Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][N:7]([CH2:10][CH3:11])[C:6]1=[O:12].[NH2:13][C:14]1[C:30]([Cl:31])=[CH:29][C:17]([C:18]([NH:20][C@H:21]2[CH2:26][CH2:25][NH:24][CH2:23][C@H:22]2[O:27][CH3:28])=[O:19])=[C:16]([O:32][CH3:33])[CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+].[K]>CN(C)C(=O)C>[NH2:13][C:14]1[C:30]([Cl:31])=[CH:29][C:17]([C:18]([NH:20][C@H:21]2[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][CH2:4][N:5]3[CH2:9][CH2:8][N:7]([CH2:10][CH3:11])[C:6]3=[O:12])[CH2:23][C@H:22]2[O:27][CH3:28])=[O:19])=[C:16]([O:32][CH3:33])[CH:15]=1
Reactant: CCN1CCN(CCCCl)C1=O
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCNC[C@H]1OC
Agent: O=C([O-])[O-]
Agent: [K]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCN1CCN(CCCN2CC[C@H](NC(=O)c3cc(Cl)c(N)cc3OC)[C@H](OC)C2)C1=O
Temperature: 70 °C
Yield: 36.6 %

Procedure:
A mixture of 6.3 parts of 1-(3-chloropropyl)-3-ethyl-2-imidazolidinone, 4.76 parts of cis-4-amino-5-chloro-2-methoxy-N-(3-methoxy-4-piperidinyl)benzamide, 2.3 parts of sodium carbonate, 0.1 parts of potassium iode and 90 parts of N,N-dimethylacetamide was stirred over weekend at 70° C. After cooling, the reaction mixture was evaporated. The residue was taken up in dichloromethane and water. The organic layer was separated, washed twice with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile and a few drops of water at 0° C. The product was filtered off and dried in vacuo at 40° C., yielding 2.83 parts (36.6%) of cis-4-amino-5-chloro-N-[1-[3-(3-ethyl-2-oxo-1-imidazolidinyl)propyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide; mp. 112.9° C. (compound 12).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH2:13]([O:20][C:21](=[O:34])[CH:22]([CH3:33])[CH2:23][CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(Br)(Br)(Br)[Br:36]>C1COCC1>[CH2:13]([O:20][C:21](=[O:34])[C:22]([Br:36])([CH3:33])[CH2:23][CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(CCOCc1ccccc1)C(=O)OCc1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(Br)(CCOCc1ccccc1)C(=O)OCc1ccccc1
Temperature: -30 °C
Reaction time: 0.75 h
Yield: 47.6 %

Procedure:
n-Butyllithium (2.5M in hexanes, 1.01 mL, 2.54 mmol) was added to a solution of diisopropylamine (0.376 mL, 2.658 mmol) in THF (10 mL) at −30° C. under a nitrogen atmosphere. Stirring at −30° C. was continued for 45 min, and the reaction mixture was cooled to −78° C. A solution of 4-benzyloxy-2-methylbutyric acid benzyl ester (0.721 g, 2.416 mmol) in THF (8 mL) was added over 5 min and stirring at −78° C. was continued for 1 h. A solution of carbon tetrabromide (CBr4) (1.20 g, 3.62 mmol) in THF (2 mL) was added and the mixture was slowly warmed to 0° C. over 3.5 h. The reaction mixture was quenched by addition of a saturated solution aqueous of NH4Cl and then extracted with EtOAc (×2). The combined organic layers were washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 3-18% EtOAc in cyclohexane) affording 4-benzyloxy-2-bromo-2-methylbutyric acid benzyl ester (0.434 g), used in the following step without further purification.
Reaction SMILES: [CH3:1][C:2]([O:6][CH2:7][CH:8]1[CH2:10][O:9]1)([CH3:5])[CH2:3][OH:4].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(=O)([O-])O.[Na+]>ClCCl>[CH3:1][C:2]1([CH3:5])[CH2:3][O:4][CH:8]([CH2:10][OH:9])[CH2:7][O:6]1
Reactant: CC(C)(CO)OCC1CO1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)COC(CO)CO1
Yield: 56.5 %

