Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1.[N-:31]=[N+:32]=[N-:33].[Na+].O>CN(C)C=O>[N:31]([CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1)=[N+:32]=[N-:33]
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(Cl)c3ccccc32)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N=[N+]=[N-])c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Chloro-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.8 g) is dissolved in dimethylformamide and thereto is added sodium azide (0.18 g) at room temperature. The mixture is stirred at room temperature overnight, and further reacted with heating at 50° C. for 5 hours. Water is added to the reaction mixture and the precipitated crystal is collected by filtration to give 5-azido-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.68 9) as light brown powder.
Reaction SMILES: [I:1][CH2:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[C:11]#[N:12])=[CH:5][CH:4]=1.[OH:18][C:19]1[C:24]([C:25]([F:28])([F:27])[F:26])=[C:23]([OH:29])[CH:22]=[CH:21][C:20]=1[C:30](=[O:32])[CH3:31]>CN(C)C=O>[I:1][CH2:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[C:11]#[N:12])=[CH:5][CH:4]=1.[C:30]([C:20]1[CH:21]=[CH:22][C:23]([O:29][CH2:2][C:3]2[CH:17]=[CH:16][C:6]([O:7][C:8]3[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=3)[C:11]#[N:12])=[CH:5][CH:4]=2)=[C:24]([C:25]([F:27])([F:26])[F:28])[C:19]=1[OH:18])(=[O:32])[CH3:31]
Reactant: CC(=O)c1ccc(O)c(C(F)(F)F)c1O
Agent: N#Cc1cccc(Oc2ccc(CI)cc2)c1
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCc2ccc(Oc3cccc(C#N)c3)cc2)c(C(F)(F)F)c1O
Temperature: 60 °C
Reaction time: 1 h
Yield: 100.9 %

Procedure:
3-(4-Iodomethyl-phenoxy)-benzonitrile is prepared by an analogous procedure described in Preparation 43. Add half of a solution of 3-(4-iodomethyl-phenoxy)-benzonitrile (470 mg, 1.4 mmol) in anhydrous dimethylformamide (10 mL) to 1-(2,4-dihydroxy-3-trifluoromethyl-phenyl)-ethanone (300 mg, 1.4 mmol) and Li2CO3 (228 mg, 3.1 mmol) in anhydrous dimethylformamide (18 mL)dimethylformamide. Heat the reaction mixture to 60° C. and stir for 1 h. Add the other half of the 3-(4-iodomethyl-phenoxy)-benzonitrile solution to the reaction mixture. Stirred at 60° C. for an additional 1 h, cool to room temperature, and quench with water (75 mL). Extract the aqueous mixture with ethyl acetate (3×75 mL). Combine the organic layers, wash with brine, dry over sodium sulfatesodium sulfate, and concentrate. Purify the residue by flash column chromatography using 50% ethyl acetate/hexane as the eluent to give the title compound (302 mg, 50%). LC-MS (m/e): 426 (M−1)
Reaction SMILES: FC(F)(F)C([O-])=O.C(OC([NH:15][C@H:16]1[CH2:21][CH2:20][CH2:19][N+:18]([CH2:38][CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH2:48][C:49](=O)[N:50]([CH3:52])[CH3:51])=[CH:43][CH:42]=2)([CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33](=O)[N:34]([CH3:36])[CH3:35])=[CH:27][CH:26]=2)[CH2:17]1)=O)(C)(C)C.[ClH:54]>O1CCCC1>[ClH:54].[ClH:54].[Cl-:54].[NH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][N+:18]([CH2:22][CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][CH2:32][CH2:33][N:34]([CH3:35])[CH3:36])=[CH:29][CH:30]=2)([CH2:38][CH2:39][CH2:40][C:41]2[CH:42]=[CH:43][C:44]([O:47][CH2:48][CH2:49][N:50]([CH3:52])[CH3:51])=[CH:45][CH:46]=2)[CH2:17]1
Reactant: CN(C)C(=O)COc1ccc(CCC[N+]2(CCCc3ccc(OCC(=O)N(C)C)cc3)CCC[C@H](NC(=O)OC(C)(C)C)C2)cc1
Agent: Cl
Agent: O=C([O-])C(F)(F)F
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc(CCC[N+]2(CCCc3ccc(OCCN(C)C)cc3)CCCC(N)C2)cc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-3-tert-butoxycarbonylamino-1,1-bis-[3-(4-dimethylcarbamoylmethoxy-phenyl)-propyl]-piperidinium trifluoroacetate (150 mg, 0.2 mmol) is dissolved in tetrahydrofurane (2 ml) and 4 M HCl (2 ml), stirred at 50° C. for 30 minutes and concentrated in vacuo. The residue is dissolved in dioxane (10 ml), a solution of lithiumaluminumhydydride (200 μl, 0.2 mmol) is added and stirred at room temperature for 2 h. 1 M HCl (1 ml) is added to the reaction mixture and concentrated in vacuo. LC (method L): tR=0.63 min; Mass spectrum (ESI+): m/z=511 [M]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN[O:18][CH3:19].Cl.CCN(C(C)C)C(C)C.CN(C([O:37]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1([CH:13]([OH:15])[C:19]([OH:18])=[O:37])[CH2:10][CH2:11][CH2:12]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1(C(O)C(=O)O)CCC1
Yield: 87 %

