Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C@@H:12]([C:13]([CH3:20])=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:11](CC2C=CC(OC)=CC=2OC)[C:10]1=[O:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].S([O-])(O)(=O)=O.[K+]>C(#N)C>[CH2:18]([O:17][C:15]([CH:14]=[C:13]([CH:12]1[NH:11][C:10](=[O:32])[CH:9]1[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH3:20])=[O:16])[CH3:19]
Reactant: CCOC(=O)C=C(C)[C@@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1Cc1ccc(OC)cc1OC
Agent: O=S(=O)([O-])O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C=C(C)C1NC(=O)C1NC(=O)OC(C)(C)C
Yield: 37.3 %

Procedure:
4.0 g (8.9 mmol) of ethyl rac-cis-3-(1-t-butoxyformamido)-1-(2,4-dimethoxybenzyl)-β-methyl-2-oxo-4-azetidineacrylate are dissolved in 300 ml of acetonitrile and the solution is treated at 90°-95° C. with 3.86 g (14.3 mmol) of potassium peroxydisulphate and 2.31 (13.3 mmol) of potassium hydrogen sulphate for 2 hours. The organic solvent is removed by evaporation and the aqueous phase is extracted with chloroform. The combined organic phases are washed with aqueous sodium chloride solution and dried over sodium sulphate. The solution is evaporated and the residue is chromatographed on silica gel using ethyl acetate for the elution. 990 mg (37%) of t-butyl 4-[2-(ethoxycarbonyl)-1-methylvinyl]-2-oxo-3-azetidinecarbamate are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]([CH:19]2[CH2:24][CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]2)[C:11]2[CH2:16][O:15][C:14](=[O:17])[NH:13][C:12]=2[N:18]=1.[ClH:32]>O1CCOCC1>[ClH:32].[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]([CH:19]2[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]2)[C:11]2[CH2:16][O:15][C:14](=[O:17])[NH:13][C:12]=2[N:18]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3ccccc3O)nc3c2COC(=O)N3)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C1Nc2nc(-c3ccccc3O)cc(C3CCCNC3)c2CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution of tert-butyl 3-[7-(2-hydroxyphenyl)-2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl]-1-piperidinecarboxylate (45 mg, 0.1.1 mmol) in 1,4-dioxane (1.0 mL) was added 4N HCl in 1,4-dioxane (2.0 mL). The mixture was stirred for 1 hr at room temperature. The resulting solid was collected by filtration, washed with 1,4-dioxane, and dried under reduced pressure to give 7-(2-hydroxyphenyl)-5-(3-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one hydrochloride as a white solid. (22.8 mg, yield; 60%)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:15])=[C:5]([C:9]([N+:12]([O-:14])=[O:13])=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].[C:16]([O-])([O-])=O.[Cs+].[Cs+].IC.O>CO>[CH3:16][O:7][C:6](=[O:8])[C:5]1[C:9]([N+:12]([O-:14])=[O:13])=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[C:4]=1[CH3:15]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc([N+](=O)[O-])c(C(=O)O)c1C
Agent: [Cs+]
Solvent: CI
Solvent: CO
Solvent: O
Product: COC(=O)c1c([N+](=O)[O-])ccc(OC)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-Methoxy-2-methyl-6-nitro-benzoic acid in 45 mL of methanol, Cs2CO3 (7.8 g, 24 mmol) is added and stirred at the room temperature for 1 hour. The solution is concentrated under reduced pressure then the resulting yellow solid is suspended in 45 ml of DMF. Iodomethane (1.5 ml 24 mol) is added at 0° C. and stirred at the room temperature for 21 hours. Water is added to the solution and the precipitates are collected and washed by water to give 3-Methoxy-2-methyl-6-nitro-benzoic acid methyl ester (4.0 g) as orange solid in 81% yields. 1H-NMR (400 MHz, δ, ppm) CDCl3: 2.2 (s, 3H), 3.93 (s, 3H), 3.98 (s, 3H), 6.91 (d, 1H), 8.11 (d, 1H).
Reaction SMILES: [CH2:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:22])[C@@H:19]([CH3:21])[NH2:20])=[CH:13][CH:12]=3)=[CH:9][C:4]=2[CH2:3][O:2]1.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>ClCCl>[CH2:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:12]=[CH:13][C:14]([N:17]4[C:18](=[O:22])[C@@H:19]([CH3:21])[NH:20][C:24]4=[O:26])=[CH:15][CH:16]=3)=[CH:9][C:4]=2[CH2:3][O:2]1
Reactant: C[C@@H](N)C(=O)Nc1ccc(Oc2ccc3c(c2)COC3)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H]1NC(=O)N(c2ccc(Oc3ccc4c(c3)COC4)cc2)C1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 36.7 %

