Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[O:9]=[C:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:11]1.O>CS(C)=O>[O:9]1[C:10]2([CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:11]2)[CH2:2]1
Reactant: C[S+](C)(C)=O
Reactant: O=C1CCCN(C(=O)OCc2ccccc2)C1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(OCc1ccccc1)N1CCCC2(CO2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.7 %

Procedure:
To a solution of trimethylsulfoxonium iodide (3.1 g) in dimethyl sulfoxide (40 mL) was added sodium hydride (570 mg), and the mixture was stirred at room temperature for 1 hr. A solution of benzyl 3-oxopiperidine-1-carboxylate (3.0 g) in dimethyl sulfoxide (10 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 16 hr. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (30% ethyl acetate/hexane to 50% ethyl acetate/hexane) to give the object product (1.9 g, 60%).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10].[CH2:12]([O:19][CH2:20][CH2:21][O:22][C:23]1[CH:30]=[CH:29][C:26](C#N)=[CH:25][C:24]=1[O:31][CH3:32])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([O:19][CH2:20][CH2:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([C:1]2[NH:2][C:3](=[O:11])[C:4]3[C:5]([CH:10]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)=[CH:25][C:24]=1[O:31][CH3:32])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CNC(=O)c1ccccc1C
Reactant: COc1cc(C#N)ccc1OCCOCc1ccccc1
Product: COc1cc(-c2cc3ccccc3c(=O)[nH]2)ccc1OCCOCc1ccccc1
Yield: 23.6 %

Procedure:
According to the method of Example 10-1, N-methyl-2-methylbenzamide (5.97 g) and 4-(2-benzyloxyethoxy)-3-methoxybenzonitrile (9.57 g) were reacted, to give 3-[4-(2-benzyloxyethoxy)-3-methoxyphenyl]isoquinolin-1-one (3.20 g)
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[C@@H:10]([C@H:21]([OH:31])[CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:51][C:52]1[CH:53]=[CH:54][C:55](O)=[N:56][CH:57]=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1>C1COCC1.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[C@@H:10]([C@@H:21]([O:31][C:55]2[CH:54]=[CH:53][C:52]([Cl:51])=[CH:57][N:56]=2)[CH2:22][O:23][Si:24]([C:27]([CH3:28])([CH3:30])[CH3:29])([CH3:26])[CH3:25])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H](O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Reactant: Oc1ccc(Cl)cn1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC[C@H](Oc1ccc(Cl)cn1)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Temperature: 45 °C
Yield: 77 %

Procedure:
(S)-1-[(3R,4S)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-2-(tert-butyl-dimethyl-silanyloxy)-ethanol (17) and PPh3 (PPh3 polymer bound, 3 mmol PPh3/g resin) (614 mg, 1.87 mmol) were suspended in THF (10 mL). To the mixture were added 5-chloro-pyridin-2-ol (0.243 g, 1.87 mmol) and then DBAD (0.431 g, 1.87 mmol). The reaction mixture was stirred at 45° C. over night. The mixture was diluted with ethyl acetate and filtered on celite and concentrated under vacuo. The residue was purified by column chromatography (SiO2, EtOAc/H, 1:15) yielded 571 mg (77%) of the title compound as a colorless oil. ES-MS m/e: 593.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26](O)=[O:27])[N:9]=2)[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(OC([N:64]1[CH2:71][C@@H:70]2[C@@H:66]([CH2:67][NH:68][CH2:69]2)[CH2:65]1)=O)(C)(C)C.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:31])[F:32])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:64]3[CH2:71][C@@H:70]4[C@@H:66]([CH2:67][NH:68][CH2:69]4)[CH2:65]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CNC[C@H]2C1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cn(CC(=O)N2C[C@H]3CNC[C@H]3C2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 17 h

