Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1)[C@@H:3]([NH:5][CH2:6][CH2:7][O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24]CC3C=CC=CC=3)=[O:23])=[CH:18][CH:17]=2)=[CH:11][C:10]=1[CH3:32])[CH3:4]>CN(C)C=O.[C].[Pd]>[OH:1][C@H:2]([C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1)[C@@H:3]([NH:5][CH2:6][CH2:7][O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][CH:17]=2)=[CH:11][C:10]=1[CH3:32])[CH3:4]
Reactant: Cc1cc(-c2ccc(C(=O)OCc3ccccc3)cc2)cc(C)c1OCCN[C@@H](C)[C@H](O)c1ccc(O)cc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc(C(=O)O)cc2)cc(C)c1OCCN[C@@H](C)[C@H](O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 27.9 %

Procedure:
A mixture of benzyl 4′-{2-[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethylamino]ethoxy}-3′,5′-dimethyl -biphenyl-4-carboxylate (0.108 g) and 10% palladium-carbon (50% wet, 0.05 g) in N,N-dimethylformamide (4 mL) was stirred at room temperature for 1.5 hrs under an atmosphere of hydrogen. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo. Methylene chloride was added to the residue. The resulting precipitate was collected by filtration, and purified by octadecyl silica gel column chromatography (eluent: acetonitrile/water=1/1) to afford the title compound (0.025 g) as a white amorphous. The structure and physical data were shown in table 1.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]([C:12]1([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])[CH2:2]2.[Cl:25][CH2:26][C:27]([NH:29][C:30]1[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32][N:31]=1)=[O:28]>CC#N>[Cl-:25].[CH3:36][C:34]1[N:33]=[CH:32][N:31]=[C:30]([NH:29][C:27]([CH2:26][N+:1]23[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]2)[C@@H:3]([O:9][C:10]([C:12]2([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])[CH2:2]3)=[O:28])[CH:35]=1
Reactant: Cc1cc(NC(=O)CCl)ncn1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C1(c2ccccc2)CCCCCC1
Solvent: CC#N
Product: Cc1cc(NC(=O)C[N+]23CCC(CC2)[C@@H](OC(=O)C2(c4ccccc4)CCCCCC2)C3)ncn1
Product: [Cl-]
Yield: 81.2 %

Procedure:
1-Phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Example 14e) (0.30 mmol) and 2-chloro-N-(6-methyl-pyrimidin-4-yl)-acetamide (Example 59a) (0.36 mmol) in MeCN (2. mL) were stirred together at room temperature for 16 h. The reaction mixture was concentrated in vacuo and the residue purified by silica gel chromatography eluting with 0-10% MeOH/dichloromethane to give the title compound as a white solid (125 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][CH:11]=[N:10][CH:9]=2)=[C:4]([O:13][CH3:14])[CH:3]=1.Cl[CH2:16][C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[O:18]>CN(C=O)C>[F:26][C:23]1[CH:22]=[CH:21][C:20]([NH:19][C:17](=[O:18])[CH2:16][NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][CH:11]=[N:10][CH:9]=3)=[C:4]([O:13][CH3:14])[CH:3]=2)=[CH:25][CH:24]=1
Reactant: COc1cc(N)ccc1-c1cnco1
Reactant: O=C(CCl)Nc1ccc(F)cc1
Solvent: CN(C)C=O
Product: COc1cc(NCC(=O)Nc2ccc(F)cc2)ccc1-c1cnco1

