Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1.[NH3:15]>CCO>[NH2:15][CH2:3][CH:2]([OH:1])[CH2:4][N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1
Reactant: N
Reactant: c1ccc2c(c1)CCN(CC1CO1)C2
Solvent: CCO
Product: NCC(O)CN1CCc2ccccc2C1
Temperature: 80 °C
Yield: 96 %

Procedure:
A solution of 2-(oxiran-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline (17 g, 0.09 mol) in EtOH (300 mL) had NH3 gas bubbled to the solution at −78° C. The reaction mixture was then sealed and heated to 80° C. for 3 h. After completion of the reaction, the mixture was concentrated and the resulting crude product used in next step without further purification (18 g, Yield 96%). LCMS (m/z): 207.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][C:5]([F:29])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.[C:31]([C:33]1[CH:34]=[C:35]([OH:40])[CH:36]=[CH:37][C:38]=1[F:39])#[N:32]>>[Cl:1][C:2]1[C:3]([O:40][C:35]2[CH:36]=[CH:37][C:38]([F:39])=[C:33]([C:31]#[N:32])[CH:34]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([NH:11][C:12]2[N:13]=[CH:14][CH:15]=[CH:16][N:17]=2)(=[O:9])=[O:10])[CH:7]=1
Reactant: N#Cc1cc(O)ccc1F
Reactant: COc1ccc(CN(c2ncccn2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Product: N#Cc1cc(Oc2cc(F)c(S(=O)(=O)Nc3ncccn3)cc2Cl)ccc1F

Procedure:
The title compound was prepared according to the method described for Library Protocol 2 using 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-2-yl)benzenesulfonamide (WO2012004743) and 3-cyano-4-fluorophenol.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]=1[CH:18]=[O:19].Cl([O-])=[O:21].[Na+].[Na]>C(O)(C)(C)C.CC(=CC)C.O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:3]=1[C:18]([OH:21])=[O:19]
Reactant: O=CC1=C(Cl)c2ccccc2OC1c1ccccc1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Agent: [Na]
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(O)C1=C(Cl)c2ccccc2OC1c1ccccc1
Reaction time: 5 h

Procedure:
To a stirred solution of 5.8 g 4-chloro-3-formyl-flav-3-ene in 500 ml tert-butanol and 100 ml 2-methylbut-2-ene at room temperature is added dropwise a solution of 17.9 g sodium chlorite and 17.9 g sodium dihydrogenophosphate in 200 ml water. Stirring is continued for 5 hours. The solution is concentrated in vacuo and water is added to the residue to give a suspension. The mixture is extracted with hexane and the clear organic extracts are discarded. Subsequently, the aqueous suspension is acidified to pH 3 and the mixture is extracted with chloroform. The combined chloroform extracts are washed with water, dried over magnesium sulfate, filtered and evaporated. The residual solid is recrystallized in a mixture of chloroform and hexane. Pure 4-chloro-3-carboxy-flav-3-ene is obtained as yellow crystals; m.p. 210° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:19][O:18][C:16](=[O:17])[CH2:15][CH2:14][N:13]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=1)[CH:10]1[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: COC(=O)CCN(Cc1ccc(Cl)cc1)C1CCN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCN(Cc1ccc(Cl)cc1)C1CCNC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-[(4-chloro-benzyl)-(2-methoxycarbonyl-ethyl)-amino]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.08 g, 0.2 mmol) in dichloromethane cooled at 0° C. was treated with trifluoroacetic acid (20%). The resulting mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and free based with 10% aqueous sodium bicarbonate. The combined organics were dried over sodium sulfate. The product was used without any further purification. ESI-MS m/z: 297 (M+1), UV retention time: 1.05 min.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[Cl:20])=[CH:9][CH:8]=1)=[O:6])[CH3:3].C(N(CC)CC)C.[CH:28]1([C:34](Cl)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>C1COCC1>[CH2:2]([O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([NH:19][C:34]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:35])[CH:16]=[CH:15][C:14]=2[Cl:20])=[CH:9][CH:8]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1ccc(-c2cc(N)ccc2Cl)cc1
Reactant: O=C(Cl)C1CCCCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(-c2cc(NC(=O)C3CCCCC3)ccc2Cl)cc1
Reaction time: 18 h

