Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:46]([O:53][C:54](=[O:57])[CH2:55][NH2:56])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CN(C)C=O>[CH2:46]([O:53][C:54](=[O:57])[CH2:55][NH:56][C:17](=[O:19])[C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Reactant: NCC(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)NCC(=O)OCc1ccccc1
Temperature: -10 °C
Yield: 91.9 %

Procedure:
13.3 g (50 mmoles) of tert.-butoxycarbonyl-D-phenylalanine and 5.6 ml (50 mmoles) of N-methylmorpholine are dissolved in 50 ml of dimethyl formamide. The solution is cooled to -10° C., and 6.6 ml (50 mmoles) of isobutyl chloroformate are added with stirring. After 10 minutes the mixture is cooled to -20° C., and a solution of 18.6 g (55 mmoles) of glycine benzyl ester p-toluenesulfonate and 6.1 ml (55 mmoles) of N-methylmorpholine in 80 ml of dimethyl formamide, cooled to -20° C., is added. The reaction mixture is stirred at -10° C. for 10 minutes, at 0° C., for one hour, and then at room temperature overnight. The mixture is filtered and evaporated under reduced pressure. The residue is dissolved in a mixture of 300 ml of ethyl acetate and 100 ml of water. The ethyl acetate phase is separated and washed successively with 5% aqueous sodium hydrocarbonate solution (2×60 ml), water (2×60 ml), 1 n aqueous hydrochloric acid cooled with ice water (2×60 ml) and with water (2×60 ml) again, dried over sodium sulfate, decolourized with carbon, filtered, and the filtrate is evaporated under reduced pressure. The crystalline residue is suspended in a 1:1 mixture of diethyl ether and n-hexane, the solid is filtered off, washed with the above solvent mixture and dried in a vacuum desiccator. 18.95 g (91.9%) of tert.-butoxycarbonyl-D-phenylalanyl-glycine benzyl ester are obtained; m.p.: 133°-134° C., Rf14 =0.28-0.38, [α]D20 =+8° (c=1%, in dimethyl formamide).
Reaction SMILES: Cl[CH2:2][CH2:3][S:4][C:5]1[CH:10]=[CH:9][N+:8]([O-:11])=[C:7]([CH3:12])[C:6]=1[CH3:13].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:12][C:7]1[C:6]([CH3:13])=[C:5]([S:4][CH2:3][CH2:2][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:10]=[CH:9][N+:8]=1[O-:11]
Reactant: Cc1c(SCCCl)cc[n+]([O-])c1C
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1c(SCCN2CCOCC2)cc[n+]([O-])c1C

Procedure:
4-(2-Chloroethylthio)-2,3-dimethylpyridine-N-oxide (6 g) was dissolved in a mixed solution of dimethylformamide-toluene (1:1) and thereto were added potassium carbonate (4.3 g), potassium iodide (4.4 g) and morpholine (1.9 ml). The mixture was reacted at 50-55° C. for 12 hours. After the completion of the reaction, inorganic matters were filtered off and the solvent was distilled away. Water was added to the residue and the mixture was extracted with chloroform. After drying over anhydrous magnesium sulfate, the chloroform was distilled away and the obtained residue was purified by silica gel column chromatography to give 3.4 g of 2,3-dimethyl-4-(2-morpholinoethylthio)pyridine-N-oxide.
Reaction SMILES: [CH:1]1([C:5]2[C:13]([CH:14]=[O:15])=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH3:16])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[C:17](=O)(O)[O-].[Na+].CI>CN(C)C=O.CCOC(C)=O>[CH:1]1([C:5]2[C:13]([CH:14]=[O:15])=[CH:12][C:8]([C:9]([O:11][CH3:17])=[O:10])=[C:7]([CH3:16])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C([O-])O
Reactant: Cc1cc(C2CCC2)c(C=O)cc1C(=O)O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C=O)c(C2CCC2)cc1C

Procedure:
Into a 100-mL round-bottom flask, was placed a mixture of 4-cyclobutyl-5-formyl-2-methylbenzoic acid (compound 82.4, 500 mg, 2.29 mmol) in N,N-dimethylformamide (10 mL) and sodium bicarbonate (390 mg, 4.64 mmol). With stirring, methyl iodide (430 μL, 6.90 mmol) was added drop-wise and the resulting mixture was stirred for 5 h at room temperature. The reaction was then diluted with EtOAc (50 mL) and the mixture was washed with brine (4×10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure to yield 0.40 g (crude) of the title compound as a brown oil
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2.Cl[CH2:22][CH2:23][CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.[H-].[Na+].[I-].[Na+]>CN(C)C=O>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:22][CH2:23][CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:18][CH:19]=2)[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: COCCc1cc2ccccc2n1-c1ccc(O)cc1
Reactant: ClCCCN1CCCC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCc1cc2ccccc2n1-c1ccc(OCCCN2CCCC2)cc1
Temperature: 70 °C
Yield: 47.4 %

