Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].Br[CH2:14][C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cn1ccc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 5-nitroindole (3.24 g, 20 mmol), methyl bromoacetate (3.36 g, 22 mmol), cesium carbonate (32.58 g, 100 mmol) in 150 mL of DMF was stirred at room temperature for 3 h. The reaction mixture was poured into water and the solid was collected and dried to give methyl (5-nitro-1H-indol-1-yl)acetate as a pale yellow solid: MS (ESI) m/z 235.
Reaction SMILES: [CH3:1][C:2]([O:4][CH2:5][C:6]1[CH2:25][S:24][C@@H:9]2[C@H:10]([NH:13]C(CCC[C@@H](N)C(O)=O)=O)[C:11](=[O:12])[N:8]2[C:7]=1[C:26]([OH:28])=[O:27])=[O:3].[Na].C(N(CC)C1C=CC=CC=1)C.C(Cl)(=O)C>O1CCCC1>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:26]([OH:28])=[O:27])=[C:6]([CH2:5][O:4][C:2](=[O:3])[CH3:1])[CH2:25][S:24][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)CCC[C@@H](N)C(=O)O)[C@H]2SC1
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCN(CC)c1ccccc1
Solvent: CC(=O)Cl
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: -35 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
Cephalosporin C, sodium salt, dihydrate, 4.8 gm (10 mmol), was suspended in 80 ml of tetrahydrofuran (dried over 5A molecular sieves). Diethyl aniline (dried over KOH), 7.4 gm (8.0 ml, 50 mmol), and acetyl chloride, 4.7 gm (4.3 ml, 60 mmol), were added. The mixture was stirred in a water bath at about 30° to 40° C. for 1 hour and then at room temperature for about 2.5 hours. Filtration removed 5.7 gm of undissolved material. The reaction solution was cooled in an ice-alcohol bath before addition to a solution of the triphenyl phosphitechlorine complex prepared as in Paragraph A above, but using tetrahydrofuran as a solvent instead methylene chloride. After mixing the two solutions, a solution of diethylaniline, 3.3 gm (22 mmol) in 20 ml of dry tetrahydrofuran, was added dropwise over a period of 10 minutes. The reaction mixture was stirred in the cold for 2 hours, cooled further to about -35° C., and then treated with 16 ml of propylene glycol. A stream of dry hydrogen chloride was passed through the reaction for about 15 seconds. The reaction solution was refrigerated overnight. Workup as described in Paragraph A immediately hereinabove yielded 1.2 gm (45%) of 7-ACA.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[N:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([OH:24])=O)=[CH:16][C:15]=2[CH3:25])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[O:32][NH2:33].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.O>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[N:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([NH:33][O:32][CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31][O:26]3)=[O:24])=[CH:16][C:15]=2[CH3:25])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NOC1CCCCO1
Reactant: Cc1cc(/C=C/C(=O)O)cnc1N[C@@H]1CCN(Cc2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(/C=C/C(=O)NOC2CCCCO2)cnc1N[C@@H]1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
To a solution of (2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-methyl-3-pyridyl)acrylic acid (338 mg, crude) in DMF (4 mL) was added O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (153 mg), HOBt (203 mg), and EDCI (233 mg) and the resulting mixture was stirred at ambient temperature for 3 hours. The reaction mixture was diluted with water and extracted with AcOEt. The organic phase was washed with sat NH4Cl aq solution, sat NaHCO3 aq solution, and brine, and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by preparative thin layer chromatography (chloroform:methanol=90:10) to give (2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-methyl-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (306 mg) as pale yellow form.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[C:17]([Cl:18])=[CH:16][S:15][CH:14]=1)=S.[OH-].[Na+].C1(C)C=CC(S([Cl:30])(=O)=O)=CC=1.C(OCC)(=O)C>C1COCC1.O>[ClH:18].[Cl:30][C:14]1[S:15][CH:16]=[C:17]([Cl:18])[C:13]=1[NH:12][C:10]1[NH:9][C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[N:1]=1
Reactant: Nc1cc(F)ccc1NC(=S)Nc1cscc1Cl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cl
Product: Fc1ccc2[nH]c(Nc3c(Cl)csc3Cl)nc2c1
Yield: 38.5 %