Procedure:
A mixture of 5′-amino-2′-chloro-biphenyl-4-carboxylic acid ethyl ester hydrochloride (521 mg), triethylamine (0.49 ml) and cyclohexanecarbonyl chloride (0.26 ml) in dry THF (25 ml) was stirred at 20 C for 18 h. The mixture was then evaporated and the residue partitioned between water and dichloromethane. The organic layer was washed with water, dried (MgSO4), filtered and evaporated under reduced pressure to give the product (714 mg) as a yellow oil.
Reaction SMILES: [OH-:1].[K+].[CH2:3]([N:5]1[C:15]2[C:10](=[C:11]([OH:16])[CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][C:6]1=[O:7])[CH3:4]>CO>[CH2:3]([N:5]1[C:15]2[C:10](=[C:11]([O:16][CH2:10][CH:11]([OH:16])[CH2:12][OH:1])[CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][C:6]1=[O:7])[CH3:4]
Reactant: [OH-]
Reactant: CCN1C(=O)CCc2c(O)cccc21
Agent: [K+]
Solvent: CO
Product: CCN1C(=O)CCc2c(OCC(O)CO)cccc21
Yield: 52.7 %

Procedure:
2.0 g of potassium hydroxide was dissolved in 80 ml of methanol, and 5.2 g of 1-ethyl-5-hydroxy-3,4-dihydrocarbostyril and 5.0 g of glycerol α-bromohydrin were added to the resulting solution followed by refluxing the mixture for 4 hours. The mixture was then worked up in the same manner as described in Example 1 to obtain a residue after removal of the chloroform by distillation. The residue thus obtained was recrystallized from ethyl acetate to give 1.9 g of 1-ethyl-5-(2,3-dihydroxy)propoxy-3,4-dihydrocarbostyril as a colorless amorphous solid having a melting point of 105° - 107° C.
Reaction SMILES: C(O)C.C(O)(=O)C.[CH3:8][N:9]([CH2:11][C:12]1[CH:13]=[C:14]([CH:43]=[CH:44][CH:45]=1)[CH2:15][N:16]1[CH2:25][CH2:24][C:23]2[C:18](=[CH:19][C:20]([N+:39]([O-])=O)=[C:21]([N:26]3[CH2:31][CH2:30][N:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[CH3:38])[CH2:28][CH2:27]3)[CH:22]=2)[C:17]1=[O:42])[CH3:10]>[Fe]>[NH2:39][C:20]1[CH:19]=[C:18]2[C:23]([CH2:24][CH2:25][N:16]([CH2:15][C:14]3[CH:43]=[CH:44][CH:45]=[C:12]([CH2:11][N:9]([CH3:10])[CH3:8])[CH:13]=3)[C:17]2=[O:42])=[CH:22][C:21]=1[N:26]1[CH2:27][CH2:28][N:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH3:38])[CH2:30][CH2:31]1
Reactant: Cc1ccccc1N1CCN(c2cc3c(cc2[N+](=O)[O-])C(=O)N(Cc2cccc(CN(C)C)c2)CC3)CC1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccccc1N1CCN(c2cc3c(cc2N)C(=O)N(Cc2cccc(CN(C)C)c2)CC3)CC1
Temperature: 75 °C
Reaction time: 4 h