Procedure:
A solution of N1-[4-(1,3-dihydro-2-benzofuran-5-yloxy)phenyl]-D-alaninamide (Intermediate 77, 100 mg, 0.335 mmol) and TEA (0.234 ml, 1.676 mmol) in dichloromethane (10 ml) was stirred under argon at 0° C. Triphosgene (49.7 mg, 0.168 mmol) in dichloromethane (4 ml) was added and the mixture was left stirring at 0° C. for 15 minutes. After 30 min an aqueous saturated solution of NaHCO3 was added. The phases were separated and the aqueous phase was extracted 3 times with dichloromethane. The gathered organic phases were dried over sodium sulphate and concentrated under vacuum. The residue obtained was purified by flash chromatography (Biotage SP1), using as eluents a gradient cyclohexane/ethyl acetate 90:10 to 65:45 to 20:80. This afforded the title compound (20 mg).
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:12]([NH2:15])(=[O:14])=[O:13])=[CH:4][CH:3]=[N:2]1.[CH2:16]([N:20]=[C:21]=[O:22])[CH2:17][CH2:18][CH3:19].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:16]([NH:20][C:21]([NH:15][S:12]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:5]1[O:1][N:2]=[CH:3][CH:4]=1)(=[O:13])=[O:14])=[O:22])[CH2:17][CH2:18][CH3:19]
Reactant: NS(=O)(=O)c1ccccc1-c1ccno1
Reactant: CCCCN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCNC(=O)NS(=O)(=O)c1ccccc1-c1ccno1
Yield: 79.7 %

Procedure:
A solution of 8.7 g of 2-(isoxazol-5-yl)benzenesulfonamide prepared in Example 5, 4.7 g of n-butyl isocyanate and 5.4 g of potassium carbonate in 125 ml of 2-butanone was refluxed for 7 hours. The resulting suspension was concentrated to dryness in vacuo. The residue was taken up in 200 ml of water and extracted once with 100 ml of ethyl ether. The aqueous layer was acidified with 2N HCl and the resulting suspension was extracted with methylene chloride. After drying the methylene chloride extract over sodium sulfate, the solvent was evaporated off under reduced pressure. The solid residue was recrystallized from acetonitrile to give 10 g of the title compound; m.p. 110°-113° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)=O.[I-:18].[Na+]>CC(C)=O>[C:12]1([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][I:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CS(=O)(=O)OCCCCCCc1ccccc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: ICCCCCCc1ccccc1

