Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:19])([CH3:18])[O:6][CH2:7][CH:8]=[CH:9][S:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)([CH3:4])[CH3:3].N1C=CC=CC=1.[F:26][C:27]([F:39])([F:38])[O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>ClCCl.O>[CH3:4][C:2]([Si:5]([CH3:18])([CH3:19])[O:6][CH2:7][CH:8]=[CH:9][S:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][C:29]([O:28][C:27]([F:26])([F:38])[F:39])=[CH:30][CH:31]=2)=[CH:13][CH:12]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCC=CSc1ccc(N)cc1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC=CSc1ccc(NC(=O)c2ccc(OC(F)(F)F)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
A 0° C. solution of Example 126B (0.92 g, 3.0 mmol) in dichloromethane (10 mL) was sequentially treated with pyridine (0.3 mL, 3.7 mmol) and 4-trifluoromethoxybenzoyl chloride (0.53 mL, 3.4 mmol), stirred at 0° C. for 0.5 hours and then at room temperature for 1 hour. The reaction was diluted with water and extracted with dichloromethane (3×15 mL). The combined extracts were washed with saturated NaHCO3, dried, filtered, concentrated and purified on silica gel by flash column chromatography eluting with 6:1 hexanes/ethyl acetate to give 1.37 g of the desired product. MS (ESI): 501 (M+NH4+), 506 (M+Na+).
Reaction SMILES: C([NH:8][CH2:9][C:10](=[O:25])[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])=[O:14])(OC(C)(C)C)=O.[BrH:26]>C(O)(=O)C>[BrH:26].[NH2:8][CH2:9][C:10](=[O:25])[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:14]
Reactant: CC(C)(C)OC(=O)CCOC(=O)CCC(=O)CNC(=O)OC(C)(C)C
Agent: Br
Solvent: CC(=O)O
Product: NCC(=O)CCC(=O)OCCC(=O)O
Yield: 79 %

Procedure:
This compound was prepared from the product of 4a (5.43 g; 15.1 mmol) and 30% HBr in acetic acid (15 mL) according to Example 1c. 3.38 g (79%) product was obtained (amber gum that did not solidify).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21][C:22]([F:25])([F:24])[F:23].ClC1C=CC=C(C(OO)=[O:34])C=1>ClCCl.C(OCC)(=O)C>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21]([C:22]([F:25])([F:24])[F:23])=[O:34]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1SC(F)(F)F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(=O)C(F)(F)F
Reaction time: 48 h
Yield: 57.8 %

Procedure:
A stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylthiopyrazole (10.0 g) in dichloromethane (100 ml) was treated with m-chloroperbenzoic acid (4.5 g). After stirring overnight additional m-chloroperbenzoic acid (1.6 g) was added in 2 portions, and left for 2 days. The reaction product was diluted with ethyl acetate (30 ml) and then washed in turn with sodium sulphite solution (50 ml), sodium carbonate solution (50 ml) and with water (50 ml). After drying over magnesium sulphate, this was filtered and evaporated in vacuo. Purification by chromatography on silica eluting with dichloromethane gave 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylsulphinylpyrazole as a white solid (6.0 g), m.p. 200.5-201° C.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=2)=[CH:17][CH:16]=1.[CH3:28][C:29]([CH3:32])([O-])[CH3:30].[K+]>C1(C)C=CC=CC=1>[C:18]1([C:21]2[CH:26]=[CH:25][C:24]([N:12]3[C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:32]=4[C:29]4[C:30]3=[CH:2][CH:1]=[CH:13][CH:28]=4)=[CH:23][CH:22]=2)[CH:19]=[CH:20][CH:15]=[C:16]([N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:17]=1
Reactant: CC(C)(C)[O-]
Reactant: Brc1ccc(-c2ccc(Br)cc2)cc1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [K+]
Solvent: Cc1ccccc1
Product: c1cc(-c2ccc(-n3c4ccccc4c4ccccc43)cc2)cc(-n2c3ccccc3c3ccccc32)c1
Temperature: 135 °C
Yield: 6.9 %

