Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C:6]1[NH:10][CH:9]=[N:8][C:7]=1[CH3:11])=[O:5])C.C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21]>>[F:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH:21][C:4]([C:6]1[N:10]=[CH:9][NH:8][C:7]=1[CH3:11])=[O:5]
Reactant: CCOC(=O)c1[nH]cnc1C
Reactant: Nc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1[nH]cnc1C(=O)Nc1ccccc1F
Temperature: 25 °C

Procedure:
To ethyl-4-methyl-5-imidazolecarboxylate (5 g, 32.4 mmol) was added 20 mL of 2-fluoroaniline and potassium carbonate (8.9 g, 64.8 mmol). The reaction mixture was heated to reflux for 18 h then cooled to room temperature and concentrated in vacuo. Water and hexane were added and the precipitate filtered to give the crude product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:13][NH:12][C:11](=[O:14])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[OH-:16].[Na+]>C(#N)C>[NH2:12][CH2:13][C@@H:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Br:1])[CH:3]=1)[CH2:10][C:11]([OH:14])=[O:16]
Reactant: [OH-]
Reactant: O=C1C[C@H](c2ccc(Cl)c(Br)c2)CN1
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Product: NC[C@H](CC(=O)O)c1ccc(Cl)c(Br)c1
Temperature: 95 °C
Yield: 30 %

Procedure:
To (4R)-4-(3-bromo-4-chlorophenyl)pyrrolidin-2-one (0.2 g, 0.73 mmol) was added 0.2 mL acetonitrile and 1 mL 6N HCl aqueous solution. The mixture was heated overnight at 95° C. The reaction mixture was then cooled to room temperature and neutralized with a 4N NaOH aqueous solution. The mixture was purified by reversed phase LC/MS to provide (3R)-4-amino-3-(3-bromo-4-chlorophenyl)butanoic acid (43 mg, 30% yield), which was then converted to the title compound as the hydrochloride salt by lyophilization from a 1N HCl aqueous solution. 1H-NMR (400 MHz, CD3OD): δ 7.68-7.69 d, J=2.00 Hz, 1H), 7.51-7.53 (d, J=8.44 Hz, 1H), 7.30-7.33 (dd, J=8.4, 2.44 Hz, 1H), 3.32-3.40 (m, 2H), 3.15-3.21 (m, 1H), 2.77-2.83 (dd, J=16.8, 6.4, 4 Hz, 1H), 2.63-2.69 (dd, J=16.4, 7.66 Hz, 1H); MS (ESI) m/z 293.89 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:24])([CH:16]([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][N:19]=1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.ClC1C=C(C=CC=1)C(OO)=[O:30]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:24])([CH:16]([C:18]1[CH:23]=[CH:22][N+:21]([O-:30])=[CH:20][N:19]=1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(c1ccncn1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Solvent: ClCCl
Product: CC(c1cc[n+]([O-])cn1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 18 h
Yield: 23.1 %

Procedure:
A solution of 2-(2,4-difluorophenyl)-3-(pyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (diastereoisomeric pair B from Example 3) (3.31 g) and 85% w/w 3-chloroperoxybenzoic acid (2.03 g) in dichloromethane (20 ml) was stirred at room temperature for 48 hours. An additional 2.03 g of 85% w/w 3-chloroperoxybenzoic acid was added and stirring was continued for a further 18 hours. Work up as described in Example 15(i) gave the title compound, (0.80 g), m.p. 157°-160°.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:43])[C:6]1[CH:11]=[CH:10][C:9]([N:12](C(OC(C)(C)C)=O)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21](F)(F)F)=[CH:16][CH:15]=2)=[C:8]([NH:32][C:33](=O)[CH2:34][O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:7]=1)[CH:2]=[CH2:3].Cl>CO.O1CCOCC1>[CH2:1]([O:4][C:5]([C:6]1[CH:11]=[CH:10][C:9]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:33]([CH2:34][O:35][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[N:32][C:8]=2[CH:7]=1)=[O:43])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1ccc(N(Cc2ccc(OC(F)(F)F)cc2)C(=O)OC(C)(C)C)c(NC(=O)COc2ccccc2)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C=CCOC(=O)c1ccc2c(c1)nc(COc1ccccc1)n2Cc1ccc(OC)cc1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
Crude 4-[tert-butoxycarbonyl-(4-trifluoromethoxy-benzyl)-amino]-3-(2-phenoxy-acetylamino)-benzoic acid allyl ester was dissolved in methanol and 4N HCl in dioxan added. The reaction was stirred at 40° C. for 16 h. The crude material was purified via reversed phase preparative HPLC. MS(ISP): 483.3 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=2[O:7][CH:8]=1)#[N:2].[H][H]>CO.[Ni]>[O:7]1[CH:8]=[C:4]([CH2:3][CH2:1][NH2:2])[C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][C:6]1=2
Reactant: N#CCc1coc2ccccc12
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: NCCc1coc2ccccc12
Yield: 69.2 %

