Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]([OH:11])=O)[N:8]=1)([CH3:3])[CH3:2].[ClH:12].[O:13]1[C:18]2([CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]2)[CH2:17][NH:16][CH2:15][CH2:14]1.C(N(CC)CC)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CC1CCCO1.O>[ClH:12].[CH:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]([N:16]2[CH2:17][C:18]3([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[O:13][CH2:14][CH2:15]2)=[O:11])[N:8]=1)([CH3:2])[CH3:3]
Reactant: CC(C)c1nc(C(=O)O)cs1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCCO2
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC1CCCO1
Solvent: O
Product: CC(C)c1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-isopropylthiazole-4-carboxylic acid (12 g) and tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride [WuXi PharmaTech] (20 g) in 2-methyltetrahydrofuran (140 mL) was cooled in ice-water and treated with triethylamine (47 mL), followed by T3P (1.6M in THF, 54 mL). The mixture was allowed to warm to RT and was stirred for 1 h. Water (140 mL) was added with stirring, then the phases were separated. The organic phase was washed with water (80 mL), and then concentrated to a volume of (˜100 mL) under reduced pressure using a temperature of <30° C. IPA (75 mL) was added, and the mixture was concentrated to a volume of (˜100 mL). More IPA (75 mL) was added, and the mixture was again concentrated to a volume of (˜100 mL). A solution of hydrogen chloride in IPA (˜6M, 81 mL) was added with cooling in ice-water, then the mixture was warmed to 40° C. and stirred for 3.5 h. The mixture was cooled to RT, diluted with MTBE (34 mL) and stirred for 30 min. The resulting precipitated solid was removed by filtration and dried in a vacuum oven at 55° C. overnight. Yield 20.5 g.
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][CH2:20][C:17]([CH2:22][CH2:23][C:24]5[N:28](CCC#N)[N:27]=[N:26][N:25]=5)([CH2:18][CH2:19]3)[CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:33])[N:3]1[CH2:34][CH2:35][CH3:36].[OH-].[Na+]>C1COCC1>[CH2:34]([N:3]1[C:4](=[O:33])[C:5]2[NH:6][C:7]([C:14]34[CH2:15][CH2:16][C:17]([CH2:22][CH2:23][C:24]5[NH:28][N:27]=[N:26][N:25]=5)([CH2:18][CH2:19]3)[CH2:20][CH2:21]4)=[N:8][C:9]=2[N:10]([CH2:11][CH2:12][CH3:13])[C:2]1=[O:1])[CH2:35][CH3:36]
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(CCc5nnnn5CCC#N)(CC3)CC4)nc2n(CCC)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCn1c(=O)c2[nH]c(C34CCC(CCc5nnn[nH]5)(CC3)CC4)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.6 %

Procedure:
To a solution of 3-(5-{2-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-ethyl}-tetrazol-1-yl)-propionitrile (150 mg, 0.30 mmol) in THF (20 ml) was added 3 ml of 1N NaOH. The resulting mixture was stirred at rt for 8 h, concentrated in vacuo and extracted with CH2Cl2 (2×10 ml). The aqueous phase was acidified by the careful addition of concentrated HCl and the resulting precipitate was collected, washed with water and dried to afford 55 mg (41%) of a white powder. MS: 441 (MH+).
Reaction SMILES: [H-].[Na+].Cl.[NH2:4][C:5]1[N:10]2[C:11]([C:15]([O:17]CC)=O)=[C:12]([CH3:14])[N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1.O>CN(C=O)C>[CH3:14][C:12]1[N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[N:10]2[C:11]=1[C:15](=[O:17])[NH:4]3
Reactant: CCOC(=O)c1c(C)nc2cccc(N)n12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2cccc3[nH]c(=O)c1n23
Reaction time: 0.5 h
Yield: 86.2 %

