Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].Br.[NH2:50][C:51]1[S:52][C:53]([Br:56])=[CH:54][N:55]=1.N1C=CC=CC=1>C(Cl)Cl.O>[Br:56][C:53]1[S:52][C:51]([NH:50][C:40](=[O:42])[C@@H:39]([C:31]2[CH:32]=[CH:33][C:34]([S:35]([CH3:38])(=[O:36])=[O:37])=[C:29]([Cl:28])[CH:30]=2)[CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)=[N:55][CH:54]=1
Reactant: Nc1ncc(Br)s1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Agent: Br
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ncc(Br)s2)cc1Cl
Temperature: 0 °C
Yield: 50.5 %

Procedure:
A solution of triphenylphosphine (595 mg, 2.27 mmol) in methylene chloride (20 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (457 mg, 2.57 mmol). The reaction mixture was stirred at 0° C. until it became homogeneous. The resulting light purple reaction mixture was then treated with 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (500 mg, 1.51 mmol). The reaction mixture was stirred at 0° C. for 20 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-amino-5-bromothiazole monohydrobromide (589 mg, 2.27 mmol) and pyridine (0.37 mL, 4.53 mmol), and then the reaction mixture was stirred at 25° C. for 16 h. The reaction was then diluted with water (15 mL) and then extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 55/45 hexanes/ethyl acetate) afforded N-(5-bromo-thiazol-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (375 mg, 51%) as a light green foam: [α]23589=−110.3° (c=0.068, chloroform); EI-HRMS m/e calcd for C18H20ClBrN2O3S2 (M+) 489.9787, found 489.9792.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[CH3:23][O:24][C:25]1[CH:26]=[CH:27][C:28]2[C:29]3[CH2:36][CH:35]([CH2:37][CH:38]4[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]4)[C:34](=O)[C:30]=3[NH:31][C:32]=2[CH:33]=1>C1(C)C=CC=CC=1>[CH3:23][O:24][C:25]1[CH:26]=[CH:27][C:28]2[C:29]3[CH2:36][CH:35]([CH2:37][CH:38]4[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]4)[C:34](=[S:10])[C:30]=3[NH:31][C:32]=2[CH:33]=1
Reactant: COc1ccc2c3c([nH]c2c1)C(=O)C(CC1CCN(C(=O)OC(C)(C)C)CC1)C3
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc2c3c([nH]c2c1)C(=S)C(CC1CCN(C(=O)OC(C)(C)C)CC1)C3
Temperature: 80 °C
Yield: 112.6 %

Procedure:
Lawesson's reagent (244 mg, 0.60 mmol) was added to a mixture of the title compound of Example 60 (400 mg, 1.01 mmol) in toluene and the resulting mixture was heated to 80° C. for 15 minutes. The reaction mixture was concentrated and the residue was purified by chromatography to give the title compound (280 mg, 67%) as an orange solid. Recrystallization from ethyl acetate gave orange crystals, mp. 188°-189° C.; Anal. Calc. for C23H30N2O3S: C, 66.64; H, 7.29; N, 6.76; Found: C, 66.42; H, 7.17; N, 6.59.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[C@H:20]([CH2:21][C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][CH:23]=3)[CH2:19][N:18]3[C@@H:31]([CH2:34]Cl)[CH2:32][CH2:33][C@@H:17]3[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>CN(C)C=O>[F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[C@H:20]([CH2:21][C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][CH:23]=3)[CH2:19][N:18]3[C@@H:31]([CH2:34][N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)[CH2:32][CH2:33][C@@H:17]3[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C1COCCN1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1C[C@H]2CC[C@H](CCl)N2C[C@H]1Cc1c[nH]c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1C[C@H]2CC[C@H](CN3CCOCC3)N2C[C@H]1Cc1c[nH]c2ccccc12
Temperature: 120 °C