Procedure:
To 6-phenylhex-1-yl methylsulfonate (4.55 g; 17.3 mmol) dissolved in acetone (100 ml) is added sodium iodide (2.5 g; 173 mmol) and the reaction mixture is heated 2 hours at reflux. The reaction mixture is then concentrated to dryness and partitioned between ether and water. The organic phase is separated, dried, concentrated to dryness and purified with silica chromatography using 10 EtOAc/90 petroleum ether to give 6-phenyl-1-hexyl iodide as a colorless oil which is used directly in Step F.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]([F:48])([F:47])[C:9]1[CH:10]=[C:11]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[CH2:12][N:13]([CH2:18][C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=1[C:29]1[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[C:31]([C:37]([OH:39])=O)[CH:30]=1)[C:14]([O:16][CH3:17])=[O:15].[C:49](=[N:52]O)([NH2:51])[CH3:50]>CN(C)C=O.C(Cl)Cl>[F:44][C:43]([F:46])([F:45])[C:41]1[CH:40]=[C:11]([CH:10]=[C:9]([C:8]([F:7])([F:48])[F:47])[CH:42]=1)[CH2:12][N:13]([CH2:18][C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=1[C:29]1[CH:30]=[C:31]([C:37]2[O:39][N:52]=[C:49]([CH3:50])[N:51]=2)[CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[C:14](=[O:15])[O:16][CH3:17]
Reactant: CC(N)=NO
Reactant: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(=O)O)ccc1OC
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(-c2nc(C)no2)ccc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (0.14 mL, 0.28 mmol) and a few drops of dimethylformamide were added to a solution of the title compound from Example 145 (86 mg, 0.14 mmol) in methylene chloride. The reaction mixture was stirred at room temperature for 1 h then concentrated in vacuo. The crude product was re-dissolved in anhydrous dichloroethane, and acetamide oxime (16 mg, 0.21 mmol) was added along with a few drops of dimethylformamide to increase solubility. The reaction was heated to and maintained at reflux overnight. Once the reaction cooled to room temperature, the solvent was removed through evaporation. The oil was taken up in methylene chloride, washed with water, then brine, dried over anhydrous sodium sulfate, filtered and concentrated. The title compound was obtained by preparative thin layer chromatography using 50% EtOAc/hexane. 1H NMR (CDCl3, 600 MHz) δ 8.15 (s, 1H), 7.86 (s, 1H), 7.71 (s, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.43-7.56 (m, 3H), 7.35 (d, J=7.8 Hz, 1H), 7.07 (m, 1H), 4.20-4.60 (m, 4H), 3.81 (s, 3H), 3.70 (m, 3H), 2.46 (s, 3H). LC-MS (M+1) 647.9 (4.40 min).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][OH:4].S(=O)(=O)(O)O.[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)O)=[CH:13][CH:12]=1.O>C1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][O:4][CH:17]([C:14]1[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=1)[C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1
Reactant: OC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: OCCCl
Agent: O=S(=O)(O)O
Solvent: O
Solvent: c1ccccc1
Product: Fc1ccc(C(OCCCl)c2ccc(F)cc2)cc1

Procedure:
A mixture of 20 parts of 2-chloroethanol, 3 parts of sulfuric acid and 16 parts of benzene was heated on a water-bath. Then there were added dropwise 35 parts of 4-fluoro-α-(4-fluorophenyl)benzenemethanol dissolved in 32 parts of benzene. After the addition was complete, the whole was stirred and refluxed for 4 hours. After cooling the reaction mixture was poured into water. The benzene layer was separated, dried over calcium chloride and evaporated. The residue was distilled in vacuo, yielding 35 parts of 1,1'-[(2-chloroethoxy)methylene]bis[4-fluorobenzene]; bp. 164°-166° C. at 1.5 mm. pressure; nD20 : 1.5462; d2020 : 1.2290 (intermediate 1).
Reaction SMILES: [C:1]1([C:7]2[C:15]([CH:16]=[C:17]3[S:21]C(=S)N[C:18]3=[O:23])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:24].[Na+].Cl>O>[C:1]1([C:7]2[C:15]([CH2:16][C:17](=[S:21])[C:18]([OH:23])=[O:24])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [OH-]
Reactant: O=C1NC(=S)SC1=Cc1c(-c2ccccc2)nn2ccccc12
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)C(=S)Cc1c(-c2ccccc2)nn2ccccc12

Procedure:
A mixture of 5-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)methylenerhodanine (13.0 g) and 15% aqueous solution of sodium hydroxide (50 ml) was refluxed for 3 hours. To the reaction mixture was added 10% hydrochloric acid (50 ml) and water (50 ml) and was stirred for an hour under ice-cooling. The precipitates were collected by filtration to give 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-2-thioxopropionic acid (7.85 g).
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.[NH2:25][C:26]1[CH:31]=[N:30][C:29](Br)=[CH:28][N:27]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:29]3[N:30]=[CH:31][C:26]([NH2:25])=[N:27][CH:28]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: Nc1cnc(Br)cn1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Nc1cnc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cn1

