Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21]([F:26])([F:25])[CH:22]([F:24])[F:23])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[F:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([C:38](O)=[O:39])=[CH:30][CH:29]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:38]([C:31]2[C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:28]([F:27])=[CH:29][CH:30]=2)=[O:39])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21]([F:26])([F:25])[CH:22]([F:24])[F:23])[CH:14]=2)=[CH:6][CH:7]=1
Reactant: NC(Cc1cccc(OCC(F)(F)C(F)F)c1)C(O)c1ccc(F)cc1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1cccc(OCC(F)(F)C(F)F)c1)C(O)c1ccc(F)cc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(3-(2,2,3,3-tetrafluoropropyloxy)phenyl)-1-propanol (197 mg, 0.53 mmol) in acetonitrile (20 ml) were added 4-fluoronaphthalenecarboxylic acid (100 mg, 0.53 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (151 mg, 0.79 mmol) and 1-hydroxy-1H-benzotriazole (81 mg, 0.53 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (240 mg, 84%).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:27])=[C:10]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=3[O:21][CH2:22][C:23]([F:26])([F:25])[F:24])C=O)[CH:11]=2)[C:6]([CH3:29])([CH3:28])[CH2:5][C:4]1=[O:30])[CH3:2].[CH2:31]([CH:33](P(O)(O)=O)/[C:34](/CC)=[C:35](\CC)/[C:36]([O-:38])=[O:37])C>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:27])=[C:10]([C:13]3[CH:14]=[C:15]([CH:31]=[CH:33][CH:34]=[CH:35][C:36]([OH:38])=[O:37])[CH:18]=[CH:19][C:20]=3[O:21][CH2:22][C:23]([F:26])([F:24])[F:25])[CH:11]=2)[C:6]([CH3:29])([CH3:28])[CH2:5][C:4]1=[O:30])[CH3:2]
Reactant: CC/C(C(=O)[O-])=C(/CC)C(CC)P(=O)(O)O
Reactant: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3cc(C=O)ccc3OCC(F)(F)F)cc21
Product: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3cc(C=CC=CC(=O)O)ccc3OCC(F)(F)F)cc21

Procedure:
Compound 23 was prepared from Compound 1D using procedures similar to those described for Example 20B and 20C, except using triethyl-4-phosphonocrotonate in step 20B. MS (electrospray): mass calculated for C27H28F3NO4, 487.20; m/z found 488.2 [M+H]+.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH:3]=1.[C-:19]#[N:20].[K+]>C1COCC1.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>[C:19]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH:3]=1)#[N:20]
Reactant: [C-]#N
Reactant: COC(=O)c1ccc(I)cc1-c1ccccc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C#N)cc1-c1ccccc1C
Yield: 88.3 %

Procedure:
The compound from Example 954B (1.55 g, 4.41 mmol) was dissolved in 10 mL of THF. Then Pd(PPh3)4 (120 mg, 2.2% eq) and powdered KCN (430 mg, 6.61 mmol, 1.5 eq) was added. The mixture was refluxed for 12 hr. GC/MS showed all the starting material was converted to the product. The mixture was extracted with ethyl acetate and water. After evaporation of solvents, the residue was purified by flash column chromatography (10:1=hexane/ethyl acetate) to give an oily product (978 mg, 88% yield). 1H NMR (CDCl3) δ 8.02 (d, J=8.1 Hz, 1H), 7.72 (d, J=7.9 Hz, 1H), 7.56 (s, 1H), 7.20-7.33 (m, 3H), 7.03 (d, J=7.4 Hz, 1H), 3.63 (s, 3H), 2.06 (s, 3H); 13C NMR (CDCl3) δ 165.9, 143.0, 138.5, 134.6, 134.2, 133.9, 130.3, 130.0, 129.3, 127.9, 127.6, 125.0, 117.3, 114.6, 51.8, 19.4.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[O:18][C:17]([C:19]([NH:21][C@@H:22]([CH2:27][N+:28]([CH3:31])([CH3:30])[CH3:29])[CH2:23][C:24]([O-:26])=[O:25])=[O:20])=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]>[Pd]>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH:14]2[O:18][CH:17]([C:19]([NH:21][C@@H:22]([CH2:27][N+:28]([CH3:31])([CH3:29])[CH3:30])[CH2:23][C:24]([O-:26])=[O:25])=[O:20])[CH2:16][CH2:15]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(C#Cc2ccc(C(=O)N[C@H](CC(=O)[O-])C[N+](C)(C)C)o2)cc1
Agent: [Pd]
Product: CCCCCc1ccc(CCC2CCC(C(=O)N[C@H](CC(=O)[O-])C[N+](C)(C)C)O2)cc1
Yield: 48 %

