Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>C(Cl)Cl>[Br:16][C:15]1[S:14][C:13]([S:17]([N:32]2[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]2)(=[O:19])=[O:18])=[CH:12][C:11]=1[C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH3:10]
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)N3CCN(C)CC3)sc2Br)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
4-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride, prepared as in Step III of Example 23 (4200 mg; 10.1 mmol; 1 eq), is dissolved in anhydrous DCM (200 ml). The reaction is put under nitrogen. Triethylamine (7.0 ml; 50.5 mmol; 5 eq) and 1-methylpiperazine (5.61 ml; 50.5 mmol; 5 eq) are added successively and the reaction mixture is stirred for 3 hours at room temperature. It is washed with water, NH4Cl sat, brine and dried over MgSO4, affording the title compound (4200 mg; 87%).
Reaction SMILES: C(O[CH2:5][C:6]1[CH:11]([C:12]([OH:14])=[O:13])[N:10]2[C:15](=[O:27])[CH:16]([NH:17][C:18](=[O:26])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@H:9]2[S:8][CH:7]=1)(=O)C.[CH3:28][N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30]1>FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>[CH3:28][N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([CH2:5][C:6]2[CH:11]([C:12]([OH:14])=[O:13])[N:10]3[C:15](=[O:27])[CH:16]([NH:17][C:18](=[O:26])[CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[C@H:9]3[S:8][CH:7]=2)=[CH:30]1
Reactant: CC(=O)OCC1=CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)O
Reactant: Cn1ccc2ccccc21
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(CC2=CS[C@@H]3C(NC(=O)Cc4ccccc4)C(=O)N3C2C(=O)O)c2ccccc21
Reaction time: 0.25 h

Procedure:
0.04 g of 3-acetoxymethyl-7-(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid is dissolved in a solution of 0.13 g of 1-methylindole in 0.3 ml of trifluoroacetic acid, and the solution is left to stand for 15 minutes at room temperature and diluted with an equal quantity of toluene. The mixture is evaporated to dryness under reduced pressure and the residue is worked up in accordance with the process described in example 6. 3-(1-Methyl-3-indolylmethyl)-7-(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid is thus obtained; in a thin layer chromatogram (silica gel), this acid shows Rf values at 0.85 (system n-butanol/acetic acid/water, 67:10:23) and at 0.58 (system n-butanol/ethanol/water, 40:10:50).
Reaction SMILES: [C:1]1(=[C:8]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19]C(C)(C)C)=[O:18])=[C:11]([F:24])[CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1(=[C:8]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])=[C:11]([F:24])[CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCCCCC2)c2cccc(O)c2)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)/C=C/c1ccc(C(=C2CCCCCC2)c2cccc(O)c2)cc1F
Yield: 92.5 %

Procedure:
The general hydrolysis procedure, described for 195 was followed. Thus, 1,1-dimethylethyl (2E)-3-{4-[cycloheptylidene(3-hydroxyphenyl)methyl]-2-fluorophenyl}-2-propenoate (198) (0.380 g, 0.9 mmol) in CH2Cl2 was treated with TFA to afford 0.305 g (92%) of the title compound as an off-white foam. 1H NMR (300 MHz, CD3OD): δ 7.76 (d, J=15.9 Hz, 1H), 7.59 (app t, J=7.8 Hz, 1H), 7.18 (app t, J=7.8 Hz, 1H), 7.04 (br d, J=8.1 Hz, 1H), 6.94 (br d, J=11.7 Hz, 1H), 6.67-6.60 (m, 3H), 6.56 (d, J=16.2 Hz, 1H), 2.34 (br s, 4H), 1.62 (br s, 8H). LCMS (ESI): m/z 365 (M−H)−. Anal. Calcd for C23H23FO3.1.5H2O, C, 70.38, H, 6.63, F, 4.84; Found: C, 69.96, H, 5.95, F, 4.73.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([OH:26])/[CH:21]=[CH:22]/[CH2:23][CH2:24][CH3:25].O[C:28]1[CH:33]=[CH:32][C:31]([C:34]2[S:35][C:36]([CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[N:37][N:38]=2)=[CH:30][CH:29]=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH2:20]([O:26][C:28]1[CH:29]=[CH:30][C:31]([C:34]2[S:35][C:36]([CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[N:37][N:38]=2)=[CH:32][CH:33]=1)/[CH:21]=[CH:22]/[CH2:23][CH2:24][CH3:25]
Reactant: CCC/C=C/CO
Reactant: CCCCCc1nnc(-c2ccc(O)cc2)s1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC/C=C/COc1ccc(-c2nnc(CCCCC)s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.1 %