Procedure:
To a solution of 1-tert-butoxycarbonylamino-cyclobutanecarboxylic acid (3 g, 13.94 mmol) in dry DMF (50 mL) was added N,O-dimethylhydroxylamine×HCl (1.36 g, 13.94 mmol) and DIEA (9.21 mL, 55.75 mmol). The reaction flask was cooled to 0° C. and after 10 minutes HATU (5.30 g, 13.94 mmol) was added to the solution (which turned yellow on addition). After 2 hrs the DMF was removed by rotary evaporation at reduced pressure. The residue was dissolved in EtOAc (100 mL) and washed twice with 10% citric acid (aq) and saturated NaHCO3(aq) solution. The organic phase was dried with Na2SO4, filtered and evaporated on silica. The product was purified by flash chromatography (heptane: ethyl acetate (1:1) to give the product as a colourless oil that slowly crystallizes (3.13 g) in 87% yield.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([O:25][CH2:26][CH3:27])[C:22](O)=[O:23])=[CH:16][CH:15]=2)[CH2:3][CH2:2]1.[CH3:28][NH2:29]>>[CH3:28][NH:29][C:22](=[O:23])[CH:21]([O:25][CH2:26][CH3:27])[CH2:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:12][CH2:11][N:4]2[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[O:1][CH2:2][CH2:3]2)=[CH:15][CH:16]=1
Reactant: CCOC(Cc1ccc(OCCN2CCOc3ccccc32)cc1)C(=O)O
Reactant: CN
Product: CCOC(Cc1ccc(OCCN2CCOc3ccccc32)cc1)C(=O)NC
Yield: 74 %

Procedure:
The title compound (0.23 g, 74%) was prepared as a white solid from 3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (0.3 g, 0.8 mmol) obtained in example 26 and methylamine (40% solution) ( 2 mL) by an analogous procedure to that described in example 32.mp: 97-99° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])[CH:15]=3)[CH:11]=[C:10]([C:30]([F:33])([F:32])[F:31])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][N:36]=1>>[F:27][C:26]([F:29])([F:28])[CH2:25][O:24][C:16]1[CH:15]=[C:14]([C:12]2[CH:11]=[C:10]([C:30]([F:33])([F:32])[F:31])[N:9]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:38]4[CH:37]=[N:36][C:35]([NH2:34])=[CH:40][CH:39]=4)[CH:7]=3)[N:13]=2)[CH:19]=[CH:18][C:17]=1[C:20]([F:23])([F:22])[F:21]
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: FC(F)(F)COc1cc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)ccc1C(F)(F)F
Product: Nc1ccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)c(OCC(F)(F)F)c4)cc(C(F)(F)F)n3)ccn2)cn1