Procedure:
To a suspension of 4.8 g (120 mmol) of sodium hydride (60% dispersion in oil) in 60 ml of DMF was added 10.23 g (40 mmol) of 5-amino-3-ethoxycarbonyl-2-methylimidazo[1,2-a]pyridine-hydrochloride with small portions. The mixture was stirred for 0.5 hour, then for 0.5 hour at 100° C., which was left standing for cooling. To the reaction mixture was added 60 ml of water. The mixture was washed with chloroform, to which was added, while stirring at room temperature, conc. HCl to make the pH of the solution 8. The resulting precipitate was collected by filtration, washed with water and ether, successively to give 5.97 g of the desired compound (86.1%, pale brown solid).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH:12]([O:18][CH2:19][CH3:20])[C:13]([O:15]CC)=[O:14])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>O.CO>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH:12]([O:18][CH2:19][CH3:20])[C:13]([OH:15])=[O:14])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(OCC)Oc1ccc2ncccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOC(Oc1ccc2ncccc2c1)C(=O)O
Reaction time: 0.08 h
Yield: 44.5 %

Procedure:
Ethyl 2-(6-quinolinyloxy)-2-(ethoxy)acetate (3.68 g) was added to a solution of sodium hydroxide (0.589 g) in water (10 ml) and methanol (30 ml) and stirred for 5 minutes. The solution was evaporated under reduced pressure, water added and the aqueous phase was washed with ethyl acetate. The aqueous phase was acidified with hydrochloric acid and extracted with ethyl acetate. The extracts were combined, dried over magnesium sulphate and evaporated under reduced pressure to give 2-(6-quinolinyloxy)-2-(ethoxy)acetic acid (1.47 g) as a cream solid.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[I:12][C:13]1[CH:14]=[CH:15][C:16]([NH2:19])=[N:17][CH:18]=1.CO>N1C=CC=CC=1>[I:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])=[N:17][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(I)cn1
Solvent: c1ccncc1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)Nc2ccc(I)cn2)cc1
Temperature: 25 °C

Procedure:
p-Toluenesulfonyl chloride (2.00 g, 10.4 mmol) was added to a solution of 5-iodo-2-aminopyridine (2.50 g, 11.4 mmol) in 6 mL of pyridine, and the resultant solution was warmed at 90° C. for 18 h. After cooling to room temperature, the solution was added portionwise to 75 mL of ice-water with stirring. The resultant precipitate was collected, washed with water, and dried in vacuo to afford a pale yellow powder, which was stirred with 20 mL of methanol for several minutes. The solid product was then collected, washed with methanol, and dried in vacuo to provide the title compound as an off-white powder. LC/MS 374.8 (M+1).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([C:10]1[CH:20]=[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:13]2[CH2:14][CH:15]([CH2:17][OH:18])[O:16][C:12]=2[CH:11]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:29]I>C1COCC1>[C:3]([O:7][C:8]([C:10]1[CH:20]=[C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:13]2[CH2:14][CH:15]([CH2:17][O:18][CH3:29])[O:16][C:12]=2[CH:11]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)c1cc(OCc2ccccc2)c2c(c1)OC(CO)C2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC1Cc2c(OCc3ccccc3)cc(C(=O)OC(C)(C)C)cc2O1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 28.5 %

