Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](/[CH:8]=[C:9]2/[C:10](=[O:15])[NH:11][C:12](=[O:14])[S:13]/2)[CH:5]=[CH:4][N:3]=1.[N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[C:26](Cl)=[O:27].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[O:14]=[C:12]1[NH:11][C:10](=[O:15])/[C:9](=[CH:8]/[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:26]([C:17]3[CH:18]=[CH:19][C:20]4[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:16]=3)=[O:27])[N:7]=2)/[S:13]1
Reactant: Nc1nccc(/C=C2\SC(=O)NC2=O)n1
Reactant: O=C(Cl)c1ccc2ccccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: O=C1NC(=O)/C(=C/c2ccnc(NC(=O)c3ccc4ccccc4n3)n2)S1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(Z)—N-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)quinoline-2-carboxamide was prepared as follows. A 2-dram vial was charged with (Z)-5-((2-aminopyrimidin-4-yl)methylene)thiazolidine-2,4-dione (22.2 mg, 0.100 mmol), Pyridine (1 mL), quinoline-2-carbonyl chloride (74.6 mg, 0.389 mmol, 3.8 equiv.), triethylamine (60.7 mg, 0.599 mmol, 5.9 equiv.), and the reaction was shaken at RT. After 16 h, the reaction was treated with saturated sodium bicarbonate (3 mL) and extracted with DCE (3×3 mL). The combined organic layer was concentrated under reduced pressure and the residue was purified using reverse phase HPLC to provide the desired product (3 mg, 37.7 mg theoretical, 8%). LC-MS m/z 378.4 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:9][CH2:10]O)=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O>ClCCl>[Cl:21][CH2:10][CH2:9][CH:8]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: OCCC(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: ClCCl
Product: Fc1ccc(C(CCCl)c2ccc(F)cc2)cc1
Yield: 76.7 %

Procedure:
A solution of 5.5 parts of 3,3-bis(4-fluorophenyl)-1-propanol and 2.92 parts of thionyl chloride in 39.9 parts of dichloromethane was stirred for 4 hours at 60° C. The reaction mixture was evaporated and then co-evaporated with methylbenzene. The residue was dissolved in ethyl acetate and this solution was washed with Na2CO3 (aq.), water and NaCl (sat.) and was then dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; (C2H5)2O/n. hexane 2:98). The eluent of the desired fraction was evaporated, yielding 4.5 parts (76.7%) of 1-[3-chloro-1-(4-fluorophenyl)propyl]-4-fluorobenzene (interm. 22).
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[C:11]([O:16]CC)(=[O:15])[C:12]([CH3:14])=[O:13].[Cl-].[NH4+]>CCCCCC.C(OCC)C>[OH:13][C:12]([C:7]1[S:6][CH:10]=[CH:9][CH:8]=1)([CH3:14])[C:11]([OH:16])=[O:15]
Reactant: c1ccsc1
Reactant: CCOC(=O)C(C)=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(O)(C(=O)O)c1cccs1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 1.6 molar solution of n-butyl-lithium in hexane (37 ml.) was added to a solution of thiophene (5 g.) in diethyl ether (50 ml.) which was maintained at 0° C., and the mixture was heated under reflux for 6 hours and then cooled to -78° C. A solution of ethyl pyruvate (5.9 g.) in diethyl ether (20 ml.) was added dropwise, the mixture was allowed to warm up to laboratory temperature and saturated aqueous ammonium chloride solution (20 ml.) was added. The mixture was extracted with ethyl acetate and the organic extract was washed with water and then with saturated aqueous sodium chloride solution, dried over magnesium sulphate and evaporated to dryness. The residue was dissolved in ethanol (30 ml.), a solution of potassium hydroxide (1.4 g.) in water (5 ml.) was added and the mixture was stirred at laboratory temperature for 2 hours and then evaporated to dryness. The residue was washed with ethyl acetate, dilute aqueous hydrochloric acid was added and the mixture was extracted with ethyl acetate. The extract was washed with water and then saturated aqueous sodium chloride solution, dried over magnesium sulphate and evaporated to dryness. There was thus obtained as residue 2-hydroxy-2-(thien-2-yl)propionic acid, which was used without further purification.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([F:29])[CH:20]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:33]O.Cl>CO.O>[F:29][C:21]1[CH:20]=[C:19]([CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=1)[CH2:18][C@H:10]1[CH2:9][C@H:8]([C:6]2[O:7][NH:33][C:4](=[O:3])[CH:5]=2)[CH2:13][CH2:12][N:11]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](Cc2cc(F)cc(C(F)(F)F)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1cc(F)cc(C(F)(F)F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 94.5 %

