Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([N:15]([C:23]1[C:28]([C:29]#[CH:30])=[N:27][C:26]([C:31]2[CH:36]=[CH:35][C:34]([S:37]([CH:40]([CH3:42])[CH3:41])(=[O:39])=[O:38])=[CH:33][CH:32]=2)=[CH:25][N:24]=1)[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:14])([CH3:11])([CH3:10])[CH3:9].[Cl:43][CH2:44][C:45]1[CH:54]=[CH:53][C:48]([C:49](Cl)=[N:50][OH:51])=[CH:47][CH:46]=1>C(Cl)Cl>[C:8]([O:12][C:13]([N:15]([C:23]1[C:28]([C:29]2[O:51][N:50]=[C:49]([C:48]3[CH:53]=[CH:54][C:45]([CH2:44][Cl:43])=[CH:46][CH:47]=3)[CH:30]=2)=[N:27][C:26]([C:31]2[CH:32]=[CH:33][C:34]([S:37]([CH:40]([CH3:42])[CH3:41])(=[O:39])=[O:38])=[CH:35][CH:36]=2)=[CH:25][N:24]=1)[C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:14])([CH3:9])([CH3:10])[CH3:11]
Reactant: ON=C(Cl)c1ccc(CCl)cc1
Reactant: C#Cc1nc(-c2ccc(S(=O)(=O)C(C)C)cc2)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3cc(-c4ccc(CCl)cc4)no3)n2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 83.8 %

Procedure:
Triethylamine (899.0 mg, 1.238 mL, 8.884 mmol) was added to a solution of tert-butyl N-tert-butoxycarbonyl-N-[3-ethynyl-5-(4-isopropylsulfonylphenyl)pyrazin-2-yl]carbamate 8 (4.05 g, 8.074 mmol) and 4-(chloromethyl)-N-hydroxy-benzimidoyl chloride (2.063 g, 8.494 mmol) in DCM (12 mL). The mixture was stirred at RT for 22 h then partitioned between DCM and an ice/water solution. The combined organic extract was dried over MgSO4 and concentrated under reduced pressure then purified by chromatography on silica gel (eluent 30-50% EtAc/petrol) yielding tert-butyl N-tert-butoxycarbonyl-N-[3-[3-[4-(chloromethyl)phenyl]isoxazol-5-yl]-5-(4-isopropylsulfonylphenyl)pyrazin-2-yl]carbamate as colourless crystals (4.53 g, 79%). 1H NMR (400 MHz, CDCl3) δ 1.41 (18H, s), 4.66 (2H, s), 7.37 (1H, s), 7.54 (2H, d, J=8.0 Hz), 7.90 (2H, d, J=8.0 Hz), 8.66 (1H, s)
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].Cl.[OH:6][CH:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8](=[NH:12])[O:9]CC.O1CCCC1>C1(C)C=CC=CC=1>[C:13]1([CH:7]2[O:6][C:1](=[O:2])[NH:9][C:8]2=[O:12])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(Cl)Cl
Reactant: CCOC(=N)C(O)c1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C1NC(=O)C(c2ccccc2)O1

Procedure:
By the procedure of Example 3, except that a reaction time of 16 hours at room temperature was used following cold perfusion with phosgene, ethyl 1-hydroxy-1-phenylmethanecarboximidate hydrochloride (22 g., 0.102 mole) in 450 ml. of tetrahydrofuran was converted to toluene recrystallized 5-phenyloxazolidine-2,4-dione (10.5 g., m.p. 103°-105° C.).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24]C(=O)OCC1C=CC=CC=1)CC.[BrH:35].[C:36](O)(=O)[CH3:37]>>[BrH:35].[CH2:10]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][CH2:36][CH3:37]
Reactant: CC(=O)O
Reactant: CCCCCCCCCC(CC)SCCCCCCCCCCNC(=O)OCc1ccccc1
Agent: Br
Product: CCCCCCCCCCCCSCCCCCCCCCCN

