Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][N:5]2[C:9]([CH:10]=1)=[C:8]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:7]([CH3:21])=[C:6]2[C:22](=[O:34])[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[C:25]([O:32][CH3:33])[CH:24]=1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>>[C:35]([NH:1][C:2]1[CH:3]=[CH:4][N:5]2[C:9]([CH:10]=1)=[C:8]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:7]([CH3:21])=[C:6]2[C:22](=[O:34])[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[C:25]([O:32][CH3:33])[CH:24]=1)(=[O:37])[CH3:36]
Reactant: COc1cc(C(=O)c2c(C)c(C(=O)OCc3ccccc3)c3cc(N)ccn23)ccc1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Product: COc1cc(C(=O)c2c(C)c(C(=O)OCc3ccccc3)c3cc(NC(C)=O)ccn23)ccc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
A suspension of 1.5 g (3.26 mmol) of benzyl [7-amino-3-(3-methoxy-4-nitrobenzoyl)-2-methylindolizin-1-yl]carboxylate in 10 mL of acetic anhydride is heated at 100° C. for 15 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10][C:9]=1[NH:15][CH2:16][C:17]([F:20])([F:19])[F:18].FC1C=CC=C(OC)C=1C1C=CN=CC=1N(CC(F)(F)F)[C:37](=[O:52])[C:38]1[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[C:40]([S:48]([CH3:51])(=[O:50])=[O:49])[CH:39]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10][C:9]=1[N:15]([CH2:16][C:17]([F:20])([F:18])[F:19])[C:37](=[O:52])[C:38]1[CH:43]=[C:42]([C:44]([F:47])([F:45])[F:46])[CH:41]=[C:40]([S:48]([CH3:51])(=[O:50])=[O:49])[CH:39]=1
Reactant: COc1cccc(F)c1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Reactant: Cc1cc(-c2ccccc2Cl)c(NCC(F)(F)F)cn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2ccccc2Cl)c(N(CC(F)(F)F)C(=O)c2cc(C(F)(F)F)cc(S(C)(=O)=O)c2)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(2-chlorophenyl)-6-methyl-N-(2,2,2-trifluoroethyl)pyridin-3-amine (0.066 g, 219 μmol) and 3-(methylsulfonyl)-5-(trifluoromethyl)benzoyl chloride (66.1 mg, 230 μmol, example 223, intermediate d) in CH2Cl2 (1 mL) was added DIPEA (56.7 mg, 76.7 μL, 439 μmol) and the clear yellow solution was stirred at room temperature for 4 hours. Another batch of 3-(methylsulfonyl)-5-(trifluoromethyl)benzoyl chloride (66.1 mg, 230 μmol, example 223, intermediate d) and DIPEA (56.7 mg, 76.7 μL, 439 μmol) were added and stirring was continued for another 48 hours. The compound was purified by silica gel chromatography on a 20 g column using an MPLC (ISCO) system eluting with EtOAc (isocratic). The product was further purified by preparative HPLC (Gemini NX column) using a gradient of MeOH:water (containing 0.1% formic acid) (20:80 to 98:2). Light brown solid (5%). MS (ESI): m/z=551.06 [M+H]+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12]/[C:11](=[CH:14]\[C:15]([O:17][CH2:18][CH3:19])=[O:16])/[CH:10]([CH3:20])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>>[CH3:20][CH:10]1[CH2:9][NH:8][CH2:13][CH2:12]/[C:11]/1=[CH:14]\[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)/C=C1\CCN(Cc2ccccc2)CC1C
Agent: CC(Cl)OC(=O)Cl
Product: CCOC(=O)/C=C1\CCNCC1C
Reaction time: 0.5 h

Procedure:
A mixture of ethyl (2E)-(1-benzyl-3-methylpiperidine-4-ylidene)acetate, 1-chloroethyl chloroformate and 1,2-dicholoroethane was stirred for 30 minutes heated to reflux and concentrated under reduced pressure. The residue was dissolved in EtOH and stirred for 10 minutes heated to reflux to give ethyl (2E)-(3-methylpiperidine-4-ylidene)acetate.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:17]([CH:18]([OH:23])[C:19]([F:22])([F:21])[F:20])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([NH:24]C(=O)OC(C)(C)C)[S:14]2)[C@H:10]1[O:32]CC1C=CC=CC=1)C1C=CC=CC=1.B(Cl)(Cl)Cl.CO.[NH4+].[OH-]>ClCCl>[NH2:24][C:13]1[S:14][C@H:15]2[O:16][C@H:17]([C@H:18]([OH:23])[C:19]([F:22])([F:21])[F:20])[C@@H:9]([OH:8])[C@H:10]([OH:32])[C@H:11]2[N:12]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](C(O)C(F)(F)F)O[C@@H]2S1
Agent: ClB(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: NC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H]([C@H](O)C(F)(F)F)O[C@@H]2S1