Procedure:
4-[2-(2-Methoxyethyl)indol-1-yl]phenol (0.39 mmol) was dissolved in N,N-dimethylformamide (4 mL), and 1-(3-chloropropyl)pyrrolidine (58 mg, 0.39 mmol), sodium hydride (19 mg, 60% dispersion in mineral oil, 0.47 mmol), and sodium iodide (59 mg, 0.39 mmol) were added. The reaction was heated at 70° C. for 1.5 hours, then carefully quenched with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, dried over MgSO4 and concentrated. The residue was purified by SiO2 chromatography to give 70 mg of the desired product. LC-MS (C24H30N2O2 calc'd 378) m/z 379 (M+H); 1H NMR (300 MHz, CDCl3) δ 7.60-7.56 (m, 1H), 7.25-7.21 (m, 2H), 7.10-7.00 (m, 5H), 6.45 (s, 1H), 4.11 (t, J=6.3 Hz, 2H), 3.57 (t, J=7.2 Hz, 2H), 3.30 (s, 3H), 2.89 (t, J=7.2 Hz, 2H), 2.74 (t, J=7.5 Hz, 2H), 2.65 (m, 4H), 2.16-2.05 (m, 2H), 1.90-1.81 (m, 4H).
Reaction SMILES: N1C=CC=CC=1.N1CCCCC1.[C:13](O)(=O)[CH2:14][C:15]([OH:17])=[O:16].[F:20][C:21]1[CH:28]=[CH:27][C:24](C=O)=[C:23]([CH3:29])[CH:22]=1>O>[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH:13]=[CH:14][C:15]([OH:17])=[O:16])=[C:23]([CH3:29])[CH:22]=1
Reactant: Cc1cc(F)ccc1C=O
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCNCC1
Product: Cc1cc(F)ccc1C=CC(=O)O
Temperature: 75 °C
Reaction time: 6 h
Yield: 92 %

Procedure:
To a mixture of pyridine (0.035 mL) and piperidine (1.43 mL) was added malonic acid (30 g), and the mixture was heated to 75° C. To this mixture was added dropwise 4-fluoro-2-methylbenzaldehyde (20 g), and the mixture was stirred at 90° C. for 6 hr. The reaction mixture was cooled to room temperature, and diluted with water (100 ml), and concentrated under reduced pressure. The residue was suspended in 0.1N hydrochloric acid (250 mL), and the mixture was stirred at room temperature for 30 min. The precipitate was collected by filtration, washed with 0.1N hydrochloric acid (250 mL) and water (50 mL, 0.3 times) and dried to give 4-fluoro-2-methylcinnamic acid (24 g, 93%) as a white powder.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]1[O:17][CH2:16][CH2:15][O:14][CH:6]1[CH2:7][CH:8]1[O:13][CH2:12][CH2:11][O:10][CH2:9]1.[I-:18].[K+].N1C=CC=CC=1.CCOCC>CC(=O)CC>[I:18][CH2:2][CH2:3][CH2:4][CH:5]1[O:17][CH2:16][CH2:15][O:14][CH:6]1[CH2:7][CH:8]1[O:13][CH2:12][CH2:11][O:10][CH2:9]1
Reactant: [I-]
Reactant: BrCCCC1OCCOC1CC1COCCO1
Agent: [K+]
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: CCC(C)=O
Product: ICCCC1OCCOC1CC1COCCO1
Yield: 95.9 %

