Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9](=[O:22])[CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])C1C=CC=CC=1>CO.[Pd]>[C:9]([OH:22])(=[O:8])[CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21]
Reactant: COCCOCCOCCOCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COCCOCCOCCOCC(=O)O

Procedure:
Benzyl-3, 6, 9, 12-Tetraoxatridecanoate (5 mmol) is dissolved in methanol (50 ml) and 10% palladium on carbon is added (100 mg catalyst/mmol). The suspension is shaken under 30 psi H2 until the starting material is consumed. The suspension is filtered through a short pad of Celite, washed thoroughly with methanol, and the solvent evaporated. The product is used directly without purification.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:32])/[CH:17]=[CH:18]/[CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:21][CH2:20]3)=[CH:12][CH:11]=2)=[N:4][CH:5]=[N:6][C:7]=1[CH3:8].C(O)C.[H][H]>[Pt]=O.O1CCOCC1>[CH3:1][C:2]1[C:3]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([C:16](=[O:32])[CH2:17][CH2:18][CH:19]3[CH2:20][CH2:21][N:22]([CH2:25][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:23][CH2:24]3)=[CH:14][CH:15]=2)=[N:4][CH:5]=[N:6][C:7]=1[CH3:8]
Reactant: [H][H]
Reactant: Cc1ncnc(Nc2ccc(C(=O)/C=C/C3CCN(Cc4ccccc4)CC3)cc2)c1C
Agent: O=[Pt]
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1ncnc(Nc2ccc(C(=O)CCC3CCN(Cc4ccccc4)CC3)cc2)c1C
Yield: 47.3 %

Procedure:
0.82 g of (E)-N-(5,6-dimethylpyrimidin-4-yl)-4-[3-(1-benzylpiperidin-4-yl)propenoyl]aniline obtained in Example 1 was added to a mixed solvent of 30 ml of ethanol and 40 ml of dioxane, and then 0.05 g of platinum oxide was added thereto. The mixture was stirred in a hydrogen stream at room temperature for 3.5 hours. After the catalyst was removed by filtration, the filtrate was condensed under reduced pressure. The obtained residue was applied to silica gel column chromatography to obtain 0.39 g of the title compound as pale yellow powder.
Reaction SMILES: Cl.C([CH:4]1[C:8]([CH3:10])([CH3:9])[C:7]2[CH:11]=[C:12]([C:19](=[NH:21])O)[CH:13]=[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=2[O:5]1)C.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.CO.C(Cl)(Cl)[Cl:30]>O1CCOCC1>[ClH:30].[C:15]([C:14]1[C:6]2[O:5][CH2:4][C:8]([CH3:10])([CH3:9])[C:7]=2[CH:11]=[C:12]([C:19](=[NH:21])[N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:13]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: C1CCNC1
Reactant: CCC1Oc2c(C(C)(C)C)cc(C(=N)O)cc2C1(C)C
Reactant: ClC(Cl)Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(C)c1cc(C(=N)N2CCCC2)cc2c1OCC2(C)C
Reaction time: 3 h
Yield: 54.2 %

Procedure:
To a solution of ethyl 7-tert-butyl-2,3-dihydro-3,3-dimethylbenzofuran-5-carboximidic acid hydrochloride (400 mg, 1.29 mmol) in dioxane (10 mL) is added excess pyrrolidine (0.6 mL). A color change from red to yellow is observed during the addition, and a precipitate forms. The reaction is also monitored by TLC (10% MeOH/CHCl3). After 3 h, the yellow precipitate is collected by filtration and purified by preparative TLC (10% MeOH/CHCl3) to give the desired product as a white powder (210 mg, 54.2%), mp=255°-256° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:5]2=[N:6][CH:7]=1.CC(N=NC(C#N)(C)C)(C#N)C.[Cl:25]C1C=CC=CC=1>>[Cl:25][CH2:1][C:2]1[CH:3]=[C:4]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1cnc2c(c1)C(=O)OC2=O
Reactant: Clc1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: O=C1OC(=O)c2ncc(CCl)cc21
Temperature: 85 °C
Reaction time: 1.5 h

