Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[CH:5]2.[F:17][CH:18]([F:35])[O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]2[N:28]=[N:29][C:30]([CH:33]=[CH2:34])=[CH:31][CH:32]=2)=[CH:22][CH:21]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[F:35][CH:18]([F:17])[O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]2[N:28]=[N:29][C:30](/[CH:33]=[CH:34]/[C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[N:7]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[N:6]=[CH:5]4)=[CH:31][CH:32]=2)=[CH:22][CH:21]=1
Reactant: Ic1ccc2c(cnn2C2CCCCO2)c1
Reactant: C=Cc1ccc(Nc2ccc(OC(F)F)cc2)nn1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: FC(F)Oc1ccc(Nc2ccc(/C=C/c3ccc4c(cnn4C4CCCCO4)c3)nn2)cc1
Temperature: 90 °C

Procedure:
To a solution of 5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.1 g, 0.305 mmol) in ACN (5 mL) were added N-(4-(difluoromethoxy)phenyl)-6-vinylpyridazin-3-amine (0.080 g, 0.305 mmol), tri-o-tolylphosphine (0.037 g, 0.122 mmol), and triethylamine (0.127 mL, 0.914 mmol). The reaction mixture was purged with nitrogen for 5 min. Tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (0.032 g, 0.030 mmol) was added and the reaction mixture was heated at 90° C. for 18 h. The reaction mixture was filtered through a pad of celite and rinsed with ethyl acetate. The organic layer was concentrated and purified by flash chromatography on silica gel using ethyl acetate/hexane to give (E)-N-(4-(difluoromethoxy)phenyl)-6-(2-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)vinyl)pyridazin-3-amine as apale yellow solid (0.13 g, 87%). LCMS (ES-API), m/z 464.6 (M+H).
Reaction SMILES: C(C1C=C([C:15]2[C:16]([O:21][CH3:22])=[N:17][CH:18]=[CH:19][CH:20]=2)C=CC=1OC(F)F)(C)(C)C.[CH3:23][CH2:24]OC(C)=O>CCO.[Pd]>[CH2:23]([C:18]1[CH:19]=[CH:20][CH:15]=[C:16]([O:21][CH3:22])[N:17]=1)[CH3:24]
Reactant: CCOC(C)=O
Reactant: COc1ncccc1-c1ccc(OC(F)F)c(C(C)(C)C)c1
Agent: [Pd]
Solvent: CCO
Product: CCc1cccc(OC)n1
Reaction time: 0.75 h

Procedure:
step 2—A mixture of 22 (1.95 g) and Pd/C (10% wt. on carbon, 50 mg) in EtOAc (15 mL) and EtOH (15 mL) at RT was stirred under 1 atmosphere of H2 for 45 min. The catalyst was filtered off and the filtrate was concentrated. The crude residue was purified by SiO2 chromatography eluting with a EtOAc/hexane gradient (0 to 5% EtOAc) to afford 560 mg of 2-ethyl-6-methoxypyridine (26) as a colorless oil.
Reaction SMILES: N[C:2]1[C:3](SC(C)(C)C)=[N:4][C:5](C)=[C:6](CC)[CH:7]=1.BrC[C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1.[CH:28]([N:31](C(C)C)CC)(C)C>C(#N)C>[C:21]1([CH2:28][NH:31][C:3]2[CH:2]=[CH:7][CH:6]=[CH:5][N:4]=2)[C:20]2[C:25](=[CH:26][CH:27]=[CH:18][CH:19]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: BrCc1ccc2ccccc2c1
Reactant: CCc1cc(N)c(SC(C)(C)C)nc1C
Solvent: CC#N
Product: c1ccc(NCc2cccc3ccccc23)nc1
Yield: 62.4 %