Procedure:
NaH (134 mg, 3.35 mmol) was added to a solution of 4-benzyloxy-2-hydroxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (204a) (994 mg, 2.79 mmol) in THF (10 mL). The resulting mixture was stirred at 0° C. for 10 min and methyl iodide (210 uL, 3.37 mmol) was added. The mixture was stirred at room temperature for 2 hr, quenched with H2O (50 mL) and extracted with EtOAc (2×50 mL). The organic layers were dried over MgSO4 and concentrated. The residue was purified by flash column chromatograph eluting with 20-30% EtOAc in hexanes to give a colorless oil (295 mg, 70% yield). 1H NMR (400 MHz, CDCl3) δ 7.34-7.45 (m, 5 H) 7.19 (d, J=1.01 Hz, 1 H) 7.11 (d, J=1.01 Hz, 1 H) 5.13 (s, 2 H)) 4.99-5.09 (m, 1 H) 3.54-3.64 (m, 2 H) 3.44 (s, 3 H) 3.23-3.33 (m, 1 H) 2.98 (dd, J=16.42, 7.33 Hz, 1 H) 1.57 (s, 9 H); LCMS for C22H26O5 m/z 371.20 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([C@H:14]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]1)[C:3]1[C:4]2[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:5]=2[N:6]=[CH:7][N:8]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:41][C:42]1[CH:43]=[C:44]([NH:49][CH2:50][C:51](O)=[O:52])[CH:45]=[C:46]([Cl:48])[CH:47]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Cl:41][C:42]1[CH:43]=[C:44]([NH:49][CH2:50][C:51]([N:16]2[CH2:17][CH2:18][CH2:19][C@H:14]([N:2]([CH3:1])[C:3]3[C:4]4[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:5]=4[N:6]=[CH:7][N:8]=3)[CH2:15]2)=[O:52])[CH:45]=[C:46]([Cl:48])[CH:47]=1
Reactant: CN(c1ncnc2c1CCC(=O)N2)[C@H]1CCCNC1
Reactant: O=C(O)CNc1cc(Cl)cc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CN(c1ncnc2c1CCC(=O)N2)[C@H]1CCCN(C(=O)CNc2cc(Cl)cc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9465.6 %

Procedure:
To a solution of (S)-4-(methyl(piperidin-3-yl)amino)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (150 mg, 0.6 mmol) in DMF (5 mL) was added EDCI (164 mg, 0.85 mmol), HOBt (114 mg, 0.85 mmol), 2-(3,5-dichlorophenylamino)acetic acid (126 mg, 0.57 mmol) and DIEA (147 mg, 1.14 mmol) at 0° C. The reaction mixture was stirred at rt overnight, diluted with EtOAc and washed with water. The aqueous layer was extracted with the EtOAc, the combined organic layer was dried over Na2SO4 and evaporated in vacuo to give the crude compound that was purified by column chromatography (silica gel, gradient MeOH in CH2Cl2) to afford (25 g, 9%) of the titled compound. 1H NMR (400 MHz, CD3OD): δ 8.29 (s, 1H), 6.61-6.60 (d, 1H), 6.59-6.58 (m, 2H), 4.28-4.01 (m, 1H), 3.99-3.95 (m, 2H), 3.68-3.66 (t, J=4.4 Hz, 1H), 3.57-3.54 (t, J=4.4 Hz, 1H), 3.34 (s, 3H), 3.08-2.97 (m, 3H), 2.60-2.53 (m, 2H), 2.03-2.00 (m, 2H), 1.43-1.26 (m, 3H). LC-MS: m/z [M+1]=463.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[O:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[O:33][CH:34]1[CH2:38][CH2:37][CH2:36][CH:35]1[CH2:39]O>C(Cl)Cl.O>[I:25][CH2:39][CH:35]1[CH2:36][CH2:37][CH2:38][CH:34]1[O:33][CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32][O:27]1
Reactant: II
Reactant: OCC1CCCC1OC1CCCCO1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: ICC1CCCC1OC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.6 %