Procedure:
A solution of 2-allyloxy-2-methyl-propionic acid ethyl ester (1.72 g, 10 mmol) in anhydrous tetrahydrofuran (40 mL) was stirred at room temperature under nitrogen. Lithium borohydride (44 mg, 20 mmol) was added portion-wise and the reaction mixture was stirred at room temperature for 20 h. The reaction mixture was cooled to 0° C. and saturated ammonium chloride solution was cautiously added followed by hydrochloric acid (2 M) to acidify the reaction mixture to pH 2. The mixture was extracted with diethyl ether and the organic extracts were combined and washed with brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated to afford 2-allyloxy-2-methyl-propan-1-ol (10 mmol) which was used crude in the next step. LCMS (m/z) 153.2 [M+Na], Tr=1.16 min. A suspension of 2-allyloxy-2-methyl-propan-1-ol (10 mmol) in dichloromethane (40 mL) was stirred at 0° C. Meta-chloroperbenzoic acid (70% pure containing 20% water and 10% meta-chlorobenzoic acid, 2.9 g, 12 mmol) was added and the reaction mixture was stirred at 0° C. for 30 min and then at room temperature for 24 h. The reaction mixture was cooled to 0° C. and saturated sodium hydrogen carbonate solution and sodium thiosulfate solution were added and the mixture was stirred at 0° C. for 15 min. The organic layer was separated and the aqueous layer was extracted with dichloromethane (4×). The organic extracts were combined and washed with brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated to afford 2-methyl-2-oxiranylmethoxy-propan-1-ol (10 mmol) which was used crude in the next step. LCMS (m/z) 169.2 [M+Na], Tr=0.72 min. A solution of 2-methyl-2-oxiranylmethoxy-propan-1-ol (10 mmol) in dichloromethane (50 mL) and racemic camphor-10-sulfonic acid (765 mg, 3.3 mmol) was stirred at room temperature for 18 h. Saturated sodium hydrogen carbonate solution was added and the organic layer separated. The aqueous layer was extracted with dichloromethane and the organic extracts were combined, filtered through a hydrophobic frit and the filtrate was evaporated. The residue was purified by silica gel chromatography using a gradient of pentane/diethyl ether 2:3 to 1:4 to afford the title compound (826 mg, 57% over 3 steps) as a yellow oil. 1H NMR (300 MHz, d6-DMSO): δ 1.02 (s, 3H), 1.20 (s, 3H), 3.23 (d, J=11.1 Hz, 1H), 3.30-3.50 (m, 6H), 4.68 (t, J=5.4 Hz, 1H). LCMS (m/z) 169.2 [M+Na], Tr=0.72 min.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][CH:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[CH:3]=1.[CH3:21][O:22][C:23]1[CH:29]=[C:28]([N:30]2[CH2:35][CH2:34][P:33]([CH3:37])(=[O:36])[CH2:32][CH2:31]2)[CH:27]=[CH:26][C:24]=1[NH2:25].Cl>COCCO.C(O)C>[CH3:21][O:22][C:23]1[CH:29]=[C:28]([N:30]2[CH2:31][CH2:32][P:33]([CH3:37])(=[O:36])[CH2:34][CH2:35]2)[CH:27]=[CH:26][C:24]=1[NH:25][C:2]1[N:7]=[N:6][CH:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[CH:3]=1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1cnnc(Cl)c1
Reactant: COc1cc(N2CCP(C)(=O)CC2)ccc1N
Agent: Cl
Solvent: COCCO
Solvent: CCO
Product: COc1cc(N2CCP(C)(=O)CC2)ccc1Nc1cc(Nc2ccccc2S(=O)(=O)C(C)C)cnn1

Procedure:
To a solution of 6-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyridazin-4-amine (prepared in Example 73: 0.02 mmol) and 2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)aniline (0.7 mmol) in 1 mL of 2-Methoxy ethanol, is added 1 mL of 2.5M HCl in Ethanol. The reaction mixture is heated in a sealed tube at 140 degree until formation of the desired compound. The reaction mixture is filtered through a syringe filter and can be purified by Prep-HPLC.
Reaction SMILES: [C:1]1([C:7]2([C:13]([OH:15])=[O:14])[CH2:9][CH:8]2[C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:16]([O-])([OH:18])=[O:17]>S(=O)(=O)(O)O>[N+:16]([C:4]1[CH:3]=[CH:2][C:1]([C:7]2([C:13]([OH:15])=[O:14])[CH2:9][CH:8]2[C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1)([O-:18])=[O:17]
Reactant: O=C(O)C1CC1(C(=O)O)c1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)C1CC1(C(=O)O)c1ccc([N+](=O)[O-])cc1

