Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][N:18]([C:21](Cl)=[O:22])[CH2:17][CH2:16]1.[N:24]1([C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)[CH:28]=[CH:27][N:26]=[CH:25]1.CCN(C(C)C)C(C)C>C1COCC1>[N:24]1([C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:21]([N:18]3[CH2:19][CH2:20][CH:15]([C:6]4[C:5]5[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=5)[N:9]=[CH:8][N:7]=4)[CH2:16][CH2:17]3)=[O:22])=[CH:31][CH:30]=2)[CH:28]=[CH:27][N:26]=[CH:25]1
Reactant: COc1cc2ncnc(C3CCN(C(=O)Cl)CC3)c2cc1OC
Reactant: Nc1ccc(-n2ccnc2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(C3CCN(C(=O)Nc4ccc(-n5ccnc5)cc4)CC3)c2cc1OC
Temperature: 65 °C
Reaction time: 3 h
Yield: 8.7 %

Procedure:
4-(6,7-Dimethoxy-quinazolin-4-yl)-piperidine-1-carbonyl chloride (16.5 mg, 0.05 mmol), prepared as described in Example 3a, was dissolved in anhydrous THF (2 mL) and to it was added 4-imidazol-1-yl-phenylamine (12 mg, 0.075 mmol) followed by DIEA (14 μL, 0.075 mmol) and the mixture was stirred at 65° C. for 3 h. It was then concentrated in vacuo and the residue was purified by Preparative TLC (silica gel, 5% MeOH/DCM) to obtain 2 mg (5%) of pure 4-(6,7-dimethoxy-quinazolin-4-yl)-piperidine-1-carboxylic acid (4-imidazol-1-yl-phenyl)-amide. 1H-NMR (300 MHz, CDCl3) δ 9.04 (s, 2H), 7.63 (m, 3H), 7.55-7.40 (m, 5H), 7.33 (s, 1H), 4.37 (m, 2H), 4.07 (s, 6H), 3.76-3.58 (m, 2H), 3.14 (m, 2H), 2.18-1.90 (m, 3H). LC/MS (ESI): calcd mass 458.2, found 459.5 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:19]([C:28]([O:30][CH3:31])=[O:29])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:42][CH2:43]/[CH:44]=[CH:45]\[CH2:46]Br>C1COCC1>[Br:42][CH2:43]/[CH:44]=[CH:45]\[CH2:46][C@@:19]1([C:28]([O:30][CH3:31])=[O:29])[CH2:18][CH2:17][C@H:16]([C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[CH:15][CH:14]=2)[N:20]1[C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22]
Reactant: BrC/C=C\CBr
Reactant: COC(=O)[C@@H]1CC[C@H](c2ccc(OCc3ccccc3F)cc2)N1C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)[C@]1(C/C=C\CBr)CC[C@H](c2ccc(OCc3ccccc3F)cc2)N1C(=O)OC(C)(C)C
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 38.2 %

Procedure:
To a solution of 1-(1,1-dimethylethyl) 2-methyl (2S,5R)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-1,2-pyrrolidinedicarboxylate (D34, 0.2 g, 0.47 mmol) in dry THF (2 mL) at −78° C. was added LiHMDS (0.51 mL of a 1M solution in THF, 0.51 mmol). The mixture was allowed to warm to −30° C. and stirred for 30 min at this temperature. The yellow slurry was cooled to −78° C. and (2Z)-1,4-dibromo-2-butene (0.30 mL, 2.81 mmol) was added. The reaction mixture was left under stirring for 40 min and then quenched with a saturated ammonium chloride solution. The aqueous layer was extracted with ethyl acetate, dried (Na2SO4) and evaporated. The crude material was purified by chromatography on silica gel using cyclohexane/ethyl acetate (9:1) affording the title compound (101 mg, 38%); Rt (HPLC) 7.42 min. MS: (ES/+) m/z: 462 and 464 [MH+—Boc]; C28H33BrFNO5 requires 562.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:23]5[S:27][C:26]([NH:28][CH2:29][C:30]6[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=6)=[N:25][N:24]=5)[CH:21]=4)[N:16](S(C4C=CC(C)=CC=4)(=O)=O)[CH:15]=3)[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[K+]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:23]5[S:27][C:26]([NH:28][CH2:29][C:30]6[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=6)=[N:25][N:24]=5)[CH:21]=4)[NH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3cccc(-c5ccc(Cl)cc5)n3)cn4S(=O)(=O)c3ccc(C)cc3)s2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CNc2nnc(-c3ccc4[nH]cc(-c5cccc(-c6ccc(Cl)cc6)n5)c4c3)s2)cc1
Temperature: 80 °C

