Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11](=O)[C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[C:13]=1[F:26].B.O>C1COCC1>[F:1][C:2]1[C:3]([NH:10][CH2:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)[C:13]=2[F:26])=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: Cc1cc(C(=O)Nc2c(F)ccc(O)c2F)c(F)c(-c2cccc(F)c2)c1
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(CNc2c(F)ccc(O)c2F)c(F)c(-c2cccc(F)c2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
To a solution of N-(2,6-difluoro-3-hydroxy-phenyl)-2-fluoro-3-(3-fluorophenyl)-5-methyl-benzamide (130 mg, 0.30 mmol, 1.0 eq) in THF (25 mL) was added dropwise a solution of borane (1M in THF, 1.2 mL, 1.2 mmol, 4 eq) under N2. The reaction was heated at 60° C. overnight. TLC showed the reaction was not complete so further borane (1 M in THF, 1.0 mL, 1 mmol) was added and heating continued at 60° C. for 2 h. The mixture was poured into water and extracted with EtOAc and the combined organic extracts washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by chromatography (EtOAc:petroleum ether, 0:1 to 1:4) to give the title compound as an oil (100 mg, 80%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)=[CH:4][NH:5][CH:6]=1.[C:17](N1C=CN=C1)(=[O:19])[CH3:18]>>[C:17]([N:5]1[CH:6]=[C:2]([Cl:1])[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:14])[F:15])[CH:8]=2)=[CH:4]1)(=[O:19])[CH3:18]
Reactant: CC(=O)n1ccnc1
Reactant: FC(F)(F)c1cccc(-c2c[nH]cc2Cl)c1
Product: CC(=O)n1cc(Cl)c(-c2cccc(C(F)(F)F)c2)c1
Reaction time: 1.5 h
Yield: 68.3 %

Procedure:
The mixture of 1 g of 4-chloro-3-(3-trifluoromethylphenyl)pyrol and 2 g of N-acetylimidazole was fused for 1.5 hours at 140°-150° C. The resulding reaction mixture was purified by silicagel chloromatography using 10% solution of aceton in n-hexane as solvent to obtain 0.8 g of the desired product (pale reddish brown crystal, m.p. 70°-71.5° C.).
Reaction SMILES: Cl[S:2]([C:5]1[CH:23]=[CH:22][C:8]2[N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])[C:10]([CH3:12])=[N:11][C:7]=2[CH:6]=1)(=[O:4])=[O:3].ClS(C1C=CC2N=C(C)[N:33](CC3C=CC(Cl)=CC=3Cl)C=2C=1)(=O)=O>N>[NH2:33][S:2]([C:5]1[CH:23]=[CH:22][C:8]2[N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])[C:10]([CH3:12])=[N:11][C:7]=2[CH:6]=1)(=[O:4])=[O:3]
Reactant: Cc1nc2cc(S(=O)(=O)Cl)ccc2n1Cc1ccc(Cl)cc1Cl
Reactant: Cc1nc2ccc(S(=O)(=O)Cl)cc2n1Cc1ccc(Cl)cc1Cl
Agent: N
Product: Cc1nc2cc(S(N)(=O)=O)ccc2n1Cc1ccc(Cl)cc1Cl

Procedure:
The mixture of 5-chlorosulfonyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole and 6-chlorosulfonyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole, which is obtained in Example 285, is immediately processed with a 25% aqueous ammonia (100 ml) for one hour at room temperature. Separation of solids through filtration produced a 1/1 mixture (2.68 g) of 5-aminosulfonyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole and 6-aminosulfonyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole. 1H-NMR (CD3OD, δ): 2.52 (3/2H, s), 2.54 (3/2H, s), 5.54 (2H, s), 6.55 (1H, d, J=6.9 Hz), 7.17 (1H, d, J=8.0 Hz), 7.52 (1H, s), 7.65-7.78 (2H, m), 7.82 (1/2H, s), 8.11 (1/2H, s).
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.O.[Cl:16][CH2:17][C:18]([CH3:20])=[CH2:19]>ClCCl>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([C:18]([CH3:20])([CH3:19])[CH2:17][Cl:16])[CH:8]=1
Reactant: C=C(C)CCl
Reactant: COc1ccc(Br)cc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: COc1ccc(Br)cc1C(C)(C)CCl

