Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[C:4]([F:25])[CH:3]=1.[CH2:26]([C@@H:28]1[CH2:32][O:31][C:30](=[O:33])[NH:29]1)[CH3:27].C(=O)([O-])[O-].[K+].[K+].CNCCNC.[Cl-].[NH4+]>[Cu]I.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH3:23][C:22]1[C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:9]([C:5]3[C:6]([F:8])=[CH:7][C:2]([N:29]4[C@H:28]([CH2:26][CH3:27])[CH2:32][O:31][C:30]4=[O:33])=[CH:3][C:4]=3[F:25])=[O:10])[CH2:12][CH2:13]2)=[N:18][CH:19]=[C:20]([CH3:24])[CH:21]=1
Reactant: CC[C@@H]1COC(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3c(F)cc(Br)cc3F)CC2)c(C)c1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC[C@@H]1COC(=O)N1c1cc(F)c(C(=O)N2CCN(c3ncc(C)cc3C)CC2)c(F)c1
Yield: 62.8 %

Procedure:
To a mixture of (4-bromo-2,6-difluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (410 mg) described in Preparation Example 60, (R)-4-ethyloxazolidin-2-one (138 mg) described in Preparation Example 26, potassium carbonate (276 mg) and copper (I) iodide (38 mg) were added toluene (1.5 mL) and N,N′-dimethylethylenediamine (43 μL), and the mixture was refluxed for 2.5 hr. Since the starting materials were left, copper (I) iodide (38 mg) and N,N′-dimethylethylenediamine (43 μL) were added and the mixture was further refluxed for 2 hr. The reaction mixture was cooled, ethyl acetate and aqueous ammonium chloride solution were added and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a 1:1 mixture of saturated aqueous ammonium chloride solution and ammonia water, and the mixture was washed once with saturated aqueous ammonium chloride solution, once with saturated aqueous sodium chloride solution, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (chloroform:methanol) to give the title compound (279 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:25]=[CH:24][C:16]([CH2:17][N:18]([CH3:23])[CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[CH:28]=[N+:29]([O-:52])[CH:30]=[C:31]([Cl:51])[C:32]=1[CH2:33][C@@H:34]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH:43]([F:45])[F:44])=[C:38]([O:46][CH2:47][CH:48]2[CH2:50][CH2:49]2)[CH:37]=1)O.C(Cl)CCl.CC#N>CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C=O)C>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[CH:15][C:16]([CH2:17][N:18]([CH3:23])[CH2:19][C:20]([O:22][C@H:34]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH:43]([F:44])[F:45])=[C:38]([O:46][CH2:47][CH:48]3[CH2:49][CH2:50]3)[CH:37]=2)[CH2:33][C:32]2[C:31]([Cl:51])=[CH:30][N+:29]([O-:52])=[CH:28][C:27]=2[Cl:26])=[O:21])=[CH:24][CH:25]=1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: CN(CC(=O)O)Cc1ccc(N(C(=O)OC(C)(C)C)S(C)(=O)=O)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CC#N
Solvent: ClCCl
Product: CN(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1)Cc1ccc(N(C(=O)OC(C)(C)C)S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.3 %