Procedure:
To a solution of (3,5-bis(trifluoromethyl)phenyl)-[(3R,6R,8aR)-6-chloromethyl-3-(1H-indol-3-ylmethyl)-hexahydropyrrolo[1,2-a]pyrazin-2-yl]-methanone (1.06 g) in dimethylformamide (15 mL) was added morpholine (5 mL). The resulting mixture was heated at 120° C. for 6 hours. After cooling to room temperature, ethyl acetate and 5% aqueous sodiumbicarbonate were added and the layers were separated. The organic layer was dried and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, MTBE/MeOH/NH4OH 95:4.5:0.5) to afford 3,5-bis(trifluoromethyl)phenyl-[(3R,6R,8aR)-3-(1H-indol-3-ylmethyl)-6-(morpholin-4-ylmethyl)-hexahydropyrrolo[1,2-a]pyrazin-2-yl]-methanone (407 mg). Rf 0.46 (MTBE/MeOH/NH4OH 95:4.5:0.5) (compound 2).
Reaction SMILES: Cl[C:2]1[C:6](=[CH:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:4][C:3]=1[C:16]([O:18][CH3:19])=[O:17].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([SH:30])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29].C(=O)([O-])[O-].[K+].[K+].O>CO>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([S:30][C:2]2[C:6](=[CH:7][CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:5][CH2:4][C:3]=2[C:16]([O:18][CH3:19])=[O:17])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: COC(=O)C1=C(Cl)C(=CCCc2ccccc2)CC1
Reactant: COc1ccc(S)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)C1=C(Sc2ccc(OC)c(OC)c2)C(=CCCc2ccccc2)CC1
Reaction time: 48 h
Yield: 57.5 %

Procedure:
A mixture of Methyl 2-chloro-3-(3-phenylpropyl-1-yl)-1-cyclopentenecarboxylate (0.2 g, 0.72 mmol), 3,4-dimethoxythiophenol (0.12 g, 0.72 mmol) and potassium carbonate (0.1 g, 0.72 mmol) in methanol (20 mL) is heated under reflux for 6 hours. After standing at room temperature for 2 days, the mixture is heated under reflux for another 4 hours. The mixture is poured into water and is extracted with ether. The organic layer is washed with water and is dried over MgSO4. The solvent is removed in vacuo and the residue is chromatographed on silica gel (4:1 hexane:ethyl acetate) to provide methyl 2-[(3,4-dimethoxyphenyl)thio]-3-(3-phenylpropyl-1-yl)-1-cyclopentenecarboxylate (0.17 g, 58%): 1H-NMR (300 MHz, CDCl3) δ (TMS) 1.10-1.70 (m, 5H), 1.88-1.98 (m, 1H), 2.31-2.40 (t, 3H), 2.58-2.70 (t, 3H), 3.78 (s, 3H), 3.84 (s, 3H), 3.90 (s, 3H), 6.68-6.75 (d, 1H), 6.95-7.09 (m, 4H), 7.17-7.30 (m, 3H); MS (EI) m/e 412 (M+).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH3:37])[O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]=[C:12]2[CH3:36])=[CH:7][CH:6]=1.[H-].[Na+].CI.[C:42](OCC)(=O)C>CN(C)C=O.O>[CH3:42][O:1][CH2:2][CH:3]([CH3:37])[O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]=[C:12]2[CH3:36])=[CH:7][CH:6]=1
Reactant: CCOC(C)=O
Reactant: CCCc1nc(C)n(-c2ccc(OC(C)CO)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CCCc1nc(C)n(-c2ccc(OC(C)COC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1

