Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12](=[O:27])[CH2:13][CH:14]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)[C:15]([F:18])([F:17])[F:16])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[CH3:28][Mg]Br>C1COCC1>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]([OH:27])([CH2:13][CH:14]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)[C:15]([F:18])([F:16])[F:17])[CH3:28])=[CH:10][CH:11]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: C[Mg]Br
Reactant: O=C(CC(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(-n2cncn2)cc1
Solvent: C1CCOC1
Product: CC(O)(CC(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(-n2cncn2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 32 %

Procedure:
To a solution of 1-(4-(1H-1,2,4-triazol-1-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluorobutan-1-one (300 mg, 0.726 mmol) in THF cooled to 0° C. was added methylmagnesium bromide (450 mg, 5 mmol) drop wise. The reaction was stirred for 3 h at 0° C., then the reaction mixture was quenched with sat aq NH4Cl solution and extracted with ethyl acetate. The combined EtOAc layer was washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 20%-25% EtOAc in petroleum ether) afforded the title compound as a solid (100 mg, 32%): 1H NMR (400 MHz, CDCl3) δ two diastereoisomers 8.58 (s, 1H, minor), 8.48 (s, 1H, major), 8.13 (s, 1H, minor), 8.09 (s, 1H, major), 7.70 (d, J=9.0 Hz, 2H, minor), 7.53 (d, J=9.0 Hz, 2H, minor), 7.40 (d, J=9.0 Hz, 2H, major), 7.31 (m, 1H, minor), 7.27 (d, J=9.0 Hz, 2H, major), 7.20 (m, 2H, minor), 7.01 (m, 1H, major), 6.75 (m, 2H, major), 350 (m, 1H), 2.50 (m, 2H), 1.56 (s, 3H, major), 1.54 (s, 3H, minor); ESIMS m/z 430.05 ([M+H]+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:21])=[N:8][C:9](Cl)=[C:10]([N+:17]([O-:19])=[O:18])[C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:5])[CH3:2].[CH2:22]([NH2:24])[CH3:23]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:21])=[N:8][C:9]([NH:24][CH2:22][CH3:23])=[C:10]([N+:17]([O-:19])=[O:18])[C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:5])[CH3:2]
Reactant: CCN
Reactant: CCCCNc1c(C(=O)OCC)c(C)nc(Cl)c1[N+](=O)[O-]
Product: CCCCNc1c(C(=O)OCC)c(C)nc(NCC)c1[N+](=O)[O-]
Yield: 86 %

Procedure:
4-Butylamino-6-chloro-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester is treated with ethylamine according to the procedure in Example 1 c and 4-butylamino-6-ethylamino-2methyl-5-nitropyridine-3-carboxylic acid ethyl ester is obtained, yield 86%, m.p. 53°-55° (methanol).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([CH:51]=[O:52])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:53][Mg]Br>O1CCCC1>[CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([CH:51]([OH:52])[CH3:53])[CH2:11][O:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](C=O)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1F
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](C(C)O)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 70.4 %

Procedure:
To a solution of (1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxy-3-fluoro-phenyl) methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-carbaldehyde 19b (3 g, 4.15 mmol) in dry tetrahydrofuran (50 mL) was added methylmagnesium bromide (2 mL, 6.22 mmol, 3M in ethyl ether) dropwise at 0° C. The mixture warmed up to room temperature and stirred for 5 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (10 mL) and extracted with ethyl acetate (100 mL×2). The combined organic layers were washed with water (50 mL×2) and then saturated aqueous sodium chloride (50 mL×2) in turn, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 19c as yellow oil (2.16 g, 70.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:3]=1[C:4]([NH:6][C@H:7]([C:23](O)=[O:24])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[CH:11][CH:10]=1)=[O:5].[C:31]([NH:35][OH:36])([CH3:34])([CH3:33])[CH3:32].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:31]([N:35]([OH:36])[C:23](=[O:24])[C@H:7]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[CH:13][CH:14]=1)[NH:6][C:4](=[O:5])[C:3]1[C:2]([Cl:1])=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:30])([CH3:34])([CH3:33])[CH3:32]
Reactant: COc1ccccc1-c1ccc(C[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)O)cc1
Reactant: CC(C)(C)NO
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccccc1-c1ccc(C[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)N(O)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.1 %