Procedure:
1-(2-Amino-4-fluoro-phenyl)-3-(4-chloro-thiophen-3-yl)-thiourea (625 mg) was dissolved in THF and a solution of NaOH (0.207 g) in water (9 ml) was added. Within 5 min a solution of p-toluenesulfonyl chloride (0.395 g) in THF (10 ml) was added dropwise. After stirring for one hour at room temperature water and ethyl acetate were added to the reaction mixture. The organic layer was separated and the aqueous phase was extracted three times with ethyl acetate. The combined organic layers were dried (MgSO4), treated with charcoal, filtered and the solvent evaporated to yield the desired product (135 mg).
Reaction SMILES: [Na].CO.[C:4]([O:8][CH3:9])(=[O:7])[CH2:5][SH:6].Cl[C:11]1[C:16]([C:17](OCC)=[O:18])=[CH:15][CH:14]=[C:13]([CH:22]([CH3:24])[CH3:23])[N:12]=1>CN(C)C=O.O>[CH3:9][O:8][C:4]([C:5]1[S:6][C:11]2=[N:12][C:13]([CH:22]([CH3:23])[CH3:24])=[CH:14][CH:15]=[C:16]2[C:17]=1[OH:18])=[O:7]
Reactant: COC(=O)CS
Reactant: CCOC(=O)c1ccc(C(C)C)nc1Cl
Agent: [Na]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1sc2nc(C(C)C)ccc2c1O
Yield: 45.1 %

Procedure:
Under ice-cooling, metal sodium (6.9 g) was added to methanol (70 ml)-and methyl thioglycolate (32 g) was added with stirring. Ethyl 2-chloro-6-isopropylpyridine-3-carboxylate (42 g) synthesized according to U.S. Pat. No. 5,001,137 (Mar. 19, 1991) was dissolved in dimethylformamide (170 ml) and the mixture was stirred at room temperature for 2 hr. The reaction mixture was treated with water, and the organic layer was extracted with ethyl acetate, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained crystals were recrystallized from water-containing methanol to give the title compound (20.9 g). melting point: 80-81° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH3:11])[N:5]=1)(=O)[CH3:2].[NH2:13][C:14]1[C:15]([CH3:20])=[CH:16][CH:17]=[CH:18][CH:19]=1>C(O)=O.C(Cl)Cl>[CH3:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:13]=[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[N:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH3:11])[N:5]=1)[CH3:2]
Reactant: CC(=O)c1cccc(C(C)=O)n1
Reactant: Cc1ccccc1N
Solvent: O=CO
Solvent: ClCCl
Product: CC(=Nc1ccccc1C)c1cccc(C(C)=Nc2ccccc2C)n1
Reaction time: 40 h
Yield: 45.9 %

Procedure:
One g of 2,6-diacetylpyridine and 3.0 ml of o-toluidine were added to an Erlenmeyer flask with 20 ml of methylene chloride. A stirbar and 5 drops of 97% formic acid were added, and the flask was sealed and the solution was stirred for 40 hours. The solvent was then removed in vacuo, and the flask was placed in the freezer at −30° C. The resulting viscous oil was washed with cold methanol, and a yellow solid formed and was isolated by filtration and identified by 1H NMR as the desired product (959 mg, 45.9%). 1H NMR (CDCl3): δ8.38(d, 2, Hpyr) 7.86(t, 1, Hpyr), 7.20(m, 4, Haryl) 7.00(t, 2, Haryl), 6.67(d, 2, Haryl) 2.32 (s, 6, N═C—CH3) 2.10(s, 6, CH3 aryl).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH:19]([C:22]1[O:23][C:24]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:25]([C:27](O)=[O:28])[N:26]=1)([CH3:21])[CH3:20]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:27]([C:25]3[N:26]=[C:22]([CH:19]([CH3:21])[CH3:20])[O:23][C:24]=3[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[O:28])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC(C)c1nc(C(=O)O)c(-c2ccccc2)o1
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3nc(C(C)C)oc3-c3ccccc3)n2)o1

Procedure:
Following general procedure A followed by B, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-isopropyl-5-phenyl-oxazole-4-carboxylic acid.
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][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(O)C.[N+:26]([C:29]1[CH:34]=[CH:33][C:32]([C:35]([N:37]=[C:38]=[S:39])=[O:36])=[CH:31][CH:30]=1)([O-:28])=[O:27]>C1(C)C=CC=CC=1>[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][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:38]([NH:37][C:35](=[O:36])[C:32]2[CH:31]=[CH:30][C:29]([N+:26]([O-:28])=[O:27])=[CH:34][CH:33]=2)=[S:39])=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(N=C=S)c1ccc([N+](=O)[O-])cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc([N+](=O)[O-])cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 110 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 4-nitro-1-benzenecarbonyl isothiocyanate (30 mg) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (80 mg, yield 94%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][OH:13])=[CH:4][CH:3]=1.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>>[CH3:14][S:15]([O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: OCCOCCc1ccc(F)cc1
Product: CS(=O)(=O)OCCOCCc1ccc(F)cc1
Yield: 87 %

