Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:8]([NH2:32])([CH2:12][CH2:13][CH2:14][C:15]1([CH2:21][C:22]([O:24]CC2C=CC=CC=2)=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([OH:11])=[O:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N+](=[CH2:35])=[N-]>C(Cl)Cl>[C:1]([C:8]([NH2:32])([CH2:12][CH2:13][CH2:14][C:15]1([CH2:21][C:22]([OH:24])=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[C:9]([O:11][CH3:35])=[O:10])([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)C(N)(CCCC1(CC(=O)OCc2ccccc2)CCCCC1)C(=O)O
Reactant: C=[N+]=[N-]
Solvent: ClCCl
Product: COC(=O)C(N)(CCCC1(CC(=O)O)CCCCC1)C(=O)OC(C)(C)C

Procedure:
The Boc-benzyl ester (J) (4 mmol) is dissolved in methylene chloride and treated with excess ethereal diazomethane at room temperature. The residual diazomethane is quenched with acetic acid and the solution is evaporated at reduced pressure. The crude diester is dissolved in methanol and hydrogenated over 10% palladium-on-carbon to give, after flash chromatography (silica gel), the titled compound.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:7][CH2:8][O:9][C:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:12][N:11]=1>>[C:15]1([C:13]2[O:12][N:11]=[C:10]([O:9][CH2:8][CH2:7][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:14]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C1CCNC1
Reactant: BrCCOc1cc(-c2ccccc2)on1
Product: c1ccc(-c2cc(OCCN3CCCC3)no2)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
Pyrrolidine (710 mg) was added to 3-(2-bromoethoxy)-5-phenylisoxazole (268 mg), and the mixture was stirred at 100° C. for one hour. After ice-cold water (20 ml) was added to the reaction mixture and the mixture was extracted with ether (20 ml×2), the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain the title compound (211 mg, 82%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: C1CCNCC1
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCCCC3)cc2n1

Procedure:
Prepared by reductive amination of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde with piperidine under the standard conditions.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[NH:19]1[C:27]2[C:22](=[CH:23][C:24]([C:28]3[CH:29]=[C:30]([CH:34]=O)[CH:31]=[N:32][CH:33]=3)=[CH:25][CH:26]=2)[CH:21]=[CH:20]1.[CH3:36][N:37]([CH3:41])[CH2:38][CH2:39][NH2:40]>ClCCCl>[NH:19]1[C:27]2[C:22](=[CH:23][C:24]([C:28]3[CH:29]=[C:30]([CH2:34][NH:40][CH2:39][CH2:38][N:37]([CH3:41])[CH3:36])[CH:31]=[N:32][CH:33]=3)=[CH:25][CH:26]=2)[CH:21]=[CH:20]1
Reactant: O=Cc1cncc(-c2ccc3[nH]ccc3c2)c1
Reactant: CN(C)CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN(C)CCNCc1cncc(-c2ccc3[nH]ccc3c2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.5 %

Procedure:
Sodium triacetoxyborohydride (855 mg, 4.05 mmol) and then enough acetic acid to bring the pH to 5 were added to a solution of 5-(1H-indol-5-yl)-pyridine-3-carbaldehyde (300 mg, 1.35 mmol) and N,N-dimethylethylene diamine (237 mg, 2.7 mmol) in 15 mL of 1,2-dichloroethane. The mixture was stirred at ambient temperature for 48 h, and then the volatiles were removed in the presence of celite. The product was eluted from the celite through silica gel (elution with methanol/dichloromethane) to give 328 mg of product. LC/MS: Retention time, 0.43 min; (M+H)=295.19.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([F:10])([F:9])[F:8].C[N+]([O-:15])(C)C>>[F:8][C:7]([F:10])([F:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=[O:15]
Reactant: C[N+](C)(C)[O-]
Reactant: FC(F)(F)CCCCCBr
Product: O=CCCCCC(F)(F)F

Procedure:
Commercially available 6-bromo-1,1,1-trifluorohexane (Oakwood) and trimethylamine oxide were processed using the method described in example 137A to afford the title compound. MS (ESI+) m/z 154 (M+NH4—H2O)+.
Reaction SMILES: [O:1]1[C@H:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C@H:2]1[C:9]([O:11][CH2:12][CH3:13])=[O:10].Br[C@@H]([C@@H](O)C(OCC)=O)C(OCC)=O.C1CCN2C(=NCCC2)CC1>CCOCC>[O:1]1[C@@H:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C@@H:2]1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)OCC
Agent: CCOC(=O)[C@@H](Br)[C@@H](O)C(=O)OCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOCC
Product: CCOC(=O)[C@@H]1O[C@H]1C(=O)OCC
Yield: 74.8 %