Procedure:
To a solution of N-(2,6-dichlorobenzoyl)-4-(2-methoxyphenyl)-L-phenylalanine (0.098 g) and tert-butylhydroxylamine (0.047 g) in CH2Cl2 (5 mL) was added BOP reagent (0.17 g) followed by DIEA (0.1 mL) and the mixture was stirred overnight at room temperature. The mixture was evaporated and the residue was dissolved in EtOAc (30 mL). The EtOAc solution was successively washed with 1 N HCl, satd. NaHCO3, satd. LiCl, dried (MgSO4), and concentrated. The residue was purified by preparative TLC (silica gel; eluent: hexane/EtOAc/CH2Cl2 6/1/1) and recrystallization from CH2Cl2/hexane to give 74 mg of N-(2,6-dichlorobenzoyl)-4-(2-methoxyphenyl)-L-phenylalanine N-(tert-butyl)-N-hydroxyamide. ESMS: m/z 515 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([NH:11][C:12]([C:14]2[N:18]3[CH:19]=[CH:20][C:21](Br)=[CH:22][C:17]3=[N:16][CH:15]=2)=[O:13])[CH:5]=1.[CH3:25][N:26]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[N:27]1.C(Cl)Cl.CC(O)=O>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:24])=[CH:5][C:6]=1[NH:11][C:12]([C:14]1[N:18]2[CH:19]=[CH:20][C:21]([C:30]3[N:26]([CH3:25])[N:27]=[CH:28][CH:29]=3)=[CH:22][C:17]2=[N:16][CH:15]=1)=[O:13]
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)n1
Reactant: COC(=O)c1ccc(F)c(NC(=O)c2cnc3cc(Br)ccn23)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Cn1nccc1-c1ccn2c(C(=O)Nc3cc(C(=O)O)ccc3F)cnc2c1
Temperature: 50 °C

Procedure:
3-[(7-Bromo-imidazo[1,2-a]pyridine-3-carbonyl)-amino]-4-fluoro-benzoic acid methyl ester (step 1) (1200 g, 3.060 mol), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (commercially available) (764 g, 3.67 mol), PdCl2(dppf).CH2Cl2 (75.0 g, 91.8 mmol) in dioxane (10 L) and aqueous Na2CO3 (2 N, 4.6 L) were heated to reflux for 6 hr. The reaction mixture was cooled to 50° C. and filtered. The filtrate was heated to reflux, to which was added AcOH (600 g, 10.0 mol) was added dropwise. During the course of addition solids came out of solution to give pale pink slurry. After addition the mixture was slowly cooled to RT and filtered. To the filter cake was added dioxane (20 L) followed by heating to reflux to obtain a solution. The solution was cooled to RT and filtered to provide the title compound as a white solid;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH2:12][C:13]#[N:14])=[N:6][C:5]2=[O:15].C(N(CC)CC)C.[Cl:23][C:24]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>O1CCOCC1>[CH:30]1[C:31]([Cl:33])=[CH:32][C:24]([Cl:23])=[C:25]([C:26](/[C:12](/[C:13]#[N:14])=[C:7]2/[NH:8][C:9]3[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][C:4]=3[C:5]([NH:6]/2)=[O:15])=[O:27])[CH:29]=1
Reactant: N#CCc1nc(=O)c2cc(Cl)ccc2[nH]1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: N#C/C(C(=O)c1ccc(Cl)cc1Cl)=C1/NC(=O)c2cc(Cl)ccc2N1
Yield: 6.9 %

