Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([SH:20])=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[F:21])=[N:6][CH:7]=1.[NH2:22][C:23]1[CH:24]=[N:25][C:26]([Cl:29])=[N:27][CH:28]=1>>[ClH:29].[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[S:20][C:26]3[N:27]=[CH:28][C:23]([NH2:22])=[CH:24][N:25]=3)=[CH:10][C:9]=2[F:21])=[N:6][CH:7]=1
Reactant: Nc1cnc(-c2ccc(-c3ccccc3S)cc2F)cn1
Reactant: Nc1cnc(Cl)nc1
Product: Cl
Product: Nc1cnc(Sc2ccccc2-c2ccc(-c3cnc(N)cn3)c(F)c2)nc1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 213 utilizing 4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-thiol and 5-amino-2-chloropyrimidine. MS (ESI): mass calcd. for C20H15FN6S, 390.11; m/z found, 391.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.36 (s, 1H), 8.24 (s, 1H), 7.95 (s, 2H), 7.88 (m, 1H), 7.65-7.59 (m, 1H), 7.53-7.38 (m, 3H), 7.27-7.16 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])=[CH:16][CH:15]=1
Reactant: COc1ccc(O)cc1
Reactant: Nc1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(Oc2ccc(N)cc2[N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 73 %

Procedure:
A solution of 4-chloro-3-nitro aniline (1.0 g, 5.79 mmol), 4-methoxyphenol (0.74 g, 6.00 mmol), cesium carbonate (1.95 g, 6.00 mmol) in dimethylformamide (10 ml) was heated at 100° C. for 16 hours. Afterwards ice water (50 mL) was added to the solution and the resultant slurry was treated with ethyl acetate (100 ml). The layers were separated and the organic layer was washed with 10% sodium bicarbonate and 10% sodium chloride, then dried over anhydrous sodium sulfate. The drying agent was filtered and solvent was removed under vacuum leaving a red solid as the title compound (1.1 g, 73%).
Reaction SMILES: [OH:1][C:2]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[OH:34])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[CH2:4][CH2:3]1.Br[CH2:36][CH2:37][CH2:38][CH2:39][O:40]C(=O)C.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.C(Cl)(Cl)Cl.O>[OH:1][C:2]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH2:36][CH2:37][CH2:38][CH2:39][OH:40])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[CH2:4][CH2:3]1
Reactant: CN(C)C(=O)C(CCN1CCC(O)(c2ccccc2O)CC1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)OCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)C(CCN1CCC(O)(c2ccccc2OCCCCO)CC1)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Yield: 24.5 %

Procedure:
In 10 mL of anhydrous dimethylformamide was dissolved 920 mg (2 mmol) of 4-(4-hydroxy-4-(2-hydroxyphenyl)piperidino)-N,N-dimethyl-2,2-diphenylbutaneamide. To the resulting solution were added 585 g (3 mmol) of 4-bromobutylacetate, 414 mg (3 mmol) of potassium carbonate and a small amount of potassium iodide. The resulting mixture was stirred under heating at 80° C. for 4 hours. After cooling, the reaction mixture was poured into water, followed by extraction with ethyl acetate, washing with water and drying. The residue obtained by distilling off the solvent under reduced pressure was dissolved in 15 mL of methanol. To the resulting solution was added 3 mL of a 1N aqueous solution of sodium hydroxide, followed by stirring at room temperature for 1 hour. From the reaction mixture, the solvent was distilled off under reduced pressure. The residue thus obtained was dissolved in chloroform. The resulting solution was washed with water and dried. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column, whereby 260 mg (yield: 24.5%) of 4-(4-hydroxy-4-(2-(4-hydroxybutyloxy)phenyl)piperidino)-N,N-dimethyl-2,2-diphenylbutaneamide (Compound No. 34) was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([OH:15])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[C:22](Cl)=[N:21][CH:20]=[CH:19][N:18]=1.CS(C)=O.CC(C)([O-])C.[Na+]>O>[Cl:16][C:17]1[C:22]([O:15][CH:13]2[CH2:14][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH2:12]2)=[N:21][CH:20]=[CH:19][N:18]=1
Reactant: Clc1nccnc1Cl
Reactant: O=C(OCc1ccccc1)N1CC(O)C1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(OCc1ccccc1)N1CC(Oc2nccnc2Cl)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.6 %