Procedure:
A mixture of 3-amino-2-tert-butylthio-5-ethyl-6-methylpyridine (0.15 g, 0.67 mmol), 2-bromomethyl-napthalene (0.15 g, 0.67 mmol), diisopropylethylamine (86 mg, 0.67 mmol) in acetonitrile (5 mL) was refluxed under an atmosphere of nitrogen for 16 hours. The resultant mixture was concentrated under reduced pressure (15 (torr). The residue was subjected to column chromatography on silica gel (50, elution with 1% methanol in chloroform). Collection and concentration of appropriate fractions provided 98 mg (40%) of the napthylmethylaminopyridine.
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12].[N+:14]([C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20](Cl)=[O:21])([O-:16])=[O:15]>>[N+:14]([C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20]([C:11]([OH:12])([C:20](=[O:21])[C:19]1[CH:23]=[CH:24][CH:25]=[C:17]([N+:14]([O-:16])=[O:15])[CH:18]=1)[CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:13])=[O:21])([O-:16])=[O:15]
Reactant: OCCOCCOCCOCCO
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Product: O=C(c1cccc([N+](=O)[O-])c1)C(O)(COCCOCCOCCO)C(=O)c1cccc([N+](=O)[O-])c1

Procedure:
Tetraethylene glycol (58.2 g, 0.3 mole) was treated with m-nitrobenzoyl chloride, following the general procedure described in Example 1, Part A. After the usual work-up, the product was crystallized from ethyl acetate/hexanes at -20° C. for 3 days to give bis-(3-nitrobenzoyl)-tetraethylene glycol (110 g) as a pale yellow solid, m.p. 38°-40° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.Br[C:13]1[CH:14]=[C:15]([C:33]([OH:42])([C:38]([F:41])([F:40])[F:39])[C:34]([F:37])([F:36])[F:35])[CH:16]=[CH:17][C:18]=1[N:19]1[CH2:24][CH2:23][N:22]([S:25]([C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)(=[O:27])=[O:26])[CH2:21][CH2:20]1>>[F:41][C:38]([F:39])([F:40])[C:33]([C:15]1[CH:16]=[C:17]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:18]([N:19]2[CH2:24][CH2:23][N:22]([S:25]([C:28]3[S:29][CH:30]=[CH:31][CH:32]=3)(=[O:26])=[O:27])[CH2:21][CH2:20]2)=[CH:13][CH:14]=1)([OH:42])[C:34]([F:37])([F:36])[F:35]
Reactant: O=S(=O)(c1cccs1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2Br)CC1
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-c2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2N2CCN(S(=O)(=O)c3cccs3)CC2)c1

Procedure:
Following the procedure outlined for Example 69, 3-methoxyphenylboronic acid (26.4 mg, 0.173 mmol, Aldrich, St. Louis, Mo.) was coupled to 2-(3-bromo-4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol to afford 1,1,1,3,3,3-hexafluoro-2-(3′-methoxy-6-(4-(2-thiophenylsulfonyl)-1-piperazinyl)-3-biphenylyl)-2-propanol. 1H NMR (400 MHz, CD3OD) δ 7.91 (dd, J=4.9, 1.2 Hz, 1H), 7.61-7.54 (m, 2H), 7.49 (d, J=1.2 Hz, 1H), 7.40 (d, J=8.8 Hz, 2H), 7.28 (dd, J=4.9, 3.9 Hz, 1H), 7.11 (d, J=8.6 Hz, 1H), 6.87 (d, J=8.6 Hz, 2H), 3.81 (s, 3H), 2.95 (br. s, 8H). m/z (ESI, +ve ion) 580.8 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=3.34 μM; GK-GKRP EC50 (LC MS/MS)=1.82 μM.
Reaction SMILES: C([C:4]1[C:13]([CH2:14][O:15][CH:16]2[CH2:21]CCC[O:17]2)=[N+:12]([O-:22])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N+:5]=1[O-:23])(=O)C>C(O)(=O)C>[OH:17][C:16]1([CH3:21])[C:4]2=[N+:5]([O-:23])[C:6]3[C:11]([N+:12]([O-:22])=[C:13]2[CH2:14][O:15]1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: CC(=O)c1c(COC2CCCCO2)[n+]([O-])c2ccccc2[n+]1[O-]
Solvent: CC(=O)O
Product: CC1(O)OCc2c1[n+]([O-])c1ccccc1[n+]2[O-]
Yield: 84 %