Procedure:
In a 1000 ml flask equipped with a stirrer, a condenser and a calcium chloride dryer tube were charged 27.0 g of the carboxylic acid synthesized in Synthetic example 21, 10.0 g of thionyl chloride, one drop of DMF and 100 ml of chloroform, and the mixture was refluxed for 2 hours on an oil bath. After completion of the reaction, chloroform and excessive thionyl chloride were removed by distillation under reduced pressure to obtain acid chloride. Whole content of the resulting acid chloride was diluted with 100 ml of acetone, and added dropwise under ice-cooling to 5.9 g of sodium azide dissolved in 60 ml of distilled water which had been previously charged in a 300 ml flask. After completion of the dropwise addition, the mixture was stirred at the same temperature for one hour and the mixture was extracted twice with 300 ml of toluene. The organic layers were combined and washed three times with distilled water and once with a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and the filtrate was refluxed for one hour. To the mixture were added 11.3 g of benzyl alcohol and 3 drops of triethylamine, and the resulting mixture was further refluxed for 2 hours. After completion of the reaction, toluene was removed under reduced pressure and the residual crystals were recrystallized from ethanol to obtain 26.5 g of benzyl N-(10-dodecylthio)decylcarbamate. In a 300 ml flask were charged 24.5 g of the resulting benzyl N-(10-dodecylthio)decylcarbamate, 20 ml of 48% hydrobromic acid and 180 ml of glacial acetic acid and the mixture was refluxed for 2 hours. After completion of the reaction, glacial acetic acid was removed under reduced pressure and the residual crystals were recrystallized from ethanol to obtain 17.0 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.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.[Br:46][C:47]1[CH:48]=[C:49]2[C:53](=[CH:54][CH:55]=1)[NH:52][CH2:51][CH2:50]2>CN(C)C=O>[Br:46][C:47]1[CH:48]=[C:49]2[C:53](=[CH:54][CH:55]=1)[N:52]([C:10](=[O:12])[CH2:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[F:1])[CH2:51][CH2:50]2
Reactant: Brc1ccc2c(c1)CCN2
Reactant: O=C(O)Cc1cc(F)ccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1cc(F)ccc1F)N1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
To a mixture of (2,5-difluorophenyl)acetic acid (0.869 g, 5.05 mmol) and HATU (2.112 g, 5.55 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was added Hunig's base (0.882 mL, 5.05 mmol), and the resulting mixture was stirred for 15 minutes at room temperature. 5-bromo-2,3-dihydro-1H-indole (1 g, 5.05 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The mixture was poured onto water, and the resulting aqueous mixture was filtered to afford 5-bromo-1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indole (1.6 g) as a tan solid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][C@@H:18]([CH3:21])[CH2:17]3)[C:6]=2[N:22]=1.[NH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=1[O:33][CH3:34].O.CC1C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[F:14][C:9]1([F:15])[CH2:8][N:7]([CH:16]2[CH2:20][CH2:19][C@@H:18]([CH3:21])[CH2:17]2)[C:6]2[N:22]=[C:2]([NH:23][C:24]3[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=3[O:33][CH3:34])[N:3]=[CH:4][C:5]=2[N:11]([CH3:12])[C:10]1=[O:13]
Reactant: C[C@@H]1CCC(N2CC(F)(F)C(=O)N(C)c3cnc(Cl)nc32)C1
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CC[C@@H](C)C1)CC(F)(F)C(=O)N2C
Temperature: 85 °C
Reaction time: 48 h

Procedure:
2-Chloro-7,7-difluoro-5-methyl-9-((3R)-3-methylcyclopentyl)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (500 mg, 1.51 mmol) and 4-amino-3-methoxybenzoic acid (316.0 mg, 1.89 mmol) were weighed into a flask. 4-Methylbenzenesulfonic acid monohydrate (230.0 mg, 1.21 mmol) was weighed into a separate flask and dissolved in dioxane (15 ml). The toxic acid solution was then added to the flask containing the two starting materials. The reaction was stirred at 85° C. for 48 hours followed by 100° C. for an additional 48 hours. The dark brown mixture was cooled to room temperature and filtered through paper. The solids were washed with ethyl acetate (15 ml). m/z 462.4 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[CH2:10]1[O:12][CH:11]1[CH2:13][OH:14].C(O)C>O>[CH2:1]([N:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:10][CH:11]([OH:12])[CH2:13][OH:14])[CH3:2]
Reactant: CCNc1ccccc1
Reactant: OCC1CO1
Solvent: O
Solvent: CCO
Product: CCN(CC(O)CO)c1ccccc1
Temperature: 120 °C
Yield: 94.7 %