Procedure:
Followed general procedure for 3a using the following quantities: 2b (34.6 g, 129 mmol): Et2O (100 ml); DBU (29.4 g, 193 mmol, in Et2O [50 ml]); yielded 3b as a colorless oil (18.1 g, 74.8%). 1H NMR (CDCl3, 400 MHz): δ 4.36-4.22 (m, 4H); 3.67 (s, 2H); 1.35-1.31 (t, 6H). 13C NMR (CDCl3, 100 MHz): 166.75, 62.21, 52.01, 14.01.
Reaction SMILES: C(O)(C)C.[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C:13]2=[O:18])=[CH:8][CH:7]=1.[O:19]1[CH2:21][C@@H:20]1[CH2:22][N:23]1[C:31](=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]1=[O:33]>O>[OH:19][C@H:20]([CH2:21][NH:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C:13]2=[O:18])=[CH:10][CH:11]=1)[CH2:22][N:23]1[C:24](=[O:33])[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:31]1=[O:32]
Reactant: Nc1ccc(N2CCOCC2=O)cc1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1CO1
Solvent: O
Solvent: CC(C)O
Product: O=C1c2ccccc2C(=O)N1C[C@H](O)CNc1ccc(N2CCOCC2=O)cc1
Temperature: 27.5 °C

Procedure:
In a four neck round bottom flask charged Isopropyl alcohol (135 ml), 4-(4-aminophenyl) morpholin-3-one (10 g), 2-[(2s)-oxiran-2yl methyl]-1H-isoindole-1,3(2H)dione ((11.6 g) and water (15 ml) at 25 to 30° C. Slowly heated the reaction mixture to reflux and maintained for 24 h at reflux temperature. Reaction mass is cooled to 25 to 30° C. after completion of the reaction. Reaction mass then maintained at 25 to 30° C. for 30 minutes. Finally obtained solid is filtered off and washed by isopropyl alcohol (25 ml)
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([O:29][CH3:30])=[CH:11][CH:12]=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[C:14]2[NH:20][C:21]1[C:26]([Cl:27])=[CH:25][N:24]=[CH:23][C:22]=1[Cl:28].[NH2:31][CH2:32][CH2:33][CH2:34][OH:35]>>[Cl:28][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([Cl:27])[C:21]=1[NH:20][C:14]1[C:13]2[C:18](=[C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:31][CH2:32][CH2:33][CH2:34][OH:35])[C:10]([O:29][CH3:30])=[CH:11][CH:12]=2)[NH:17][C:16](=[O:19])[CH:15]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCCl
Reactant: NCCCO
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCNCCCO

Procedure:
The title compound was prepared from 8-(6-chlorohexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one (Intermediate 4) and 3-aminopropan-1-ol following the procedure outlined in Example 18, Step 2 (modifications: 40° C., 24 h). 1H NMR (400 MHz, DMSO-d6): δ 8.67 (s, 2H), 7.85 (d, 1H), 7.00 (d, 1H), 4.68 (s, 1H), 3.95 (t, 2H), 3.88 (s, 3H), 3.43 (t, 2H), 2.59 (t, 2H), 2.52 (m, 2H), 1.74 (m, 2H), 1.54 (m, 2H), 1.48-1.28 (m, 6H) [NH's & OH not seen]; MS (ESI): 509.3.
Reaction SMILES: [N+:1]([CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6])([O-:3])=[O:2].CS[C:15]1[S:16][CH2:17][CH2:18][CH2:19][N:20]=1>[Cl-].[Zn+2].[Cl-]>[N+:1]([C:4](=[C:15]1[NH:20][CH2:19][CH2:18][CH2:17][S:16]1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6])([O-:3])=[O:2]
Reactant: CSC1=NCCCS1
Reactant: O=C(C[N+](=O)[O-])c1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Product: O=C(C(=C1NCCCS1)[N+](=O)[O-])c1ccccc1
Reaction time: 2.5 h