Procedure:
Triphenylphosphine (0.95 g) is added in small portions to a solution of (E)-hex-2-en-1-ol (0.40 g), 2-(4-hydroxyphenyl)-5-pentyl-1,3,4-thiadiazole (0.71 g), diethylazodicarboxylate (0.63 g) in dry tetrahydrofuran (40 cm3) at 0° C. under an atmosphere of nitrogen. The reaction mixture is stirred at room temperature overnight. The solvent is removed under reduced pressure and the crude product was purified by column chromatography on silica gel using a 4:1 petroleum (40-60° C.) ether/ethyl acetate mixture as eluent, followed by recrystallisation from ethanol to yield 0.19 g of 2-(4-[(E)-hex-2-enyloxy]phenyl)-5-pentyl-1,3,4-thiadiazole.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]#[C:7][CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[CH3:14][N:15]([CH3:19])[C:16](Cl)=[O:17].C(OC(=O)C)(=O)C>CO>[CH3:14][N:15]([CH3:19])[C:16]([N:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]#[C:7][CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:17]
Reactant: CN(C)C(=O)Cl
Reactant: C(#C[C@H]1CCCN1)CN1CCCC1
Solvent: CC(=O)OC(C)=O
Solvent: CO
Product: CN(C)C(=O)N1CCC[C@H]1C#CCN1CCCC1

Procedure:
This compound was obtained following Example 51, Part A but substituting (S)-1-[3-(2-pyrrolidinyl)-2-propynyl]pyrrolidine for (R)-1-[3-(2-pyrrolidinyl)-2-propynyl]pyrrolidine and dimethyl carbamoyl chloride for acetic anhydride. [α]D -78° (c 1.13, MeOH).
Reaction SMILES: [O:1]1[CH:6]2[CH:2]1[CH2:3][N:4]([C:7]([O:9][CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12])=[O:8])[CH2:5]2.[C:15]1([OH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+]>C(#N)C.O>[OH:1][C@H:2]1[C@H:6]([O:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]([Cl:14])([Cl:12])[Cl:13])=[O:8])[CH2:3]1
Reactant: O=C(OCC(Cl)(Cl)Cl)N1CC2OC2C1
Reactant: Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: O=C(OCC(Cl)(Cl)Cl)N1C[C@@H](O)[C@H](Oc2ccccc2)C1

Procedure:
2.6 g (0.01 mol) of the 3,4-epoxy-1-(β,β,β-trichloroethoxycarbonyl)-pyrrolidine described in Example 1 are heated together with 1.88 g (0.02 mol) of phenol and 10 ml of 1 N sodium hydroxide solution in 30 ml of acetonitrile for 5 hours under reflux. After cooling, the reaction mixture is diluted with water and extracted 3 times with methylene chloride, and the organic phase is washed twice with 2 N sodium hydroxide solution and then once with water, dried over sodium sulphate and evaporated under a water pump vacuum. The resulting oil crystallises from methylene chloride/hexane and gives trans-3-hydroxy-4-phenoxy-1-(β,β,β-trichloroethoxycarbonyl)-pyrrolidine with a melting point of 100°-103°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:20][C:21]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:22]=1[CH2:23]Cl>CN(C=O)C.C(OCC)(=O)C>[CH3:20][C:21]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:22]=1[CH2:23][O:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1cccc(O)c1
Reactant: Cc1ccc(CCl)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cccc(OCc2ccc(C)cc2C)c1
Reaction time: 16 h