Procedure:
Sulfuric acid (2 mL, 0.033 mol) was added dropwise under argon to 4-bromoanisole (14.6 mL, 0.117 mol). The mixture was warmed to 40–43° C. (warm water bath) and 3-chloro-2-methyl propene was added dropwise in 4 equal portions over 2 hrs. After 2 hrs at 40–43° C. the solution was diluted with dichloromethane and washed successively with water, saturated aqueous NaHCO3, water and brine, dried (Mg2SO4), filtered and evaporated. The residue was crystallized from hexanes to give 14.1 g of 4-bromo-2-(2-chloro-1,1-dimethyl-ethyl)-1-methoxy-benzene. The mother liquor was further purified on silica gel (10% ethyl acetate in hexane) to afford additional 4.8 g of product. 58% yield. 1H NMR (300 MHz; CDCl3): δ 1.43 (s, 6 H), 3.82 (s, 3 H), 3.93 (s, 2 H), 6.75 (dd, J=2.4 Hz and 7.2 Hz, 1 H), 7.32 (m, 2 H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3[CH:13]=[C:14]([NH:19][C:20](=[O:26])[CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]2([CH3:28])[CH3:27])=[CH:4][CH:3]=1.C([Li])CCC.CN([CH:37]=[O:38])C.O>C1COCC1>[CH:37]([C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3[CH:13]=[C:14]([NH:19][C:20](=[O:26])[CH2:21][C:22]([CH3:23])([CH3:24])[CH3:25])[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]2([CH3:28])[CH3:27])=[CH:4][CH:3]=1)=[O:38]
Reactant: CN(C)C=O
Reactant: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.9 %

Procedure:
To a solution of N-(3-(4-bromophenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (500 mg, 1.13 mmol) obtained in Example 284 in THF (10 mL) was added dropwise at −78° C. under an argon atmosphere n-butyllithium (1.59 M hexane solution, 1.56 mL, 2.48 mmol), and the mixture was stirred for 30 minutes. DMF (90 mg, 1.24 mmol) was added to the reaction solution at the same temperature, and the mixture was stirred for 30 minutes, warmed to room temperature, and stirred for 1 hour. Water was added to the reaction solution and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:3) and recrystallized from ethyl acetate-hexane to obtain 204 mg (yield: 46%) of the title compound. Melting point: 169-170° C.
Reaction SMILES: Br[C:2]1[C:11]([F:12])=[C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[C:9]([F:20])=[C:8]2[C:3]=1[C:4](=[O:29])[C:5]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:6][N:7]2[CH:21]1[CH2:23][CH2:22]1.C([Sn](C#[C:44][Si:45](C)([CH3:47])[CH3:46])(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:21]1([N:7]2[C:8]3[C:3](=[C:2]([Si:45]([CH3:47])([CH3:46])[CH3:44])[C:11]([F:12])=[C:10]([N:13]4[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]4)[C:9]=3[F:20])[C:4](=[O:29])[C:5]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:6]2)[CH2:23][CH2:22]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(N3CCN(C)CC3)c(F)c(Br)c2c1=O
Reactant: CCCC[Sn](C#C[Si](C)(C)C)(CCCC)CCCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(N3CCN(C)CC3)c(F)c([Si](C)(C)C)c2c1=O
Yield: 58.1 %