Procedure:
A mixture of 3.3 g of 2-nitroacetophenone and 2.94 g of 2-(methylthio)-5,6-dihydro-4H-1,3-thiazine was heated to 115° and 100 milligrams of zinc chloride was added. Heating and stirring was continued at 115°-120° for 2.5 hours. After cooling, the mixture was filtered (with the aid of ethyl acetate) through a short column of florosil to give an amber oil. The oil was chromatographed on silica gel using dry-column technique and a 1:1:2 mixture of tetrahydrofuran/ethyl acetate/hexane for development to give 1 as a salmon-colored solid, m.p.: 137°-140°.
Reaction SMILES: [CH3:1][CH:2](C(C)=O)[C:3](OCC)=[O:4].N.[NH2:12]/[C:13](/[CH3:21])=[C:14](/[CH3:20])\[C:15]([O:17]CC)=O.CC(C(OCC)=O)C(OCC)=O>>[CH3:21][C:13]1[C:14]([CH3:20])=[C:15]([OH:17])[C:2]([CH3:1])=[C:3]([OH:4])[N:12]=1
Reactant: CCOC(=O)/C(C)=C(/C)N
Reactant: CCOC(=O)C(C)C(C)=O
Agent: CCOC(=O)C(C)C(=O)OCC
Agent: N
Product: Cc1nc(O)c(C)c(O)c1C

Procedure:
U.S. Pat. No. 4,785,113 discloses the preparation of the title compounds from ethyl 2-methylacetoacetate by reaction with NH3 to give ethyl 3-amino-2-methylcrotonate, reaction with diethyl monomethylmalonate to give 2,3,5-trimethyl-4,6-dihydroxypyridine, chlorination to give 2,4-dichloro-3,5,6-trimethylpyridine, selective cleavage of the 2-Cl substituent and exchange of the 4-Cl substituent for a methoxy group, and then oxidation to give the N-oxide. The subsequent reactions are carried out analogously to the process described in U.S. Pat. No. 4,472,409.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.[F:15][C:16]([F:29])([CH3:28])[CH2:17][O:18][C:19]1[N:24]=[CH:23][C:22]([CH2:25][NH2:26])=[CH:21][C:20]=1[CH3:27]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:26]([CH2:25][C:22]3[CH:23]=[N:24][C:19]([O:18][CH2:17][C:16]([F:29])([F:15])[CH3:28])=[C:20]([CH3:27])[CH:21]=3)[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: Cc1cc(CN)cnc1OCC(C)(F)F
Product: Cc1cc(CN2Cc3c(ccnc3Cl)C2=O)cnc1OCC(C)(F)F
Yield: 87 %

Procedure:
The title compound is prepared in 87% yield (742 mg, pale yellow oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (644 mg, 2.31 mmol, Step-1 of Intermediate-1) and (6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)methanamine (500 mg, 2.31 mmol, Amine-84) in a similar manner to Intermediate-2.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]2[C:14]([C:15]3[C:16]([F:21])=[N:17][CH:18]=[CH:19][CH:20]=3)=[C:13]([F:22])[C:12]([CH2:23][N:24](C)[C:25](=O)OC(C)(C)C)=[CH:11]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.C(OCC)(=O)C.Cl>C(OCC)(=O)C.CC(O)C>[ClH:1].[Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]2[C:14]([C:15]3[C:16]([F:21])=[N:17][CH:18]=[CH:19][CH:20]=3)=[C:13]([F:22])[C:12]([CH2:23][NH:24][CH3:25])=[CH:11]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2ccc(Cl)s2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CNCc1cn(S(=O)(=O)c2ccc(Cl)s2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 130 %

Procedure:
To a solution of tert-butyl {[1-[(5-chloro-2-thienyl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (229 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethyl acetate-ethanol to give the title compound as a white solid (yield 130 mg, 65%).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10](=[O:16])[CH2:11][NH:12][CH:13]2[CH2:15][CH2:14]2)=[CH:5][C:4]=1[C:17]#[N:18]>>[NH2:2][C:3]1[C:8]([F:9])=[CH:7][C:6]([CH:10]([OH:16])[CH2:11][NH:12][CH:13]2[CH2:15][CH2:14]2)=[CH:5][C:4]=1[C:17]#[N:18]
Reactant: N#Cc1cc(C(=O)CNC2CC2)cc(F)c1N
Agent: Cl
Product: N#Cc1cc(C(O)CNC2CC2)cc(F)c1N