Procedure:
Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-fluoro-5-(trifluoromethyl)benzyl)piperidine-1-carboxylate (0.75 g, 1.73 mmol) (from example 137, step 1) was dissolved in MeOH (15 mL) and cooled to −40° C. Sodium hydroxide (0.073 g, 1.82 mmol) dissolved in water (1 mL) was added over 1 min and the resulting solution was stirred at −40° C. for 20 min. Then hydroxylamine (50% by weight in water, 0.115 mL, 1.88 mmol) was added over 1 min and stirring continued at −40° C. for 2 h 20 min. The reaction mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (30 mL, 180.00 mmol) and the mixture was continued to be stirred at 80° C. for 1 h. Then cooled to room temperature. Methanol was evaporated, then water was added. Extracted three times with DCM. Combined organic layers dried over MgSO4 and evaporated. Trans-methyl 2-(3-fluoro-5-(trifluoromethyl)benzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (658 mg, 95%) was isolated as an off-white solid. MS m/z 403 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2(C(C3CCCCO3)=O)[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]4[N:23]=[CH:22][N:21](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:20]=4)[CH:17]=3)[NH:12][NH:11]2)=[CH:4][CH:3]=1>O1CCOCC1.Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]4[N:23]=[CH:22][NH:21][N:20]=4)[CH:17]=3)[NH:12][N:11]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(/C=C/C2(C(=O)C3CCCCO3)NNc3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc32)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(/C=C/c2n[nH]c3ccc(-c4nc[nH]n4)cc23)cc1
Reaction time: 6.5 h
Yield: 81 %

Procedure:
Hydrolysis was performed by stirring 2-{3-[(1E)-2-(4-methylphenyl)vinyl]-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazoyl}perhydro-2H-pyran (0.269 g, 0.42 mmol) in 4 mL of 4.0 N commercial solution of HCl in dioxane and 2 mL of 6.0 N aqueous HCl, at room temperature for 6.5 hours. The title compound was purified by column chromatography (5% MeOH in dichloromethane) and isolated as a 97:3 ratio of 2 isomers (0.103 g, 81% yield): 1H NMR (DMSO-d6) δ 8.8 (s, 1H), 8.6 (br s, 1H), 8.1 (d, 1H), 7.6 (m, 3H), 7.5 (d, 2H), 7.0 (d, 2H), 2.34 (s, 3H); ES-MS (m/z) 302 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([CH:10]=O)=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([CH3:23])([CH3:22])[NH2:21])=[CH:15][CH:14]=1>>[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([NH:21][CH2:10][CH:8]([OH:9])[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)([CH3:22])[CH3:23])=[CH:15][CH:14]=1
Reactant: O=CC(=O)c1cccc(Cl)c1
Reactant: Cc1ccc(CC(C)(C)N)cc1
Product: Cc1ccc(CC(C)(C)NCC(O)c2cccc(Cl)c2)cc1

Procedure:
The title compound was prepared in the manner described in Example 9 using 3-chlorophenylglyoxal and 2-(4-Methylphenyl)-1,1-dimethyl ethanamine. The chromatographed material was recrystallized from cyclohexane to give the title compound m.p. 104-105. τ(CDCL3), 8.9 (6H, s), 7.7 (3H, s), 7.4 (2H, s), 7.1 (2H, dd,), 5.45 (1H, dd), 3.0 (4H, s), 2.5-2.8 (4H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)[N:6]=[CH:5]2.[O:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28]([O-])=[O:29])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1>>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([NH:1][C:28](=[O:29])[C:27]4[CH:26]=[CH:25][C:24]([N:21]5[CH2:22][CH2:23][O:18][CH2:19][CH2:20]5)=[CH:32][CH:31]=4)=[CH:10][CH:9]=3)[CH:5]=[N:6]2)=[CH:12][CH:13]=1
Reactant: O=C([O-])c1ccc(N2CCOCC2)cc1
Reactant: Nc1ccc(-n2ncc3cc(N)ccc32)cc1
Product: Nc1ccc(-n2ncc3cc(NC(=O)c4ccc(N5CCOCC5)cc4)ccc32)cc1