Procedure:
A solution of triphenylphosphine (1.70 g, 6.49 mmol) and imidazole (884 mg, 12.98 mmol) in methylene chloride (8.32 mL) cooled to 0° C. was treated with iodine (1.64 g, 6.49 mmol). After the iodine was completely dissolved, a solution of [2-(tetrahydro-pyran-2-yloxy)-cyclopentyl]-methanol (1.0 g, 4.99 mmol) was added to the reaction mixture. The reaction was stirred at 0° C. for 1 h and at 25° C. for 2 h. At this time, the reaction was poured into water (100 mL) and extracted with methylene chloride (1×30 mL). The organics were washed with a saturated aqueous sodium thiosulfate solution (1×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo at 25° C. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded 2-(2-iodomethyl-cyclopentyloxy)-tetrahydropyran (1.17 g, 75.8%) as a clear liquid: EI-HRMS m/e calcd for C11H19IO2 (M+) 309.0352. found 309.0348.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([CH:13]([CH3:15])[CH3:14])[C:5]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[PH2:22])([CH3:3])[CH3:2].[CH3:23][C:24](=[CH:26][C:27](=[O:32])[CH:28]=[C:29]([CH3:31])[CH3:30])[CH3:25]>>[CH3:30][C:29]1([CH3:31])[CH2:28][C:27](=[O:32])[CH2:26][C:24]([CH3:25])([CH3:23])[P:22]1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:5]1[C:6]([CH:13]([CH3:14])[CH3:15])=[CH:7][C:8]([CH:10]([CH3:11])[CH3:12])=[CH:9][C:4]=1[CH:1]([CH3:2])[CH3:3]
Reactant: CC(C)c1cc(C(C)C)c(-c2ccccc2P)c(C(C)C)c1
Reactant: CC(C)=CC(=O)C=C(C)C
Product: CC(C)c1cc(C(C)C)c(-c2ccccc2P2C(C)(C)CC(=O)CC2(C)C)c(C(C)C)c1
Temperature: 25 °C
Yield: 76.1 %

Procedure:
A flask was charged with 10.8 g of (2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (66% potent, 7.13 g, 22.8 mmol, 1.0 equiv) and 6.6 g of 2,6-dimethyl-2,5-heptadien-4-one (47.7 mmol, 2.1 equiv). The vessel was purged with argon gas and immersed in an oil bath at 170° C. with magnetic stirring. The flask was sealed with a Teflon stopcock and the reaction was allowed to proceed under a static argon atmosphere. The flask was removed from the oil bath after 14 h and the contents allowed to cool to room temperature under argon gas. Anhydrous ethanol (70 mL) was added to the unpurified solids and the solids were broken up manually. The slurry was warmed to 80° C., held for an hour, and cooled to room temperature. The product was isolated by filtration, washes with ethanol and dried in vacuo to give 7.82 g of 2,2,6,6-tetramethyl-1-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphinan-4-one (98 area % by HPLC, 74% yield).
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[O:10][C:11]1[CH:12]=[C:13]2[O:19][C:18]([CH2:20]O)=[CH:17][C:14]2=[N:15][CH:16]=1.S(Cl)([Cl:24])=O>C(Cl)Cl>[Cl:24][CH2:20][C:18]1[O:19][C:13]2[C:14](=[N:15][CH:16]=[C:11]([O:10][C:2]3[S:1][C:9]4[C:4]([N:3]=3)=[N:5][CH:6]=[CH:7][CH:8]=4)[CH:12]=2)[CH:17]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc2ncc(Oc3nc4ncccc4s3)cc2o1
Solvent: ClCCl
Product: ClCc1cc2ncc(Oc3nc4ncccc4s3)cc2o1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98.1 %