Procedure:
A mixture of 2-((4-(N-(tert-butoxycarbonyl)methylsulfonamido)benzyl)-(methyl)amino)acetic acid (0.398 g, 1.069 mmol), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.345 g, 0.822 mmol), EDC (0.473 g, 2.466 mmol), and DMAP (0.151 g, 1.233 mmol) in DCM was stirred at RT for 30 minutes. CH3CN (10 ml) and DMF (5 ml) were added to dissolve insoluble residue, and the mixture was stirred at RT for 2 days. The mixture was diluted with DCM and washed twice with HCl 1N and with NaHCO3. The organic layer was dried over Na2SO4, and the solvent was removed. The crude was purified by filtration on SCX cartridge (DCM/MeOH 1/1; MeOH/conc.aq.NH4OH 90/10). The basic fraction was portioned between EtOAc and water, and the organic phase was washed with brine and dried over Na2SO4. The solvent was removed, and the crude (S)-4-(2-(2-((4-(N-(tert-butoxycarbonyl)-methylsulfonamido)benzyl)(methyl)amino)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide was obtained as a colorless amorphous solid (0.250 g, 0.323 mmol, 39.3% yield, MS/ESI+ 774.5 [MH]+) and used in the next step without any further purification.
Reaction SMILES: [C:1]([CH2:4]CN(CC)CCNC([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(O)=O)=CC=2)=CC3)CC1)=O)(O)=O.C[O:53][C:54](=[O:103])[CH2:55][CH2:56][NH:57][CH2:58][CH2:59][CH2:60][NH:61][C:62]([C@:64]12[CH2:99][CH2:98][C@@H:97]([C:100]([CH3:102])=[CH2:101])[C@@H:65]1[C@@H:66]1[C@@:79]([CH3:82])([CH2:80][CH2:81]2)[C@@:78]2([CH3:83])[C@@H:69]([C@:70]3([CH3:96])[C@@H:75]([CH2:76][CH2:77]2)[C:74]([CH3:85])([CH3:84])[C:73]([C:86]2[CH:95]=[CH:94][C:89]([C:90]([O:92]C)=[O:91])=[CH:88][CH:87]=2)=[CH:72][CH2:71]3)[CH2:68][CH2:67]1)=[O:63].ICC>>[C:54]([CH2:55][CH2:56][N:57]([CH2:1][CH3:4])[CH2:58][CH2:59][CH2:60][NH:61][C:62]([C@:64]12[CH2:99][CH2:98][C@@H:97]([C:100]([CH3:102])=[CH2:101])[C@@H:65]1[C@@H:66]1[C@@:79]([CH3:82])([CH2:80][CH2:81]2)[C@@:78]2([CH3:83])[C@@H:69]([C@:70]3([CH3:96])[C@@H:75]([CH2:76][CH2:77]2)[C:74]([CH3:85])([CH3:84])[C:73]([C:86]2[CH:87]=[CH:88][C:89]([C:90]([OH:92])=[O:91])=[CH:94][CH:95]=2)=[CH:72][CH2:71]3)[CH2:68][CH2:67]1)=[O:63])([OH:53])=[O:103]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN(CC)CCC(=O)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
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCCNCCC(=O)OC)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
Solvent: CCI
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCCN(CC)CCC(=O)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

Procedure:
The title compound was prepared following the method described above for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-((2-carboxyethyl)(ethyl)amino)ethylcarbamoyl)-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 (example 89) using methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(3-methoxy-3-oxopropylamino)propylcarbamoyl)-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 as amine and iodoethane as alkylating reagent. The product was isolated as a white solid (3 mg, 30%). LCMS: m/e 715.49 (M+H)+, 2.11 min (method 1). 1H NMR (500 MHz, Acetic Acid-d4) δ ppm 8.03 (d, J=8.24 Hz, 2H), 7.30 (d, J=8.24 Hz, 2H), 5.37 (d, J=5.19 Hz, 1H), 4.78 (s, 1H), 4.65 (s, 1H), 3.50 (t, J=7.17 Hz, 2H), 3.46-3.40 (m, 2H), 3.39-3.31 (m, 2H), 3.27 (t, J=7.63 Hz, 2H), 3.21-3.08 (m, 1H), 2.97 (t, J=7.02 Hz, 2H), 2.67-2.54 (m, 1H), 2.25-2.17 (m, 2H), 1.74 (s, 3H), 1.39 (t, J=7.17 Hz, 3H), 2.05-1.10 (m, 21H), 1.08 (s, 3H), 1.06 (s, 6H), 1.01 (s, 3H), 0.99 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=[CH:10][C:4]=2[CH:3]=1.Cl.[CH3:15]O>>[CH3:15][O:12][C:11]([C:7]1[C:5]2[S:6][C:2]([CH3:1])=[CH:3][C:4]=2[CH:10]=[CH:9][CH:8]=1)=[O:13]
Reactant: Cc1cc2cccc(C(=O)O)c2s1
Reactant: CO
Agent: Cl
Product: COC(=O)c1cccc2cc(C)sc12