Procedure:
Compound 381 was prepared according to the procedure described in Scheme IV from 5-amino-1-(4-aminophenyl)indazole and 4-morpholinobenzoate. [M+H]+ calcd for C24H23N5O2: 414.19; found: 414.01.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[I:15])=[O:4].C([O-])([O-])=O.[K+].[K+].[CH2:24](Br)[CH:25]=[CH:26][CH3:27]>CN(C)C=O.CCOC(C)=O>[CH2:24]([N:5]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[I:15])[C:3](=[O:4])[C:2]([F:16])([F:1])[F:17])[CH:25]=[CH:26][CH3:27]
Reactant: CC=CCBr
Reactant: O=C(NCCc1ccc(Cl)cc1I)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC=CCN(CCc1ccc(Cl)cc1I)C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 36.7 %

Procedure:
A solution of N-trifluoroacetyl-2-iodo-4-chlorophenethylamine (6.2 g, 15.8 mmol) in dimethylformamide (350 mL) was treated with K2CO3 (15.8 g, 114 mmol) and crotyl bromide (6.0 g, 44 mmol) sequentially, the mixture was stirred at 60 C for 16 hours and then cooled to 20 C. The mixture was diluted with EtOAc (350 mL), washed with water (3×300 mL), dried with Na2SO4 and concentrated. Flash chromatography (5-15% EtOAc in hexane) resulted in 2.5 g of a clear oil. MS calculated for C14H14ClF3INO+H: 432, observed: 432.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1>C(O)C>[CH2:13]1[CH:14]2[N:10]([CH2:2][CH:3]=[C:4]([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][N:5]=4)[NH:1][CH:2]=3)[CH2:9]2)[CH2:11][CH2:12]1
Reactant: C1CCNC1
Reactant: c1cnc2cc[nH]c2c1
Solvent: CCO
Product: C1=C(c2c[nH]c3cccnc23)CC2CCCN2C1

Procedure:
from 4-azaindole (1.0 g, 8.46 mmol), 1,2,3,5,6,8,8a-heptahydrohydro-7-oxo-indolizine (1.77 g, 12.7 mmol) and pyrrolidine (3.5 g, 42.3 mmol) in ethanol (8 mL), heating at reflux for 3 hrs.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][O:2]1.C([O-])([O-])=O.[K+].[K+].[Cl:15][CH2:16][CH2:17][CH2:18]Br>CC(C)=O>[Cl:15][CH2:16][CH2:17][CH2:18][N:7]1[CH2:6][CH:5]2[CH2:1][O:2][CH2:3][CH:4]2[CH2:8]1
Reactant: C1NCC2COCC12
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: ClCCCN1CC2COCC2C1
Yield: 51.7 %

Procedure:
To a solution of hexahydro-1H-furo[3,4-c]pyrrole (0.15 g) in acetone (50 mL) was added K2CO3 (0.46 g) and 1-chloro-3-bromopropane (0.42 g, 2.0 eq) in turn. The reaction mixture was heated to reflux for 12 h and filtered. The filtrate was concentrated in vacuo and the residue was dissolved in EtOAc (100 mL). The solution was washed with water twice followed by brine once. The solution was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) EA/CH3OH) to give the title compound (0.13 g, 50.04%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 190.7 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][NH:10][C:9](=[O:13])[N:8]=2)=[C:5]([CH3:14])[O:4][N:3]=1.[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][CH2:21][Cl:22].O>CN(C=O)C>[Cl:22][CH2:21][CH2:20][CH2:19][CH2:18][N:10]1[CH:11]=[CH:12][C:7]([C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[CH3:14])=[N:8][C:9]1=[O:13]
Reactant: Cc1noc(C)c1-c1cc[nH]c(=O)n1
Reactant: ClCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1noc(C)c1-c1ccn(CCCCCl)c(=O)n1
Temperature: 100 °C
Yield: 35.1 %

Procedure:
To a solution of 4-(3,5-dimethyl-isoxazol-4-yl)-1H-pyrimidin-2-one (156 mg, 0.82 mmol) in dry DMF (20 ml), 60% NaH (40 mg, 1.06 mmol) was added portionwise under inert atmosphere. After heating the mixture at 100° C. for 1 hour, 1-bromo-4-chloro-butane (123 μl, 1.06 mmol) was added at room temperature and the mixture was heated at 100° C. for 2 hours. Water was added and the mixture extracted with diethyl ether to remove the dialkylated product and finally with ethyl acetate. Ethyl acetate phase was dried (Na2SO4) and evaporated to afford 81 mg of the title compound that was used in the next step without further purification (35% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7](C=C[CH2:10][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:14](=[O:17])(O)[O-].[Na+].Cl[C:20]1C=CC=C(C(OO)=O)C=1.C(=O)(O)[O-]>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:12]2[C:13]=1[CH:20]1[O:17][CH:14]1[CH2:10][CH2:11]2)([O-:3])=[O:2]
Reactant: O=C([O-])O
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=[N+]([O-])c1ccc2c(c1)CCC=C2
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc2c1C1OC1CC2