Procedure:
The title compound was prepared from 2-(2-chloro-pyridin-4-yl)-4-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-6-trifluoromethyl-pyrimidine (example E.56) (0.25 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.13 g, 0.6 mmol) according to the general procedure VI. Obtained as a light brown solid (0.21 g, 77%). MS (ISP) 560.0 [(M+H)+]; mp 223° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[CH:7]=O.[N+:11]([CH2:14][CH3:15])([O-:13])=[O:12].C1(N)CCCCC1>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:7]=[C:14]([N+:11]([O-:13])=[O:12])[CH3:15])[CH:9]=1
Reactant: CC[N+](=O)[O-]
Reactant: Cc1ccc(F)cc1C=O
Solvent: CC(=O)O
Solvent: NC1CCCCC1
Product: CC(=Cc1cc(F)ccc1C)[N+](=O)[O-]
Temperature: 80 °C
Yield: 84.2 %

Procedure:
A mixture of 5-fluoro-2-methylbenzaldehyde (50.0 g, 0.382 mol), nitroethane (54.34 g, 0.724 mol), and cyclohexylamine (35.90 g, 0.382 mol) in 300 mL of acetic acid was heated at 80° C. for 5-6 h under an argon atmosphere. After the end of the reaction was established by TLC, the reaction mixture was cooled to rt and the solvent was removed under vacuum. The residue was diluted with water, extracted with ethyl acetate three times. The combined extracts were dried over anhydrous MgSO4, filtered, and concentrated under vacuum. Product was purified by a silica gel chromatography using ethyl acetate and hexanes (1:6 to 1:4) as eluent to afford 62.8 g (89%) of the designed compound as yellow solid. Mass (ESI, positive) m/z 217.9 [M+Na]+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([CH2:12]Br)[CH:3]=1.[CH:14]1([NH2:17])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:10][CH:11]=1)[C:6](=[O:8])[N:17]([CH:14]1[CH2:16][CH2:15]1)[CH2:12]2
Reactant: NC1CC1
Reactant: COC(=O)c1ccc(Br)cc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C1c2ccc(Br)cc2CN1C1CC1
Temperature: 40 °C
Reaction time: 3 h
Yield: 94.4 %

Procedure:
A mixture of methyl 4-bromo-2-(bromomethyl)benzoate (0.13 g, 0.42 mmol), cyclopropylamine (0.034 mL, 0.49 mmol) and potassium carbonate (0.090 g, 0.65 mmol) in ethanol (0.9 mL) was stirred at 40° C. for 3 h. The reaction mixture was quenched with saturated sodium bicarbonate and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by chromatography on silica gel with 30% EtOAc in hexanes to afford the desired product (0.10 g, 94%). LCMS: (M+H)=252.0/254.0.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]2[CH2:13][CH:12]3[N:14]([CH2:15][CH2:16][C:17]4([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]2[CH:29]=[CH:30][CH:31]=[CH:32][C:4]=2[N:3]=1.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:39](O[C:42](=[O:43])[C:34]=12)=[O:40].C([N:46](CC)CC)C.N.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH3:1][C:2]1[N:6]([CH:7]2[CH2:13][CH:12]3[N:14]([CH2:15][CH2:16][C:17]4([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH2:18][CH2:19][N:20]([C:42]([C:34]5[N:33]=[CH:38][CH:37]=[CH:36][C:35]=5[C:39]([NH2:46])=[O:40])=[O:43])[CH2:21][CH2:22]4)[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]2[CH:29]=[CH:30][CH:31]=[CH:32][C:4]=2[N:3]=1
Reactant: CCN(CC)CC
Reactant: O=C1OC(=O)c2ncccc21
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: ClCCl
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=O)c2ncccc2C(N)=O)CC1
Reaction time: 2 h
Yield: 73.7 %

