Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[C:7]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)OC(=O)[C:4]=1[C:20]([O:22][CH3:23])=[O:21].[C:24]1([N:30]2[CH:38]=[C:37]3[C:32]([CH2:33][CH2:34][CH2:35][C:36]3=O)=[N:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[OH-].[K+].Cl>CN(C=O)C>[CH3:1][S:2][C:3]1[CH:8]=[C:7]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)[C:35]2[CH2:34][CH2:33][C:32]3[C:37](=[CH:38][N:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:31]=3)[C:36]=2[C:4]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: O=C1CCCc2nn(-c3ccccc3)cc21
Reactant: COC(=O)c1c(SC)cc(-c2cccc3ccccc23)oc1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)c1c(SC)cc(-c2cccc3ccccc23)c2c1-c1cn(-c3ccccc3)nc1CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.8 %

Procedure:
A mixture of methyl 4-(methylthio)-6-(naphthalen-1-yl)-2-oxo-2H-pyran-3-carboxylate (326 mg, 1 mmol), 2-phenyl-6,7-dihydro-2H-indazol-4(5H)-one (212 mg, 1 mmol) and powdered KOH (84 mg, 1.5 mmol) in dry DMF (5 mL) was stirred at 25° C. for 8 hr. At the end the reaction mixture was poured into ice water with vigorous stifling and finally neutralized with dilute HCl. The solid thus obtained was filtered and purified on a neutral alumina column using 15% chloroform in hexane as eluent to yield 228 mg (48%) of methyl 8-(methylthio)-6-(naphthalen-1-yl)-2-phenyl-4,5-dihydro-2H-benzo[e]indazole-9-carboxylate.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=1.[CH:19]1([C:22](N2C3C=CC=CC=3N=N2)=[O:23])[CH2:21][CH2:20]1.O>C1COCC1>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH2:17][C:22]([CH:19]2[CH2:21][CH2:20]2)=[O:23])=[CH:12][CH:11]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: O=C(C1CC1)n1nnc2ccccc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(CC(=O)C1CC1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.9 %

Procedure:
To a −78C solution of LDA (generated from 8 ml of 2.5 M nBuLi and 2.1 ml of diisopropylamine) in THF (120 ml) was added dropwise, over 80 min, a solution a 4′-bromoacetophenone (2.98 g, 14.97 mmol) in THF (45 ml). The mixture continued to stir at −78C for 1 h, followed by addition of 1-(cyclopropylcarbonyl)-1H-1,2,3-benzotriazole (2.56 g, 13.65 mmol) in THF (45 ml). The mixture was warmed to rt overnight. The yellow mixture was poured into water and extracted with Et2O (2×300 ml). The combined organic phases were washed with water, dried with MgSO4, and concentrated in vacuo. The crude material was purified by flash chromatography (CH2Cl2/hexanes, 10:90 to 30:70) to yield 1-(4-bromophenyl)-3-cyclopropyl-1,3-propanedione as an orange solid (1.60 g, 44%).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:32])=[C:4]([F:31])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[C:17]([F:18])=[CH:16][C:15]([F:19])=[C:14]([NH:20]C(C)(C)C)[N:13]=1)[CH:9]=[C:8]([C:25]([O:27]CC)=[O:26])[C:7]2=[O:30].Cl.C(O)(=O)C>O>[NH2:20][C:14]1[N:13]=[C:12]([N:10]2[C:11]3[C:6](=[CH:5][C:4]([F:31])=[C:3]([F:32])[C:2]=3[Br:1])[C:7](=[O:30])[C:8]([C:25]([OH:27])=[O:26])=[CH:9]2)[C:17]([F:18])=[CH:16][C:15]=1[F:19]
Reactant: CCOC(=O)c1cn(-c2nc(NC(C)(C)C)c(F)cc2F)c2c(Br)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Br)c32)c(F)cc1F
Yield: 95.2 %