Procedure:
A mixture of 0.578 g. (1.8 mmol.) of 2-acetyl-3-(2-tetrahydropyranyloxymethyl)quinoxaline 1,4-dioxide and 5.7 ml. of 40% aqueous acetic acid (prepared by mixing 40 parts of glacial acetic acid and 60 parts of water) was maintained at 40° C. for 3 hours. The solvents were removed by evaporation in vacuo. To the residue was added a small quantity of ethyl acetate, which was then removed by evaporation in vacuo. This procedure of adding ethyl acetate and then removing it by evaporation in vacuo was repeated several times. The residue was then washed with methyl isobutyl ketone, which finally afforded 0.354 g. (84% yield) of 1-hydroxy-1-methyl-1,3-dihydrofuro[3,4-b]quinoxaline 4,9-dioxide, m.p. 160°-162° C. (dec.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([Cu])#[N:25]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:12]=[CH:11][C:10]=1[N:16]1[CH2:17][C:18](=[O:23])[NH:19][S:20]1(=[O:22])=[O:21])[C:24]#[N:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: N#Cc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Temperature: 110 °C

Procedure:
To a solution of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (108.4 mg, 0.243 mmol) in DMF (2 mL) is added KHCO3 (0.488 mL, 0.5M aqueous solution), CuCN (19 mg, 0.212 mmol) and resin-bound PPh3Pd (10 mol %) in DMF (2 mL) and the mixture is heated in a microwave apparatus at 110° C. for 20 min. The solvent is removed under reduced pressure and the residue purified by reverse phase MPLC to give the title compound.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[CH:16][C:17]=2[O:19][CH3:20])[C:12]([C:23](=[O:34])[N:24]([CH3:33])[CH:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:26])=[CH:11][N:10]=1)(C)(C)C.[ClH:36]>CCOC(C)=O>[ClH:36].[CH3:33][N:24]([CH:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:26])[C:23]([C:12]1[C:13]2[C:18](=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=2)[C:9]([CH2:8][NH2:7])=[N:10][CH:11]=1)=[O:34]
Reactant: COc1cc(OC)c2c(CNC(=O)OC(C)(C)C)ncc(C(=O)N(C)C(C)c3ccccc3)c2c1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1cc(OC)c2c(CN)ncc(C(=O)N(C)C(C)c3ccccc3)c2c1
Yield: 97 %

Procedure:
As described in example 1, 112 mg of {6,8-dimethoxy-4-[methyl-(1-phenyl-ethyl)-carbamoyl]-isoquinolin-1-ylmethyl}-carbamic acid tert-butyl ester was treated with HCl in EtOAc to give 86 mg (97%) of 1-aminomethyl-6,8-dimethoxy-isoquinoline-4-carboxylic acid methyl-(1-phenyl-ethyl)-amide hydrochloride. MS: APCI (M+H) calc'd for C22H25N3O3+H 380.5; found 380.2.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:7]2[CH:8]=[C:9]([C:12]3[N:17]=[C:16]([CH2:18][C:19]#[N:20])[CH:15]=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=O)[O:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>CC1C=CC(C)=CC=1>[CH3:1][C:2]1([CH3:22])[C:7]2[CH:8]=[C:9]([C:12]3[N:17]=[C:16]([CH2:18][C:19]#[N:20])[CH:15]=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[S:32])[O:3]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cccc(CC#N)n3)cc21
Solvent: Cc1ccc(C)cc1
Product: CC1(C)OC(=S)Nc2ccc(-c3cccc(CC#N)n3)cc21
Temperature: 25 °C
Yield: 92.3 %