Procedure:
A glass microwave reaction vessel was charged with 5-(3-(6-(4-chlorophenyl)pyridin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-thiadiazol-2-amine (225 mg, 0.332 mmol) in THF (5 mL) followed by KOH (1.5 mL, 1.50 mmol, 1 M). The mixture was heated in microwave at 80° C. for 90 min, then cooled to RT. The mixture was diluted with water and extracted with DCM. The combined organic layers were dried, filtered and concentrated to give the crude material. MS (ESI, pos. ion) m/z: 524 (M+1).
Reaction SMILES: [CH2:1]([O:3][C@H:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][C:12]([OH:14])=O)=[CH:8][CH:7]=1)[CH3:2].Cl.[F:23][C:24]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:25]=1[CH2:26][NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:23][C:24]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:25]=1[CH2:26][N:27]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:12](=[O:14])[CH2:11][O:10][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][C@H:4]([O:3][CH2:1][CH3:2])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:16][CH:15]=1
Reactant: CCCCCCCNCc1ccc(F)cc1F
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCCCCCN(Cc1ccc(F)cc1F)C(=O)COc1ccc(C[C@H](OCC)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.3 %

Procedure:
To a solution of {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.104 g, 0.35 mmol) in methylene chloride (3.5 mL) was added N-(2,4-difluorobenzyl)-N-heptylamine hydrochloride (0.098 g, 0.35 mmol) and DMAP (0.094 g, 0.77 mmol) followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.067 g, 0.35 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with methylene chloride (50 mL), and the organic phase was washed with 5% HCl (3×25 mL), aqueous NaHCO3 (25 mL) and brine (25 mL), dried over Na2SO4, and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 5 g Si/25 mL) with methanol (0-1% gradient) in methylene chloride as the eluent afforded 0.066 g (36%) of a colourless oil.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH3:14]O>>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9][CH3:14])=[O:8]
Reactant: CO
Reactant: O=C1CC[C@@H](C(=O)O)N1
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H]1CCC(=O)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2S)-5-pyrrolidone-2-carboxylic acid (75 g) in methanol (580 ml) was added dropwise thionyl chloride (150 ml) at 0° C. After the addition, the reaction mixture was allowed to warm to room temperature and stirred for two hours. The solvent was removed in vacuo, and the residue was diluted with a mixture of ethyl acetate (1 l), methanol (50 ml) and water (10 ml). To this mixture was added by portions potassium carbonate (50 g), and the mixture was stirred for two hours. The precipitate was filtered off, and the filtrate was dried over magnesium sulfate. Evaporation of the solvent gave methyl (2S)-5-pyrrolidone-2-carboxylate (82.5 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([N:8]=[C:9]=[S:10])[CH:7]=1.Cl.[CH2:13]([NH2:16])[C:14]#[CH:15].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([NH:8][C:9]([NH:16][CH2:13][C:14]#[CH:15])=[S:10])[CH:7]=1
Reactant: Cc1ccc(Cl)cc1N=C=S
Reactant: C#CCN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCNC(=S)Nc1cc(Cl)ccc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.4 %

Procedure:
5-Chloro-2-methylphenyl isothiocyanate (18.3 g; 0.1 mol) was added dropwise to the mixture of 2-propynylamine hydrochloride (9.2 g, 0.1 mol) and triethyl amine (20 mL) in methylene chloride (200 mL). The mixture was stirred for 18 hours at ambient temperature. The mixture was evaporated to dryness. The residue was stirred in water (200 mL) for 1 hour then filtered. The solid was dissolved in ethyl acetate (300 mL) and washed with 1N hydrochloric acid (2×200 mL) then with water (300 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness to give 16.8 g of N-(5-chloro-2-methylphenyl)-N′-(2-propynyl)thiourea.
Reaction SMILES: [CH:1]([C:4]1[C:8]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[C:16]([CH3:18])[CH:17]=2)[C:13]#[N:14])=[C:7]([CH3:19])[NH:6][N:5]=1)([CH3:3])[CH3:2].Cl.Cl[CH2:22][CH2:23][NH2:24]>>[NH3:5].[NH2:24][CH2:23][CH2:22][N:6]1[C:7]([CH3:19])=[C:8]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[C:16]([CH3:18])[CH:17]=2)[C:13]#[N:14])[C:4]([CH:1]([CH3:3])[CH3:2])=[N:5]1
Reactant: Cc1cc(C#N)cc(Oc2c(C(C)C)n[nH]c2C)c1
Reactant: NCCCl
Agent: Cl
Product: Cc1cc(C#N)cc(Oc2c(C(C)C)nn(CCN)c2C)c1
Product: N
Yield: 62.1 %