Procedure:
The bromide from Example XIX (7.5 g, 0.024 mol) was dissolved in butan-2-one (70 ml), after which powdered potassium iodide (6.8 g, 0.04 mol) and pyridine (0.2 ml) were added. The mixture was refluxed for 11/2 hours, mixed with ether, and filtered. Evaporation yielded 8.2 g product (95% by weight yield).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18](=[O:34])[N:19]([CH3:33])[N:20]([CH3:32])[C:21]=2[C:22]2[CH:27]=[CH:26][N:25]=[C:24](S(C)(=O)=O)[N:23]=2)=[CH:13][CH:12]=1>C1COCC1>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18](=[O:34])[N:19]([CH3:33])[N:20]([CH3:32])[C:21]=2[C:22]2[CH:27]=[CH:26][N:25]=[C:24]([O:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:23]=2)=[CH:13][CH:12]=1
Reactant: Cn1c(-c2ccnc(S(C)(=O)=O)n2)c(-c2ccc(F)cc2)c(=O)n1C
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(-c2ccnc(Oc3ccccc3)n2)c(-c2ccc(F)cc2)c(=O)n1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of phenol (0.12 g, 1.29 mmol) in THF (5 mL) is added sodium hydride (0.04 g, 1.08 mmol). After stirring at room temperature for 10 min, a solution of 4-(4-fluorophenyl)-1,2-dimethyl-5-(2-methanesulfonyl-pyrimidin-4-yl)-1,2-dihydropyrazol-3-one, 30, (0.20 g, 0.55 mmol) in THF (5 mL) is added to the reaction mixture. The mixture is stirred at room temperature for 4 hours. The reaction is then quenched with H2O and diluted with EtOAc. The organic phase is washed with 1N NaOH (×2), dried (MgSO4), filtered and concentrated in vacuo. The crude residue is purified by preparatory HPLC to the desired product: 1H NMR (300 MHz, CDCl3) δ 8.51 (d, J=4.8 Hz, 1H), 7.48 (t, J=8.1 Hz, 2H), 7.36-7.31 (m, 3H), 7.24 (dd, J=7.5, 1.2 Hz, 2H), 7.04 (t, J=9.0 Hz, 2H), 6.94 (d, J=5.1 Hz, 1H), 3.53 (s, 3H), 3.38 (s, 3H); HRMS calcd for C21H18FN4O2 (M+H)+377.1418; found 377.1397.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)#[N:2].CN1CCOCC1.ClC(OCC)=O.[NH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[C:32]#[N:33]>CN(C)C=O.C(OCC)(=O)C>[C:32]([C:31]1[CH:30]=[C:29]([CH:36]=[CH:35][CH:34]=1)[O:28][CH2:27][CH2:26][NH:25][C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=1)#[N:33]
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: N#Cc1cccc(OCCN)c1
Agent: CCOC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: N#Cc1ccc(C(=O)NCCOc2cccc(C#N)c2)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
1.13 g (7.68 mmol) of 4-cyanobenzoic acid and 1.6 ml (14.1 mmol) of N-methylmorpholine were dissolved in 30 ml of dimethylformamide. 0.67 ml (7.05 mmol) of ethyl chloroformate was added to the solution under cooling with ice/water. After stirring for 5 minutes, 1.27 g (6.41 mmol) of 3-(2-aminoethoxy)benzonitrile was added to the reaction mixture, and the obtained mixture was stirred at room temperature for one hour. After the treatment with ethyl acetate as the extractant in an ordinary manner, the title compound was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Ca+2].[C:14](Cl)(Cl)=[S:15].[Br:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]=[C:26]=[S:27])=[N:23][CH:24]=1.[N-]=C=S>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:7]=1)[C:14](=[S:15])[N:25]([C:22]1[CH:21]=[CH:20][C:19]([Br:18])=[CH:24][N:23]=1)[C:26](=[S:27])[N:8]=2
Reactant: S=C=Nc1ccc(Br)cn1
Reactant: Nc1ccc(Br)cn1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Agent: [N-]=C=S
Solvent: CC#N
Product: S=c1nc2ccc(Br)cn2c(=S)n1-c1ccc(Br)cn1
Reaction time: 8 h