Procedure:
A mixture of N-ethylaniline (1.21 g, 10 mmol), glycidol (1.11 g, 15 mmol) and ethanol (1 ml) was heated by microwave irradiation for 10 min at 120° C. The mixture was dissolved in water (10 ml) and extracted with ethyl acetate (3 times 25 ml). The combined organic layers were dried over magnesium sulfate and evaporated. The residue was purified by chromatography (SiO2, ethyl acetate/heptane=1:2) to yield a colorless liquid (1.85 g, 94%); MS (ISP): 196.3 ((M+H)+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](F)=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH:19]([CH3:21])[CH3:20])[N:3]=1.[N-:22]=[N+]=[N-].[Na+].O>CN1C(=O)CCC1>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH2:22])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH:19]([CH3:21])[CH3:20])[N:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)c1cc(-c2ccc(F)c3ccccc23)nc(N)n1
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)c1cc(-c2ccc(N)c3ccccc23)nc(N)n1
Reaction time: 16 h
Yield: 53 %

Procedure:
2-Amino-4-(4-fluoronaphth-1-yl)-6-isopropyl-pyrimidine (0.288 g) was dissolved in N-methy pyrrolidinone (5 mL) and sodium azide (0.288 g) was added. The mixture was brought to a temperature of 160° C. under an inert atmosphere for 16 hours. After cooling the reaction mixture was poured into water (50 mL) and the reaction product was extracted with ethyl acetate (3×30 mL). The organic layer was dried over sodium sulfate and evaporated to dryness. The product was purified by column chromatography on silica gel, eluting with hexane/ethyl acetate, and recrystallized from tert-butyl methyl ether to give 2-amino-4-(4-aminonaphth-1-yl)-6-isopropylpyrimidine (0.151 g), m.p. 185-186° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[CH:12][NH:11][N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:14]N1C(=O)CCC1=O>ClCCl>[Cl:14][C:13]1[C:9]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)=[N:10][NH:11][CH:12]=1
Reactant: Clc1cc(Cl)cc(-c2cc[nH]n2)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: Clc1cc(Cl)cc(-c2n[nH]cc2Cl)c1
Reaction time: 96 h
Yield: 37.2 %

Procedure:
2.3 g (0.0152 mol) of 3-(3,5-dichlorophenyl)-1H-pyrazole are dissolved, at room temperature and with stirring, in 300 ml of dichloromethane. 2.07 g (0.016 mol) of N-chlorosuccinimide are then added and then stirring is continued for 4 days at room temperature. The reaction mixture is then concentrated and then chromatographed on a silica column (eluent 70/30 heptane/ethyl acetate). 1.4 g (yield: 57%, melting point: 192° C.) of 4-chloro-3-(3,5-dichlorophenyl)-1H-pyrazole are obtained.
Reaction SMILES: [CH:1]1[C:2]2[N:3]([CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:5][N:6]=1.Cl.[CH2:11]=[O:12].[OH-].[Na+]>O>[CH:1]1[C:2]2[N:3]([C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:5][N:6]=1
Reactant: C=O
Reactant: c1cc2cnccn2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=Cc1ccc2cnccn12
Temperature: 60 °C
Reaction time: 240 h
Yield: 19.3 %