Procedure:
Carbazole (1.80 g, 10.9 mmol), 4,4′-dibromobiphenyl (0.75 g, 2.4 mmol), and potassium tbutoxide (2.24 g, 20 mmol) were dissolved in dry toluene and heated at 135° C. for 24 h. The solution was filtered and the solvent was removed in vacuo, the residue was dry-packed on SiO2 and chromatographed using 10% acetone in hexanes to afford (0.08 g, 6%) of the product. 1H NMR (CDCl3) δ 8.22-8.16 (m, 4H), 7.93-7.65 (m, 8H), 7.56-7.49 (m, 8H), 7.47-7.28 (m, 4H). 13C NMR (CDCl3+DMSO-d6) δ 142.1, 140.8, 140.7, 139.0, 138.3, 137.3, 130.5, 128.5, 127.3, 126.1, 126.0, 125.9, 125.6, 123.4, 120.3, 120.2, 120.0, 109.7. EI MS m/z 484 [M+], m.p.=244-246° C.
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21]CC=C)=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=O)C=C.[C:27]([C:30]1[N:31]2[CH:37]=[N:36][CH:35]=[C:32]2[S:33][CH:34]=1)(=[O:29])[CH3:28]>>[OH:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O-:21])=[O:20])=[C:14]([CH2:17][N:36]3[CH:35]=[C:32]4[S:33][CH:34]=[C:30]([C:27](=[O:29])[CH3:28])[N+:31]4=[CH:37]3)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9]
Reactant: CC(=O)c1csc2cncn12
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Product: CC(=O)c1csc2cn(CC3=C(C(=O)[O-])N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)c[n+]12
Yield: 14.2 %

Procedure:
The same procedure as in Example 1 was repeated except that 104 mg of allyl (1S,5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-methyl-1-carbapen-2-em-3-carboxylate and 95 mg of 3-acetylimidazo[5,1-b]thiazole were used, thereby obtaining 15.7 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:16][CH2:15][N:14]([CH3:17])[C:13](=[N:18][C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:28](OC(=O)C)(=[O:30])[CH3:29].O>N1C=CC=CC=1>[C:28]([N:16]1[C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:12][C:13](=[N:18][C:19]2[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=2[CH3:27])[N:14]([CH3:17])[CH2:15]1)(=[O:30])[CH3:29]
Reactant: COc1ccc(C2=CC(=Nc3c(C)cc(C)cc3C)N(C)CN2)cc1OC
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(C2=CC(=Nc3c(C)cc(C)cc3C)N(C)CN2C(C)=O)cc1OC
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 6-(3,4-dimethoxyphenyl)-3-methyl-1,2,3,4-tetrahydro-4-(2,4,6-trimethylphenylimino)pyrimidine (0.5 g) in pyridine (5 ml) was added acetic anhydride (1.0 ml), and the mixture was stirred at ambient temperature for 2.5 hours. The mixture was poured into water (150 ml) and extracted with chloroform. The organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with chloroform to give 1-acetyl-6-(3,4-dimethoxyphenyl)-3-methyl-1,2,3,4-tetrahydro-4-(2,4,6-trimethylphenylimino)pyrimidine (0.22 g).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[N+:14]([O-])([O-:16])=[O:15].[K+]>S(=O)(=O)(O)O>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:3])=[O:4]
Reactant: O=[N+]([O-])[O-]
Reactant: CS(=O)(=O)c1cccc(C(=O)O)c1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Temperature: 110 °C
Yield: 0.1 %