Procedure:
2.45 g of the product of Step 1, 36 ml of methylene chloride, 47 ml of 0.5N sodium bicarbonate solution and 3.40 g of metachloroperbenzoic acid were stirred at 20° C. for 5 hours. 0.7 g of per-acid and 9.30 ml of bicarbonate solution were added after 2 hours. After decanting, extraction was done with methylene chloride and the extracts were washed with water, dried and the solvent was evaporated. After crystallization from ether, 1.6 g of the expected product melting at 67° C. and after crystallization from isopropanol melting at 73° C. were obtained.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[CH:16]=[C:15]3[C:10]([CH:11]=[CH:12][C:13]([NH2:17])=[CH:14]3)=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([OH:35])=O)=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21]C=1.Cl.C(N=C=NC(C)(C)CC)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[O:25]([C:26]1[CH:27]=[CH:28][C:29]([CH2:32][C:33]([NH:17][C:13]2[CH:12]=[CH:11][C:10]3[C:15](=[CH:16][N:8]([CH2:7][CH2:6][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[N:9]=3)[CH:14]=2)=[O:35])=[CH:30][CH:31]=1)[C:18]1[CH:19]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccc2nn(CCN3CCCC3)cc2c1
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Agent: CCN=C=NC(C)(C)CC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(Oc2ccccc2)cc1)Nc1ccc2nn(CCN3CCCC3)cc2c1
Reaction time: 6 h

Procedure:
A mixture of 2-(2-pyrrolidin-1-yl-ethyl)-2H-indazol-5-ylamine (56.0 mg, 0.243 mmol), (4-benzyloxy-phenyl)-acetic acid (60.0 mg, 0.248 mmol), ethyldimethypropylcarbodiimide hydrochloride (57.0 mg, 0.298 mmol), N-hydroxybenzotriazole (40.0 mg, 0.296 mmol), N-methylmorpholine (64.0 mg, 0.633 mmol) and 2 mL of N,N-dimethylformamide, were shaken for 6 hours. The solvents were removed under vacuo and the residue was dissolved in 1.5 mL of a 1:1 mixture of dimethylsulfoxide/methanol and purified by preparative reverse-phase HPLC. 1H NMR (300 MHz, DMSO-d6) ppm 1.82(m, 2H), 1.99 (m, 2H), 3.03(m, 2H), 3.52 (m, 2H), 3.64 (s, 2H), 3.80 (m, 2H), 4.78 (t, 2H, J=6.24), 6.97–7.00 (m, 4H), 7.12 (m, 1H), 7.29–7.39 (m, 5H), 7.59 (m, 1H), 8.18 (s, 1H), 8.38 (s, 1H), 10.13 (s, 1H); MS (DCI/NH3) m/z 441 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:8]2[CH2:12][CH:11]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH3:23])=[CH:17][C:16]=3[O:24][CH3:25])[O:10]C2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C(C2C=CC=CC=2)N2CC(C[Cl:45])OC2)C=CC=CC=1.COC1C=C(CCC)C=CC=1[O-].[Na+].Cl>>[ClH:45].[CH3:25][O:24][C:16]1[CH:17]=[C:18]([CH2:21][CH2:22][CH3:23])[CH:19]=[CH:20][C:15]=1[O:14][CH2:13][CH:11]([OH:10])[CH2:12][NH:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCCc1ccc(OCC2CN(C(c3ccccc3)c3ccccc3)CO2)c(OC)c1
Reactant: ClCC1CN(C(c2ccccc2)c2ccccc2)CO1
Agent: CCCc1ccc([O-])c(OC)c1
Agent: Cl
Agent: [Na+]
Product: CCCc1ccc(OCC(O)CNC(c2ccccc2)c2ccccc2)c(OC)c1

