Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([CH2:14][CH3:15])[CH2:7][NH:8][C@H:9]([C:11]([OH:13])=[O:12])[CH3:10])=[O:5])[CH3:2].C(N(CC)CC)C.Cl[C:24]([O:26][CH3:27])=[O:25]>CC(C)=O>[CH2:1]([O:3][C:4]([CH:6]([CH2:14][CH3:15])[CH2:7][N:8]([C:24]([O:26][CH3:27])=[O:25])[C@H:9]([C:11]([OH:13])=[O:12])[CH3:10])=[O:5])[CH3:2]
Reactant: COC(=O)Cl
Reactant: CCOC(=O)C(CC)CN[C@@H](C)C(=O)O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CC)CN(C(=O)OC)[C@@H](C)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of N-[2-(ethoxycarbonyl)butyl]alanine (4.35 g, 20 mmol) in acetone (50 mL) was added a solution of triethylamine (5.5 mL, 4.05 g, 40 mmol) in acetone (10 mL) followed by methyl chloroformate (4.0 mL, 4.91 g, 52 mmol) at 0-5° C. After stirring for 2 h at ambient temperature the solvent was evaporated and the residue was stirred with a mixture of water (40 mL) and concentrated hydrochloric acid (0.4 mL) for 8 h at ambient temperature. The mixture was extracted with ethyl acetate (40 mL) and the solution in ethyl acetate was extracted with cold aqueous sodium hydroxide solution [prepared from ice (20 g) and aqueous sodium hydroxide solution (1N, 40 mL)]. Concentrated hydrochloric acid (3 mL) was added to the aqueous layer and the mixture was extracted with ethyl acetate (40 mL). After drying and evaporation N-[2-(ethoxycarbonyl)butyl]-N-methoxycarbonylalanine (3.84 g, 70%) was obtained as a yellow oil which can be used in the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].F[C:12]1[CH:20]=[N:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH:6][C:17]1[CH:18]=[N:19][CH:20]=[CH:12][C:13]=1[C:14]([OH:16])=[O:15]
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1ccncc1F
Product: O=C(O)c1ccncc1NCc1ccc(Cl)c(Cl)c1
Yield: 37 %

Procedure:
The title compound was prepared in 37% yield from 3,4-dichlorobenzylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 13.48 (br s, 1H), 8.10 (s, 1H), 7.84 (d, 1H, J=5.0 Hz), 7.57-7.65 (m, 3H), 7.35 (dd, 1H, J=8.3, 1.9 Hz), 4.59 (s, 2H). [M+H] calc'd for C13H10Cl2N2O2, 297, 299. found 297, 299.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1)([O-:14])=[O:13].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:5]2[C:1](=[O:11])[C:2]3=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]3[C:4]2=[O:6])=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccc([N+](=O)[O-])cc1
Temperature: 150 °C
Reaction time: 1.5 h

Procedure:
A mixture of phthalimide (4 g), p-nitrophenylmethylchloride (4,7 g), potassium carbonate (4 g) and DMF (20 ml) was stirred at 150° C. for 1.5 h. After cooling, the mixture was diluted with water. The precipitate was filtered and the crude product (I) was recrystallized from ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:5]([C:6]([O:8]C)=O)=[C:4]([N+:13]([O-:15])=[O:14])[C:3]=1[O:16][CH3:17].[CH2:18]([NH2:21])[CH2:19][CH3:20]>S(Cl)(Cl)=O>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:5]([C:6]([NH:21][CH2:18][CH2:19][CH3:20])=[O:8])=[C:4]([N+:13]([O-:15])=[O:14])[C:3]=1[O:16][CH3:17]
Reactant: COC(=O)c1c(Cl)cc(Cl)c(OC)c1[N+](=O)[O-]
Reactant: CCCN
Solvent: O=S(Cl)Cl
Product: CCCNC(=O)c1c(Cl)cc(Cl)c(OC)c1[N+](=O)[O-]
Temperature: 0 °C
Yield: 92 %

