Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:33]=[CH:32][C:5]([C:6](/[N:8]=C2\NC3C=CC(CO)=CC=3N\2[C@H]2CC[C@@H](C(=O)NC(C)C)CC2)=[O:7])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.Cl.N1CC(C(O)(C)C)C1.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[C:6]([NH2:8])(=[O:7])[C:5]1[CH:32]=[CH:33][CH:2]=[CH:3][CH:4]=1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CO)cc32)CC1
Agent: CC(C)(O)C1CNC1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: NC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
To a 0° C. cooled solution of (E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide (100 mg, 0.221 mmol) in DCM (5 mL) was added thionyl chloride (0.081 mL, 1.105 mmol) dropwise, and the reaction was stirred at 0° C. for 30 minutes. The solvent was removed on a rotovap, and the residue suspended in ACN (2 mL) and re-concentrated to remove residual thionyl chloride. The residue was resuspended in DMF (2 mL), cooled to 0° C., and 2-(azetidin-3-yl)propan-2-ol hydrochloride (101 mg, 0.663 mmol) and DBU (0.10 mL, 0.663 mmol) were added. After stirring for 16 hours at RT, the reaction mixture was concentrated and purified by reverse-phase preparative HPLC, using 0.1% TFA in ACN/water, (gradient 15% to 90%). The product fractions were combined, neutralized with saturated aqueous NaHCO3, and extracted with EtOAc (×2). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to provide (E)-4-fluoro-N-(6-((3-(2-hydroxypropan-2-34)azetidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene) as a white powder benzamide (26 mg, 21.4% yield). MS, m/z (C31H40FN5O3): calcd, 549.3. found, 549.9 [M+H].
Reaction SMILES: [C:1]1([N:7]2[C:25](=[O:26])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[CH:15][C:16]([N:19]5[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]5)=[N:17][C:18]=4[C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:27]C1CNCCN1>>[CH3:27][CH:23]1[NH:22][CH2:21][CH2:20][N:19]([C:16]2[CH:15]=[CH:14][C:13]3[NH:12][CH:11]=[C:10]4[C:25](=[O:26])[N:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[N:8]=[C:9]4[C:18]=3[N:17]=2)[CH2:24]1
Reactant: CC1CNCCN1
Reactant: O=c1c2c[nH]c3ccc(N4CCNCC4)nc3c-2nn1-c1ccccc1
Product: CC1CN(c2ccc3[nH]cc4c(=O)n(-c5ccccc5)nc-4c3n2)CCN1

Procedure:
The title compound was prepared following the procedure described for 6a using 2-methylpiperazine instead of piperazine. 1H-NMR (DMSO-d6) δ (ppm): 1.00 (3H, s), 2.78 (4H, brm), 3.05 (1H, m), 4.30 (2H, m), 7.07 (2H, m), 7.39 (2H, dd, J=8.24, 7.97 Hz), 7.75 (1H, d, J=9.34 Hz), 8.27 (2H, dd, J=7.42, 1.10 Hz), 8.37 (1H, s). m/z 361.4 (MH+).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=1[F:21].C(O[B:26]1[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]1)(C)C>C1COCC1.CCOCC>[F:13][C:14]1[C:15]([F:21])=[C:16]([CH3:20])[CH:17]=[CH:18][C:19]=1[B:26]1[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Cc1cccc(F)c1F
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1F
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 50.5 %