Procedure:
To a solution of 3-hydroxy-azetidine-1-carboxylic acid benzyl ester (5.19 g, 27.4 mmol, purchased from Ace Synthesis), 2,3-dichloropyrazine (4.116 g, 27.6 mmol, Oakwood) and DMSO (40 mL) was added sodium tert-butoxide (2.64 g, 27.4 mmol) in three portions. The solution was allowed to stir at room temperature. After 2 hours, the reaction was poured into water (200 mL) and the aqueous solution was extracted with ether (3×50 mL). The combined ether layers were washed with water (50 mL), brine (50 mL), and then concentrated in vacuo. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (80 g), eluting with 0% to 20% EtOAc in hexane, to provide benzyl 3-(3-chloropyrazin-2-yloxy)azetidine-1-carboxylate (5.4 g, 61.6% yield), as a yellow oil. MS (ESI) m/z 320.1 (MH+). IC50 (uM): 1.33.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[C@H:4]([CH2:20][O:21][CH2:22][CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=2)=[O:26])[CH2:3]1.C(N(CC)CC)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>O1CCCC1.ClCCl>[CH3:45][S:46]([O:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[O:8])[C@H:4]([CH2:20][O:21][CH2:22][CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=2)=[O:26])[CH2:3]1)(=[O:48])=[O:47]
Reactant: O=C(NCCOC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1)OCc1ccc([N+](=O)[O-])cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CS(=O)(=O)O[C@@H]1C[C@@H](COCCNC(=O)OCc2ccc([N+](=O)[O-])cc2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1

Procedure:
To a solution of (2S,4R)-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)-2-[2-(4-nitrobenzyloxycarbonylamino)ethyloxymethyl]pyrrolidine (0.87 g) and triethylamine (0.35 ml) in a mixture of tetrahydrofuran (5 ml) and dichloromethane (10 ml) was dropwise added a solution of methanesulfonyl chloride (0.16 ml) in dichloromethane (2 ml) with stirring at 0°-5° C. and the mixture was stirred at 0°-5° C. for 30 minutes. The reaction mixture was washed with water (20 ml), dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (20 g) and eluted with a mixture of methanol and chloroform (1:99 V/V) to give (2S,4R)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)2-[2-(4-nitrobenzyloxycarbonylamino)ethyloxymethyl]pyrrolidine (0.92 g).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[Cl:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([C:15]2[CH:16]=[N:17][C:18]3N[CH2:20][CH2:21][CH2:22][C:23]=3[CH:24]=2)[C:11]=1[CH:12]([OH:14])[CH3:13]>>[Cl:5][C:6]1[C:11]([CH:12]([OH:14])[CH3:13])=[C:10]([C:15]2[CH:24]=[C:23]3[C:18](=[N:17][CH:16]=2)[N:1]([C:2]([NH2:4])=[O:3])[CH2:20][CH2:21][CH2:22]3)[CH:9]=[N:8][CH:7]=1
Reactant: NC(N)=O
Reactant: CC(O)c1c(Cl)cncc1-c1cnc2c(c1)CCCN2
Product: CC(O)c1c(Cl)cncc1-c1cnc2c(c1)CCCN2C(N)=O

Procedure:
6-[5-Chloro-4-(1-hydroxy-ethyl)-pyridin-3-yl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide is synthesized according to the procedure of Urea Formation Method II using 1-[3-chloro-5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-4-yl]-ethanol.
Reaction SMILES: Cl.[CH3:2][O:3]CN.C([N:8]([CH2:11]C)CC)C.[CH3:13][C:14]1[O:15][CH:16]=[CH:17][C:18]=1[C:19](Cl)=[O:20]>ClCCl.O>[CH3:11][N:8]([O:3][CH3:2])[C:19]([C:18]1[CH:17]=[CH:16][O:15][C:14]=1[CH3:13])=[O:20]
Reactant: COCN
Reactant: Cc1occc1C(=O)Cl
Reactant: CCN(CC)CC
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)c1ccoc1C
Temperature: 0 °C
Yield: 79.2 %