Procedure:
1.1 g of ethyl 5-bromo-1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylate, 1.2 g of tributylstannyl-trimethylsilyl-acetylene and 0.135 g of tetrakis(triphenylphosphine)-palladium(0) are refluxed for 3 hours in 10 ml of absolute toluene. The reaction mixture is treated with a further 5 ml of toluene and filtered while hot. The product crystallizes out of the filtrate. After filtration with suction and drying, 0.63 g of the title compound is obtained (56% of theory).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14](O)=[O:15])=[CH:11][CH:12]=2)[CH:7]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:6][CH:5]1[CH3:30])(=[O:3])[CH3:2].Cl.C1C=CC2N(O)[N:39]=[N:38]C=2C=1.O.NN.C(=O)([O-])O.[Na+]>ClCCl.O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH:38][NH2:39])=[O:15])=[CH:11][CH:12]=2)[CH:7]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)=[CH:20][CH:19]=2)[CH2:6][CH:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(C(=O)O)cc2C(Nc2ccc(N3CCOCC3)cc2)CC1C
Reactant: On1nnc2ccccc21
Agent: Cl
Agent: NN
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1c2ccc(C(=O)NN)cc2C(Nc2ccc(N3CCOCC3)cc2)CC1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
[Step 4] 102 mg of 1-acetyl-4-[(4-morpholinophenyl)amino]-2-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid, 125 mg of WSCD.HCl, and 72 mg of HOBt.H2O were dissolved in 1 mL of dichloromethane, and 0.12 mL of hydrazine monohydrate was added to the solution. The mixture was stirred overnight at room temperature. After completion of the reaction, a saturated aqueous solution of sodium hydrogen carbonate was added to the mixture, and the mixture was extracted three times with chloroform. The extraction product was washed with saturated brine, dehydrated over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by using silica gel chromatography (methanol:chloroform=1:10), and thus 83 mg (cis:trans=3:1, 79) of the title compound was obtained as a brown oily substance.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[C:4]([CH3:13])([CH3:12])[CH:3]1[CH3:14].[N+:16]([O-])([OH:18])=[O:17].S(=O)(=O)(O)O>C(O)(=O)C>[CH3:1][C:2]1([CH3:15])[C:10]2[C:5](=[CH:6][C:7]([N+:16]([O-:18])=[O:17])=[C:8]([CH3:11])[CH:9]=2)[C:4]([CH3:13])([CH3:12])[CH:3]1[CH3:14]
Reactant: Cc1ccc2c(c1)C(C)(C)C(C)C2(C)C
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1cc2c(cc1[N+](=O)[O-])C(C)(C)C(C)C2(C)C
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
To a 500 ml reaction vessel equipped with stirrer, thermometer, reflux condensor, addition funnel and cooling bath is placed 51 grams of 1,1,2,3,3,6-hexamethyl indane having the structure: ##STR40## (51 grams) in admixture with 100 grams of acetic acid. The resulting mixture is cooled to 10° C. Over a period of 0.5 hours, 40 grams of fuming nitric acid is added to the reaction mass, while maintaining the reaction mass at 10° C. Over a period of 10 minutes, 10 grams of concentrated sulfuric acid is then added to the reaction mass. The reaction mass is then heated to 25° C. and maintained at 25° C. for a period of 3.5 hours. At the end of the 3.5 hour period, the reaction mass is quenched with ice water (500 ml) and crystals are formed. The crystals are then re-crystallized from water. The melting point of the resulting crystals is 115.7° C. NMR, IR and mass spectral anaylses yield the information that the compound has the structure: ##STR41##
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[N:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10](Cl)=[O:11])[CH:2]=1.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[CH:22]=[N:23][NH2:24]>C1COCC1.CCN(CC)CC>[F:17][C:18]([F:28])([F:29])[C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[CH:22]=[N:23][NH:24][C:10]([C:9]1[C:8]([O:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:16][CH:15]=[CH:14][CH:13]=1)=[O:11]
Reactant: NN=Cc1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)c1cccnc1Oc1cccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NN=Cc1cccc(C(F)(F)F)c1)c1cccnc1Oc1cccnc1
Yield: 55 %