Procedure:
To a solution of 4′-({1-[4-(2-hydroxy-1-methylethoxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.70 g) in N,N-dimethylformamide (7 mL) were added 60% sodium hydride (0.07 g) and then methyl iodide (0.18 mL) at 0° C., and the mixture was stirred for 1 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.53 g, 74%).
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](Cl)=[O:14].[CH3:16][NH:17][C:18]([CH3:23])([C:20]([OH:22])=[O:21])[CH3:19].C(N(CC)CC)C>ClCCl>[O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([N:17]([CH3:16])[C:18]([CH3:23])([C:20]([OH:22])=[O:21])[CH3:19])=[O:14]
Reactant: O=C(Cl)CCCCCN1C(=O)C=CC1=O
Reactant: CNC(C)(C)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)CCCCCN1C(=O)C=CC1=O)C(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirring solution of #248 (600 mg, 2.61 mM) in 10 mL of dichloromethane, N,2-dimethylalanine (306 mg, 2.61 mM) was added followed by triethylamine (1.09 mL, 7.84 mM). The reaction was allowed to stir at room temperature for three hours. Dichloromethane was added to the reaction and the organic layer was washed three times with water and two times with brine. The organic layer was separated and then dried over sodium sulfate before being concentrated in vacuo. The crude residue was purified by silica chromatography (0-30% methanol in dichloromethane) on silica which had been previously neutralized with triethylamine yielding a white solid #249 (127 mg, 16%). LC-MS (Protocol Q): m/z 309.0 [M−H−], retention time=0.96 minutes.
Reaction SMILES: [H-].[Na+].C(O[C:6](=[O:14])/[CH:7]=[C:8](\[NH2:13])/[C:9]([F:12])([F:11])[F:10])C.[Cl:15][C:16]1[C:21]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][C:19]([N:30]=[C:31]=[O:32])=[C:18]([F:33])[CH:17]=1>CN(C)C=O.C1(C)C=CC=CC=1>[Cl:15][C:16]1[C:21]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][C:19]([N:30]2[C:6](=[O:14])[CH:7]=[C:8]([C:9]([F:10])([F:11])[F:12])[NH:13][C:31]2=[O:32])=[C:18]([F:33])[CH:17]=1
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: O=C=Nc1cc(OCc2ccccc2)c(Cl)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1cc(OCc2ccccc2)c(Cl)cc1F
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
To a solution of 312 mg (7.82 mmol) of sodium hydride (60% oil dispersion) in 10 mL of N,N-dimethylformamide was added 1.43 g (7.82 mmol) of ethyl-3-amino-4,4,4-trifluorocrotonate in 7 mL of toluene over a period of 30 min at -5° C. The resulting mixture was stirred for an additional 30 min before it was cooled to -70° C. Then a solution of 2.17 g (7.82 mmol) of 4-chloro-2-fluoro-5-(phenylmethoxy)phenyl isocyanate in 7 mL of toluene was added dropwise at a rate that maintained the reaction temperature below -60° C. After the addition, the thick reaction mixture was maintained at -60° C. for an additional 1 h before the cooling bath was removed. The mixture was gradually warmed to room temperature and stirring was continued for 1.5 h. Then the mixture was poured into a solution of 10 mL of concentrated HCl in 200 mL of water. The toluene layer was separated and the aqueous layer was further extracted twice with 200 mL of ether, dried (MgSO4), concentrated in vacuo to give yellow oil which was flash chromatographed over silica gel eluting with a 1:4 v:v mixture of ethyl acetate and hexane to give 1.85 g of the title compound as a pale yellow foam: 1 -NMR (CDCl3, 200 MHz): ppm 7.40 (m, 6H), 6.85 (d, 1H), 6.2 (s, 1H), 5.05 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([NH:18][CH:19]([CH3:21])[CH3:20])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:22]([O:24]C)=[O:23])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:29][CH3:30].Cl>O1CCCC1.O>[CH2:29]([N:18]([CH:19]([CH3:21])[CH3:20])[C:17]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:22]([OH:24])=[O:23])=[CH:12][CH:11]=2)[CH3:30]
Reactant: CCI
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(NC(C)C)nc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCN(c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1)C(C)C
Reaction time: 0.17 h
Yield: 28.7 %