Procedure:
A 2.5 M solution of n-butyllithium (3.4 mL, 8.5 mmol) was added to a stirred solution of diisopropylamine (1.2 mL, 8.5 mmol) in THF (25 mL) at −20° C. The resulting solution was stirred at −20° C. for 10 minutes, then cooled to −78° C. A solution of 1,2-difluoro-3-methylbenzene (1.0 g, 7.8 mmol) in THF was added dropwise and stirred at −78° C. for 2 h. 2-Isopropoxy-4,4,5,5-tetramethyl[1,3,2]dioxaborolane (1.6 g, 8.6 mmol) in THF was then added and the brown solution was slowly warmed to 23° C. over 16 hours. The reaction mixture was then added to ether and extracted with water and with 0.1N sodium hydroxide. The combined aqueous extracts were acidified with concentrated HCl then extracted with dichloromethane. The organic phase was dried and concentrated to give the title compound (1.0 g, 50% yield): 1H NMR (CDCl3): δ 7.32 (m, 1H), 6.92 (m, 1H), 2.31 (s, 3H), 1.32 (s, 12H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:17]2[CH:18]=[N:19][C:20]([C:23](=[O:26])[NH:24][CH3:25])=C[CH:22]=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4].COC(C1C=C(OC2C=[N:45]C(C(O)=O)=NC=2)C2CC(C)(C)OC=2C=1)=O.CN>>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[N:45][C:20]([C:23](=[O:26])[NH:24][CH3:25])=[N:19][CH:18]=2)[C:8]2[CH2:9][C:10]([CH3:12])([CH3:13])[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(Oc2cnc(C(=O)O)nc2)c2c(c1)OC(C)(C)C2
Reactant: CNC(=O)c1ccc(Oc2cc(C(=O)OC)cc3c2CC(C)(C)O3)cn1
Agent: CN
Product: CNC(=O)c1ncc(Oc2cc(C(=O)OC)cc3c2CC(C)(C)O3)cn1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 166b, from 5-(6-methoxycarbonyl-2,2-dimethyl-2,3-dihydro-benzofuran-4-yloxy)-pyrimidine-2-carboxylic acid (171c) (72.3 mg, 0.21 mmol) and methyl amine (2 mL, 2.0 M solution in THF) to give a white solid (45 mg, 60% yield). 1H NMR (400 MHz, CDCl3) δ 8.53 (s, 2 H) 7.88 (d, J=3.79 Hz, 1 H) 7.28 (d, J=110.11 Hz, 1 H) 7.19 (s, 1 H) 3.88 (s, 3 H) 3.08 (d, J=5.05 Hz, 3 H) 2.92 (s, 2 H) 1.49 (s, 6 H); LCMS for C18H19N3O5 m/z 358.20 (M+H+).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][C:4]=1[F:17].[H-].[Na+].[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1.O>CN(C)C=O.C(OCC)(=O)C>[CH2:10]([O:9][C:6]1[CH:7]=[CH:8][C:3]([N:2]([CH3:1])[C:28]([NH:27][C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)=[O:29])=[C:4]([F:17])[CH:5]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CNc1ccc(OCc2ccccc2)cc1F
Reactant: O=C=Nc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)Nc1ccc(F)cc1)c1ccc(OCc2ccccc2)cc1F
Temperature: 95 °C
Reaction time: 0.75 h
Yield: 26.7 %

Procedure:
N-Methyl-4-benzyloxy-2-fluoroaniline (250 mg, 1.0805 mmol) was dissolved in N,N-dimethylformamide (5.0 ml), and then sodium hydride (65 mg, 1.6207 mmol, 60% in oil) was added and the mixture was stirred at 95° C. for 45 minutes under a nitrogen atmosphere. After adding 4-fluorophenyl isocyanate (0.14 ml, 1.1836 mmol), the mixture was stirred at 85° C. for 45 minutes under a nitrogen atmosphere. There was further added 4-fluorophenyl isocyanate (0.14 ml, 0.5094 mmol), and the mixture was stirred at 85° C. for 30 minutes under a nitrogen atmosphere. After cooling to room temperature, water was added to the reaction solution, extraction was performed with ethyl acetate, the extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was adsorbed onto NH silica gel and purified by NH silica gel column chromatography (hexane-ethyl acetate system) to obtain the title compound (0.105 g, 0.2881 mmol, 21.67%) as a light yellow oil.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([NH:14][C:15]3([C:18]([F:21])([F:20])[F:19])[CH2:17][CH2:16]3)=[O:13])[CH:9]=[CH:8][C:7]=2[N:22]2[CH2:25][C:24]([F:27])([F:26])[CH2:23]2)[CH2:3][CH2:2]1.[CH3:28][C:29]([O-])(CC)C.[Na+].ICC>CN(C=O)C>[CH2:28]([N:14]([C:15]1([C:18]([F:21])([F:20])[F:19])[CH2:16][CH2:17]1)[C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:22]2[CH2:25][C:24]([F:27])([F:26])[CH2:23]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)[N:11]=1)=[O:13])[CH3:29]
Reactant: CCC(C)(C)[O-]
Reactant: O=C(NC1(C(F)(F)F)CC1)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCI
Product: CCN(C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)C1(C(F)(F)F)CC1
Reaction time: 1 h
Yield: 75 %