Procedure:
A solution of 1D, (101 mg, 0.53 mmol) and 2-chloro-4′-fluoroacetanilide (50 mg, 0.27 mmol) in DMF (0.15 mL) was heated at 100° C. for 15 h. After the reaction had cooled, the solvent was removed under reduced pressure, and the residue was subjected to preparative HPLC to give 1 as a tan solid. LC/MS: ret. timeA=3.527 min., MS (M+H)+=342.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH3:15][C@@H:16]1[CH2:20]OS(=O)(=O)[N:17]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.Cl>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C@@H:16]([CH3:20])[NH:17][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[CH2:11][CH2:10]1
Reactant: C[C@@H]1COS(=O)(=O)N1c1ccccn1
Reactant: COc1ccccc1N1CCNCC1
Agent: Cl
Solvent: CC#N
Product: COc1ccccc1N1CCN(C[C@@H](C)Nc2ccccn2)CC1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
9.16 grams (46.6 millimoles) of 1-(2-methoxyphenyl)piperazine in one portion was added under argon to a solution of 10 grams (46.6 millimoles) of (R)-4-methyl-3-pyridin-2-yl[1,2,3]oxathiazolidine-2,2-dioxide in 200 milliliters of acetonitrile. The mixture became yellow. After ½ hour, the reaction mixture was heated to 50° C. for 1 hour and then stirred at room temperature overnight Then dilute hydrochloric acid was added. The mixture was washed with ethyl acetate, basified to pH 12 and extracted twice with ethyl acetate. The organic phases were washed with brine, dried (Mg SO4) and subjected to evaporation to give 12.053 grams of the title compound which was purified by columning in the system ethyl ether/hexane (1:1) Al2O3 to afford 9.96 grams of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([NH:16][C:17](=O)[C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([O:28][CH2:29][CH2:30][CH:31]=[CH2:32])[CH:19]=2)([C:14]#[N:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].OO.CS(C)=[O:40]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([N:16]=[C:17]([C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([O:28][CH2:29][CH2:30][CH:31]=[CH2:32])[CH:19]=3)[NH:15][C:14]2=[O:40])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(C)=O
Reactant: C=CCCOc1cc(C(=O)NC2(C#N)CCN(C(=O)OC(C)(C)C)CC2)cc(C(F)(F)F)c1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C=CCCOc1cc(C2=NC3(CCN(C(=O)OC(C)(C)C)CC3)C(=O)N2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
4-(3-But-3-enyloxy-5-trifluoromethyl-benzoylamino)-4-cyano-piperidine-1-carboxylic acid tert-butyl ester (3.0 g) was dissolved in ethanol, and a 5 N aqueous sodium hydroxide solution (6.9 ml, 34.5 mmol) and a 30% aqueous hydrogen peroxide solution (3 ml) were added. After stirring at room temperature for two hours, DMSO (19 ml) was added to the reaction solution, and the mixture was stirred at 50° C. for four hours. The reaction solution was cooled, and then quenched with a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was sequentially washed with a saturated aqueous ammonium chloride solution, water and saturated brine, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 2-(3-but-3-enyloxy-5-trifluoromethyl-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-carboxylic acid tert-butyl ester (2.39 g, 67% in two steps).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][C@@H:14]([CH2:17][NH2:18])[N:13]([C@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:20])[CH2:12][C:11]=2[S:10][C:9]=1[NH2:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C[O:36][C:37](=O)[C:38]1[C:43]([O:44][CH3:45])=[CH:42][CH:41]=[CH:40][C:39]=1[CH2:46]Cl>C(#N)C>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][C@@H:14]([CH2:17][N:18]3[CH2:46][C:39]4[C:38](=[C:43]([O:44][CH3:45])[CH:42]=[CH:41][CH:40]=4)[C:37]3=[O:36])[N:13]([C@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:20])[CH2:12][C:11]=2[S:10][C:9]=1[NH2:27])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](c1ccccc1)N1Cc2sc(N)c(C(=O)OC(C)(C)C)c2C[C@H]1CN
Reactant: COC(=O)c1c(CCl)cccc1OC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1cccc2c1C(=O)N(C[C@@H]1Cc3c(sc(N)c3C(=O)OC(C)(C)C)CN1[C@@H](C)c1ccccc1)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.8 %

Procedure:
2-Amino-5-(S)-aminomethyl-6-(1-(S)-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (0.55 g, 1.42 mmol) and triethylamine (396 I, 2.84 mmol) was heated in acetonitrile (15 ml) under an atmosphere of nitrogen to 60° C. whereupon a solution of 2-chloromethyl-6-methoxy-benzoic acid methyl ester (0.32 g, 1.49 mmol) in acetonitrile (5 ml) was added dropwise over the course of 3 hours, keeping the reaction mixture at 60° C. The reaction was allowed to cool to room temperature and was left for 16 hours before the solvent was evaporated in vacuo. The product was purified by column chromatography (SiO2, Flash 40, ethyl acetate-petrol ether) to give 400 mg (53%) of 2-amino-5-(S)-(7-methoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-6-((S)-1-phenyl-ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:31])=[C:4]2[N:10]=[C:9]([CH2:11][CH2:12][CH3:13])[N:8]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[S:27]([NH2:30])(=[O:29])=[O:28])=[CH:17][CH:16]=3)[C:5]2=[N:6][CH:7]=1.C1COCC1.CN(C=O)C.[C:42](Cl)(=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CO>[C:42]([NH:1][C:2]1[C:3]([CH3:31])=[C:4]2[N:10]=[C:9]([CH2:11][CH2:12][CH3:13])[N:8]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[S:27]([NH2:30])(=[O:29])=[O:28])=[CH:19][CH:20]=3)[C:5]2=[N:6][CH:7]=1)(=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCc1nc2c(C)c(N)cnc2n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CO
Product: CCCc1nc2c(C)c(NC(=O)c3ccccc3)cnc2n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Reaction time: 12 h