Procedure:
m.p. of the hydrochloride: 188°-190° C. (decomp.), was prepared from 4'-amino-3'-cyano-2-cyclopropylamino-5'-fluoroacetophenone analogous to Example 49.
Reaction SMILES: C([O:8][C:9]([CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:13][CH2:12]1)=[O:10])C1C=CC=CC=1>CO.[Pd]>[C:20]1([CH2:19][CH2:18][CH2:17][N:14]2[CH2:15][CH2:16][CH:11]([C:9]([OH:10])=[O:8])[CH2:12][CH2:13]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(OCc1ccccc1)C1CCN(CCCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: O=C(O)C1CCN(CCCc2ccccc2)CC1
Reaction time: 2 h
Yield: 0.1 %

Procedure:
Pd/C (378 mg) was added to a stirred solution of 1-(3-phenyl-propyl)-piperidine-4-carboxylic acid benzyl ester (1.89 g, 5 mmol) in MeOH (38 mL) and stirring was continued under hydrogen atmosphere for 2 hrs. The mixture was filtered over a bed of celite. The celite was washed with MeOH and the filtrate was concentrated under reduced pressure to afford 1.502 mg (93.93% yield) of 1-(3-phenyl-propyl)-piperidine-4-carboxylic acid. LCMS Purity: 95.08%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[CH:20]=[CH2:21]>C(#N)C>[CH2:21]([O:12][C:3]1[C:2]([F:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[C:5]([F:11])[CH:4]=1)[CH:20]=[CH2:19]
Reactant: O=[N+]([O-])c1cc(F)c(O)cc1F
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCOc1cc(F)c([N+](=O)[O-])cc1F
Yield: 44.2 %

Procedure:
The product of step (a) (3.4 g, 20 mmol), 50 ml acetonitrile, 3.3 g potassium carbonate and 3 g allyl bromide were combined, heated to reflux for one hour and stripped. The mixture was extracted with dichloromethane, treated with water and separated. The organics were dried over magnesium sulfate and stripped to yield 1.9 g of 4-allyloxy-2,5 difluoro nitrobenzene product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17]CC1C=CC=CC=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17])[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CCc1ccccc1OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CN(CCc1ccccc1O)C(=O)OC(C)(C)C
Yield: 82.8 %

Procedure:
N-(2-(2-Benzyloxyphenyl)ethyl)-N-methylcarbamic acid tert-butyl ester (4.66 g, 13.65 mmol) was dissolved in ethanol (35.6 ml) and was hydrogenated at room pressure in the presence of 10% palladium on activated carbon for 16 h. The reaction mixture was filtered through a plug of celite. The celite was washed with ethyl acetate (50 ml). The liquid phases were collected. The solvents were removed in vacuo. The crude product was purified by flash chromatography on silica (300 g), using ethyl acetate/heptane (1:2) as eluent, to give 2.84 g of N-(2-(2-hydroxyphenyl)ethyl)-N-methylcarbamic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([CH:9]2[C:17](=[O:18])[CH:16]3[CH:11]([CH:12]4[O:19][CH:15]3[CH2:14][CH2:13]4)[C:10]2=[O:20])=[C:5]([CH3:8])[S:6][CH:7]=1)[CH3:2].[Br:21]Br>C(Cl)Cl>[Br:21][C:7]1[S:6][C:5]([CH3:8])=[C:4]([CH:9]2[C:17](=[O:18])[CH:16]3[CH:11]([CH:12]4[O:19][CH:15]3[CH2:14][CH2:13]4)[C:10]2=[O:20])[C:3]=1[CH2:1][CH3:2]
Reactant: BrBr
Reactant: CCc1csc(C)c1C1C(=O)C2C3CCC(O3)C2C1=O
Solvent: ClCCl
Product: CCc1c(Br)sc(C)c1C1C(=O)C2C3CCC(O3)C2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.6 %