Procedure:
A solution of 6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)-N-(1-(trifluoromethyl)cyclopropyl)picolinamide (Example 16 a), 15 mg, 38 μmol) and sodium 2-methylbutan-2-olate (5 mg, 46 μmol) in DMF (150 μL) was stirred for 15 minutes at ambient temperature. Iodoethane (9 mg, 7 μL, 58 μmol) was added and stirring was continued for 1 h. The reaction mixture was poured onto ice/sat. aqueous NaHCO3 solution (15 mL) and extracted with EtOAc (2×25 mL). The combined extracts were washed with ice/brine (2×20 mL), dried over Na2SO4 and brought to dryness. The crude product was purified by preparative TLC (silica gel, 1 mm, heptan/EtOAc 2:1, elution with EtOAc) to give the title compound (12 mg, 75%) as colorless oil; MS (EI): m/e=420.2 [MH]+.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([Cl:13])[N:12]=1)[C:7]([OH:9])=[O:8].[CH2:14]([OH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.I[CH2:23]I.[Cl-].[Na+]>CN(C=O)C>[CH3:23][O:9][C:7](=[O:8])[C:6]1[CH:10]=[C:11]([Cl:13])[N:12]=[C:4]([O:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:5]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)c1cc(Cl)nc(Cl)c1
Reactant: ICI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)nc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79 %

Procedure:
Add sodium hydride (1.15 g, 28.75 mmol 60% in mineral oil) to a suspension of 2,6-dichloroisonicotinic acid (2 g, 10.42 mmol) at 0° C. in DMF (40 mL). Warm to room temperature and stir for 10 min. Add benzyl alcohol (1.35 mL, 13.045 mmol) dropwise and heat to 80° C. for 1 h. Cool to room temperature, add diiodomethane (2 mL) and stir for 30 min. Pour into saturated aqueous sodium chloride and partition between ethyl acetate and water. Dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 5:95 ethyl acetate:hexanes) to give the title compound as a colorless oil (2.3 g, 79%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[F:12][C:13]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:14]=1[NH2:15]>>[F:12][C:13]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:14]=1[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Nc1ccc(I)cc1F
Product: O=C(O)Cc1ccccc1Nc1ccc(I)cc1F

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2-fluoro-4-iodoaniline to yield 2-[(2-fluoro-4-iodophenyl)amino]phenylacetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C:8](=O)[CH2:7][CH2:6]2.[N+](C1C=CC=CC=1S([N:26]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1)[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][NH2:35])=[CH:30][CH:29]=1)(=O)=O)([O-])=O.[BH3-]C#N.[Na+].C(OC)(OC)OC>CO.C(O)(=O)C>[N:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[CH2:36][NH:26][CH2:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][NH:35][CH:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:9]2)=[CH:32][CH:33]=1
Reactant: NCc1ccc(CN(Cc2ccccn2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Reactant: COc1ccc2c(c1)CCC(=O)C2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: COC(OC)OC
Product: COc1ccc2c(c1)CCC(NCc1ccc(CNCc3ccccn3)cc1)C2
Yield: 58.5 %