Procedure:
To a stirred solution of Ethyl 2-(3-hydroxyphenyl)acetate (3 g, 16.6 mmol) in DMF (20 ml) was added potassium carbonate (2.99 g, 21.6 mmol) at room temperature followed by drop wise addition of 2,4-Dimethylbenzyl chloride (3.11 g, 18.3 mmol). The reaction mixture was stirred for 16 hours and taken in ethyl acetate, washed with water (2×), brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (hex:ethyl acetate 4:1) to give the title compound.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[CH2:13]([O:15][C:16](=[O:34])[C:17]([CH3:33])([O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][C:30]#[CH:31])=[CH:22][C:21]=1[CH3:32])[CH3:18])[CH3:14]>N1CCCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH2:13]([O:15][C:16](=[O:34])[C:17]([CH3:33])([O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][C:30]#[C:31][C:2]2[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=2)=[CH:22][C:21]=1[CH3:32])[CH3:18])[CH3:14]
Reactant: FC(F)(F)Oc1ccc(I)cc1
Reactant: C#CCCCOc1ccc(OC(C)(C)C(=O)OCC)c(C)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCCC#Cc2ccc(OC(F)(F)F)cc2)cc1C
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 81.8 %

Procedure:
The synthesis was performed following a procedure of Stara, Irena G.; Stary, Ivo; Kollarovic, Adrian; Teply, Filip; Saman, David; Fiedler, Pavel, Coupling reactions of halobenzenes with alkynes. The synthesis of phenylacetylenes and symmetrical or unsymmetrical 1,2-diphenylacetylenes, Collect. Czech. Chem. Commun. (1999), 64(4), 649-672. To a degassed (argon) solution of 178 mg (0.60 mmol) 1-iodo-4-trifluoromethoxy-benzene in 2 ml piperidine was added 29 mg (0.03 mmol) Pd(PPh3)4 and 5 mg (0.03 mmol) CuI. The reaction mixture was stirred at 50° C. for 10 min, then a solution of 152 mg (0.50 mmol) 2-methyl-2-(2-methyl-4-pent-4-ynyloxy-phenoxy)-propionic acid ethyl ester (example 13A]) in 2 ml piperidine was added dropwise within 1 h. During the addition the oil bath was slowly heated to 80° C. starting after 30 min. The reaction mixture was stirred at this temperature for 3 h and then extracted with chilled aqueous 10% KHSO4/Et2O (three times). The organic phases were washed with aqueous 10% NaCl, dried (Na2SO4) and evaporated. Purification by flash-chromatography on silica gel (n-heptane/EtOAc 95:5 to 9:1) yielded 190 mg of the title compound as a light yellow viscous oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:6][CH:5]([O:7]COCCOC)[C:4]([CH2:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:14][CH3:15])[O:3]1.CO.Cl>C(OCC)C>[CH3:25][C:2]1([CH3:1])[CH2:6][CH:5]([OH:7])[C:4]([CH2:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:14][CH3:15])[O:3]1
Reactant: CCC1(COCc2ccccc2)OC(C)(C)CC1OCOCCOC
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CCC1(COCc2ccccc2)OC(C)(C)CC1O
Yield: 91.4 %

Procedure:
The compound of Example 25 (3.85 g) was added to methanol (50 ml) containing 0.6 ml of 36% hydrochloric acid and the resulting mixture was refluxed for 21/2 hours. The mixture was then cooled and the methanol was evaporated to give an oily residue. This residue was dissolved in diethyl ether, washed with brine, dried over magnesium sulphate and evaporated to give 2.64 g (91.7%) of the pure desired product. This product was shown to be pure, and to consist of a mixture of isomers, by thin layer chromatography.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14].N1C=CC=CC=1>O1CCCC1>[C:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[CH:7][CH:8]=1)(=[O:15])[CH3:14]
Reactant: Oc1ccc(-c2cccs2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(-c2cccs2)cc1
Reaction time: 1 h
Yield: 79.5 %