Procedure:
To a stirred solution of 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole (51 mg, 0.12 mmol) in dichloro-methane (4 mL) was added 2,3-pyridinedicarboxylic anhydride (18 mg, 0.12 mmol) and triethylamine (17 μL, 0.12 mmol). The resulting mixture was stirred for 2 hours at ambient temperature before addition of ammonia (1 mL, 0.5 M in dioxane) and 47 mg of HATU. The reaction mixture was then stirred for another 2 hours. After being diluted with methylene chloride and washed with saturated sodium bicarbonate solution, the organic phase was dried over anhydrous sodium sulfate. Evaporation of the solvent and purification by flash chromatography afforded 2-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]nicotinamide as a foam (51 mg, 69%). 1H NMR (300 MHz, CDCl3) δ 8.63-8.61 (m, 1H), 8.17 (d, J=6.8 Hz, 1H), 7.66-7.64 (m, 2H), 7.38-7.33 (m, 3H), 7.30-7.22 (m, 4H), 7.20-7.10 (m, 2H), 5.79 (s, 1H), 4.61-4.55 (m, 1H), 4.27-4.22 (m, 1H), 3.40-3.08 (m, 5H), 2.54 (s, 3H), 2.47-2.33 (m, 3H), 2.19-2.15 (m, 1H), 1.97-1.80 (m, 10H), 1.63-1.61 (m, 2H). HRMS m/z (M+H)+ calcd: 577.3291, obsd: 577.3286.
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[O:7]=[C:8]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([O:37][CH3:38])[CH:35]=2)[N:30]=[CH:29][CH:28]=1)[CH2:9][CH2:10][C@@H:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][C@@H:12]1[CH2:24][CH:25]=[O:26].S([O-])([O-])=[O:40].[Na+].[Na+]>O.CC(C)=O>[O:7]=[C:8]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([O:37][CH3:38])[CH:35]=2)[N:30]=[CH:29][CH:28]=1)[CH2:9][CH2:10][C@@H:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:13][C@@H:12]1[CH2:24][C:25]([OH:40])=[O:26]
Reactant: COc1ccc2nccc(C(=O)CC[C@@H]3CCN(C(=O)OC(C)(C)C)C[C@@H]3CC=O)c2c1
Reactant: O=S([O-])[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc2nccc(C(=O)CC[C@@H]3CCN(C(=O)OC(C)(C)C)C[C@@H]3CC(=O)O)c2c1
Temperature: 10 °C
Reaction time: 3 h
Yield: 59.5 %

Procedure:
A solution of 0.85 g of potassium permanganate in 25 cm3 of water and 120 cm3 of acetone was added over approximately 1 hour, with stirring and at a temperature in the region of 25° C., to a solution of 1.2 g of (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]-1-(tert-butyloxycarbonyl)piperidine-3-acetaldehyde in 60 cm3 of acetone. The mixture was stirred for 3 hours at this same temperature and then cooled to approximately 10° C. A solution of 5 g of sodium sulfite in 200 cm3 of water was added to the reaction mixture and then the mixture obtained was filtered through celite. The acetone of the filtrate was evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. and then the evaporation residue was taken up in 200 cm3 of water and washed with 200 cm3 of diethyl ether. The aqueous phase was separated by settling, acidified with citric acid in the solid state to a pH in the region of 3-4 and extracted with 200 cm3 of diethyl ether. The ethereal solution, separated by settling, was dried over magnesium sulfate, filtered, and evaporated under the above conditions. 0.74 g of (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]-1-(tert-butyloxycarbonyl)piperidine-3-acetic acid was obtained in the form of a yellow solid.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[N:10]([C@@H:21]3[C:29]4[C:24](=[C:25]([F:31])[CH:26]=[C:27]([F:30])[CH:28]=4)[CH2:23][C@H:22]3[OH:32])[N:11]=[C:12]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])[C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[CH3:33][Si]([N-][Si](C)(C)C)(C)C.[Na+].IC>CN(C=O)C>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[N:10]([C@@H:21]3[C:29]4[C:24](=[C:25]([F:31])[CH:26]=[C:27]([F:30])[CH:28]=4)[CH2:23][C@H:22]3[O:32][CH3:33])[N:11]=[C:12]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])[C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(=O)N1CCc2c(c(-c3cccc(C#N)c3)nn2[C@@H]2c3cc(F)cc(F)c3C[C@H]2O)C1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CO[C@@H]1Cc2c(F)cc(F)cc2[C@H]1n1nc(-c2cccc(C#N)c2)c2c1CCN(C(C)=O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.1 %