Procedure:
A solution of 142 (1 g, 1.7 mmol) in dichloromethane (30 mL) was treated with BCl3 (17 mL, 17 mmol, 1M dichloromethane) at −78° C. for 4 hours. The reaction was quenched by addition of methanol (10 mL). Removal of volatiles gave a residue, which was dissolved into methanol (5 mL) and neutralized with concentrated NH4OH (2 mL). After concentrated under reduced pressure, the crude product was purified by a silica gel column, eluted with 5%-20% methanol in dichloromethane to give a mixture of the above two compounds. Separation by Prep-HPLC with the following conditions (Column, Sun fire prep. C18; mobile phase, water with 0.03% NH4OH and CH3CN (10% up to 45% in 10 min); Detector, UV 220 nm) gave (3aR,5S,6S,7R,7aR)-2-amino-5-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]-3aH,5H,6H,7H,7aH-pyrano[3,2-d][1,3]thiazole-6,7-diol Example 164 as a light yellow solid (49 mg, 20%, faster eluting isomer); (ES, m/z): [M+H]+ 289.0; 1H NMR (400 MHz, D2O) δ 6.25 (d, J=6.8 Hz, 1H), 4.29-4.26 (m, 2H), 4.07 (t, J=4.0 Hz, 1H), 3.93 (dd, J=8.4, 3.2 Hz, 1H), 3.73 (dd, J=8.4, 4.8 Hz, 1H); and (3aR,5S,6S,7R,7aR)-2-amino-5-[(1R)-2,2,2-trifluoro-1-hydroxyethyl]-3aH,5H,6H,7H,7aH-pyrano[3,2-d][1,3]thiazole-6,7-diol as a light yellow solid (74 mg, 30%, slower eluting isomer); (ES, m/z): [M+H]+ 289.0; 1HNMR (400 MHz, D2O) δ 6.32 (d, J=6.4 Hz, 1H), 4.31 (q, J=7.6 Hz, 1H), 4.15 (t, J=6.0 Hz, 1H), 4.00 (t, J=5.0 Hz, 1H), 3.83-3.76 (m, 2H).
Reaction SMILES: [CH:1]1[N:9]2[C:4]([C:5]3([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)=[CH:3][CH:2]=1.ClS([N:30]=[C:31]=O)(=O)=O.CN(C=O)C>C1COCC1>[C:31]([C:1]1[N:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]3([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[C:4]2=[CH:3][CH:2]=1)#[N:30]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1ccccc1-n1cccc12
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1ccccc1-n1c(C#N)ccc12
Temperature: -75 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
To tert-butyl spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate (54.6 g, 160.5 mmol) in THF (500 mL) at −75° C. was added chlorosulfonyl isocyanate (17.5 mL, 200.6 mmol) in THF (100 mL) dropwise over a 30 minutes period keeping the temperature below −70° C. and the mixture was stirred at −75° C. for 1 hr. To this mixture was added DMF (37.3 mL, 481.5 mmol) dropwise at −75° C. and the mixture was warmed to ambient temperature, stirring for a total of 2 h. The mixture was quenched with 1 L of 1N NaOH and transferred to a separatory funnel with 500 mL of methyl-tert-butyl ether. The aqueous phase was separated and extracted with an additional 500 mL of methyl-tert-butyl ether. The combined organic phases were washed twice with 500 mL of brine, dried over MgSO4, filtered and concentrated in vacuo to yield a crude mixture that was purified by column chromatography with a 0-100% EtOAc/hexane gradient to yield tert-butyl 1-cyanospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-carboxylate (45 g, 76%) as an oil that crystallized upon standing. ESI-MS m/z calc. 365.2. found 266.2 (M-Boc+1)+. Retention time: 2.43 minutes (3 min run).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:20]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:18]=[C:17]([O:27][CH2:28][CH2:29][C:30]([OH:32])=O)[C:16]=2[O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[O:40][CH3:41])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:42]([C:45]1[CH:46]=[C:47]([CH:49]=[CH:50][CH:51]=1)[NH2:48])([CH3:44])[CH3:43]>>[CH:42]([C:45]1[CH:46]=[C:47]([NH:48][C:30](=[O:32])[CH2:29][CH2:28][O:27][C:17]2[C:16]([O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[O:40][CH3:41])=[C:15]([NH:14][S:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:10][CH:9]=3)(=[O:13])=[O:12])[N:20]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:18]=2)[CH:49]=[CH:50][CH:51]=1)([CH3:44])[CH3:43]
Reactant: CC(C)c1cccc(N)c1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCOCC2)nc1OCCC(=O)O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCOCC2)nc1OCCC(=O)Nc1cccc(C(C)C)c1