Procedure:
Pyrrolo[1,2-a]pyrazine (1.92 g, 16.3 mmol) was dissolved in water (16 mL) and treated with conc. aq. HCl (4 mL, 46.4 mmol) and 37% wt aqueous formaldehyde (5.6 mL, 67 mmol). The solution was heated to 60° C. for 4 h, allowed to cool to RT and the pH adjusted to 10. The solution was extracted with EtOAc (3×50 mL) and the combined fractions dried over Na2SO4 and concentrated to dryness under vacuum. The organic residue was purified (SGC using DCM:MeOH:NH4OH eluant in 96:3:1 ratio). Recovered starting material was dissolved in water (20 mL) and conc. HCl (5 mL, 0.6 mol) and formaldehyde (7 mL, 0.9 mol). The solution was heated to 60° C. for 120 h, and then allowed to stir at RT for 240 h. The solution pH was then brought to 12 with sodium hydroxide solution (30% w/v aq) and extracted with EtOAc (4×30 mL). The organic fractions were combined, dried over Na2SO4, and concentrated to dryness under vacuum. The product was purified (SGC using DCM:MeOH:NH4OH eluant in 95:4:1 ratio) yielding the title compound (0.46 g). MS (ESI+) for m/z 149 (M+H)+. 1H NMR (CDCl3) δ 8.46 (s, 1H), 7.85 (dd,1H), 7.19 (d, 1H), 6.72 (d, 1H), 6.63 (d, 1H), 4.83 (s, 1H), 4.78 (bs,1H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:31]=[O:32])[CH:8]=[C:9]2[C:17]=1[CH:16]([CH2:18][O:19][C:20](=[O:22])[NH2:21])[C:15]1([O:24][C:25](=[O:27])[CH3:26])[O:23][N:10]2[CH2:11][CH:12]2[CH:14]1[N:13]2[C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:31][OH:32])[CH:8]=[C:9]2[C:17]=1[CH:16]([CH2:18][O:19][C:20](=[O:22])[NH2:21])[C:15]1([O:24][C:25](=[O:27])[CH3:26])[O:23][N:10]2[CH2:11][CH:12]2[CH:14]1[N:13]2[C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(C=O)cc2c1C(COC(N)=O)C1(OC(C)=O)ON2CC2C1N2C(C)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)Oc1cc(CO)cc2c1C(COC(N)=O)C1(OC(C)=O)ON2CC2C1N2C(C)=O
Reaction time: 2 h
Yield: 84.6 %

Procedure:
11-Acetyl-4-formyl-8-carbamoyloxymethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-6,9-diyl diacetate (20 mg) was dissolved in ethyl acetate (5 ml) and the solution was subjected to catalytic reduction for 2 hours using 10% palladium on carbon under atmospheric pressure at room temperature. The reaction mixture was filtered and the filtrate was evaporated to dryness in vacuo. The residual oil was subjected to preparative thin layer chromatography, which was developed with a mixture of methanol and chloroform (5:95, v/v) to yield 11-acetyl-8-carbamoyloxymethyl-4-hydroxymethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-6,9-diyl diacetate (17 mg).
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: COc1ccc(C=O)c(SC)c1
Reactant: Br
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.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:12]([O:16][CH3:17])(=[O:15])[CH:13]=[CH2:14]>>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2](/[CH:14]=[CH:13]/[C:12]([O:16][CH3:17])=[O:15])[CH:3]=1
Reactant: C=CC(=O)OC
Reactant: Brc1cnc2ccccc2c1
Product: COC(=O)/C=C/c1cnc2ccccc2c1
Yield: 67 %

Procedure:
The title compound was prepared from 3-bromoquinoline (16a) and methyl acrylate using methods as described in the literature for similar compounds (Frank et al., 1978) in 67% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:24]=[CH:23][C:7]([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH:13]([CH:16]3[CH2:21][O:20][C:19](=[O:22])[CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[C:6]([F:25])[C:5]=1[F:26])[CH3:2].[CH2:27]([Li])[CH2:28][CH3:29].[Cl-].[NH4+]>C1COCC1>[CH2:1]([O:3][C:4]1[CH:24]=[CH:23][C:7]([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH:13]([CH:16]3[CH2:21][O:20][C:19]([CH2:27][CH2:28][CH3:29])([OH:22])[CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[C:6]([F:25])[C:5]=1[F:26])[CH3:2]
Reactant: [Li]CCC
Reactant: CCOc1ccc(OCC2CCC(C3CCC(=O)OC3)CC2)c(F)c1F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC1(O)CCC(C2CCC(COc3ccc(OCC)c(F)c3F)CC2)CO1
Temperature: -70 °C
Reaction time: 1 h
Yield: 872.7 %