Procedure:
Ethyl 8-bromo-1-[6-(t-butylamino)-3,5-difluoro-pyridin-2-yl]-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (1.38 g) was added to a liquid mixture of 12% hydrochloric acid (3.5 mL) and acetic acid (3.5 mL), and the mixture was heated for 5 hours under stirring and reflux. Subsequent to addition of distilled water (5 mL), the mixture was allowed to cool down. The precipitate was collected by filtration, and washed successively with ethanol and diisopropyl ether in this order to obtain the title compound (1.10 g) as a colorless powder.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH3:13].[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH:19]=O.[O-]CC.[Na+]>C(O)C>[Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1/[CH:13]=[CH:19]/[C:15]1[S:14][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1nc2ccccn2c(=O)c1Br
Reactant: O=Cc1cccs1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=c1c(Br)c(/C=C/c2cccs2)nc2ccccn12

Procedure:
The title compound was prepared from 3-bromo-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (500 mg, 2.091 mmol) and thiophene-2-carboxaldehyde (351 mg, 3.129 mmol) in the presence of sodium ethoxide (284 mg, 4.175 mmol) in absolute ethanol (25 ml) as described in Intermediate 1 to give 283 mg of the product as a light yellow solid; 1H NMR (300 MHz, CDCl3) δ 7.06 (s, 2H), 7.31-7.43 (m, 3H), 7.63 (dd, J=2.4, 16.2 Hz, 2H), 8.15 (d, J=14.7 Hz, 1H), 8.94 (d, J=6.9 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:15]O.Cl>C(Cl)Cl>[CH3:15][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[N:10][C:2]=1[Cl:1]
Reactant: CO
Reactant: O=C(O)c1cccnc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccnc1Cl
Temperature: 40 °C
Reaction time: 8 h

Procedure:
52 was prepared according to the method of Synth. Comm. 26(12), 2257–2272 (1996). To a nitrogen purged flask was charged 2-chloro-nicotinic acid (1000.0 g, 6.0 moles, 1.0 eq) followed by 9 L methylene chloride. To this was added thionyl chloride (1.4 L, 19.7 moles, 3.2 eq.) and the reaction was heated to 40° C. with vigorous stirring under nitrogen overnight. The acid chloride solution was cooled in an ice bath and methanol (3 L, 74 moles, 12 eq.) was slowly added while keeping the temperature at 20° C. The rate limiting parameter is the vigorous evolution of copious quantities of HCl gas. After the addition, HPLC analysis [Tret starting material=7.5 min, Tret 52=11 min] showed the product had formed immediately. The volatiles were removed in vacuo and the residue extracted from 10% Na2CO3 with EtOAc. The combined organics were dried (MgSO4), filtered, and concentrated to a pale yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][CH2:5][NH:6][C:7](=[O:33])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH:27]2[CH2:30][C:29]([CH3:32])([CH3:31])[CH2:28]2)[NH:15][C:16]2[C:25]([CH3:26])=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)=[CH:10][CH:9]=1.[OH-].[Na+]>CO.C1COCC1>[CH3:31][C:29]1([CH3:32])[CH2:30][CH:27]([CH:14]([NH:15][C:16]2[C:25]([CH3:26])=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)[C:11]2[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:34])=[O:2])=[O:33])=[CH:9][CH:10]=2)[CH2:28]1
Reactant: COC(=O)CCNC(=O)c1ccc(C(Nc2nc3ccccc3cc2C)C2CC(C)(C)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2ccccc2nc1NC(c1ccc(C(=O)NCCC(=O)O)cc1)C1CC(C)(C)C1