Procedure:
The procedure described in Example 2 was repeated by use of 3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-morpholino-4-pyrimidinyloxy]propionic acid and 3-isopropylaniline, to thereby obtain the title compound as a colorless oil.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][NH:14][C:15]([C:17]1[S:18][C:19]([Cl:22])=[CH:20][CH:21]=1)=[O:16].[F:23][C:24]1[CH:32]=[C:31]([N:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]2=[O:39])[CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27]>>[F:23][C:24]1[CH:32]=[C:31]([N:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]2=[O:39])[CH:30]=[CH:29][C:25]=1[C:26]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][NH:14][C:15]([C:17]1[S:18][C:19]([Cl:22])=[CH:20][CH:21]=1)=[O:16])=[O:27]
Reactant: O=C(NCC1CCCN1)c1ccc(Cl)s1
Reactant: O=C(O)c1ccc(-n2ccccc2=O)cc1F
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCC1CCCN1C(=O)c1ccc(-n2ccccc2=O)cc1F)c1ccc(Cl)s1

Procedure:
Using general method H, rac-5-chloro-thiophene-2-carboxylic acid (pyrrolidin-2-ylmethyl)-amide trifluoro acetate (example 75.2) was reacted with 2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-benzoic acid (prepared according to example 54.1) to give rac-5-chloro-thiophene-2-carboxylic acid {1-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-benzoyl]-pyrrolidin-2-ylmethyl}-amide. White solid. MS 460.0 ([M+H]+)
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[C:23]([O:27][C:28]([N:30]1[CH2:34][C@@H:33]([OH:35])[C@H:32]([F:36])[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>ClCCl>[C:23]([O:27][C:28]([N:30]1[CH2:34][C:33](=[O:35])[CH:32]([F:36])[CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](F)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(=O)C(F)C1
Temperature: 25 °C

Procedure:
Cool down a suspension of Dess Martin periodinane (279 mg, 0.65 mmol) in dry dichloromethane (1 mL) under nitrogen with an ice bath and add a solution of trans-3-fluoro-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (90 mg, 0.44 mmol) in dry dichloromethane (1 mL). Stir under nitrogen and allow to warm up to room temperature overnight. Add saturated aqueous sodium hydrogen carbonate, then saturated aqueous sodium thiosulfate and extract with dichloromethane. Combine the organic layers, wash with saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give 3-fluoro-4-oxopyrrolidine-1-carboxylic acid tert-butyl ester which may be used without further purification. Characteristic peaks in the NMR include the proton alpha to the fluorine atom (5.01, 1H, ddd, J=51.52, 7.54, 7.25 Hz).
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C@@H:8]([C:15]1[C:16]([CH3:45])=[N:17][C:18]([CH3:44])=[C:19]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)=[CH:30][CH:29]=2)[C:20]=1[N:21]1[CH2:26][CH2:25][CH:24]([CH3:27])[CH2:23][CH2:22]1)[C:9]([O:11]C(C)C)=[O:10])([CH3:6])([CH3:5])[CH3:4].Cl>C(O)C>[C:3]([O:7][C@@H:8]([C:15]1[C:16]([CH3:45])=[N:17][C:18]([CH3:44])=[C:19]([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH2:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)=[CH:32][CH:33]=2)[C:20]=1[N:21]1[CH2:26][CH2:25][CH:24]([CH3:27])[CH2:23][CH2:22]1)[C:9]([OH:11])=[O:10])([CH3:6])([CH3:5])[CH3:4]
Reactant: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CCC(C)CC2)c1-c1ccc(OCCc2ccc(F)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(N2CCC(C)CC2)c1-c1ccc(OCCc2ccc(F)cc2)cc1
Temperature: 85 °C
Reaction time: 24 h
Yield: 48 %