Procedure:
A solution of 2-methylbenzo[b]thiophene-7-carboxylic acid (5.1 g) in methanol (100 ml) was saturated with hydrogen chloride and then heated under reflux for 18 hours. The solution was evaporated and the residue was dissolved in ether. The ether solution was washed with sodium carbonate solution and dried (Na2SO4). Evaporation of the ether gave 2-methylbenzo[b]thiophene-7-carboxylic acid methyl ester (4.7 g), m.p. 48°-49°.
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([S:11]([NH2:14])(=[O:13])=[O:12])[C:5]=2[S:4][CH2:3][CH2:2]1.C[Al](C)C.[CH3:19][O:20][C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([NH:28][C:29](=O)[O:30]C)[N:22]=1.O>C(Cl)Cl.Cl.C(O)(=O)C>[CH3:19][O:20][C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([NH:28][C:29]([NH:14][S:11]([C:10]2[C:5]3[S:4][CH2:3][CH2:2][S:1][C:6]=3[CH:7]=[CH:8][CH:9]=2)(=[O:12])=[O:13])=[O:30])[N:22]=1
Reactant: COC(=O)Nc1nc(C)cc(OC)n1
Reactant: NS(=O)(=O)c1cccc2c1SCCS2
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2cccc3c2SCCS3)n1
Temperature: 25 °C

Procedure:
To a solution of 2.5 g 1,4-benzodithian-5-sulfonamide, prepared in Example 18, in 50 ml methylene chloride at ambient temperature under nitrogen is added 5.5 ml trimethylaluminum (2M in toluene). After stirring 15 minutes at ambient temperature 2.0 g of methyl [4-methoxy-6-methylpyrimidin-2-yl]carbamate, prepared according to the procedure of Example 3, is added and the reaction mixture is heated at reflux for 16 hours. The reaction mixture is cooled to ambient temperature and 75 ml water, 10 ml glacial acetic acid, and 10 drops hydrochloric acid are sequentially added. The organic phase is separated, dried, and the solvent removed under reduced pressure to give an oil. Crystallization of the oil from n-butyl chloride/ether gives a solid.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:30])[C:8]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22]CC)=[O:21])=[C:9]2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[N:31]1[CH:36]=[CH:35][C:34]([C:37]([OH:41])([C:39]#[CH:40])[CH3:38])=[CH:33][CH:32]=1>>[C:26]([O:25][C@@H:19]([C:8]1[C:7]([CH3:30])=[CH:6][C:5]2[C:10](=[CH:11][C:2]([C:40]#[C:39][C:37]([OH:41])([C:34]3[CH:35]=[CH:36][N:31]=[CH:32][CH:33]=3)[CH3:38])=[CH:3][CH:4]=2)[C:9]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:20]([OH:22])=[O:21])([CH3:29])([CH3:27])[CH3:28]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Reactant: C#CC(C)(O)c1ccncc1
Product: Cc1cc2ccc(C#CC(C)(O)c3ccncc3)cc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(2S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-7-(3-hydroxy-3-(pyridin-4-yl)but-1-ynyl)-3-methylnaphthalen-2-yl)acetic acid was prepared by the method Example 8 from ethyl 2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate and 2-(pyridin-4-yl)but-3-yn-2-ol. 1H-NMR: 400 MHz, (CD3OD) δ: 8.80 (d, J=5 Hz, 2H), 8.27 (d, J=5H, 2H), 7.80 (d, J=8 Hz, 1H), 7.71 (s, 1H), 7.56 (m, 3H), 7.48 (d, J=8 Hz, 1H), 7.34 (s, 1H), 7.30 (d, J=8 Hz, 1H), 5.16 (s, 1H), 2.61 (s, 3H), 1.83 (s, 3H), 0.98 (s, 9H). LCMS-ESI+ (m/z): [M+H]+ calcd for C32H30ClNO4: 528.2. found: 528.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)N=N[C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[C:27]1(C)C=CC(C)=C[CH:28]=1.C12CC(C=C1)C=C2.O>C(OCC)(=O)C.CCCCCC>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[CH:27]=[CH:28][C:10]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[N:9][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:15][CH:16]=1
Reactant: Cc1ccc(C)cc1
Reactant: Brc1ccc(-c2nnc(-c3ccncc3)nc2-c2ccc(Br)cc2)cc1
Agent: C1=CC2C=CC1C2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O
Product: Brc1ccc(-c2ccc(-c3ccncc3)nc2-c2ccc(Br)cc2)cc1
Temperature: 140 °C
Reaction time: 14 h