Procedure:
Following the procedures of Examples 1 and 2, 25.4 g. of 5-bromo-2-aminopyridine, 31 g. of calcium carbonate and 18.1 g. of thiophosgene is converted to 5-bromo-2-pyridylisothiocyanate with a b.p. of 105° C. at 0.5 mm. of Hg. 5 G. of the above freshly distilled isothiocyanate is dissolved in 50 ml. of acetonitrile and allowed to stand overnight at room temperature. The reaction mixture is filtered and the solid material washed with acetonitrile affording 7-bromo-3-(5-bromo-2-pyridyl) pyrido(1,2-a) 1,3,5-triazine 2,4-dithione m.p. 77° C.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Cl:10][C:11]1[C:16]([S:17](Cl)(=[O:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=1.[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)([O-:23])=[O:22]>CN(C=O)C.C(OCC)(=O)C>[Cl:10][C:11]1[C:16]([S:17]([O:30][C:27]2[CH:28]=[CH:29][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=2)(=[O:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(OS(=O)(=O)c2cccnc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
N,N-Diisopropylethylamine (0.45 ml) was added to a solution of 2-chloropyridine-3-sulphonyl chloride (0.53 g) and 4-nitrophenol (0.35 g) in DMF (5 ml). The mixture was stirred at ambient temperature for 30 minutes then diluted with ethyl acetate (25 ml) and washed with water (2×25 ml), saturated sodium carbonate solution (3×20 ml), water (20 ml) and saturated sodium chloride solution. Aqueous layers were back-extracted with ethyl acetate (25 ml) and the organic layers were combined and dried (MgSO4). Volatile material was removed by evaporation to give 4-nitrophenyl 2-chloropyridine-3-sulphonate (0.52 g) as a solid, m.p. 127-128° C.; 1H NMR (d6-DMSO): 7.5 (d, 2H), 7.7 (dd, 1H), 8.3 (d, 2H), 8.4 (dd, 1H), 8.8 (dd, 1H); mass spectrum (+ve FAB, NBA/DMSO): 315 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][CH2:6][NH:7][C:8]([C:10]1[CH:11]=[N:12][C:13]([NH:16][C@H:17]([C:22]2[CH:23]=[N:24][C:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)=[N:26][CH:27]=2)[CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:14][CH:15]=1)=[O:9])C.C(OCC)(=O)C.[OH-].[Na+].Cl>O1CCCC1.CO>[CH3:20][CH:19]([CH3:21])[CH2:18][C@H:17]([NH:16][C:13]1[N:12]=[CH:11][C:10]([C:8]([NH:7][CH2:6][CH2:5][C:4]([OH:38])=[O:3])=[O:9])=[CH:15][CH:14]=1)[C:22]1[CH:23]=[N:24][C:25]([C:28]2[CH:29]=[CH:30][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:32][CH:33]=2)=[N:26][CH:27]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N[C@@H](CC(C)C)c2cnc(-c3ccc(C(F)(F)F)cc3)nc2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)C[C@H](Nc1ccc(C(=O)NCCC(=O)O)cn1)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
3-[(6-{(S)-3-Methyl-1-[2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-butylamino}-pyridine-3-carbonyl)-amino]-propionic acid ethyl ester (29.2 g wet with ethyl acetate, theoretically 54.0 mmol) was dissolved in tetrahydrofuran (135 mL) and methanol (45 mL), and 1.0 M sodium hydroxide (135 mL) was added. This was stirred at room temperature for 20 min before most of the organics were rotovapped off. A small amount of tetrahydrofuran was added and the mostly aqueous contents were stirred in an ice bath. 1 N HCl (130 mL) was added until pH 5. Ethyl acetate was added and stirred for ˜20 min to ensure constant pH. The material was added to a sep funnel and the layers separated. The aqueous was back extracted with additional ethyl acetate and the combined organics were washed with brine and dried over MgSO4. This was concentrated and the solid was placed in a vacuum oven for two days to give 3-[(6-{(S)-3-methyl-1-[2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-butylamino}-pyridine-3-carbonyl)-amino]-propionic acid as a white foam. 1H NMR (400 MHz, DMSO-d6, δ): 12.16 (s, 1H) 8.97 (s, 2H) 8.54 (d, J=8.2 Hz, 2H) 8.41 (d, J=2.0 Hz, 1H) 8.19 (t, J=5.4 Hz, 1H) 7.87 (d, J=8.4 Hz, 2H) 7.78 (dd, J=8.8, 2.3 Hz, 1H) 7.68 (d, J=8.0 Hz, 1H) 6.58 (d, J=8.6 Hz, 1H) 5.09-5.26 (m, 1H) 3.38 (q, J=6.7 Hz, 2H) 2.44 (t, J=7.0 Hz, 2H) 1.80-1.94 (m, 1H) 1.57-1.77 (m, 2H) 0.96 (d, J=6.1 Hz, 3H) 0.92 (d, J=6.3 Hz, 3H); MS (M+1): 502.3.
Reaction SMILES: O=C(Cl)[O:3][C:4](Cl)(Cl)Cl.[C:9]([CH:13]1[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]1)([CH3:12])([CH3:11])[CH3:10].C>C(OCC)(=O)C>[N-:19]=[C:4]=[O:3].[C:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)C1CCC(N)CC1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)C1CCCCC1
Product: [N-]=C=O
Yield: 48 %