Procedure:
{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid (3.35 g, 7.25 mmol) was dissolved in DMF (30 mL) and HATU (2.85 g, 9.42 mmol) was added. cis-hexahydropyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (2.0 g, 9.42 mmol) and DIPEA (1.63 mL, 9.42 mmol) were added and the mixture was stirred at room temperature for 17 hours. The volatiles were evaporated and the resultant residue azeotroped with toluene. The solid was partitioned between water and DCM and the organic layer was separated, dried (Na2SO4) and evaporated. The residue was dissolved in DCM (10 mL) and TFA (10 mL) was added. The solution was stirred at room temperature for 4 hours and then evaporated. The residue was dissolved in MeOH and loaded onto an SCX-2 cartridge which had been conditioned with MeOH. After flushing with MeOH, the product was eluted with 2M ammonia in MeOH. The solvent was evaporated and the product was crystallised from MeOH/Et2O. The desired product was obtained as an off-white solid (3.7 g, 90%). LCMS (Method 5) [M+H]+=556.9, RT=2.83 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.76 (s, 1H), 9.35 (dd, 1H, J=1.6, 7.0 Hz), 9.38-9.22 (m, 2H), 8.69 (dd, 2H, J=1.7, 4.2 Hz), 8.67 (s, 1H), 8.31 (s, 1H), 7.64 (dd, 1H, J=2.7, 8.8 Hz), 7.56 (d, 1H, J=2.6 Hz), 7.47 (d, 1H, J=8.8 Hz), 7.30 (dd, 2H, J=4.3, 7.0 Hz), 7.27 (t, 1H, J=73.4 Hz), 5.15 (s, 2H), 3.80-3.67 (m, 2H), 3.65-3.53 (m, 2H), 3.49-3.32 (m, 3H), 3.16-2.94 (m, 4H).
Reaction SMILES: O[Li].O.[C:4]1([N:10]2[C:18]3[CH2:17][CH2:16][CH2:15][CH:14]([CH2:19][C:20]([O:22]CC)=[O:21])[C:13]=3[CH:12]=[N:11]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O.CO>[C:4]1([N:10]2[C:18]3[CH2:17][CH2:16][CH2:15][CH:14]([CH2:19][C:20]([OH:22])=[O:21])[C:13]=3[CH:12]=[N:11]2)[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)CC1CCCc2c1cnn2-c1ccccc1
Agent: [Li]O
Solvent: O
Solvent: CO
Product: O=C(O)CC1CCCc2c1cnn2-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.8 %

Procedure:
LiOH.H2O (120 mg, 2.85 mmol), dissolved in 1 ml of water, is added to a solution of ethyl 2-(4,5,6,7-tetrahydro-1-phenyl-1H-indazol-4-yl)acetate (808 mg, 2.85 mmol) in methanol (20 mL) and is stirred at room temperature for 1 hour following the reaction by means of TLC. The methanol is evaporated under reduced pressure, the residue is suspended in water and acidified with diluted HCl forming a pulp that is extracted with ethyl acetate. The organic phase is washed with water, dried and evaporated at reduced pressure, giving 2-(4,5,6,7-tetrahydro-1-phenyl-1H-indazol-4-yl)acetic acid (410 mg, 1.59 mmol, 53%, solid).
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2]O.[Cl:6][C:7]1[CH:8]=[C:9]([NH2:22])[C:10]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)=[CH:11][CH:12]=1.C([O-])(O)=O.[Na+].C(Cl)Cl>Cl.O>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]2[N:13]([CH2:14][CH2:15][CH2:16][N:17]3[CH:21]=[CH:20][N:19]=[CH:18]3)[C:2]([CH2:1][OH:5])=[N:22][C:9]=2[CH:8]=1
Reactant: O=C(O)CO
Reactant: Nc1cc(Cl)ccc1NCCCn1ccnc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: OCc1nc2cc(Cl)ccc2n1CCCn1ccnc1
Temperature: 90 °C
Yield: 29.3 %