Procedure:
To solution of 2-(6-chloro-4-oxo-1,4-dihydroquinazolin-2-yl)acetonitrile (52.0 mg, 237 μmol) and triethylamine (36.3 μL, 260 μmol) in dioxane (4 mL) was added 2,4-dichlorobenzoyl chloride (33.1 μL, 237 μmol) and the resulting mixture was refluxed overnight with stirring. A solid precipitate formed upon cooling of the reaction mixture, which was recovered by vacuum filtration and washed sequentially with methanol, water, methanol, and dichloromethane. The solid was then dried to yield ciliobrevin C (4) (6.4 mg, 7%). 1H NMR (500 MHz, DMSO-d6) δ ppm 7.50 (d, J1=8.3 Hz, 1H), 7.56 (dd, J1=8.3 Hz, J2=1.9 Hz, 1H), 7.77 (d, J=1.9 Hz, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.88 (dd, J1=8.9 Hz, J2=2.3 Hz, 1H), 8.00 (d, J2=2.4 Hz, 1H). 13C NMR (500 MHz, DMSO-d6) δ ppm 72.1, 117.52, 118.98, 121.22, 125.61, 127.67, 129.22, 129.66, 129.99, 130.49, 134.88, 135.64, 38.11, 138.58, 155.05, 157.52, 188.76. HRMS (m/z): [M+Na]+ calc. for C17H8N3O2Cl3Na, 413.9580; observed, 413.9583.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][N:20]([CH3:22])[CH3:21])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1>CCO.O=[Pt]=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH2:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CN(C)CC#Cc1ccc2c(-c3ccc(Cl)cc3)nsc2c1
Agent: O=[Pt]=O
Solvent: CCO
Product: CN(C)CCCc1ccc2c(-c3ccc(Cl)cc3)nsc2c1
Yield: 52 %

Procedure:
80 mg (0.25 mmol) {3-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-dimethyl-amine in 2 ml EtOH were hydrogenated in the presence of 20 mg PtO2. H2O, purification by flash silica gel column (CH2Cl2/MeOH 9:1) yielded 43 mg (53%) {3-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-propyl}-dimethyl-amine as a colorless oil, MS: 331 (MH+, 1Cl).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][N:5](C2CCCCO2)[C:6]=1[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([NH:17][C:18]([CH:20]3[CH2:22][CH2:21]3)=[O:19])[N:13]=[CH:14]2)=[CH:9][CH:8]=1.CO.[ClH:31]>O1CCOCC1>[ClH:31].[CH3:1][C:2]1[CH:3]=[N:4][NH:5][C:6]=1[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([NH:17][C:18]([CH:20]3[CH2:22][CH2:21]3)=[O:19])[N:13]=[CH:14]2)=[CH:9][CH:8]=1
Reactant: Cc1cnn(C2CCCCO2)c1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cn[nH]c1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
