Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]([CH2:14][CH3:15])[C:12](=[O:16])[CH2:11][N:10]=[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:8]=2[CH:24]=1)(=O)[CH3:2].Cl.[NH2:26][OH:27]>N1C=CC=CC=1.C(O)C.C(Cl)Cl>[CH2:14]([N:13]1[C:7]2[CH:6]=[CH:5][C:4]([C:1](=[N:26][OH:27])[CH3:2])=[CH:24][C:8]=2[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])=[N:10][CH2:11][C:12]1=[O:16])[CH3:15]
Reactant: NO
Reactant: CCN1C(=O)CN=C(c2ccccc2F)c2cc(C(C)=O)ccc21
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCN1C(=O)CN=C(c2ccccc2F)c2cc(C(C)=NO)ccc21
Reaction time: 4 h

Procedure:
A solution of 13.0 g (40.1 mmol) of 7-acetyl-1-ethyl-5-(o-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one and 13.0 g of hydroxylamine hydrochloride in 65 ml of pyridine and 65 ml of ethanol is left to stand at room temperature for 4 hours. The mixture is taken up in methylene chloride, washed with 2 N hydrochloric acid and water, dried and evaporated. Traces of pyridine are removed by azeotropic evaporation with toluene. The residue gives, from methylene chloride/hexane, 1-ethyl-5-(o-fluorophenyl)-1,3-dihydro-7-[1-(hydroxyimino)ethyl]-2H-1,4-benzodiazepin-2-one of melting point 236°-238°.
Reaction SMILES: C(OC([N:8]1[C:16]2[CH2:15][CH2:14][N:13]([CH:17]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])([CH3:25])[CH3:24])[CH2:12][C:11]=2[CH:10]=[CH:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH2:29]([O:28][C:26](=[O:27])[C:23]([CH3:25])([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH:17]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[Cl:37])[N:13]1[CH2:14][CH2:15][C:16]2[NH:8][CH:9]=[CH:10][C:11]=2[CH2:12]1)[CH3:30]
Reactant: CCOC(=O)C(C)(C)CCCCCC(c1ccccc1Cl)N1CCc2c(ccn2C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)(C)CCCCCC(c1ccccc1Cl)N1CCc2[nH]ccc2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
5-[1-(2-Chlorophenyl)-7-ethoxycarbonyl-7-methyloctyl]-4,5,6,7-tetrahydropyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (0.12 g, 0.23 mmol) was dissolved in dichloromethane (5 mL) with stirring under an argon atmosphere. TFA (0.48 mL, 4.75 mmol) was added to the solution. After 1 hour, TLC showed the starting material was gone. The mixture was poured into ice cold water (50 mL) and extracted with dichloromethane (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, ethyl acetate/heptane=1/9 to 1/3) to afford 8-(2-chlorophenyl)-2,2 dimethyl-8-(1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-yl)-octanoic acid ethyl ester (Compound Ir, 65 mg, 65.9% yield) as a yellow oil. 1H NMR (Field: 300 MHz, Solvent: CD3OD/TMS) δ (ppm): 7.80 (s, 1H), 7.54 (d, 1H, J=7.5 Hz), 7.37 (d, 1H, J=7.8 Hz), 7.26-7.16 (m, 2H), 6.60 (s, 1H), 5.94 (s, 1H), 4.17 (m, 1H), 4.08 (q, 2H, J=7.2 Hz), 3.75 (d, 1H, J=13.2 Hz), 3.35 (d, 1H, J=13.2 Hz), 2.83-2.57 (m, 4H), 2.01-1.56 (m, 4H), 1.45-1.40 (m, 2H), 1.21 (t, 3H, J=7.2 Hz), 1.24-1.11 (m, 4H), 1.11 (s, 6H). 13C NMR (Field: 75 MHz, Solvent: CDCl3/TMS) δ (ppm): 178.14, 140.07, 134.95, 129.43, 129.25, 127.82, 126.79, 125.12, 116.43, 115.93, 105.80, 63.89, 60.37, 48.79, 48.32, 42.37, 40.94, 33.34, 30.64, 25.55, 25.41, 25.08, 24.07, 14.56. HRMS (HR, DART-TOF): Calculated for C25H35ClN2O2 (M+H)+: 431.2460. found 431.2476.
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([Cl:12])[CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:37][N:38]1[CH2:43][CH2:42][CH:41]([NH2:44])[CH2:40][CH2:39]1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([NH:44][CH:41]2[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]2)=[O:8])=[C:4]([Cl:12])[CH:3]=1
Reactant: O=C(O)c1cc(F)c(Br)cc1Cl
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(NC(=O)c2cc(F)c(Br)cc2Cl)CC1
Reaction time: 8 h
Yield: 72.2 %