Procedure:
In a reactor under nitrogen atmosphere, 100 mL of THF was added to 4.5 g of 5-[4-(4-ethoxy-2,3-difluorophenoxymethyl)cyclohexyl]tetrahydropyran-2-one obtained in the twelfth step, and the mixture was cooled to −70° C., to which 15 mL of n-propyllithium (about 1.0 mmol) was added dropwise. After stirring the mixture at −70° C. for 1 hour, the temperature of the reaction mixture was increased to room temperature, and 50 mL of a saturated ammonium chloride aqueous solution was added thereto, followed by separating. The aqueous layer was extracted three times with 30 mL of diethyl ether, and the mixture including the organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by silica gel column chromatography to provide 3.6 g of 5-[4-(4-ethoxy-2,3-difluorophenoxymethyl)cyclohexyl]2-propyltetrahydropyran-2-ol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:5]([O:26][CH3:27])=[C:6](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[CH:12][C:13]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[C:14]([CH:20]=2)CNC(=O)C)[CH:7]=1.[O:32]=[C:33]1[C:38](B(O)O)=[CH:37][CH:36]=[CH:35][NH:34]1>>[C:28]([C:4]1[C:5]([O:26][CH3:27])=[C:6](/[CH:8]=[CH:9]/[C:10]2[CH:20]=[CH:14][C:13]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:12][C:11]=2[CH2:35][NH:34][C:33](=[O:32])[CH3:38])[CH:7]=[C:2]([C:38]2[C:33](=[O:32])[NH:34][CH:35]=[CH:36][CH:37]=2)[CH:3]=1)([CH3:29])([CH3:30])[CH3:31]
Reactant: COc1c(/C=C/c2ccc(NS(C)(=O)=O)c(CNC(C)=O)c2)cc(Br)cc1C(C)(C)C
Reactant: O=c1[nH]cccc1B(O)O
Product: COc1c(/C=C/c2ccc(NS(C)(=O)=O)cc2CNC(C)=O)cc(-c2ccc[nH]c2=O)cc1C(C)(C)C

Procedure:
step 3—Palladium-catalyzed coupling of 212 and B-(1,2-dihydro-2-oxo-3-pyridinyl)-boronic acid (213, CASRN 951655-49-5) was carried out in accord with the procedure in step 4 of example 38 to afford the title compound. The product was purified on a SiO2 preparative TLC plate developed with 5% MeOH/DCM to afford 17.5 mg of I-160
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:11]=[C:10]([C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[O:9][N:8]=1)(=O)=O.[Br-:18].[Li+].O>CC(C)=O>[Br:18][CH2:6][C:7]1[CH:11]=[C:10]([C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[O:9][N:8]=1
Reactant: [Br-]
Reactant: CS(=O)(=O)OCc1cc(-c2ncccn2)on1
Agent: [Li+]
Solvent: CC(C)=O
Solvent: O
Product: BrCc1cc(-c2ncccn2)on1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(3-methanesulfonyloxymethyl-isoxazol-5-yl)-pyrimidine (19 gm), lithium bromide (13 gm) in acetone (190 ml) was stirred at 30° C. temperature over a period of 2 h. The reaction was monitored by TLC. The reaction mixture was evaporated under vacuum to provide a crude mass which upon stirring with water (150 ml) provided suspension. Filtration of suspension under suction afforded the title compound in 15.2 gm quantity (75.3%) as a solid.
Reaction SMILES: Cl.[C:2]1([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:14]([C:16]1[CH:31]=[CH:30][C:19]([O:20][C:21]2[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][N:22]=2)=[CH:18][CH:17]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[C:2]1([CH:8]2[CH2:9][CH2:10][N:11]([CH2:14][C:16]3[CH:31]=[CH:30][C:19]([O:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][N:22]=4)=[CH:18][CH:17]=3)[CH2:12][CH2:13]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: NC(=O)c1ccc(Oc2ccc(CN3CCC(c4ccccc4)CC3)cc2)nc1
Yield: 93.3 %