Procedure:
To a stirred slurry of 20.6 g of 1-phenylcyclopropane-1,2-dicarboxylic acid in 25 ml of concentrated sulfuric acid at 0° C. is added 15 ml of concentrated nitric acid over 30 minutes. The resultant solution is then stirred at ambient tmperature for 30 minutes and then poured onto ice. The crystalline product is recrystallized from hexane-ethyl acetate to give 1-(p-nitrophenyl)-cyclopropane-1,2-dicarboxylic acid as colorless crystals, m.p. 138°-144° C.
Reaction SMILES: [CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2([CH3:20])[CH3:19].[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=1>>[CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:21]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)=[O:28])[C:13](=[O:18])[C:12]2([CH3:19])[CH3:20]
Reactant: O=C(Cl)c1cccnc1
Reactant: CC1SC(=O)NN=C1c1ccc2c(c1)C(C)(C)C(=O)N2
Product: CC1SC(=O)NN=C1c1ccc2c(c1)C(C)(C)C(=O)N2C(=O)c1cccnc1
Yield: 55 %

Procedure:
Starting from 1,3-dihydro-5(3,6-dihydro-6-methyl-2-oxo-2H-1,3,4 thiadiazin-5-yl)-3,3 dimethyl-2H-indol-2-one (Example 3) and according to the method described in Example 23, but using nicotinoyl chloride instead of isonicotinoyl chloride, afforded the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=O.C[Si]([C:20]#[N:21])(C)C.[Al+3].[Cl-].[Cl-].[Cl-]>C1C=CC=CC=1>[C:20]([C:8]1[C:9]2[C:4](=[C:3]([O:2][CH3:1])[C:12]([O:13][CH3:14])=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH:7]=1)#[N:21]
Reactant: COc1ccc2c(c1OC)CCCC2=O
Reactant: C[Si](C)(C)C#N
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: COc1ccc2c(c1OC)CCC=C2C#N
Yield: 96.9 %

Procedure:
A solution of 5,6-dimethoxy-1-tetralone (30 g, 0.14 mole), trimethylsilylcyanide (15.8 g, 0.156 mole), ca. 15 mLs dry benzene, and catalytic AlCl3 was stirred under N2 at 70° (oil bath) for 15 hours. Benzene was removed (in-vacuo), 300 mL MeOH was added to the crude product, and the solution was stirred at 0°-10° C. as HCl was bubbled through the solution for 3 hours. Methanol was evaporated (in-vacuo) and ca. 500 mL water was added to the residue. The resultant solid was filtered, washed with water, and dried (under high-vacuum) to yield 29.2 g of yellow solid. (99.8%); M+ 215; mp 139°-40° C.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O>>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Product: Nc1nnc(-c2ccccc2Cl)c(-c2ccccc2)n1
Yield: 45.5 %

Procedure:
6-(2-Chlorophenyl)-5-phenyl-1,2,4-triazin-3-amine (103 mg, 45%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.21 g, 0.80 mmol) and 2-chlorophenylboronic acid (0.125 g, 0.80 mmol) according to the general procedure of Example 1.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.Cl[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[CH3:23]>>[CH3:23][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:17]=1[O:14][CH:11]1[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Cc1cnccc1Cl
Agent: Cl
Product: Cc1cnccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 72 h