Procedure:
To a mixture of 6-amino-7-methyl-2-propyl-3-[2'-(aminosulfonyl)[1,1']-biphenyl-4-yl]methyl-3H-imidazo[4,5-b]pyridine (189 mg, 0.435 mmol) in 14:1 THF/DMF (7.5 mL) at -15° C. was added benzoyl chloride (0.045 mL, 0.392 mmol). The mixture was stirred for 12 h, then 1 mL of MeOH was added and the mixture was o concentrated. Purification (SiO2, 93:3:4 CH2Cl2/MeOH/HOAc) gave the title compound as a solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][N:18]([CH3:20])[C:17](=[O:21])[N:16]([CH3:22])[CH2:15]2)=[CH:10][CH:9]=1)(C)(C)C.C1C(=O)N([Br:31])C(=O)C1.C(Cl)Cl.C([O-])(O)=O.[Na+].[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]>>[F:43][C:42]([F:45])([F:44])[C:40]([OH:46])=[O:41].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][N:18]([CH3:20])[C:17](=[O:21])[N:16]([CH3:22])[CH2:15]2)=[CH:10][C:9]=1[Br:31]
Reactant: O=C1CCC(=O)N1Br
Reactant: CN1CC(c2ccc(NC(=O)OC(C)(C)C)cc2)CN(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CC(c2ccc(N)c(Br)c2)CN(C)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
[4-(1,3-Dimethyl-2-oxo-hexahydro-pyrimidin-5-yl)-phenyl]-carbamic acid tert-butyl ester (as prepared in the previous step, 106 mg, 0.333 mmol) was dissolved in TFA (2 mL). The resulting mixture was stirred at RT for 30 min and concentrated. The residue obtained was dried in vacuo for 30 min and redissolved in DCM (5 mL). The resulting solution was cooled to 0° C. and NBS (64 mg, 0.35 mmol) was added. The reaction mixture was stirred at RT for 30 min and treated with DCM (20 mL) and satd aq NaHCO3 (20 mL). The organic layer was separated, dried (Na2SO4) and concentrated to afford the title compound (92 mg, 92%), which was directly used in next step without further purification. Mass spectrum (ESI, m/z): Calcd. for C12H16BrN3O, 298.0 and 300.0 (M+H). found 298.2 and 300.2.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:14](=[O:16])[CH3:15])[CH:5]=[C:6]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])[CH:7]=1.N([O-])=[O:18].[Na+]>S(=O)(=O)(O)O.O>[OH:18][C:2]1[CH:3]=[C:4]([C:14](=[O:16])[CH3:15])[CH:5]=[C:6]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])[CH:7]=1
Reactant: CC(=O)c1cc(N)cc(S(F)(F)(F)(F)F)c1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(=O)c1cc(O)cc(S(F)(F)(F)(F)F)c1
Temperature: -5 °C
Reaction time: 0.67 h
Yield: 54.7 %