Procedure:
The 1.32 mL of 1M sodium hydroxide (52.8 mg, 1.32 mmol) was added to a (S)-isopropyl 2-(tert-butoxy)-2-(5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethyl-4-(4-methylpiperidin-1-yl)pyridin-3-yl)acetate (130 mg, 0.22 mmol) in ethanol (1 mL) and stirred for 24 h at 85° C. An additional 0.31 mL sodium hydroxide was added and the reaction was continued for 24 h. The reaction mixture was neutralized with 1N HCl solution, extracted with EtOAc, and the organic layer was washed with brine, and dried (MgSO4). The crude material was purified by prep HPLC to afford (S)-2-(tert-butoxy)-2-(5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethyl-4-(4-methylpiperidin-1-yl)pyridin-3-yl)acetic acid 58 mg (48%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 7.40-7.37 (m, 2H), 7.19 (d, J=9.2 Hz, 1H), 7.14 (t, J=8.8 Hz, 2H), 7.00-6.95 (m, 3H), 5.84 (s, 1H), 4.22 (t, J=6.6 Hz, 2H), 3.44-3.39 (m, 4H), 3.06 (t, J=6.6 Hz, 2H), 2.43 (s, 3H), 2.03 (s, 3H), 1.72-1.68 (m, 1H), 1.49 (d, J=12.1 Hz, 1H), 1.34 (d, J=7.0 Hz, 1H), 1.24-1.20 (m, 1H), 1.12 (s, 9H), 1.06-1.01 (m, 1H), 0.83 (d, J=3.7 Hz, 3H). UPLC (M+H)=549.6.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:9][C:8]2[CH:10]=[C:11]3[O:16][CH2:15][O:14][C:12]3=[CH:13][C:7]=2[C:6]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)=[N:5][NH:4]1.C(N(CC)CC)C.[C:33](Cl)(Cl)=[O:34]>C1(C)C=CC=CC=1>[N+:23]([C:20]1[CH:21]=[CH:22][C:17]([C:6]2[C:7]3[CH:13]=[C:12]4[O:14][CH2:15][O:16][C:11]4=[CH:10][C:8]=3[CH2:9][CH:3]3[CH2:2][O:1][C:33](=[O:34])[N:4]3[N:5]=2)=[CH:18][CH:19]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccc(C2=NNC(CO)Cc3cc4c(cc32)OCO4)cc1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C1OCC2Cc3cc4c(cc3C(c3ccc([N+](=O)[O-])cc3)=NN12)OCO4
Yield: 67 %

Procedure:
A solution of 1.0 g (2.93 mmol) of 8-hydroxymethyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxolo[4,5-h][2,3]-benzodiazepine is mixed in succession with 0.98 ml (7.03 mmol) of triethylamine and 2.23 ml (3.52 mmol) of a 15.6% phosgene solution in toluene while being stirred and cooled. Then, the reaction mixture is heated for 3 hours to 25° C. The precipitate of the crude product is separated, the filtrate is concentrated by evaporation and the residue is treated with water. The combined residues are boiled with ethanol, and after suctioning-off, 0.72 g (67%) of the title compound with a melting point >250° C. (decomposition) is obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH2:18][C@H:19]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH:20]=[CH2:21])(=O)=O)=CC=1.Cl.[N:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[C:33]([C:41]2[C:49]3[C:48]([NH2:50])=[N:47][CH:46]=[N:45][C:44]=3[NH:43][CH:42]=2)[CH:32]=1.O>CN(C=O)C>[Si:23]([O:22][C@H:19]([CH:20]=[CH2:21])[CH2:18][N:43]1[C:44]2[N:45]=[CH:46][N:47]=[C:48]([NH2:50])[C:49]=2[C:41]([C:33]2[CH:32]=[N:31][C:40]3[C:35]([CH:34]=2)=[CH:36][CH:37]=[CH:38][CH:39]=3)=[CH:42]1)([C:26]([CH3:27])([CH3:28])[CH3:29])([CH3:24])[CH3:25]
Reactant: Nc1ncnc2[nH]cc(-c3cnc4ccccc4c3)c12
Reactant: C=C[C@H](COS(=O)(=O)c1ccc(C)cc1)O[Si](C)(C)C(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C[C@H](Cn1cc(-c2cnc3ccccc3c2)c2c(N)ncnc21)O[Si](C)(C)C(C)(C)C
Temperature: 90 °C
Reaction time: 20 h
Yield: 73.3 %