Procedure:
Using a method similar to Example 342, using 4-phenyl-piperidine hydrochloride salt (0.0823 g, 0.416 mmol), 6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1) (0.100 g, 0.415 mmol), sodium triacetoxyborohydride (0.136 g, 0.642 mmol), and acetic acid (0.034 mL, 0.594 mmol) in 1,2-dichloroethane (8.0 mL) provides 0.150 g (94%) of the title compound as a white solid: high resolution mass spectrum (electrospray): m/z calc for C24H26N3O2 388.2025, found 388.2039; 1H NMR (methanol-d4): 8.67 (d, 1H, J=2.6 Hz), 8.30 (dd, 1H, 2.6, 8.8 Hz), 7.49 (d, 2H, J=8.8 Hz), 7.35-7.25 (m, 4H), 7.23-7.15 (m, 3H), 7.05 (d, 1H, J=8.8 Hz), 3.65 (s, 2H), 3.12 (d, 2H, J=11.9 Hz), 2.65-2.54 (m, 1H), 2.24 (dt, 2H, J=4.0, 11.0 Hz), 1.94-1.78 (m, 4H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][OH:4].[H-].[Na+].Br[CH2:8][C:9](=[O:29])[CH2:10][C:11]([O:13][CH2:14][CH2:15][CH:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:12].Cl>O1CCCC1>[Cl:1][CH2:2][CH2:3][O:4][CH2:8][C:9](=[O:29])[CH2:10][C:11]([O:13][CH2:14][CH2:15][CH:16]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:12]
Reactant: O=C(CBr)CC(=O)OCCC(c1ccccc1)c1ccccc1
Reactant: OCCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(COCCCl)CC(=O)OCCC(c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
A solution of 2.09 g (26 mmol) of 2-chloroethanol in 10 ml of tetrahydrofuran was added dropwise to a suspension of 1.84 g (46 mmol) of sodium hydride (60% oily) in 100 ml of tetrahydrofuran at −50° C., and they were stirred for 2 hours. A solution of 7.51 g (20 mmol) of 3,3-diphenylpropyl 4-bromoacetoacetate in 3 ml of tetrahydrofuran was added dropwise to the reaction mixture at −50° C. The temperature was elevated to room temperature, and they were stirred overnight. A small amount of hydrochloric acid was added to the reaction mixture. After the concentration followed by the fractionation with ethyl acetate and water, the extract was washed with 1 N sodium hydroxide and saturated aqueous sodium chloride solution and then dried over sodium sulfate to obtain the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH:14]=1)([O-:3])=[O:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH:14]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc2[nH]cc(C3=CCNCC3)c2c1
Reaction time: 3 h
Yield: 98.8 %

Procedure:
A solution of tert-butyl 4-(5-nitro-1H-indol-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.8 g, 2.330 mmol) in CH2Cl2 (16 mL) was treated with TFA (4 mL) at 0° C. and the resulting mixture was stirred at same temperature for 3 h. The reaction was evaporated and crude was basified with 1 N NaOH solution (pH ˜14). The solid was filtered off, washed with water (2×10 mL). The crude was dried under vacuum and treated with 10% ethyl acetate in hexanes (20 mL). The solid was filtered and washed with hexanes (2×5 mL). The yellow solid was dried under vacuum to obtain 5-nitro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.56 g, 99%). 1H NMR (DMSO-d6) δ 8.69 (d, 1H, J=2.1 Hz), 8.00 (dd, 1H, J=2.1, 9.0 Hz), 7.63 (s, 1H), 7.55 (d, 1H, J=9.0 Hz), 6.21 (s, 1H), 3.42-3.30 (m, 2H, merged with DMSO-peak), 2.93 (t, 2H, J=5.4 Hz), 2.40-2.30 (m, 2H); ESI-MS (m/z, %): 244 (MH+, 77), 215 (100).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:6][C:7]1[CH:19]=[CH:18][C:10]([O:11][C:12]([CH3:17])([CH3:16])[C:13](Cl)=[O:14])=[CH:9][CH:8]=1.Cl>CC#N.[Cl-].[Na+].O>[Br:6][C:7]1[CH:19]=[CH:18][C:10]([O:11][C:12]([CH3:16])([CH3:17])[C:13]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:14])=[CH:9][CH:8]=1
Reactant: CC(C)(Oc1ccc(Br)cc1)C(=O)Cl
Reactant: C1CCNC1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)(Oc1ccc(Br)cc1)C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.3 %

Procedure:
Pyrrolidine (1.54 g, 21.6 mmol) in anhydrous MeCN (10 mL) was added with stirring to 2-(4-bromophenoxy)-2-methylpropanoyl chloride (2 g, 7.2 mmol) in anhydrous MeCN (10 mL) at 0° C. The mixture was stirred at room temperature for 18 h and acidified with HCl (aq. 1M, 40 mL). Brine was added and the mixture was extracted with CH2Cl2. The combined extracts were washed with NaHCO3 (aq. sat) and brine, dried (Na2SO4), and concentrated to give the sub-title compound (2.12 g, 94%).