Procedure:
1-[3-Amino-5-(pentafluorosulfanyl)phenyl]ethanone (3.00 g) was dissolved while heating in 35% aqueous sulfuric acid (25 ml). The solution was cooled to −5° C. and a solution of sodium nitrite (780 mg) in 15 ml of water was added dropwise within 10 min. After 40 min at −5° C., the cooling bath was removed and the mixture was heated to 100° C. for 2 h. After cooling, the mixture was extracted twice with EA. The combined EA phases were washed with saturated sodium hydrogencarbonate solution, dried, filtered and concentrated. The residue was purified using silica gel (80 g cartridge, n-heptane/MtB ether gradient of 0-100% within 40 min). 1.62 g of the title compound were obtained.
Reaction SMILES: C(C1C=CC(C#C)=CC=1)(C)(C)C.C[Si]([C:17]#[C:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH3:32])([CH3:31])[CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:21][CH:20]=1)(C)C>>[CH3:32][C:25]([C:22]1[CH:21]=[CH:20][C:19]([C:18]#[CH:17])=[CH:24][CH:23]=1)([CH3:31])[CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29]
Reactant: CC(C)CCC(C)(C)c1ccc(C#C[Si](C)(C)C)cc1
Agent: C#Cc1ccc(C(C)(C)C)cc1
Product: C#Cc1ccc(C(C)(C)CCC(C)C)cc1

Procedure:
Using the same general procedure as described for Compound 19, but using instead trimethylsilyl [4-(1,1,4-trimethylpentyl)] phenylethyne (Compound 34), the title compound was synthesized as a colorless oil. PMR (CDCl3) & 0.81 (6H, d, J~6.6 Hz), 0.85-0.96 (2H, m), 1.29 (6H, s), 1.32-1.48 (1H, m). 1.55-1.66 (2H, m)., 3.04 (1H, s), 7.29 (2H, d, J~8.4 Hz), 7.44 (2H, d, J~8.4 Hz).
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[F:8][C:9]([F:15])([F:14])[C:10]([CH3:13])([NH2:12])[CH3:11].[C:16]([N:21]=[C:22]=[S:23])(=[O:20])[O:17][CH2:18][CH3:19].II>>[CH2:3]([C:2]1=[CH:1][N:12]([C:10]([CH3:13])([CH3:11])[C:9]([F:15])([F:14])[F:8])[S:23]/[C:22]/1=[N:21]\[C:16](=[O:20])[O:17][CH2:18][CH3:19])[CH2:4][CH2:5][CH3:6]
Reactant: CCOC(=O)N=C=S
Reactant: CC(C)(N)C(F)(F)F
Reactant: CCCCCC=O
Agent: II
Product: CCCCc1cn(C(C)(C)C(F)(F)F)s/c1=N\C(=O)OCC

Procedure:
Commercially available hexanal (Aldrich), 1,1,1-trifluoro-2-methylpropan-2-amine (Chemcollect), O-ethyl carbonisothiocyanatidate (Aldrich) and iodine were processed using the method described in Example 110A to afford the title compound. MS (ESI+) m/z 339 (M+H)+.
Reaction SMILES: [C:1]1(C)C=CC(S(O)(=O)=O)=CC=1.[C:12]1([CH3:19])[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:20][OH:21]>>[OH:21][CH2:20][C:14]1[C:15]([CH3:1])=[CH:16][C:17]([OH:18])=[C:12]([CH3:19])[CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CO
Reactant: Cc1ccccc1O
Product: Cc1cc(CO)c(C)cc1O
Yield: 904.5 %

Procedure:
Into a 1 liter of four-necked flask were charged 4.76 g of para-toluenesulfonic acid, 54.07 g of ortho-cresol and 108.14 g of methanol. Further, keeping the temperature at 30° C., 38.05 g of 4-hydroxymethyl-2,5-dimethylphenol obtained above was added in ten portions over 1 hour. The mixture was stirred at the same temperature for 2 more hours. After completion of the reaction, 200 g of toluene and 200 gof ethyl acetate was added. Thereafter, 200 g of deionized water was added and the resulting mixture was stirred and a phase separation was carried out. Then, metal content was removed by adding 200 g of 1% aqueous oxalic acid solution, followed by stirring the mixture and by carrying out a phase separation. Thereafter, washing with 200 g of deionized water was repeated four times, and the oil phase was concentrated. To the concentrated mass, 200 g of toluene was added and the resulting solution was cooled to 20° C. and filtered. The filter cake was rinsed with 200 g of toluene and dissolved in 200 g of ethyl acetate. After adding 200g of toluene thereto, the resulting mixture was concentrated. To the concentrated mass, 200 g of toluene was added and the resulting mass was cooled to 20° C. and filtered. The filter cake was rinsed with 200 g of toluene and dried a whole day and night under reduced pressure at 45° C. to obtain 20.12 g of 4-(4-hydroxy-3-methylbenzyl)-2,5-dimethylphenol.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[CH3:12][NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:14]([N:13]([CH3:12])[CH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CNCc1ccccc1
Reactant: OC(CCCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(CCC(O)c1ccccc1)Cc1ccccc1
Temperature: 25 °C