Procedure:
The 2-[2-(4-fluorophenyl)ethoxy]ethanol obtained according to the preceding paragraph was sulfonylated with methanesulfonyl chloride in a manner analogous to that described in Example 1(c) to give 8.2 g (87%) of 2-[2-(4-fluorophenyl)ethoxy]ethyl methanesulfonate in the form of an oil which was homogeneous according to chromatography.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[C@H:9]2[O:10][C:11]([CH3:14])([CH3:13])[O:12][C@H:8]2[C@H:7]([N:15]2[C:19]3[N:20]=[CH:21][N:22]=[C:23]([NH:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=4[O:34][CH3:35])[C:18]=3[CH:17]=[CH:16]2)[CH2:6]1)=[N+]=[N-].C1COCC1.CP(C)C.O>C(Cl)Cl>[NH2:1][CH2:4][C@@H:5]1[C@H:9]2[O:10][C:11]([CH3:14])([CH3:13])[O:12][C@H:8]2[C@H:7]([N:15]2[C:19]3[N:20]=[CH:21][N:22]=[C:23]([NH:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=4[O:34][CH3:35])[C:18]=3[CH:17]=[CH:16]2)[CH2:6]1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN=[N+]=[N-])[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Agent: CP(C)C
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
A solution of 7-((3aS,4R,6R,6aR)-6-(azidomethyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (2.23 g, 4.65 mmol) in THF (33 mL, 410 mmol) was cooled to 0° C. and treated dropwise with a 1.0 M solution of trimethylphosphine in THF (9.3 mL, 9.3 mmol). The cold bath was removed and the reaction mixture was allowed to warm to RT with stirring for 1 h; no starting material remained by HPLC. At 1.5 h, water (4.3 mL, 240 mmol) was added and the reaction mixture was stirred for 1 h 15 min; TLC indicated one product. The reaction mixture was concentrated in vacuo to afford a light orange paste. The residue was diluted with CH2Cl2 (120 mL) and washed with water (2×40 mL) and brine (1×40 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo to afford an orange oil. Purification by column chromatography (2×22 cm silica; 0-5% 7 N NH3 in CH3OH/CH2Cl2) afforded the title compound (1.97 g, 53% over 3 steps) as a colorless foam: MS (ESI+) for C24H31N5O4 m/z 454.3 (M+H)+; HPLC purity>95% (ret. time, 2.541 min).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[F:36][CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][CH:42]([C:45]2[CH:51]=[CH:50][C:48]([NH2:49])=[C:47]([O:52][CH3:53])[CH:46]=2)[CH2:41][CH2:40]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:49][C:48]3[CH:50]=[CH:51][C:45]([CH:42]4[CH2:41][CH2:40][N:39]([CH2:38][CH2:37][F:36])[CH2:44][CH2:43]4)=[CH:46][C:47]=3[O:52][CH3:53])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: COc1cc(C2CCN(CCF)CC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: COc1cc(C2CCN(CCF)CC2)ccc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 175 °C
Reaction time: 72 h

Procedure:
To 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (238 mg, 0.50 mmol) and 4-[1-(2-fluoroethyl)-4-piperidinyl]-2-(methyloxy)aniline (140 mg, 0.50 mmol) in iPrOH (1 mL) in a microwave vial was added p-toluenesulfonic acid monohydrate (190 mg, 1.0 mmol). The reaction was heated in a microwave at 175° C. for 1000 seconds. After cooling to rt the material was transferred to another flask, rinsing with a solution of DCM/MeOH. Silica gel was added and the solvent removed on the rotovap. The preabsorbed solids were purified by flash chromatography. The desired fractions were combined and the solvent removed on the rotovap to give product contaminated with an impurity. The material was placed under vacuum for 3 days then triturated with diethyl ether. The desired product was obtained as a white solid (23 mg, 0.033 mmol, 6.6% yield). 1H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 9.35 (d, J=6.2 Hz, 1H), 8.47 (s, 1H), 8.22 (d, J=5.1 Hz, 1H), 8.08, (s, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.71-7.60 (m, 2H), 7.42 (dd, J=8.4, 7.3 Hz, 1H), 7.35 (dd, J=7.1, 6.6 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 7.15 (dd, J=8.1, 7.9 Hz, 2H), 6.97-6.90 (m, 2H), 6.77 (d, J=8.2 Hz, 1H), 6.56 (d, J=5.1 Hz, 1H), 4.51 (dt, J=48.0, 4.8 Hz, 2H), 3.95, (s, 3H), 3.80 (s, 3H), 2.97 (d, J=11.0 Hz, 2H), 2.60 (dt, J=28.2, 4.8 Hz, 2H), 2.08 (dd, J=11.5, 8.8 Hz, 2H), 1.77-1.59 (m, 4H). MS (ESI) m/z=708 [M+1].
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([CH3:19])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:26][O:27][CH2:28][CH2:29][O:30][CH2:31]Cl>C(#N)C>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31])[C:13](=[O:18])[N:12]([CH3:19])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCOCCl
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCOCn1c(=O)c2c(ncn2Cc2ccccc2)n(C)c1=O
Temperature: 50 °C
Reaction time: 5 h