Procedure:
A mixture of methoxymethylamine hydrochloride (5.85 g, 60.0 mmol) and triethylamine (16.73 ml, 120 mmol) in dichloromethane (100 ml) was stirred at 0° C. A solution of 2-methyl-3-furancarbonyl chloride (7.23 g, 50 mmol) in dichloromethane (20 ml) was added and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with water. The organic layer was separated, washed with saturated sodium hydrogen carbonate solution, water and brine, dried and evaporated to give the title compound as an oil (6.7 g, 79%); LC/MS [M+H]+=170.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N:17](Cl)[C:18](=[O:23])C(Cl)(Cl)Cl)=[CH:13][CH:12]=2)[CH:7]=[CH:6][N:5]=1.N12CCCN=C1CCCCC2.[F:37][C:38]([F:48])([F:47])[C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][C:45]=1[Cl:46])[NH2:42]>CN(C)C=O.C(OCC)(=O)C>[Cl:46][C:45]1[CH:44]=[CH:43][C:41]([NH:42][C:18](=[O:23])[NH:17][C:14]2[CH:13]=[CH:12][C:11]([O:10][C:8]3[CH:7]=[CH:6][N:5]=[C:4]([C:3]([NH:2][CH3:1])=[O:25])[CH:9]=3)=[CH:16][CH:15]=2)=[CH:40][C:39]=1[C:38]([F:37])([F:47])[F:48]
Reactant: CNC(=O)c1cc(Oc2ccc(N(Cl)C(=O)C(Cl)(Cl)Cl)cc2)ccn1
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1
Temperature: 110 °C
Yield: 66.8 %

Procedure:
N-methyl-4-(4-(2,2,2-trichlorochloroacetamido)phenoxy)picolinamide (25 g, 0.0644 mol) was dissolved in N,N-dimethyl formamide (75 ml). 1,8-Diazabicyclo[5.4.0]undec-7-ene (11.35 ml, 0.0805 mol) and 3-trifluoromethyl-4-chloroaniline (12.60 g, 0.0644 mol) were added in one lot. The reaction mass was then heated to 110° C. for 8-9 hours, cooled to room temperature and quenched in water (250 ml). The quenched mass was extracted repeatedly with ethyl acetate and the combined ethyl acetate layer was back washed with water to remove DMF traces. It was dried over sodium sulfate and evaporated under vacuum to obtain solid. The obtained solid was slurried in ethyl acetate (350 ml) at ambient temperature and filtered to give 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)-N-methylpicolinamide (sorafenib base) (20 g).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[N:5]=[C:4]([C:16]#[N:17])[CH:3]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH2:42][CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45]>O1CCOCC1>[C:16]([C:4]1[CH:3]=[C:2]([NH:42][CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[N:5]=1)#[N:17]
Reactant: N#Cc1cc(O)c2cc(C(F)(F)F)ccc2n1
Reactant: CC(C)(C)OC(=O)CN
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CNc1cc(C#N)nc2ccc(C(F)(F)F)cc12
Reaction time: 2 h