Procedure:
The pyrazole from Example 205 (70 mg, 0.27 mmol) and 2-chloroethylamine hydrochloride (38 mg, 0.33 mmol) were heated as a melt at 150° C. for 18 hours. The residue was cooled and purified by flash chromatography on silica gel eluting with dichloromethane:methanol:0.88 ammonia (95:5:0.5, by volume) to give the title compound (25 mg).
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Br)C1C=CC=CC=1.[N-:16]=[N+:17]=[N-:18].[Na+].[C:20]([O:24][CH2:25][CH3:26])(=[O:23])[CH:21]=[CH2:22]>C(O)C.O>[CH2:7]([N:16]1[CH:22]=[C:21]([C:20]([O:24][CH2:25][CH3:26])=[O:23])[N:18]=[N:17]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccccc1
Reactant: C=CC(=O)OCC
Agent: BrCc1ccccc1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cn(Cc2ccccc2)nn1

Procedure:
To a mixed solvent of toluene (100 mL)/ethanol (100 mL)/water (50 mL) were added benzyl bromide (10.7 g) and sodium azide (10.1 g), and the mixture was heated under reflux for 5 hr. A solution of ethyl acrylate (38.8 mL) in ethanol (200 mL) was added dropwise to the reaction mixture, and the mixture was heated under reflux for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (5.66 g) as an oil.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]1([CH2:19][O:20][P:21]([CH2:36][C:37]([OH:39])=O)([CH:23]([NH:25][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH3:24])=[O:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(#N)C.[NH:43]1[CH2:57][CH2:56][CH2:55][C@H:44]1[C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46]>C(OCC)(=O)C>[C:13]1([CH2:19][O:20][P:21]([CH2:36][C:37]([N:43]2[CH2:57][CH2:56][CH2:55][C@H:44]2[C:45]([O:47][CH2:48][C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)=[O:46])=[O:39])([CH:23]([NH:25][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH3:24])=[O:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CC(NC(=O)OCc1ccccc1)P(=O)(CC(=O)O)OCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(NC(=O)OCc1ccccc1)P(=O)(CC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)OCc1ccccc1
Reaction time: 1 h

Procedure:
1,1'-Carbonyldiimidazole (1 g. 0.066 mole) is added to a chilled (0°) solution of the product from part (c) (2.5 g., 0.063 mole) in 40 ml. of acetonitrile. The mixture is stirred for one hour at 0°. A solution of L-proline, benzyl ester (1.3 g., 0.066 mole) in 20 ml. of acetonitrile is added. The mixture is stirred at ambient temperature for 16 hours. The solvent is removed in vacuo. The residue is dissolved in dichloromethane (125 ml.), washed with 5% potassium bisulfate, saturated sodium bicarbonate solution, brine, and dried (MgSO4). The solution is concentrated in vacuo to give an oil residue of 3.3 g. Tlc, silica gel, ethyl acetate shows a major spot at Rf 0.10. A portion (2.2 g.) is chromatographed on silica gel, eluting with ethyl acetate to give 1.7 g. of (±)-1-[(phenylmethoxy)[1-[[(phenylmethoxy)carbonyl]amino]ethyl]phosphinyl]acetyl]-L-proline, phenylmethyl ester.
Reaction SMILES: [OH-].[Na+].[CH:3]1([C:9]2[C:10]3[CH:11]=[CH:12][C:13]([C:32]([O:34][CH3:35])=[O:33])=[CH:14][C:15]=3[N:16]3[CH2:22][C:21]([C:24]([O:26]C)=[O:25])([F:23])[CH2:20][C:19]4[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=4[C:17]=23)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl>CO.O1CCCC1>[CH:3]1([C:9]2[C:10]3[CH:11]=[CH:12][C:13]([C:32]([O:34][CH3:35])=[O:33])=[CH:14][C:15]=3[N:16]3[CH2:22][C:21]([C:24]([OH:26])=[O:25])([F:23])[CH2:20][C:19]4[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=4[C:17]=23)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(F)(C(=O)OC)Cc1ccccc1-3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(F)(C(=O)O)Cc1ccccc1-3
Temperature: 65 °C
Yield: 85 %