Procedure:
To a stirred solution of 2-(pyridin-3-yloxy)-nicotinic acid (0.432 g, 2.0 mmol) in THF (15 mL) at 0° C. was added oxalylchloride (2 mL, 2M in CH2Cl2, 4.0 mmol) dropwise. The solution was stirred at room temperature for 3 h. The solvent was evaporated in vacuo to yield 2-(pyridin-3-yloxy)-nicotinoyl chloride as a solid. To a solution of 2-(pyridin-3-yloxy)-nicotinoyl chloride in 15 mL THF was added 3-trifluoromethyl-benzylidene-hydrazine (0.376 g, 2.0 mmol) in 5 mL THF and 1 mL Et3N at 0° C. The reaction mixture was refluxed for 6 h and the solvent was evaporated. The residue was purified by chromatography with EtOAc:hexanes, 1:2, yielding (0.425 g, 55%) of the title compound. 1H NMR (DMSO-d6): 12.20 (s, 1H), 8.70 (s, 1H), 8.37 (s, 1H), 8.24 (s, 1H), 8.21 (d, J=7.8 Hz, 1H), 8.01 (d, J=7.5 Hz, 1H), 7.90 (m, 2H), 7.78 (t, J=7.8 Hz, 1H), 7.41 (m, 2H), 6.43 (m, 2H).
Reaction SMILES: [NH3:1].C1COCC1.Cl[C:8]1[C:9]2[N:10]([C:14]([CH:18]3[CH2:21][CH:20]([N:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[CH2:19]3)=[N:15][C:16]=2[I:17])[CH:11]=[CH:12][N:13]=1>C(O)(C)C>[I:17][C:16]1[N:15]=[C:14]([CH:18]2[CH2:21][CH:20]([N:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[CH2:19]2)[N:10]2[CH:11]=[CH:12][N:13]=[C:8]([NH2:1])[C:9]=12
Reactant: CN1CCN(C2CC(c3nc(I)c4c(Cl)nccn34)C2)CC1
Reactant: N
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CN1CCN(C2CC(c3nc(I)c4c(N)nccn34)C2)CC1
Temperature: -78 °C

Procedure:
A solution of 2N ammonia in isopropyl alcohol (350 mL) and THF (30 mL, 0.4 mol) was added to 8-chloro-1-iodo-3-[3-(4-methyl-piperazin-1-yl)-cyclobutyl]-imidazo[1,5-a]pyrazine (19.91 g, 0.04612 mol) in a Parr bomb and cooled to −78° C. Ammonia was bubbled into the solution for 8-10 min. The bomb was sealed, stirred and heated to at 110° C. over 3 d. The solvent was then evaporated in vacuo and purified by flash silica gel chromatography (wetted with CHCl3, dried loaded with silica, and eluted with 8% (7N NH3) MeOH in CHCl3), which afforded the title compound; 1H NMR (CDCl3, 400 MHz) δ 7.31 (1H, d, J=5.01), 7.16 (1H, d, J=6.25), 5.83 (2H, s), 3.49 (1H, m), 3.06 (1H, m), 2.76 (4H, m), 2.64 (8H, m), 2.46 (3H, s); MS (ES+): m/z 412.89/413.91 (50/10) [MH+]; HPLC: tR=0.31 min. (OpenLynx, polar—5 min.).
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[N:11]=[CH:10][C:9]([CH:12]([CH:18]([CH3:20])[CH3:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[ClH:27]>O>[Cl:27][C:6]1[N:11]=[CH:10][C:9]([CH:12]([CH:18]([CH3:20])[CH3:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][N:7]=1
Reactant: CCOC(=O)C(c1cnc(N)nc1)C(C)C
Reactant: Cl
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)C(c1cnc(Cl)nc1)C(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of sodium nitrite (1.33 gm) in water (5 cm3) was added dropwise to a cooled solution of ethyl (RS)-2-(2-aminopyrimidin-5-yl)-3-methylbutanoate (1.08 g) in concentrated aqueous hydrochloric acid solution (14.5 cm3), the temperature of the reaction mixture being maintained at less than 5° C. during the addition. The mixture was stirred at 0° C. for 3 hours, then allowed to warm to the ambient temperature and stood for 16 hours. The mixture was then cooled in an ice bath and neutralised by dropwise addition of aqueous potassium carbonate solution (the temperature of the mixture being maintained below 4° C.). The products were extracted into dichloromethane, the organic layers being washed with water and dried over anhydrous magnesium sulphate. Removal of the solvent by evaporation under reduced pressure gave a mixture of two products which was separated by column chromatography on a silica gel support, eluting firstly with dichloromethane containing 2% by volume ethyl acetate to give ethyl (RS)-2-(2-chloropyrimidin-5-yl)- 3-methylbutanoate (0.27 g), Product A, and secondly with dichloromethane containing 10% by volume methanol to give ethyl (RS)-2-(pyrimidin-2-one-5-yl)-3-methylbutanoate, (0.34 g), Product B.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([NH:8][C:9]2[N:14]=[CH:13][N:12]=[C:11]3[NH:15][N:16]=[CH:17][C:10]=23)[CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:39][C:40]1[CH:41]=[C:42]([NH:47][CH2:48][C:49](O)=[O:50])[CH:43]=[C:44]([Cl:46])[CH:45]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[NH:15]1[C:11]2=[N:12][CH:13]=[N:14][C:9]([NH:8][CH:3]3[CH2:4][CH2:5][CH2:6][CH2:7][N:1]([C:49](=[O:50])[CH2:48][NH:47][C:42]4[CH:41]=[C:40]([Cl:39])[CH:45]=[C:44]([Cl:46])[CH:43]=4)[CH2:2]3)=[C:10]2[CH:17]=[N:16]1
Reactant: O=C(O)CNc1cc(Cl)cc(Cl)c1
Reactant: c1nc(NC2CCCCNC2)c2cn[nH]c2n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CNc1cc(Cl)cc(Cl)c1)N1CCCCC(Nc2ncnc3[nH]ncc23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.1 %