Procedure:
The title compound was prepared by treating 3-{4-[(3,3-dimethyl-cyclobutyl)-(3-methyl-quinolin-2-ylamino)-methyl]-benzoylamino}-propionic acid methyl ester, isomer 2 (intermediate 71) with 1N NaOH (2.5 eq.) in methanol/THF in a similar manner as described in Example 19 to provide the title compound. Analytical chiral SFC: (Chiralpak AD-H column, 4.6 mm×25 cm, 30% methanol/carbon dioxide eluent, 2.5 mL/min flow rate, 4.60 retention time); 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J=8.4 Hz, 2H), 7.58-7.63 (m, 2H), 7.44-7.51 (m, 3H), 7.37-7.44 (m, 1H), 7.10-7.18 (m, 1H), 6.81 (t, J=5.8 Hz, 1H), 5.30 (d, J=9.6 Hz, 1H), 3.67 (q, J=5.9 Hz, 2H), 2.52-2.70 (m, 3H), 2.29 (s, 3H), 1.94 (ddd, J=11.1, 8.0, 3.1 Hz, 1H), 1.72-1.82 (m, 1H), 1.63-1.72 (m, 2H), 1.13 (s, 3H), 1.08 (s, 3H); MS (M+1): 446.3.
Reaction SMILES: [C:1]([N:3]=[C:4](SC)SC)#[N:2].[NH2:9][CH2:10][C:11]1[N:19]=[C:18]2[C:14]([N:15]=[CH:16][N:17]2[C@@H:20]2[O:24][C@H:23]([C:25]([NH:27][CH2:28][CH3:29])=[O:26])[C@@H:22]([OH:30])[C@H:21]2[OH:31])=[C:13]([NH:32][CH2:33][CH:34]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:12]=1.[NH2:47][CH2:48][CH2:49][N:50]1[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1>C(O)C>[NH3:2].[C:1](/[N:3]=[C:4](/[NH:9][CH2:10][C:11]1[N:19]=[C:18]2[C:14]([N:15]=[CH:16][N:17]2[C@@H:20]2[O:24][C@H:23]([C:25]([NH:27][CH2:28][CH3:29])=[O:26])[C@@H:22]([OH:30])[C@H:21]2[OH:31])=[C:13]([NH:32][CH2:33][CH:34]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:12]=1)\[NH:47][CH2:48][CH2:49][N:50]1[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1)#[N:2]
Reactant: NCCN1CCCCC1
Reactant: CSC(=NC#N)SC
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Solvent: CCO
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN/C(=N/C#N)NCCN4CCCCC4)nc32)[C@H](O)[C@@H]1O
Product: N
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.3 %

Procedure:
Dimethyl cyanodithioimidocarbonate (77 mg, 0.48 mmol) was added to a solution of (2S,3S,4R,5R)-5-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide (250 mg, 0.48 mmol) (Preparation 11) in ethanol (10 ml). The reaction mixture was stirred for 3 hours at room temperature and then 2-aminoethylpiperidine (88μl, 0.68 mmol) was added. The reaction mixture was heated under reflux for 2 hours, more 2-aminoethylpiperidine (0.17 ml, 1.2 mmol) was added and then the reaction mixture was heated under reflux for a further 4 hours. The reaction was cooled and evaporated to dryness and the residue was purified by flash chromatography on silica gel eluting with dichloromethane:methanol (98:2 by volume) increasing in polarity to dichloromethane methanol:0.88 concentrated aqueous ammonia (90:10:1 by volume) to give the title compound (64 mg) a foam.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]([CH3:12])=[CH:5][C:6]=1[C:7](OCC)=[O:8].C(O)=O.[CH3:16][N:17](C=O)C>C(N)=O>[CH3:12][C:4]1[NH:3][C:2]2[N:1]=[CH:16][N:17]=[C:7]([OH:8])[C:6]=2[CH:5]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cc(C)[nH]c1N
Solvent: NC=O
Solvent: O=CO
Product: Cc1cc2c(O)ncnc2[nH]1
Yield: 51 %