Procedure:
The mixture of 25.6 g (0.1 mol) of 7-benzyl-3-methylxanthine (prepared according to Example 1a), 15.2 g (0.11 mol) of potassium carbonate and 16.2 g (0.13 mol) of 2-methoxyethoxymethyl chloride in 500 ml of acetonitrile was heated at 50° C. with stirring for 5 hours, then worked up analogously to Example 1b) and the oily product obtained was purified by means of filtration on a silica gel column in the eluent chloroform/methanol (10/1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][N:9]=[C:10](Cl)[S:11]([CH3:14])(=[O:13])=[O:12])[CH:5]=[CH:6][CH:7]=1.[I:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][CH:26]=[C:25](N3CCOCC3)[C:24]2=[O:35])=[CH:19][CH:18]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:25]3[C:24](=[O:35])[N:23]([C:20]4[CH:21]=[CH:22][C:17]([I:16])=[CH:18][CH:19]=4)[CH2:28][CH2:27][C:26]=3[C:10]([S:11]([CH3:14])(=[O:13])=[O:12])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C(N2CCOCC2)=CCCN1c1ccc(I)cc1
Reactant: CS(=O)(=O)C(Cl)=NNc1cccc(Cl)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1nn(-c2cccc(Cl)c2)c2c1CCN(c1ccc(I)cc1)C2=O
Temperature: 70 °C
Reaction time: 14 h
Yield: 63.7 %

Procedure:
The methanehydrazonoyl chloride (8.47 g, 31.7 mmol) and 1-(4-iodo-phenyl)-3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one (12.17 g, 31.7 mmol) were combined in anhydrous toluene. The solution heated to 70° C. and triethylamine (13.2 mL, 95.1 mmol) was added dropwise. After the addition was complete the reaction was warmed to 90° C. and stirred at this temperature for 14 h. Analysis by LC/MS indicated formation of 1-(3-chloro-phenyl)-6-(4-iodo-phenyl)-3-methanesulfonyl-7-a-morpholin-4-yl-1, 3a, 4,5,6,7a-hexahydro-pyrazolo[3,4-c]pyridin-7-one complete with less than 5% of 1-(4-iodo-phenyl)-3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one remaining. The solvent was removed in vacuo. To the viscous oil was added dichloromethane (50 mL) then trifluoroacetic acid (30 mL) and heated to reflux for 4 h. The solvent was evaporated and the residue purified by flash column chromatography eluting with a gradient of hexane to 40% ethylacetate/hexane to give 10.65 g (64%) of 1-(3-chloro-phenyl)-6-(4-iodo-phenyl)-3-methanesulfonyl-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one.
Reaction SMILES: Cl[C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]([C@H:15]2[C@H:19]([OH:20])[CH2:18][N:17]([CH2:21][CH3:22])[CH2:16]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[C:25]([O-:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([O-:30])=[O:29]>C(O)C.[Pd]>[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29].[CH2:21]([N:17]1[CH2:18][C@@H:19]([OH:20])[C@H:15]([N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6](=[O:7])[C:5]2[CH:23]=[CH:24][CH:2]=[CH:3][CH:4]=2)[CH2:16]1)[CH3:22]
Reactant: O=C([O-])/C=C/C(=O)[O-]
Reactant: CCN1C[C@@H](O)[C@H](N(C(=O)c2ccc(Cl)cc2)c2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Product: CCN1C[C@@H](O)[C@H](N(C(=O)c2ccccc2)c2ccccc2)C1
Product: O=C(O)/C=C/C(=O)O