Procedure:
Glycolic acid (1.98 g, 26 mmol, 3 eq.) was added to a solution of 4-chloro-N1-[3-(1H-imidazol-1-yl)propyl]benzene-1,2-diamine (12, 2.18 g, 8.7 mmol) in HCl (6N, 20 mL) at room temperature. The reaction mixture was heated up until 90° C. during 16 hours. After cooling to ambient temperature the reaction mixture was diluted with 100 mL water followed by addition of NaHCO3 until the pH was approximately 7. CH2Cl2 (30 ml) was added and the organic layer was separated and the aqueous layer was further extracted with additional CH2Cl2 (20 mL). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo and purified by flash chromatography (0 to 10% MeOH in CH2Cl2) to give {5-chloro-1-[3-(1H-imidazol-1-yl)propyl]-1H-benzimidazol-2-yl}methanol (13, 740 mg, 30%) as a white solid; LCMS m/z=291 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C@H:16]([NH2:24])[CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[CH2:11][CH2:10]1.C(N(CC)CC)C.[CH3:32][C:33]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C@H:16]([NH:24][C:39]([C:33]2([CH3:32])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[O:40])[CH2:17][C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCN(C[C@H](N)Cc2ccncc2)CC1
Reactant: CC1(C(=O)Cl)CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1N1CCN(C[C@@H](Cc2ccncc2)NC(=O)C2(C)CCCCC2)CC1
Temperature: 25 °C
Yield: 69.2 %

Procedure:
To a solution of (1R)-2-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-1-pyridin-4-ylmethyl-ethylamine (726 mg.; 2.23 mmol, from Example 8) in dichloromethane (30 mL) at 0° C. was added triethylamine (0.62 mL; 4.45 mmol) and 1-methyl-1-cyclohexanecarbonyl chloride (356 mg.; 2.23 mmol). The reaction mixture was stirred while allowing to warm to ambient temperature over 1 hour, washed sequentially with saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered, and the solvent removed in vacuo. The crude residue was purified by flash chromatography on silica gel (2% methanol/chloroform) to yield the free base of the title compound as a clear oil (695 mg.; 69%). Treatment with an equimolar amount of fumaric acid in ethanol afforded the fumarate salt as a white amorphous solid, m.p. 145° C.; MS EI M+ @ m/z 450; 1H NMR, 400 MHz, DMSO-d6. Analysis for C27H38N4O2C4H4O4.0.5H2O Calculated: C, 64.68; H, 7.53; N, 9.73 Found: C, 64.97; H, 7.53; N, 9.66
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].O.C1COCC1.[Cl:15][C:16]1[CH:17]=[C:18](/[CH:22]=[CH:23]/[S:24](Cl)(=[O:26])=[O:25])[CH:19]=[CH:20][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][S:24](/[CH:23]=[CH:22]/[C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([Cl:15])[CH:17]=2)(=[O:25])=[O:26])[CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)(Cl)/C=C/c1cccc(Cl)c1
Reactant: Nc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(/C=C/c1cccc(Cl)c1)Nc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 85.7 %