Procedure:
In a sealed tube, ethyl 2-amino-5-methyl-1H-pyrrole-3-carboxylate (150 mg, 0.9 mmol, prepared according to literature procedures, J. Heterocyclic Chem., 23:1555 (1985)) was dissolved in formamide (4.5 ml), formic acid (2.3 ml) and DMF (1.0 ml) and heated to 155° C. for 12 h. The reaction was concentrated, taken up with NaHCO3 solution, and extracted with DCM to afford 6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ol (70 mg, 0.46 mmol, 51%, MS (ES+) [M+H]+=150). This material was dissolved in phosphorous oxychloride (5 ml) and heated to 110° C. for 1 h. The reaction was concentrated, taken up with NaHCO3, and extracted with DCM to give 4-chloro-6-methyl-7H-pyrrolo[2,3-d]pyrimidine (40 mg, 0.23 mmol, 50%). MS (ES+) [M+H]+=168.
Reaction SMILES: [OH-].[Na+].CC[O:5][C:6]([CH3:8])=[O:7].CO.[CH3:11][C:12](O)=O.C(Cl)Cl.[CH2:18]1[CH2:22]OC[CH2:19]1.CO>>[C:6]([OH:5])(=[O:7])/[CH:8]=[CH:19]/[CH2:18][CH2:22][CH2:12][CH3:11]
Reactant: CC(=O)O
Reactant: C1CCOC1
Reactant: CCOC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CCCC/C=C/C(=O)O
Yield: 25 %

Procedure:
To a cooled (0° C.) solution of 293.6 mg (0.74 mmol) of the pyridyl ketone and 670.4 mg (1.48 mmol) of (5-carboxypentyl)-triphenylphosphonium bromide in 2.5 mL of THF was added dropwise 2.95 mL (2.95 mmol) of 1.0 M t-BuOK in THF over 10 min period. The dark brown solution was stirred at 0° C. for 1.5 h, and then the reaction was quenched with 20 mL of saturated aqueous NH4Cl. The mixture was extracted with 3×50 mL of CH2Cl2. The combined extract was dried over MgSO4, concentrated and purified by preparative HPLC with MeOH-AcOH-CH2Cl2 (2:1:97) as the eluent to afford 56.1 mg (8.4%) of the less polar (Z)-heptenoic acid and 434.9 mg of the (E)-isomer containing a byproduct from the Wittig salt. In order to purify it, the (E)-isomer was therefore esterified with CH2N2 which was generated by a standard method from MNNG and aqueous NaOH in Et2O. The ester was isolated cleanly by flash chromatography with EtOAc-hexanes-CH2Cl2 (2:1:1) as the eluent. The ester (102.5 mg) was then hydrolyzed with 1 N NaOH in THF-MeOH (1:1). Flash chromatography with EtOAc-MeOH-AcOH-CH2Cl2 (50:1:1:48) yielded 92.5 mg (25%) of the pure (E)-heptenoic acid: mp 56-61° C.; 1H NMR (CDCl3) δ8.58 (s, 1H), 8.47 (d, J=4.1 Hz, 1H), 8.26 (s, 1H), 8.02 (d, J=8.2 Hz, 2H), 7.44 (dt, J=8.0, 1.5 Hz, 1H), 7.35-7.16 (m, 9H), 6.19 (t, J=7.4 Hz, 1H), 3.70 (dt, J=6.9, 6.7 Hz, 2H), 2.94 (t, J=7.2 Hz, 2H), 2.32 (t, J=7.8 Hz, 2H), 2.20 (ddd, J=7.3, 7.2, 7.0 Hz, 2H), 1.68-1.5:(m, 4H); FDMS 496 (M+1). Anal. (C30H29N3O4.0.1C2H4O2) C, H, N.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].[Cl:11][CH2:12][C:13]#[C:14][CH2:15]Cl>CN(C)C=O>[Cl:11][CH2:12][C:13]#[C:14][CH2:15][N:6]1[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]1
Reactant: ClCC#CCCl
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccn(CC#CCCl)n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 29.7 %