Procedure:
Sodium hydroxide (50 μL of 1N, 0.05 mmol) was added to a solution of methyl (±)-13-cyclohexyl-6,7-dihydro-6-carbomethoxy-6-fluoro-5H-indolo[2,1-a][2]benzazepine-10-carboxylate (12.0 mg, 0.027 mmol) in methanol (0.5 mL) and tetrahydrofuran (0.5 mL) in a microwave vial. The vial was sealed and the contents heated at 65° C. for 20 min in a microwave apparatus. The solution was acidified with dilute hydrochloric acid to precipitate the crude acid. The solid was collected and was purified on the Shimadzu preparative liquid chromatograph. The product containing fraction was concentrated on a Speed Vac® to leave the titled compound as a white solid (10 mg, 85%). ESI-MS m/z 436 (MH+).
Reaction SMILES: [C:1](Cl)(=O)[C:2](Cl)=O.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]([C:20]([OH:22])=O)=[CH:18][C:17]([S:23][CH3:24])=[N:16]2)=[CH:11][CH:10]=1.N[C:26]1[CH:38]=[CH:37][C:29]([C:30](N2CCCC2)=[O:31])=[CH:28][CH:27]=1>CN(C=O)C.C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:30]([CH:2]1[CH2:1][N:15]([NH:16][C:20]([C:19]2[N:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][CH3:7])=[CH:14][CH:13]=3)[N:16]=[C:17]([S:23][CH3:24])[CH:18]=2)=[O:22])[CH2:12][CH2:11]1)(=[O:31])[C:29]1[CH:28]=[CH:27][CH:26]=[CH:38][CH:37]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(-n2nc(SC)cc2C(=O)O)cc1
Reactant: Nc1ccc(C(=O)N2CCCC2)cc1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(-n2nc(SC)cc2C(=O)NN2CCC(C(=O)c3ccccc3)C2)cc1
Reaction time: 1.67 h
Yield: 212.6 %

Procedure:
Oxalyl chloride (140 μl, 1.6 mmol) and dry DMF (2 drops) were added at room temperature to 1-(4-methoxyphenyl)-3-methylthio-1H-pyrazole-5-carboxylic acid (275 mg, 1.0 mmol) in dry CH2Cl2 (8 mL) and stirred for 100 minutes under N2. The resulting solution was evaporated and placed briefly under high vacuum before redissolving in CH2Cl2 (8 mL). (4-aminobenzoyl)pyrrolidine (198 mg, 1.0 mmol) was added, followed by 4-dimethylaminopyridine (190 mg, 1.6 mmol). The resulting mixture was stirred at room temperature for 17 hours, diluted with CH2Cl2, and extracted with H2O. The aqueous extract was extracted with CH2Cl2, the combined organic extracts were extracted with brine. The organic layer was dried over Na2SO4, filtered, and evaporated. The crude product was chromatographed on silica gel (75-100% EtOAc/hexanes) to yield the desired product (464 mg, 100%). 1H NMR (CDCl3): δ 7.91 (bs, 1H), 7.44 (s, 4H), 7.39 (d, 2H, J=8.8), 6.97 (d, 2H, J=8.8), 6.83 (s, 1H), 3.84 (s, 3H), 3.62 (t, 2H, J=6.6), 3.42 (t, 2H, J=6.6), 2.57 (s, 3H), 1.91 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([N:11]2[CH2:15][C@H:14]([C:16](=[O:19])[CH:17]=[CH2:18])[CH2:13][C:12]2=[O:20])[CH3:10])=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[CH3:26][OH:27]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([N:11]2[CH2:15][C@H:14]([C:16](=[O:19])[CH2:17][CH2:18][O:27][CH3:26])[CH2:13][C:12]2=[O:20])[CH3:10])=[CH:5][CH:4]=1
Reactant: C=CC(=O)[C@@H]1CC(=O)N([C@H](C)c2ccc(OC)cc2)C1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COCCC(=O)[C@@H]1CC(=O)N([C@H](C)c2ccc(OC)cc2)C1
Temperature: 0 °C