Procedure:
The acid 2-2 (1.41 g, 5.3 mmol) was heated to reflux in thionyl chloride (20 mL) for 2 h. After cooling, the volatiles were removed in vacuo and the residue was azeotroped with toluene. The resulting acid chloride was dried at high vacuum and then dissolved in anhydrous CH2Cl2 (50 mL), cooled to 0° C. then treated with propylamine (2.45 mL, 29.9 mmol). The reaction was warmed to room temperature for 2 h. The solvent was removed in vacuo and the residue was taken up in EtOAc and brine. The aqueous layer was extracted three times into EtOAc and the combined organic layers were washed with H2O, dried over Na2SO4, filtered and concentrated to provide the amide in which R is propyl 4-5 as a light orange solid. (1.5 g, 92% yield). 1H NMR (400 MHz, d6-DMSO) δ 0.91 (t, J=7.0 Hz, 3H), 1.40 (q, J=7.0 Hz, 2H), 3.07 (q, J=7.0 Hz, 2H), 3.84 (s, 3H), 8.13 (s, 1H), 8.84 (br s, 1H).
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][CH:6]([CH2:11][P:12]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])=[O:13])[CH2:7][CH:8]([CH3:10])[CH3:9])C.[OH-].[Na+]>CCO>[CH2:18]([O:17][P:12]([CH2:11][CH:6]([CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:5][C:4]([OH:20])=[O:3])([O:14][CH2:15][CH3:16])=[O:13])[CH3:19]
Reactant: CCOC(=O)CC(CC(C)C)CP(=O)(OCC)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOP(=O)(CC(CC(=O)O)CC(C)C)OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.5 %

Procedure:
3-(Diethoxy-phosphorylmethyl)-5-methyl-hexanoic acid ethyl ester (1.0 g, 3.2 mmol) and NaOH (1.8 mL, 2.0 M) are combined in 10 mL of EtOH at 0° C. After 15 minutes, the reaction mixture is warmed to room temperature and stirred overnight. The EtOH is evaporated, and 50 mL of 2.0 M NaOH is added. The solution is extracted with Et2O (2×50 mL), and then acidified to pH=1 with concentrated HCl. The acidic solution is extracted with EtOAc (3×50 mL), and the combined extracts are dried over MgSO4 and evaporated to give 0.65 g (72% yield) of 3-(diethoxy-phosphorylmethyl)-5-methyl-hexanoic acid as an oil. NMR (HI, 400 MHz, CDCl3) δ 0.9 (6H, d); δ 1.3 (8H, m); δ 1.6 (1H, m); δ 1.8 (2H, m); δ 2.3 (1 H, m); δ 2.5 (2H, m); δ 4.1 (4H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:12][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: Cc1cccc2cccnc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cccc2cccnc12
Yield: 54.9 %

Procedure:
A mixture of 8-methylquinoline (45 g, 0.3 14 mol), N-bromosuccinimide (55 g, 0.309 mol) and benzoyl peroxide (1.5 g) in carbon tetrachloride (250 mL) was refluxed for 7 hours. The reaction was filtered and evaporated, and the crude product was crystallized from methanol (70 mL) to give 37.7 g of product. The mother liquors were chromatographed on silica gel in chloroform to give 17 g of material which was crystallized from ethyl acetate: hexane to give an additional 12.0 g of product.
Reaction SMILES: O1CCOCC1.Cl[C:8]1[C:13]([NH:14][C:15](=[O:24])[C:16]2[CH:21]=[CH:20][CH:19]=[N:18][C:17]=2[CH2:22][CH3:23])=[C:12]([NH:25][CH:26]2[CH2:28][CH2:27]2)[N:11]=[CH:10][N:9]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:35][C:36]1[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:37]=1B(O)O>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:26]1([NH:25][C:12]2[C:13]([NH:14][C:15](=[O:24])[C:16]3[CH:21]=[CH:20][CH:19]=[N:18][C:17]=3[CH2:22][CH3:23])=[C:8]([C:39]3[CH:38]=[CH:37][C:36]([Cl:35])=[CH:41][C:40]=3[Cl:42])[N:9]=[CH:10][N:11]=2)[CH2:28][CH2:27]1
Reactant: CCc1ncccc1C(=O)Nc1c(Cl)ncnc1NC1CC1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCc1ncccc1C(=O)Nc1c(NC2CC2)ncnc1-c1ccc(Cl)cc1Cl
Temperature: 90 °C
Reaction time: 3 h