Procedure:
106.8 g (0.65 mol) of 5-methyl-2,3-pyridine dicarboxylic acid anhydride were dissolved in 427 g chlorobenzene and heated up to 85° C. A solution of 0.64 g (0.004 mol) AIBN in 99.0 g (0.66 mol) SO2Cl2 was added during 45 min. The mixture was stirred for additional 90 min at 85° C. Chlorobenzene was partly distilled off and the solution was cooled to 10° C. via 10 h ramp. The precipitate was filtered off and washed with chlorobenzene/hexane.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:27][C:28]1[CH:29]=[C:30]([S:34][C:35]2[CH:36]=[CH:37][C:38]3[N:39]([CH:41]=[C:42]([NH:44][C:45]([CH:47]4[CH2:49][CH2:48]4)=[O:46])[N:43]=3)[N:40]=2)[CH:31]=[CH:32][CH:33]=1>CN(C)C(=O)C.O1CCCC1>[CH:47]1([C:45]([NH:44][C:42]2[N:43]=[C:38]3[CH:37]=[CH:36][C:35]([S:34][C:30]4[CH:29]=[C:28]([NH:27][C:13]([C:4]5[CH:3]=[C:2]([CH3:1])[N:6]([C:7]6[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=6)[N:5]=5)=[O:15])[CH:33]=[CH:32][CH:31]=4)=[N:40][N:39]3[CH:41]=2)=[O:46])[CH2:48][CH2:49]1
Reactant: Cc1cc(C(=O)O)nn1-c1ccccc1
Reactant: Nc1cccc(Sc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(=O)Nc2cccc(Sc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)nn1-c1ccccc1
Yield: 49.9 %

Procedure:
Using 5-methyl-1-phenyl-1H-pyrazole-3-carboxylic acid (196 mg, 0.97 mmol), tetrahydrofuran (2.0 mL), N,N-dimethylformamide (30 μL, 0.39 mmol), oxalyl chloride (80 μL, 0.92 mmol), N-{6-[(3-aminophenyl)thio]imidazo[1,2-b]pyridazin-2-yl}cyclopropanecarboxamide (200 mg, 0.61 mmol) and N,N-dimethylacetamide (4.0 mL), and in the same manner as in Example 255, the title compound (155 mg, 49%) was obtained as a white powder.
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([Cl:12])[CH:3]=1.Cl.[CH3:14][C:15]1[C:16]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[N:17][CH:18]=[C:19]([CH3:21])[CH:20]=1>>[Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([N:25]2[CH2:26][CH2:27][N:22]([C:16]3[C:15]([CH3:14])=[CH:20][C:19]([CH3:21])=[CH:18][N:17]=3)[CH2:23][CH2:24]2)=[O:7])=[C:4]([Cl:12])[CH:3]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: O=C(Cl)c1cc(F)c(Br)cc1Cl
Agent: Cl
Product: Cc1cnc(N2CCN(C(=O)c3cc(F)c(Br)cc3Cl)CC2)c(C)c1
Yield: 95.6 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 8 and using 4-bromo-2-chloro-5-fluorobenzoyl chloride (1 g) and 1-(3,5-dimethylpyridin-2-yl)piperazine hydrochloride (843 mg) described in Preparation Example 64, the title compound (1.5 g) was obtained.
Reaction SMILES: [CH2:1]1[C:15](=O)[C:14]2[C:5](=[C:6]([OH:18])[C:7]3[C:12]([C:13]=2[OH:17])=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3](=O)[CH2:2]1.[NH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.[OH2:29]>N1C=CC=CC=1>[OH:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH2:20][NH:19][C:15]2[C:14]3[C:13](=[O:17])[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:6](=[O:18])[C:5]=3[C:3]([NH:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([OH:29])=[CH:24][CH:23]=3)=[CH:2][CH:1]=2)=[CH:23][CH:24]=1
Reactant: O=C1CCC(=O)c2c1c(O)c1ccccc1c2O
Reactant: NCCc1ccc(O)cc1
Reactant: O
Solvent: c1ccncc1
Product: O=C1c2ccccc2C(=O)c2c(NCCc3ccc(O)cc3)ccc(NCCc3ccc(O)cc3)c21
Temperature: 25 °C
Yield: 60 %