Procedure:
Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of (4R)-1-[(1R)-1-(4-methoxyphenyl)ethyl]-4-(prop-2-enoyl)pyrrolidin-2-one 1.19 (12 g, 43.90 mmol, 1.00 equiv) in methanol (120 mL), followed by the addition of sulfuric acid (6.24 mL, 98%) dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature, quenched by the addition of 100 mL of water/ice and extracted with 3×300 mL of ethyl acetate. The organic layers were combined, washed with 3×300 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford (R)-1-((R)-1-(4-methoxyphenyl)ethyl)-4-(3-methoxypropanoyl)pyrrolidin-2-one 1.20.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[F:7][C:8]([F:20])([F:19])[O:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][CH:15]=1.ClCCl.[CH3:24][O:25][C:26]1[CH:56]=[C:55]([O:57][CH3:58])[CH:54]=[CH:53][C:27]=1[CH2:28][N:29]1[CH2:34][CH:33]([CH:35]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]2)[N:32]2[CH:48]=[C:49](I)[CH:50]=[C:31]2[C:30]1=[O:52]>O1CCOCC1.O>[CH3:24][O:25][C:26]1[CH:56]=[C:55]([O:57][CH3:58])[CH:54]=[CH:53][C:27]=1[CH2:28][N:29]1[CH2:34][CH:33]([CH:35]2[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:39][CH2:40]2)[N:32]2[CH:48]=[C:49]([C:12]3[CH:13]=[CH:14][CH:15]=[C:10]([O:9][C:8]([F:20])([F:19])[F:7])[CH:11]=3)[CH:50]=[C:31]2[C:30]1=[O:52]
Reactant: COc1ccc(CN2CC(C3CCN(C(=O)OC(C)(C)C)CC3)n3cc(I)cc3C2=O)c(OC)c1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CN2CC(C3CCN(C(=O)OC(C)(C)C)CC3)n3cc(-c4cccc(OC(F)(F)F)c4)cc3C2=O)c(OC)c1
Yield: 31.8 %

Procedure:
Cesium carbonate (32.6 mg, 0.1 mmol), [3-(trifluoromethoxy)phenyl]boronic acid (20 mg, 0.1 mmol), and 1,1′-bis(diphenylphosphino)ferrocenepaladium (4 mg, 0.005 mmol) complex with dichloromethane, were subsequently added to a solution of tert-butyl 4-[2-(2,4-dimethoxybenzyl)-7-iodo-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl]piperidine-1 carboxylate (30 mg, 0.05 mmol) in 3 ml of 1,4-dioxane and 1 ml of water, under argon atmosphere. The mixture was heated at 90° for 4 hours in a sealed vial. The reaction was filtered through a celite pad and the solvent evaporated to dryness. The crude was portioned between ethyl acetate and water, the organic layer dried over sodium sulphate and the solvent removed in vacuo. Purification by flash chromatography on silica gel column (Hex/EtOAc 8/2) afforded the compound tert-butyl 4-{2-(2,4-dimethoxybenzyl)-1-oxo-7-[3-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl}piperidine-1-carboxylate as oil (10 mg, 32%).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([NH:15][CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:11]=[CH:12][C:13]=1[Cl:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[F:29][C:30]([F:37])([F:36])[CH2:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH2:1]([C:8]1[CH:9]=[C:10]([N:15]([CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[S:32]([CH2:31][C:30]([F:37])([F:36])[F:29])(=[O:34])=[O:33])[CH:11]=[CH:12][C:13]=1[Cl:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccc(NCc2cccnc2)cc1Cc1ccccc1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(CC(F)(F)F)N(Cc1cccnc1)c1ccc(Cl)c(Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(3-benzyl-4-chlorophenyl)pyrid-3-ylmethylamine (0.04 g, 0.13 mmol)and pyridine (1 ml) was dissolved in DCM. The reaction was cooled in an ice-bath to which was added dropwise 2,2,2-trifluoroethylsulfonyl chloride (0.59 g, 0.32 mmol). The mixture was stirred at room temperature overnight. After evaporation of solvent, the residue was dissolved in EtOAc and washed with cold NaHCO3 and brine, and evaporated to dryness. Chromatography gave the title compound. 1H NMR: 8.51 (d,1H,J=3.9 Hz), 8.27 (s,1H), 7.59 (d,1H,J=7.8 Hz), 7.34 (t,1H,J=8.3 Hz), 7.28 (d,2H,J=7.8 Hz), 7.21 (m,2H), 8.03 (m,3H), 6.89 (d,1H,J=2.4 Hz), 4.78 (s,2H), 4.01 (s,2H), 3.73 (q,2H,J=9.3 Hz). MS calcd 454.1; MS (M+1) 455.0.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[H-].[Na+].Cl[CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20]>CN(C)C=O>[Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][N:8]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2c(Cl)nc(Cl)nc21
Temperature: 0 °C
Reaction time: 0.38 h
Yield: 66.1 %