Procedure:
To a solution of N-(azepan-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (200 mg, 0.862 mmol) in DMF (4 mL) was added EDCI (196 mg, 1.03 mmol), HOBt (139 mg, 1.03 mmol), 2-(3,5-dichlorophenylamino)acetic acid (189 mg, 0.862 mmol) and DIEA (0.22 mL, 1.29 mmol) at 0° C. The reaction mixture was stirred overnight at rt, diluted with EtOAc (100 mL) and washed with water (50 mL). The organic layer was dried over Na2SO4 and evaporated in vacuo to give the crude compound that purified by column chromatography (silica gel, gradient MeOH in CH2Cl2) to afford the titled compound (150 mg, 40%). 1H NMR (DMSO-d6, 400 MHz): δ 13.49-13.36 (m, 1H), 8.27-7.96 (m, 2H), 6.74 (s, 1H), 6.67 (s, 1H), 6.62 (s, 1H), 6.34 (s, 1H), 4.50-4.30 (m, 1H), 4.08-3.8 (m, 5H), 3.36 (m, 2H), 1.8-2.2 (m, 2H), 1.8-1.35 (m, 2H), 1.3-1.1 (m, 2H), LCMS: m/z [M+1]=434 & [M+23]=456.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][N:24]([C:30](=[O:32])[CH3:31])[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.CO.[OH-].[Na+]>C1COCC1.C(Cl)Cl.Cl>[C:30]([N:24]([CH2:23][C:14]1[CH:15]=[C:16]([C:19]([F:20])([F:22])[F:21])[CH:17]=[CH:18][C:13]=1[C:7]1[C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([OH:33])=[O:2])[CH:6]=1)[CH2:25][C:26]([CH3:28])([CH3:29])[CH3:27])(=[O:32])[CH3:31]
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC(C)(C)C)C(C)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(CC(=O)O)cc1-c1ccc(C(F)(F)F)cc1CN(CC(C)(C)C)C(C)=O

Procedure:
(2′-{[Acetyl-(2,2-dimethyl-propyl)-amino]-methyl}-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.152 g, 0.33 mmol) was dissolved in THF (1.5 mL), MeOH (1.2 mL), and aqueous 1N NaOH (0.72 mL), and the mixture was stirred at room temperature for 4 hours. Once no starting material was seen by analytical LCMS, the mixture was diluted with CH2Cl2 and aqueous 1N HCl, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [CH2:1]([N:5]1[C:13](=[O:14])[C:12]2[N:11]([CH2:15][CH:16]=[CH2:17])[C:10]([C:18]([O:20]C)=[O:19])=[N:9][C:8]=2[N:7]([CH2:22][CH2:23][CH2:24][CH3:25])[C:6]1=[O:26])[CH2:2][CH2:3][CH3:4].[Li+].[OH-].Cl.CCOC(C)=O>CO.O>[CH2:1]([N:5]1[C:13](=[O:14])[C:12]2[N:11]([CH2:15][CH:16]=[CH2:17])[C:10]([C:18]([OH:20])=[O:19])=[N:9][C:8]=2[N:7]([CH2:22][CH2:23][CH2:24][CH3:25])[C:6]1=[O:26])[CH2:2][CH2:3][CH3:4]
Reactant: C=CCn1c(C(=O)OC)nc2c1c(=O)n(CCCC)c(=O)n2CCCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: C=CCn1c(C(=O)O)nc2c1c(=O)n(CCCC)c(=O)n2CCCC
Yield: 85 %