Procedure:
To a suspension of 3-(methylsulfonyl)-benzoic acid (32.5 g; 0.16 mol) in 130 mL 98% sulphuric acid at 0° C. was slowly added potassium nitrate (32.8 g; 0.32 mol). The reaction mixture was heated for 3 hours at 110° C., subsequently cooled to room temperature and poured onto ice and the precipitate collected. 28 g (0.114 mmol; 71% yield) of 3-(methylsulfonyl)-5-nitro-benzoic acid were obtained as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH:16]=1)[C:5]([NH:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1)=[O:6].[N:24]1([C:28]([C:30]2[CH:35]=[N:34][C:33](Cl)=[CH:32][N:31]=2)=[O:29])[CH2:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:24]1([C:28]([C:30]2[N:31]=[CH:32][C:33]([O:1][C:2]3[CH:3]=[C:4]([CH:14]=[C:15]([O:17][CH:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[CH:16]=3)[C:5]([NH:7][C:8]3[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=3)=[O:6])=[N:34][CH:35]=2)=[O:29])[CH2:27][CH2:26][CH2:25]1
Reactant: O=C(c1cnc(Cl)cn1)N1CCC1
Reactant: Cn1ccc(NC(=O)c2cc(O)cc(OC3CCOCC3)c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cn1ccc(NC(=O)c2cc(Oc3cnc(C(=O)N4CCC4)cn3)cc(OC3CCOCC3)c2)n1
Temperature: 120 °C
Yield: 12.3 %

Procedure:
3-Hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzamide (209 mg, 0.66 mmol), 2-(azetidin-1-ylcarbonyl)-5-chloropyrazine (159 mg, 0.80 mmol) and potassium carbonate (184 mg, 1.33 mmol) were dissolved/suspended in acetonitrile (3.5 mL). The reaction mixture was heated in a microwave reactor for 4 hours at 120° C. then cooled, filtered and reduced in vacuo. The crude product was purified by chromatography on silica, eluting with 0-5% methanol in DCM, to give the required product as a white foam (39 mg). 1H NMR δ (d6-DMSO): 1.57-1.68 (m, 2H), 1.97-2.05 (m, 2H), 2.26-2.36 (m, 2H), 3.47-3.55 (m, 2H), 3.78 (s, 3H), 3.84-3.91 (m, 2H), 4.10 (t, 2H), 4.57 (t, 2H), 4.67-4.75 (m, 1H), 6.58 (d, 1H), 7.11 (t, 1H), 7.43 (t, 1H), 7.54 (t, 1H), 7.60 (d, 1H), 8.56 (d, 1H), 8.68 (d, 1H), 10.80 (s, 1H); m/z 479 (M+H)+
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6](C=O)=[CH:5][CH:4]=1)#[N:2].[N:11]1([CH:17]=O)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(O)=O.Cl>C(O)C>[N:11]1([CH2:17][C:6]2[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: O=CN1CCNCC1
Reactant: N#Cc1ccc(C=O)cc1
Agent: Cl
Solvent: CCO
Solvent: O=CO
Product: N#Cc1ccc(CN2CCNCC2)cc1
Reaction time: 0.17 h

Procedure:
A mixture of 13.1 g. of p-cyanobenzaldehyde and 15 ml. of piperazine-1-carboxaldehyde was heated to 100° C. Over 10 minutes, 6 g. of 99% formic acid were added. The mixture was heated for 3 hours, then 200 ml. of 3.6 N hydrochloric acid in ethanol were added and the mixture was refluxed for 4 hours. The solid was collected, washed with ether and suspended in water. 10 N Sodium hydroxide extracted with three 100 ml. portions of chloroform and the combined extracts were evaporated. The residue was suspended in a mixture of 6 N hydrochloric acid and chloroform and filtered. The filtrate was adjusted to pH>7 with 10 N sodium hydroxide, extracted with chloroform, and the extract dried and evaporated to an oil which was distilled, giving α-(1-piperazinyl)-p-tolunitrile as a colorless liquid, b.p. 207°-209° C. (15 mm.).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][S:21]([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O)(=[O:23])=[O:22]>>[CH3:20][S:21]([C:24]1[CH:25]=[C:26]([CH2:27][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)[CH:29]=[CH:30][CH:31]=1)(=[O:22])=[O:23]
Reactant: CS(=O)(=O)c1cccc(C=O)c1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: CS(=O)(=O)c1cccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-methylsulfonylbenzaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(3-methylsulfonylphenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:17]2[CH2:19][O:18]2)=[CH:4][C:5]([O:15][CH3:16])=[C:6]([CH:14]=1)[O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]>C(OCC)(=O)C.[C].[Pd]>[Cl:1][C:2]1[C:3]([CH2:17][CH2:19][OH:18])=[CH:4][C:5]([O:15][CH3:16])=[C:6]([CH:14]=1)[O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)COc1cc(Cl)c(C2CO2)cc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cc(Cl)c(CCO)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.2 %