Procedure:
A mixture of 21 grams (0.09 mole) of leucoquinizarine, 30 grams (0.22 mole) of p-(2-aminoethyl)phenol in 150 milliliters of pyridine was refluxed for 12 hours. The mixture was cooled to room temperature and poured into 2 liters of water. Thereafter, the product resulting was filtered, washed with water, and recrystallized from acetic acid to yield 26 grams, (60 percent) of 1,4-bis[2-(p-hydroxyphenyl)ethylamino] anthraquinone as a blue powder, m.p. 240° to 242° C.; vis(DMF), λmax 644 nm(ε 16,600); 598 nm(ε 14,100); ms 478 (M+); Analysis Calculated for C30H26N2O4 : C, 75.29; H, 5.48; N, 5.86; O, 13.38. Found: C, 75.46; H, 5.32; N, 5.69; O, 13.26.
Reaction SMILES: [Cl:1][CH:2]([CH2:6][C:7]1[CH:12]=[C:11]([N:13]2[C:17](=[O:18])[N:16]([CH:19]([F:21])[F:20])[C:15]([CH3:22])=[N:14]2)[C:10]([F:23])=[CH:9][C:8]=1[Cl:24])[C:3]([OH:5])=[O:4].[CH2:25](O)[CH3:26]>C1C=CC=CC=1>[CH3:25][CH2:26][O:4][C:3]([CH:2]([Cl:1])[CH2:6][C:7]1[CH:12]=[C:11]([N:13]2[N:14]=[C:15]([CH3:22])[N:16]([CH:19]([F:20])[F:21])[C:17]2=[O:18])[C:10]([F:23])=[CH:9][C:8]=1[Cl:24])=[O:5]
Reactant: CCO
Reactant: Cc1nn(-c2cc(CC(Cl)C(=O)O)c(Cl)cc2F)c(=O)n1C(F)F
Solvent: c1ccccc1
Product: CCOC(=O)C(Cl)Cc1cc(-n2nc(C)n(C(F)F)c2=O)c(F)cc1Cl

Procedure:
adding 1 mol of the 2-chloro-3-{2-chloro-5-[4-(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl]-4-fluorophenyl}propionic acid of the step (1), 4˜10 mol of ethanol and 0.03˜0.2 mol of an acid catalyst into 6˜12 mol of the solvent of benzene class; refluxing the reaction mixture until an esterification is completed; washing successively with water, with aqueous alkali base and then with water; and removing the solvent totally from the organic layer, to give a product carfentrazone-ethyl.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[N:3]=1.[CH3:9][N:10]([CH3:15])[CH2:11][CH2:12][NH:13][CH3:14].C(N(C(C)C)C(C)C)C>C(O)CC>[ClH:1].[ClH:1].[CH3:9][N:10]([CH3:15])[CH2:11][CH2:12][N:13]([CH3:14])[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[N:3]=1
Reactant: CNCCN(C)C
Reactant: Nc1nccc(Cl)n1
Solvent: CCCO
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCN(C)c1ccnc(N)n1
Product: Cl
Temperature: 200 °C
Yield: 33.9 %

Procedure:
A mixture of 4-chloropyrimidin-2-amine (CAS#3993-78-0, 0.100 g, 0.00077 mole), N1,N1,N2-trimethylethane-1,2-diamine (CAS#142-25-6, 0.082 g, 0.00077 mole), and N-ethyl-N-isopropylpropan-2-amine (0.94 mL, 0.00540 mole) in n-propanol (2 mL) was heated at 200° C. under microwave irradiation for 15 minutes. Volatiles were removed under reduced pressure and the residue was partitioned between ethyl acetate and saturated aqueous sodium carbonate. The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography with silica gel, eluting with 97:3:0.5 to 95:5:1 DCM/MeOH/Et3N. Fractions containing product were combined and concentrated under reduced pressure. The residue was dissolved in ethyl acetate. This solution was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure and the residue was dissolved in a minimum of methanol. This solution was acidified with a 4.0 M solution of HCl in dioxane. Ether was added to induce crystallization. Crystals were collected by filtration to provide N4-(2-(dimethylamino)ethyl)-N4-methylpyrimidine-2,4-diamine dihydrochloride (0.035 g, 15.8% yield). 1H NMR (300 MHz, CD3OD) δ ppm 3.00 (s, 6H), 3.25 (s, 3H), 3.46 (t, J=6 Hz, 2H), 4.14 (t, J=6 Hz, 2H), 6.40 (d, J=7 Hz, 1H), 7.75 (d, J=7 Hz, 1H). MS (DCl—NH3) m/z=196 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Cl.[Cl:11][C:12]([NH2:14])=[NH:13].C1COCC1>C1C=CC=CC=1>[ClH:11].[N:1]1[N:2]([C:12]([NH2:14])=[NH:13])[CH:3]=[C:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2
Reactant: c1ccc2[nH]ncc2c1
Reactant: N=C(N)Cl
Agent: Cl
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: N=C(N)n1cc2ccccc2n1
Yield: 52.8 %