Procedure:
3-Nitro-1H-pyrazole (prepared in example 3, 1.30 g, 11.50 mmol) was dissolved in N,N-dimethylformamide (20 mL) and chilled to 0° C. A 60% dispersion of sodium hydride in mineral oil (552 mg, 13.80 mmol) was added portion wise, the ice bath was removed and the reaction continued to stir for 20 min. The 1,4-dichloro-but-2-yne (2.83 g, 23.00 mmol) was dissolved in N,N-dimethylformamide (5 mL) and chilled to 0° C. The 3-nitro-1H-pyrazole solution was added dropwise to the 1,4-dichloro-but-2-yne solution while stirring at 0° C. The ice bath was removed and the reaction continued to stir for 20 min. The solution was diluted with ethyl acetate (400 mL), washed with water (2×200 mL), saturated aqueous brine solution (2×100 mL), dried over magnesium sulfate and concentrated in vacuo to give a yellow oil. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 40% ethyl acetate/hexanes) afforded 1-(4-chloro-but-2-ynyl)-3-nitro-1H-pyrazole (682 mg, 30%) as a yellow oil which eventually solidified: H1-NMR (400 MHz, CDCl3) δ 4.18 (2H, t, J=2.0 Hz), 5.08 (2H, t, J=2.0 Hz), 6.92 (1H, d, J=2.4 Hz), 7.70 (2H, d, J=2.4 Hz).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.B.O1CCCC1.C([Li])CCC.[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:28]3[CH:29]=[C:30]4[C@:35]([CH:37]=[O:38])([CH2:36][C:27]=3[CH:26]=[N:25]2)[CH2:34][N:33]([S:39]([C:42]2[CH:47]=[CH:46][C:45]([C:48]([F:51])([F:50])[F:49])=[CH:44][CH:43]=2)(=[O:41])=[O:40])[CH2:32][CH2:31]4)=[CH:20][CH:19]=1>O1CCCC1.C(O)C.C(O)(=O)C>[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:28]3[CH:29]=[C:30]4[C@:35]([CH:37]([C:2]5[O:1][CH:5]=[CH:4][N:3]=5)[OH:38])([CH2:36][C:27]=3[CH:26]=[N:25]2)[CH2:34][N:33]([S:39]([C:42]2[CH:43]=[CH:44][C:45]([C:48]([F:51])([F:49])[F:50])=[CH:46][CH:47]=2)(=[O:41])=[O:40])[CH2:32][CH2:31]4)=[CH:20][CH:19]=1
Reactant: c1cocn1
Reactant: O=C[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(C(F)(F)F)cc1)C2
Agent: B
Agent: [Li]CCCC
Solvent: CCO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(C(O)c2ncco2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.3 %

Procedure:
To a solution of oxazole (99 μL, 0.5 mmol) in dry tetrahydrofuran (2.5 mL) was added borane-tetrahydrofuran complex (1.0 M in tetrahydrofuran, 1.65 mmol, 1.65 mL) and the mixture was stirred at room temperature for 1 hour. The mixture was cooled to −78° C. and butyl lithium (1.6 M solution in hexanes, 1.20 mL, 1.95 mmol) was added dropwise. The reaction mixture was stirred for 40 minutes at −78° C. A solution of (R)-1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carbaldehyde (250 mg, 0.5 mmol) in dry tetrahydrofuran (3 mL) was added dropwise and the reaction mixture was stirred at −78° C. for 2 hours. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was poured into ethanol/acetic acid mixture (95:5, v/v; 50 mL) and stirred at room temperature for 18 hours. The solvent was evaporated and the residue was dissolved in ethyl acetate (30 mL). The organic phase was washed with water (20 mL), saturated sodium bicarbonate (2×20 mL) and brine (20 mL). The organic phase was dried over sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (gradient: 0-4% methanol in dichloromethane) to afford, as a mixture of diastereoisomers, (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(oxazol-2-yl)-(R/S)-methanol as a white foam (136 mg). LCMS (Method A, ESI): RT 3.68 min, m+H=575.0.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][C@H:2]1[C:5]([OH:7])=[O:6].S(Cl)([Cl:10])=O.[CH3:12]O>>[ClH:10].[NH:1]1[CH2:4][CH2:3][C@H:2]1[C:5]([O:7][CH3:12])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: CO
Reactant: O=C(O)[C@@H]1CCN1
Product: COC(=O)[C@@H]1CCN1
Product: Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 96 %

