Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:9]([CH2:10][CH3:11])=[N:8][C:7]2[N:12]([CH2:15][CH3:16])[N:13]=[CH:14][C:6]=2[C:5]=1[NH:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.[CH3:24][C:25]([CH3:32])([C:29](O)=[O:30])[C:26]([OH:28])=[O:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[CH2:15]([N:12]1[C:7]2=[N:8][C:9]([CH2:10][CH3:11])=[C:4]([CH2:3][NH:2][C:29](=[O:30])[C:25]([CH3:32])([CH3:24])[C:26]([OH:28])=[O:27])[C:5]([NH:17][CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[C:6]2[CH:14]=[N:13]1)[CH3:16]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Reactant: CC(C)(C(=O)O)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)C(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.5 %

Procedure:
A mixture of 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine hydrochloride (400 mg, 1.18 mmol), dimethylpropanedioic acid (156 mg, 1.18 mmol), HBTU (535 mg, 1.41 mmol) and Et3N (0.82 mL, 5.89 mmol) in DCM (8 mL) was stirred at room temperature overnight. It was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were washed with water followed by a brine wash. The organic layers were dried over sodium sulfate, filtered, concentrated and purified with CombiFlash eluting with 10% methanol in DCM. The product fractions were combined and concentrated to give 3-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-2,2-dimethyl-3-oxopropanoic acid as a solid (165 mg, 34%). LC-MS m/z 418 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][C@H:20]2[C@H:18]([CH2:19]2)[C@H:17]1[CH:22]=O)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[C:9]([O:13][C:14]([N:16]1[CH2:21][C@H:20]2[C@H:18]([CH2:19]2)[C@H:17]1[CH2:22][NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H]2[C@H]1C=O
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H]2[C@H]1CNCc1ccccc1
Reaction time: 15 h

Procedure:
Benzylamine (2.95 mmol, 1.2 eq) is added to a solution of (1S,2S,5R)-2-Formyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (2.46 mmol, 1.0 eq) in chloroform (6.0 mL). After 10 min the mixture is treated with sodium triacetoxyborohydride (2.95 mmol), stirred for additional 15 h and poured into a sat. aq. NaHCO3 solution. The layers are separated and the aq. layer is extracted once with chloroform. The combined organic layers are washed twice with sat. NaHCO3 solution and water. The solvents are removed in vacuo and the residue is dissolved in ether (30 mL). Aq. HCl (0.1 M, 40 mL) is added, the layers are separated and the organic layer is extracted twice with aq. HCl (0.1 M, 30 mL each). The combined aq. layers are washed with ether (20 mL), made alkaline by addition of NaOH solution (1.0 M, 20 mL) and extracted three times with ether (40 mL each). The combined organic layers are dried over MgSO4 and concentrated in vacuo to give a crude product which is used without further purification. LC-MS (basic): tR=0.96 min; [M+H]+=303.3.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([OH:10])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].[CH2:13]([O:15][CH2:16]Cl)[CH3:14].O>CN(C=O)C>[CH2:13]([O:15][CH2:16][O:10][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH:2]=[CH:3][C:4]=2[CH:9]=1)[CH3:14]
Reactant: CCOCCl
Reactant: Oc1ccc2occc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCOc1ccc2occc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of benzofuran-5-ol (2) (257 mg, 1.92 mmol) in DMF (3 mL), NaH (81 mg, 1.92 mmol, 57% dispersion in oil) was added at 0° C. The reaction mixture was warmed to room temperature and stirred 1 hour. Chloromethyl ethyl ether (214 μL, 2.30 mmol) was then added drop wise to 0° C. and the mixture was stirred at room temperature for additional 1 hour. Water (10 mL) was added and the reaction mixture was extracted with ethyl acetate (2×50 mL). The organic extracts were washed with water, brine, dried over Na2SO4, and concentrated in vacuo. Purification of the crude product by flash column chromatography using 10% ethyl acetate in hexane afforded compound (3) (273 mg) as a colourless oil.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:8])[CH2:4][C:5](Cl)=[O:6].O>ClCCl.FC(F)(F)S([O-])(=O)=O.[Sc+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[Cl:1][CH2:2][C:3]1[O:8][C:3]([CH2:2][Cl:1])=[CH:4][C:5](=[O:6])[CH:4]=1
Reactant: O=C(Cl)CC(=O)CCl
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: O
Solvent: ClCCl
Product: O=c1cc(CCl)oc(CCl)c1
Yield: 0.1 %