Procedure:
A solution of 6.4 g (0.0186 mole) of trans-4-chloro-N-(1-ethyl-4-hyroxy-3-pyrrolidinyl)-N-phenylbenzamide base in 75 ml of ethanol was hydrogenated over 10% palladium-on-charcoal at 60° overnight. The mixture was filtered through Celite and the filtrate was concentrated. The residue was partitioned between 10% sodium hydroxide and methylene chloride. The methylene chloride layer was dried over anhydrous sodium sulfate and concentrated to give 5.6 g. (97%) of oil as residue. The oil was converted to the fumarate and the salt was recrystallized from 95% ethanol to yield an off-white powder; m.p. 191°-193° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[CH:4](O)OC.[C:9]1([C@H:15]([NH2:17])[CH3:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[C:9]1([C@H:15](/[N:17]=[CH:4]\[C:3]([O:2][CH3:1])=[O:8])[CH3:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)C(O)OC
Reactant: C[C@@H](N)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)/C=N\[C@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-hydroxy-2-methoxyacetic acid methyl ester (151 g) in toluene (300 mL), was added (R)-(+)-1-phenylethylamine (150 g) dropwise. The mixture was then stirred for 1 hr at room temperature. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated to obtain the target compound as a yellow oil. The target compound was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([O:10][CH3:11])[CH:3]=1.C(C1C=C(C=C(C)C=1O)C#[N:18])C>>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:18])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: CCc1cc(C#N)cc(C)c1O
Reactant: COc1cc(O)ccc1C=O
Product: COc1cc(O)ccc1C#N

Procedure:
The title compound is prepared from commercially available 4-hydroxy-2-methoxy-benzaldehyde in analogy to literature procedures (see 3-ethyl-4-hydroxy-5-methyl-benzonitrile). LC-MS: tR=0.74 min. 1H NMR (D6-DMSO): δ 3.84 (s, 3H), 6.47 (d, J=8.5 Hz, 1H), 6.54 (s, 1H), 7.49 (d, J=8.5 Hz, 1H), 10.60 (s, 1H).
Reaction SMILES: [F:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14](=[O:24])[NH:15][C@@H:16]2[C@@H:23]3[C@@H:19]([CH2:20][NH:21][CH2:22]3)[CH2:18][CH2:17]2)[CH2:3]1.Br[C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=1.C(N(CC)CC)C.O.C(O)C>C(O)C>[F:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:12])([CH3:13])[CH3:11])=[O:8])[C@H:4]([C:14](=[O:24])[NH:15][C@@H:16]2[C@@H:23]3[C@@H:19]([CH2:20][N:21]([C:26]4[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=4)[CH2:22]3)[CH2:18][CH2:17]2)[CH2:3]1
Reactant: FC(F)(F)c1ccnc(Br)c1
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)N[C@H]1CC[C@@H]2CN(c3cc(C(F)(F)F)ccn3)C[C@@H]21
Temperature: 82 °C

Procedure:
In a 4 mL vial were combined (2S,4R)-tert-butyl 4-fluoro-2-((3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-ylcarbamoyl)pyrrolidine-1-carboxylate from Example 617 Step 2 (80 mg, 0.234 mmol), 2-bromo-4-(trifluoromethyl)pyridine (74.1 mg, 0.328 mmol), and triethylamine (0.131 mL, 0.937 mmol) in ethanol (0.1 mL). The reaction was heated at 82° C. for 1 day. To the reaction mixture was added 90% water/ethanol (1 mL), and then the liquid layer was decanted. This crude material was purified using a 12 g silica gel cartridge eluted with a gradient of 0-60% acetone/hexane over 20 minutes to give (2S,4R)-tert-butyl 4-fluoro-2-((3aR,4S,6aS)-2-(4-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-ylcarbamoyl)pyrrolidine-1-carboxylate: 1H NMR (400 MHz, pyridine-d5, 90° C.) δ ppm 8.34 (d, J=5.2, 1H), 7.93 (bs, 1H), 6.73 (d, J=5.1, 1H), 6.60 (s, 1H), 5.33-5.10 (m, 1H), 4.62 (t, J=7.9, 1H), 4.34-4.22 (m, 1H), 3.96 (dd, J=21.9, 13.0, 1H), 3.66 (tdd, J=16.6, 12.2, 5.7, 3H), 3.57-3.50 (m, 1H), 3.30 (dd, J=10.9, 4.3, 1H), 2.76 (tdd, J=13.1, 8.5, 4.5, 2H), 2.54-2.35 (m, 2H), 2.16 (dd, J=12.5, 5.8, 1H), 2.04-1.91 (m, 1H), 1.72 (ddd, J=15.3, 12.9, 7.8, 1H), 1.51 (s, 9H), 1.44 (dd, J=9.2, 4.0, 1H); MS (ESI+) m/z 487 (M+H)+.