Procedure:
4-bromo-2-chloro-5-fluoro-benzoic acid (Apollo Scientific; 5.0 g, 19.8 mmol) was added to DMF (250 mL), to this was added HBTU (9.8 g, 25.7 mmol), N-methyl-4-aminopiperidine (Fluorochem; 2.5 g, 21.8 mmol) and DIPEA (7.0 mL, 39.5 mmol). The reaction was stirred overnight, evaporated to dryness, quenched with 2.0 N NaOH (100 mL), extracted with DCM (3×100 mL), dried and solvent removed in vacuo. The residue was dissolved in hot acetonitrile, allowed to cool filtered, and the filtrate passed through a SCX column and the residue, after evaporation of product containing fractions, recrystallised from hot acetonitrile to yield the title compound as a white solid (5.0 g, 82%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[OH:10][C:11]1[N:16]=[C:15]([OH:17])[CH:14]=[C:13]([O:18][CH3:19])[N:12]=1>>[OH:10][C:11]1[N:16]=[C:15]([OH:17])[C:14]([N+:1]([O-:4])=[O:2])=[C:13]([O:18][CH3:19])[N:12]=1
Reactant: O=[N+]([O-])O
Reactant: COc1cc(O)nc(O)n1
Agent: O=S(=O)(O)O
Product: COc1nc(O)nc(O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of barbituric acid (51.2 g) in methanol (1 L) was added concentrated sulfuric acid (80 mL) in a dropwise manner over 20 minutes, and the mixture was stirred at room temperature for 22 hours. The crystals were collected by filtration. The collected crystals were washed with methanol, cold water and diethyl ether successively, and dried under reduced pressure to give 2,4-dihydroxy-6-methoxypyrimidine (52.9 g). To a mixture of fuming nitric acid (20 mL) and concentrated sulfuric acid (10 mL) was added 2,4-dihydroxy-6-methoxypyrimidine (14.2 g) slowly at around 15° C., and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added ice water (150 mL), and the mixture was stirred at room temperature for 30 minutes. The crystals were collected by filtration. The collected crystals were washed with water, and dried under reduced pressure to give the title compound (7.4 g).
Reaction SMILES: [NH2:1][C@H:2]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[N:12]=[C:13]([C:29]#[N:30])[C:14]2[C:19]([C:20]=1[OH:21])=[CH:18][CH:17]=[C:16]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:15]=2)=[O:10])[C:3]([OH:5])=[O:4].C(N(CC)CC)C.[C:38](OC(=O)C)(=[O:40])[CH3:39].Cl>C(Cl)Cl.CCOC(C)=O.O>[C:38]([NH:1][C@H:2]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[N:12]=[C:13]([C:29]#[N:30])[C:14]2[C:19]([C:20]=1[OH:21])=[CH:18][CH:17]=[C:16]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:15]=2)=[O:10])[C:3]([OH:5])=[O:4])(=[O:40])[CH3:39]
Reactant: N#Cc1nc(C(=O)NCC[C@@H](N)C(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(=O)N[C@H](CCNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)C(=O)O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
(R)-2-Amino-4-(1-cyano-4-hydroxy-7-phenoxyisoquinoline-3-carboxamido)butanoic acid (15 mg, 0.03 mmol) in CH2Cl2 (1 mL) was cooled to 0° C. To the solution were added triethylamine (0.03 mL, 0.21 mmol) and acetic anhydride (4 μL, 0.05 mmol). After stirring for 5 minutes at 0° C., H2O (10 mL) and EtOAc (10 mL) were added. To the stirred mixture was added 1 N hydrochloric acid (1 mL). The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-20% MeOH/CH2Cl2 with 0.5% formic acid) to give the title compound in 10 mg. MS: (−) m/z 447.21 (M−1).
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11]/[C:10]/1=[CH:34]\[CH2:35][OH:36])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>ClCCl.[O-2].[O-2].[Mn+4]>[Si:1]([O:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:11]/[C:10]/1=[CH:34]\[CH:35]=[O:36])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\C=O
Temperature: 25 °C
Reaction time: 45 h
Yield: 89.1 %