Procedure:
The title compound was prepared from 1-Boc-4-hydroxypiperidine and 4-chloro-3-methylpyridine hydrochloride, using a similar method to preparation 27. The reaction mixture was stirred for 72 hours to afford the title compound the desired product in 87% yield. 1H NMR(CDCl3, 400 MHz) δ: 1.44(s, 9H), 1.75-1.85(m, 2H), 1.87-1.97(m, 2H), 2.18(s, 3H), 3.42-3.53(m, 2H), 3.56-3.65(m, 2H), 4.57-4.65(m, 1H), 6.72(d, 1H), 8.29(s, 1H), 8.35(d, 1H); LRMS APCI m/z 293 [M+H]+
Reaction SMILES: [CH3:1][CH2:2][C:3]1([OH:29])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:16](=[CH:17][C:4]1=2)[C:15]1[N:18]=[C:19]2[C:24](=[CH:25][C:14]=1[CH2:13]3)[CH:23]=[C:22]([N+:26]([O-])=O)[CH:21]=[CH:20]2)=[O:11]>C(O)C.O1CCOCC1.[Pt]=O>[CH3:1][CH2:2][C@@:3]1([OH:29])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:16](=[CH:17][C:4]1=2)[C:15]1[N:18]=[C:19]2[C:24](=[CH:25][C:14]=1[CH2:13]3)[CH:23]=[C:22]([NH2:26])[CH:21]=[CH:20]2)=[O:11]
Reactant: CCC1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3cc([N+](=O)[O-])ccc3nc2-1
Agent: O=[Pt]
Solvent: C1COCCO1
Solvent: CCO
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3cc(N)ccc3nc2-1
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
10-Nitrocamptothecin (108 mg, 0.275 m-mol) is dissolved in ethanol (30 ml) and dioxane (20 ml). To this solution is added platinum oxide (20 mg), and the mixture is subjected to catalytic reduction for 30 minutes at room temperature under normal pressure. The catalyst is removed by filtration and the reaction mixture is evaporated under reduced pressure until dryness whereby 96 mg (yield: 96.2%) of 10-aminocamptothecin is obtained as a yellowish brown solid.
Reaction SMILES: [CH:1]([C:3]1[S:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=O.[S:21]=[C:22]([C:24](=[S:26])[NH2:25])[NH2:23]>>[CH2:17]([CH:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:9][O:8][C:7]1[CH:6]=[CH:5][S:4][C:3]=1[C:1]1[S:21][C:22]2[N:23]=[C:1]([C:3]3[S:4][CH:5]=[CH:6][C:7]=3[O:8][CH2:9][CH:10]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[S:26][C:24]=2[N:25]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCC(CCCC)COc1ccsc1C=O
Reactant: NC(=S)C(N)=S
Product: CCCCCCC(CCCC)COc1ccsc1-c1nc2sc(-c3sccc3OCC(CCCC)CCCCCC)nc2s1
Temperature: 200 °C
Reaction time: 5 h
Yield: 29 %

Procedure:
Under a nitrogen atmosphere, 2-formyl-3-(2-butyloctoxy)thiophene (7 g, 23.6 mmol) and rubeanic acid (1.42 g, 11.8 mmol) were added to a flask equipped with Dean-Stark, then heated to 200° C., and stirred for five hours. Then, the reaction mixture was extracted with chloroform, and an organic layer was washed with a saturated saline solution and water. The organic layer was dried with anhydrous magnesium sulfate, and, after filtration, the solvent was distilled off under reduced pressure. By separating and purifying the obtained reaction mixture by silica gel column chromatography in which a mixed solvent of hexane and chloroform was used as a mobile phase, a target substance was obtained as a yellow solid (29% yield). 1H-NMR (400 MHZ, CDCl3, TMS) δ 7.31 (d, J=5.6 Hz, 1 H), 6.88 (d, J=5.6 Hz, 1 H), 4.13 (d, J=4.8 Hz, 2 H), 1.25 (m, 17 H), 0.88 (m, 6 H)
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([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.[NH:22]1[CH2:27][CH2:26][CH2:25][C:24](=[O:28])[CH2:23]1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([N:22]1[CH2:27][CH2:26][CH2:25][C:24](=[O:28])[CH2:23]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([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: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCCNC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.9 %