Procedure:
To [6-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)pyridin-2-yl]acetonitrile (80 mg, 0.27 mmol, 1 eq) in p-xylene (10 mL) was added Lawesson's reagent (55 mg, 0.14 mmol, 0.5 eq) and the reaction was heated to reflux for 2 hours. The reaction was cooled to room temperature and adsorbed onto silica gel. Purification by flash column chromatography (50% ethyl acetate/hexane) on silica gel gave the title compound (40 mg, 48%) as an off-white solid: mp 215-217° C.; 1H NMR (d6-DMSO, 300 MHz) δ 1.71 (s, 6H), 4.28 (s, 2H), 7.15 (d, 1H, J=8.3 Hz), 7.36 (d, 1H, J=7.3 Hz), 7.89-7.99 (m, 2H), 8.04-8.11 (m, 2H), 12.32 (s, 1H); MS (ESI) [M−H]−=308; Anal. Calcd. for C17H15N3OS: C, 66.00; H, 4.89; N, 13.58. Found: C, 64.43; H, 4.65; N, 12.95.
Reaction SMILES: [I-].[CH2:2]([N+:4]1[C:8]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:7]=2[S:6][C:5]=1[CH3:15])[CH3:3].[C:16](OC(=O)C)(=[O:18])[CH3:17].C(N(CC)CC)C>C(#N)C>[CH2:2]([N:4]1[C:8]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:7]=2[S:6]/[C:5]/1=[CH:15]\[C:16](=[O:18])[CH3:17])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC[n+]1c(C)sc2ccc(OC)cc21
Agent: [I-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCN1/C(=C/C(C)=O)Sc2ccc(OC)cc21
Temperature: 25 °C
Yield: 54.1 %

Procedure:
A series of benzothiazole compounds including TG003 were synthesized according to the procedures reported by Gupta et al. (27). In the case of TG003, a mixture of commercially available 5-methoxy-2-methylbenzothiazole (202 mg, 1.12 mmol) and ethyl iodide (2.70 ml, 33.7 mmol) was refluxed for 24.5 h. The precipitate was filtrated, washed with ethyl acetate (20 ml) on a funnel, and dried under reduced pressure to afford 3-ethyl-5-methoxy-2-methylbenzothiazolium iodide (270 mg, 0.805 mmol, 71.9%) as a pale green solid. To a suspension of 3-ethyl-5-methoxy-2-methylbenzothiazolium iodide (502 mg, 1.49 mmol) in acetonitrile (2.0 ml), acetic anhydride (330 μl, 3.49 mmol) and triethylamine (490 μl, 3.51 mmol) were successively added at room temperature. After refluxing for 2 h, the mixture was cooled to room temperature and concentrated under reduced pressure. Water (50 ml) was added to the residue, and the mixture was extracted with ethyl acetate (three times with 15 ml). The combined organic extracts were washed with brine (30 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (18 g, CH2Cl2/ethyl acetate, 4:1) to afford (Z)-1-(3-ethyl-5-methoxy-2,3-dihydrobenzothiazol-2-ylidene) propan-2-one (TG003) (201 mg, 0.806 mmol, 54.1%) as a pale yellow solid.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]1[CH:14]=[C:15]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([Cl:29])[CH:25]=3)[C:20]2=[O:30])[CH:16]=[N:17][CH:18]=1)(C)(C)C.Cl.O1CCOCC1>CO>[Cl:29][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:30])[N:19]([C:15]1[CH:16]=[N:17][CH:18]=[C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@H:8]3[CH2:7][OH:6])[CH:14]=1)[CH2:28][CH2:27]2
Reactant: CC(C)(C)[SiH2]OC(C)(C)[C@@H]1CCCN1c1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C1c2ccc(Cl)cc2CCN1c1cncc(N2CCC[C@H]2CO)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
To a solution of 2-{5-[(S)-2-(tert-butyl-dimethyl-silanyloxymethyl)-pyrrolidin-1-yl]-pyridin-3-yl}-6-chloro-3,4-dihydro-2H-isoquinolin-1-one (0.110 g, 0.233 mmol) in MeOH (2 mL) was added 4M HCl in dioxane (0.233 ml, 0.932 mmol) and the reaction mixture was stirred at room temperature for 2 h. The mixture was evaporated to dryness, the residue was diluted with DCM (20 mL) and washed with NaHCO3 (10 mL). The organic layer was dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 5% MeOH (1% NH4OH)-DCM gradient to give the title compound (0.06 g, 72%) as a light yellow solid. MS: 358.0 (M+H+).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:9]([CH3:10])[N:8]=[CH:7][C:6]=1[C:11]1[CH:39]=[CH:38][C:14]([C:15]([N:17]([C:31]2[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][N:32]=2)[C@@H:18]2[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]2)=[O:16])=[CH:13][CH:12]=1)=[O:4]>CO.[OH-].[K+]>[C:27]([O:26][C:24]([N:20]1[CH2:21][CH2:22][CH2:23][C@@H:18]([N:17]([C:31]2[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][N:32]=2)[C:15]([C:14]2[CH:38]=[CH:39][C:11]([C:6]3[CH:7]=[N:8][N:9]([CH3:10])[C:5]=3[C:3]([OH:4])=[O:2])=[CH:12][CH:13]=2)=[O:16])[CH2:19]1)=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: COC(=O)c1c(-c2ccc(C(=O)N(c3ncccc3C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc2)cnn1C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1cccnc1N(C(=O)c1ccc(-c2cnn(C)c2C(=O)O)cc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 70 °C
Reaction time: 1 h
Yield: 261 %