Procedure:
To a suspension of 4-(4-ethyl-2-methyl-thiophen-3-yl)-10-oxa-tricyclo[5.2.1.0*2,6*]decane-3,5-dione (73 mg, 0.25 mmol) in DCM (2 ml), at 0° C., is added bromine (26 μl, 0.5 mmol) in one portion, and the reaction allowed to warm to ambient and stirred at room temperature for 3 hours. The reaction is concentrated in vacuo, re-dissolved in methanol (10 ml), potassium carbonate (250 mg) added and the resulting suspension stirred at room temperature for a further 17 hours. The reaction is quenched by the addition if 2N aqueous HCl (10 ml) and extracted with DCM (2×10 ml). The combined organics extracts are dried, filtered, concentrated in vacuo, and purified by flash chromatography on silica gel to give 4-(5-bromo-4-ethyl-2-methyl-thiophen-3-yl)-10-oxa-tricyclo[5.2.1.0*2,6*]decane-3,5-dione as a brown solid (43 mg).
Reaction SMILES: [CH:1]1([S:4][C:5]2[CH:10]=[CH:9][C:8](/[C:11](/[C:28]3[CH:33]=[CH:32][C:31](I)=[CH:30][CH:29]=3)=[CH:12]/[CH2:13][O:14][C:15]3[CH:26]=[CH:25][C:18]([O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:17]([CH3:27])[CH:16]=3)=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.[CH2:35]([N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)[C:36]#[CH:37].C(NC(C)C)(C)C>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:1]1([S:4][C:5]2[CH:10]=[CH:9][C:8](/[C:11](/[C:28]3[CH:33]=[CH:32][C:31]([C:37]#[C:36][CH2:35][N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[CH:30][CH:29]=3)=[CH:12]/[CH2:13][O:14][C:15]3[CH:26]=[CH:25][C:18]([O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:17]([CH3:27])[CH:16]=3)=[CH:7][CH:6]=2)[CH2:3][CH2:2]1
Reactant: C#CCN1CCOCC1
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(SC3CC3)cc2)cc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN3CCOCC3)cc2)c2ccc(SC3CC3)cc2)cc1C
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a degassed solution of the above ester (1 g, 1.705 mmol), N-propargylmorpholine (440 mg, 3.515 mmol) and diisopropylamine (1.12 mL, 7.96 mmol) in anhydrous tetrahydrofuran (27 mL), bis(triphenylphosphine)palladium(II) dichloride (95 mg, 0.135 mmol) and copper(I) iodide (27.0 mg, 0.142 mmol) were added. The reaction mixture was stirred at 50° C. overnight under nitrogen. The solvents were evaporated in vacuo and the residue was twice purified by flash column chromatography (silica gel Fluka 60, chloroform/methanol 100:0-95:5 and then chloroform/ethyl acetate/methanol 80:13:7) yielding methyl (E)-[4-[3-(4-cyclopropylsulfanylphenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methylphenoxy]acetate as yellow oil.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)(=[O:4])=[O:3].[I:13]N1C(=O)CCC1=O>CN(C)C=O>[I:13][C:11]1[CH:12]=[C:6]([CH2:5][S:2]([CH3:1])(=[O:3])=[O:4])[CH:7]=[CH:8][C:9]=1[NH2:10]
Reactant: CS(=O)(=O)Cc1ccc(N)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: CS(=O)(=O)Cc1ccc(N)c(I)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.6 %

Procedure:
To a solution of Example 3b (1.12 g, 6.03 mmol) in dimethylformamide (60.3 mL) was added N-iodosuccinimide (1.49 g, 6.63 mmol). The reaction mixture was stirred at ambient temperature for 90 minutes. The reaction mixture was quenched with 10% sodium thiosulfate and saturated aqueous sodium bicarbonate, and extracted with ethyl acetate three times. The combined organic layers were washed with saturated aqueous sodium chloride, dried with anhydrous magnesium sulfate, filtered, and concentrated. Water was added to the residue, and the mixture was stirred at ambient temperature for 10 minutes and filtered to give the title compound (1.55 g, 83%).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[C:9]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([NH:23][NH2:24])=[O:22])=[CH:17][CH:16]=3)[C:10]([CH3:14])=[C:11]([F:13])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[Cl:25][CH2:26][C:27](OCC)(OCC)OCC>>[Cl:25][CH2:26][C:27]1[O:22][C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:9]3[C:10]([CH3:14])=[C:11]([F:13])[CH:12]=[C:7]([C:5]([NH:4][CH:1]4[CH2:3][CH2:2]4)=[O:6])[CH:8]=3)=[CH:16][CH:17]=2)=[N:23][N:24]=1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NN)cc1
Reactant: CCOC(CCl)(OCC)OCC
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CCl)o2)cc1