Procedure:
To a solution of 3.1 g of 3-cyanomethylbenzo[b]furan in 40 mL of methanol was added 2.4 g of Raney nickel. The reaction was agitated at 25° C. in a Parr apparatus under 40 psi hydrogen for 21/2 hours. The suspension was filtered through a pad of filter aid and the filtrate was evaporated to give 2.2 g (71% yield) of oily product.
Reaction SMILES: Br[C:2]1[C:3]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=2)[N:5]([Si](C(C)C)(C(C)C)C(C)C)[CH:6]=1.Br[C:32]1[C:33](C2C=CN=CC=2)=[C:34]([C:47]2[CH:52]=[CH:51][C:50](F)=CC=2)[N:35]([Si](C(C)C)(C(C)C)C(C)C)[CH:36]=1.C1C2N(CCC(=O)C2)CC1.C(N1CCC(=O)CC1)C1C=CC=CC=1>>[F:24][C:19]1[CH:18]=[C:17]([C:4]2[NH:5][CH:6]=[C:2]([C:52]3[CH2:47][CH:34]4[N:35]([CH2:36][CH2:32][CH2:33]4)[CH2:50][CH:51]=3)[C:3]=2[C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[CH:22]=[CH:21][C:20]=1[F:23]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(Br)c(-c2ccncc2)c1-c1ccc(F)c(F)c1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(Br)c(-c2ccncc2)c1-c1ccc(F)cc1
Agent: O=C1CCN(Cc2ccccc2)CC1
Agent: O=C1CCN2CCCC2C1
Product: Fc1ccc(-c2[nH]cc(C3=CCN4CCCC4C3)c2-c2ccncc2)cc1F

Procedure:
In a similar manner to the procedures described in Examples 9(i) and 9(iii) above, coupling, dehydration and desilylation reactions were carried out using 4-bromo-2-(3,4-difluorophenyl)-3-(pyridin-4-yl)-1-triisopropylsilyl-1H-pyrrole (prepared as described in Preparative Example 5 below), instead of 4-bromo-2-(4-fluorophenyl)-3-(pyridin-4-yl)-1-triisopropylsilyl-1H-pyrrole, and (±)-1,2,3,5,6,7,8,8a-octahydroindolizine-7-one, instead of 1-benzylpiperidine-4-one, as starting materials to afford a mixture of the title compound and the (1,2,3,5,6,8a-hexahydroindolizin-7-yl) isomer thereof (which is the compound of Example 92 below). The mixture was separated by chromatography on a silica gel column using a 100:10:1 by volume mixture of ethyl acetate, methanol and isopropylamine as the eluant to give the title compound (yield 29%, Rf value=0.66) as a pale pink powder.
Reaction SMILES: C(S[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([C@@H]1CCCC[C@H]1O)[C:14](=[O:26])[CH:13]=[CH:12]2)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].O1CCCC1.IC.[Cl-].[NH4+]>CCOC(C)=O>[NH:15]1[C:16]2[C:11](=[CH:10][CH:9]=[CH:18][CH:17]=2)[CH:12]=[CH:13][C:14]1=[O:26]
Reactant: O=c1ccc2cc(SCc3ccccc3)ccc2n1[C@@H]1CCCC[C@H]1O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CI
Product: O=c1ccc2ccccc2[nH]1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 76.6 %