Procedure:
To a solution of methyl 2-(4-fluorophenyl)-3-(isopropylamino)quinoxaline-6-carboxylate (95 mg, 0.28 mmol) in tetrahydrofuran (20 mL) was added sodium hydride (23 mg, 0.96 mmol) and stirred for 10 minutes. Subsequently, iodoethane (43.7 mg, 0.28 mmol) was added and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (25 mL) and the pH adjusted to 6 with hydrochloric acid (3N). The product precipitated and was filtered to afford 3-(ethyl(isopropyl)amino)-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid as a light yellow solid (28.4 mg, 29%).
Reaction SMILES: C(OC(=O)[CH:5]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([I:21])[CH:19]=2)[N:14]=[CH:13][C:12]=1[C:22]#[N:23])C(OCC)=O)C.[Cl-].[Li+].O>CS(C)=O>[I:21][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][C:12]([C:22]#[N:23])=[C:11]2[CH3:5]
Reactant: CCOC(=O)C(C(=O)OCC)c1c(C#N)cnc2ccc(I)cc12
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1c(C#N)cnc2ccc(I)cc12

Procedure:
Similar procedure as described in example 71b was used, starting 2-(3-cyano-6-iodo-quinolin-4-yl)-malonic acid diethyl ester (example 73a), lithium chloride, water, and dimethylsulfoxide to give 6-iodo-4-methyl-quinoline-3-carbonitrile. LC-MS m/e 295 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][C@@H:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][C@@H:20]1[OH:28]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([C@@:19]2([NH2:18])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][C@@H:20]2[OH:28])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)[C@@]1(N)c2ccccc2C[C@@H]1O

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 1-(R)-amino-2-(S)-indanol, the title compound was prepared.
Reaction SMILES: [CH2:1]([C:5]1([CH2:26][CH3:27])[CH2:11][N:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[CH:18]=[C:19]([O:22]C)[CH:20]=[CH:21][C:8]=2[S:7](=[O:25])(=[O:24])[CH2:6]1)[CH2:2][CH2:3][CH3:4].[Br-].[Al+3].[Br-].[Br-].C(S)C>>[CH2:1]([C:5]1([CH2:26][CH3:27])[CH2:11][N:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[CH:18]=[C:19]([OH:22])[CH:20]=[CH:21][C:8]=2[S:7](=[O:24])(=[O:25])[CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(CC)CN(c2ccccc2)c2cc(OC)ccc2S(=O)(=O)C1
Agent: [Al+3]
Agent: [Br-]
Solvent: CCS
Product: CCCCC1(CC)CN(c2ccccc2)c2cc(O)ccc2S(=O)(=O)C1
Yield: 88.9 %

Procedure:
The compound of Example 26 (1.05 g, 2.71 mmol) was treated with aluminum bromide and ethanethiol according to the procedure for Example 18 giving the title product (0.90 g, 89%). 1H NMR (DMSO-d6) δ 9.99 (s, 1H); 7.27-6.74 (m, 8H); 3.61 (br s, 2H), 3.20 (s, 2H); 1.50-1.00 (m, 8H); 0.73 (m, 6H). MS Da/e=374 (MH+). Calcd for C21H27NSO3 ×0.25 H2O: C, 66.73; H, 7.33, N, 3.71, S, 8.48. Found: C, 66.67; H, 7.32; N, 3.67; S, 8.49.
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[C:4]([F:21])[C:5]([O:19][CH3:20])=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18].BrC1C(F)=C([F:43])C(OC)=C2C=1N(C1CC1)C=C(C(O)=O)C2=O.C1(N2C3C(=C(OC)C(F)=C(F)C=3C(F)(F)F)C(=O)C(C(O)=O)=C2)CC1.C1(N2C3C(=C(OC)C(F)=C(F)C=3)C(=O)C(C(O)=O)=C2)CC1>>[CH:12]1([N:10]2[C:11]3[C:6](=[C:5]([O:19][CH3:20])[C:4]([F:21])=[C:3]([F:22])[C:2]=3[F:43])[C:7](=[O:18])[C:8]([C:15]([OH:17])=[O:16])=[CH:9]2)[CH2:14][CH2:13]1
Reactant: COc1c(F)c(F)c(Cl)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: COc1c(F)c(F)c(Br)c2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: COc1c(F)c(F)c(C(F)(F)F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: COc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Product: COc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1