Procedure:
To a solution of (E)-4-(t-butyldimethylsilyloxy)-3-(2-hydroxyethylidene)-1-(triphenylmethyl)piperidine (8.50 g) in dichloromethane (120 ml) was added manganese dioxide (8.87 g) at room temperature, and the resulting mixture was stirred at room temperature for 45 hours. After stirring, the insoluble materials were filtered off. The filtrate was evaporated in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (3:17) as the eluent to afford the title compound (7.54 g, yield: 89%) as a colourless amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.Cl>C(O)(C)C>[Cl:1][C:2]1[N:11]=[C:10]([NH:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: Nc1ccncc1
Agent: Cl
Solvent: CC(C)O
Product: Clc1nc(Nc2ccncc2)c2ccccc2n1
Reaction time: 8 h
Yield: 61.9 %

Procedure:
To a stirred suspension of 2,4-dichloroquinazoline (42 mg, 0.21 mmol) and 4-aminopyridine (21 mg, 0.22 mmol) in 3 mL of anhydrous isopropanol was added a drop of concentrated HCl and the mixture was stirred overnight. Solid precipitates were observed and the mixture was filtered. The solid was washed with cold isopropanol and dried to give the title compound as white solid (38 mg, 0.13 mmol, 61%). 1H NMR (DMSO-d6): 8.60 (d, J=7.5 Hz, 2H), 8.18-8.20 (m, 2H), 8.07-8.10 (m, 1H), 7.90-7.96 (m, 1H), 7.18 (d, J=7.8 Hz, 2H).
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:11][C:12]1[C:13]([OH:19])=[CH:14][C:15](=[O:18])[NH:16][CH:17]=1>N1C=CC=CC=1>[Cl:11][C:12]1[C:13]([O:19][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:14][C:15](=[O:18])[NH:16][CH:17]=1
Reactant: O=c1cc(O)c(Cl)c[nH]1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: c1ccncc1
Product: O=C(Cc1ccccc1)Oc1cc(=O)[nH]cc1Cl
Yield: 14 %

Procedure:
A 3.63 ml quantity of phenylacetyl chloride was added to a suspension of 2.00 g of 5-chloro-4-hydroxy-2-pyridone in 60 ml of pyridine. The same subsequent procedure as in Example 39 was conducted, thereby producing 500 mg of the title compound in a yield of 14%.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9]Cl)([O:3][CH3:4])=[O:2].[C:15]([CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:30]=[C:29]([OH:31])[CH:28]=[CH:27][C:24]=1[CH:25]=[O:26])([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:15]([CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:30]=[C:29]([O:31][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[O:6][CH2:5][C:1]([O:3][CH3:4])=[O:2])[CH:28]=[CH:27][C:24]=1[CH:25]=[O:26])([O:17][CH3:18])=[O:16]
Reactant: COC(=O)CCCOc1cc(O)ccc1C=O
Reactant: COC(=O)COc1ccccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCCOc1cc(OCc2ccccc2OCC(=O)OC)ccc1C=O