Procedure:
A 10-mL RBF was charged with 6-(benzylthio)-1-((1R,2R)-2-hydroxycyclohexyl)quinolin-2(1H)-one (150 mg, 0.410 mmol) and purged with nitrogen for 10 min. TI-IF (2.1 mL) was introduced and the resultant solution cooled to −78° C. A solution of potassium bis(trimethylsilyl)amide in tetrahydrofuran (1.0M, 451 μl, 0.451 mmol) was added dropwise to the stirred reaction mixture over 2 min via syringe to produce a dark purple solution. After 15 min, iodomethane (28.0 μl, 0.451 mmol) was added dropwise via syringe and the resultant reaction mixture was allowed to warm to 0° C. After 15 min, a solution of saturated aqueous ammonium chloride was added and the reaction mixture was allowed to warm to ambient temperature and diluted with EtOAc (10 mL). The layers were separated, and the aqueous layer was further extracted with. EtOAc (3×10 mL). The combined organic layers were then washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (25-g Biotage column, eluent: gradient, 0 to 20% EtOAc in heptane) to afford (±)-6-(benzylthio)-141R,2R)-2-methoxycyclohexyl)quinolin-2(1H)-one (119 mg, 0.314 mmol, 76% yield) as a yellow solid. m/z (ESI) 380.2 (M+H)+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:18](=[O:20])[CH3:19])=[CH:9][C:10]([Cl:17])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)(=O)=O.Cl.[CH3:24][O:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:17][C:10]1[CH:9]=[C:8]([C:18](=[O:20])[CH3:19])[C:7]([N:29]2[CH2:30][CH2:31][CH:26]([O:25][CH3:24])[CH2:27][CH2:28]2)=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1OS(=O)(=O)C(F)(F)F
Reactant: COC1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC1CCN(c2c(C(C)=O)cc(Cl)c3cccnc23)CC1
Yield: 19 %

Procedure:
A stirred mixture of 7-acetyl-5-chloroquinolin-8-yl trifluoromethanesulfonate (0.12 g, 0.34 mmol, from Example 47, Step 2), 4-methoxypiperidine hydrochloride (0.062 g, 0.41 mmol), palladium acetate (1.5 mg, 0.0067 mmol), (S)-(+2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (6.3 mg, 0.010 mmol), and cesium carbonate (0.42 g, 1.3 mmol) in tetrahydrofuran (4 mL) was heated at 65° C. overnight. The mixture was cooled, diluted with dichloromethane and filtered. The filtrate was washed with brine, dried over MgSO4 and evaporated to dryness. The residue was purified on silica gel (eluting with 0 to 5% methanol in dichloromethane) to give the desired product (20.6 mg, 19%). LCMS calculated for C17H20ClN2O2 (M+H)+: m/z=319.1; Found: 319.1.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].O.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([O:17][OH:18])=[O:16])[CH:10]=1.[Cl:19][CH:20]([CH2:24][CH3:25])[C:21](Cl)=[O:22]>C(Cl)(Cl)Cl>[Cl:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[C:15]([O:17][O:18][C:21](=[O:22])[CH:20]([Cl:19])[CH2:24][CH3:25])=[O:16]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCC(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCC(Cl)C(=O)OOC(=O)c1cccc(Cl)c1
Temperature: -2 °C
Yield: 97.7 %

Procedure:
To 6.4 g. (0.06 moles) anhydrous sodium carbonate in 60 cc. H2O was added 10.2 g. (0.05 moles) of m-chloroperbenzoic acid of 84.35% purity. The stirred mixture was chilled to -2° C. and 8.5 g. (0.06 moles) 2-chlorobutyryl chloride in 30 cc. chloroform was added over 17 minutes. After a total reaction time of 60 minutes, the reaction was worked up as in Example I and gave 15.2 g. product. Product A.O. analysis: theory, 5.77; found, 5.15; 89.30% pure; 97.7% yield.
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl.Cl.[NH2:36][C:37]1[N:45]=[C:44]([O:46][CH2:47][CH2:48][CH2:49][CH3:50])[N:43]=[C:42]2[C:38]=1[NH:39][C:40](=[O:62])[N:41]2[CH2:51][CH2:52][CH2:53][NH:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1.CCN(CC)CC.[CH3:70][O:71][C:72](=[O:78])[CH2:73][CH2:74][C:75](O)=[O:76]>CN(C=O)C.CO>[NH2:36][C:37]1[N:45]=[C:44]([O:46][CH2:47][CH2:48][CH2:49][CH3:50])[N:43]=[C:42]2[C:38]=1[NH:39][C:40](=[O:62])[N:41]2[CH2:51][CH2:52][CH2:53][N:54]([CH2:55][C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)[C:75](=[O:76])[CH2:74][CH2:73][C:72]([O:71][CH3:70])=[O:78]
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCNCc3ccccc3)c2n1
Reactant: COC(=O)CCC(=O)O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(Cc3ccccc3)C(=O)CCC(=O)OC)c2n1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
PyBop (0.47 g) was added to a mixture of the product from example 1 step (viii) (0.25 g), Et3N (0.7 ml) and succinic acid monomethyl ester (0.16 g) in DMF (8 ml) and stirred at rt for 4 days. MeOH (10 ml) was added, the solvent evaporated under reduced pressure and the residue purified by RPHPLC, yield 46 mg.
Reaction SMILES: [Cl:1][C:2]1[C:15]([S:16]([C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)(=[O:18])=[O:17])=[CH:14][C:5]2[O:6][CH:7]([C:9]([O:11]CC)=[O:10])[O:8][C:4]=2[CH:3]=1.[OH-].[Na+].Cl>>[Cl:1][C:2]1[C:15]([S:16]([C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)(=[O:18])=[O:17])=[CH:14][C:5]2[O:6][CH:7]([C:9]([OH:11])=[O:10])[O:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)C1Oc2cc(Cl)c(S(=O)(=O)c3cc(Cl)cc(Cl)c3)cc2O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1Oc2cc(Cl)c(S(=O)(=O)c3cc(Cl)cc(Cl)c3)cc2O1