Procedure:
The title compound was prepared from 7-difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (169 mg, 0.5 mmol) and commercially available 2-amino-5-bromo-pyrazine (87 mg, 0.5 mmol) according to general procedure II. Obtained as an orange solid (53 mg, 25%). MS (ISP) 431.2 [(M+H)+]; mp 233° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:15][C:14](=[O:16])[NH:13][C:12]1=[O:17]>CO>[OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[C:12](=[O:17])[NH:13][C:14](=[O:16])[CH:15]=1
Reactant: O=C1CC(c2c[nH]c3ccc(O)cc23)C(=O)N1
Solvent: CO
Product: O=C1C=C(c2c[nH]c3ccc(O)cc23)C(=O)N1

Procedure:
3-(5-hydroxy-1H-indol-3-yl)-2,5-pyrrolidinedione 10% palladium-on-carbon (135 mg) is added to a solution of the compound of Step A of Preparation H (450 mg) in dry methanol (90 ml). After having purged in vacuo for 20 minutes, the reaction mixture is placed under a hydrogen atmosphere (1 atm) for 3 hours. Following filtration over Celite and evaporation of the filtrate, the expected product is obtained.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>FC(F)(F)C(O)=O>[CH2:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCOc1ccc(N2CCNCC2)cc1
Yield: 44.3 %

Procedure:
A solution of 1-(4-n-Octyloxyphenyl)-4-tert-butoxycarbonylpiperazine (2.61 g) in trifluoroacetic acid (20 ml) was stirred for 4 hours at ambient temperature. The reaction mixture was evaporated under reduced pressure, and to the residue was added a mixture of 1N NaOH aqueous solution and ethyl acetate. The organic layer was taken, and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 1-(4-n-Octyloxyphenyl)piperazine (0.86 g).
Reaction SMILES: CS([C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[CH:15]=3)[C:11](=[O:24])[N:10]([CH2:25][CH3:26])[C:8]=2[N:9]=1)=O.[ClH:27].[NH2:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1>C(#N)C.C(O)C>[ClH:27].[NH:28]=[C:29]1[CH:34]=[CH:33][N:32]([C:4]2[N:5]=[CH:6][C:7]3[CH:13]=[C:12]([C:14]4[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[CH:15]=4)[C:11](=[O:24])[N:10]([CH2:25][CH3:26])[C:8]=3[N:9]=2)[CH:31]=[CH:30]1
Reactant: CCn1c(=O)c(-c2cc(OC)cc(OC)c2)cc2cnc(S(C)=O)nc21
Reactant: Nc1ccncc1
Agent: Cl
Solvent: CCO
Solvent: CC#N
Product: CCn1c(=O)c(-c2cc(OC)cc(OC)c2)cc2cnc(-n3ccc(=N)cc3)nc21
Temperature: 40 °C
Reaction time: 6 h
Yield: 99 %

Procedure:
To a solution of 220 g (0.59 mol) of the product of Example 2, 2-methylsulfinyl-6-(3,5-dimethoxy-phenyl)8-ethyl-8H-pyrido[2,3-d]pyrimidine-7-one, in 2 L of acetonitrile was added a solution of 100 g (0.765 mol, 1.3 eq) of 4-aminopyridine hydrochloride in 700 mL of ethanol. The mixture was heated to 40° C. and stirred for 6 hours. The mixture was then cooled to 24° C. and filtered to provide 256 g (99%) of 2-(4-imino-4H-pyridin-1-yl)-6-(3,5-dimethoxyphenyl)-8-ethyl-8H-pyrido[2,3-d]-pyrimidin-7-one hydrochloride; mp 295-300° C. (dec).
Reaction SMILES: Br[C:2]1[C:3](=[O:19])[C:4]([CH3:18])([CH3:17])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.[S:20]1[C:24](B(O)O)=[CH:23][C:22]2[CH:28]=[CH:29][CH:30]=[CH:31][C:21]1=2>>[S:20]1[C:24]([C:2]2[C:3](=[O:19])[C:4]([CH3:18])([CH3:17])[O:5][C:6]=2[C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:23][C:22]2[CH:28]=[CH:29][CH:30]=[CH:31][C:21]1=2
Reactant: OB(O)c1cc2ccccc2s1
Reactant: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(Br)C1=O
Product: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(c2cc3ccccc3s2)C1=O
Yield: 26 %