Procedure:
A stirred solution of methyl 1,3-dibutyl-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-purine-8-carboxylate (1.30 g, 3.6 mmol) in MeOH (15 ml) was treated with LiOH (215 mg) and water (1.5 ml). After 3 hours at rt the mixture was diluted with water and the pH adjusted to ca. pH5 with 2M HCl(aq). EtOAc was added and then separated, washed with brine, dried (MgSO4) and concentrated to afford the title compound as a yellow solid 85% pure (1.2 g, 88%). m/z. 349.2 [MH+].
Reaction SMILES: [OH-].[Na+].C1COCC1.CO.[OH:10][CH:11]([CH2:32][OH:33])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=2)=[CH:16][CH:15]=1>C(O)(=O)C>[OH:10][CH:11]([CH2:32][OH:33])[CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]#[C:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:30][CH:31]=2)=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc(C#Cc2ccc(OCC(O)CO)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: O=C(O)c1ccc(C#Cc2ccc(OCC(O)CO)cc2)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 90.9 %

Procedure:
A 10% aqueous solution (5.5 mL) of sodium hydroxide was added to a THF (25 mL)-MeOH (15 mL) solution of methyl 4-{[4-(2,3-dihydroxypropoxy)phenyl]ethynyl}benzoate (0.92 g) as obtained in Example 11-(1), and the mixture was stirred for 3.5 hours at room temperature. Then, acetic acid (1.2 mL) was added for neutralization. The reaction mixture was concentrated, and water was added. The precipitated solid was filtered off and dried to obtain 4-{[4-(2,3-dihydroxypropoxy)phenyl]ethynyl}benzoic acid (light green solid) (0.80 g, 91%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C(N=C=NCCCN(C)C)C.[CH3:19][O:20][C:21]1[C:22](=[O:49])[C:23]([CH3:48])=[C:24]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[C:35]([CH:39]=2)[C:36](O)=[O:37])[C:25](=[O:29])[C:26]=1[O:27][CH3:28]>C(Cl)Cl>[CH3:19][O:20][C:21]1[C:22](=[O:49])[C:23]([CH3:48])=[C:24]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:40][CH2:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[C:35]([CH:39]=2)[C:36]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:37])[C:25](=[O:29])[C:26]=1[O:27][CH3:28]
Reactant: C1CCNCC1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OCc3ccccc3)c(C(=O)O)c2)=C(C)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OCc3ccccc3)c(C(=O)N3CCCCC3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 43.3 %

Procedure:
Piperidine (0.025 g, 0.296 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.068 g, 0.355 mmol) were added to a methylene chloride solution (5 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-benzyloxybenzoic acid (0.050 g, 0.118 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) to obtain the titled compound (0.025 g, 0.0511 mmol, 43%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:19]=3[C:11]=2[CH2:10][CH2:9][NH:8][CH:7]=1)=[O:5])[CH3:2].[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1.FC1C=C(C=CC=1F)C(Cl)=O>>[CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([O:20][CH2:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:19]=3[C:11]=2[CH2:10][CH2:9][N:8]([C:33](=[O:34])[C:32]2[CH:36]=[CH:37][C:29]([F:28])=[CH:30][CH:31]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=CNCCc2c1[nH]c1cccc(OCc3ccccc3)c21
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: O=C(Cl)c1ccc(F)c(F)c1
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1cccc(OCc3ccccc3)c21

Procedure:
In a manner similar to Step A, but replacing ethyl 1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate with 10-benzyloxy-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester and 4-fluorobenzoyl chloride with 3,4-difluorobenzoyl chloride, the following compound was prepared: