Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]#[C:2][NH2:3].[Pb].[CH3:5][NH:6][C:7]([NH:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[NH:18][CH:17]=[N:16][C:15]=1[CH3:19])=S.C[N:21](C)C=O>C(#N)C>[C:2]([NH:3][C:7]([NH:6][CH3:5])=[N:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[NH:18][CH:17]=[N:16][C:15]=1[CH3:19])#[N:1].[NH2:1][C:2]([NH2:21])=[NH:3]
Reactant: N#CN
Reactant: CN(C)C=O
Reactant: CNC(=S)NCCSCc1[nH]cnc1C
Agent: [Pb]
Solvent: CC#N
Product: CNC(=NCCSCc1[nH]cnc1C)NC#N
Product: N=C(N)N
Reaction time: 24 h

Procedure:
Lead cyanamide (3.0 g.) was added to a solution of N-methyl-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]thiourea (2.44 g.) in acetonitrile (50 ml.). Dimethylformamide (20 ml.) was added subsequently and the suspension was heated under reflux, with stirring, for 24 hours. Filtration, followed by concentration under reduced pressure and purification of the product by chromatography on a column of silica gel with acetonitrile as eluant and recrystallisation from the same solvent afforded N-cyano-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)-methylthio)ethyl]guanidine, methylthio)ethyl]guanidine, m.p. 139°-141°. (Found: C, 47.3; H, 6.6; N, 33.4; S, 12.6. C10N16N6S requires: C, 47.6; H, 6.4; N, 33.3; S, 12.7).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:1][C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][C:8]([NH:32][CH2:31][C:30]2[CH:33]=[CH:34][C:27]([F:26])=[CH:28][CH:29]=2)=[N:9]3)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: NCc1ccc(F)cc1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Product: O=S(=O)(Nc1cccc2nc(NCc3ccc(F)cc3)ccc12)c1ccc(F)cc1

Procedure:
The title compound, MS: m/e=426.0 (M+H+), was prepared in accordance with the general method of example 61 from 5-nitro-2-chloroquinoline, 4-fluorobenzenesulphonylchloride and 4-fluorobenzylamine.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:18]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:16]=[C:15]([Cl:23])[C:14]=1[N:24]1[CH:32]=[C:27]2[CH:28]=[N:29][CH:30]=[CH:31][C:26]2=[N:25]1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[Cl:12][C:13]1[CH:18]=[C:17]([S:19]([CH3:22])(=[O:20])=[O:21])[CH:16]=[C:15]([Cl:23])[C:14]=1[N:24]1[CH:32]=[C:27]2[CH:28]=[N+:29]([O-:9])[CH:30]=[CH:31][C:26]2=[N:25]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CS(=O)(=O)c1cc(Cl)c(-n2cc3cnccc3n2)c(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)c1cc(Cl)c(-n2cc3c[n+]([O-])ccc3n2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
mCPBA (569 mg, 3.3 mmol) was added to a cooled (0° C.) solution of 2-(2,6-dichloro-4-methanesulfonylphenyl)-2H-pyrazolo[4,3-c]pyridine (752 mg, 2.2 mmol) in DCM (20 mL) under nitrogen. The reaction was stirred for 1 hour, warmed to room temperature, and stirred for an additional 2 hours. Further mCPBA (150 mg) was added and the reaction mixture was stirred at room temperature for 4 hours before adding sodium thiosulfate (aq.). The organic layer was separated, washed with sodium hydrogen carbonate (sat. aq.) and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (5-10% methanol in DCM) to afford the title compound as a white solid (640 mg, 81% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.94 (dd, J=1.8, 0.9 Hz, 1H), 8.88 (d, J=1.0 Hz, 1H), 8.33 (s, 2H), 7.96 (dd, J=7.5, 1.8 Hz, 1H), 7.86 (dt, J=7.5, 1.0 Hz, 1H), 3.48 (s, 3H). LCMS (Method D): RT=2.13 min, m/z: 358 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH:12]([CH3:15])[CH2:11]2)=[CH:4][C:3]=1[N:16]1[C:20](=[O:21])[C:19]2[CH2:22][CH2:23][CH2:24][CH2:25][C:18]=2[C:17]1=[O:26].[CH2:27]([NH2:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C(N(CC)CC)C>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH:12]([CH3:15])[CH2:11]2)=[CH:4][C:3]=1[NH:16][C:17](=[O:26])[C:18]1[CH2:25][CH2:24][CH2:23][CH2:22][C:19]=1[C:20]([NH:33][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:21]
Reactant: CCCCCCN
Reactant: CC1CCC(Oc2cc(N3C(=O)C4=C(CCCC4)C3=O)c(F)cc2Cl)C1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCCCCNC(=O)C1=C(C(=O)Nc2cc(OC3CCC(C)C3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
N-{2-Fluoro-4-chloro-5-(3-methylcyclopentyl)oxyphenyl}-3,4,5,6-tetrahydrophthalimide (1.26 g, 3.33 mmol), hexylamine (0.410 g, 4.05 mmol), triethylamine (0.380 g, 3.76 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-{2-fluoro-4-chloro-5-(3-methylcyclopentyl)oxyphenyl}-N'-hexyl-3,4,5,6-tetrahydrophthalamide as white crystals (1.29 g, 80.8% yield).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH:5]([OH:11])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.[OH-].[Na+]>Cl>[Cl:1][CH2:2][CH2:3][CH2:4][CH:5]([O:11][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][O:12]1)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: C1=COCCC1
Reactant: CCCCCC(O)CCCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCCC(CCCCl)OC1CCCCO1
Reaction time: 2 h