Procedure:
Using General Procedure G: 6-methoxy-2-tetralone (112 mg, 0.63 mmol), N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-1,4-benzenedimethanamine (186 mg, 0.45 mmol) and NaBH3CN (110 mg, 1.76 mmol) in a mixture of MeOH (5 mL), trimethyl orthoformate (2.8 mL) and acetic acid (5 drops) were reacted for 3.5 hours. Purification of the crude material by chromatography on silica gel (CH2Cl2/MeOH/NH4OH 98:1:1) gave the desired product (102 mg, 40%) as a yellow foam.
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O.[O:17]=[C:18]1[C:27]2([CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:26][C:25]2[C:20](=[N:21][CH:22]=[C:23](/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36])[CH:24]=2)[NH:19]1>ClCCCl>[CH3:1][N:30]1[CH2:31][CH2:32][C:27]2([CH2:26][C:25]3[C:20](=[N:21][CH:22]=[C:23](/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36])[CH:24]=3)[NH:19][C:18]2=[O:17])[CH2:28][CH2:29]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=C(O)/C=C/c1cnc2c(c1)CC1(CCNCC1)C(=O)N2
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Product: CN1CCC2(CC1)Cc1cc(/C=C/C(=O)O)cnc1NC2=O
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Sodium triacetoxyborohydride (671 mg, 3.17 mmol) and paraformaldehyde (95 mg, 3.17 mmol) were successively added to a suspension of (E)-3-(2-oxo-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4′-piperidine]-6-yl)acrylic acid (455 mg, 1.58 mmol) in 1,2-dichloroethane (40 mL) at room temperature. The reaction mixture was then heated to 70° C. and stirred for 2 hours. The reaction mixture was cooled to room temperature, the precipitated product filtered and washed with H2O (50 mL) and MeOH (3×50 mL) and dried. The title product was obtained as a white solid (319 mg, 66%, py 74.1%).
Reaction SMILES: Cl[C:2]([N:4]1[CH2:10][C:9]2[CH:11]=[C:12]([C:15]3[CH:16]=[CH:17][C:18]4[N:22]=[CH:21][N:20](C(OC(C)(C)C)=O)[C:19]=4[CH:30]=3)[CH:13]=[CH:14][C:8]=2[O:7][CH2:6][CH2:5]1)=[O:3].[NH:31]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.F[C:39](F)(F)C(O)=O>ClCCl>[N:31]1([C:2]([N:4]2[CH2:10][C:9]3[CH:11]=[C:12]([C:15]4[CH:16]=[CH:17][C:18]5[N:22]=[C:21]([CH3:39])[NH:20][C:19]=5[CH:30]=4)[CH:13]=[CH:14][C:8]=3[O:7][CH2:6][CH2:5]2)=[O:3])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)n1cnc2ccc(-c3ccc4c(c3)CN(C(=O)Cl)CCO4)cc21
Reactant: C1CCCNCC1
Solvent: ClCCl
Product: Cc1nc2ccc(-c3ccc4c(c3)CN(C(=O)N3CCCCCC3)CCO4)cc2[nH]1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1,1-dimethylethyl 6-[4-(chlorocarbonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]-1H-benzimidazole-1-carboxylate (33 mg, 0.08 mmol), was taken into dichloromethane (1.5 mL) followed by addition of homopiperidine (0.1 mL, 0.89 mmol) and the mixture was allowed to stir for 12 h at room temperature. The mixture was then concentrated and the residue partitioned with ethyl acetate and 10% aqueous citric acid. The organic phase was separated and dried over magnesium sulfate then filtered and concentrated. The residue obtained was taken into trifluoroacetic acid (1 mL) and allowed to stand for 1 h at room temperature. The solution was then concentrated and the residue taken into a minimum of aqueous acetonitrile and purified by preparative reverse phase HPLC. Lyophilization of the combined pure fractions afforded 4-(azepan-1-ylcarbonyl)-7-(2-methyl-1H-benzimidazol-6-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (18 mg) as an amorphous solid. 1H NMR (400 MHz, d6-DMSO): 7.91 (s, 1H), 7.83 (d, 1H), 7.76 (dd, 1H), 7.64 (d, 1H), 7.55 (dd, 1H), 7.06 (d, 1H), 4.42 (s, 2H), 4.22 (br s, 2H), 3.55 (br s, 2H), 3.29 (tr, 4H), 2.64 (s, 3H), 1.65 (br s, 4H), 1.49 (br s, 4H). MS (EI) for C24H28N4O2: 406 (MH+).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.Cl.[CH3:23][C:24]1([NH2:28])[CH2:27][NH:26][CH2:25]1.C(N(CC)CC)C>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:26]4[CH2:27][C:24]([CH3:23])([NH2:28])[CH2:25]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CC1(N)CNC1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC1(N)CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1