Procedure:
To a suspension of [6-(thiazolo[4,5-b]pyridin-2-yloxy)-furo[3,2-b]pyridin-2-yl]-methanol (50 mg, 0.17 mmol) in DCM (1.6 mL) was added thionyl chloride (0.020 mL, 0.25 mmol). After 5 min, more thionyl chloride (0.020 mL, 0.25 mmol) was added to the suspension. After 2 h, additional thionyl chloride (0.020 mL, 0.25 mmol) was added. The solution was stirred (rt, 16 h) and concentrated to remove all volatiles to provide the product as a beige solid (53 mg, 99%). MS (ESI): mass calcd. for C14H8ClN3O2S, 317.00; m/z found, 317.9 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:11]2[CH2:16][CH2:15][C@:14]([CH2:23][CH3:24])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:13][C:12]2=[O:25])[CH2:9][CH3:10])=[CH:4][CH:3]=1.I[C:27]1[CH:32]=[CH:31][N:30]([CH3:33])[C:29](=[O:34])[CH:28]=1>>[CH2:23]([C@@:14]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:13][C:12](=[O:25])[N:11]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:27]3[CH:32]=[CH:31][N:30]([CH3:33])[C:29](=[O:34])[CH:28]=3)=[CH:3][CH:4]=2)[CH2:9][CH3:10])[CH2:16][CH2:15]1)[CH3:24]
Reactant: CC[C@@H](c1ccc(Br)cc1)N1CC[C@](CC)(c2ccccc2)OC1=O
Reactant: Cn1ccc(I)cc1=O
Product: CC[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CC[C@](CC)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)propyl)-6-ethyl-6-phenyl-1,3-oxazinan-2-one following procedures analogous to those described in Example 32 Method 2 Steps 3 and 4 using 4-iodo-1-methylpyridin-2(1H)-one in Step 4. LC-MS Method 1 tR=1.58 min, m/z=431 (M+1); 1H NMR (CDCl3) 7.33 (1H, d, J=7.03 Hz), 7.29-7.21 (7H, m), 7.01 (2H, d, J=8.20 Hz), 6.75 (1H, d, J=2.05), 6.39 (1H, dd, J=2.05, 7.03), 5.48 (1H, ap dd, J=6.44, 9.66), 3.58 (3H, s), 2.95-2.87 (1H, m), 2.37-2.14 (3H, m), 2.06-1.81 (m, 4H), 1.00 (3H, t, J=7.32), 082 (3H, t, J=7.61).
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:17]=[C:16]3[C:12]([C:13]([C:18](=O)[CH3:19])=[CH:14][NH:15]3)=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)(=O)C>C(O)C.[Pd]>[CH2:18]([C:13]1[C:12]2[C:16](=[CH:17][C:9]([C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)=[O:8])=[CH:10][CH:11]=2)[NH:15][CH:14]=1)[CH3:19]
Reactant: CC(=O)c1c[nH]c2cc(C(=O)N3CCOCC3)ccc12
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCc1c[nH]c2cc(C(=O)N3CCOCC3)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-(6-(Morpholine-4-carbonyl)-1H-indol-3-yl)ethanone (730 mg, 2.68 mmol) in acetic acid (1.53 ml, 26.8 mmol) and ethanol (50 ml) was hydrogenated in the presence of 10% Pd/C (285 mg, 0.27 mmol) for 72 h at room temperature, and then for 3 h at 50° C. After cooling to room temperature, the suspension was filtered over Celite and washed with ethanol. The solvent was evaporated and the residue repeatedly co-distilled with toluene and dichloromethane. White solid. Yield: 228 mg (33% of theory). HPLC-MS: m/z [M+H]+=259
Reaction SMILES: [O:1]=[C:2]([N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)[C@H:3]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[N:14](C(OC(C)(C)C)=O)[CH:15]=[C:16]([C:17]([O:19]C)=[O:18])[C:9]=12)[CH2:4][CH3:5].CO.[OH-].[Na+]>C1COCC1>[O:1]=[C:2]([N:28]1[CH2:29][CH2:30][CH2:31][CH2:32]1)[C@H:3]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[NH:14][CH:15]=[C:16]([C:17]([OH:19])=[O:18])[C:9]=12)[CH2:4][CH3:5]
Reactant: CC[C@@H](NCc1ccnc2c1c(C(=O)OC)cn2C(=O)OC(C)(C)C)C(=O)N1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC[C@@H](NCc1ccnc2[nH]cc(C(=O)O)c12)C(=O)N1CCCC1
Temperature: 53 °C
Reaction time: 16 h
Yield: 7.7 %