Procedure:
To a solution of 4-hydroxy-6-(trifluoromethyl)quinoline-2-carbonitrile (2 g, 8.4 mmol) from example 21, step D, in dry dioxane was added TEA (2.9 mL, 21 mmol) and PyBroP (4.75 g, 10 mmol) and stirred at 50 C for 2 hour. To this solution tert-butyl 2-aminoacetate (1.3 g, 10.1 mmol) was added and stirred at 30° C. for 24 h. The solution was concentrated in vacuo. Water was added to the residue and extracted with EtOAc. The ethyl acetate was removed under vacuum and the residue was purified by flash chromatography (silica gel, 0 to 80% EtOAc in hexane) to give the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C([Li])CCC.[CH:14]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:15].[CH2:22]([O:24][C:25](=[O:29])[CH:26](Br)[CH3:27])[CH3:23].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH2:22]([O:24][C:25](=[O:29])[CH:26]([S:8][C:5]1[CH:6]=[CH:7][C:2]([CH:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[OH:15])=[CH:3][CH:4]=1)[CH3:27])[CH3:23]
Reactant: Sc1ccc(Br)cc1
Reactant: CCOC(=O)C(C)Br
Reactant: O=Cc1cccnc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C(C)Sc1ccc(C(O)c2cccnc2)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 44.1 %

Procedure:
A solution of 0.95 g of 4-bromothiophenol in 20 ml of tetrahydrofuran was added dropwise to 7.5 ml of a 1.4 M solution of butyllithium in hexane at -70° to -60° C. After allowed to warm to 0° C., the mixture was stirred at 0° C. for 5 minutes. To it was added a solution of 0.505 g of 3-formylpyridine in 10 ml of tetrahydrofuran at -70° C., and the mixture was stirred at -70° C. for 30 minutes. To the mixture was added 0.91 g of 2-bromopropionic acid ethyl ester at -70° C., and the mixture was stirred at room temperature for one hour. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride, extracted with diethyl ether, and the extract was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (1:4) as eluent to give 0.66 g of the title compound having the following physical characteristic:
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[Na].[CH2:16]([OH:18])[CH3:17]>>[CH2:16]([O:18][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1)[CH3:17]
Reactant: CCO
Reactant: O=[N+]([O-])c1c(Cl)ccc2cccnc12
Agent: [Na]
Product: CCOc1ccc2cccnc2c1[N+](=O)[O-]
Yield: 87 %

Procedure:
A mixture of 7-chloro-8-nitroquinoline (3.00 g, 14.4 mmol), sodium (2.65 g) and absolute ethanol (100 mL) was refluxed for 4.5 hr and cooled. The tan precipitate was filtered off, slurried with water and dried to give title compound as tan solid (2.72 g, 87%); mp 161°-164°. Anal. Calcd for C11H10N2O3 : C, 60.55; H, 4.62; N, 12.84. Found: C, 60.34; H, 4.68; N, 12.78.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]([OH:16])=[O:15])=[C:12]([C:17]2[CH:18]=[N:19][N:20]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[C:21]=2[C:22]([F:25])([F:24])[F:23])[O:11][N:10]=1.S(Cl)(Cl)=O.[CH3:36]O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]([O:16][CH3:36])=[O:15])=[C:12]([C:17]2[CH:18]=[N:19][N:20]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[C:21]=2[C:22]([F:25])([F:23])[F:24])[O:11][N:10]=1
Reactant: O=C(O)c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2cccnc2)c1C(F)(F)F
Reactant: CO
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2cccnc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 9 %

Procedure:
To a mixture of 3-(2-chloro-6-fluorophenyl)-5-(1-(pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole-4-carboxylic acid (30 mg, 0.1 mmol) in methanol (1.5 mL) was added thionylchloride (5 μL, 0.1 mmol). The mixture was stirred at room temperature for 60 h and for 5 h at reflux. The mixture was diluted with dichloromethane and washed with water (3×), dried over sodium sulfate, filtered and concentrated under reduced pressure. The product (example B-67) was purified by pTLC (1:1 EE/PE) to give 3 mg of a white solid (yield 9%).
Reaction SMILES: [NH2:1][CH2:2]C1C=NC=CC=1.Cl.[O:10]1[CH:14]=[CH:13][N:12]=[C:11]1NC.[F:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][N:23]2[C:27](=[O:28])[N:26]([C:29]3[S:33][C:32]([C:34]([OH:36])=O)=[C:31]([CH3:37])[CH:30]=3)[CH:25]=[N:24]2)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][N:23]2[C:27](=[O:28])[N:26]([C:29]3[S:33][C:32]([C:34]([NH:1][CH2:2][C:11]4[O:10][CH:14]=[CH:13][N:12]=4)=[O:36])=[C:31]([CH3:37])[CH:30]=3)[CH:25]=[N:24]2)=[CH:20][CH:19]=1
Reactant: Cc1cc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Reactant: CNc1ncco1
Reactant: NCc1cccnc1
Agent: Cl
Product: Cc1cc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)NCc1ncco1
Yield: 50 %