Procedure:
3-Diphenylmethyl-5-(2-methoxy-4-n-propyl-phenoxymethyl)oxazolidine from 3-diphenylmethyl-5-chloromethyl-oxazolidine and sodium 2-methoxy-4-n-propyl-phenolate; this product is hydrolysed with alcoholic-aqueous hydrochloric acid to give 1-(2-methoxy-4-n-propyl-phenoxy)-2-hydroxy-3-diphenylmethylamino-propane hydrochloride with a melting point of 108°-110°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([C:10]1[C:18]2[N:17]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])[NH:15][C:14]=2[CH:13]=[CH:12][CH:11]=1)=[O:9].C1C=C(Cl)C=C(C(OO)=[O:37])C=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[F:27][C:25]([F:28])([F:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:16]1[NH:15][C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([C:8]([NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N+:1]=3[O-:37])=[O:9])[C:18]=2[N:17]=1
Reactant: O=C(Nc1ccccn1)c1cccc2[nH]c(-c3ccccc3C(F)(F)F)nc12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(Nc1cccc[n+]1[O-])c1cccc2[nH]c(-c3ccccc3C(F)(F)F)nc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 57.9 %

Procedure:
To a solution of N-(pyridin-2-yl)-2-(2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide (10; 100 mg, 0.26 mmol) in CH2Cl2 (10 mL) was added mCPBA (140 mg, 0.81 mmol) under nitrogen. The mixture was stirred at room temperature for 12 h. A saturated aqueous solution of K2CO3 (10 mL) was added and the mixture was extracted with CH2Cl2 (3×10 mL). The combined organic layers were dried (Na2SO4), concentrated under reduced pressure. The resulting residue was purified by chromatography (CH2Cl2:methanol=20:1) to give 2-(2-(2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4-carboxamido)pyridine 1-oxide (Compound 329) (60.0 mg, 58%) as a colorless solid. MS (ESI) calcd for C20H13F3N4O2: 398.10; found: 399 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[C:10]([S:15](Cl)(=[O:17])=[O:16])[CH:9]=2)=[CH:4][C:3]=1[S:19](Cl)(=[O:21])=[O:20].[F:23][C:24]([F:30])([F:29])[S:25]([NH2:28])(=[O:27])=[O:26].C(N(CC)CC)C.[OH-:38].[Na+]>O.C(#N)C>[F:23][C:24]([F:30])([F:29])[S:25]([NH:28][S:19]([C:3]1[CH:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[C:10]([S:15]([NH:28][S:25]([C:24]([F:30])([F:29])[F:23])(=[O:26])=[O:38])(=[O:17])=[O:16])[CH:9]=2)[CH:6]=[CH:7][C:2]=1[Br:1])(=[O:21])=[O:20])(=[O:27])=[O:26]
Reactant: NS(=O)(=O)C(F)(F)F
Reactant: O=S(=O)(Cl)c1cc(-c2ccc(Br)c(S(=O)(=O)Cl)c2)ccc1Br
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=S(=O)(NS(=O)(=O)C(F)(F)F)c1cc(-c2ccc(Br)c(S(=O)(=O)NS(=O)(=O)C(F)(F)F)c2)ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
Inside a glove box, a 250 mL round-bottom flask equipped with a stirring bar, reflux condenser, and a septum was charged with 4,4′-dibromo-biphenyl-3,3′-disulfonyl dichloride (10.95 g, 21.5 mmoles), trifluoromethanesulfonamide (6.41 g, 43 mmoles), and acetonitrile (75 mL). Triethylamine (13 mL, 93 mmoles) was added slowly by syringe. The solution was heated to a reflux and stirred overnight under nitrogen. The solution was cooled to room temperature and poured into an aqueous solution of sodium hydroxide (3.5 g, 88 mmoles) in 400 mL water. The solvents were evaporated on a rotary evaporator and the solids were dried under vacuum. The solids were dissolved in n-propanol at reflux, filtered to remove insolubles and salt, treated with decolorizing carbon, filtered to remove the carbon, evaporated on a rotary evaporator, and dried under vacuum to give 16.8 g (100%). The solids were recrystallized from n-propanol using decolorizing carbon again and collecting three crops for a combined weight of 13.75 g (82% yield). The solids were recrystallized from n-propanol as needles in two crops by allowing for slow evaporation of the solvent. The crystals were dried under vacuum to give a total of 9.61 g (57%) of N,N′-bis(trifluoromethanesulfonyl)-4,4′-dibromo-biphenyl-3,3′-disulfonamide, disodium salt. 1H NMR (DMSO-d6): 7.69 (dd, J=8.2 and 2.4 Hz, 2H), 7.87 (d, J=8.2 Hz, 2H), 8.03 (d, J=2.4 Hz, 2H). 19F NMR (DMSO-d6): −78.2 (s). The compound was redried at 150° C. overnight in a nitrogen-purged vacuum oven then transferred immediately to the glove box.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[Cl:12])[N:3]=1.C([Sn](CCCC)(CCCC)[C:18]([O:20]CC)=[CH2:19])CCC.Cl.[OH-].[Na+]>O1CCOCC1.C(OCC)(=O)C>[Cl:12][C:8]1[CH:7]=[CH:6][N:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]([C:18](=[O:20])[CH3:19])=[N:3]2
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Clc1ccc2c(Cl)ccnc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc2c(Cl)ccnc2n1
Temperature: 80 °C
Yield: 33.6 %