Procedure:
4-Chloroacetoacetyl chloride (14.8 g, 33.4 mol) in dichloromethane (35% strength solution) and scandium trifluoromethanesulphonate (1.45 g, 2.5 mol) were stirred at 25° C. for 6.5 days under a nitrogen atmosphere. Water (10 g, 0.55 mol) was then added and the organic phase was concentrated. 4.2 g of product were obtained (according to GC 68% crude product). After chromatography on a silica gel column, 0.7 g of pure product corresponding to a yield of 10.8% were obtained.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]2[CH2:15][NH:14][C:13]2=[O:16])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17](Cl)([Cl:19])=[O:18].C1(C)C=CC=CC=1>ClCCl>[Cl:19][C:17]([N:14]1[CH2:15][C@H:12]([NH:11][C:9]([O:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:10])[C:13]1=[O:16])=[O:18]
Reactant: O=C(N[C@H]1CNC1=O)OCc1ccccc1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(N[C@H]1CN(C(=O)Cl)C1=O)OCc1ccccc1
Temperature: -10 °C

Procedure:
(S)-3-[[(Phenylmethoxy)carbonyl]amino]-2-azetidinone was suspended in 5 ml of dichloromethane and cooled to -10° C. A solution of 12.5% phosgene in toluene (2.9 ml, 3.4 mmol) was added dropwise to the rapidly stirring mixture. After stirring at -10° C. for 2 hours, the volatiles were evaporated without external heating. The residue was cooled to -10° C. and dissolved in 5 ml of dichloromethane to give (S)-1-chlorocarbonyl-3-[[(phenylmethoxy)carbonyl]amino]-2-azetidinone. The compound was not characterized, but was used as a crude intermediate.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][O:21][CH2:22][C@H:23]([O:28][C:29]1[N:34]=[CH:33][N:32]=[C:31]2[N:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[Cl:44])[N:36]=[CH:37][C:30]=12)[C:24]([O:26]C)=O)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1C=CC=CC=1)[C:2]1C=CC=CC=1.[Cl:45][C:46]1[CH:47]=[CH:48][C:49]([NH2:52])=[N:50][CH:51]=1>>[Si:1]([O:18][CH2:19][CH2:20][O:21][CH2:22][C@H:23]([O:28][C:29]1[C:30]2[CH:37]=[N:36][N:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[Cl:44])[C:31]=2[N:32]=[CH:33][N:34]=1)[C:24]([NH:52][C:49]1[CH:48]=[CH:47][C:46]([Cl:45])=[CH:51][N:50]=1)=[O:26])([C:14]([CH3:15])([CH3:17])[CH3:16])([CH3:8])[CH3:2]
Reactant: COC(=O)[C@H](COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ncnc2c1cnn2-c1ccccc1Cl
Reactant: Nc1ccc(Cl)cn1
Product: CC(C)(C)[Si](C)(C)OCCOC[C@H](Oc1ncnc2c1cnn2-c1ccccc1Cl)C(=O)Nc1ccc(Cl)cn1