Procedure:
To a mixture of 4-(2-thienyl)phenol (1.00 g) and acetic anhydride (869 mg) in tetrahydrofuran (10 ml) was added pyridine (494 mg) with ice-cooling. The mixture was stirred for 1 hour at said temperature and 1 hour at ambient temperature. After concentration, the mixture was partitioned between AcOEt and H2O. The separated organic layer was washed with 1% aqueous citric acid, 3% aqueous NaHCO3 solution and brine, dried over sodium sulfate and concentrated. The residue was triturated with hexane to give 985 mg of 2-(4-acetoxyphenyl)thiophene as a powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:15]([CH3:18])=[N:16][N:17]=3)[C:9]=2[CH:8]=[C:7]1[C:19]1[NH:23][N:22]=[CH:21][CH:20]=1.[C:27]([O:31][CH3:32])(=[O:30])[CH:28]=[CH2:29].N12CCCN=C1CCCCC2>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:15]([CH3:18])=[N:16][N:17]=3)[C:9]=2[CH:8]=[C:7]1[C:19]1[CH:20]=[CH:21][N:22]([CH2:29][CH2:28][C:27]([O:31][CH3:32])=[O:30])[N:23]=1
Reactant: Cc1nnc2ccc3c(cc(-c4ccn[nH]4)n3Cc3cccc(Cl)c3)n12
Reactant: C=CC(=O)OC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COC(=O)CCn1ccc(-c2cc3c(ccc4nnc(C)n43)n2Cc2cccc(Cl)c2)n1
Reaction time: 1.17 h

Procedure:
6-(3-Chlorobenzyl)-1-methyl-7-(1H-pyrazol-5-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (25 mg, 0.069 mmol, from Example 103, Step 5) in acetonitrile (0.90 mL) was treated with methyl acrylate (19 μL, 0.21 mmol, Aldrich) and 1,8-diazabicyclo[5.4.0]undec-7-ene (10. μL, 0.069 mmol, Aldrich) and stirred for 70 minutes. Purification via preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) followed by evaporation of eluent afforded methyl 3-(3-(6-(3-chlorobenzyl)-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-7-yl)-1H-pyrazol-1-yl)propanoate. The ester intermediate was dissolved in THF (0.45 mL) and was treated with 1.0 M NaOH in water (0.45 mL, 0.45 mmol). After 25 minutes, the reaction was acidified to pH 3-4 by the addition of 1 N HCl. Water was added (3 mL), and the precipitated product was isolated by filtration and air dried. Yield: (21 mg, 70%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][CH2:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=4)=[CH:25][N:24]=3)=[CH:18][CH:17]=2)=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:43]([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([N:29]([CH3:43])[CH2:30][C:31]4[CH:32]=[CH:33][C:34]([C:37]([F:39])([F:40])[F:38])=[CH:35][CH:36]=4)=[CH:25][N:24]=3)=[CH:20][CH:21]=2)=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: O=C(c1ccc(Oc2ccc(NCc3ccc(C(F)(F)F)cc3)cn2)cc1)N1CCN(Cc2ccccc2)CC1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(Cc1ccc(C(F)(F)F)cc1)c1ccc(Oc2ccc(C(=O)N3CCN(Cc4ccccc4)CC3)cc2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (4-benzylpiperazin-1-yl){4-[5-(4-trifluoromethylbenzylamino)pyridin-2-yloxy]phenyl}methanone (5.40 g, 9.88 mmol) in methanol (150 mL) were added 37% aqueous formaldehyde (2.8 mL), sodium cyanoborohydride (1.86 g, 29.6 mmol) and acetic acid (1.7 mL) under ice cooling, and the resulting solution was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure. Water was added to the residue, and this solution was neutralized with a saturated sodium bicarbonate solution, and extracted with chloroform. The organic layer was washed with water, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (chloroform:methanol=60:1). To the resulting product was then added a solution of 4 M hydrogen chloride in ethyl acetate until the resulting solution had a pH of 1. The precipitates were collected by filtration and recrystallized from ethanol (80 mL), to thereby yield 2.5 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[O:12]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[F:11][C:8]1[CH:9]=[CH:10][C:2]([NH:1][C:23](=[O:24])[C:22]2[CH:21]=[CH:20][C:19]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:27][CH:26]=2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: Nc1ccc(F)cc1C(=O)O
Reactant: O=C(Cl)c1ccc(Oc2ccccc2)cc1
Product: O=C(Nc1ccc(F)cc1C(=O)O)c1ccc(Oc2ccccc2)cc1