Procedure:
A solution of 3-chloro-1-phenylpropan-1-ol (2 g, 11.7 mmol), N-methylbenzylamine (2.12 g, 17.5 mmol), potassium iodide (2.6 g, 22 mmol), and potassium carbonate (3.2 g, 23.4 mmol) in dimethylformamide (120 mL) was stirred at 90° C. in a reacti-vial for 16 h. After this time the reaction was allowed to cool to room temperature. The reaction mixture was purified by an SCX-2 column eluting with Methanol followed by ammonia:methanol solution (7 N). The organics were then evaporated and the compound taken directly onto the next step without any further purification. (M+H+1 [256]); δH (300 MHz, CDCl3) 7.2–7.4 (10H, m, Ar), 4.9 (1H, t, CH—OH), 3.55 (1H, d, CH2—Ph), 3.45 (1H, d, CH2—PH), 2.8–3 (1H, m, CH2), 2.55–2.65 (1H, m, CH2), 2.25 (3H, s, CH3), 1.8–1.9 (2H, m, CH2), 1.6 (1H, brs, OH).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.O1CCNC1=O.[C:25](Cl)(=[O:30])[CH2:26][CH2:27][CH:28]=[CH2:29]>O1CCCC1.Cl.C(OCC)C>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:25](=[O:30])[CH2:26][CH2:27][CH:28]=[CH2:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: C=CCCC(=O)Cl
Agent: Cl
Agent: O=C1NCCO1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reaction time: 0.5 h

Procedure:
Flush with nitrogen a 12 L 3-neck round bottom flask equipped with a mechanical stirrer, internal temperature probe/N2 inlet, and 1 L addition funnel for 20 min and then add (R)-4-benzyl-2-oxazolidinone (250 g, 1.41 mol). Dilute with tetrahydrofuran (THF) (1.8 L) and cool in a dry ice/acetone bath until the internal temperature is −74° C. Transfer a 1.6M hexanes solution of n-butyllithium (970 mL, 1.552 mol) to the addition funnel via cannula, and add to the oxazolidinone solution at a rate such that the internal temperature does not reach above −65° C. After the addition is complete, allow the reaction to stir in the cooling bath 30 min. Transfer 4-pentenoyl chloride (175 mL, 1.585 mol) to the addition funnel and add dropwise to the anion solution over a 25 min period. Stir the reaction for 45 min in the cooling bath. Remove the cooling bath and stir the reaction 18 hr as it slowly reaches room temperature. Dilute the mixture with 1N aqueous hydrochloric acid (1.5 L) and diethyl ether (1 L). Separate the layers and wash the organic phase with water (2×1 L) then brine (1 L). Extract the combined aqueous washes with ether (1 L). Dry the combined organic phases over anhydrous magnesium sulfate, filter, and concentrate to 390 g of a light tan oil. Purify this material by silica gel chromatography using hexanes:ethyl acetate to obtain 345 g (94.5%) of a clear, yellow oil.
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=1[C:21](=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.C1(C)C=CC=CC=1>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=1[C:21](=[CH2:1])[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C(=O)c1c(OC)cccc1OC
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=C(C(=O)OCC)c1c(OC)cccc1OC
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 81 %