Procedure:
Into a 100 mL three-neck flask, 2.2 g (4.7 mmol) of 5,6-bis(4-bromophenyl)-3-(4-pyridyl)-1,2,4-triazine, 45 mL of para-xylene, 2.5 mL (23 mmol) of 2,5-Norbornadiene were put, and the solution was stirred at 140° C. for 14 hours under a nitrogen stream. After a certain time, water was added to the solution, and an aqueous layer was extracted with chloroform. The obtained extract was washed with a saturated saline together with the organic layer and then dried over magnesium sulfate. The obtained mixture was subjected to gravity filtration, and the obtained filtrate was concentrated to give a solid. The obtained solid was refined with silica gel column chromatography (hexane:ethyl acetate=2:1), so that 1.7 g of a target substance, yellow powder was obtained in a yield of 78%.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:7]([C:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)=[O:8].[CH2:24](Br)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C)C=O>[CH3:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:7]([C:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:10]=1)=[O:8]
Reactant: BrCCc1ccccc1
Reactant: Cc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2cn(CCc3ccccc3)c3ccccc3c2=O)cc1C

Procedure:
Compound 4aa was prepared following the procedure outlined in Step 3 of Example 1 using 26 mg (0.65 mmol) of sodium hydride (60%), 138.6 mg (0.50 mmol) of 3-(3,4-dimethyl-benzoyl)-2,3-dihydro-1H-quinolin-4-one 3a, 3 mL of anhydrous dimethylformamide, and 120.3 mg (0.65 mmol) of phenethylbromide. The crude product was purified by flash chromatograph to yield 44 mg of a colorless solid 4aa: LC-MSD, m/z for C26H23NO2, [M+H]+=382.5, [M+2H]+=383.5; Reverse phase HPLC (gradient acetonitrile 0.1% TFA 20-95% in 4 min) retention time=2.551 min; 1H NMR (400 MHz, CDCl3/HCl): δ 2.30 (d, 6H), 3.20 (t, 2H), 4.40 (t, 3H), 7.08 (d, 2H), 7.13 (d, 1H), 7.20-7.32 (m, 3H), 7.38-7.47 (m, 2H), 7.53-7.58 (d, 2H), 7.73 (t, 1H), 7.80 (s, 1H), 8.48 (d, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([OH:13])[CH:10]2[N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:15][CH2:16][CH:9]12)=O)(C)(C)C.[ClH:27].O1CCOCC1>C(Cl)Cl.C1(C)C=CC=CC=1>[ClH:27].[CH2:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][CH:9]2[NH:8][CH2:12][CH:11]([OH:13])[CH:10]12)=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CC(O)C2C1CCN2C(=O)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)N1CCC2NCC(O)C21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of bicyclic alcohol 43 (6.5 g, 17.9 mmol) in DCM (20 mL) at 0° C. was added 4N HCl/1,4-dioxane (20 mL, 80 mmol) and the reaction mixture was slowly warming to ambient temperature. After 90 min, an additional portion of 4N HCl/1,4-dioxane (20 mL) was added. After 3 h, the reaction mixture was diluted with toluene and concentrated in vacuo. The crude 52 (HCl salt) was used in the next step without further purification. Mass spectrum, m/z [262.5] (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]#[C:11][CH2:12][OH:13].N1C=CN=C1.[CH3:19][C:20]([Si:23](Cl)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:22])[CH3:21]>C(Cl)Cl>[C:20]([Si:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[O:13][CH2:12][C:11]#[C:10][CH2:9][CH2:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)([CH3:22])([CH3:19])[CH3:21]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCC#CCCOC1CCCCO1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](OCC#CCCOC1CCCCO1)(c1ccccc1)c1ccccc1
Yield: 96 %