Procedure:
To a well-stirred solution of 3-chloroaniline (367.9 mg, 2.87 mmol, 1 eq.) in a solvent system of H2O-THF (14 mL, 1:1 ratio) was sequentially added first compound 1 (676.6 mg, 2.87 mmol, 1 eq.) and then a 1M-solution of Na2CO3 (2.2 mL, 0.77 mmol, 0.77 eq.) until the pH was about 8. After the reaction mixture was stirred for 22 hours at room temperature, water was added and the product was extracted 3 times with EtOAc from the aqueous phase. The resulting organic phase was washed with brine, dried under Na2SO4 and the solvent evaporated. After the product was purified from the crude by flash column chromatography (10% EtOAc/hexanes), compound 2 (808.5 mg, 2.46 mmol) was obtained in an 86% yield. 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J=15.4 Hz, C═CH, 1H), 7.43 (s, ArH, 1H), 7.39 (dt, J=6.8, 2.3 Hz, ArH, 1H), 7.33 (m, ArH, 2H), 7.25 (t, J=8.0, ArH, 1H), 7.22 (t, J=2.1, ArH, 1H), 7.13 (ddd, J=8.0, 1.9, 0.9 Hz, ArH, 1H), 7.07 (ddd, J=8.0, 2.1, 0.9 Hz, ArH, 1H), 6.79 (d, J=15.4 Hz, C═CH, 1H), 6.61 (s, NH, 1H). 13C NMR (100 MHz, CDCl3, δ): 142.03 (CH), 137.53 (C), 135.17 (C), 133.76 (C), 131.14 (CH), 130.55 (CH), 130.36 (CH), 128.11 (CH), 126.67 (CH), 125.38 (CH), 125.30 (CH), 120.49 (CH), 118.46 (CH). GC-MS m/z (% relative intensity, ion): 330.85 (0.8, M+4), 328.95 (4, M+2), 326.90 (6, M+), 262.95 (28), 151.95 (48), 136.95 (99), 126.95 (54), 102.00 (100), 98.80 (51), 90.95 (19).
Reaction SMILES: Cl[C:2](Cl)(Cl)[C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[NH3:14].Cl.C(OCC)(=O)C>C(O)C>[C:2]([C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:14]
Reactant: ClC(Cl)(Cl)c1nc2ccccc2[nH]1
Reactant: N
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: N#Cc1nc2ccccc2[nH]1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3.2 Grams of a 2-(trichloromethyl)benzimidazole compound [compound (101)] of the formula (XI) in which X is H and Z is OCF2CFHO was dissolved in 30 ml of ethanol. The resulting solution was added by drops to 4 ml of a 25% aqueous ammonia at 5° C. After stirring for 1 hour at 5° to 15° C., the reaction solution was poured into an ice/conc. hydrochloric acid mixture and extrac.ted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. Removing the solvent from the dried layer by distillation gave 2.83 g of a 2-cyanobenzimidazole compound [compound (i)] of the formula (II) in which X is H and Z is OCF2CFHO.
Reaction SMILES: N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(OC)=O)=CC=2)=CC3)CC1.CN(C)CC[C:45]([NH:47][C@:48]12[CH2:82][CH2:81][C@@H:80]([C:83]([CH3:85])=[CH2:84])[C@@H:49]1[C@@H:50]1[C@@:63]([CH3:66])([CH2:64][CH2:65]2)[C@@:62]2([CH3:67])[C@@H:53]([C@:54]3([CH3:79])[C@@H:59]([CH2:60][CH2:61]2)[C:58]([CH3:69])([CH3:68])[C:57]([C:70]2[CH:78]=[CH:77][C:73]([C:74]([OH:76])=[O:75])=[CH:72][CH:71]=2)=[CH:56][CH2:55]3)[CH2:52][CH2:51]1)=[O:46].[O:87]=[C:88]1[N:92]([CH2:93]C(O)=O)[CH2:91][CH2:90][O:89]1>>[CH3:66][C@:63]12[C@@:62]3([CH3:67])[C@@H:53]([C@:54]4([CH3:79])[C@@H:59]([CH2:60][CH2:61]3)[C:58]([CH3:69])([CH3:68])[C:57]([C:70]3[CH:78]=[CH:77][C:73]([C:74]([OH:76])=[O:75])=[CH:72][CH:71]=3)=[CH:56][CH2:55]4)[CH2:52][CH2:51][C@@H:50]1[C@H:49]1[C@H:80]([C:83]([CH3:85])=[CH2:84])[CH2:81][CH2:82][C@:48]1([NH:47][C:45](=[O:46])[CH2:93][N:92]1[CH2:91][CH2:90][O:89][C:88]1=[O:87])[CH2:65][CH2:64]2
Reactant: O=C(O)CN1CCOC1=O
Reactant: C=C(C)[C@@H]1CC[C@]2(NC(=O)CCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)CN3CCOC3=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 29 %