Procedure:
Following the procedure as described in Example 31, making variations as required to replace 3-(aminomethyl)pyridine with oxazol-2-yl-methylamine hydrochloride to react with 5-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-3-methylthiophene-2-carboxylic acid, the title compound was obtained as a colorless solid in 50% yield: mp 163-165° C.; 1H NMR (300 MHz, CDCl3) δ 7.72 (s, 1H), 7.64 (s, 1), 7.40-7.34 (m, 2H), 7.08 (s, 1H), 7.06-6.99 (m, 2H), 6.91 (s, 1H), 6.64 (br s, 1H), 4.96 (s, 2H), 4.72 (d, J=5.2 Hz, 2H), 2.53 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.6 (d, JC-F=247.0 Hz), 162.3, 150.4, 140.6, 139.3, 135.0, 132.3, 131.2 (d, JC-F=3.3 Hz), 130.3 (d, JC-F=8.3 Hz), 127.1, 125.4, 120.4, 115.7 (d, JC-F=21.6 Hz), 48.9, 37.3, 16.0; MS (ES+) m/z 414.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:11][N:12]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[C:13]=2[CH:14]([CH3:16])[CH3:15])=[CH:4][CH:3]=1.[CH3:33][C:34]1[C:38]2[CH:39]=[C:40]([N+:43]([O-])=O)[CH:41]=[CH:42][C:37]=2[O:36][N:35]=1>CCCCCC.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([NH:43][C:40]2[CH:41]=[CH:42][C:37]3[O:36][N:35]=[C:34]([CH3:33])[C:38]=3[CH:39]=2)[C:9]2[C:10]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:11][N:12]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[C:13]=2[CH:14]([CH3:16])[CH3:15])=[CH:6][CH:7]=1
Reactant: Cc1noc2ccc([N+](=O)[O-])cc12
Reactant: CCOC(=O)c1nn(-c2cnc(OC)nc2OC)c(C(C)C)c1C(O)c1ccc(Cl)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)c1nn(-c2cnc(OC)nc2OC)c(C(C)C)c1C(Nc1ccc2onc(C)c2c1)c1ccc(Cl)cc1

Procedure:
The title product was prepared in analogy to the procedure described in Step 46.12 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-(2,4-dimethoxypyrimidin-5-yl)-5-isopropyl-1H-pyrazole-3-carboxylate (Step 46.11) and 3-methyl-5-nitrobenzo[d]isoxazole (Step 33.3). tR: 1.34 min (LC-MS 2); ESI-MS: 591 [M+H]+ (LC-MS 2); Rf=0.25 (hexane/EtOAc 1:1).
Reaction SMILES: Cl.C(OCC)(=O)C.C(Cl)[Cl:9].[O:11]=[C:12]1[N:16]([C:17]2[CH:26]=[C:25]3[C:20]([CH:21]=[C:22]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:37])([F:36])[F:35])[NH:23][C:24]3=[O:27])=[CH:19][CH:18]=2)[CH2:15][C@H:14]([CH2:38][O:39][C:40](=[O:51])[CH2:41][N:42](C(OC(C)(C)C)=O)[CH3:43])[O:13]1>CCOCC>[ClH:9].[O:11]=[C:12]1[N:16]([C:17]2[CH:26]=[C:25]3[C:20]([CH:21]=[C:22]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:37])([F:35])[F:36])[NH:23][C:24]3=[O:27])=[CH:19][CH:18]=2)[CH2:15][C@H:14]([CH2:38][O:39][C:40](=[O:51])[CH2:41][NH:42][CH3:43])[O:13]1
Reactant: ClCCl
Reactant: CN(CC(=O)OC[C@H]1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C(=O)O1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CNCC(=O)OC[C@H]1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C(=O)O1
Temperature: 25 °C
Reaction time: 5 h
Yield: 95 %