Procedure:
To a stirred solution of 1-chloro-4-hydroxynonane (Example A, Step 2) (11.0 g., 0.062 mole) and dihydropyrane (5.2 g., 0.062 mole), cooled in an ice bath is added 5 drops of hydrochloric acid (conc.). A slight exothermic reaction is noted and when this is complete the reaction is allowed to come to room temperature then stand at this temperature for 2 hours. At the end of this period, several pellets of sodium hydroxide are added and the reaction is distilled in vacuo. The yield of 1-chloro-4-(2-tetrahydropyranyloxy)nonane is 12.5 g. (77%), boiling 96°-102°C./0.1 mm. Upon redistillation, a boiling point of 90°-92°C./0.1 mm. is obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][CH2:21][Cl:22].O>CS(C)=O>[Cl:22][CH2:21][CH2:20][CH2:19][CH2:18][N:6]1[CH:7]=[C:2]([CH3:1])[C:3]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:4][C:5]1=[O:8]
Reactant: Cc1c[nH]c(=O)nc1-c1cccnc1
Reactant: ClCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cn(CCCCCl)c(=O)nc1-c1cccnc1
Temperature: 60 °C
Yield: 67.9 %

Procedure:
To a solution of 5-methyl-4-pyridin-3-yl-1H-pyrimidin-2-one (100 mg, 0.53 mmol) in DMSO (2 ml), 60% NaH (23 mg, 0.59 mmol) was added portionwise. After heating the mixture at 60° C. for 1 hour, 1-bromo-4-chloro-butane (100 mg, 0.59 mmol) dissolved in DMSO (0.8 ml) was added at 60° C. and the heating was maintained for further 2 hours. After cooling to room temperature, water was added and the mixture extracted with diethyl ether to remove the dialkylated product and finally with ethyl acetate. Ethyl acetate was washed with brine, dried (Na2SO4) and evaporated to afford 100 mg of the title compound as yellow oil (68% yield).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]#[N:9].C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[N+](C1C=CC([O:29][C:30]([C:32]2[C:40]3[S:39][C:38]([C:41]([F:44])([F:43])[F:42])=[N:37][C:36]=3[C:35]([O:45][CH3:46])=[CH:34][CH:33]=2)=O)=CC=1)([O-])=O>CN(C)C=O.O1CCCC1>[C:8]([C:3]1[CH:4]=[N:5][N:6]([CH3:7])[C:2]=1[NH:1][C:30]([C:32]1[C:40]2[S:39][C:38]([C:41]([F:44])([F:43])[F:42])=[N:37][C:36]=2[C:35]([O:45][CH3:46])=[CH:34][CH:33]=1)=[O:29])#[N:9]
Reactant: COc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2sc(C(F)(F)F)nc12
Reactant: Cn1ncc(C#N)c1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2c(C#N)cnn2C)c2sc(C(F)(F)F)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.8 %