Procedure:
To a suspension of azetidine-2(S)-carboxylic acid (19.8 mmol, 2.0 g) in methanol (120 mL) at 0° C. was added thionyl chloride (4.0 equiv; 79.2 mmol, 9.43 g, 5.8 mL) dropwise. Dissolution was observed during the addition and the reaction mixture was stirred at ambient temperature overnight (20 h). After this time, solvent was evaporated and the oily residue was azeotroped with toluene and placed under high vacuum to give rise to azetidine-2(S)-carboxylic acid, methyl ester hydrochloride salt as an off-white solid (2.9 g, 96% yield).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:22])([CH3:21])[O:6][CH2:7][CH:8]([NH:12][C:13](=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:9]([OH:11])[CH3:10])([CH3:4])[CH3:3].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CN(C)C=O.O>[CH3:1][C:2]([Si:5]([CH3:21])([CH3:22])[O:6][CH2:7][C@H:8]([NH:12][C:13](=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:9](=[O:11])[CH3:10])([CH3:3])[CH3:4]
Reactant: CCCCCCC(=O)NC(CO[Si](C)(C)C(C)(C)C)C(C)O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCC(=O)N[C@@H](CO[Si](C)(C)C(C)(C)C)C(C)=O
Reaction time: 18 h
Yield: 81.8 %

Procedure:
A mixture of (10c), (2.30 g, 6.94 mmol) and pyridinium dichromate (10.62 g, 28.2 mmol) in 20 mL of N,N-dimethylformamide is stirred under argon for 18 h. The reaction mixture is diluted with 100 mL of water and extracted with ethyl acetate (3×40 mL). The organic layer is separated, washed with water and brine, dried and evaporated to give 1.87 g of a residual brown liquid. The liquid is purified by chromatography using 1:6 ethyl acetate/hexane to give 997 mg of the desired product as an oil. NMR δ 0.83 (s, 9 H), 1.61 (m, 2 H), 2.22 (t, 2 H), 2.23 (s, 3 H), 3.82 (dd, 1 H), 4.09 (dd, 1 H), 4.57 (m, 1 H), 6.42 (brd, 1 H); MS (FAB) m/z 330 (M+H calc'd for C17H36NO3Si 330).
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[C:8]([O:11][CH3:12])=[CH:7][N:6]([C:13]2[CH:18]=[C:17]([I:19])[CH:16]=[CH:15][C:14]=2[F:20])[N:5]=1)(=O)[CH3:2].[CH3:21]C(O)=O.[C:25]1([NH:31][NH2:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>COC(OC)N(C)C>[F:20][C:14]1[CH:15]=[CH:16][C:17]([I:19])=[CH:18][C:13]=1[N:6]1[CH:7]=[C:8]([O:11][CH3:12])[C:9](=[O:10])[C:4]([C:1]2[N:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:32]=[CH:21][CH:2]=2)=[N:5]1
Reactant: NNc1ccccc1
Reactant: COc1cn(-c2cc(I)ccc2F)nc(C(C)=O)c1=O
Reactant: CC(=O)O
Agent: COC(OC)N(C)C
Product: COc1cn(-c2cc(I)ccc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Yield: 60 %