Procedure:
In analogy to example 1,5-Fluoro-2-(4-phenoxy-benzoylamino)-benzoic acid was prepared form 2-amino-5-fluoro-benzoic acid and 4-phenoxy-benzoyl chloride [1623-95-6]. MS (m/e): 350.4 (M−H−, 100%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]4[C:24](=[O:25])[N:23]5[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:22]5=[N:21][C:20]=4[CH3:31])[CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>C(O)(=O)C>[C:32]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:10]=2)[C:6]([CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]3[C:24](=[O:25])[N:23]4[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:22]4=[N:21][C:20]=3[CH3:31])[CH2:13][CH2:12]2)=[N:7]1)(=[O:34])[CH3:33]
Reactant: Cc1nc2c(C)cccn2c(=O)c1CCN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)n1nc(C2CCN(CCc3c(C)nc4c(C)cccn4c3=O)CC2)c2ccc(F)cc21
Reaction time: 2 h
Yield: 95.3 %

Procedure:
A mixture of 3.2 parts of 3-[2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]ethyl]-2,9-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one, 27 parts of acetic anhydride and 15.7 parts of acetic acid was stirred for 2 hours at reflux temperature. The reaction mixture was evaporated and the residue was poured into 100 parts of water. After basifying with NH4OH, the product was extracted with dichloromethane. The extract was dried, filtered and evaporated and the residue was crystallized from 2-propanol, yielding 3.3 parts (95.3%) of 3-[2-[4-(1-acetyl-6-fluoro-1H-indazol-3-yl)-1-piperidinyl]ethyl]-2,9-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one; mp. 210.3° C. (compound 46). All other compounds listed in tables 1 to 3 were obtained following methods of preparation analogous to those described in examples 2 to 6, as is indicated in the column headed by Ex. No.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[S:18]1[CH:22]=[CH:21][C:20]2[CH:23]=[C:24]([CH:27]([OH:43])[CH2:28][O:29][CH2:30][CH2:31][O:32][S:33]([C:36]3[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:25]=[CH:26][C:19]1=2.[O:44]1[CH:49]=[CH:48][CH2:47][CH2:46][CH2:45]1>C(Cl)Cl>[S:18]1[CH:22]=[CH:21][C:20]2[CH:23]=[C:24]([CH:27]([O:43][CH:45]3[CH2:46][CH2:47][CH2:48][CH2:49][O:44]3)[CH2:28][O:29][CH2:30][CH2:31][O:32][S:33]([C:36]3[CH:37]=[CH:38][C:39]([CH3:42])=[CH:40][CH:41]=3)(=[O:35])=[O:34])[CH:25]=[CH:26][C:19]1=2
Reactant: C1=COCCC1
Reactant: Cc1ccc(S(=O)(=O)OCCOCC(O)c2ccc3sccc3c2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOCC(OC2CCCCO2)c2ccc3sccc3c2)cc1
Temperature: 42.5 °C
Reaction time: 0.5 h