To a solution of N-(7-(4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)isoquinolin-3-yl)cyclopropanecarboxamide (43 mg, 0.11 mmol) in methanol (3 mL, 70 mmol) was added 4.0 M of hydrogen chloride in 1,4-dioxane (0.30 mL). The reaction mixture was stirred at 40° C. for 1 hour and then evaporated in vacuo. The residue was triturated with 0.5 mL N,N-dimethylformamide, and the resulting light yellow precipitate was collected, rinsed with ethyl acetate, and dried under vacuum to yield 17.3 mg (46%) of N-(7-(4-methyl-1H-pyrazol-5-yl)isoquinolin-3-yl)cyclopropanecarboxamide hydrochloride. LCMS (ESI): RT (Min)=3.816, M+H=293.0, method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 9.22 (s, 1H), 8.44 (s, 1H), 8.27 (s, 1H), 8.06 (d, J=8.8 Hz, 1H), 7.92 (d, J=8.7 Hz, 1H), 7.63 (s, 1H), 2.31 (s, 3H), 2.14-2.01 (m, 1H), 0.93-0.76 (m, 4H).
Reaction SMILES: [C:1]([C:5]1[CH:23]=[CH:22][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18](=[O:21])(=[O:20])[NH2:19])[CH:13]=2)=[O:10])=[C:7]([S:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].OO.C([O-])(O)=[O:34].[Na+].C(Cl)Cl>FC(F)(F)C(O)C(F)(F)F>[C:1]([C:5]1[CH:23]=[CH:22][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18](=[O:20])(=[O:21])[NH2:19])[CH:13]=2)=[O:10])=[C:7]([S:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:34])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])O
Reactant: CC(C)(C)c1ccc(C(=O)Nc2cccc(S(N)(=O)=O)c2)c(Sc2ccccc2)c1
Agent: OO
Agent: [Na+]
Solvent: OC(C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C(=O)Nc2cccc(S(N)(=O)=O)c2)c(S(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 4-tert-butyl-2-(phenylthio)-N-(3-sulfamoylphenyl)benzamide (15.4 mg, 0.035 mmol) in 1,1,1,3,3,3-hexafluoropropan-2-ol (0.3 mL) was added H2O2 (30% wt in water, 0.01 mL, 0.07 mmol). The reaction was stirred at room temperature for 40 min, and saturated NaHCO3(aq) and CH2Cl2 (1 mL each) were added. The organic layer was filtered through a pad of Na2SO4 and concentrated. The product was purified by reverse phase HPLC (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)) to give 4-tert-butyl-2-(phenylsulfinyl)-N-(3-sulfamoylphenyl)benzamide. LC/MS: m/z 457.4 (M+H)+ at 1.54 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]I)[CH:2]=[CH2:3].C[O:17][C:18]([C:20]1[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=1)=[O:19].C(=O)([O-])[O-].[K+].[K+].[OH-].[K+].Cl>C(O)C>[CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]([OH:19])=[O:17])=[CH:21][CH:22]=1)[CH:2]=[CH2:3]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: C=CCOCCCCCCCCCCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C=CCOCCCCCCCCCCOc1ccc(C(=O)O)cc1
Temperature: 80 °C
Yield: 79.9 %