Procedure:
Trityl chloride (13.1 g, 47.0 mmol) was added to a stirred suspension of 3-piperidone hydrochloride (5.79 g, 42.7 mmol) and triethylamine (14.9 ml, 107 mmol) in CH2Cl2 (100 ml) and the reaction was stirred for 16 h under N2 at room temperature. The resulting mixture was filtered and the filtrate washed sequentially with H2O and 5% aqueous citric acid, dried over MgSO4 and evaporated under reduced pressure. Trituration with pentane afforded the subtitle compound as a colourless solid (4.8 g, 33%). Rf 0.23 (CH2Cl2/pentane 2/3, v/v). 1H NMR (CDCl3) δ: 2.05 (2H, m), 2.35 (2H, m), 2.45 (2H, m), 2.85 (2H, s), 7.06-7.55 (15H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13])([O-])=O.[H][H]>[Pd].CN(C=O)C>[CH:11]1[CH:10]=[C:9]2[C:8](=[O:13])[N:7]([CH:14]3[C:15](=[O:21])[NH:16][C:17](=[O:20])[CH2:18][CH2:19]3)[CH2:6][C:5]2=[C:4]([NH2:1])[CH:12]=1
Reactant: [H][H]
Reactant: O=C1CCC(N2Cc3c(cccc3[N+](=O)[O-])C2=O)C(=O)N1
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Temperature: 30 °C

Procedure:
Into a 5.0 L 4 necked RB flask, charged 100.0 g of 3-(4-nitro-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione, 10.0 g of 10% Pd/C and 3200 ml of DMF under nitrogen atmosphere. Stirred the mass and raise the reaction mass temperature to 60 -65° C. Started the hydrogen gas bubbling into reaction mass at temperature 60-65° C. for 6 hours. The progress of the reaction is monitored by TLC. Cooled the mass to temperature 25to 30° C. Filtered the catalyst Pd/C under plant vacuum in the presence of nitrogen atmosphere and wash with dimethylformamide; wet Pd/C is transferred into a polythene bag for recovery. Distilled off the above organic layer solvent completely under vacuum below 60° C. Charged ethyl acetate 800 ml (lot-I) to the mass and stirred for 60 min. Filtered the solid and wash with 200 mL of ethyl acetate (Lot-II). Dried the above wet material in a oven at temperature 65-75° C. for 120-180 min. Dried Weight of the compound is 78.0 g.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[CH3:14])=[O:5].[F:22][CH2:23][C:24](Cl)=[O:25]>N1C=CC=CC=1>[F:22][CH2:23][C:24]([NH:1][C:2]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[CH3:14])=[O:5])=[O:25]
Reactant: O=C(Cl)CF
Reactant: Cc1ccc(Cl)cc1NC(=O)c1cc([N+](=O)[O-])ccc1N
Solvent: c1ccncc1
Product: Cc1ccc(Cl)cc1NC(=O)c1cc([N+](=O)[O-])ccc1NC(=O)CF
Yield: 94 %

Procedure:
4.0 g of N-(2-amino-5-nitrobenzoyl)-2-methyl-5-chloroaniline, 1.54 g of pyridine and 1.88 g of fluoroacetyl chloride are treated in the same manner as described in Example 1-(1), whereby 4.5 g of N-(2-fluoroacetamido-5-nitrobenzoyl)-2-methyl-5-chloroaniline are obtained as pale yellow needles.
Reaction SMILES: [OH-].[Li+].C([O:6][CH2:7][C:8]([NH:10][C:11]1[N:40]=[C:14]2[N:15]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=3)[C:16]([CH3:29])=[C:17]([C:27]#[N:28])[C@@H:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)[N:13]2[N:12]=1)=[O:9])(=O)C.Cl>O.C1COCC1>[C:27]([C:17]1[C@@H:18]([C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=2)[N:13]2[N:12]=[C:11]([NH:10][C:8](=[O:9])[CH2:7][OH:6])[N:40]=[C:14]2[N:15]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:38])([F:39])[F:37])[CH:31]=2)[C:16]=1[CH3:29])#[N:28]
Reactant: CC(=O)OCC(=O)Nc1nc2n(n1)[C@H](c1ccc(C#N)cc1)C(C#N)=C(C)N2c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)CO)nc2N1c1cccc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
At RT, a solution of lithium hydroxide (2.3 mg, 95.9 μmol, 5 eq.) in water (125 μl) was added to a solution of 2-((7R)-6-cyano-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-2-ylamino)-2-oxoethyl acetate (10.0 mg, 19.2 μmol; Example 31) in THF (625 μl). After 1 h of stirring, conversion was found to be complete. 1 N hydrochloric acid (153 μl, 8 eq.) was added, and the reaction mixture was directly purified by preparative HPLC (Kromasil C18 column, 5 μm, 50×20 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (6.5 mg, 71% of theory).
Reaction SMILES: [CH3:1][C:2]1(C)OC(=O)[CH:5]([CH:9]([C:20]2[C:28]3[C:23](=[C:24]([CH2:29][S:30][CH3:31])[CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[C:4](=[O:32])[O:3]1>N1C=CC=CC=1.C(O)C.[Cu]>[CH3:31][S:30][CH2:29][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:23]=1[NH:22][CH:21]=[C:20]2[CH:9]([C:10]1[CH:11]=[CH:12][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:14][CH:15]=1)[CH2:5][C:4]([O:3][CH2:2][CH3:1])=[O:32]
Reactant: CSCc1cccc2c(C(c3ccc(C(F)(F)F)cc3)C3C(=O)OC(C)(C)OC3=O)c[nH]c12
Agent: [Cu]
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)CC(c1ccc(C(F)(F)F)cc1)c1c[nH]c2c(CSC)cccc12