Procedure:
A pre-cooled solution of diphosgene (168.0 mmol) in ethyl acetate was added dropwise via addition funnel into the cold solution of 4-(t-butyl)cyclohexylamine (140.0 mmol) and charcoal (catalytic) in ethyl acetate at −10° C. After the addition, the reaction was heated to reflux overnight, and filtered through a Celite plug. The solution was concentrated to give a thick oil, which was distilled in vacuo to yield 4-(tert-butyl)cyclohexanisocyanate as a clear liquid (48%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[S:32]([C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH2:41])=[CH:38][CH:37]=1)(=[O:35])(=[O:34])[NH2:33]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:29])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:41][CH2:40][C:39]4[CH:38]=[CH:37][C:36]([S:32](=[O:35])(=[O:34])[NH2:33])=[CH:43][CH:42]=4)=[O:24])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2
Reactant: NCc1ccc(S(N)(=O)=O)cc1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: NS(=O)(=O)c1ccc(CNC(=O)c2ccc(-c3cnc4c(c3)N(Cc3cc(Cl)ccc3C(F)(F)F)CCN4)cc2)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-sulfamoylbenzylamine as in General Procedure 10 to give the title compound. LCMS: m/z=615.91 (M+H+); retention time=0.75 minutes.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[I-].[Na+].[OH-].[Na+].Cl[CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1>C(O)(CC)(C)C.C1(C)C=CC=CC=1>[C:12]1([CH2:11][N:1]2[CH:5]=[CH:4][N:3]=[N:2]2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.[C:12]1([CH2:11][N:2]2[N:3]=[CH:4][CH:5]=[N:1]2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: c1c[nH]nn1
Reactant: ClCc1cccc2ccccc12
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCC(C)(C)O
Solvent: Cc1ccccc1
Product: c1ccc2c(Cn3ccnn3)cccc2c1
Product: c1ccc2c(Cn3nccn3)cccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %
Yield: 5 %

Procedure:
1,2,3-Triazole (1454 mg, 21.05 mmol), sodium iodide (2103 mg, 14.03 mmol) and sodium hydroxide (842 mg, 21.05 mmol) were added to t-amyl alcohol (5.5 ml), and the mixture was refluxed under stirring for 1 hour. 1-(Chloromethyl)naphthalene (2478 mg, 14.03 mmol) was dissolved in t-amyl alcohol (5.5 ml) and added dropwise under reflux over 1 hour. The mixture was refluxed under stirring for 1 hour. The mixture was cooled to room temperature and toluene (50 ml) was added. The mixture was washed with water (50 ml×2), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1→1/3) to give 1-(1-naphthylmethyl)-1H-1,2,3-triazole (2.47 g) as white crystals (yield 84%), and 2-(1-naphthylmethyl)-2H-1,2,3-triazole as a colorless oil (136 mg, yield 5%). 1-(1-naphthylmethyl)-1H-1,2,3-triazole
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10](C(OCC)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21]1[CH:22]=[C:23]([NH2:29])[C:24]([NH2:28])=[CH:25][C:26]=1[CH3:27].[C:30](OCC)(=[O:32])C.CO>C1(C)C(C)=CC=CC=1>[CH3:20][C:21]1[C:26]([CH3:27])=[CH:25][C:24]2[N:28]([C:11]3[CH2:12][CH2:13][N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:9][CH:10]=3)[C:30](=[O:32])[NH:29][C:23]=2[CH:22]=1
Reactant: Cc1cc(N)c(N)cc1C
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCC1=O
Reactant: CCOC(C)=O
Solvent: CO
Solvent: Cc1ccccc1C
Product: Cc1cc2[nH]c(=O)n(C3=CCN(Cc4ccccc4)CC3)c2cc1C
Reaction time: 5 h
Yield: 35 %

Procedure:
A solution of 1-benzyl-3-carbethoxy-4-piperidone (3 mmol, 784 mg) in xylene (20 mL) was treated at room temperature with 4,5-dimethyl-1,2-benzenediamine (3 mmol, 408.6 mg, 1 eq) and the suspension was stirred under reflux under argon overnight then further for 5 h. The mixture was concentrated under reduced pressure to give a brown residue, which was treated with ethyl acetate and a touch of methanol. Beige crystals formed from the brown solution and were filtered off and dried under reduced pressure (vacuum oven) to give the title compound (1.05 mmol, 350 mg, 35% yield). M+H 334.3.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C@H:12]([CH2:30][O:31][C:32](=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:13][CH2:14][O:15][C:16](=[O:29])[C@H:17]([CH:26]([CH3:28])[CH3:27])[NH:18]C(OC(C)(C)C)=O)=[CH:4][N:3]=1.FC(F)(F)C(O)=O>>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C@H:12]([CH2:30][O:31][C:32](=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:13][CH2:14][O:15][C:16](=[O:29])[C@H:17]([CH:26]([CH3:28])[CH3:27])[NH2:18])=[CH:4][N:3]=1
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC[C@H](CCOC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)Cn1cnc2cnc(N)nc21
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCCCCCCC(=O)OC[C@H](CCOC(=O)[C@@H](N)C(C)C)Cn1cnc2cnc(N)nc21
Yield: 124.4 %