Procedure:
A mixture of 0.23 g (0.82 mmoles) of 1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid, 0.26 g (1.64 mmoles) of 3-methyl-3-aminoazetidine dihydrochloride and 0.5 ml of triethylamine is refluxed in 10 ml of pyridine for 2 hours. Filtering and washing with water and ethanol yield 0.250 g (87%) of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(3-methyl-3-amino-1-azetidinyl)-4-oxo-3-quinolinecarboxylic acid having a melting point and spectroscopic data identical to those of the derivative obtained by Method E.
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[CH2:7][C@H:8]([OH:10])[CH2:9][C@@H:2]12.C(N(CC)CC)C.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24]>ClCCl>[OH:10][C@H:8]1[CH2:7][N:3]2[CH2:4][CH2:5][N:6]([C:23]([C:22]3[CH:26]=[CH:27][CH:28]=[C:20]([C:19]([F:18])([F:29])[F:30])[CH:21]=3)=[O:24])[CH2:1][C@@H:2]2[CH2:9]1
Reactant: O[C@@H]1C[C@H]2CNCCN2C1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cccc(C(F)(F)F)c1)N1CCN2C[C@H](O)C[C@H]2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (7R,8aS)-2-benzyloctahydropyrrolo[1,2-a]pyrazin-7-ol (Example 54D, 1 g, 4.30 mmol) and ethanol (10 mL) were added to 20% palladium hydroxide on carbon, wet (0.100 g) in a pressure bottle. The mixture was stirred at 50° C. for 16 hours under 30 psi of hydrogen. The mixture was filtered through a nylon membrane to give a crude intermediate (7R,8aS)-octahydropyrrolo[1,2-a]pyrazin-7-ol. To a solution of crude (7R,8aS)-octahydropyrrolo[1,2-a]pyrazin-7-ol (1.422 g, 10 mmol) and triethylamine (1.62 g, 16 mmol) in dichloromethane (50 mL) was slowly added a solution of 3-(trifluoromethyl)benzoyl chloride (2.09 g, 10 mmol) in dichloromethane (3 mL). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated, diluted with ethyl acetate (100 mL), washed with water (20 mL), dried over sodium sulfate, and filtered. The organic solution was concentrated, and the residue was purified by chromatography on silica gel (dichloromethane/methanol=10:1) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43-1.63 (m, 2H), 2.10-2.27 (m, 3H), 2.50 (m, 1H), 2.80-3.00 (m, 2H), 3.20-3.50 (m, 2H), 4.22 (m, 1H), 4.42-4.60 (m, 1H), 4.80 (m, 1H), 7.70 (m, 3H), 7.82 (m, 1H); MS (ESI) m/z 315 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:29]([CH3:36])([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31]>CN(C=O)C>[CH3:35][C:29]([O:21][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][CH2:12][C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][CH:9]=2)=[CH:20][CH:19]=1)([CH3:36])[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: Oc1ccc(OCCc2coc(-c3ccccc3)n2)cc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2coc(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 49.4 %