Procedure:
A suspension of the product of Step 1 of EXAMPLE 13, tert-butyl (3R)-3-[{4-[5-(methoxycarbonyl)-1-methyl-1H-pyrazol-4-yl]benzoyl}(3-methylpyridin-2-yl)amino]piperidine-1-carboxylate (0.85 g, 0.59 mmol) in MeOH (2 mL) and potassium hydroxide solution in MeOH (1.67 mL, 1M solution, 1.67 mmol) was heated to 70° C. in a sealed pressure tube for 2 h. The reaction mixture was then concentrated and toluene (10 mL) was added to the mixture. The solvents were evaporated in vacuo and dried under vacuum for 2 h. The solid was then slurried in methyl tert-butyl ether (15 mL) and heptanes (15 mL) for 1 h, collected via filtration and dried under vacuum for 16 h to afford 4-(4-{[(3R)-1-(tert-butoxycarbonyl)piperidin-3-yl](3-methylpyridin-2-yl)carbamoyl}phenyl)-1-methyl-1H-pyrazole-5-carboxylic acid (800 mg, 90%).
Reaction SMILES: [O:1]=[CH:2][C:3]([Cl:6])([Cl:5])[Cl:4].[CH3:7][C:8]1([C:11](=[O:18])[CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[CH2:10][CH2:9]1.C(O)(=O)C.C([O-])(=O)C.[Na+]>CCOCC.O>[Cl:4][C:3]([Cl:6])([Cl:5])[CH:2]([OH:1])[CH:12]([N:13]1[CH:17]=[N:16][CH:15]=[N:14]1)[C:11]([C:8]1([CH3:7])[CH2:9][CH2:10]1)=[O:18]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: CC1(C(=O)Cn2cncn2)CC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: O
Product: CC1(C(=O)C(C(O)C(Cl)(Cl)Cl)n2cncn2)CC1
Temperature: 45 °C
Reaction time: 8 h
Yield: 19.8 %