Procedure:
A solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (0.30 g, 1.6 mmol) in anhydrous N,N-dimethylformamide (5.5 mL) cooled to 0° C. was treated with a 60% dispersion of sodium hydride in mineral oil (82.5 mg, 2.06 mmol) under nitrogen. The reaction was stirred at 0° C. for 20-25 min. At this time, the reaction was then treated with (2-(chloromethoxy)ethyl)trimethylsilane (340 μL, 1.92 mmol) and was purged with nitrogen. The ice/water bath was removed, and the reaction was allowed to warm to room temperature where it stirred over 3 nights. At this time, the reaction was diluted with water (50 mL) and was extracted with ethyl acetate (2×50 mL). The combined organics were washed with water (50 mL) and a saturated aqueous sodium chloride solution (50 mL), dried over magnesium sulfate, filtered and rinsed with ethyl acetate, and concentrated in vacuo onto Celite®. Flash chromatography (12 g silica gel column, 1-30% ethyl acetate/hexanes) afforded 2,4-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine as a viscous yellow oil (336.5 mg, 66.3%). 1H NMR (300 MHz, DMSO-d6) δ ppm −0.26-0.05 (m, 9H) 0.74-0.98 (m, 2H) 3.44-3.65 (m, 2H) 5.60 (s, 2H) 6.78 (d, J=3.77 Hz, 1H) 7.90 (d, J=3.77 Hz, 1H). LC-MS calcd. for C12H18Cl2N3OSi [(M+H)+] 318, obsd. 317.9.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:3]([NH:5][C:6]1[N:10]([CH3:11])[N:9]=[C:8]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)[CH:7]=1)=[O:4].CCN(C(C)C)C(C)C.O.[C:37]([OH:41])(=[O:40])[CH:38]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:56]CCCl>CC(O)=O>[ClH:56].[ClH:56].[F:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][C@H:2]([NH:1][CH2:38][C:37]([OH:41])=[O:40])[C:3]([NH:5][C:6]2[N:10]([CH3:11])[N:9]=[C:8]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=3)[CH:7]=2)=[O:4])=[CH:25][CH:24]=1
Reactant: ClCCCl
Reactant: Cc1cc(-c2cc(NC(=O)[C@@H](N)Cc3ccc(F)cc3)n(C)n2)ccn1
Reactant: O=CC(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2cc(NC(=O)[C@H](Cc3ccc(F)cc3)NCC(=O)O)n(C)n2)ccn1
Product: Cl
Temperature: 65 °C
Reaction time: 0.08 h

Procedure:
To a 100 ml flask was added (2S)-2-amino-3-(4-fluorophenyl)-N-(1-methyl-3-(2-methylpyridin-4-yl)-1H-pyrazol-5-yl)propanamide diTFA (120 mg, 0.21 mmole), 3 ml of DCE, DIEA (90 μl, 0.52 mmole, make sure pH=7), 75 μl of AcOH and glyoxylic acid monohydrate (19 mg, 0.21 mmole). The reaction was stirred at 65° C. for 5 minutes at which time was added sodium triacetoxyborohydride (131 mg, 0.62 mmole) and stirred at 65° C. for an additional 18 hours. The solvent was then removed and the crude purified by reverse phase preparative HPLC to give 2-((S)-3-(4-fluorophenyl)-1-(1-methyl-3-(2-methylpyridin-4-yl)-1H-pyrazol-5-ylamino)-1-oxopropan-2-ylamino)acetic acid dihydrochloride 16.2 as a yellow solid (20.7 mg, 21 mmol, yield) after salt exchange using 4 M HCl in dioxane (155 μl, 0.62 mmole). LCMS ESI (pos.) m/e: 412.1 (M+1): 1H NMR (400 MHz, MeOH) δ ppm 8.61 (d, J=6.26 Hz, 1H), 8.21 (d, J=6.65 Hz, 1H), 8.26 (s, 1H), 7.39 (dd, J=8.41, 5.28 Hz, 2H), 7.07-7.20 (m, 3H), 4.52 (br. s., 1H), 3.94-4.06 (m, 2H), 3.67-3.70 (m, 3H), 3.46 (m, 1H), 3.29 (m, 1H), 2.80 (s, 3H).