Procedure:
0.7 mg (0.01 mmol) of copper powder was added to 504 mg (1.06 mmol) of the compound from Example 12A in 8 ml of pyridine and 2 ml of ethanol. The reaction mixture was heated under reflux for 1 h. It was concentrated, and the crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 241 mg (54% of theory) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Br:10])[C:8]=1[F:9])[NH2:5].N1C=CC=CC=1.Cl[C:18]([O:20][CH3:21])=[O:19]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:18](=[O:19])[O:20][CH3:21])[CH:6]=[C:7]([Br:10])[C:8]=1[F:9]
Reactant: Nc1cc(Br)c(F)c(Br)c1
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)Nc1cc(Br)c(F)c(Br)c1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
3,5-dibromo-4-fluoroaniline (1.6 g, 4.16 mmol) was dissolved in DCM (41.6 ml). Pyridine (0.90 ml, 11.13 mmol) was added and the reaction mixture cooled to 0-5° C. Methyl chloroformate (0.66 ml, 8.52 mmol) was added drop wise via syringe. The reaction mixture was stirred at 0-5° C. for 1 hour. The reaction mixture was diluted with additional 50 ml dichloromethane and washed with 0.5 M citric acid twice, NaHCO3 solution once and brine once, then dried over MgSO4, filtered and evaporated to dryness. Chromatography on silica (gradient from 100% hexanes to 100% DCM) gave methyl (3,5-dibromo-4-fluorophenyl)carbamate (1.22 g) as a colorless fluffy solid.
Reaction SMILES: [NH:1]([C:3]([C:5]1[N:10]=[C:9]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=[CH:7][CH:6]=1)=O)[NH2:2].[CH:22]1([NH:25][CH:26]=O)[CH2:24][CH2:23]1.C1(N)CC1.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH:22]1([N:25]2[CH:26]=[N:2][N:1]=[C:3]2[C:5]2[N:10]=[C:9]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:8]=[CH:7][CH:6]=2)[CH2:24][CH2:23]1
Reactant: NNC(=O)c1cccc(NC(=O)OCc2ccccc2)n1
Reactant: O=CNC1CC1
Agent: NC1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C(Nc1cccc(-c2nncn2C2CC2)n1)OCc1ccccc1
Temperature: 100 °C
Yield: 29.4 %

Procedure:
To a sealable flask containing benzyl 6-(hydrazinecarbonyl)pyridin-2-ylcarbamate (1.97 g, 6.89 mmol, 1.0 eq) was added N-cyclopropyl formamide (1.8 mL, 20.7 mmol, 3.0 eq), cyclopropylamine (1.4 mL, 20.7 mmol, 3.0 eq), toluene (0.2 M), and trifluoracetic acid (0.511 mL, 6.89 mmol, 1.0 eq). The flask was sealed and heated to 100° C. for 24 hours. The reaction mixture was concentrated under reduced pressure to provide a yellow oil, which was purified by flash chromatography (Rf=0.44 in 10% methanol/ethyl acetate, gradient flash: 3%→10% methanol in ethyl acetate). The product, which consisted of a mixture of the desired compound with cyclopropyl formamide, was suspended in acetonitrile, sonicated, and the resultant suspension filtered to provide benzyl 6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-ylcarbamate (680 mg).