Procedure:
To a suspension of methyltriphenylphosphonium bromide (61.1 g, 1.2 equiv) in THF (350 ml) at 0 C was added potassium bis(trimethylsilyl)amide (260 ml of a 15% solution in toluene, 1.2 equiv) and this mixture was stirred at 0 C for 15 min and at r.t. for 45 min. Then, a solution of the ketoester 16 (33.7 g, 141 mmol) in THF (70 ml) was added at 0 C and stirring was continued at r.t. for 1 h. The reaction was quenched by addition of a saturated solution of NH4Cl and ice. The product was extracted into i-PrOAc and the organics were dried over Na2SO4 and filtered through small pad of silica. Purification of the residue by filtration through a plug of silica (1.5 L) with EtOAc/hexane 10 and 15% yielded 26.92 g (81%) of 17 as a colorless oil.
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:39][C:40]1[C:41]([NH:58][CH:59]2[CH2:64][CH2:63][N:62]([CH:65]([CH3:69])[CH2:66][C:67]#[N:68])[CH2:61][CH2:60]2)=[C:42]2[CH:48]=[CH:47][N:46]([S:49]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)(=[O:51])=[O:50])[C:43]2=[N:44][CH:45]=1>CN(C=O)C.C(Cl)Cl>[C:52]1([S:49]([N:46]2[C:43]3=[N:44][CH:45]=[C:40]([NH:39][C:1](=[O:5])[CH2:2][CH3:3])[C:41]([NH:58][CH:59]4[CH2:60][CH2:61][N:62]([CH:65]([CH3:69])[CH2:66][C:67]#[N:68])[CH2:63][CH2:64]4)=[C:42]3[CH:48]=[CH:47]2)(=[O:50])=[O:51])[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: CC(CC#N)N1CCC(Nc2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Reactant: CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCC(=O)Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCN(C(C)CC#N)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Propionic acid (0.0176 ml, 0.320 mmol), HATU (0.122 g, 0.320 mmol), and diisopropylethylamine (0.062 ml, 0.358 mmol) were added sequentially to a solution of 3-[4-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-piperidin-1-yl]-butyronitrile (0.134 g, 0.305 mmol) in a 4:1 mixture of CH2Cl2 and DMF (5 ml) at 25° C. The reaction mixture was stirred for 14 h at 25° C., then was partitioned between saturated NaHCO3 (4 ml) and CH2Cl2 (3 ml). The phases were separated using a phase separator column (Biotage) and the organic layer was concentrated under reduced pressure to afford crude N-{1-benzenesulfonyl-4-[1-(2-cyano-1-methyl-ethyl)-piperidin-4-ylamino]-1H-pyrrolo[2,3-b]pyridin-5-yl}-propionamide as a brown oil. LCMS (Method G, ESI): RT=0.60 min, m+H=495.3. This material was used in the next step below without additional purification or characterization.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[C:6]([CH3:12])=[N:7]2.[CH:22]1([C:25](Cl)=O)C[CH2:23]1.[O:28]1CC[CH2:30][CH2:29]1>>[CH:22]1([CH2:30][C:29]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[C:4](=[O:21])[N:5]([CH:13]2[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]2=[O:20])[C:6]([CH3:12])=[N:7]3)=[O:28])[CH2:25][CH2:23]1
Reactant: C1CCOC1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1nc2cccc(N)c2c(=O)n1C1CCC(=O)NC1=O
Product: Cc1nc2cccc(NC(=O)CC3CC3)c2c(=O)n1C1CCC(=O)NC1=O
Temperature: 80 °C
Yield: 23 %

Procedure:
To a stirred mixture of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione (0.41 g, 1.3 mmol) in tetrahydrofuran (8 mL), was added cyclopropanecarbonyl chloride (0.24 mL, 2.7 mmol) and heated at 80° C. for one hour. The mixture was quenched with a few drops of methanol. The solvent was evaporated and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 2-cyclopropyl-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-yl]-acetamide as a white solid (110 mg, 23% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 35/65 CH3CN/0.1% H3PO4, 2.78 min (98.2%); mp, 239-241° C.; 1HNMR (DMSO-d6) δ 0.87 (d, J=5 Hz, 4H, CH2CH2), 1.70-1.75 (q, J=6 Hz, 1H, CH), 2.20-2.25 (m, 1H, CHH), 2.59-2.88 (m, 5H, CH2, CH3), 5.33 (dd, J=6, 12 Hz, 1H, CH), 7.26-8.52 (m, 3H, Ar), 11.10 (s, 1H, NH), 12.03 (s, 1H, NH); 13C NMR (DMSO-d6) δ 7.88, 7.99, 16.26, 20.68, 23.34, 30.56, 56.73, 115.24, 120.29, 135.64, 139.80, 147.85, 154.72, 163.14, 169.34, 171.92, 172.60. LCMS MH=355; Anal Calcd For C18H18N4O4+1.7H2O: C, 56.16; H, 5.60; N, 14.55. Found: C, 55.90; H, 5.50; N, 14.31.