Procedure:
Prepared from (2S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate (Intermediate AG2) (950 mg, 1.51 mmol) according to the method for Intermediate AE3 using 5-chloropyridin-2-amine. 1H NMR (400 MHz, DMSO) δ 0.88 (9H, s), 3.71-3.84 (4H, m), 4.02-4.07 (1H, m), 4.13-4.18 (1H, m), 5.97-5.99 (1H, m), 7.34-7.43 (6H, m), 7.56-7.67 (7H, m), 7.74-7.77 (1H, m), 7.86-7.89 (1H, m), 8.00-8.03 (1H, m), 8.40-8.41 (1H, m), 8.52 (1H, s), 8.57 (1H, s), 11.25 (1H, s); m/z (ESI+) (M+H)+=727; HPLC tR=3.49 min.
Reaction SMILES: FC(F)(F)C(O)=O.C([SiH](CC)CC)C.C1(C([O:28][C:29]([C:31]2[N:32]3[CH:35]([CH2:36][CH2:37][C:38]=2[S:39][C:40]2[S:41][C:42]([NH2:45])=[N:43][N:44]=2)[C@@H:34]([NH:46][C:47](=[O:77])/[C:48](/[C:70]2[N:71]=[C:72]([NH2:76])[S:73][C:74]=2[Cl:75])=[N:49]\[O:50]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:33]3=[O:78])=[O:30])C2C=CC=CC=2)C=CC=CC=1>ClCCl>[NH2:76][C:72]1[S:73][C:74]([Cl:75])=[C:70](/[C:48](=[N:49]/[OH:50])/[C:47]([NH:46][C@H:34]2[C:33](=[O:78])[N:32]3[CH:35]2[CH2:36][CH2:37][C:38]([S:39][C:40]2[S:41][C:42]([NH2:45])=[N:43][N:44]=2)=[C:31]3[C:29]([OH:30])=[O:28])=[O:77])[N:71]=1
Reactant: Nc1nnc(SC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@H](NC(=O)/C(=N\OC(c4ccccc4)(c4ccccc4)c4ccccc4)c4nc(N)sc4Cl)C3CC2)s1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nnc(SC2=C(C(=O)O)N3C(=O)[C@H](NC(=O)/C(=N\O)c4nc(N)sc4Cl)C3CC2)s1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of trifluoroacetic acid (10 mL), triethylsilane (5 mL) and dichloromethane (10 mL) was cooled to 0° C. and (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(triphenylmethoxyimino]acetamido]-3-[5-amino-1,3,4-thiadiazol-2-ylthio]-8-oxo-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate diphenylmethyl ester from the previous step (2.3 g) was added in portions. The reaction mixture was stirred for 3 hours at 0° C., allowed to warm up to room temperature and evaporated to dryness. The residue was treated with diethyl ether (50 mL) and the solid that formed was filtered and dried to give 2.4 g of crude product. The crude product was purified on HP 20 initially with water elution until the pH was neutral, after which the product was eluted with acetonitrile:water 80:20. The solvent was evaporated to give the 0.65 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([S:7]([NH:10][C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[F:18])(=[O:9])=[O:8])[C:3]=1[C:19]([O:21][CH3:22])=[O:20].[C:23](OCC)(OCC)([O:25][CH2:26]C)[CH3:24]>C(O)(=O)C.C(#N)C>[F:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[NH:10][S:7]([C:4]1[C:3]([C:19]([O:21][CH3:22])=[O:20])=[C:2]([N:1]=[C:23]([O:25][CH3:26])[CH3:24])[NH:6][N:5]=1)(=[O:8])=[O:9]
Reactant: CCOC(C)(OCC)OCC
Reactant: COC(=O)c1c(S(=O)(=O)Nc2c(F)cccc2F)n[nH]c1N
Solvent: CC#N
Solvent: CC(=O)O
Product: COC(=O)c1c(S(=O)(=O)Nc2c(F)cccc2F)n[nH]c1N=C(C)OC

Procedure:
5.0 g (15mmol) 5-amino-N-(2,6-difluorophenyl)-4-methoxycarbonylpyrazole-3-sulphonamide was heated under reflux with 50 ml acetonitrile, 2.1 ml (17.5 mmol) triethyl orthoacetate and 3 drops acetic acid for 8 hours. The undissolved residue was filtered and the filtrate concentrated. The residue was chromatographed with hexane/ethyl acetate over silica gel and recrystallised from ether.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH2:16][CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[S:10][CH:11]=1.[CH2:18]([Sn](CCCC)(CCCC)C=C)[CH2:19]CC>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>[CH:18]([C:2]1[CH:3]=[N:4][N:5]([CH2:16][CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[S:10][CH:11]=1)=[CH2:19]
Reactant: CCn1ncc(Br)c1-c1csc(C(=O)OC)c1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C=Cc1cnn(CC)c1-c1csc(C(=O)OC)c1
Temperature: 90 °C
Yield: 89.9 %