Procedure:
A solution of 5-amino-1-methyl-1H-pyrazole-4-carbonitrile (93 mg) in dimethyl formamide (10 ml) was treated with a solution of sodium hexamethyldisilazide in tetrahydrofuran (0.76 ml, 1.0M). After three minutes the mixture was treated with 4-methoxy-2-trifluoromethylbenzothiazole-7-carboxylic acid 4-nitrophenyl ester (150 mg) and the reaction stirred at room temperature for 2 hours. The solvent was removed in vacuo. Purification by flash chromatography (eluent ethyl acetate) to yield the title compound as an off-white solid (50 mg). TLC Rf 0.48 (ethyl acetate); MS found M+1 382.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][C:24]3[C:29]([Cl:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=3[Cl:32])=[CH:16][CH:15]=2)[C@@H:10]([C:33](=[O:51])[N:34]([CH2:38]C2C=C(Cl)C=CC=2CCCOC)[CH:35]2[CH2:37][CH2:36]2)[CH2:9]1)=O)(C)(C)C.Cl.[CH2:53]([Cl:55])Cl>O1CCOCC1>[Cl:55][C:53]1[CH:18]=[CH:19][C:14]([CH2:15][CH2:16][CH2:17][O:20][CH3:21])=[CH:11][C:10]=1[CH2:38][N:34]([CH:35]1[CH2:37][CH2:36]1)[C:33]([C@@H:10]1[C@@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][C:24]3[C:25]([Cl:32])=[CH:26][C:27]([CH3:31])=[CH:28][C:29]=3[Cl:30])=[CH:16][CH:15]=2)[CH2:12][CH2:13][NH:8][CH2:9]1)=[O:51]
Reactant: ClCCl
Reactant: COCCCc1ccc(Cl)cc1CN(C(=O)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1c1ccc(OCCOc2c(Cl)cc(C)cc2Cl)cc1)C1CC1
Agent: Cl
Solvent: C1COCCO1
Product: COCCCc1ccc(Cl)c(CN(C(=O)[C@H]2CNCC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
Compound D4 (0.076 g, 0.10 mmol) was dissolved in CH2Cl2 (1 mL) and the sol. was cooled to 0° C. 4M HCl in dioxane (1 mL) was added and the reaction mixture was stirred for 1 h at rt. The solvents were evaporated under reduced pressure. Purification of the residue by HPLC yielded the title compound (44 mg, 67%). LC-MS: tR=0.99 min, ES+=661.41.
Reaction SMILES: [F:1][C:2]([C:5]([CH2:7][CH3:8])=[O:6])([F:4])[F:3].[C:9]([Mg]Br)#[C:10][CH3:11]>C1COCC1>[F:1][C:2]([F:4])([F:3])[C:5]([OH:6])([C:9]#[C:10][CH3:11])[CH2:7][CH3:8]
Reactant: CCC(=O)C(F)(F)F
Reactant: CC#C[Mg]Br
Solvent: C1CCOC1
Product: CC#CC(O)(CC)C(F)(F)F
Reaction time: 1 h

Procedure:
To ethyl trifluoromethyl ketone (5.00 g, 40.0 mmol) in THF (20 ml) at room temperature was added 1-propynyl magnesium bromide (0.5 M in THF, 60 mL, 30.0 mmol). The reaction mixture was allowed to stand at rt 1 h, and concentrated in vacuo. The residue was partitioned between Et2O and aq. NH4OAc, the phases were separated, and the organic phase washed with brine, dried over MgSO4, filtered and concentrated (not to complete dryness), to afford a 50 wt. % solution (estimated by 1H NMR) of the title compound (remainder THF and Et2O), which was used without further purification. 1H NMR (400 MHz, DMSO-d6): 6.63 (s, 1H), 1.87 (s, 3H), 1.75-1.63 (m, 2H), 1.04 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.O=[C:16]([CH3:24])[CH2:17][C:18]([O:20][CH2:21][CH2:22][CH3:23])=[O:19].[NH2:25][C:26]([CH3:40])=[CH:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=1)=[O:29].C(O)(=O)C>CC(O)C>[CH3:24][C:16]1[NH:25][C:26]([CH3:40])=[C:27]([C:28](=[O:29])[C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:38])([F:39])[F:37])=[CH:32][CH:31]=2)[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:17]=1[C:18]([O:20][CH2:21][CH2:22][CH3:23])=[O:19]
Reactant: CC(N)=CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Reactant: CCCOC(=O)CC(C)=O
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CCCOC(=O)C1=C(C)NC(C)=C(C(=O)c2ccc(C(F)(F)F)cc2)C1c1cccc2c(=O)cc(C)oc12