Procedure:
To a solution of ethyl 2-(5-chloro-2-methoxy-4-oxiranylphenoxy)acetate (129 mg) in ethyl acetate (2.5 ml) was added 10% palladium carbon (13 mg), and the mixture was stirred for 3 hours at room temperature under a hydrogen atmosphere. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. Purification of the residue by flash column chromatography on silica gel (eluent: hexane/ethyl acetate=1/1) gave ethyl 2-[5-chloro-4-(2-hydroxyethyl)-2-methoxyphenoxy]acetate (86 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([NH:12][CH2:13][CH2:14][NH:15][CH3:16])=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.Br[CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:23][O:22][C:20](=[O:21])[CH2:19][CH2:18][N:15]([CH2:14][CH2:13][NH:12][C:10]([C:3]1[C:2]([NH2:1])=[N:7][C:6]([NH2:8])=[C:5]([Cl:9])[N:4]=1)=[O:11])[CH3:16]
Reactant: COC(=O)CCBr
Reactant: CNCCNC(=O)c1nc(Cl)c(N)nc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCN(C)CCNC(=O)c1nc(Cl)c(N)nc1N
Yield: 63.4 %

Procedure:
A mixture of 2.44 g (10.0 mmol) of 3,5-diamino-6-chloro-N-(2-methylaminoethyl)pyrazine-2-carboxamide, 1.67 g (10.0 mmol) of methyl 3-bromopropionate and 1.38 g (10.0 mmol) of potassium carbonate was stirred in 20 ml of DMF for 18 hours at ambient temperature. Water (100 ml) was added and the solid was filtered and air dried. Crystallization from ethanol provided 2.1 g (6.34 mmol, 63%) of N-[2-[[(3,5-diamino-6-chloropyrazinyl)carbonyl]amino]ethyl]-N-methyl-beta-alanine methyl ester as white crystals; mp 136.5°-137° C.
Reaction SMILES: [C:1]1([C:7]2([C:10]#[N:11])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:12][S:13](O)(=[O:15])=[O:14]>C(Cl)(Cl)Cl>[C:10]([C:7]1([C:1]2[CH:6]=[CH:5][C:4]([S:13]([Cl:12])(=[O:15])=[O:14])=[CH:3][CH:2]=2)[CH2:8][CH2:9]1)#[N:11]
Reactant: O=S(=O)(O)Cl
Reactant: N#CC1(c2ccccc2)CC1
Solvent: ClC(Cl)Cl
Product: N#CC1(c2ccc(S(=O)(=O)Cl)cc2)CC1
Temperature: 25 °C

Procedure:
To a solution of 1-phenylcyclopropanecarbonitrile (0.5 g, 3.5 mmol) in 5 mL of chloroform was added 0.5 mL of ClSO3H at 0° C. After stirring at rt stirred overnight, the reaction mixture was poured into ice-water (50 mL) and the product was extracted with CHCl3 (75 mL). The extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous MgSO4, and concentrated to give the title compound. 1H NMR (500 MHz, CD3OD): δ 8.08 (2H, d), 7.77 (2H, d), 1.60 (2H, t), 1.21 (2H, t).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([CH3:13])([CH3:12])[CH2:7][CH2:6][C:5]([CH3:15])([CH3:14])[C:4]=2[CH:3]=1.[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>Cl[Ti](Cl)(Cl)Cl.ClCCl>[C:17]([C:16]([C:11]1[C:2]([OH:1])=[CH:3][C:4]2[C:5]([CH3:15])([CH3:14])[CH2:6][CH2:7][C:8]([CH3:13])([CH3:12])[C:9]=2[CH:10]=1)=[O:21])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC1(C)CCC(C)(C)c2cc(O)ccc21
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Ti+4]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)(C)C(=O)c1cc2c(cc1O)C(C)(C)CCC2(C)C
Temperature: 120 °C
Reaction time: 1 h