Procedure:
In a test tube which had been dried by heating and preheated to 100° C., the degassed diluent mixture dioxane (2 ml)/water (0.7 ml) was added to N-(4-chloro-6-cyclopropylaminopyrimidin-5-yl)-2-ethylnicotinamide (0.41 mmol), sodium carbonate (3 eq) and 2,4-dichlorophenylboronic acid (2 eq). 5 mol % of tetrakis(triphenylphosphine)palladium(0) were added, and the reaction mixture was stirred at 90° C. for 3 hours. The mixture was then diluted with water and extracted 3× with methylene chloride, and the combined organic phases were washed with aqueous NaHCO3 solution, dried 20 over Na2SO4, filtered and concentrated under reduced pressure.
Reaction SMILES: [Mg].[Cl:2][C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][CH:4]=1.[C:10]([C:12]1[N:13]=[CH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2)#[N:11].[Cl-].[NH4+]>CCOCC>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:10](=[NH:11])[C:12]2[N:13]=[CH:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:5][CH:4]=1
Reactant: N#Cc1cc2ccccc2cn1
Reactant: Clc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: N=C(c1ccc(Cl)cc1)c1cc2ccccc2cn1
Temperature: 25 °C
Yield: 60 %

Procedure:
The starting substance is prepared as follows: To a mixture of 0.62 g (26 millimoles) of metallic magnesium and 8 ml of anhydrous ether a solution of 5.0 g (26 millimoles) of 4-chloro-bromobenzene in ether is dropwise added, the Grignard solution thus-obtained is admixed with 3.1 g (20 millimoles) of 3-cyano-isoquinoline, and the reaction mixture is stirred at room temperature for an hour. The Grignard complex is decomposed with an ammonium chloride solution, the solvent is distilled off and the residue is recrystallized from ethanol. 3.2 g (60%) of 3-(4-chlorobenzoyl)-isoquinoline imine are obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:4]([CH2:5][C:6]([Cl:9])([Cl:8])Cl)[CH:3]1[C:10]([O:12]C)=[O:11].[OH-].[Na+].[CH3:17]O>>[CH3:17][C:3]1([C:10]([OH:12])=[O:11])[CH:4]([CH:5]=[C:6]([Cl:8])[Cl:9])[C:2]1([CH3:1])[CH3:14]
Reactant: COC(=O)C1C(CC(Cl)(Cl)Cl)C1(C)C
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Product: CC1(C)C(C=C(Cl)Cl)C1(C)C(=O)O
Reaction time: 5 h
Yield: 78 %

Procedure:
A mixture of 9.0 g (0.035 mole) of methyl 2,2-dimethyl-3-(2,2,2-trichloroethyl)cyclopropane-1-carboxylate (compound Z, C/T=75/25) in 30 ml of a 20% aqueous solution of sodium hydroxide (0.15 mole) and 10 ml of methanol was heated to 98° over 30 minutes. Heating was continued at this temperature for 5 hours. The reaction mixture was cooled, washed with ether, and the aqueous phase made acidic by the addition of concentrated hydrochloric acid. The acidic mixture was extracted with ether, and the ether extracts were combined, washed with brine, dried over magnesium sulfate, and concentrated to give, after distillation, 5.68 g (78% yield) of methyl 3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropane-1-carboxylic acid, the acid corresponding to compound C, 95% purity, C/T=78/22.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][C:13](=[O:15])[CH2:12][C:11](=O)[CH2:10]1.Cl.[NH2:18][CH2:19][C:20]#[C:21][CH3:22].O1CCCC1>C(N(CC)CC)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:10][C:11]2[N:18]=[CH:19][CH:20]=[C:21]([CH3:22])[C:12]=2[C:13](=[O:15])[CH2:14]1
Reactant: O=C1CC(=O)CC(c2ccc(F)cc2F)C1
Reactant: CC#CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccnc2c1C(=O)CC(c1ccc(F)cc1F)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.3 %