Procedure:
70 mmol (22.7 g) of 10-iododecyl allyl ether, 70 mmol (10.6 g) of methyl p-hydroxybenzoate, and 70 mmol (9.6 g) of potassium carbonate were refluxed in absolute ethanol for 15 hours. After addition of an aqueous potassium hydroxide solution (containing 4.0 g of potassium hydroxide) into the reaction solution, the resulting mixture was further heated at 80° C. for 5 hours. After conclusion of the reaction, the reaction solution was acidified with hydrochloric acid, and the acidified reaction solution was then concentrated under reduced pressure. Water was added to the residue to form a suspension, and the insoluble matter was collected and was then dried, to obtain 18.7 g of 4-(10-allyloxydecyloxy)benzoic acid. (Yield: 80%)
Reaction SMILES: [NH:1]([C:8]1([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[OH-].[Na+].Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>O1CCCC1>[NH:1]([C:8]1([C:14]([OH:16])=[O:15])[CH2:9][CH2:10][N:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cl
Reactant: O=C(O)C1(Nc2ccccc2)CCNCC1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(Nc2ccccc2)(C(=O)O)CC1
Reaction time: 3 h

Procedure:
To a stirred and cooled (ice-salt bath) mixture of 12.1 parts of 4-anilinoisonipecotic acid, sodium salt, 200 parts of sodium hydroxide solution 1N and 20 parts of tetrahydrofuran are added dropwise 6.45 parts of ethyl chloroformate in 25 parts of tetrahydrofuran over 15 minutes and at a temperature between 2° and 5° C. Upon completion, stirring is continued for 3 hours in the cool-bath. The whole is extracted with ether. The aqueous phase is separated and degassed on a rotavapor without heating. The mixture is acidified with glacial acetic acid, whereupon an oil is separated. The latter is stirred in fresh water and extracted with chloroform. The extract is washed three times with water, dried, filtered and evaporated. The residue is crystallized from a mixture of ethyl acetate and petroleumether, yielding 4-anilino-1-(ethoxycarbonyl)isonipecotic acid; mp. 149°-156° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH:11]1([CH:14]([OH:42])[C:15]2[C:39]([F:40])=[CH:38][C:18]([CH2:19][O:20][CH2:21][C@@H:22]3[CH2:24][C@@H:23]3[CH:25]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]3)=[CH:17][C:16]=2[F:41])[CH2:13][CH2:12]1.CCN(CC)CC>C(Cl)Cl>[CH:11]1([C:14]([C:15]2[C:16]([F:41])=[CH:17][C:18]([CH2:19][O:20][CH2:21][C@@H:22]3[CH2:24][C@@H:23]3[CH:25]3[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH2:30]3)=[CH:38][C:39]=2[F:40])=[O:42])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC([C@H]2C[C@H]2COCc2cc(F)c(C(O)C3CC3)c(F)c2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC([C@H]2C[C@H]2COCc2cc(F)c(C(=O)C3CC3)c(F)c2)CC1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
Oxalyl chloride (0.09 mL of a 2M soln in DCM, 0.177 mmol) was dissolved in DCM (0.8 mL) at −78° C. DMSO (35 mg, 0.44 mmol) was added, and the resulting solution was stirred at −78° C. for 5 minutes. A solution of the product from step A (40 mg, 0.09 mmol) in DCM (1 mL) was added followed by Et3N (90 mg, 0.89 mmol). The reaction was warmed to room temperature, and stirred at that temperature for 15 minutes. The reaction was quenched with sat. NH4Cl(aq.), and extracted with DCM. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified via silica gel column chromatography (0-15% EtOAc in hexanes) which provided title compound. 1H NMR (500 MHz, CDCl3) δ 6.94 (dd, 2H), 4.58 (d, 1H), 4.49 (d, 1H), 4.18-4.00 (br m, 2H), 3.58-3.46 (m, 2H), 2.74-2.61 (m, 2H), 1.83 (d, 1H), 1.73 (d, 1H), 1.47 (s, 9H), 1.38-1.19 (m, 5H), 1.13-1.09 (m, 2H), 0.97-0.88 (m, 1H), 0.80-0.68 (m, 2H), 0.06-0.00 (m, 1H). MS (ESI) m/z 450 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27]COC[CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.N1CC1>>[N:22]1([C:7]2[C:8]3[N:13]=[N:12][N:11]([CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:21])[C:9]=3[N:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[N:6]=2)[CH2:27][CH2:23]1
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: C1CN1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Product: CC(C)(C)c1nc(N2CC2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and aziridine and isolated as white solid (4.9 mg, 30%). MS (m/e): 343.3 (MH+).
Reaction SMILES: OC(C(F)(F)F)=O.Br[C:9]1[CH:10]=[C:11]2[C:18]3([CH2:23][C:22](=[O:24])[N:21]([CH3:25])[C:20](=[NH:26])[NH:19]3)[CH2:17][CH:16]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:15][C:12]2=[CH:13][CH:14]=1.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35](B(O)O)[CH:34]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1>[NH:26]=[C:20]1[NH:19][C:18]2([C:11]3[C:12](=[CH:13][CH:14]=[C:9]([C:35]4[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=4)[CH:10]=3)[O:15][CH:16]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:17]2)[CH2:23][C:22](=[O:24])[N:21]1[CH3:25]
Reactant: OB(O)c1cccnc1
Reactant: CN1C(=N)NC2(CC1=O)CC(c1ccccc1)Oc1ccc(Br)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=N)NC2(CC1=O)CC(c1ccccc1)Oc1ccc(-c3cccnc3)cc12