Procedure:
The synthesis process is as set forth in the chemical reaction formula below. The TiCl4 in the reaction path stands for titanium chloride. To 5,6,7,8-tetrahydro-2-hydroxy-5,5,8,8-tetramethylnaphthalene (409 mg, 2.00 mmol) were added titanium chloride (417 mg, 2.20 mmol) and pivaloyl chloride (361 mg, 2.99 mmol) followed by stirring at 120° C. for 1 hour. The reaction solution was diluted by dichloromethane, and the organic layer was washed by water, a saturated sodium hydrogen carbonate aq. solution, and a saturated saline solution, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography using hexane/ethyl acetate (40/3) as an elution solvent. The yield was 53.6 mg (9.0%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C[O:8][C:9](=[O:22])[CH:10]([NH:19][CH:20]=O)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1>C(Cl)Cl.O>[Cl:18][C:15]1[CH:16]=[C:17]2[C:12]([CH:11]=[C:10]([C:9]([OH:8])=[O:22])[N:19]=[CH:20]2)=[CH:13][CH:14]=1
Reactant: COC(=O)C(Cc1ccc(Cl)cc1)NC=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Product: O=C(O)c1cc2ccc(Cl)cc2cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.9 %

Procedure:
Oxalyl choride (5.7 mL) was added dropwise to a solution of 3-(4-chlorophenyl)-2-formylamino-propanoic acid methyl ester (14.5 g, 60 mmol) in CH2Cl2 (400 mL) at room temperature. After stirring for 0.5 hour, ferric chloride (11.7 g) was added and the mixture was stirred for 48 hours. The reaction mixture was diluted with water (500 mL). The organic layer was separated, and the aqueous layer was re-extracted with CH2Cl2 (2×300 mL). The organic layers were combined, washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was dissolved in MeOH (400 mL), sulfuric acid (20 mL, 98%) was added and the mixture was heated under reflux for 48 hours. After cooled to room temperature, the reaction mixture was diluted with 5% sodium bicarbonate solution (1 L). The organic layer was separated, and the aqueous layer was re-extracted with CH2Cl2 (2×500 mL). The organic layers were combined, washed with brine (500 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The crude material was further purified by silica gel chromatography (EtOAc/Hexane=1/3) and afforded the title compound (3.1 g, 23.3% yield) as a yellow solid. 1H NMR (300 MHz, CDCl3): 9.26 (s, 1H), 8.51 (s, 1H), 8.05 (d, J=1.8 Hz, 1H), 7.93 (d, J=8.7 Hz, 1H), 7.73 (dd, J=1.8 and 8.7 Hz, 1H), 4.06 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]([F:43])([F:42])[C:20]([F:41])([F:40])[C:21]([F:39])([F:38])[O:22][C:23]([F:37])([C:28]([F:36])([F:35])[O:29][C:30]([F:34])=[C:31]([F:33])[F:32])[C:24]([F:27])([F:26])[F:25]>C1COCC1>[F:33][C:31]([F:32])([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[CH:30]([F:34])[O:29][C:28]([F:35])([F:36])[C:23]([F:37])([O:22][C:21]([F:38])([F:39])[C:20]([F:40])([F:41])[C:19]([F:18])([F:42])[F:43])[C:24]([F:27])([F:26])[F:25]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: FC(F)=C(F)OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC(F)(F)C(F)OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