Procedure:
A mixture of methyl 4-(4-bromo-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (200 mg, 0.64 mmol), Pd(Ph3P)4 (73.3 mg, 0.06 mmol), and tributyl(ethenyl)stannane (302 mg, 0.95 mmol) was heated at 90° C. for 1 h under N2 in a sealed tube. The mixture was purified on Silica (10P/0-20% EtOAc in Hex) to give the title compound (151 mg, 76%): LC-MS (ES) m/z 263 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][C:18]([F:21])([F:20])[F:19])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1.Cl>>[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([N:10]2[C:11]3[C:16](=[CH:15][C:14]([O:17][C:18]([F:21])([F:19])[F:20])=[CH:13][CH:12]=3)[C:8]([C:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH:6]=3)=[CH:9]2)=[O:28])=[CH:25][CH:24]=1
Reactant: CN1CC=C(c2c[nH]c3ccc(OC(F)(F)F)cc23)CC1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Product: CN1CC=C(c2cn(C(=O)c3ccc(F)cc3)c3ccc(OC(F)(F)F)cc23)CC1

Procedure:
(19.2 mg, 59%); from 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-5-trifluoromethoxy-1H-indole (Example 4h, 20 mg, 0.068 mmol) and 4-fluorobenzoyl chloride (17.0 mg, 0.107 mmol), HRMS-FAB+ for C22H18N2O2F4.HCl, calculated MH (-HCl): 419.13828; found: 419.13870.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[N:22]=3)[CH:16]=2)=[CH:11][C:10]=1[O:31][CH3:32])C1C=CC=CC=1.Br.C(O)(=O)C>ClCCl>[CH3:32][O:31][C:10]1[CH:11]=[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[N:22]=3)[CH:16]=2)[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: COc1cc(-c2cccc(-c3cccc(C(F)(F)F)n3)c2)ccc1OCc1ccccc1
Agent: Br
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc(-c2cccc(-c3cccc(C(F)(F)F)n3)c2)ccc1O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 2-(4′-(benzyloxy)-3′-methoxybiphenyl-3-yl)-6-(trifluoromethyl)pyridine (1.061 g, 2.44 mmol) in dichloromethane (20 mL) cooled in an ice-water bath was added a 30% solution of hydrogen bromide in acetic acid (4 mL, 20 mmol) dropwise. The resulting solution was allowed to stir at room temperature for six hours then poured onto ice-water (100 mL). The phases were separated and the aqueous phase was extracted with dichloromethane (10 mL). The combined organic layers were washed with water and brine, then dried over anhydrous sodium sulphate and filtered. Evaporation of the solvent left a brown oil that was chromatographed over silica gel (petroleum ether/ethyl acetate, 4:1) to give 3-methoxy-3′-(6-(trifluoromethyl)pyridin-2-yl)biphenyl-4-ol as a clear oil, 0.547 g (65%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([N:14]3[CH2:19][CH2:18][N:17]([S:20]([CH2:23][C@H:24]([CH:29]([CH3:31])[CH3:30])[C:25]([NH:27][OH:28])=[O:26])(=[O:22])=[O:21])[CH2:16][CH2:15]3)=N[CH:13]=2)=[CH:4][CH:3]=1.F[C:33]1C=CC(C2C=CC(N3CCN(S(C[C@H](C(C)C)C(O)=O)(=O)=O)CC3)=NC=2)=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:33][C:11]([N:14]3[CH2:19][CH2:18][N:17]([S:20]([CH2:23][C@H:24]([CH:29]([CH3:31])[CH3:30])[C:25]([NH:27][OH:28])=[O:26])(=[O:22])=[O:21])[CH2:16][CH2:15]3)=[N:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ccc(-c3ccc(F)cc3)cn2)CC1)C(=O)O
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)NO
Product: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ccc(-c3ccc(F)cc3)cn2)CC1)C(=O)NO
Yield: 61 %