Procedure:
According to Scheme 10: To a solution of 3-[5-acetyl-1-((1R,2R)-4,6-difluoro-2-hydroxy-indan-1-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (11t) (0.10 g, 0.276 mmol) in dry DMF (1 ml) at −10° C. NaHMDS (50 mg) was added. After 5 min iodomethane (39 mg, 0.276 mmol) was added and the mixture was allowed to warm to 25° C. After 90 min the mixture was cooled to −10° C. and the same amount of both NaHMDS and iodomethane was added again. After stirring overnight the mixture was purified by reverse phase HPLC (CH3CN/water gradient with 0.1% trifluoroacetic acid) to give 27 mg of 3-[5-acetyl-1-((1R,2R)-4,6-difluoro-2-methoxy-indan-1-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (16a). Rt=1.29 min (LC method 4). Detected mass: 449.32 [M+H+]
Reaction SMILES: [OH-:1].[K+].OO.[C:5]([N:9]1[C:13]([NH2:14])=[C:12]([C:15]#[N:16])[CH:11]=[N:10]1)([CH3:8])([CH3:7])[CH3:6]>O>[C:5]([N:9]1[C:13]([NH2:14])=[C:12]([C:15]([NH2:16])=[O:1])[CH:11]=[N:10]1)([CH3:8])([CH3:7])[CH3:6]
Reactant: [OH-]
Reactant: CC(C)(C)n1ncc(C#N)c1N
Agent: OO
Agent: [K+]
Solvent: O
Product: CC(C)(C)n1ncc(C(N)=O)c1N
Temperature: 0 °C
Reaction time: 4 h
Yield: 75.1 %

Procedure:
To a mixture of water (500 ml) and 85% KOH (37.91 g) at 0° C. was added 30% H2O2 (49.4 ml, 483 mmol), followed by 1-tert-butyl-5-amino-1H-pyrazole-4-carbonitrile (15.83 g, 96.5 mmol). The reaction mixture was stirred for four hours at 0° C. and then at room temperature for 1 hour. A yellow precipitate had formed which was collected by filtration and air dried to afford 13.2 g (75%) of 1-tert-butyl-5-amino-1H-pyrazole-4-carboxamide, m.p. 193°-195° C.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH2:20])[N:13]([C@@H:21]3[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]3)[N:12]=2)=[CH:7][CH:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[C:63]([CH2:65][C:66](O)=[O:67])#[N:64]>ClCCl>[NH2:20][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[N:13]([C@@H:21]3[CH2:26][CH2:25][CH2:24][N:23]([C:66](=[O:67])[CH2:65][C:63]#[N:64])[CH2:22]3)[N:12]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([O:4][C:3]4[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:2]=4[F:1])=[CH:10][CH:9]=3)[C:19]=12
Reactant: N#CCC(=O)O
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3cc(F)ccc3F)cc1)nn2[C@@H]1CCCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CCC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cc(F)ccc4F)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 10 h
Yield: 57.5 %