Procedure:
In a 100 ml round bottom flask equipped with a magnetic stir bar and fitted with a septum with a nitrogen inlet, the iron powder (382.70 mg, 6.85 mmol) was suspended in clean, dry, reagent-grade ethanol (30.00 ml, 513.81 mmol) under nitrogen and at room temperature. To the stirred reaction was added the acetic acid (3.00 ml, 52.40 mmol) and the mixture was stirred to ensure homogeneity. The 2-(3-dimethylaminomethyl-benzyl)-7-nitro-6-(4-o-tolyl-piperazin-1-yl)-3,4-dihydro-2H-isoquinolin-1-one 11a (140.80 mg, 0.27 mmol) was then added in one portion and the reaction was warmed to 75° C. and allowed to stir under nitrogen for 4 h. After 4 h, the reaction was cooled to room temperature and the reaction solution was filtered through Celite, eluting heavily with methanol. The collected solution was then concentrated under reduced pressure and the solvent was removed under reduced pressure. The resultant red oil was taken up in 50 ml of ethyl acetate and washed with 50 ml of saturated NaHCO3 (aq) solution. The product was then extracted from the aqueous using ethyl acetate (3×30 ml) and the organic phases were combined and washed with brine (1×100 ml). The solution was then dried over Na2SO4; the solution was decanted and the solvent was removed under reduced pressure. The resultant brown solid was then purified using silica gel column chromatography, eluting a gradient of 100% dichloromethane to 10% MeOH in dichloromethane. 7-amino-2-(3-dimethylaminomethyl-benzyl)-6-(4-o-tolyl-piperazin-1-yl)-3,4-dihydro-2H-isoquinolin-1-one 1 b (73.70 mg, 0.15 mmol) was isolated as a tan solid and was carried on without further purifications. LCMS (m/e)=483 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[S:36]1[CH:40]=[CH:39][CH:38]=[C:37]1[C:41]1([C:47]([NH2:49])=[O:48])[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:44]3[CH2:45][CH2:46][C:41]([C:37]4[S:36][CH:40]=[CH:39][CH:38]=4)([C:47]([NH2:49])=[O:48])[CH2:42][CH2:43]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: NC(=O)C1(c2cccs2)CCNCC1
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4cccs4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.3 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (5 mmol) and 4-(thiophen-2-yl)-piperidine-4-carboxylic acid amide hydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [CH:1]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=2)=[CH:5][CH:4]=[C:3]([OH:14])[CH:2]=1.[CH3:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>N1C=CC=CC=1>[CH3:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([O:14][C:3]2[CH:2]=[CH:1][C:6]([C:7]3[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=3)=[CH:5][CH:4]=2)=[O:22])=[CH:19][CH:18]=1
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Oc2ccc(-c3ccc(O)cc3)cc2)cc1
Temperature: -15 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
3.72 g of 4,4'-hydroxybiphenyl was put in an 100 ml two-necked. flask and dissolved by the addition of 60 ml of pyridine. The flask was set up in an ice bath. 3.41 g of 4-methoxybenzoyl chloride was added over 1.5 hours while maintaining the reaction mixture at -15° C. The mixture was reacted in the ice bath for 3 hours and then at an ambient temperature for 2 hours. The reaction mixture was poured into chipped ice to obtain a white precipitate. This precipitate was filtered, dried and re-crystallized with acetone. The yield was 63% and 1HNMR and IR spectra of the product were as follows.
Reaction SMILES: [F:1][C:2]1[C:7]([B:8](C2C(F)=C(F)C(F)=C(F)C=2F)[C:9]2[C:14]([F:15])=[C:13]([F:16])[C:12]([F:17])=[C:11]([F:18])[C:10]=2[F:19])=[C:6]([F:31])[C:5]([F:32])=[C:4]([F:33])[C:3]=1[F:34].[OH2:35]>C1(C)C=CC=CC=1>[F:1][C:2]1[C:7]([B:8]([C:9]2[C:14]([F:15])=[C:13]([F:16])[C:12]([F:17])=[C:11]([F:18])[C:10]=2[F:19])[OH:35])=[C:6]([F:31])[C:5]([F:32])=[C:4]([F:33])[C:3]=1[F:34]
Reactant: Fc1c(F)c(F)c(B(c2c(F)c(F)c(F)c(F)c2F)c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Reactant: O
Solvent: Cc1ccccc1
Product: OB(c1c(F)c(F)c(F)c(F)c1F)c1c(F)c(F)c(F)c(F)c1F
Temperature: 100 °C
Reaction time: 2 h

Procedure:
20 g (39 mmol) of tris(pentafluorophenyl)borane together with 150 ml of toluene are placed in a reaction vessel and the mixture is subsequently heated 100° C. 1.8 ml (97.5 mmol) of water in 40 ml of toluene are subsequently added dropwise to this solution over a period of 30 minutes. The mixture is subsequently stirred for another two hours at 100° C. After this time, the solvent is taken off in an oil pump vacuum. The residue does not have to be purified further. This gives 12.6 g (89%) of colorless bis(pentafluorophenyl)hydroxyborane. The boroxin content is 5%. 1H-NMR(C6D6, 400 MHz): −133.1 (m, 4 F, o-B(C6F5)2), −147.9 (m, 2 F, p-B(C6F5)2), −161.1 (m, 4 F, m-B(C6F5)2) ppm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=[O:39])[NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:41][O:42][C:43](=[O:68])[NH:44][CH:45]([C:49]([N:51]1[CH2:55][CH2:54][CH2:53][CH:52]1[C:56]1[NH:57][C:58]([C:61]2[CH:66]=[CH:65][C:64](Br)=[CH:63][CH:62]=2)=[CH:59][N:60]=1)=[O:50])[CH:46]([CH3:48])[CH3:47].C(=O)([O-])[O-].[K+].[K+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:40])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=[O:39])[NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:64]3[CH:65]=[CH:66][C:61]([C:58]4[NH:57][C:56]([CH:52]5[CH2:53][CH2:54][CH2:55][N:51]5[C:49](=[O:50])[CH:45]([NH:44][C:43]([O:42][CH3:41])=[O:68])[CH:46]([CH3:48])[CH3:47])=[N:60][CH:59]=4)=[CH:62][CH:63]=3)=[CH:28][CH:29]=2)=[CH:22][CH:23]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CCCC1C(=O)Nc1ccc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)NC(C(=O)N1CCCC1C(=O)Nc1ccc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)cc1)C(C)C
Temperature: 85 °C
Yield: 27.3 %