Procedure:
164 mg (0.87 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde are dissolved with 125 mg (0.87 mmol) of n-propyl 3-oxobutanoate, 200 mg (0.87 mmol) of 3-amino-1-[4-(trifluoromethyl)phenyl]but-2-en-1-one and 5 μl (0.087 mmol) of acetic acid in 8 ml of 2-propanol and heated under reflux under argon for 30 h. The solvent is removed in vacuo, and the residue is purified by preparative HPLC. 60 mg (13% of theory) of the title compound are obtained as a yellow solid.
Reaction SMILES: [O:1]([CH2:8][CH2:9][S:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20](C(O)=O)[CH:19]=2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([N:34]1[CH:38]=[CH:37][N:36]=[CH:35]1)(N1C=CN=C1)=[O:28].[CH3:39]NCCNC>>[CH3:39][N:36]([CH3:35])[CH2:37][CH2:38][NH:34][C:27]([C:22]1[CH:23]=[C:18]([C:15]2[CH:16]=[CH:17][C:12]([CH2:11][S:10][CH2:9][CH2:8][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:13][CH:14]=2)[CH:19]=[CH:20][CH:21]=1)=[O:28]
Reactant: O=C(O)c1cccc(-c2ccc(CSCCOc3ccccc3)cc2)c1
Reactant: CNCCNC
Reactant: O=C(n1ccnc1)n1ccnc1
Product: CN(C)CCNC(=O)c1cccc(-c2ccc(CSCCOc3ccccc3)cc2)c1
Yield: 93.5 %

Procedure:
Prepared in the same manner as described for example 1. A solution of 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid(0.68 g, 1.87 mmol, 1 eq.) was treated with 1,1′-carbonyldiimidazole (0.31 g, 1.91 mmol, 1.02 eq.) and warmed as described. The reaction was allowed to cool and then treated with N′,N-dimethylethylenediamine (0.20 g, 2.24 mmol, 1.2 eq.). The reaction was treated as described in example 1 to give 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid(2-dimethylamino-ethyl)-amide (0.76 g, 94% yield) as a faint yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.[C:16]([C:18]1[C:23]2[N:24]=[C:25]([C:27]3[S:28][CH:29]=[C:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[N:31]=3)[O:26][C:22]=2[C:21](F)=[C:20]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:19]=1[CH3:44])#[N:17]>CS(C)=O>[C:16]([C:18]1[C:23]2[N:24]=[C:25]([C:27]3[S:28][CH:29]=[C:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[N:31]=3)[O:26][C:22]=2[C:21]([N:5]2[CH2:6][CH2:7][C@H:3]([N:2]([CH3:8])[CH3:1])[CH2:4]2)=[C:20]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:19]=1[CH3:44])#[N:17]
Reactant: CCOC(=O)c1csc(-c2nc3c(C#N)c(C)c(-c4ccccc4)c(F)c3o2)n1
Reactant: CN(C)[C@H]1CCNC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1csc(-c2nc3c(C#N)c(C)c(-c4ccccc4)c(N4CC[C@H](N(C)C)C4)c3o2)n1
Temperature: 100 °C
Reaction time: 3 h
Yield: 66.3 %

Procedure:
(3S)-3-(Dimethylamino)pyrrolidine (91.6 μl, 0.722 mmol) and triethylamine (101 μl, 0.722 mmol) were added to a dimethyl sulfoxide (2 ml) solution of ethyl 2-(4-cyano-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazol-2-yl)-1,3-thiazole-4-carboxylate (I-197) (147 mg, 0.361 mmol), followed by stirring in an oil bath at 100° C. for 3 hours. The reaction liquid was concentrated under reduced pressure, the residue was dissolved in chloroform (100 ml) and washed with water (50 ml) and saturated brine (50 ml). After drying over anhydrous sodium sulfate and concentration, the resulting residue was purified by silica gel column chromatography (eluent, chloroform:methanol=100:1→100:3), and the obtained yellow solid was purified in slurry with isopropanol (3 ml) to obtain the entitled compound (120 mg, 66.3%) as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=O)[NH:9]2)=[N:4][CH:3]=1.O=P(Cl)(Cl)[Cl:15]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([Cl:15])=[N:9]2)=[N:4][CH:3]=1
Reactant: O=c1ccc2ncc(Br)cc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccc2ncc(Br)cc2n1
Yield: 62.9 %