Procedure:
A mixture of 2-carbomethoxymethoxybenzyl chloride (0.1 mol) and 3-carbomethoxypropoxy-4-hydroxybenzaldehyde (0.08 mol) in 8:1-acetone: dimethylformamide (900 mL) is refluxed with anhydrous potassium carbonate (0.1 mol). When the reaction is complete, the cooled reaction mixture is filtered and evaporated. The resulting oil is diluted with ethyl acetate and washed with water (6X's). The dried ethyl acetate solution is absorbed on silica gel and eluted through a column of flash silica (500 g) with a mixture of ethyl acetate: petroleum ether. Condensation of the appropriate fraction gives 3-carbomethoxypropoxy-4-(2-(carbomethoxymethoxy)phenyl)methyloxybenzaldehyde which is used directly in the next step.
Reaction SMILES: [NH2:1][NH2:2].[C:3]([O:18]C)(=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>CO>[C:3]([NH:1][NH2:2])(=[O:18])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: NN
Reactant: CCCCCCCCCCCCCC(=O)OC
Solvent: CO
Product: CCCCCCCCCCCCCC(=O)NN
Yield: 43.9 %

Procedure:
Hydrazine (1.9 mL, 0.058 mol) was added to a solution of methyl tetradecanoate (13.96 g, 0.058 mol) in methanol (300 mL) and the solution refluxed for 3 days. The mixture was allowed to cool and filtered to yield 6.17 g of a crystalline solid, m.p. 107°-111° C.
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[Cl:11][C:12]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:13]=1[NH2:14].P(Cl)(Cl)Cl.ClCCl>>[Cl:11][C:12]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:13]=1[NH:14][C:1](=[O:10])[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4]
Reactant: Nc1ccc([N+](=O)[O-])cc1Cl
Reactant: O=C(O)c1ccccc1O
Solvent: ClP(Cl)Cl
Solvent: ClCCl
Product: O=C(Nc1ccc([N+](=O)[O-])cc1Cl)c1ccccc1O
Temperature: 137 °C

Procedure:
The method disclosed in U.S. Pat. No. 3,079,297 to Shraufstatter et al with minor variations was utilized. A boiling solution of salicylic acid (1.03 g, 7.46 mmol) and 2-chloro-4-nitroaniline (1.29 g, 7.46 mmol) in xylenes (20 mL) was treated dropwise with a solution of phosphorous trichloride in dichloromethane 2.0M, 1.50 mL, 0.40 equiv.), and the resulting solution was refluxed (137° C.) for four hours. The solution was cooled to about 125° C. An oily residue covered the bottom and sides of the reaction vessel. The hot reaction solution was transferred by glass pipette to a beaker and was allowed to cool to room temperature while being stirred rapidly. The product separated, was collected by filtration, and washed with hexanes, then recrystallized from ethanol. The title compound was obtained, MP 218-220° C. (dec.). 1HNMR (500 MHz, DMSO-d6): δ 7.02 (m, 1H, H3), 7.07 (m, 1H, H5), 7.49 (m, 1H, H4), 8.04 (m, 1H, H6), 8.28 (m, 1H, H5′), 8.41 (m, 1H, H3′), 8.85 (m, 1H, H6′), 11.8 (s, 1H, NH), 12.34 (s, 1H, OH).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[N:7]([CH2:9][CH2:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[S:18][Si](C(C)C)(C(C)C)C(C)C)[CH3:8])([CH3:4])([CH3:3])[CH3:2].F.F.F.C(N(CC)CC)C>C1COCC1>[C:1]([O:5][C:6](=[O:29])[N:7]([CH2:9][CH2:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[SH:18])[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)[Si](Sc1ccc(F)cc1CCN(C)C(=O)OC(C)(C)C)(C(C)C)C(C)C
Agent: F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(CCc1cc(F)ccc1S)C(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 69.7 %