Procedure:
To a mixture of 5-(2,4-difluorophenyl)cyclohexane-1,3-dione (2.0 g), 1-amino-2-butyne hydrochloride (0.94 g), molecular sieves 4A (4 g) and tetrahydrofuran (40 ml) was added triethylamine (0.90 g), and the mixture was stirred at room temperature for 1 hour, refluxed for 12 hours and cooled. Insoluble materials were filtered off. Under reduced pressure, the solvent was evaporated, and the residue was stirred for 5 hours at 220° C., to which were added ethyl acetate and sodium hydrogen carbonate solution. The organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give, the residue was purified with silica gel column chromatography (EtOAc/hexane). The resulting crystals were recrystallized from isopropylether and hexane to give colorless crystals of 7-(2,4-difluorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.47 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25](O)=[O:26])[CH:4]=[N:3]1.Cl.[F:29][CH:30]1[CH2:33][NH:32][CH2:31]1.C(N(C(C)C)C(C)C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>O1CCCC1>[N:18]1([C:16]2[N:17]=[C:11]3[CH:10]=[C:9]([NH:8][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[CH:4][C:5]=4[C:25]([N:32]4[CH2:33][CH:30]([F:29])[CH2:31]4)=[O:26])=[O:24])[CH:14]=[CH:13][N:12]3[N:15]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: FC1CNC1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(N3CCOCC3)nc2c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(C(=O)N2CC(F)C2)c1C(=O)Nc1ccn2nc(N3CCOCC3)nc2c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 39.3 %

Procedure:
A mixture of 1-methyl-5-(2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (150 mg, 0.404 mmole), 3-fluoroazetidine hydrochloride (135 mg, 1.21 mmole), N-ethyldiisopropylamine (353 ul, 2.02 mmole) and 1-propanephosphonic acid cyclic anhydride (50% in ethyl acetate, 606 ul, 1.01 mmole) in tetrahydrofurane (7 ml) is stirred for 22 h at room temperature. The solvent is removed under reduced pressure and the residue (994 mg) is triturated for 2 hrs with sat. aqueous sodium bicarbonate solution (30 ml). The solid is collected by filtration, washed with water and dried affording 4-(3-fluoro-azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid (2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-amide (68 mg, 39.3%) as an off-white solid. mp.: 247-250° C. MS: m/z=425.1 (M+H+)
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[CH:23]=[CH:22][C:21]([CH3:24])=[N:20]1)=[O:11].Cl[C:26]1[N:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][N:27]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10](=[O:11])[C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[CH:23]=[CH:22][C:21]([CH3:24])=[N:20]2)[C@@H:3]1[CH2:2][NH:1][C:26]1[N:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][N:27]=1
Reactant: N#Cc1cnc(Cl)nc1
Reactant: Cc1ccc(-n2ccc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-n2ccc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(C#N)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)methanone and 2-chloropyrimidine-5-carbonitrile. ESI-MS (m/z): 430 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[H-].[Na+].[CH2:9]1[O:13][C:12]2[CH:14]=[C:15]([Cl:20])[C:16]([CH2:18]Cl)=[CH:17][C:11]=2[O:10]1>CN(C)C=O>[Cl:20][C:15]1[C:16]([CH2:18][N:3]2[CH:4]=[CH:5][N:6]=[C:2]2[CH3:1])=[CH:17][C:11]2[O:10][CH2:9][O:13][C:12]=2[CH:14]=1
Reactant: Cc1ncc[nH]1
Reactant: ClCc1cc2c(cc1Cl)OCO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nccn1Cc1cc2c(cc1Cl)OCO2