Procedure:
The title compound was prepared in 29% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except 2-(2-oxooxazolidin-3-yl)acetic acid was used instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 657.5 (M+H)+, 1.97 min (method 6). 1H NMR (500 MHz, 1:1 CDCl3:MeOD) δ=7.92 (d, J=8.2 Hz, 2H), 7.20 (d, J=8.5 Hz, 2H), 6.82 (s, 1H), 5.29 (dd, J=1.7, 6.3 Hz, 1H), 4.76 (d, J=1.5 Hz, 1H), 4.64 (s, 2H), 4.43 (dt, J=1.7, 8.2 Hz, 2H), 3.98-3.84 (m, 2H), 3.74 (t, J=8.1 Hz, 2H), 2.69-2.56 (m, 2H), 2.40 (dd, J=8.1, 12.4 Hz, 1H), 2.13 (dd, J=6.4, 17.1 Hz, 1H), 1.98-1.81 (m, 2H), 1.81-1.75 (m, 1H), 1.73 (br. s., 1H), 1.71 (s, 3H), 1.70-1.65 (m, 1H), 1.61-1.43 (m, 7H), 1.42-1.29 (m, 4H), 1.29-1.21 (m, 2H), 1.16-1.12 (m, 1H), 1.10 (s, 3H), 1.02 (s, 3H), 1.02 (s, 3H), 0.95 (s, 3H), 0.94 (s, 3H).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[N:13][CH:14]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]1COCC1>>[C:2]1([C:1]([C:9]2[CH:10]=[N:11][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)=[N:13][CH:14]=2)=[CH2:28])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C(=O)c3ccccc3)cn2)CC1
Product: C=C(c1ccccc1)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
The above solution was added to a solution of tert-butyl 4-(5-benzoylpyrimidin-2-yl)piperazine-1-carboxylate (1 g, 2.7 mmol) in dry THF (20 mL) at 0° C., and the reaction solution was stirred at room temperature for 2 h. The reaction was quenched by water (20 mL) and extracted with ethyl acetate (200 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography eluting with petroleum ether:ethyl acetate 10:1 to give tert-butyl 4-(5-(1-phenylvinyl)pyrimidin-2-yl)piperazine-1-carboxylate (890 mg, 89%) as a white solid. MS (ES+) C21H26N4O2 requires: 366, found: 367 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:11]([CH:19]3[CH2:21][CH:20]3[C:22]([O:24]CC)=[O:23])[N:10]([CH2:27][CH2:28][OH:29])[N:9]=2)=[CH:4][CH:3]=1.C1CC(NC2C3C(=CC(Cl)=C(Cl)C=3)C(C3C=CN=CC=3)=NN=2)CC1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:11]([CH:19]3[CH2:21][CH:20]3[C:22]([OH:24])=[O:23])[N:10]([CH2:27][CH2:28][OH:29])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CC1c1c(-c2ccncc2)c(-c2ccc(F)cc2)nn1CCO
Agent: Clc1cc2c(NC3CCCC3)nnc(-c3ccncc3)c2cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1CC1c1c(-c2ccncc2)c(-c2ccc(F)cc2)nn1CCO

Procedure:
To a solution of ethyl 2-[3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridinyl)-1H-pyrazol-5-yl]cyclopropanecarboxylate prepared in accordance with Example A-196 (0.21 g, 0.00045 mol) in 10 mL of methanol was added a solution of sodium hydroxide (0.09 g, 0.0022 mol) in 2 mL of water. The reaction mixture was stirred at reflux for 6 hours. After the solvent was removed, the residue was dissolved with 10 mL of 1N HCl and stirred for 30 minutes. The pH was then adjusted to 5–6 by addition of 1N sodium hydroxide solution and then extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium and filtered. The filtrate was concentrated and the crude was purified by recrystallization from ethanol and ether to give 0.1 g of product, 2-[3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridinyl)-1H-pyrazol-5-yl]cyclopropanecarboxylic acid, as a white solid (60% yield), mp: 253–255° C.; 1H NMR (CD3OD): δ 8.46 (m, 2H), 7.32 (m, 2H), 7.25 (m, 2H), 7.04 (m, 2H), 4.39 (t, J=5.0 Hz, 2H), 4.03 (m, 2H), 2.60 (m, 1H), 1.51 (m, 2H), 0.97 (m, 2H); Anal. Calc'd For C20H18FN3O3: C, 65.39; H, 4.94; N, 11.44. Found: C, 64.92; H, 4.77; N, 11.20.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8]C(=O)C)[CH:5]=[CH:4][CH:3]=1.[N+:12]([O-])([OH:14])=[O:13]>OS(O)(=O)=O>[Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1cccc(Br)n1
Agent: O=S(=O)(O)O
Product: Nc1ccc([N+](=O)[O-])c(Br)n1
Temperature: 0 °C
Reaction time: 4 h
Yield: 86 %