Procedure:
According to the method described in example S64, (R)-3-(5-((4-pentylphenyl)ethynyl)furan-2-carboxamido)-4-(trimethylammonio)butanoate was treated with 10% Pd/C under hydrogen overnight and the product purified to give the title compound as a white powder (16.5 mg, 48%). 1H NMR (400 MHz, D2O) δ 6.86 (d, 2H, J=8.2 Hz), 6.75 (d, 2H, J=7.6 Hz), 4.60-4.53 (m, 1H), 4.08-4.01 (m, 1H), 3.61-3.36 (m, 3H), 3.02 (s, 9H), 2.45-2.32 (m, 6H), 1.87-1.50 (m, 5H), 1.35-1.27 (m, 2H), 1.25-1.05 (m, 5H), 0.60-0.55 (m, 3H); MS ESI [M+H]+, calcd for [C25H40N2O4+H]+ 433.31; found m/z 433.3.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH:12]=[C:13]([CH2:23][O:24]CC2C=CC=CC=2)[CH2:14][O:15]CC2C=CC=CC=2)=[C:4](Cl)[N:3]=1.FC(F)(F)C(O)=[O:36]>O>[OH:15][CH2:14][C:13]([CH2:23][OH:24])=[CH:12][CH2:11][N:8]1[CH:7]=[N:6][C:5]2[C:4](=[O:36])[NH:3][C:2]([NH2:1])=[N:10][C:9]1=2
Reactant: O=C(O)C(F)(F)F
Reactant: Nc1nc(Cl)c2ncn(CC=C(COCc3ccccc3)COCc3ccccc3)c2n1
Solvent: O
Product: Nc1nc2c(ncn2CC=C(CO)CO)c(=O)[nH]1
Reaction time: 0.02 h
Yield: 41 %

Procedure:
A solution of 4-(2-amino-6-chloropurin-9-yl)-1-benzyloxy-2-benzyloxymethyl-2-butene (148 mg, 0.329 mmol), 1.8 ml of trifluoroacetic acid and 0.2 ml of water in a sealed ampoule was kept at 110° C. for 17 h. After cooling the mixture was diluted with 2 ml of water, heated to boiling for one minute, and evaporated to dryness in vacuum, dissolved in water and re-evaporated. Chromatography (silica gel, ethyl acetate+methanol+water 70+20+10 parts of volume) afforded 34 mg (41%) of 9-[4-hydroxy-3-(hydroxymethyl)-2-butenyl]guanine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][C@@H:7]([NH:15][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])[CH2:6][C:5]2=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25](F)[CH:24]=1>>[CH2:22]([N:11]1[C:10]2[CH2:9][CH2:8][C@@H:7]([NH:15][C:16](=[O:20])[CH:17]([CH3:18])[CH3:19])[CH2:6][C:5]=2[C:4]2[C:12]1=[CH:13][CH:14]=[C:2]([Br:1])[CH:3]=2)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Fc1cccc(CBr)c1
Reactant: CC(C)C(=O)N[C@@H]1CCc2[nH]c3ccc(Br)cc3c2C1
Product: CC(C)C(=O)N[C@@H]1CCc2c(c3cc(Br)ccc3n2Cc2ccccc2)C1