Procedure:
(2-Methyl-1-{2-[4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-4-ylcarbamoyl]-pyrrolidine-1-carbonyl}-propyl)-carbamic acid methyl ester (102 mg, 0.227 mmol), (1-{2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (125 mg, 0.227 mmol), Pd(PPh3)4 (13 mg, 0.0114 mmol) and a 2 M aqueous solution of potassium carbonate (0.227 mL, 0.454 mmol) were degassed in 1,2-dimethoxyethane (2 mL) for 15 min. The stirred suspension was heated to 85° C. for 4 hours then concentrated, brought up in DMF/water and purified by reverse phase preparative HPLC to provide {1-[2-(4″-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-[1,1′;4′,1″]terphenyl-4-ylcarbamoyl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (49 mg, 27%). (DMSO-d6, 400 MHz) 11.78 (s, 1H), 10.14 (s, 1H), 7.82-7.67 (m, 11H), 7.52 (d, J=1.8 Hz, 1H), 7.34-7.28 (m, 2H), 5.08 (m, 1H), 4.49 (m, 1H), 4.05 (m, 2H), 3.81 (m, 3H), 3.64 (m, 1H), 3.54 (s, 3H), 3.53 (s, 3H), 2.17-1.88 (m, 10H), 0.97-0.85 (m, 12H); MS (ESI) m/z 792 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]3[N:20]=[C:19]([CH3:21])[N:18]=[C:17]([N:22](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)[N:16]=3)=[CH:13][C:12]([C@H:41]([N:43]3[CH2:48][CH2:47][N:46]([S:49]([CH3:52])(=[O:51])=[O:50])[CH2:45][CH2:44]3)[CH3:42])=[CH:11][N:10]=2)=[CH:4][C:3]=1[O:53][CH3:54].FC(F)(F)S(O)(=O)=O>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]3[N:20]=[C:19]([CH3:21])[N:18]=[C:17]([NH2:22])[N:16]=3)=[CH:13][C:12]([C@H:41]([N:43]3[CH2:44][CH2:45][N:46]([S:49]([CH3:52])(=[O:51])=[O:50])[CH2:47][CH2:48]3)[CH3:42])=[CH:11][N:10]=2)=[CH:4][C:3]=1[O:53][CH3:54]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc([C@@H](C)N4CCN(S(C)(=O)=O)CC4)cnc3Nc3cnc(Cl)c(OC)c3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Nc2ncc([C@@H](C)N3CCN(S(C)(=O)=O)CC3)cc2-c2nc(C)nc(N)n2)cnc1Cl
Temperature: 80 °C
Yield: 78 %

Procedure:
A solution of (R)-4-(2-(6-chloro-5-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (130 mg, 0.168 mmol) in 3 mL of TFA was treated with 0.1 mL of trifluoromethanesulfonic acid. It was heated in an oil bath at 80° C. for 3 h. The dark solution was concentrated and the residue was treated with ice cube followed by 0.5N NaOH until the pH was about 8. The mixture was extracted with 2×30 mL of EtOAc followed by 2×15 mL of DCM. The combined organic solution was dried and concentrated. The residue was loaded on a silica gel column and eluted with 1 to 10% MeOH in DCM to give (R)-4-(2-(6-chloro-5-methoxypyridin-3-ylamino)-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (70 mg, 78% yield) as a yellow crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.22 (s, 1H), 8.74 (d, J=2.4 Hz, 1H), 8.44 (d, J=2.2 Hz, 1H), 8.36 (dd, J=10.4, 2.2 Hz, 2H), 7.95 (br., 1H), 7.83 (br., 1H), 3.94 (s, 3H), 3.60 (m, 1H), 3.09 (m, 4H), 2.86 (s, 3H), 2.46 (s, 3H), 2.44 (m, 4H), 1.36 (d, J=6.7 Hz, 3H). m/z (ESI, positive ion) 534.2 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[C:13]([Si:17](Cl)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:16])([CH3:15])[CH3:14]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Si:17]([O:5][CH2:4][CH2:3][NH:2][CH3:1])([C:13]([CH3:16])([CH3:15])[CH3:14])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CNCCO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 40 °C
Reaction time: 8 h
Yield: 52.8 %