Procedure:
A solution of compound 3 and imidazole in CH2Cl2 was treated with TBDPSCl dropwise at 0° C. for 2 h. The reaction mixture was diluted with CH2Cl2 (300 mL) and washed with water (200 mL). The organic layer was dried over MgSO4 and concentrated. The residue was purified with 10% EtOAc in hexanes by silica gel column chromatography to give 18.0 g of compound 4 (42.6 mmol, 96% yield): 1H NMR (CDCl3) δ 7.80˜7.64 (m, 4H), 7.49˜7.34 (m, 6H), 4.63 (t, J=3.6 Hz, 1H), 4.31 (t, J=1.9 Hz, 2H), 3.93˜3.83 (m, 1H), 3.77 (dt, J=9.7, 7.1 Hz, 1H), 3.55˜3.44 (m, 2H), 2.48 (tt, J=7.1, 2.1 Hz, 2H), 1.89˜1.46 (m, 6H), 1.06 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=3)C(=O)[O:9][N:8]=2)=[N:4][O:5][N:6]=1.[C:20]1([CH2:26][C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:7](=[N:8][OH:9])[C:3]2[C:2]([NH:1][C:27](=[O:28])[CH2:26][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:6][O:5][N:4]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1nonc1-c1noc(=O)n1-c1cccc(Cl)c1
Reactant: O=C(Cl)Cc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: O=C(Cc1ccccc1)Nc1nonc1C(=NO)Nc1cccc(Cl)c1
Reaction time: 4 h
Yield: 45.2 %

Procedure:
A solution of 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-chlorophenyl)-1,2,4-oxadiazol-5(4H)-one (30.0 mg, 0.107 mmol) and 4-dimethylaminopyridine (2.6 mg, 0.021 mmol) in pyridine (0.50 mL) was treated with benzeneacetyl chloride (42.6 μL, 0.322 mmol) and stirred for 4 h. The reaction mixture was concentrated and rediluted with ethanol (1.0 mL) and 2 M of sodium hydroxide in water (0.30 mL) stirred for 45 min. Purification of the crude reaction mixture by preparative HPLC gave the desired product (18 mg, 45%). LCMS for C17H15ClN5O3 (M+H)+: m/z=371.9.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[N:12]O)[C:8]2=[O:11])=[C:4]([CH3:14])[CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:16]>C(Cl)(Cl)(Cl)Cl>[Cl:16][C:7]1[NH:12][C:8](=[O:11])[C:9]2[C:5]([CH:6]=1)=[C:4]([CH3:14])[CH:3]=[C:2]([F:1])[CH:10]=2
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cc1cc(F)cc2c1CC(=NO)C2=O
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(F)cc2c(=O)[nH]c(Cl)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.1 %

Procedure:
To a solution of 6-fluoro-2-(hydroxyimino)-4-methyl-2,3-dihydro-1H-inden-1-one (800 mg, 4.12 mmol) in anhydrous CCl4 (100 mL) was added PCl5 (1.28 g, 6.18 mmol) and stirred at RT for 16 h. The reaction mixture was concentrated in vacuo and the residue dissolved in anhydrous 1,4-dioxane (100 mL), cooled 0° C., the solution was saturated with HCl gas and allowed to stir RT for 16 h. The reaction mixture was heated at 60° C. for 2 h, cooled to RT and diluted with EtOAc (50 mL), washed with water (25 mL), saturated NaHCO3 solution (25 mL), brine solution (25 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude material was washed with diethyl ether (10 mL), n-pentane (10 mL) and was dried in vacuo to obtain 3-chloro-7-fluoro-5-methylisoquinolin-1(2H)-one as a pale yellow solid (550 mg, 68%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([O:11][CH3:12])=[O:10].[CH:13]1([C:17]2[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][CH:18]=2)[CH2:16][CH2:15][CH2:14]1>C(#N)C>[Cl:8][C:6]1[N:5]=[N:4][C:3]([C:9]([O:11][CH3:12])=[O:10])=[C:2]([NH:23][C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([CH:13]3[CH2:16][CH2:15][CH2:14]3)[N:22]=2)[CH:7]=1
Reactant: Nc1cccc(C2CCC2)n1
Reactant: COC(=O)c1nnc(Cl)cc1Cl
Solvent: CC#N
Product: COC(=O)c1nnc(Cl)cc1Nc1cccc(C2CCC2)n1
Temperature: 80 °C
Reaction time: 48 h
Yield: 17.5 %