Procedure:
In a similar manner, the following compounds were prepared: 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methoxy-4-oxo-3-quinolinecarboxylic acid; 8-bromo-1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methoxy-4-oxo-3-quinolinecarboxylic acid; 1-cyclopropyl-6,7-difluoro-8-trifluoromethyl-5-methoxy-4-oxo-3-quinolinecarboxylic acid; and 1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methoxy-4-oxo-3-quinolinecarboxylic acid.
Reaction SMILES: [CH3:1][C:2]([CH3:33])([CH3:32])[C:3]([O:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[C:14]([N+:16]([O-])=O)[CH:15]=1)[NH:12][C:11]([C:19]1[S:20][CH2:21][C@@H:22]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[N:23]=1)=[CH:10]2)=[O:4].[C:34]1(=O)[CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH:34]1([NH:16][C:14]2[CH:15]=[C:7]([CH2:6][O:5][C:3](=[O:4])[C:2]([CH3:33])([CH3:32])[CH3:1])[CH:8]=[C:9]3[C:13]=2[NH:12][C:11]([C:19]2[S:20][CH2:21][C@@H:22]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[N:23]=2)=[CH:10]3)[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: CC(C)(C)C(=O)OCc1cc([N+](=O)[O-])c2[nH]c(C3=N[C@H](COC(=O)C(C)(C)C)CS3)cc2c1
Reactant: O=C1CCCC1
Product: CC(C)(C)C(=O)OCc1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](COC(=O)C(C)(C)C)CS3)cc2c1

Procedure:
2,2-Dimethyl-propionic acid (R)-2-[5-(2,2-dimethyl-propionyloxymethyl)-7-nitro-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl-methyl ester prepared in Preparation 43 and cyclopentanone were reacted according to the same procedure as Example 1 to give the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:4]=1[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C@@H:15]2[CH2:20][CH2:19][NH:18][C@H:17]([CH3:21])[CH2:16]2)[CH:9]=1)=[O:6].[C:27](O)(=O)C.C([BH3-])#N.[Na+].C=O.C(=O)(O)[O-].[Na+].[Cl-].[NH4+]>CO.ClCCl>[ClH:2].[Cl:2][C:3]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:4]=1[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C@@H:15]2[CH2:20][CH2:19][N:18]([CH3:27])[C@H:17]([CH3:21])[CH2:16]2)[CH:9]=1)=[O:6]
Reactant: CC(=O)O
Reactant: C[C@@H]1C[C@H](Nc2cccc(NC(=O)c3ccc(F)cc3Cl)c2)CCN1
Agent: C=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CO
Product: C[C@@H]1C[C@H](Nc2cccc(NC(=O)c3ccc(F)cc3Cl)c2)CCN1C
Temperature: 0 °C
Reaction time: 18 h
Yield: 135.8 %