Procedure:
The operation is carried out as in Stage 1 of Example 11 starting with 12.3 g of 2-methyl-1H-imidazole, 7.92 g of sodium hydride with 50% oil, 150 ml of N dimethylformamide and 33.8 g of 6-chloropiperonyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16](O)=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[CH:3]=1.S(Cl)([Cl:22])=O>>[F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([Cl:22])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[CH:3]=1
Reactant: CC1CCc2cc(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: O=S(Cl)Cl
Product: CC1CCc2cc(F)cc3c(=O)c(C(=O)Cl)cn1c23

Procedure:
6,7Dihydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo[ij]-quinolizine-2-carboxylic acid (5.0 g., 0.0192 mole) is stirred with thionyl chloride (75 ml.), and the mixture is heated to its reflux temperature and maintained at reflux for about 18 hours. The mixture is evaporated to dryness, then azeotroped thrice with 50 ml. portions of benzene to provide an off-white solid, 6,7-dihydro-9-fluoro-5-methyl-1-oxo-1H-benzo[ij]quinolizine-2-carboxylic chloride, m.p. 183°-186° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]([N:13]([CH:27]([CH3:29])[CH3:28])[C@@H:14]1[CH2:19][CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]1)=[O:12])[N:7]([CH2:30][CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:6](=[O:36])[C:5]2([CH3:38])[CH3:37].Cl.O1CCOCC1>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]([N:13]([CH:27]([CH3:28])[CH3:29])[C@@H:14]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]1)=[O:12])[N:7]([CH2:30][CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:6](=[O:36])[C:5]2([CH3:38])[CH3:37]
Reactant: COCCCCN1C(=O)C(C)(C)c2cc(Cl)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21
Agent: Cl
Solvent: C1COCCO1
Product: COCCCCN1C(=O)C(C)(C)c2cc(Cl)c(C(=O)N(C(C)C)[C@@H]3CCCNC3)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 158.3 %

Procedure:
To a solution of tert-butyl (3R)-3-[{[5-chloro-1-(4-methoxybutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate (100 mg) in 1,4-dioxane (3 ml) was added a 4N hydrochloric acid/dioxane solution (2 ml), and the mixture was stirred at 25° C. for 2 hours, and concentrated under reduced pressure to give the title compound (70 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]1.C(N(CC)CC)C.FC(F)(F)S(O[Si:30]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])(=O)=O.[Cl-].[NH4+]>ClCCl>[CH:31]([Si:30]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[O:16][C:13]1[CH2:12][CH2:11][CH:10]([C:3]2[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=2[F:1])[CH2:15][CH:14]=1)([CH3:33])[CH3:32]
Reactant: O=C1CCC(c2cc(F)c(F)cc2F)CC1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[Si](OC1=CCC(c2cc(F)c(F)cc2F)CC1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A three-neck flask (1 L) containing a stirred solution of 4-(2,4,5-trifluorophenyl)cyclohexanone (15.8 g) in dichloromethane (160 mL) under a nitrogen atmosphere was cooled to 0° C. and then treated with triethylamine (22 mL) followed by triisopropylsilyl trifluoromethanesulfonate (25.4 g) while maintaining the temperature below 5° C. The solution was stirred at 0° for 30 min and then allowed to rise to ambient temperature over a period of 0.5 h. It was then treated with saturated aqueous ammonium chloride solution. The organic layer was separated, dried over anhydrous magnesium sulfate and evaporated. The crude product was chromatographed (silica gel, 3% ether in hexane) to yield the title compound.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[CH:3]=1.C([Li])CCC.[O:14]1[CH2:18][CH2:17][C:16](=[O:19])[CH2:15]1.[NH4+].[Cl-]>C1COCC1>[I:8][C:4]1[CH:3]=[C:2]([C:16]2([OH:19])[CH2:17][CH2:18][O:14][CH2:15]2)[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1CCOC1
Reactant: Ic1cccc(I)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1(c2cccc(I)c2)CCOC1
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
A solution of 1,3-diiodobenzene (3.0 g, 9.09 mmol) in dry THF (40 mL) was cooled to −78° C. under a nitrogen before addition of n-butyl lithium (1.6 M in hexane, 5.6 mL, 9.09 mmol) dropwise over 10 min. The reaction mixture was stirred for 30 min and then a solution of dihydrofuran-3(2H)-one (782 mg, 9.09 mmol) in THF (3 mL) added over 5 min. The reaction mixture was stirred for 1 h at −78° C. then poured into saturated NH4Cl solution. The mixture was extracted with ethyl acetate and the organic layer dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, 9:1 hexanes/ethyl acetate) to give 3-(3-iodophenyl)tetrahydrofuran-3-ol (2.0 g, 76%) as a colorless liquid: 1H NMR (CDCl3, 300 MHz) δ 7.87 (t, J=1.8 Hz, 1H), 7.64 (td, J=7.8 Hz, 1H), 7.45 (td, J=7.8 Hz, 1H), 7.10 (t, J=8.1 Hz, 1H), 4.26-4.06 (m, 2H), 3.98-3.82 (m, 2H), 2.46-2.32 (m, 1H), 2.30-2.21 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](=O)[C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[O:10][C:9]=2[C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](=[S:38])[C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[O:10][C:9]=2[C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CS(=O)(=O)c1ccc(-c2oc3ccccc3c(=O)c2-c2ccc(F)cc2)cc1
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(-c2oc3ccccc3c(=S)c2-c2ccc(F)cc2)cc1
Yield: 171 %