Procedure:
A heavy walled resealable tube was charged with methyl 4,6-dichloropyridazine-3-carboxylate (1.3 g, 6.28 mmol) and 6-cyclobutylpyridin-2-amine (931 mg, 6.28 mmol) in acetonitrile (6.00 mL). The tube was heated with stirring in an oil bath at 80° C. for 48 h. Solvent was evaporated under vacuum, the residue was dissolved in dichloromethane and then purified by flash chromatography (spherical silica 20-45 μM, 50 g, Versaflash Supelco) eluting with 0 to 10% over 20 min dichloromethane/acetone to give methyl 6-chloro-4-(6-cyclobutylpyridin-2-ylamino)pyridazine-3-carboxylate (350 mg, 17.5% yield) as a light yellow solid. 1H NMR (CHLOROFORM-d) δ: 10.62 (s, 1H), 9.49 (s, 1H), 7.59 (t, J=7.9 Hz, 1H), 6.85 (d, J=7.6 Hz, 1H), 6.73 (d, J=8.3 Hz, 1H), 4.10 (s, 3H), 3.67 (quin, J=8.6 Hz, 1H), 2.24-2.58 (m, 4H), 1.85-2.22 (m, 2H); LC-MS 319.0 [M+H]+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([O:14][CH2:15][CH:16]1[CH2:20][N:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:18][CH:17]1[CH2:25][S:26]C(=O)C)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.Cl>CCOCC>[CH2:7]([O:14][CH2:15][CH:16]1[CH2:20][N:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:18][CH:17]1[CH2:25][SH:26])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)SCC1CN(S(C)(=O)=O)CC1COCc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: CS(=O)(=O)N1CC(CS)C(COCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
To a solution of LiAlH4 (0.23 mmol, 1 M in THF) in Et2O (6 ml) was added a suspension of thioacetic acid (3RS,4RS)—S-(4-benzyloxymethyl-1-methanesulfonyl-pyrrolidin-3-ylmethyl) ester (75.5 mg, 0.21 mmol) in Et2O. The mixture was stirred at RT for 30 min and refluxed for 2 h. After cooling to r.t., water and 1 M aqueous HCl were added. The organic phase was dried and evaporated to give 63 mg (95%) of [(3RS,4RS)-4-benzyloxymethyl-1-methanesulfonyl-pyrrolidin-3-yl]-methanethiol as a colorless oil, MS: 333 (M+NH4)+.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:38])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17][CH:16]2[C:35]([OH:37])=O)[CH:12]=[CH:13][CH:14]=1.CC1(C)[O:44][C@H:43]([CH2:45][CH2:46][NH2:47])[CH2:42][O:41]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[OH:44][C@@H:43]([CH2:42][OH:41])[CH2:45][CH2:46][NH:47][C:35]([CH:16]1[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=2[F:38])[C:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:34])([CH3:32])[CH3:33])[NH:17]1)=[O:37]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CC1(C)OC[C@@H](CCN)O1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)NCC[C@@H](O)CO)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 68 %

Procedure:
In a manner similar to the method described in Example 72a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 53b (0.44 g, 0.769 mmol) was reacted with 2-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.33 g, 2.3 mmol), HATU (0.52 g, 1.36 mmol) and iPr2NEt (0.66 mL, 3.8 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide as a white solid (0.29 g, 68%).
Reaction SMILES: [SH:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[Br:7][C:8]([F:15])([F:14])[CH:9]([F:13])[CH2:10][CH2:11]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:7][C:8]([F:15])([F:14])[CH:9]([F:13])[CH2:10][CH2:11][S:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1
Reactant: Sc1nccs1
Reactant: FC(CCBr)C(F)(F)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: FC(CCSc1nccs1)C(F)(F)Br
Reaction time: 1.5 h
Yield: 96.5 %

Procedure:
2-Mercaptothiazole (11.7 g) in acetone (30 cm3) containing 1,4-dibromo-1,1,2-trifluorobutane (27.0 g) was treated portionwise with anhydrous potassium carbonate (13.8 g) under an atmosphere of nitrogen. The reaction was stirred for 1.5 hours, filtered and the insolubles washed with further acetone (4×25 cm3). The filtrate was evaporated under reduced pressure and the residue fractionated by chromatography (silica, eluant 10% ethyl acetate in hexane) to give 2-(4-bromo-3,4,4-trifluorobutylthio)thiazole (29.5 g). 1H NMR: δ 2.2-2.5(2H,m); 3.2-3.6(2H,m); 4.7-5.0(1H,m); 7.23(1H,d); 7.68(1H,d).