Procedure:
940 mg of indazole and 920 mg of chloroformamidine hydrochloride were heated under reflux in 30 ml of benzene of THF for 5 hours, and the crystals formed were removed by filtration. These were recrystallized from ethanol ether to obtain 826 mg of 2H-indazole-2-carboxamidine hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[N+:20]([O-])([OH:22])=[O:21]>>[Cl:1][C:2]1[C:10]([N+:20]([O-:22])=[O:21])=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1Cl
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl

Procedure:
After dissolving at room temperature 2-chloro-5-trifluoromethylbenzoic acid (2.25 g; 10 mmol) in fuming sulfuric acid comprising 20% oleum (6 ml), fuming nitric acid (1.7 ml) is added dropwise over 30 minutes, so as to maintain the temperature of the reaction medium below 60° C. After cooling, ice is added and the precipitate is separated out, washed with water and dried. After recrystallisation from water, 2.15 g of solid corresponding to 2-chloro-3-nitro-5-trifluoromethylbenzoic acid are obtained (m.p.=173° C.).
Reaction SMILES: C([O:5][C:6](=[O:42])[C@@H:7]([NH:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH2:8][NH:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[CH2:19][CH2:20][CH2:21][C:22](=[O:30])[NH:23][C:24]1[NH:25][CH2:26][CH2:27][CH2:28][N:29]=1)(C)(C)C>FC(F)(F)C(O)=O.O>[CH2:35]([O:34][C:32]([NH:31][C@@H:7]([CH2:8][NH:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[CH2:19][CH2:20][CH2:21][C:22](=[O:30])[NH:23][C:24]1[NH:25][CH2:26][CH2:27][CH2:28][N:29]=1)[C:6]([OH:42])=[O:5])=[O:33])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)[C@H](CNc1ncnc2c1ncn2CCCC(=O)NC1=NCCCN1)NC(=O)OCc1ccccc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCCn1cnc2c(NC[C@H](NC(=O)OCc3ccccc3)C(=O)O)ncnc21)NC1=NCCCN1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
70 mg (Q.12 mmol) of (2S)-2-benzyloxycarbonylamino-3-{9-[3-(1,4,5,6-tetrahydro-pyrimidin-2-ylcarbamoyl)-propyl]-9H-purin-6-ylamino}-propionic acid tert-butyl ester was dissolved in 3 ml of trifluoroacetic acid/water (95/5). The solution was stirred at room temperature for 3 hours. The solvent was removed in vacuo and toluene was added to the residue and then removed in vacuo. The residue was dissolved in acetonitrile/water 1/1 and lyophilized. Yield: 51 mg (trifluoroacetate salt).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>C(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:25](=[O:26])[O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:7]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(-n2nc(C(C)(C)C)cc2N)ccn1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1cc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)ccn1
Yield: 16.9 %

Procedure:
Using the procedure described in Example 306A, to a solution of 3-tert-butyl-1-(2-methylpyridin-4-yl)-1H-pyrazol-5-amine (496 mg, 2.2 mmol), from the previous step, and potassium carbonate (395 mg, 2.9 mmol) in anhydrous DCM (8 ml) was added dropwise phenyl chloroformate (0.83 ml, 6.6 mmol) as a solution in DCM (5 ml). The crude was purified by silica gel chromatography (DCM/MeOH 0-10%) to afford phenyl 3-tert-butyl-1-(2-methylpyridin-4-yl)-1H-pyrazol-5-ylcarbamate (130 mg, 17%). 1H NMR (300 MHz, CDCl3) δ 1.27 (s, 9H), 2.54 (s, 3H), 6.45 (s, 1H), 6.81 (d, J=8 Hz, 1H), 7.12-7.28 (m, 5H), 7.29-7.43 (m, 2H) 8.49 (d, J=6 Hz, 1H); LC-MS (ESI) m/z 351 (M+H)+.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:13]([CH2:15]P(=O)(OCC)OCC)#[N:14].[H-].[Na+]>O1CCCC1>[C:13]([CH2:15][CH2:9][C:8]1[CH:11]=[CH:12][C:5]([S:2]([NH2:1])(=[O:4])=[O:3])=[CH:6][CH:7]=1)#[N:14]
Reactant: NS(=O)(=O)c1ccc(C=O)cc1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCCc1ccc(S(N)(=O)=O)cc1