Procedure:
N-Cyclopropyl-5-fluoro-4′-(hydrazinocarbonyl)-6-methyl-1,1′-biphenyl-3-carboxamide (Intermediate 29) (580 mg) in 2-chloro-1,1,1-triethoxyethane (2.5 ml) was heated at 80° C. for 20 hours. The reaction was absorbed onto silica and purified by chromatography on a biotage column (silica, 40 g), eluting with cyclohexane and then with ethyl acetate/cyclohexane (2:3). The product fractions were reduced to dryness under vacuum to give 4′-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-5-fluoro-6-methyl-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1([C:6](O)=[O:7])[CH2:5][CH2:4]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].Cl>CCOCC>[F:1][C:2]([F:10])([F:9])[C:3]1([CH2:6][OH:7])[CH2:5][CH2:4]1
Reactant: O=C(O)C1(C(F)(F)F)CC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: OCC1(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
Treat a 0° C. solution of 1-(trifluoromethyl)cyclopropanecarboxylic acid (9 g, 58.4 mmol) in ether (140 mL), under N2, portion-wise with LAH (2.9 g, 76 mmol), allow to warm to RT and stir overnight. Re-cool to 0° C., slowly add HCl, warm to RT and separate the layers. Extract the aqueous layer with ether (2×), wash the combined organics with brine, dry over Na2SO4 and concentrate under reduced pressure (water bath temp<30° C.) to afford the title compound (7 g, 86%). 1HNMR (400 MHz, DMSO-d6): δ 4.94 (t, J=6.0 Hz, 1H), 3.54 (d, J=6.0 Hz, 2H), 0.87-0.84 (m, 2H), 0.81-0.79 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[I-].[CH3:11][S+](C)C.[OH-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[CH2:11][O:5]1
Reactant: C[S+](C)C
Reactant: O=Cc1ccccc1Cl
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Clc1ccccc1C1CO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Chloro-benzaldehyde (5 mL, 44 mmol) was dissolved in dichloromethane (45 mL) and treated with trimethylsulfonium iodide (10.25 g, 49.28 mmol) and aqueous sodium hydroxide solution (50%, 44 g) subsequently. The mixture was stirred vigorously at room temperature for overnight. The organic phase was separated and concentrated to give clear oil, which was stored in the refrigerator and used directly without further purification.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[C:10]1([N:16]=[C:17]=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:17](=[O:18])[NH:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:2]2
Reactant: OC1CN2CCC1CC2
Reactant: O=C=Nc1ccccc1
Product: O=C(Nc1ccccc1)OC1CN2CCC1CC2
Yield: 86 %

Procedure:
1-Azabicyclo[2.2.2]octan-3-ol and phenyl isocyanate were used. The residual solid resulting from the above described procedure was purified via column chromatography eluting with a 1:10 ratio of methanol:chloroform to afford the title compound (86%) as a white solid: NMR (CDCl3) δ7.60-7.0 (m, 5H, Ph), 4.81 (m, 1H, CH--OCO), 3.27 (m, 1H, one of NCH2C--O), 2.9 (m, 5H, N(CH2)2 and one of NCH2C--O), 2.1 (m, 1H, methine at C4), 2.05-1.30 (m, 4H, CH2 at C5 and C8); FAB LRMS m /z (relative intensity, %) 247 ([MH+ ], 100).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]([O:8][CH3:9])=[O:7])#[N:4].[CH3:10][O:11][CH:12]([O:15][CH3:16])[CH2:13]Br.[Na+].[Br-]>CN(C)C=O.C1C=CC=CC=1>[C:3]([CH:5]([CH2:13][CH:12]([O:15][CH3:16])[O:11][CH3:10])[C:6]([O:8][CH3:9])=[O:7])#[N:4]
Reactant: COC(CBr)OC
Reactant: COC(=O)CC#N
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: COC(=O)C(C#N)CC(OC)OC
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A vigorously stirred suspension of sodium hydride (36 g, 1.5 mole) in a mixture of 1400 ml of anhydrous N,N-dimethylformamide and 450 ml of anhydrous benzene was cooled to -10° C. under an argon atmosphere and methyl cyanoacetate (163.5 g, 1.65 mole) dissolved in 150 ml of anhydrous benzene was added dropwise over a period of 60 minutes. The temperature of this solution was allowed to slowly reach the room temperature and further stirred for 60 minutes until all the sodium hydride dissolved. A solution of bromoacetaldehyde dimethyl acetal (228.2 g, 1.35 mole) was added at once and the temperature of the reaction mixture was slowly rised to about 100° C. over a period of 60 minutes and further maintained for additional 120 minutes until the precipitation of all NaBr occurred. The solution was filtered, and the filtrate was concentrated to a small volume by evaporation under vacuum and then partitioned between ether and water. The ether portion was washed with water, dried over anhydrous Na2SO4 which was then removed by filtration, and evaporated to leave a liquid residue. This liquid was distilled at reduced pressure. The fraction distilling at 65°-68° C. and 0.15 Torr was collected yielding 83.2 g (32.9% theory).