Procedure:
Into a 100 mL round-bottom flask, was placed a solution of 3-[4-(2,5-difluoro-phenoxy)phenyl]-1-[(3R)-piperidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (300 mg, 0.71 mmol, 1.00 equiv) in dichloromethane (30 mL), HATU (400 mg, 1.05 mmol, 1.5 equiv), triethylamine (220 mg, 2.17 mmol, 3.0 equiv), and 2-cyanoacetic acid (90 mg, 1.06 mmol, 1.5 equiv). The resulting solution was stirred for 10 h at 25° C. and then washed with water and brine and dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (10/1) to give 200 mg (58%) of 3-[(3R)-3-[4-amino-3-[4-(2,5-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-3-oxopropanenitrile as a white solid.
Reaction SMILES: C(O)CCC.C(O)C.O.N.[CH3:11][C@H:12]1[C@H:41]([CH3:42])[C@@H:40]2[C@@:15]([C:44]([O:46][C@@H:47]3[O:52][C@H:51]([CH2:53][O:54][C@@H:55]4[O:60][C@H:59]([CH2:61][OH:62])[C@@H:58]([O:63][C@@H:64]5[O:69][C@@H:68]([CH3:70])[C@H:67]([OH:71])[C@@H:66]([OH:72])[C@H:65]5[OH:73])[C@H:57]([OH:74])[C@H:56]4[OH:75])[C@@H:50]([OH:76])[C@H:49]([OH:77])[C@H:48]3[OH:78])=[O:45])([CH2:16][CH2:17][C@:18]3([CH3:43])[C@:23]4([CH3:39])[CH2:24][C@@H:25](O)[C@H:26]5[C@@:31]([CH2:33][OH:34])([CH3:32])[C@@H:30]([OH:35])[C@H:29]([OH:36])[CH2:28][C@:27]5([CH3:37])[C@H:22]4[CH2:21][CH:20]=[C:19]32)[CH2:14][CH2:13]1>O>[CH3:11][C@H:12]1[C@H:41]([CH3:42])[C@@H:40]2[C@@:15]([C:44]([O:46][C@@H:47]3[O:52][C@H:51]([CH2:53][O:54][C@@H:55]4[O:60][C@H:59]([CH2:61][OH:62])[C@@H:58]([O:63][C@@H:64]5[O:69][C@H:68]([CH3:70])[C@H:67]([OH:71])[C@@H:66]([OH:72])[C@H:65]5[OH:73])[C@H:57]([OH:74])[C@H:56]4[OH:75])[C@@H:50]([OH:76])[C@H:49]([OH:77])[C@H:48]3[OH:78])=[O:45])([CH2:16][CH2:17][C@@:18]3([CH3:43])[C@:23]4([CH3:39])[CH2:24][CH2:25][C@H:26]5[C@@:31]([CH2:33][OH:34])([CH3:32])[C@@H:30]([OH:35])[C@H:29]([OH:36])[CH2:28][C@:27]5([CH3:37])[C@H:22]4[CH2:21][CH:20]=[C:19]32)[CH2:14][CH2:13]1
Reactant: C[C@H]1[C@H](C)CC[C@]2(C(=O)O[C@@H]3O[C@H](CO[C@@H]4O[C@H](CO)[C@@H](O[C@@H]5O[C@@H](C)[C@H](O)[C@@H](O)[C@H]5O)[C@H](O)[C@H]4O)[C@@H](O)[C@H](O)[C@H]3O)CC[C@@]3(C)C(=CC[C@@H]4[C@@]5(C)C[C@@H](O)[C@H](O)[C@@](C)(CO)[C@@H]5[C@H](O)C[C@]43C)[C@H]12
Agent: N
Solvent: CCCCO
Solvent: O
Solvent: CCO
Product: C[C@H]1[C@H](C)CC[C@]2(C(=O)O[C@@H]3O[C@H](CO[C@@H]4O[C@H](CO)[C@@H](O[C@@H]5O[C@H](C)[C@H](O)[C@@H](O)[C@H]5O)[C@H](O)[C@H]4O)[C@@H](O)[C@H](O)[C@H]3O)CC[C@]3(C)C(=CC[C@@H]4[C@@]5(C)C[C@@H](O)[C@H](O)[C@@](C)(CO)[C@@H]5CC[C@]43C)[C@H]12