Procedure:
A mixture of 3-acetyl-1-(2-fluoro-5-iodophenyl)-5-methoxypyridazin-4(1H)-one (3.88 g, 10.0 mmol) in N,N-dimethylformamide dimethyl acetal (38.8 mL) was heated to reflux for 3 h. The mixture was concentrated in vacuo. To the residue were added AcOH (38.8 mL) and phenylhydrazine (1.97 mL, 20.0 mmol). The mixture was heated to reflux for 5 h. The mixture was concentrated in vacuo, diluted with 1 M HCl aqueous solution, extracted with AcOEt, washed with saturated NaHCO3 aqueous solution, dried over Na2SO4, filtered, concentrated in vacuo, purified by column chromatography on basic silica gel (hexane/AcOEt=50/50 to 0/100) and triturated with AcOEt/hexane to yield the title compound (2.95 g, 60% yield) as a yellow solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 3.77 (3H, s), 6.99 (1H, d, J=1.5 Hz), 7.23-7.50 (7H, m), 7.79 (1H, d, J=1.9 Hz), 7.84 (1H, ddd, J=8.7, 4.5, 2.3 Hz), 8.49 (1H, d, J=2.6 Hz).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7](=[O:9])[CH3:8].C([Li])CCC.[O:15]=[C:16]1[C:21]2[CH:22]=[CH:23][CH:24]=[C:25]([C:26]([F:29])([F:28])[F:27])[C:20]=2[N:19]=[C:18]([C@@H:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:31][CH3:32])[O:17]1>CCCCCC.O1CCCC1>[O:15]=[C:16]([C:21]1[CH:22]=[CH:23][CH:24]=[C:25]([C:26]([F:29])([F:28])[F:27])[C:20]=1[NH:19][C:18](=[O:17])[C@@H:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:37])[CH3:39])[CH2:31][CH3:32])[CH2:8][C:7](=[O:9])[NH:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)Nc1nccs1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)c1nc2c(C(F)(F)F)cccc2c(=O)o1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1c(C(=O)CC(=O)Nc2nccs2)cccc1C(F)(F)F

Procedure:
Using the procedure of Step B of Example 3, 7.78 g of N-(2-thiazolyl)-acetamide, 240 ml of tetrahydrofuran and 78.3 ml of a solution of n-butyllithium in hexane and 10.2 g of the product of Step A in 75 ml of tetrahydrofuran were reacted to obtain 8.3 g of 1,1-dimethylethyl N-[(S) 2-[[2-[1,3-dioxo-3-(1,1-dimethylethyl N-[(S) 2-[[2-[1,3-dioxo-3-(2-thiazolylamino)-propyl]-6-(trifluoromethyl)-phenyl]-amino]-1-ethyl-2-oxoethyl]-carbamate melting at 190° C. and having a specific rotation of [α]D =-36.5°±2° (c=0.5% in CH3COOH).
Reaction SMILES: [N:1]1([C:8]([NH:10][C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.O.Cl.[NH2:52][CH2:53][CH2:54][CH2:55][C:56]1([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[N:58]([CH3:65])[C:57]1=[O:66]>CN(C=O)C>[CH3:17][CH:16]([CH3:18])[CH2:15][C@H:11]([NH:10][C:8]([N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)=[O:9])[C:12](=[O:14])[NH:52][CH2:53][CH2:54][CH2:55][C:56]1([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[N:58]([CH3:65])[C:57]1=[O:66]
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Reactant: CN1C(=O)C(CCCN)(c2ccccc2)c2ccccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)NCCCC1(c2ccccc2)C(=O)N(C)c2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
(S)-2-[(Azepane-1-carbonyl)-amino]-4-methyl-pentanoic acid (0.39 g, 1.5 mmol, Example 1, Step B) was dissolved in dry DMF (5 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N-methylmorpholine (0.66 mL, 6.0 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.60 g, 1.6 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; then a solution of 3-(3-amino-propyl)-1-methyl-3-phenyl-1,3-dihydro-indol-2-one monohydrochloride monohydrate (0.49 g, 1.5 mmol) in dry DMF (7 mL) was added. After additional 20 minutes stirring at 0° C., the ice-water bath was removed and the reaction mixture was stirred and allowed to warm up to ambient temperature for 15 minutes. The reaction mixture was poured into 50 mL of EtOAc, the resulting mixture was successively washed with 3% aqueous HCl solution, brine, saturated aqueous NaHCO3 solution, brine, and was dried over Na2SO4. The solution was concentrated in vacuo affording a white solid. Recrystallization from EtOAc-hexanes afforded 0.56 g (72%) of the pure titled compound as a white powder: mp 181-182° C. APCI-MS m/z 519.1 (MH+).