Procedure:
9.2 g (0.0625 mol) of chloral were added dropwise to 8.3 g (0.05 mol) of 1-methyl-1-(1,2,4-triazol-1-yl-acetyl)-cyclopropane, 20 ml of glacial acetic acid and 13.6 g (0.1 mol) of sodium acetate, the internal temperature increasing to approx. 45° C. The reaction mixture was stirred overnight at 80° C. and was thereafter cooled to room temperature and stirred with a mixture of 100 ml of water and 100 ml of ether. The resulting solid was filtered off under suction and recrystallized from methanol. 3.1 g (20% of theory) of 1,1,1-trichloro-2-hydroxy-3-(1,2,4-triazol-1yl)-4-(1-methylcycloprop-1-yl)-butan-4-one of melting point 216° to 218° C. were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:42])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:29]([O:31]C)=[O:30])([CH2:27][CH3:28])[CH2:25][CH3:26])[CH2:14][C:13](=[O:33])[NH:12][CH:11]3[C:34]3[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=3[CH3:41])[C:5]2=[CH:4][C:3]=1[F:43].O[Li].O.O.Cl>CO>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:42])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:29]([OH:31])=[O:30])([CH2:27][CH3:28])[CH2:25][CH3:26])[CH2:14][C:13](=[O:33])[NH:12][CH:11]3[C:34]3[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=3[CH3:41])[C:5]2=[CH:4][C:3]=1[F:43]
Reactant: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)c(F)cc12)C(=O)OC
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: O
Product: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)c(F)cc12)C(=O)O
Temperature: 80 °C

Procedure:
A mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-methoxycarbonyl-1-ethyl-propoxy)-phenyl]-5-fluoro-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (120 mg, 0.19 mmol), LiOH.H2O (140 mg, 3.3 mmol), H2O (1.25 mL) and methanol (3.75 mL) was heated at 80° C. for 1 h. After cooled to room temperature, the mixture was acidified by addition of 0.5 N HCl and partitioned between EtOAc and water. The organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated to give the crude product, which was used for the next step reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11](=[O:21])[NH:12][CH2:13][CH:14](OCC)[O:15]CC)[CH2:7][CH2:6]1)=[O:4].FC(F)(F)S(O)(=O)=O>COCCOC>[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11](=[O:21])[NH:12][CH2:13][CH:14]=[O:15])[CH2:7][CH2:6]1)=[O:4]
Reactant: CCOC(CNC(=O)[C@H]1CC[C@H](C(=O)OC)CC1)OCC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COCCOC
Product: COC(=O)[C@H]1CC[C@H](C(=O)NCC=O)CC1
Temperature: 25 °C

Procedure:
A solution of trans-4-(2,2-diethoxy-ethylcarbamoyl)-cyclohexanecarboxylic acid methyl ester (900 mg, 2.99 mmol) and trifluoromethanesulfonic acid (996 mg, 4.48 mmol) in 1,2-dimethoxyethane (30 ml) was heated at 40° C. for 4 h. After cooling to room temperature the reaction mixture was partitioned between ethyl acetate (100 ml) and saturated aqueous sodium bicarbonate solution (50 ml). The layers were separated. The aqueous layer was extracted with two 100 ml-portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (740 mg, quantitative) as light brown viscous oil, which was used in the next step without further purifications. MS m/e: 228 ([M+H]+)
Reaction SMILES: Cl[CH2:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]2[O:29][C:28]([C:30]([O:32][CH2:33][CH2:34][CH3:35])=[O:31])=[N:27][C:26]=2[C:36]=1[OH:37].[I-].[K+]>CC(C)=O.CN(C)C=O>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]2[O:29][C:28]([C:30]([O:32][CH2:33][CH2:34][CH3:35])=[O:31])=[N:27][C:26]=2[C:36]=1[O:37][CH2:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1
Reactant: ClCc1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: CCCOC(=O)c1nc2c(O)c(Cl)ccc2o1
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCOC(=O)c1nc2c(OCc3ccc(OCc4ccc5ccccc5n4)cc3)c(Cl)ccc2o1