Procedure:
p-Aminosulphonylbenzaldehyde was reacted with diethyl cyanomethylphosphonate/sodium hydride in tetrahydrofuran to give 1-cyano-2-(4-aminosulphonylphenyl)-ethane which was hydrogenated in methanol with Raney-cobalt as the catalyst to give 3-(4-aminosulphonylphenyl)-propylamine.
Reaction SMILES: [NH2:1][C@H:2]([C:15]([O:17]C)=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.[NH3:19]>CO>[NH2:1][C@H:2]([C:15]([NH2:19])=[O:17])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1
Reactant: N
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)c(C(C)(C)C)c1
Solvent: CO
Product: CC(C)(C)c1cc(C[C@H](N)C(N)=O)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a solution of Tyr(3-tBu)-OCH3 (1.5 g, 5.97 mmol) in MeOH (10 ml), aqueous ammonia (10 ml) was added and stirred at room temperature overnight. The mixture was evaporated to remove the solvent under reduced pressure and the thus obtained residue was subjected to silica gel column chromatography (developing solvent: methylene chloride:methanol=10:1), giving Tyr(3-tBu)-NH2 (1.4 g, 99%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.[H-].[Na+].[C:22](OCC)(=O)C>O1CCCC1.O>[C:1]([O:5][C:6]([N:8]([C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])[CH3:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(C)=O
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: CN(C(=O)OC(C)(C)C)C(C)(C)C/C=C/C(=O)O
Temperature: 0 °C
Reaction time: 96 h

Procedure:
(2E)-5-(tert-Butyloxycarbonylamino)-5-methylhex-2-enoic acid (5.00 g; 20.6 mmol) was dissolved in tetrahydrofuran (70 ml). Methyliodide (10.3 ml; 164 mmol) was added and the solution was cooled to 0° C. Sodium hydride (60% in oil)(2.07 g; 61.6 mmol) was added in portions and the solution was stirred at room temperature for four days. Ethyl acetate (70 ml) and water (60 ml) was added dropwise and the solvent was removed in vacuo. The crude product was dissolved in water (40 ml) and ether (40 ml). The organic phase was washed with a saturated aqueous solution of sodium hydrogencarbonate (30 ml). The aqueous phases were mixed and 5% aqueous citric acid was added to pH 3. The aqueous phase was extracted with ethylacetate (4×50 ml). The organic phase was washed with water (2×40 ml), an aqueous solution of sodium thiosulfate (5%; 40 ml), water (40 ml), dried over MgSO4 and the solvent was removed in vacuo. The residue was dissolved in ethylacetate (45 ml) and washed with an aqueous solution of sodium hydrogensulfate (10%; 3×30 ml), dried over MgSO4 and and concentrated in vacuo to give 4.00 g of (2E)-5-(N-(tert Butoxycarbonyl)-N-methylamino)-5-methylhex-2-enoic acid.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].C(N(CC)CC)C.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.O>CC(C)=O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: C1COCCN1
Solvent: CC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: Clc1nc(Cl)nc(N2CCOCC2)n1
Temperature: -5 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
Cyanuric chloride (10.0 g, 54 mmol) dissolved in acetone (100 ml) was cooled to −5° C., slowly added with triethylamine (4.7 ml, 49 mmol) dropwise and further, slowly added with morpholine (7.5 g, 54 mmol) dropwise. The reaction mixture was stirred at the same temperature for one hour and then stirred at room temperature for one hour. The reaction solution was poured into water (500 ml). The precipitated crystals were collected by filtration, washed with trace amount of acetone and dried to obtain 9.7 g (yield: 69%) of 2,4-dichloro-6-morpholino-1,3,5-triazine as colorless crystals with melting point of 155° C.-157° C.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:25]#[N:26])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:10]=2)=[O:5])C.[NH2:27][C:28]([CH3:34])([CH3:33])[CH2:29][C:30]([OH:32])=[O:31].C[O-].[Na+]>CN(C=O)C.O>[CH2:18]([O:17][C:11]1[CH:10]=[C:9]2[C:14]([C:15]([OH:16])=[C:6]([C:4]([NH:27][C:28]([CH3:34])([CH3:33])[CH2:29][C:30]([OH:32])=[O:31])=[O:5])[N:7]=[C:8]2[C:25]#[N:26])=[CH:13][CH:12]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(N)CC(=O)O
Reactant: CCOC(=O)c1nc(C#N)c2cc(OCc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(CC(=O)O)NC(=O)c1nc(C#N)c2cc(OCc3ccccc3)ccc2c1O
Temperature: 140 °C
Yield: 92 %