Procedure:
To a solution of N-(6-bromopyridin-2-yl)acetamide (9.0 g, 40 mmol) in H2SO4 (100 mL) was added HNO3 (69%, 5.5 g, 60 mmol) dropwise at 0° C. The mixture was stirred at this temperature for 4 hours, and was then poured into ice-water. The mixture was extracted with EtOAc (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give 6-bromo-5-nitropyridin-2-amine (7.5 g, 82%). 1H NMR (400 MHz, DMSO) δ 8.10 (d, J=8.8 Hz, 1H), 7.73 (brs, 2H), 6.46 (d, J=8.8 Hz, 1H).
Reaction SMILES: [H-].[Na+].[CH:3]1([SH:8])[CH2:7][CH2:6][CH2:5][CH2:4]1.[Br:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17](Br)[CH:18]=1)[C:13]([OH:15])=[O:14].Cl>CS(C)=O.O>[Br:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([S:8][CH:3]2[CH2:7][CH2:6][CH2:5][CH2:4]2)[CH:18]=1)[C:13]([OH:15])=[O:14]
Reactant: SC1CCCC1
Reactant: O=C(O)c1cc(Br)cc(Br)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1cc(Br)cc(SC2CCCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred mixture of sodium hydride (60% in mineral oil, 0.82 g, 20.5 mmol) and DMSO (15 mL) in a sealable flask at 0° C. was slowly added cyclopentanethiol (1.23 mL, 11.9 mmol). The mixture was stirred at room temperature for 30 min and then a solution of 3,5-dibromobenzoic acid (2.5 g, 8.9 mmol) in DMSO (10 mL) was added. The reaction was sealed and stirred at 80° C. overnight. After cooling, the reaction mixture was poured into water and adjusted to pH 5-6 with 15% HCl (aq.) and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated to afford the crude product which was used for the next step reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C@H:27]([CH2:28][OH:29])[CH2:26][O:25][C:24]4=[O:30])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[H-].[Na+].I[CH3:34].O>CN(C)C=O>[CH3:1][C:2]1[C:3]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C@H:27]([CH2:28][O:29][CH3:34])[CH2:26][O:25][C:24]4=[O:30])=[CH:19][CH:18]=3)=[O:16])[CH2:13][CH2:14]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4CO)cc3)CC2)c(C)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9 %

Procedure:
(R)-3-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-4-hydroxymethyloxazolidin-2-one (205 mg) described in Example 72 was dissolved in N,N-dimethylformamide (1 mL), sodium hydride (32 mg) was added, and the mixture was stirred at room temperature for 30 min. Iodomethane (142 mg) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform:methanol) to give the title compound (19 mg).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][O:5][C:3]1=[O:4].C(N(CC)CC)C.[C:15](=O)([O:24]N1C(=O)CCC1=O)[O:16][N:17]1[C:21](=[O:22])[CH2:20][CH2:19][C:18]1=[O:23]>C(#N)C>[O:4]=[C:3]1[C@H:2]([O:1][C:15]([O:16][N:17]2[C:21](=[O:22])[CH2:20][CH2:19][C:18]2=[O:23])=[O:24])[CH2:7][CH2:6][O:5]1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: O=C1OCC[C@H]1O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(O[C@@H]1CCOC1=O)ON1C(=O)CCC1=O

Procedure:
(R)-alpha-Hydroxybutyrolactone (8 μL, 0.11 mmol) was dissolved in acetonitrile (0.5 mL) and treated with triethylamine (45 μL, 1.5 equivalents), and disuccinimidyl carbonate (42 mg, 1.5 equivalent) at 25° C. for 16 hrs. The solvents were evaporated and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate, the organic layer was separated, washed with brine, dried over magnesium sulfate, filtered and evaporated.