Procedure:
Prepared according to the method for the preparation of 2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-N-hydroxy-3-methylbutyramide, from 2-(R)-{4-[5-(4-fluorophenyl)pyridin-2-yl]piperazine-1-sulfonylmethyl}-3-methylbutyric acid (0.072 g), to give the title compound as a white solid (0.047 g, 61%).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl>[CH3:16][S:17]([O:1][CH2:2][C@@H:3]1[CH2:4][CH2:5][C:6](=[O:8])[NH:7]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1CC[C@@H](CO)N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@@H]1CCC(=O)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (5S)-5-(hydroxymethyl)pyrrolidin-2-one (1.0 g, 8.69 mmol) in dichloromethane (40 mL) at 0° C. was added triethylamine (1.816 mL, 13.03 mmol) followed by dropwise addition of methanesulfonyl chloride (0.812 mL, 10.42 mmol). The resulting mixture was stirred at room temperature for two hours, and then it was partitioned between water and dichloromethane (3×). The organic extracts were combined and dried over Na2SO4, the drying agent was removed by filtration, and the solution was concentrated in vacuo to give the title compound as a colorless, waxy solid (1.68 g, quantitative).
Reaction SMILES: C([O:4][C:5]([C@@H:7]1[CH2:22][C@@:15]2([C:19](=[O:20])[NH:18][C:17](=[O:21])[NH:16]2)[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:23])[CH:13]=2)[O:8]1)=O)CC.O.[NH2:25][NH2:26]>C(O)C>[F:23][C:12]1[CH:13]=[C:14]2[C@:15]3([C:19](=[O:20])[NH:18][C:17](=[O:21])[NH:16]3)[CH2:22][C@@H:7]([C:5]([NH:25][NH2:26])=[O:4])[O:8][C:9]2=[CH:10][CH:11]=1
Reactant: NN
Reactant: CCCOC(=O)[C@@H]1C[C@]2(NC(=O)NC2=O)c2cc(F)ccc2O1
Solvent: O
Solvent: CCO
Product: NNC(=O)[C@@H]1C[C@]2(NC(=O)NC2=O)c2cc(F)ccc2O1
Yield: 46.7 %

Procedure:
To a solution of (2S,4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carboxylic acid n-propyl ester (30.0 g, 93.1 mmol) in 600 ml of ethanol was added hydrazine hydrate (46.6 g, 0.931 mol). After refluxing the mixture under an argon atmosphere for 2 hours, the reaction mixture was evaporated in vacuo to dryness. To the residue was added 100 ml of saturated aqueous sodium chloride and the aqueous layer was extracted with ethyl acetate (300 ml×5). The combined ethyl acetate layers were washed with water, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to give 17.3 g (Yield: 63.1%) of crude crystals. The crystals were recrystallized from ethanol to give colorless needles of the desired compound (12.8 g, 46.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10](OS(C(F)(F)F)(=O)=O)[C:11]3[S:17][CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([OH:36])=[O:35])=[CH:29][CH:28]=1.CS(C)=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:26][C:27]3[CH:28]=[CH:29][C:30]([CH2:33][C:34]([OH:36])=[O:35])=[CH:31][CH:32]=3)[C:11]3[S:17][CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Oc1nc(-c2cccc(Cl)c2)nc2c1SCCC2)C(F)(F)F
Reactant: Nc1ccc(CC(=O)O)cc1
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)Cc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2SCCC3)cc1
Temperature: 110 °C
Reaction time: 6 h
Yield: 97 %

Procedure:
A 8-mL vial was charged with [2-(3-chlorophenyl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl]trifluoromethanesulfonate (100 mg, 0.243 mmol, 1 eq.), 2-(4-aminophenyl)acetic acid (37 mg, 0.245 mmol, 1 eq.) and DMSO (1 ml). The resulting mixture was stirred at 110° C. under Ar for 6 hr. After cooling to room temperature, water was added to the mixture (15 ml). The precipitate was collected by filtration and washed with water (15 ml). After drying, the title compound was obtained (97.5 mg, 97% yield). The product thus obtained was forwarded to the next step without any further purification.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([C:24]1[CH:25]=[C:26]2[C:31](=[O:32])[NH:30][C:28](=[O:29])[C:27]2=[CH:33][CH:34]=1)([OH:23])=[O:22].CCN(C(C)C)C(C)C>C(#N)C>[C:1]([N:30]1[C:31](=[O:32])[C:26]2=[CH:25][C:24]([C:21]([OH:23])=[O:22])=[CH:34][CH:33]=[C:27]2[C:28]1=[O:29])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1ccc2c(c1)C(=O)NC2=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1ccc2c(c1)C(=O)N(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2=O