Procedure:
0.97 g of pyridinium p-toluenesulfonate was added, at room temperature, to a solution of 7.6 g of 1-(benzo[b]thiophen-5-yl)-2-[2-(p-toluenesulfonyloxy)-ethoxy]ethanol and 3.5 ml of 3,4-dihydro-2H-pyran dissolved in 40 ml of methylene chloride. The mixture was stirred at the same temperature for 20 minutes and further at 40-45° C. for 30 minutes. The reaction mixture was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 8.7 g of colorless, oily 1-(benzo[b]-thiophen-5-yl)-1-(2-tetrahydropyranyloxy)-2-[2-(p-toluenesulfonyloxy)ethoxy]ethane.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([C:18](O)=[O:19])=[C:9]1[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][Li]>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([C:18](=[O:19])[CH3:24])=[C:9]1[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1c(C(=O)O)c2cc(O)ccc2n1Cc1ccccc1
Reactant: [Li]C
Product: CC(=O)c1c(C(C)C)n(Cc2ccccc2)c2ccc(O)cc12
Reaction time: 4 h

Procedure:
General Procedure F. To a solution of 1-benzyl-5-hydroxy-2-isopropyl-1H-indole-3-carboxylic acid (Compound 28, 242 mg, 0.78 mmol) under argon was added methyllithium (3.0 M in diethoxymethane, 5.2 ml, 15.7 mmol) at room temperature. The reaction was stirred for 4 h and was quenched with 1 M HCl, extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 0-50% EtOAc-hexanes to yield 1-(1-benzyl-5-hydroxy-2-isopropyl-1H-indol-3-yl)ethanone (Compound 29) as a yellow solid.
Reaction SMILES: Cl.[O:2]1[CH2:8][CH2:7][CH2:6][O:5][C:4]2[C:9]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:10][CH:11]=[CH:12][C:3]1=2.[O:19]=[C:20]1[NH:29][C:28]2[N:27]=[C:26]([O:30][CH2:31][CH2:32][CH2:33][CH:34]=O)[CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21]1>>[O:2]1[CH2:8][CH2:7][CH2:6][O:5][C:4]2[C:9]([N:13]3[CH2:14][CH2:15][N:16]([CH2:34][CH2:33][CH2:32][CH2:31][O:30][C:26]4[N:27]=[C:28]5[C:23]([CH2:22][CH2:21][C:20](=[O:19])[NH:29]5)=[CH:24][CH:25]=4)[CH2:17][CH2:18]3)=[CH:10][CH:11]=[CH:12][C:3]1=2
Reactant: O=CCCCOc1ccc2c(n1)NC(=O)CC2
Reactant: c1cc2c(c(N3CCNCC3)c1)OCCCO2
Agent: Cl
Product: O=C1CCc2ccc(OCCCCN3CCN(c4cccc5c4OCCCO5)CC3)nc2N1

Procedure:
In a manner similar to that of other examples above, 1-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-6-yl)-piperazine hydrochloride (J. Med. Chem. 1988, 31, 1934–1940) was coupled by reductive amination to 4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followed by typical workup and purification to give the intermediate compound. MS: APCI: M+1: 453.6 (Exact Mass: 452.55).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C(O)(=O)C.C(O)(=O)C.[I:18]C1C=CC=CC=1.II.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([I:18])[CH:3]=1
Reactant: COc1ccc(Br)cc1
Reactant: Ic1ccccc1
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: COc1ccc(Br)cc1I
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-Bromo-anisole (4.417 g, 23.6 mmol) was dissolved in acetonitrile (200 mL) and placed under an argon atmosphere in the absence of light. Iodobenzene diacetate (9.18 g, 28.5 mmol) was added followed by iodine (3.6 g, 14.2 mmol). The mixture was stirred for 16 hours at ambient temperature. The mixture was then poured into 1M Na2S2O3 (200 mL) and stirred until the solution was colourless. The solution was then extracted with diethyl ether (3×100 mL). The combined organic extracts were then washed with brine, dried with Na2SO4, filtered and evaporated to dryness. The crude product was filtered through a silica gel plug eluting with heptane/ethyl acetate (3:1) (200 mL). The filtrate was concentrated and the residue was distilled using a Kugelrohr apparatus collecting the compound at 75° C., 0.01 mbar.