Procedure:
To a 20 mL round bottom flask with a stirrer was added (R)-1-tert-butyl 3-methyl 4-((1-oxo-1-(pyrrolidin-1-yl)butan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (150 mg, 0.337 mmol), MeOH (1 mL) and THF (1 mL). Aqueous NaOH (12 N, 1 mL) was added and the reaction mixture was stirred at 53° C. for 16 h. The solvent was removed and the resulting residue was further purified via preparative mass trigger LC-MS (AcCN/H2O, 5-50%). The fractions were collected, concentrated, and dried in vacuo to afford the title compound as a yellow oil (8.7 mg, 0.026 mmol, 7.80%). [M+H] calc'd for C17H22N4O3, 331; found, 331.6.
Reaction SMILES: C([O-])(O)=O.[Na+].[C:6](=[S:9])([NH2:8])[CH3:7].Cl[CH2:11][C:12]([C:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([NH:23][C:24](=[O:40])[C:25]3[C:30]([F:31])=[CH:29][CH:28]=[C:27]([NH:32][S:33]([CH2:36][CH2:37][CH3:38])(=[O:35])=[O:34])[C:26]=3[F:39])[CH:21]=2)[NH:16][CH:15]=1)=O.CO>C1COCC1>[F:39][C:26]1[C:27]([NH:32][S:33]([CH2:36][CH2:37][CH3:38])(=[O:34])=[O:35])=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[C:24]([NH:23][C:20]1[CH:21]=[C:22]2[C:14]([C:12]3[N:8]=[C:6]([CH3:7])[S:9][CH:11]=3)=[CH:15][NH:16][C:17]2=[N:18][CH:19]=1)=[O:40]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(C(=O)CCl)c3c2)c1F
Reactant: CC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(-c4csc(C)n4)c3c2)c1F
Temperature: 70 °C
Reaction time: 9 h
Yield: 18.5 %

Procedure:
NaHCO3 (0.00098 g, 0.012 mmol) and ethanethioamide (0.00096 g, 0.013 mmol) were added to N-(3-(2-chloroacetyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (0.005 g, 0.011 mmol) in THF (0.1 mL), and the reaction mixture was warmed to 70° C. for 4 hours. MeOH (0.2 mL) was added, along with another equivalent of ethanethioamide (0.00096 g, 0.013 mmol) and NaHCO3 (0.00098 g, 0.012 mmol). After 9 hours at 70° C., the reaction mixture was cooled and partitioned between EtOAc and aqueous sodium bicarbonate. The organic layers were dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified via column chromatography (10% MeOH-DCM) to provide 2,6-difluoro-N-(3-(2-methylthiazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (1 mg, 19%). 1H NMR (400 MHz, CHCl3-d1) δ 8.84-8.85 (m, 1H), 7.86 (s, 1H), 7.60-7.66 (m, 1H), 7.32 (s, 1H), 7.02-7.06 (m, 1H), 3.06-3.12 (m, 2H), 2.80 (s, 3H), 1.85-1.93 (m, 2H), 1.04-1.08 (m, 3H); m/z (APCI-pos) M+1=492.1.
Reaction SMILES: O.NN.[C:4]([C:6]1[CH:7]=[C:8]([CH:21]=[CH:22][CH:23]=1)[CH2:9][N:10]1C(=O)C2=CC=CC=[C:12]2[C:11]1=[O:20])#[N:5].Cl>CO.O1CCCC1>[C:4]([C:6]1[CH:7]=[C:8]([CH:21]=[CH:22][CH:23]=1)[CH2:9][NH:10][C:11](=[O:20])[CH3:12])#[N:5]
Reactant: N#Cc1cccc(CN2C(=O)c3ccccc3C2=O)c1
Agent: Cl
Agent: NN
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(=O)NCc1cccc(C#N)c1
Yield: 66 %