Procedure:
Dissolve 2-chloro-4-fluoro-N-((2R,4R)-3-(2-methyl-piperidin-4-ylamino)-phenyl)-benzamide hydrochloride (Example 41, 30 mg, 0.075 mmol) in methanol (5 mL). Add acetic acid (13 μL, 0.225 mmol) followed by sodium cyanoborohydride (7.1 mg, 0.113 mmol). Cool to 0° C. and add 37% formaldehyde (6.7 μL, 0.083 mmol). Warm to room temperature and stir for 18 hr. Add aqueous saturated sodium bicarbonate and dichloromethane. Separate organic layer and extract aqueous with dichloromethane (2×25 mL). Combine organic extracts, dry (MgSO4), filter, and concentrate in vacuo. Purify by column chromatography (0%-10% 2M NH3 in methanol/CH2Cl2) to yield an oil. Make the hydrochloride salt by sonication with one equivalent of ammonium chloride dissolved in methanol to yield 21 mg (68%) of the title compound. Mass spectrum (ion spray): m/z=376.4 (M+1); mp 159-62° C.
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][C:10]2[O:9][CH2:8][CH2:7][N:6]3[CH:13]=[C:14]([C:16]4[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=[CH:18][N:17]=4)[N:15]=[C:5]3[C:4]=2[CH:3]=1.C(#N)C.O.C([O-])(=O)C.[K+].[F:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][N:35]=1>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>[F:33][C:34]1[N:35]=[CH:36][C:37]([C:2]2[N:12]=[CH:11][C:10]3[O:9][CH2:8][CH2:7][N:6]4[CH:13]=[C:14]([C:16]5[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=[CH:18][N:17]=5)[N:15]=[C:5]4[C:4]=3[CH:3]=2)=[CH:38][CH:39]=1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(Cl)ncc1OCC2
Reactant: OB(O)c1ccc(F)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(-c3ccc(F)nc3)ncc1OCC2
Temperature: 25 °C

Procedure:
10-Chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine (85.0 mg, 0.257 mmol) dissolved in Acetonitrile (2 mL, 50 mmol) and Water (2 mL, 100 mmol) with dissolved Potassium acetate (85.5 mg, 0.871 mmol). Degas by bubbling nitrogen for 5 min. 2-Fluoropyridine-5-boronic acid (47.1 mg, 0.334 mmol) was added, then Tetrakis(triphenylphosphine)palladium(0) (4.0E1 mg, 0.035 mmol). The reaction was microwaved at 145 C 35 min, cooled to RT, and extracted with ethyl acetate. Combined organics were concentrated to give fluoro intermediate, 10-(6-fluoropyridin-3-yl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine, which was dissolved in 1,2-Dimethoxyethane (3.00 mL, 28.9 mmol). 10% aqueous HCl (3 mL) was added. The reaction was allowed to stir and heat at 80° C. overnight. The reaction was allowed to cool to room temperature and concentrated under reduced pressure to give 306, analyzed by rHPLC. MS: (ESI+)=390.1
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][C@@H:28]4[CH2:32][OH:33])[CH2:23][CH2:22]3)=[O:20])=[C:15](I)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[N:35]1[CH:40]=[CH:39][CH:38]=[C:37](B(O)O)[CH:36]=1>>[CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][C@@H:28]4[CH2:32][OH:33])[CH2:23][CH2:22]3)=[O:20])=[C:15]([C:37]3[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=3)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1cccc(-c2nc(I)c(C(=O)N3CCC(N4CCC[C@@H]4CO)CC3)n2C)c1
Reactant: OB(O)c1cccnc1
Product: CCCCCCc1cccc(-c2nc(-c3cccnc3)c(C(=O)N3CCC(N4CCC[C@@H]4CO)CC3)n2C)c1

Procedure:
In analogy to the procedure described for example 7, [2-(3-hexyl-phenyl)-5-iodo-3-methyl-3H-imidazol-4-yl]-[4-((R)-2-hydroxymethyl-pyrrolidin-1-yl)-piperidin-1-yl]-methanone (example 45) was reacted with pyridin-3-yl-boronic acid to give the title compound as light brown oil. MS: 530.3 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][CH:6]=1.[C:7]([C:10]1[O:11][CH:12]=[CH:13][CH:14]=1)(=[O:9])[CH3:8]>>[O:11]1[CH:12]=[CH:13][CH:14]=[C:10]1[C:7]([C:6]1[S:5][CH:4]=[N:3][C:2]=1[CH3:1])([OH:9])[CH3:8]
Reactant: CC(=O)c1ccco1
Reactant: Cc1cscn1
Product: Cc1ncsc1C(C)(O)c1ccco1

Procedure:
Starting with 4-methylthiazole and 2-acetylfuran and following the general method of Example 15 the title compound was prepared. M.p. 127°-128° C.