Procedure:
To a solution of 6-bromo-2′-imino-1′-methyl-2-phenyl-2′,3′-dihydro-1′H-spiro[chroman-4,4′-pyrimidin]-6′(5′H)-one TFA salt (12 mg, 0.023 mmol) and pyridin-3-ylboronic acid (9 mg, 0.070 mmol) in 1,4-dioxane (3 mL) charged in a 10-mL microwave test tube is added Cs2CO3 (63 mg, 0.195 mmol) and H2O (0.5 mL), followed by
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:11])[CH:7]=[C:8]([NH2:10])[CH:9]=1)([O-])=O>[Pt].O1CCOCC1>[NH2:1][C:4]1[CH:5]=[C:6]([NH2:11])[CH:7]=[C:8]([NH2:10])[CH:9]=1
Reactant: Nc1cc(N)cc([N+](=O)[O-])c1
Agent: [Pt]
Solvent: C1COCCO1
Product: Nc1cc(N)cc(N)c1
Temperature: 80 °C
Reaction time: 0.42 h
Yield: 88.2 %

Procedure:
5-nitro-m-phenylenediamine (100.0 g) was dissolved in acetone (100 ml) and insolubles were filtered off by means of suction. 15.0 g of activated carbon was added into the solution, after stirring for 5 minutes it was removed by suction filtration. The solution was concentrated till crystals were slightly deposited, and 200 ml of water was added. The precipitated solids were filtered by means of suction, and dried under a reduced pressure to obtain 68.5 g of purified 5-nitro-m-phenylenediamine. The purified 5-nitro-m-phenylenediamine (55.0 g), platinum/carbon (5%) (1.06 g) and dioxane (580 ml) were placed in a tightly closed vessel and stirred at the rate of 851 rpm under a hydrogen pressure of 1 to 4 kg/cm2 at 80° C. Hydrogen absorption was ceased within 25 minutes, and the mixture was stirred further one hour at 80° C. followed by left to cool. After filtering off the catalyst, the mixture was concentrated to 250 ml, then added with n-hexane (250 ml), and the white precipitate produced were filtered off. This white solid was washed with n-hexane and dried to obtain 1,3,5-triaminobenzene (39 g). The yield was 88%.
Reaction SMILES: [C:1]([C:5]1[CH:36]=[CH:35][C:8]([C:9]([NH:11][C@@H:12]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[N:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][N:28]=3)=[CH:23][CH:22]=2)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-].[N-:39]=[N+:40]=[N-:41].[Na+]>CN(C=O)C.CC(=O)OCC>[N:34]1[NH:39][N:40]=[N:41][C:33]=1[C:30]1[CH:29]=[N:28][C:27]([C:24]2[CH:23]=[CH:22][C:21]([CH2:20][C@H:12]([NH:11][C:9](=[O:10])[C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:36][CH:35]=3)[C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14])=[CH:26][CH:25]=2)=[N:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(-c2ncc(C#N)cn2)cc1)NC(=O)c1ccc(C(C)(C)C)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(-c2ncc(-c3nn[nH]n3)cn2)cc1)NC(=O)c1ccc(C(C)(C)C)cc1
Temperature: 100 °C
Yield: 12 %

Procedure:
Into a solution of tert-butyl (S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-cyanopyrimidin-2-yl)phenyl)propanoate INT-18 (34 mg, 0.07 mmol) in DMF (2 mL) were added NH4Cl (7.5 mg, 1.4 mmol) and NaN3 (7 mg, 0.1 mmol). The reaction mixture was heated at 100° C. for 3 h then diluted with EA and washed with NaHCO3. The organic layer was dried over Na2SO4, concentrated, and purified by preparatory HPLC to provide 4.6 mg (12%) of tert-butyl (S)-3-(4-(5-(2H-tetrazol-5-yl)pyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propanoate. LCMS-ESI (m/z) calculated for C29H33N7O3: 527.6; no m/z observed, tR=3.83 min (Method 1). 1H NMR (400 MHz, CDCl3) δ 9.35 (s, 2H), 8.42 (d, J=8.1 Hz, 2H), 7.75 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.5 Hz, 2H), 7.43 (d, J=8.2 Hz, 2H), 7.11 (d, J=7.8 Hz, 1H), 5.13 (dd, J=14.4, 7.1 Hz, 1H), 3.28 (ddd, J=21.0, 13.6, 6.7 Hz, 2H), 1.47 (d, J=6.8 Hz, 9H), 1.33 (s, 9H).