Procedure:
To a solution of 2-(methylamino)ethanol (2.14 mL, 26.6 mmol) in DCM (60 mL) was added triethylamine (4.1 mL, 29.3 mmol),N,N-dimethylpyridin-4-amine (1.63 g, 13.3 mmol) and tert-butylchlorodiphenylsilane (7.6 mL, 29.3 mmol). The reaction was stirred overnight at 40° C. After cooling to RT, the reaction was quenched with water (20 mL) and ether (100 mL). The organic phase was washed with water, brine, dried over magnesium sulfate and concentrated to afford the crude product which was purified by flash chromatography on silica gel eluting with 0 to 10% MeOH in DCM. The solvent was evaporated to dryness to afford 2-(tert-butyldiphenylsilyloxy)-N-methylethanamine (4.4 g, 53%) as a colorless oil. NMR Spectrum (DMSOd6): 0.99 (s, 9H), 2.27 (s, 3H), 2.63 (t, 2H), 3.68 (t, 2H), 7.40-7.49 (m, 6H), 7.60-7.65 (m, 4H).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH3:15][O:16][CH:17]([O:20][CH3:21])[CH2:18][NH2:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:15][O:16][CH:17]([O:20][CH3:21])[CH2:18][NH:19][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COC(CN)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COC(CNC1CCN(C(=O)OC(C)(C)C)CC1)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
tert-Butyl 4-oxopiperidine-1-carboxylate (10.56 g, 53.0 mmol) was dissolved in 1,2-dichloroethane (100 ml). 4 Å Molecular sieves were added to the mixture followed by aminoacetaldehyde dimethyl acetal (8.0 ml, 73.4 mmol). Mixture was heated to reflux and held with stirring for 2 hours. Mixture was cooled to room temperature. Sodium triacetoxyborohydride (12.05 g, 56.9 mmol) was added to the mixture. Reaction stirred at room temperature for 3 hours. Another 3.22 g of sodium triacetoxyborohydride was added to the mixture. Reaction stirred at room temperature for 17 hours. Mixture was filtered over celite. Solids were washed with 50 mL dichloromethane. Material was extracted from the filtrate 3 times with 1N hydrochloric acid and the organic phase was discarded. Aqueous phase was made basic with sodium carbonate. Material was extracted three times with dichloromethane and the aqueous phase was discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Title compound was obtained as amber oil in 74% yield. MS (M+H)+=289.1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:11][C:12]([C:21]1[N:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[N:22]=1)([CH:18]([CH3:20])[CH3:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(N(C(C)C)C(C)C)C>C(OCC)(=O)C>[CH3:20][CH:18]([CH3:19])[C:12]([C:21]1[N:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[N:22]=1)([NH:11][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[Cl:1])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)C(N)(c1nc(OC)cc(OC)n1)C(C)C
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(NC(=O)c1ccccc1Cl)(c1nc(OC)cc(OC)n1)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.5 %

Procedure:
2-Chlorobenzoyl chloride (0.35 g) in ethyl acetate (3 ml) was added to a stirred solution of ethyl 2-amino-3-methyl-2-(4,6-dimethoxypyrimidin-2-yl)butanoate (0.566 g) and ethyl diisopropylamine (0.258 g) in ethyl acetate (15 ml). The mixture was stirred at room temperature for 2 hours, filtered, and the filtrate was washed with water, dried and evaporated to dryness under vacuum. The residual solid was triturated with 60°-80° petroleum ether to give 0.4 g of the desired product as a white solid, mp 94°-95° C.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([C:12]1[C:16]([CH3:17])=[C:15]([CH:18]=[N:19][N:20]=[C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([F:30])[CH:28]=3)[NH:23][C:22]2=[O:31])[NH:14][C:13]=1[CH3:32])=[O:11].CO.[Li+].[OH-].Cl>O>[F:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:31])[C:21]2=[N:20][N:19]=[CH:18][C:15]1[NH:14][C:13]([CH3:32])=[C:12]([C:10]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:33])=[O:2])=[O:11])[C:16]=1[CH3:17]
Reactant: COC(=O)CCCCCNC(=O)c1c(C)[nH]c(C=NN=C2C(=O)Nc3ccc(F)cc32)c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1[nH]c(C=NN=C2C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 36.9 %

Procedure:
6-(5-(((5-fluoro-2-oxoindolin-3-ylidene)hydrazono)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamido)-hexanoic acid methyl ester (455 mg, 1 mmol) and 300 ml of CH3OH were stirred at room temperature while 25 ml of 4 N solution of LiOH in H2O was added. The mixture was stirred for 24 hours at room temperature. The mixture is neutralized with concentrated hydrochloric acid to pH 7 and evaporated under vacuum to remove methanol. The residue was adjusted to pH 3 with concentrated hydrochloric acid. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (163 mg, 37% yield) as a red solid. LC-MS (m/z) 442 (M+1).