Procedure:
A solution of 3-(4-fluorophenyl)-2-(4-(methylsulfonyl)phenyl)-4H-1-benzopyran-4-one(0.45 g, 1.14 mmol) from Example 1 and Lawesson's reagent(0.23 g, 0.57 mmol) in toluene(10 ml) was refluxed for 1 hour. The resulting mixture was concentrated and subjected to flash chromatography using a mixture of hexane:ethyl acetate:dichloroethane(1:1:1) as an eluant to yield the title compound as a deep green solid(0.4 g, 85%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH2:10]([O:17][CH2:18][C:19]1[O:24][C:23](=[O:25])[C:22]([CH3:26])=[C:21]([OH:27])[C:20]=1[CH3:28])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:29][O:30][CH2:31]Cl>C1COCC1>[CH2:10]([O:17][CH2:18][C:19]1[O:24][C:23](=[O:25])[C:22]([CH3:26])=[C:21]([O:27][CH2:29][O:30][CH3:31])[C:20]=1[CH3:28])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1c(COCc2ccccc2)oc(=O)c(C)c1O
Reactant: COCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1c(C)c(COCc2ccccc2)oc(=O)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Diisopropylethylamine (2.1 ml) was added to a solution of 6-(benzyloxy)methyl-3,5-dimethyl-4-hydroxy-2H-pyran-2-one (2.60 g) in THF (50 ml), and after stirring the mixture at room temperature for one hour, chloromethyl methyl ether (921 μl) was added at 0° C. and the mixture was stirred at room temperature for one hour. After concentrating the reaction solution under reduced pressure, water was added to the residue, extraction was performed with AcOEt, and the organic layer was dried with Na2SO4 and then filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=5/1→1/1) to obtain 6-(benzyloxy)methyl-3,5-dimethyl-4-methoxymethoxy-2H-pyran-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[O:11]1[CH2:16][CH2:15][CH:14]([CH2:17]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:17][CH:14]2[CH2:15][CH2:16][O:11][CH2:12][CH2:13]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCOCC2)cc1
Reactant: O=Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(Cl)ccc1OCC1CCOCC1
Temperature: 75 °C
Yield: 85.9 %

Procedure:
A mixture of 5-chlorosalicylaldehyde (5.0 g, 32 mmol), toluene-4-sulfonic acid tetrahydro-pyran-4-ylmethyl ester (8.6 g, 32 mmol) and K2CO3 (9.5 g, 68.8 mmol) in DMF (50 mL) was heated at 75° C. overnight. After cooled to room temperature, the mixture was poured into water. The aqueous phase was extracted with EtOAc twice. The combined organic phases were washed with water and brine, dried and concentrated. The residue was purified by column chromatography to give the title compound (7.0 g).