Procedure:
A solution of hydrazine hydrate (4.0 g) in methanol was added dropwise to a mixture of N-(3-cyanobenzyl)phthalimide (17.0 g) in tetrahydrofuran (150 ml) and methanol (120 ml) at ambient temperature under stirring and the resultant mixture was stirred for 3 hours at ambient temperature. To the reaction mixture was added dropwise 6N-hydrochloric acid (25 ml) and the mixture was stirred for one hour at ambient temperature. The reaction mixture was evaporated in vacuo. To the residue was added water (60 ml) and the mixture was stirred at 10 minutes and filtrated. The filtrate was washed with ethyl acetate and adjusted to pH 8.0 with 20% potassium carbonate solution. Acetic anhydride (15 ml) was added dropwise to the resulting solution at 8° to 20° C. under stirring and the mixture was stirred for one hour at 10° to 20° C. The reaction mixture was extracted with ethyl acetate, and extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was recrystallized from a mixture of ethyl acetate and diisopropyl ether to give N-(3-cyanobenzyl)acetamide (7.45 g).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([NH:10][OH:11])(=O)[CH3:8].[F:12][C:13]1C=[CH:19][CH:18]=[C:17](F)[C:14]=1C#N.C[N:23](C)C=O>>[NH2:23][C:7]1[C:8]2[C:13]([F:12])=[CH:14][CH:17]=[CH:18][C:19]=2[O:11][N:10]=1
Reactant: CN(C)C=O
Reactant: CC(=O)NO
Reactant: N#Cc1c(F)cccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: Nc1noc2cccc(F)c12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
4.00 g (35.65 mmol) of potassium tert-butoxide and 2.60 g (34.64 mmol) of acetohydroxamic acid are dissolved in 50 ml of dry dimethylformamide and stirred at room temperature for 45 minutes. After the addition of 3.30 g (23.72 mmol) of 2,6-difluorobenzonitrile, the mixture is stirred at 50° C. for 16 hours. The mixture is concentrated under reduced pressure, and the residue is dissolved in dichloromethane and washed with water. After drying and concentration of the organic phase, 3.2 g of a yellow resin are obtained, which, according to 1H NMR, is about 85% pure.
Reaction SMILES: [C:1]([O-:4])([O-:3])=[O:2].[K+].[K+].O[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:19])[C:16]([CH3:18])=[CH2:17]>O1CCCC1>[C:16]([O:2][C:1]([O:4][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:19])[C:16]([CH3:18])=[CH2:17])=[O:3])([CH3:18])([CH3:17])[CH3:15]
Reactant: C=C(C)C(=O)Nc1ccccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)C(=O)Nc1ccccc1OC(=O)OC(C)(C)C

Procedure:
K2CO3 (30 g) is added to a solution of 20.0 g (0.112 tool) of N-(2-hydroxyphenyl)methacrylamide in tetrahydrofuran (THF). A solution of 27 g (0.124 tool) of di-tert-butyl pyrocarbonate (di-tert-butyl dicarbonate) in THF is then added dropwise at room temperature while stirring. The reaction is complete after a few hours. The reaction mixture is poured onto ice and extracted with ethyl acetate, the organic phase is dried and the solvent is distilled off. A yellowish oil is obtained which decomposes on distillation. The product is used for polymerization without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:55])[C@H:4]([N:41]1[CH2:45][CH2:44][C@H:43]([NH:46]C(OC(C)(C)C)=O)[C:42]1=[O:54])[CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][C:17]([F:20])([F:19])[F:18])[C:12]([NH:21]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[N:11][CH:10]=[CH:9]2.[ClH:56]>C(Cl)Cl>[ClH:56].[ClH:56].[CH3:1][O:2][C:3](=[O:55])[C@H:4]([N:41]1[CH2:45][CH2:44][C@H:43]([NH2:46])[C:42]1=[O:54])[CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][C:17]([F:19])([F:20])[F:18])[C:12]([NH2:21])=[N:11][CH:10]=[CH:9]2
Reactant: COC(=O)[C@@H](Cc1cc2ccnc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)c2cc1OC(F)(F)F)N1CC[C@H](NC(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@@H](Cc1cc2ccnc(N)c2cc1OC(F)(F)F)N1CC[C@H](N)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 1.09 g (1.45 mmol) of (R)-2-((S)-3-tert-Butoxycarbonylamino-2-oxo-pyrrolidin-1-yl)-3-[7-trifluoromethoxy-1-(trityl-amino)-isoquinolin-6-yl]-propionic acid methyl ester, dissolved in 6 ml abs. CH2Cl2, 1.7 ml (6 eq) etheric HCl-solution are added at 0° C. The reaction mixture is stirred for 3 h at this temperature. After warming up to r.t., the solid product is isolated by filtration: 588 mg are obtained.