Procedure:
7-Benzyloxy-1-cyano-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester (US Patent Publication No. 2007/627906) (40 mg, 0.115 mmol) was dissolved in anhydrous DMF (2 mL). 3-Amino-3-methyl-butyric acid (68 mg, 0.5742 mmol) and solid sodium methoxide (25 mg, 0.459 mmol) were added sequentially and the mixture heated to 140° C. in an oil bath for 3.5 h. Upon completion, the reaction mixture was cooled and diluted with water. The solution was acidified to pH 3 with 1M hydrochloric acid inducing precipitation of the product. The free acid was isolated by filtration and dried to provide the title compound as a tan solid in 92% yield. MS ESI(−) m/e: 417.9596 (M−1), MS ESI(+) m/e: 419.9934 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)=[O:21])=[CH:16][CH:15]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:28][CH:29]1[CH2:31][O:30]1.C([O-])([O-])=O.[K+].[K+]>CC(=O)CC>[O:30]1[CH2:31][CH:29]1[CH2:28][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)=[O:21])=[CH:16][CH:15]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cn2nccc2-c2ccc(O)cc2)cc1)N1CCCC1
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(c1ccc(Cn2nccc2-c2ccc(OCC3CO3)cc2)cc1)N1CCCC1
Yield: 99.6 %

Procedure:
(4-((5-(4-hydroxyphenyl)-1H-pyrazol-1-yl)methyl)phenyl)(pyrrolidin-1-yl)methanone (173 mg, 0.5 mmol), 2-(bromomethyl)oxirane (544 mg, 3 mmol) and K2CO3 (552 mg, 4 mmol) were charged to a 100-mL flask containing 2-butanone (20 mL) and heated at reflux temperature for 17 h. The mixture was cooled, filtered and evaporated in vacuuo to give crude product as an oil (201 mg, 98%). This crude material was used without further purification. LCMS (m/z): 404.2 [M+H]
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[NH2:15][CH2:16][CH2:17][CH2:18][OH:19]>CO.[Pd]>[OH:19][CH2:18][CH2:17][CH2:16][NH:15][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1
Reactant: NCCCO
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC(NCCCO)C1

Procedure:
A mixture of tert-butyl 3-oxo-1-piperidinecarboxylate (5.0 g, 25.1 mmol) and 3-amino-1-propanol (5.66 mL, 73.8 mmol) in MeOH (75 mL) was hydrogenated over 10% Pd on C (200 mg) for 1 day (Yokoyama et al., Bioorg. Med. Chem. 2008, 16, 7968) to give tert-butyl 3-[(3-hydroxypropyl)amino]-1-piperidinecarboxylate as an oil: 1H NMR (CDCl3) (rotamers) δ 3.80 (t, J=5.1 Hz, 2H), 3.80 (br, 1H), 3.65 and 3.67 (2t, J=4.7 Hz, 1H), 3.06-2.86 (m, 4H), 2.62-2.56 (m, 1H), 1.90-1.86 (m, 1H), 1.72-1.62 (m, 3H), 1.50-1.30 (m, 2H), 1.46 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([SH:13])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Hg](C#N)C#N.[C:21]([O:24][C@@H:25]1[C@@H:30]([O:31][C:32](=[O:34])[CH3:33])[C@H:29]([O:35][C:36](=[O:38])[CH3:37])[CH2:28][S:27][C@@H:26]1Br)(=[O:23])[CH3:22]>>[C:21]([O:24][C@@H:25]1[C@@H:30]([O:31][C:32](=[O:34])[CH3:33])[C@H:29]([O:35][C:36](=[O:38])[CH3:37])[CH2:28][S:27][C@H:26]1[S:13][C:5]1[CH:4]=[C:3]([C:2]([F:14])([F:1])[F:15])[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Reactant: FC(F)(F)c1cc(S)cc(C(F)(F)F)c1
Agent: N#C[Hg]C#N
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](Sc2cc(C(F)(F)F)cc(C(F)(F)F)c2)SC[C@H]1OC(C)=O
Yield: 35.5 %

Procedure:
If the procedure described in Preparation I is followed starting from 1.6 g (6.5.10-3 mol) of 3,5-bis(trifluoromethyl)benzenethiol, 1.64 g (6.5.10-3 mol) of mercuric cyanide, Hg(CN)2, and 2.54 g (7.5.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide, 1.2 g (yield: 35.7%) of the expected product are obtained.