 1-bromo-3-chloropropane in admixture with butanol, water and potassium carbonate to give N-benzhydrylazetidine and separating said N-benzhydrylazetidine therefrom;
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].[CH3:28][NH:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:24][O:23][C:13]1[C:11]2[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([N:29]([CH3:28])[CH2:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[CH:3]=3)[S:9][C:10]=2[C:16]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:15][CH:14]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: CNCCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(N(C)CCc4ccccn4)c3)nc12
Temperature: 140 °C
Yield: 70.5 %

Procedure:
A stirred suspension of 200 mg (0.45 mmol) 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide, 1.23 ml (8.90 mmol) 2-(2-methylaminoethyl)pyridine and 290 mg (0.89 mmol) cesium carbonate in a thick-walled glass pressure tube fitted with a teflon cap was heated at 140° C. for 24 h. The reaction mixture was then cooled to room temperature and poured onto water. The mixture was extracted three times with dichloromethane, and the combined organic phases were washed with saturated brine, dried over sodium sulfate, and concentrated in vacuo. Flash chromatography (0/100-2.5/97.5 methanol/dichlormoethane) followed by trituration in ether afforded 160 mg (71%) N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-[methyl-(2-pyridin-2-yl-ethyl)-amino]-isonicotinamide as a light yellow crystalline solid. ES-MS m/e (%): 505 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH:7]2[CH2:10][NH:9][CH2:8]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Cl:22][C:23]1[CH:28]=[C:27](Cl)[CH:26]=[CH:25][N:24]=1>C(O)(C)C>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:9]2[CH2:8][CH:7]([O:6][C:5]3[CH:11]=[CH:12][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:10]2)[N:24]=1
Reactant: Fc1ccc(OC2CNC2)cc1
Reactant: Clc1ccnc(Cl)c1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(OC2CN(c3cccc(Cl)n3)C2)cc1
Temperature: 80 °C
Yield: 53.2 %

Procedure:
To a solution of 3-(4-fluorophenoxy)azetidine (557 mg, 3.37 mmol) [prepared as described in Example AAA] in isopropanol (10 mL, 3 mL/mmol) was added DIPEA (1.5 mL, 8.42 mmol) and 2,4-dichloropyridine (500 mg, 3.37 mmol) and the mixture was heated at 80° C. for 7 h. The reaction mixture was concentrated under reduced pressure and extracted with EtOAc (2×20 mL). The organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Purification by silica gel column chromatography provided 2-chloro-6-(3-(4-fluorophenoxy)azetidin-1-yl)pyridine (500 mg, 55%) as a solid. Observed mass (M+1): 279.1.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH2:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=1.O.[OH-].[Li+]>CO.O>[O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc(CN2CCCCC2=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(CN2CCCCC2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
Methyl 4-[(2-oxopiperidino)methyl]benzoate (2.47 g, 10.0 mmol) obtained in Step 1 was dissolved in a mixed solvent of methanol (30 mL) and water (10 mL), and lithium hydroxide monohydrate (2.10 g, 50.0 mmol) was added thereto, followed by stirring at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and 6 mol/L hydrochloric acid was added to the resulting residue to adjust the pH to 1, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure to afford 4-[(2-oxopiperidino)methyl]benzoic acid (629 mg. 27%).