Procedure:
21.9 g (0.05 mole) of ethyl 5-chloro-6-(3,5-dichlorophenylsulfonyl)-1,3-benzodioxole-2-carboxylate are covered with 75 ml of 2-n sodium hydroxide solution and the batch is heated for 1 hour in a boiling water bath, cooled, acidified with hydrochloric acid and then extracted with ethyl acetate. The extract is concentrated by evaporation, affording 5-chloro-6-(3,5-dichlorophenylsulfonyl)-1,3-benzodioxole-2-carboxylic acid. Melting point 166°-169° C. (crystallisation from ethyl acetate/toluene).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10](Cl)=[O:11])[CH:6]=[CH:7][CH:8]=1.[NH2:13][C:14]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17]>ClCCl>[Cl:24][C:22]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([NH:13][C:10](=[O:11])[CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:23]=1
Reactant: COC(=O)c1ccc(Cl)cc1N
Reactant: COc1cccc(CC(=O)Cl)c1
Solvent: ClCCl
Product: COC(=O)c1ccc(Cl)cc1NC(=O)Cc1cccc(OC)c1
Yield: 90.5 %

Procedure:
3-Methoxyphenylacetyl chloride (1.11 g, 6 mmol) was added to methyl 2-amino-4-chlorobenzoate (0.93 g, 5 mmol) in dichloromethane (30 ml) and the solution stirred under reflux for 18 h. The oily residue remaining on evaporation of the solvent was triturated with diethyl ether to afford methyl 4-chloro-2-(3-methoxyphenyl)acetamidobenzoate as a colourless solid (1.51 g), m.p. 144°-146° C.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([CH:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20](OCC)=[O:21])[CH2:15][CH2:14]3)=[O:12])[CH2:10][CH:5]2[C:4]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:3]1.[H-].[Li+].[Al+3].[H-].[H-].[H-].C(OCC)(=O)C>O1CCCC1.O>[OH:21][CH2:20][CH2:19][N:16]1[CH2:15][CH2:14][CH:13]([C:11]([N:9]2[CH2:8][CH2:7][N:6]3[C:2](=[O:1])[O:3][C:4]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:5]3[CH2:10]2)=[O:12])[CH2:18][CH2:17]1
Reactant: CCOC(=O)CN1CCC(C(=O)N2CCN3C(=O)OC(c4ccccc4)(c4ccccc4)C3C2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(C1CCN(CCO)CC1)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 21.4 %

Procedure:
To a solution of ethyl [4-[(tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-7(1H)-yl)carbonyl]piperidin-1-yl]acetate (0.13 g, 0.26 mmol) in tetrahydrofuran (3 mL) was added aluminum lithium hydride (10 mg, 0.26 mmol) at 0° C., and the mixture was stirred at 0° C. for 30 minutes. An excessive amount of ethyl acetate was added thereto, and the mixture was further stirred at 0° C. for 5 minutes. The reaction solution was diluted with water and then extracted with ethyl acetate. The organic layer was washed with a 1 N aqueous sodium hydroxide solution, water and saturated brine, and dried over magnesium sulfate. The solid was filtered off, and the filtrate was concentrated. The residue was purified with amino silica gel column chromatography (ethyl acetate to ethyl acetate:methanol=9:1), and then recrystallized from diisopropyl ether-ethyl acetate to obtain the title compound (25 mg, yield 21%).
Reaction SMILES: [F:1][CH:2]([F:15])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[C:5]=1[C:6]#[N:7].[Sn](Cl)Cl.Cl.[OH-].[Na+]>C(O)(C)C.O>[NH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:4]([O:3][CH:2]([F:1])[F:15])[C:5]=1[C:6]#[N:7]
Reactant: N#Cc1c(OC(F)F)cccc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: N#Cc1c(N)cccc1OC(F)F
Temperature: 25 °C
Yield: 121 %