Procedure:
7-bromo-1,5-naphthyridin-2(1H)-one (C-4) (3.1 g, 13.78 mmol, 1.0 eq) was dissolved in POCl3 (20 mL) and the resulting mixture was stirred at reflux for 1 h. The reaction was complete based on TLC analysis. The mixture was concentrated in vacuo to remove POCl3. The residue was poured into ice water (30 mL) and neutralized with saturated aqueous Na2CO3 solution to adjust the pH value to 7-8 while keeping the temperature below 10° C. The resulting mixture was extracted with ethyl acetate (3×30 mL), the combined organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to afford the desired product 7-bromo-2-chloro-1,5-naphthyridine (F-31) (2.11 g, 62.9% yield). ESI-MS m/z: 242.9 [M+H]+.
Reaction SMILES: [CH3:1][C@@:2]1([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=3)[CH:9]=2)[CH2:6][O:5]C(=O)[NH:3]1.C(O)C.[OH-].[Li+].O>>[NH2:3][C@@:2]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=3)[CH:14]=2)[CH:9]=1)([CH3:1])[CH2:6][OH:5]
Reactant: C[C@@]1(c2ccc3cc(Oc4cccc(C(F)(F)F)c4)ccc3c2)COC(=O)N1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C[C@](N)(CO)c1ccc2cc(Oc3cccc(C(F)(F)F)c3)ccc2c1
Temperature: 80 °C
Yield: 53.2 %

Procedure:
(R)-4-Methyl-4-(6-(3-(trifluoromethyl)phenoxy)naphthalen-2-yl)oxazolidin-2-one (20.0 mg, 0.000052 mol) was dissolved in ethanol (2 mL, 0.03 mol), followed by 4 M of lithium hydroxide in water (1 mL, 0.004 mol). The reaction mixture was then heated at 80° C. for 5 hours. All solvent was removed. The solid was extracted with DCM, and was purified via HPLC to give the desired product (10 mg, 52%). 1H NMR (MeOD) δ: 7.91-8.00 (m, 2H), 7.77 (d, J=8.8 Hz, 1H), 7.64 (dd, J=8.8, 1.8 Hz, 1H), 7.51-7.58 (m, 1H), 7.35-7.44 (m, 2H), 7.22-7.30 (m, 3H), 3.64-3.78 (m, 2H), 1.52 (s, 3H).
Reaction SMILES: CCOCCOCCO.[BH4-].[Na+].[CH3:12][NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.S(=O)(=O)(O)O>C1(C)C(C)=CC=CC=1>[CH3:12][NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH2:14]([OH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CNC(=O)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCCOCCO
Solvent: Cc1ccccc1C
Product: CNCc1ccccc1
Product: OCc1ccccc1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
29.8 g (0.222 mole) of ethyl carbitol was added dropwise to a mixture consisting of 2.8 g (0.074 mole) of sodium borohydride, 5 g (0.037 mole) of N-methyl benzamide and 25 ml of xylene at 120° C. over two hours. Subsequently, the mixture was agitated at the same temperature for 40 hours. After cooling to room temperature, the mixture was neutralized with dilute sulfuric acid. As a result, N-methyl benzylamine was obtained in 67.5% yield and benzyl alcohol in 7.7% yield, respectively. 23.6% of N-methyl benzamide was remained unreactive.
Reaction SMILES: [CH3:1][N:2]1[C:10](=[O:11])[C:9]2[NH:8][C:7]([C:12]3[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][C:13]=3[O:22][CH3:23])=[N:6][C:5]=2[N:4]([CH3:24])[C:3]1=[O:25].[CH3:26][NH:27][CH3:28]>>[CH3:1][N:2]1[C:10](=[O:11])[C:9]2[NH:8][C:7]([C:12]3[CH:17]=[CH:16][C:15]([S:18]([N:27]([CH3:28])[CH3:26])(=[O:20])=[O:19])=[CH:14][C:13]=3[O:22][CH3:23])=[N:6][C:5]=2[N:4]([CH3:24])[C:3]1=[O:25]
Reactant: CNC
Reactant: COc1cc(S(=O)(=O)Cl)ccc1-c1nc2c([nH]1)c(=O)n(C)c(=O)n2C
Product: COc1cc(S(=O)(=O)N(C)C)ccc1-c1nc2c([nH]1)c(=O)n(C)c(=O)n2C