Procedure:
4-[2-(2-Phenyloxazol-4-yl)ethoxy]phenol (3.7 g, 13.0 mmol) and cesium carbonate (4.71 g, 14.5 mmol) were suspended in anhydrous DMF (100 mL) and treated with dropwise addition of ethyl 2-bromoisobutyrate (2.54 g, 13.0 mmol, 1.93 mL). The reaction mixture was stirred at ambient temperature for 24 h and then partitioned between ether (200 mL) and 1.0 N HCl (200 mL). The organic layer was washed with water (100 mL), dried over MgSO4 and concentrated to a brown oil, which was purified by gradient column chromatography (200 mL SiO2, 100% hexanes to 20% EtOAc/hexanes) to provide 2-methyl-2-{4-[2-(2-phenyloxazol-4-yl)ethoxy]phenoxy}propionic acid, ethyl ester (2.54 g, 50%) as a colorless, viscous oil: Rf=0.5 in 20% EtOAc/hexanes; 1H NMR (250 MHz, CDCl3) δ 7.96-8.02 (m, 2H), 7.37-7.46 (m, 3H), 6.81 (s, 4H), 4.32 (q, 2H), 4.20 (t, 2H), 3.03 (t, 2H), 1.52 (s, 6H), 1.27 (t, 3H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][C:21]([F:30])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17].[F:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[C:34]([CH3:39])[CH:33]=1>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:36][C:35]3[CH:37]=[CH:38][C:32]([F:31])=[CH:33][C:34]=3[CH3:39])=[C:3]([C:16]([N:18]3[CH2:19][CH2:20][C:21]([F:30])([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:22][CH2:23]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC(F)(c4ccccc4)CC3)cnc12
Reactant: Cc1cc(F)ccc1N
Product: CCOC(=O)c1cnn2c(Nc3ccc(F)cc3C)c(C(=O)N3CCC(F)(c4ccccc4)CC3)cnc12
Yield: 72.7 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(4-fluoro-4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine (250 mg, 0.58 mmol) obtained in step 2 and 4-fluoro-2-methylaniline (0.1 mL, 0.87 mmol), the title compound (219 mg, 73%) was obtained.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11]([N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: C1CNCCN1
Solvent: CC#N
Product: Cc1c(F)c(N2CCNCC2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
A suspension of 0.85 g (2.85 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 1.00 g (11.6 mmol) of anhydrous piperazine, and 20 ml of acetonitrile was refluxed for five hours, then stirred at room temperature overnight. The precipitate was filtered, washed with water and acetonitrile, and dried to give 0.91 g of the title compound, mp 205°-206° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:15])[CH2:9][NH:10][C:11](=O)[CH2:12][CH3:13])=[CH:4][C:3]=1[O:16][CH3:17]>Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:15])[CH2:9][NH:10][CH2:11][CH2:12][CH3:13])=[CH:4][C:3]=1[O:16][CH3:17]
Reactant: CCC(=O)NCC(O)c1ccc(F)c(OC)c1
Agent: Cl
Product: CCCNCC(O)c1ccc(F)c(OC)c1
Yield: 81.4 %

Procedure:
Prepared following the same method as for example 3 starting with the amide from example 18 (585 mg, 2.42 mmol). After refluxing in 6M HCl (aq) the reaction mixture was cooled and extracted with diethyl ether (2×50 ml). The organic layers were discarded and the aqueous layer basified by the addition of potassium carbonate. The aqueous residue was then extracted with ethyl acetate (3×50 ml). The organic extracts were combined and dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give the title compound as a pale yellow oil (448 mg, 1.97 mmol, 81%). 1H NMR (CD3OD, 400 MHz) δ: 0.96 (t, 3H), 1.58 (m, 2H), 2.63 (m, 2H), 2.79 (d, 2H), 3.96 (s, 3H), 4.77 (t, 1H), 6.90 (m, 1H), 7.03 (t, 1H), 7.11 (d, 1H). LRMS: m/z 228 (M−H+).
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:10]([NH2:13])[CH2:11][CH3:12].C(N(CC)CC)C>C(O)C>[CH2:10]([NH:13][CH2:2]/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:11][CH3:12]
Reactant: CCOC(=O)/C=C/CBr
Reactant: CCCN
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCNC/C=C/C(=O)OCC
Reaction time: 1.5 h

Procedure:
Ethyl 4-bromocrotonate (21.4 g) was added dropwise to a solution of n-propylamine (11.8 g) and triethylamine (20.2 g) in ethanol (80 ml) at 0° C. under stirring and taking 1.5 hours, followed by stirring for 0.5 hours at room temperature. After removing the solvent, to the residue was added ethyl acetate, and the mixture was extracted with 1N hydrochloric acid. The extract was alkalified with potassium carbonate powder and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and distilled to remove the solvent to give 13.5 of the title compound as pale yellow oily substance.