Procedure:
To a solution of 2-difluoromethoxy-6-nitro-benzonitrile (4.0 g, 14.9 mmol) (Example I3) in isopropanol (100 ml) is added tin(II) chloride (10.2 g, 53.6 mmol). Aqueous hydrochloric acid (concentrated) (14.4 ml) is added slowly and the reaction mixture is heated to reflux for 30 minutes. The reaction mixture is cooled to room temperature, diluted with water and the pH is adjusted to 10 by addition of NaOH (2M). The mixture is extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated to yield 2-amino-6-difluoromethoxy-benzonitrile (3.32 g, 93% yield) in pure form. 1H-NMR (CDCl3, 400 MHz): 7.05 (t, 1H), 6.65 (d, 1H), 6.55 (t, 1H), 6.50 (t, 1H), 4.25 (s, br, 2H) ppm.
Reaction SMILES: [NH:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[NH2:2].[CH2:13]([O:15][CH2:16][CH2:17][C:18](O)=O)[CH3:14].[OH-].[Na+]>>[CH2:13]([O:15][CH2:16][CH2:17][C:18]1[N:4]2[C:5]3[C:10]([CH:11]=[CH:12][C:3]2=[N:1][N:2]=1)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH3:14]
Reactant: CCOCCC(=O)O
Reactant: NNc1ccc2ccccc2n1
Agent: [Na+]
Agent: [OH-]
Product: CCOCCc1nnc2ccc3ccccc3n12

Procedure:
2-Hydrazinoquinoline (50.0 grams; about 0.3 mole) and 3-ethoxypropionic acid (100 grams; about 0.85 mole) were mixed and refluxed for eight hours. The reaction mixture was then allowed to cool and made basic with 50 percent sodium hydroxide. A precipitate, the desired 1-(2-ethoxyethyl)-s-triazolo(4,3-a)quinoline, formed. It was separated by filtration and recrystallized from ethanol, m.p., 93°C. The identity of the product was confirmed by NMR and by microanalysis.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[CH3:13])=[C:2]=[O:3].[Cl:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19]>C1(C)C=CC=CC=1>[CH3:13][C:5]1[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:4]=1[NH:1][C:2](=[O:3])[O:19][CH2:18][CH2:17][CH2:16][CH2:15][Cl:14]
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=O
Reactant: OCCCCCl
Solvent: Cc1ccccc1
Product: Cc1cc([N+](=O)[O-])ccc1NC(=O)OCCCCCl

Procedure:
17.8 g (0.10 mol) 4-isocyanato-3-methyl-1-nitro-benzene are placed in 750 ml of toluene and a solution of 11.7 ml (0.10 mol) 4-chloro-butan-1-ol in 50 ml of toluene is added dropwise. Then the reaction mixture is heated for 16 hours to 75° C., then evaporated down i. vac. and twice taken up with toluene and concentrated by evaporation completely i. vac. The residue is purified by recrystallisation from cyclohexane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([NH:22][NH2:23])[C:3]=1[O:24][CH3:25].[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1.C(N(CC)CC)C.O>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:17])([F:19])[F:18])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([NH:22][NH:23][C:29]([CH:26]2[CH2:28][CH2:27]2)=[O:30])[C:3]=1[O:24][CH3:25]
Reactant: O=C(Cl)C1CC1
Reactant: COc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1NN
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1NNC(=O)C1CC1
Reaction time: 1 h