Procedure:
Prepared analogously to Example 11 from 1,3-dimethyl-8-(2-methoxy-4-chlorosulfonyl-phenyl)-1H,3H-purin-2,6-dione and dimethylamine.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[S:8][CH:7]=[N:6][C:5]=1[CH3:9].[C:10]1([CH3:21])[CH:15]=[CH:14][C:13]([S:16]([O:19]C)(=[O:18])=[O:17])=[CH:12][CH:11]=1>>[C:10]1([CH3:21])[CH:11]=[CH:12][C:13]([S:16]([O-:19])(=[O:17])=[O:18])=[CH:14][CH:15]=1.[CH3:10][N+:6]1[C:5]([CH3:9])=[C:4]([CH2:3][CH2:2][OH:1])[S:8][CH:7]=1
Reactant: Cc1ncsc1CCO
Reactant: COS(=O)(=O)c1ccc(C)cc1
Product: Cc1c(CCO)sc[n+]1C
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Yield: 148.8 %

Procedure:
The procedures of Reference Example 10 were repeated using 0.71 g of 5-(2-hydroxyethyl)-4-methylthiazole and 0.95 g of methyl p-toluenesulfonate to give 1.25 g of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:5](=[NH:8])[NH:6][OH:7].[C:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=O)=[CH:20][CH:19]=1)#[N:17].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[N:8]=[C:22]([C:21]3[CH:25]=[CH:26][C:18]([C:16]#[N:17])=[CH:19][CH:20]=3)[O:7][N:6]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)Oc1ccc(C(=N)NO)cc1Cl
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2noc(-c3ccc(C#N)cc3)n2)cc1Cl
Temperature: 110 °C
Yield: 84.7 %

Procedure:
3-Chloro-N-hydroxy-4-isopropoxybenzimidamide (10 g, 43.7 mmol) was dissolved in DMF (219 ml) under nitrogen. The mixture was heated at about 110° C. for about 10 min. A solution of 4-cyanobenzoyl chloride (7.24 g, 43.7 mmol) dissolved in DMF (30 mL) was added dropwise over about 20 min and the reaction heated at about 110° C. for about 4 h. until LCMS shows reaction complete. The reaction was cooled in an ice bath and poured into rapidly stirred water (1000 mL). The resulting white precipitate was collected by vacuum filtration and washed with water. The precipitate was dissolved in methylene chloride and washed with 1 N HCl and then brine. The methylene chloride was dried over sodium sulfate, filtered, and evaporated. Heptane and DCM were added to the residue and the mixture heated until the DCM had boiled off after which the mixture was allowed to cool. Solids did not dissolve in hot heptane. The resulting solid was collected by vacuum filtration and washed with heptane to provide 4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)benzonitrile (12.568 g, 37.0 mmol, 85% yield) as a tan solid: LCMS (Table 1, Method a) Rt=4.58 min.; MS m/z: 340.20 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:48])[NH:7][C@H:8]([CH2:23][NH:24][C@@H:25]([C:29]1[N:38]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:37](=[O:46])[C:36]2[C:31](=[CH:32][C:33]([Cl:47])=[CH:34][CH:35]=2)[N:30]=1)[CH:26]([CH3:28])[CH3:27])[CH2:9][CH2:10][CH2:11][NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:56]1([CH3:65])[CH:61]=[CH:60][C:59]([C:62](Cl)=[O:63])=[CH:58][CH:57]=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:48])[NH:7][CH:8]([CH2:23][N:24]([CH:25]([C:29]1[N:38]([CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:37](=[O:46])[C:36]2[C:31](=[CH:32][C:33]([Cl:47])=[CH:34][CH:35]=2)[N:30]=1)[CH:26]([CH3:28])[CH3:27])[C:62]([C:59]1[CH:60]=[CH:61][C:56]([CH3:65])=[CH:57][CH:58]=1)=[O:63])[CH2:9][CH2:10][CH2:11][NH:12][C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)[C@@H](NC[C@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)N(CC(CCCNC(=O)OCc2ccccc2)NC(=O)OC(C)(C)C)C(c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Temperature: 80 °C
Yield: 80 %

Procedure:
To a solution of ((S)-1-{[(R)-1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propylamino]-methyl}-4-benzyloxycarbonylamino-butyl)-carbamic acid tert-butyl ester (250 mg, 0.37 mmol) in toluene (4 mL) was added triethylamine (0.10 mL, 0.74 mmol) followed by dropwise addition of p-toluoyl chloride (0.049 mL, 0.37 mmol). The reaction mixture was heated to 80° C. for 18 h, then reflux for 4 h. The reaction mixture was allowed to cool to room temperature, quenched with saturated aqueous NaHCO3 (10 mL) and diluted with CH2Cl2 (10 mL). The extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (3:1 hexanes:ethyl acetate) to provide 235 mg (79%) of the title compound as a pale yellow powder. MS(ES+) m/e 794.2 [M+H]+.