Procedure:
Potassium carbonate (4.0 g) and (R)-2-((tert-butyldimethylsilyl)oxy)but-3-en-1-yl 4-methylbenzenesulfonate (1.43 g) were added to a solution of 5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine hydrochloride (1.22 g) obtained in Step 4 in DMF (12.2 ml) at room temperature, and the mixture was stirred at 90° C. for 20 hours. After the reaction mixture was cooled, water (49 ml) was added thereto, and the resulting mixture was stirred at room temperature for 3 hours. The resulting precipitate was collected by filtration, washed with water, and dried under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: methanol/ethyl acetate) to obtain the title compound (1.31 g) as a light-yellow solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)=[CH2:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(=O)([O-])[OH:22].[Na+].ClC1C=CC=C(C(OO)=O)C=1>C(Cl)Cl>[Si:1]([O:8][CH2:9][CH2:10][C:11]1([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[O:22][CH2:12]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C([O-])O
Reactant: C=C(CCO[Si](C)(C)C(C)(C)C)c1ccc(Cl)c(Cl)c1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCC1(c2ccc(Cl)c(Cl)c2)CO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.9 %

Procedure:
3.00 g (9.05 mmole) of 3-(3,4-dichlorophenyl)-3-butenol t-butyldimethylsilyl ether [prepared as described in Example 1(b)] were dissolved in 60 ml of methylene chloride, and 2.52 g (30.0 mmole) of sodium hydrogencarbonate and 3.88 g (15.7 mmole) of 3-chloroperbenzoic acid (content: 70%) were added to the resulting solution. The mixture was then stirred at room temperature for 3 hours. At the end of this time, the reaction mixture was diluted with methylene chloride and then washed with a 1 N aqueous solution of sodium hydroxide and with a saturated aqueous solution of sodium chloride. The organic layer was then dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure. The resulting residue was then purified by silica gel column chromatography, using a gradient elution method, with mixtures of hexane and diethyl ether ranging from 24:1 to 19:1 by volume as the eluent, to obtain 2.70 g of the title compound.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[CH3:5][C:6]1[CH:7]=[C:8]([NH:13][C:14]([C:16]2[C:17]([S:22][CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26](S(C)=O)[N:25]=3)=[N:18][CH:19]=[CH:20][CH:21]=2)=[O:15])[CH:9]=[C:10]([CH3:12])[CH:11]=1.C(O)C>C(OCC)(=O)C>[CH:1]1([NH:4][C:26]2[N:25]=[C:24]([CH2:23][S:22][C:17]3[C:16]([C:14]([NH:13][C:8]4[CH:9]=[C:10]([CH3:12])[CH:11]=[C:6]([CH3:5])[CH:7]=4)=[O:15])=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:29]=[CH:28][N:27]=2)[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: Cc1cc(C)cc(NC(=O)c2cccnc2SCc2ccnc(S(C)=O)n2)c1
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(NC(=O)c2cccnc2SCc2ccnc(NC3CC3)n2)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
Cyclopropylamine (6.0 mL) was added to N-(3,5-dimethylphenyl)-2-(2-methylsulfinylpyrimidin-4-ylmethylthio) pyridine-3-carboxamide (990 mg, 2.4 mmol, Compound No. 1-27), and the mixture was stirred for 30 minutes at 80° C. The reaction mixture was diluted with ethyl acetate (80 mL), washed twice with water (50 mL), and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, then the residue was purified by silica gel column chromatography to give 650 mg (recrystallized from ethanol) of the target compound as a colorless solid (Yield: 67%).
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH3:13])[C:4](=[O:12])[CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9].CN(C=O)C.C1C(=O)N([Br:26])C(=O)C1>CCOC(C)=O>[Br:26][C:5]1[C:4](=[O:12])[N:3]([CH3:13])[C:2]([Cl:1])=[C:7]([C:8]([O:10][CH3:11])=[O:9])[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(=O)n(C)c1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)c(=O)n(C)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
A 250-mL round-bottom flask was charged with methyl 2-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (10 g, 50 mmol), DMF (100 mL) and NBS (17.8 g, 100 mmol). The resulting mixture was stirred at room temperature for 8 hours and diluted with EtOAc (100 mL). The organic layer was washed with sat aq. NaHSO3 solution, water, dried (Na2SO4) and concentrated under reduced pressure yielding to desired product as a white solid (13.7 g, 97%)
Reaction SMILES: [F:1][C:2]1[C:7]2=[N:8][O:9][C:10]([CH3:11])=[C:6]2[CH:5]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:3]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23].[I:24]N1C(=O)CCC1=O.C(O)(C(F)(F)F)=O>CN(C=O)C>[F:1][C:2]1[C:7]2=[N:8][O:9][C:10]([CH3:11])=[C:6]2[CH:5]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:3]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([I:24])=[CH:19][C:18]=1[F:23]
Reactant: COC(=O)c1cc2c(C)onc2c(F)c1Nc1ccccc1F
Reactant: O=C1CCC(=O)N1I
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(C)onc2c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.4 %