Procedure:
[2-(5-Fluoro-2-triisopropylsilanylsulfanyl-phenyl)-ethyl]-methyl-carbamic acid tert-butyl ester (1.60 g, 3.62 mmol) is dissolved in dry THF (12 mL) and triethylamine trihydrofluoride (0.59 g, 3.66 mmol) is added. The resulting mixture is heated at 60° C. for 5 minutes, then cooled and concentrated in vacuo. The product is purified by eluting through a plug of silica with ethyl acetate-heptane (1:4) to give 0.72 g (72%) of the title compound as an oil.
Reaction SMILES: C(OC([CH2:8][NH:9][C:10]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:18][C:17]=2[O:28][CH2:29][CH3:30])[CH:13]=[CH:12][CH:11]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[CH2:29]([O:28][C:17]1[CH:18]=[C:19]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:20]=[CH:21][C:16]=1[C:14]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:9][CH3:8])[N:15]=1)[CH3:30]
Reactant: CCOc1cc(CCC(=O)OC)ccc1-c1cccc(NCC(=O)OC(C)(C)C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc(CCC(=O)OC)ccc1-c1cccc(NC)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 81 %

Procedure:
g of methyl 3-{4-[6-(tert-butoxycarbonylmethylamino)pyrid-2-yl]-3-ethoxyphenyl}propionate is dissolved in 10 mL of dichloromethane and 4 mL of trifluoroacetic acid are then added. The mixture is stirred for 48 hours at room temperature. After hydrolysis of the reaction with sodium hydrogen carbonate solution and then extraction with ethyl acetate, the solvents are evaporated off. 615 mg of methyl 3-[3-ethoxy-4-(6-methylaminopyrid-2-yl)phenyl]propionate are obtained. Yield=81%.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][C:13]([NH:15][C:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)([CH3:18])[CH3:17])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C)C=O.ClCCl>[CH2:5]([O:12][C:13]([NH:15][C:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([Cl:3])=[O:24])=[CH:21][CH:20]=1)([CH3:18])[CH3:17])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(NC(=O)OCc1ccccc1)c1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(NC(=O)OCc1ccccc1)c1ccc(C(=O)Cl)cc1

Procedure:
Thionyl chloride (0.21 ml) and dimethylformamide (2 drops) were added to a solution of 4-(1-benzyloxycarbonylamino-1-methylethyl)-benzoic acid (780 mg) in dichloromethane (10 ml), and the mixture was refluxed under heating for 1 hour. After the reaction, the solvent was evaporated under reduced pressure to give 4-(1-benzyloxycarbonylamino-1-methylethyl)benzoyl chloride as crystals. Then, the crystals were dissolved in acetonitrile (10 ml), and the solution was dropwise added to a solution of 4-aminopyridine (195 mg) and diisopropylethylamine (0.5 ml) in acetonitrile (10 ml) under ice-cooling. The mixture was stirred at room temperature for 5 hours. After the reaction, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated under reduced pressure, and the obtained crystals were recrystallized from ethyl acetate-hexane to give 750 mg of N-(4-pyridyl)-4-(1-benzyloxycarbonylamino-1-methylethyl)benzamide.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[F:15][C:16]([F:48])([F:47])[O:17][C:18]1[CH:46]=[CH:45][C:21]([CH2:22][N:23]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[N:25]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])=[CH:35][CH:34]=3)[C:24]2=O)=[CH:20][CH:19]=1.[OH-].[Na+]>C1(C)C=CC(C)=CC=1.O>[F:15][C:16]([F:48])([F:47])[O:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][N:23]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[N:25]([CH2:32][C:33]3[CH:34]=[CH:35][C:36]([NH:39][S:40]([CH3:43])(=[O:41])=[O:42])=[CH:37][CH:38]=3)[C:24]2=[S:2])=[CH:45][CH:46]=1
Reactant: CS(=O)(=O)Nc1ccc(Cn2c(=O)n(Cc3ccc(OC(F)(F)F)cc3)c3ccccc32)cc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccc(C)cc1
Solvent: O
Product: CS(=O)(=O)Nc1ccc(Cn2c(=S)n(Cc3ccc(OC(F)(F)F)cc3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.3 %