Procedure:
A stirred solution of 2,5-dichloro-[1,8]naphthyridine (Barlin, G. B.; Tan, W.-L. Aust. J. Chem. 1984, 37, 1065) (0.1001 g, 0.503 mmol) in 1,4-dioxane (5 mL) was degassed by bubbling nitrogen through for 15 min. Tetrakis-(triphenylphosphine)palladium(0) (30.0 mg, 0.0259 mmol) and tributyl(1-ethoxyvinyl)tin (0.170 mL, 0.503 mmol) was added and the mixture was heated at 80° C. for 17 h under nitrogen. The mixture was diluted with ethyl acetate (20 mL) and shaken with 2 N aqueous HCl (15 mL) for 1 min. The mixture was adjusted to pH 6 with 4 N aqueous NaOH and the organic layer was separated. The aqueous layer was further extracted with ethyl acetate (2×15 mL), and the combined organic extracts were dried (MgSO4) and evaporated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 15% EtOAc/CH2Cl2, followed by a further column on silica gel eluting with 50% EtOAc/isohexane, to afford 34.9 mg (34%) of the title compound as a white solid. δH (360 MHz, CDCl3) 2.95 (3H, s), 7.68 (1H, d, J 4.6), 8.33 (1H, d, J 8.4), 8.76 (1H, d, J 8.8), 9.12 (1H, d, J 4.9).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][C:8]2[C:9]([CH3:19])=[N:10][CH:11]=[N:12][C:13]=2[C@H:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[N:31]([C:34]1[C:35]([CH3:40])=[N:36][O:37][C:38]=1[CH3:39])=[C:32]=[O:33]>ClCCl>[Cl:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][C:8]2[C:13]([C@H:14]3[CH2:18][CH2:17][CH2:16][N:15]3[C:32]([NH:31][C:34]3[C:35]([CH3:40])=[N:36][O:37][C:38]=3[CH3:39])=[O:33])=[N:12][CH:11]=[N:10][C:9]=2[CH3:19])=[CH:5][CH:4]=1
Reactant: Cc1ncnc([C@H]2CCCN2)c1Cc1ccc(Cl)cc1
Reactant: Cc1noc(C)c1N=C=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ncnc([C@H]2CCCN2C(=O)Nc2c(C)noc2C)c1Cc1ccc(Cl)cc1
Yield: 28.1 %

Procedure:
(R)-5-(4-chlorobenzyl)-4-methyl-6-(pyrrolidin-2-yl)pyrimidine hydrochloride (30 mg, 0.066 mmol) and N,N-diisopropylethylamine (0.041 mL) were dissolved in dichloromethane (2 mL). 4-isocyanato-3,5-dimethylisoxazole (15 mg, 0.11 mmol) was added while stirring. The reaction mixture was stirred for 16 h then evaporated to dryness. Purification by semi-preparative HPLC afforded the desired product (7.9 mg, 27.8%).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([O:30]CC)=O)[C:24]=2[CH:33]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([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.[Cl-].[NH4+:44]>>[Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:36][C@H:37]([CH3:42])[O:38][C@H:39]([CH3:41])[CH2:40]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([NH2:44])=[O:30])[C:24]=2[CH:33]=1)([C:14]([CH3:15])([CH3:17])[CH3:16])([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
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Reactant: [NH4+]
Agent: [Cl-]
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc3c(C(N)=O)noc3c2F)C[C@H](C)O1

Procedure:
Starting materials: Ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and ammonium chloride.