Procedure:
To a suspension of methyl 7-fluoro-6-(2-fluorophenylamino)-3-methylbenzo[c]isoxazole-5-carboxylate (1.31 g, 4.12 mmol) in DMF (40 ml) was added N-iodosuccinimide (1.39 g, 6.17 mmol) and TFA (2.4 ml). After stirring at room temperature for 4 h, the reaction was quenched with saturated aqueous NH4Cl solution (100 ml) and extracted with EtOAc (2×100 ml). The combined organic solution was washed with brine (100 ml), dried over MgSO4 and concentrated. Silica gel chromatography (EtOAc:Hexanes=25:75) yielded 1.71 g (93%) of methyl 7-fluoro-6-(2-fluoro-4-iodophenylamino)-3-methylbenzo[c]isoxazole-5-carboxylate as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([N:13]([CH2:21][C:22]#[CH:23])C(=O)OC(C)(C)C)[C:10]([CH3:24])=[N:9]2)[CH:5]=[N:6][CH:7]=1.[ClH:25]>O1CCOCC1.C(OCC)C>[ClH:25].[F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([NH:13][CH2:21][C:22]#[CH:23])[C:10]([CH3:24])=[N:9]2)[CH:5]=[N:6][CH:7]=1
Reactant: C#CCN(C(=O)OC(C)(C)C)c1cn(-c2cncc(F)c2)nc1C
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: C#CCNc1cn(-c2cncc(F)c2)nc1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.3 %

Procedure:
To a solution of tert-butyl 1-(5-fluoropyridin-3-yl)-3-methyl-1H-pyrazol-4-yl(prop-2-ynyl)carbamate (1.03 g, 3.11 mmol) in dioxane (5 mL) was added 4 molar (M) hydrogen chloride (HCl; 3.9 mL, 15.5 mmol) in diethyl ether (Et2O). The mixture was stirred at room temperature for 48 h and the resulting white solid was filtered, washed with Et2O and dried under vacuum to give the title compound as a white solid (741 mg, 89%): mp 167-168° C.; 1H NMR (400 MHz, DMSO d6) δ 8.92-8.85 (m, 1H), 8.42 (d, J=2.5 Hz, 1H), 8.15 (s, 1H), 8.12-8.02 (m, 1H), 3.85 (d, J=2.5 Hz, 2H), 3.27-3.19 (m, 1H), 2.22 (s, 3H); ESIMS m/z 230.4 ([M]+).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:6]1)=[O:4].[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]O>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:22][C:21]3[CH:24]=[CH:25][CH:26]=[C:19]([F:18])[CH:20]=3)=[CH:15][CH:16]=2)[CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1CC(=O)N(c2ccc(O)cc2)C1
Reactant: OCc1cccc(F)c1
Product: COC(=O)[C@@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1

Procedure:
In an analogous manner to that described in Example 28b), the alkylation of the (R)-1-(4-hydroxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester [Example 28a)] with 3-fluorobenzylalcohol yields the (R)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methyl ester as a white solid. MS: m/e=344 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[C:10]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](Cl)=[N:20][N:19]=2)=[C:9]1[CH3:29])([CH3:4])([CH3:3])[CH3:2].[OH-:31].[Na+]>CC(O)=O>[C:1]([O:5][C:6](=[O:30])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[C:10]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](=[O:31])[NH:20][N:19]=2)=[C:9]1[CH3:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(-c2nnc(Cl)c3ccccc23)c2cc(Cl)ccc2n1CC(=O)OC(C)(C)C
Reactant: [OH-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1c(-c2n[nH]c(=O)c3ccccc23)c2cc(Cl)ccc2n1CC(=O)OC(C)(C)C
Temperature: 70 °C

Procedure:
The product of step b) (300 mg) was treated with 10 mL HOAc and 2 mL of 1 M NaOH. The suspension was heated to 70° C. for 4 h. The reaction was cooled and partitioned between EtOAc and water. The organic layer was dried over MgSO4 and concentrated to give 300 mg of the sub-title compound as a yellow oil. MS: ESI (negative): 422, 424 (M−H).