Procedure:
To trityl chloride resin (5 g; 10.25 retool; 200-400 mesh: 1% divinylbenzene-crosslinked polystyrene) presoaked in 80 mL dry acetonitrile for 30 min., 5 g (26 mmol) 4-carboxyphthalimide (2) from Example 2 and 6 mL (34 mmol) DIPEA were added, and the suspension was refluxed for 72 h. Following filtration, the polymer was washed with 300 mL DMF and then 300 mL CH2Cl2. The loading was determined by weight difference, and confirmed to be 0.5 mmol/g resin by TFA-induced cleavage of 4-carboxyphthalimide from the resin.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](Br)=[C:6]([CH3:11])[CH:5]=1.[CH3:13][N:14](C=O)C>CCOC(C)=O.[Zn].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]([CH3:11])[CH:5]=1
Reactant: COC(=O)c1ccc(Br)c(C)c1
Reactant: CN(C)C=O
Agent: [Pd]
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C#N)c(C)c1
Temperature: 120 °C
Reaction time: 4 h
Yield: 39.8 %

Procedure:
Zinc cyamide (6.2 g, 52 mmol) and tetrakis(triphenylphosphine) palladium (0) (4 g, 3 mmol) was added to a solution of 4-bromo-3-methyl-benzoic acid methyl ester (20 g, 87 mmol) and DMF (100 mL) and stirred for 4 hours at 120° C. The reaction mixture was cooled to room temperature, diluted with EtOAc (700 mL), washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash chromatography (silica, 1:3 EtOAc:hexanes) provided the title compound (12.3 g, 39.8% yield) as a solid.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:44])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[N:23]=[C:24]([S:32]([CH3:35])(=[O:34])=[O:33])[N:25]5[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=45)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:44])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[N:23]=[C:24]([S:32]([CH3:35])(=[O:34])=[O:33])[N:25]5[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=45)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nc(S(C)(=O)=O)n4cc(F)ccc34)nc12)C(=O)N1CC(C#N)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3nc(S(C)(=O)=O)n4cc(F)ccc34)nc12)C(=O)N1CC(C#N)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 31.3 %

Procedure:
In a round-bottomed flask, 2-(6-fluoro-3-methanesulfonyl-imidazo[1,5-a]pyridin-1-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (0.024 g, 37.5 μmol, Eq: 1.00) was dissolved in dichloromethane (0.3 ml) and trifluoroacetic acid (0.12 ml, 1.6 mmol) was added. The reaction mixture was stirred at room temperature for 2.5 h then concentrated. The residue was redissolved in dichloromethane/methanol/ammonium hydroxide (60:10:1) (3.5 ml). The solution was stirred at room temperature overnight then concentrated. The residue was absorbed on silica gel and chromatographed with MeOH/CH2Cl2/0.5% NH4OH (gradient 0-7% MeOH) to afford 6 mg (30%) of 2-(6-fluoro-3-methanesulfonyl-imidazo[1,5-a]pyridin-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a yellow solid. MS: (M+H)+=511; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.92 (br. s., 1H), 9.17 (s, 1H), 9.01-9.10 (m, 1H), 8.95 (d, J=3.0 Hz, 1H), 8.47-8.53 (m, 1H), 8.42 (d, J=7.6 Hz, 1H), 7.43-7.53 (m, 1H), 4.51-4.80 (m, 3H), 4.27 (q, J=9.6 Hz, 1H), 4.11-4.21 (m, 1H), 3.81-3.94 (m, 1H), 3.57 (s, 3H), 1.40 (t, J=6.4 Hz, 3H).