Procedure:
A 4 N hydrochloric acid-ethyl acetate solution (5 ml, 20 mmol) was added at 0° C. to a methylene chloride solution (10 ml) that contained the N-tert-butoxycarbonyl-N-methylaminoacetic acid (R)-2-oxo-3-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]oxazolidin-5-ylmethyl ester (1.15 g, 2.0 mmol) obtained in step A. The obtained mixture was stirred at a room temperature for 5 hours. Thereafter, ether was added to the reaction mixture, so that powders were completely precipitated and collected by filtration. The filtrate was washed with ether and hexane, and was then dried under reduced pressure, so as to obtain methylaminoacetic acid (R)-2-oxo-3-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]oxazolidin-5-ylmethyl ester hydrochloride (967 mg, 95%) in the form of white powders.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([CH:24]=O)[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.[CH3:28][NH:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C([BH3-])#N.[Na+].C(O)(=O)C>CCO>[CH2:30]([N:29]([CH2:24][CH:21]1[CH2:22][CH2:23][N:18]([C:16]([C:8]2[N:7]([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([F:1])=[CH:3][CH:4]=3)[C:15]3[C:10]([CH:9]=2)=[CH:11][CH:12]=[CH:13][CH:14]=3)=[O:17])[CH2:19][CH2:20]1)[CH3:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CNCc1ccccc1
Reactant: O=CC1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CN(Cc1ccccc1)CC1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(F)cc2)CC1
Reaction time: 14 h

Procedure:
1-(1-(4-fluorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carbaldehyde (86 mg, 0.236 mmol) was dissolved in EtOH (5 mL) and N-methylbenzylamine (0.027 mL, 0.283 mmol), sodium cyanoborohydride (30 mg, 0.472 mmol), and a catalytic drop of glacial acetic acid were added. Stirring was permitted for 14 h, at which time the solvent was removed in vacuo, the residue was taken up in EtOAc. The organic phase was washed with 10% aq. sodium carbonate, dried over magnesium sulfate, and concentrated. Purification was accomplished via silica gel flash chromatography (30 g silica gel, 100% EtOAc.) The title compound was obtained as an oil. (Yield: 23 mg, 0.049 mmol, 20%) 1H NMR (400 MHz, CDCl3) 7.62, 7.37-7.23, 7.14, 7.08-7.02, 6.82, 6.57, 5.45, 4.60, 4.04, 3.44, 2.75, 2.16, 2.10, 1.83-1.59, 0.91, 0.51
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:32]=[CH:31][C:12]2[N:13]([CH2:17][CH:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)#[N:2].CO.Cl.CCOC(C)=O>C(Cl)Cl>[O:16]=[C:14]1[N:13]([CH2:17][CH:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]2)[C:12]2[CH:31]=[CH:32][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]#[N:2])=[CH:10][C:11]=2[S:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(Cn2c(=O)sc3cc(-c4ccccc4C#N)ccc32)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1-c1ccc2c(c1)sc(=O)n2CC1CCNCC1
Reaction time: 2 h

Procedure:
To a round bottom flask was added tert-butyl 4-{[6-(2-cyanophenyl)-2-oxo-1,3-benzothiazol-3(2H)-yl]methyl}piperidine-1-carboxylate (11-2) (0.242 g, 0.538 mmol), MeOH (2.5 mL), DCM (2.5 mL), and a sat'd solution of HCl in EtOAc (˜4N) (1.346 mL, 5.38 mmol). The reaction mixture was capped and permitted to stir for two hours then concentrated to give 2-[2-oxo-3-(piperidin-4-ylmethyl)-2,3-dihydro-1,3-benzothiazol-6-yl]benzonitrile (11-3) as a tan solid. HRMS (M+H)+: observed=350.1322, calculated=350.1322.