Procedure:
200 mg of 4-bromo-2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone was coupled with 125 mg of (2-benzo[b]thienyl)boronic acid according to a procedure similar to the procedure in Example 2 to afford 60 mg of 4-(2-benzo[b]thienyl)-2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone as a solid. mp: 204-206° C. NMR: δ1.61 (s, 6H), 3.11 (s, 3H), 7.32˜7.43 (m, 4H), 7.51˜7.53 (m, 1H), 7.74˜7.84 (m, 2H), 8.01 (s, 2H). IR (cm−1): 1702, 1620, 1382, 1147, 957, 750.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C@H:2]1[CH2:7][OH:8].[C:9](ON1C(=O)CCC1=O)([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].O.C([O-])(O)=O.[Na+]>CC#N.CC(N(C)C)=O.O.CC(N(C)C)=O>[OH:8][CH2:7][C@H:2]1[NH:1][CH2:6][CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1
Reactant: OC[C@@H]1CNCCN1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(OCc1ccccc1)N1CCN[C@H](CO)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 57.5 %

Procedure:
To a solution of compound 1B (207 mg, 1.78 mmol) in CH3CN/DMA/H2O (1 mL, 0.3 mL, 0.7 mL) cooled to 0° C. was added dropwise CBZ-OSu (444 mg, 1.78 mmol) in DMA (0.5 mL). The reaction was stirred for 15 min at 0° C. then slowly warmed to RT. To the reaction was added H2O (30 mL) and sat'd NaHCO3 (5 mL), and then the product was extracted three times with EtOAc (20 mL). The combined EtOAc layers were washed twice with brine, dried over MgSO4 then concentrated in vacuo to give crude (S)-benzyl 3-(hydroxymethyl)piperazine-1-carboxylate (256 mg). HPLC RT: 1.082 min (4 min Chromolith column TFA). (M+H)+:251.
Reaction SMILES: C(OC([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[C:11]2[C:10]([C:22](=[O:32])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29]C)[C:24]=2[F:31])=[CH:9]1)=O)(C)(C)C.B(Br)(Br)Br>C(Cl)Cl>[F:31][C:24]1[C:25]([OH:29])=[CH:26][CH:27]=[CH:28][C:23]=1[C:22]([C:10]1[C:11]2[C:12](=[N:13][CH:14]=[C:15]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)[NH:8][CH:9]=1)=[O:32]
Reactant: COc1cccc(C(=O)c2cn(C(=O)OC(C)(C)C)c3ncc(-c4cccs4)cc23)c1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(c1cccc(O)c1F)c1c[nH]c2ncc(-c3cccs3)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-(2-fluoro-3-methoxy-benzoyl)-5-thiophen-2-yl pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (87, 200 mg, 0.44 mmol) in methylene chloride (10 mL), under an atmosphere of nitrogen, cooled in a −78° C. acetone/dry ice bath, was added boron tribromide (1.0 M in hexane, 2.0 mL). The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with methanol (3.0 mL), poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The desired compound was isolated by silica gel column chromatography eluting with 5% methanol in methylene chloride to give a white solid (P-0521, 119 mg, 82.6%). MS (ESI) [M−H+]−=337.
Reaction SMILES: [CH:1]1[O:2][C:3]([CH2:10][C:11]([N:13]([CH:15]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([O:36]CC3C=CC=CC=3)[CH:31]=2)[CH2:16][N:17]2[CH2:21][CH2:20][CH:19]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:18]2)[CH3:14])=[O:12])=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12>C(O)C.[Pd]>[CH:1]1[O:2][C:3]([CH2:10][C:11]([N:13]([CH:15]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=2)[CH2:16][N:17]2[CH2:21][CH2:20][CH:19]([O:22][Si:23]([C:26]([CH3:28])([CH3:29])[CH3:27])([CH3:24])[CH3:25])[CH2:18]2)[CH3:14])=[O:12])=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CN(C(=O)Cc1occ2ccccc12)C(CN1CCC(O[Si](C)(C)C(C)(C)C)C1)c1cccc(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: CN(C(=O)Cc1occ2ccccc12)C(CN1CCC(O[Si](C)(C)C(C)(C)C)C1)c1cccc(O)c1
Reaction time: 5.5 h