In the dry box, THF (500 mL) and methyl 4-hydroxybenzoate (26.6 g, 0.175 mol) were added to an oven dry RB flask equipped with a stirrer, Potassium carbonate (12.00 g, 0.087 mol) was then added. 1,1,1,2,2,3,3-Heptafluoro-3-(1,1,1,2,3,3-hexafluoro-3-(1,2,2-trifluorovinyloxy)propan-2-yloxy)propane (94.5 g, 0.219 mol) was then added via the addition funnel and the reaction allowed to stir at room temperature. The reaction mixture was heated to a gentle reflux, oil temperature about 80° C., under nitrogen overnight. An aliquot was withdrawn and concentrated under vacuum and analyzed via proton NMR that showed the complete conversion to the desired material. The cooled reaction mixture was then filtered through silica gel and then concentrated at reduced pressure, resulting in 101.52 g (99.33%) yield of the desired material.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:20]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH2:19][N:18]([C:28]3[CH2:32][CH2:31][C:30](=[O:33])[C:29]=3[CH2:34][C:35]#[N:36])[CH2:17]2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(=O)([O-])[O-:40].[K+].[K+]>CS(C)=O.OO>[F:38][C:2]([F:1])([F:37])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:20]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[CH2:19][N:18]([C:28]3[CH2:32][CH2:31][C:30](=[O:33])[C:29]=3[CH2:34][C:35]([NH2:36])=[O:40])[CH2:17]2)[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: C[C@@H](O[C@H]1CN(C2=C(CC#N)C(=O)CC2)C[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@@H](O[C@H]1CN(C2=C(CC(N)=O)C(=O)CC2)C[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 5.8 mg (0.0107 mmol) {2-[(3R,4S)-3-({(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethyl}oxy)-4-(4-fluorophenyl)pyrrolidin-1-yl]-5-oxocyclopent-1-en-1-yl}acetonitrile (step C) in 5 drops DMSO was added 10 mg (0.072 mmol) potassium carbonate and 5 drops 30% aq. hydrogen peroxide. The reaction mixture was stirred at RT for 4 h, then the volatiles removed overnight using a nitrogen gas stream. The residue was purified by prep TLC on silica gel eluting with methylene chloride/methanol (9/1). The UV active band (˜Rf=0.7) was isolated to afford the title compound as a glassy clear solid. 1H-NMR (CD3OD): δ: 1.44 (d, 3H, 6.5 Hz), 2.43 (br. s, 2H), 2.76 (br. s, 2H), 3.3-4.45 (m, 8H), 4.77 (q, 1H, 6.5 Hz), 6.98 (t, 2H, 8.5 Hz), 7.18 (m, 2H), 7.72 (s, 2H), 7.83 (s, 1H)ppm. MS: 559.1 (M+H) observed.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:4](=[O:16])[C:3]=1[C:17]#[N:18].[Br:19]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl.ClCCl>[Br:19][CH2:8][C:6]1[N:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:4](=[O:16])[C:3]([C:17]#[N:18])=[C:2]([Cl:1])[CH:7]=1
Reactant: Cc1cc(Cl)c(C#N)c(=O)n1-c1ccccc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1c(Cl)cc(CBr)n(-c2ccccc2Cl)c1=O
Temperature: 25 °C
Yield: 61.9 %

Procedure:
To a solution of 4-chloro-1-(2-chlorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step E (1.55 g) in carbon tetrachloride (69.4 mL) were added N-bromosuccinimide (1.19 g) and 2,2′-azobis(isobutyronitrile) (0.0910 g) at room temperature. The reaction mixture was refluxed for 3 hr, and cooled to room temperature. The reaction mixture was diluted with dichloromethane, and the mixture was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.23 g).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:42]=[CH:41][N:40]([CH2:43][CH:44]([CH3:48])[CH2:45][O:46][CH3:47])[C:39](=[O:49])[CH:38]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:42]=[CH:41][N:40]([CH2:43][CH:44]([CH3:48])[CH2:45][O:46][CH3:47])[C:39](=[O:49])[CH:38]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: COCC(C)Cn1ccc(Br)cc1=O
Product: COCC(C)Cn1ccc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cc1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one and 4-bromo-1-(3-methoxy-2-methyl-propyl)-1H-pyridin-2-one following a procedure analogous to that described in Example 75 Method 1. Mass spectrum (ESI+): m/z=533 [M+H]+.