Procedure:
A silica gel (70-230 mesh) was filled in a column with a diameter of 6 cm and a length of 26 cm by using a mobile phase (normal butanol:ethanol:ammonia water:water=60:40:5:10). Thereafter, 1 g of WS-TECA was dissolved in as little amount of the mobile phase as possible and loaded thereon. The mobile phase was allowed to flow at a constant rate and fractionated in 25 ml bottles to obtain 400 mg of pure asiaticoside and madecassoside each.
Reaction SMILES: [C:1]([S:4][CH:5]([CH2:9][C:10](=[O:25])[C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].[OH-].[Na+:27].C(OCC)C>C(O)C>[C:1]([S:4][CH:5]([CH2:9][C:10](=[O:25])[C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)[C:6]([O-:8])=[O:7])(=[O:3])[CH3:2].[Na+:27]
Reactant: CC(=O)SC(CC(=O)c1ccc(Oc2ccc(C)cc2)cc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: CC(=O)SC(CC(=O)c1ccc(Oc2ccc(C)cc2)cc1)C(=O)[O-]
Yield: 799.1 %

Procedure:
3.58 g of 2-acetylthio-3-[4-(4-methylphenoxy)benzoyl]-propionic acid were dissolved in 50 ml of ethanol, then a solution of 0.04 g of sodium hydroxide in 10 ml of ethanol was added dropwise, under ice-cooling and with stirring. The mixture was stirred at the same temperature for a further one hour. 20 ml of diethyl ether were added to the reaction mixture and the precipitate was collected by filtration, then washed with diethyl ether, to give 3.04 g of sodium 2-acetylthio-3-[4-(4-methylphenoxy)benzoyl]propionate.
Reaction SMILES: [CH:1]1([N:7]2[CH2:16][C:15]3[C:10](=[N:11][C:12](S(C)(=O)=O)=[N:13][CH:14]=3)[N:9]([CH3:21])[C:8]2=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:23]([N:25]([CH2:36][CH3:37])[CH2:26][CH2:27][O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)[CH3:24]>>[CH:1]1([N:7]2[CH2:16][C:15]3[C:10](=[N:11][C:12]([NH:33][C:32]4[CH:31]=[CH:30][C:29]([O:28][CH2:27][CH2:26][N:25]([CH2:36][CH3:37])[CH2:23][CH3:24])=[CH:35][CH:34]=4)=[N:13][CH:14]=3)[N:9]([CH3:21])[C:8]2=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN(CC)CCOc1ccc(N)cc1
Reactant: CN1C(=O)N(C2CCCCC2)Cc2cnc(S(C)(=O)=O)nc21
Product: CCN(CC)CCOc1ccc(Nc2ncc3c(n2)N(C)C(=O)N(C2CCCCC2)C3)cc1
Temperature: 180 °C
Yield: 17.8 %

Procedure:
A mixture of 100 mg (0.31 mmol) of 3-cyclohexyl-7-methanesulfonyl-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2-(1H)-one and 400 mg (1.9 mmol) of 4-[2-(diethylamino)ethoxy]aniline was heated at 180° C. for 35 minutes and then cooled. The residue was chromatographed on silica gel using dichloromethane/methanol/acetic acid/water (240:24:3:2) for the elution. Product-containing fractions were combined and evaporated. The residue was evaporated with toluene and then dissolved in 40 ml of dichloromethane. The solution was washed with 40 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. The residue was triturated in hexane, filtered off and dried to give 25 mg (18%) 3-cyclohexyl-7-[4-[2-(diethylamino)ethoxy]anilino]-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 90-92° C.