Procedure:
3-[4-chloro-2-diazanyl-6-fluoro-3-methoxyphenyl]-1-methyl-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (0.15 g, 0.4 mmol) was dissolved in dioxane (10 ml) and added with cyclopropanecarbonyl chloride (0.04 g, 0.4 mmol) and triethylamine (0.04 g, 0.4 mmol). After stirred for 1 hr, the mixture was poured into water (15 ml) and extracted with ethyl acetate (10 ml×3). Organic phase was washed with brine and dried over Na2SO4. Final purification involved column chromatography (silica gel, ether). Yield: 0.15 g, 0.34 mmol.
Reaction SMILES: C1CCC=CC=1.O.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][N:24]2C(OCC2C=CC=CC=2)=O)=[O:22])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>CCO.[Pd]>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][NH:24]2)=[O:22])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)C2CCCCN2C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: O
Solvent: CCO
Solvent: C1=CCCC=C1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)C2CCCCN2)CC1
Reaction time: 24 h
Yield: 82.7 %

Procedure:
3.9 ml of cyclohexadiene and then 1.3 g of 10% Pd/C with a 50% water content are added, under an inert atmosphere, to a solution of 1.79 g of the compound obtained in step 5.1, in 14 ml of EtOH. The medium is stirred at AT for 24 hours and then filtered. The filtrate is evaporated, to give 1.02 g of the desired compound.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]#[C:4][C:5]([F:8])([F:7])[F:6].[CH3:11][C:12]1[O:13][CH:14]=[CH:15][CH:16]=1>>[CH3:11][C:12]12[O:13][CH:14]([CH:15]=[CH:16]1)[C:3]([C:2]([F:10])([F:9])[F:1])=[C:4]2[C:5]([F:8])([F:7])[F:6]
Reactant: FC(F)(F)C#CC(F)(F)F
Reactant: Cc1ccco1
Product: CC12C=CC(O1)C(C(F)(F)F)=C2C(F)(F)F
Yield: 91.4 %

Procedure:
Hexafluoro-2-butyne (21.0 g, 0.13 mol) was transferred into a reaction bottle and 2-methylfuran (12.86 g, 0.157 mol) was added. This resulting mixture bottle was sealed and heated for 15 hr. at 120° C. After cooling, the excess 2-methylfuran was rotoevaporated in vacuo at rt, to give crude title product (29 g, 92%), which was used directly.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([O:8][CH2:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:11]=2[C:12]([O-:14])=[O:13])[CH2:3]1.[C:20]([O-])(=O)C>>[OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([O:8][CH2:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:11]=2[C:12]([O:14][CH3:20])=[O:13])[CH2:3]1
Reactant: CC(=O)[O-]
Reactant: Cc1cccc(CO[C@H]2CCC[C@@H](O)C2)c1C(=O)[O-]
Product: COC(=O)c1c(C)cccc1CO[C@@H]1CCC[C@H](O)C1

Procedure:
The enantiomer 2-((1S,3R)-3-hydroxycyclohexyloxymethyl)-6-methylbenzoate is generated from the acetate obtained in the chromatography forerun after saponification and re-methylation, and is used to prepare the corresponding enantiomeric example structures.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][N:3]=1.[CH3:10][Mg]Br.O.[Cl-].[NH4+]>C1COCC1.CCOC(C)=O>[F:1][C:2]1[N:3]=[CH:4][C:5]([CH:6]([OH:7])[CH3:10])=[CH:8][CH:9]=1
Reactant: O=Cc1ccc(F)nc1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1ccc(F)nc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a stirred mixture of 6-fluoronicotinaldehyde (Frontier Science, 3.14 g, 25.1 mmol) in THF (40 mL) in 250 mL round-bottomed flask, methylmagnesium bromide (Aldrich, 3 M in diethyl ether, 9.21 mL, 27.6 mmol) was added dropwise at about 5 to 10° C. The mixture was stirred at about 5° C. for 30 min. A mixture of water (30 mL) and saturated aqueous ammonium chloride (30 mL) was added slowly and EtOAc (20 mL) was added. The layers were separated. The aqueous phase was extracted with EtOAc (2×60 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (100 g, eluent: EtOAc in hexanes 20% to 70%) to afford (2.30 g, 65% yield) as a clear oil. 1H NMR (400 MHz, CDCl3) δ ppm 8.19 (d, J=1.76 Hz, 1H) 7.85 (td, J=8.07, 2.45 Hz, 1H) 6.92 (dd, J=8.41, 2.93 Hz, 1H) 4.94-5.02 (m, 1H) 2.00 (d, J=3.72 Hz, 1H) 1.53 (d, J=6.46 Hz, 3H). m/z (ESI, positive ion): 142.1 (M+H)+.