Procedure:
Phosphorus pentasulfide (444 mg, 1.0 mmol) was added to a suspension of N-{4-[3-(4-trifluoromethoxybenzyl)-2-oxo-2,3-dihydrobenzimidazol-1-ylmethyl]phenyl}methanesulfonamide (7) (300 mg, 0.61 mmol) in para-xylene (20 mL) under a blanket of argon. The reaction mixture was heated to the boil over a period of 10 h. Following cooling, there was added to the reaction mixture water (1 mL) followed by 2N NaOH solution in water (10 mL), and the mixture was stirred at RT for 30 min. The reaction mixture was extracted with ethyl acetate (4×20 mL). The combined organic phases were dried over Na2SO4 and the solvent removed in vacuo. After purifying the residue by means of column chromatography (SiO2; cyclohexane/EtOAc 2:1), the desired product N-{4-[3-(4-trifluoromethoxybenzyl)-2-thioxo-2,3-dihydrobenzimidazol-1-ylmethyl]phenyl}methanesulfonamide (8) (162 mg, 52% of theory, mp: 167-170° C.) was obtained. After recrystallizing from methanol, there were obtained crystals having a melting point of 175-179° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17][CH2:16]1)=[CH:11][C:10](Br)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[Cl:30][C:31]1[CH:36]=[C:35](B2CC(C)(C)C(C)(C)C2)[CH:34]=[C:33]([O:46][CH3:47])[C:32]=1[OH:48]>>[C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17][CH2:16]1)=[CH:11][C:10]([C:35]1[CH:34]=[C:33]([O:46][CH3:47])[C:32]([OH:48])=[C:31]([Cl:30])[CH:36]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Reactant: COc1cc(B2CC(C)(C)C(C)(C)C2)cc(Cl)c1O
Product: COc1cc(-c2ccc3ncc(C(C)=O)c(N[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)c3c2)cc(Cl)c1O

Procedure:
Following general procedure D, tert-butyl trans-4-(3-acetyl-6-bromoquinolin-4-ylamino)cyclohexylcarbamate (56 mg, 0.200 mmol) was reacted with 2-chloro-6-methoxy-4-(3,3,4,4-tetramethylborolan-1-yl)phenol (47 mg, 0.100 mmol) to afford the desired product (35 mg, 65%) as a yellow solid: ESI MS m/z 541 [C29H34ClN3O5+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[C:28](F)[CH:27]=2)[N:3]=1.CCO.CCN(C(C)C)C(C)C.[NH2:47][NH2:48]>CO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:26]2[CH:27]=[C:28]3[C:29]([C:32]([NH2:33])=[N:47][NH:48]3)=[CH:30][CH:31]=2)[N:3]=1
Reactant: NN
Reactant: C[C@@H]1CC[C@H](C(=O)N[C@H](C)c2ccccc2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: C[C@@H]1CC[C@H](C(=O)N[C@H](C)c2ccccc2)CN1c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 110 °C
Reaction time: 8 h
Yield: 40.4 %

Procedure:
Into a sealable tube, (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-N-[(1R)-1-phenylethyl]-3-piperidinecarboxamide (188 mg, 0.41 mmol), EtOH (5 ml), Hunig's base (0.072 ml, 0.41 mmol), and hydrazine anhydrous (0.077 mL, 2.46 mmol) were added, and the yellow suspension mixture was heated overnight at 110° C. in an oil bath. When the temperature of the reaction reached to 100° C., the solid in the mixture was all dissolved. After overnight, there was a yellow solution as well as a little amount of black colored solid formed. LCMS showed mainly product. CH3OH (5 mL) was added to the solution. The black solid was filtered from the yellow solution. Water (20 mL) was added to the yellow solution, and a solid was formed. The solid was filtered, washed by water, and dried in vacuum. The solid was recrystallized from CH3CN, and the solid was filtered, washed by CH3CN, and dried in vacuum to afford the title compound (78 mg) as a light yellow solid. LC-MS (ES) m/z=471 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.06-1.21 (m, 4H), 1.38 (m, 3H), 1.71 (m, 4H), 2.25-2.41 (m, 1H), 2.92 (m, 1H), 4.84-5.01 (m, 1H), 5.38 (s, H), 6.09 (s, 2H), 6.59 (s, 1H), 7.12-7.40 (m, 6H), 7.53-7.62 (m, 1H), 7.71 (d, J=8.6 Hz, 1H), 7.95 (s, 1H), 8.41 (d, J=8.1 Hz, 1H), 11.50 (s, 1H).