Procedure:
0.78 g of 2-(4-chloromethylphenoxy)methylquinoline, 6.84 g of n-propyl 5-chloro-4-hydroxybenzoxazole-2carboxylate and a catalytic amount of potassium iodide are combined in 50 ml of acetone and 2 ml of dimethylformamide, and refluxed for 19 hours. The crude solid obtained on cooling is purified by flash chromatography to give n-propyl 5-chloro-4-(4-(quinolin-2-ylmethyloxy)benzyloxy)benzoxazole-2-carboxylate.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:10][CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].Br[CH:20]([C:25]1[CH:30]=[CH:29][C:28]2[O:31][CH2:32][O:33][C:27]=2[CH:26]=1)[C:21]([O:23][CH3:24])=[O:22]>CC(C)=O>[CH2:10]([C:3]1[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[CH:9][C:2]=1[O:1][CH:20]([C:25]1[CH:30]=[CH:29][C:28]2[O:31][CH2:32][O:33][C:27]=2[CH:26]=1)[C:21]([O:23][CH3:24])=[O:22])[CH2:11][CH3:12]
Reactant: CCCc1cc(C#N)ccc1O
Reactant: COC(=O)C(Br)c1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1cc(C#N)ccc1OC(C(=O)OC)c1ccc2c(c1)OCO2
Reaction time: 0.17 h

Procedure:
To a stirred solution of 4.50 g (27.95 mmol) of the product of Step B in 30 mL of acetone was added 4.64 g (33.54 mmol) of powdered potassium carbonate and the reaction mixture was stirred for 10 minutes. Methyl α-bromo-3,4-methylenedioxyphenylacetate (8.01 g; 29.35 mmol) was then added and the reaction mixture refluxed overnight. The reaction mixture was cooled, filtered, and the filtrate evaporated in vacuo, dried in a vacuum to afford 10.30 g (9.87 g theoretical) of the title compound which was used without purification in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11](=[O:13])[NH:10][N:9]=2)=[CH:4][CH:3]=1.O1[CH:19]=[CH:18][C:17](=[O:20])[CH:16]=[CH:15]1.Cl.N>O>[O:20]=[C:17]1[CH:18]=[CH:19][N:1]([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[O:12][C:11](=[O:13])[NH:10][N:9]=3)=[CH:6][CH:7]=2)[CH:15]=[CH:16]1
Reactant: Nc1ccc(-c2n[nH]c(=O)o2)cc1
Reactant: O=c1ccocc1
Agent: Cl
Agent: N
Solvent: O
Product: O=c1ccn(-c2ccc(-c3n[nH]c(=O)o3)cc2)cc1

Procedure:
A mixture of 5-(4-aminophenyl)-1,3,4-oxadiazol-2(3H)-one (0.41 g), 4H-pyran-4-one (0.24 g), and hydrochloric acid (2N, 1.15 ml) in water (25 ml) was stirred under reflux for 3 hours to afford a yellow solid. This solid was added to hot water with stirring and the resulting suspension was made alkaline (pH 8) with aqueous ammonia and was then filtered. The collected solid was dissolved in aqueous potassium carbonate and the resulting solution was neutralised with dilute acetic acid to afford an emulsion from which after centrifugation was obtained the title compound, 0.47 g, m.p. 220° C. (decomp), contaminated with potassium acetate.
Reaction SMILES: [C:1]1([CH2:11][C:12]([OH:14])=[O:13])[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1.[C:15](Cl)(=O)[CH3:16].[CH2:19](O)[CH3:20]>>[C:1]1([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:2]=[CH:3][C:4]([CH2:7][C:8]([O:10][CH2:19][CH3:20])=[O:9])=[CH:5][CH:6]=1
Reactant: CC(=O)Cl
Reactant: CCO
Reactant: O=C(O)Cc1ccc(CC(=O)O)cc1
Product: CCOC(=O)Cc1ccc(CC(=O)OCC)cc1

Procedure:
2,2′-(1,4-phenylene)diacetic acid (10.0 g, 51 mmol) was dissolved in ethanol (100 ml) and the solution treated dropwise with catalytic acetyl chloride (2.5 ml). The reaction mixture was stirred at reflux for 18 hours before being allowed to cool and concentrated in vacuo. The residue was taken up in ethyl acetate (100 ml) and extracted with sodium bicarbonate solution (3×50 ml) and brine (3×50 ml). The organic phase was then dried (magnesium sulphate) and concentrated in vacuo. The residue was triturated with pentane to yield the title product, 11.8 g.