Procedure:
A solution of Example 24 (3.00 g, 5.01 mmol) in absolute ethanol (50 mL) with palladium on charcoal (0.34 g) was hydrogenated at 30° C. and 50 psi for 5.5 hours. The catalyst was removed by filtration through Celite and the filtrate concentrated in vacuo to give the product, 2.195 g. This was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]([O:13][C:14]1[C:22]3[N:21]=[C:20]([CH3:23])[NH:19][C:18]=3[CH:17]=[C:16]([C:24]([OH:26])=O)[CH:15]=1)[CH2:5][CH2:6][O:7]2.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]([O:13][C:14]1[C:22]3[N:21]=[C:20]([CH3:23])[NH:19][C:18]=3[CH:17]=[C:16]([C:24]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:26])[CH:15]=1)[CH2:5][CH2:6][O:7]2
Reactant: C1CCNC1
Reactant: Cc1nc2c(OC3CCOc4cc(F)cc(F)c43)cc(C(=O)O)cc2[nH]1
Product: Cc1nc2c(OC3CCOc4cc(F)cc(F)c43)cc(C(=O)N3CCCC3)cc2[nH]1
Yield: 56 %

Procedure:
The title compound was prepared as a white solid (70 mg, 56% yield for 3 steps) from 4-[(5,7-difluoro-3,4-dihydro-2H-chromen-4-yl)oxy]-2-methyl-1H-benzimidazole-6-carboxylic acid (100 mg, crude, STEP 4) and pyrrolidine (59 mg, 0.832 mmol) by the same manner in STEP 5 of Example 1.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[I:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]Br>O1CCCC1.[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-]>[I:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:15]([CH2:16][O:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:14]=1
Reactant: BrCc1cccc(I)c1
Reactant: OCCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [H-]
Solvent: C1CCOC1
Product: Ic1cccc(COCCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
Into a 100 mL round-bottom flask was placed under N2 a solution of 2-phenylethanol (110 mg, 0.90 mmol) in tetrahydrofuran (10 mL). Sodium hydride (26 mg, 1.08 mmol, 1.2 equiv.) was added with ice cooling. The mixture was stirred for 2 h at 25° C., then 3-iodobenzyl bromide (320 mg, 1.08 mmol, 1.2 equiv.) and n-Bu4NBr (30 mg, 0.09 mmol, 0.10 equiv.) were added. The resulting solution was stirred for 20 h at 25° C. The reaction progress was monitored by TLC (SiO2, EtOAc/petroleum ether 1:5). The reaction was quenched by the addition of saturated aqueous NH4Cl solution. The resulting solution was extracted with EtOAc, and the organic layers were combined, dried over Na2SO4, and concentrated under vacuum. The residue was chromatographed on silica gel with EtOAc/petroleum ether 1:20 to obtain 300 mg (99%) of 1-iodo-3-(phenethoxymethyl)benzene as a yellow oil.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.Cl.[NH2:13][OH:14]>>[CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][C:8](=[N:13][OH:14])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1
Reactant: O=C1CCN(CC2CC2)CC1
Reactant: NO
Agent: Cl
Product: ON=C1CCN(CC2CC2)CC1

Procedure:
1-(Cyclopropylmethyl)-4-piperidone oxime is prepared from 1-(cyclopropylmethyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[O:10])=[C:5]([S:11][CH3:12])[CH:4]=1.[BrH:13].C([O-])(O)=O.[Na+]>C(O)(=O)C>[Br:13][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:6]2[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][C:5]=2[S:11][CH3:12])=[O:10])=[CH:5][CH:4]=1
Reactant: Br
Reactant: COc1ccc(C=O)c(SC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CSc1cc(O)ccc1C(=O)c1ccc(Br)cc1

Procedure:
1.0 g of 4-bromo-phenyl)-(4-methoxy-2-methylsulphanyl-phenyl)-methanone (Ex. C) are suspended in 6 ml of acetic acid and 3.5 ml of 62% HBr and stirred at 125° C. overnight. The suspension is added to sat. NaHCO3 solution, the phases are separated and the inorganic phase is extracted with ethyl acetate. The organic phases are washed with sat. NaHCO3 solution and with saturated sodium chloride solution and dried. 920 mg of (4-bromo-phenyl)-(4-hydroxy-2-methylsulphanyl-phenyl)-methanone are obtained as brown crystals.