Procedure:
(R)-2-Amino-9-(2-Stearoyloxymethyl-4-(N-tert-butoxycarbonyl-L-valyloxy)butyl)purine (180 mg, 0.26 mmole) was treated with trifluoroacetic acid (5 ml) at 0° C. for 40 min. It was then evaporated in vacuo and coevaporated successively with toluene and methanol. The residue was freeze-dried overnight to give 195 mg of the desired product.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]([C:22]3[N:23]([CH3:28])[N:24]=[C:25]([CH3:27])[CH:26]=3)=[O:21])[CH:14]=2)=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH3:29][S:30]([C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][C:41]([O:43][CH3:44])=[O:42])=[CH:35][CH:34]=1)(=[NH:32])=[O:31]>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:32]=[S:30]([C:33]2[CH:34]=[CH:35][C:36]([CH2:39][CH2:40][C:41]([O:43][CH3:44])=[O:42])=[CH:37][CH:38]=2)([CH3:29])=[O:31])=[O:8])=[CH:9][C:10]=1[C:11]#[C:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]([C:22]2[N:23]([CH3:28])[N:24]=[C:25]([CH3:27])[CH:26]=2)=[O:21])[CH:14]=1
Reactant: Cc1cc(C(=O)Nc2cccc(C#Cc3cc(C(=O)O)cnc3N)c2)n(C)n1
Reactant: COC(=O)CCc1ccc(S(C)(=N)=O)cc1
Product: COC(=O)CCc1ccc(S(C)(=O)=NC(=O)c2cnc(N)c(C#Cc3cccc(NC(=O)c4cc(C)nn4C)c3)c2)cc1
Yield: 41.9 %

Procedure:
In a manner similar to that described in Example 480 (step 6), 6-Amino-5-{3-[(2,5-dimethyl-2H-pyrazole-3-carbonyl)-amino]-phenylethynyl}-nicotinic acid (0.250 g, 0.666 mmol) and methyl 3-(4-(S-methylsulfonimidoyl)-phenyl)propanoate (0.160 g, 0.666 mmol) were reacted to give the title compound (0.167 g, 42%)
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[CH3:22])=[N:6][CH:7]=1.Cl[CH2:31][CH2:32][CH2:33][S:34]([N:37]1[CH2:40][CH2:39][CH2:38]1)(=[O:36])=[O:35].[I-].[Na+]>CN1C(=O)CCC1>[N:37]1([S:34]([CH2:33][CH2:32][CH2:31][N:19]2[CH2:20][CH2:21][CH:16]([C:12]3[C:13]([CH3:15])=[CH:14][C:9]([NH:8][C:5]4[N:4]=[C:3]([NH:23][C:24]5[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=5)[C:2]([Cl:1])=[CH:7][N:6]=4)=[C:10]([CH3:22])[CH:11]=3)[CH2:17][CH2:18]2)(=[O:36])=[O:35])[CH2:40][CH2:39][CH2:38]1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3C)ncc2Cl)n[nH]1
Reactant: O=S(=O)(CCCCl)N1CCC1
Agent: [I-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(CCCS(=O)(=O)N5CCC5)CC4)cc3C)ncc2Cl)n[nH]1
Temperature: 150 °C

Procedure:
A mixture of 5-chloro-N2-(2,5-dimethyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (42 mg, 0.1 mmol), 1-(3-chloropropylsulfonyl) azetidine (Step 1, 0.1 mmol), TEA (70 μL) and sodium iodide (150 mg) in NMP (1 mL) was placed in a sealed vial which was heated in a microwave for 30 min at 150° C. The reaction was purified by RP-HPLC to give N2-(4-(1-(3-(azetidin-1-ylsulfonyl)propyl)piperidin-4-yl)-2,5-dimethylphenyl)-5-chloro-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine as a white powder; ESMS m/z 573.3 (M+H+).