Procedure:
Alkylate (R)-N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-3-yl)isobutyramide with 1-bromomethyl-3-fluorobenzene using procedures essentially as described in Example 1 to give the title compound. MS (ES): m/z 443 (M+1), 445 (M+1+2); m.p.=204-207° C. (Alkylate the S isomer in a similar fashion to obtain (S)-N-(9-Benzyl-6-bromo-2,3,4,9-tetrahydro-1H-carbazol-3-yl)isobutyramide.)
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH:12](OCC)(OCC)[O:13][CH2:14][CH3:15].C(OC(=O)C)(=O)C>>[C:1]([C:6](=[CH:12][O:13][CH2:14][CH3:15])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)CC(=O)C(C)C
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)C(C)C

Procedure:
A mixture of ethyl isobutyrylacetate (60.5 g, 0.38 mol), triethyl orthoformate (126 ml, 0.76 mol) and acetic anhydride (36 ml, 0.38 mol) was heated at reflux for 24 hours, then the volatile components removed in vacuo, finally at 100°/0.5 mm. The residue consisted mainly of ethyl 2-isobutyryl-3-ethoxyacrylate as a mixture of E/Z isomers, and was used without further purification.
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][CH:8]([S:17]([N:20]1[CH2:25][CH2:24][CH:23]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:22][CH2:21]1)(=[O:19])=[O:18])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:26]([CH:23]1[CH2:24][CH2:25][N:20]([S:17]([CH:8]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][C:6]([OH:33])=[O:5])(=[O:19])=[O:18])[CH2:21][CH2:22]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)CC(CCc1ccccc1)S(=O)(=O)N1CCC(Cc2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CC(CCc1ccccc1)S(=O)(=O)N1CCC(Cc2ccccc2)CC1
Temperature: 0 °C
Yield: 99.9 %

Procedure:
3-(4-Benzy-piperidine-1-sulfonyl)-5-phenyl-pentanoic acid tert-butyl ester (1.04 g, 2.2 mmol) was taken up in DCM (5 mL) with stirring and cooled to 0° C. TFA (5 mL) was added slowly and the resulting solution placed in the fridge overnight. Solvents evaporated under reduced pressure to give the title compound as a yellow oil (913 mg, Quant). 1H-NMR δ(MeOD) 7.56-7.11 (10H, m), 3.66-3.56 (3H, m), 2.90-2.59 (6H, m), 2.51 (2H, d, J=6.7 Hz), 2.20 (1H, m), 1.90 (1H, m), 1.62-1.47 (3, m) and 1.25-1.11 (2H, m). 13C-NMR δ(MeOD) 174.5, 142.6, 141.7, 130.6, 130.1, 130.0, 129.7, 127.7, 127.4, 58.7, 47.6, 44.2, 39.2, 35.5, 33.9, 33.7, 33.0. IR Vmax (ATR) 2915, 1709, 1451, 1304, 1133, 1041, 937, 746, 698. ESMS=(M+1) 416.0, (M−1) 414.0.
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][C:4]1[N:5]=[C:6]([CH3:9])[S:7][CH:8]=1.[CH:10]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[ClH:2].[ClH:1].[ClH:2].[CH:10]([N:23]1[CH2:28][CH2:27][N:26]([CH2:3][C:4]2[N:5]=[C:6]([CH3:9])[S:7][CH:8]=2)[CH2:25][CH2:24]1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: Cc1nc(CCl)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)cs1
Temperature: 70 °C
Yield: 84.6 %

Procedure:
A mixture of 4-chloromethyl-2-methylthiazole hydrochloride (1.84 g), 1-benzhydrylpiperazine (2.52 g) and potassium carbonate (2.7 g) in N,N-dimethylformamide (15 ml) was stirred at 70° C. for an hour. After the reaction mixture was poured into ice-water, it was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and then evaporated to give a residue, which was transformed into its hydrochloride in a conventional manner, followed by recrystallization from a mixture of methanol and diethyl ether to obtain white crystals (2.0 g) of 4-(4-benzhydrylpiperazin-1-ylmethyl)-2-methylthiazole trihydrochloride, mp 166°-170° C. (dec.).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH3:26])=[C:19]([N+:27]([O-:29])=[O:28])[CH:18]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8]C(C)C.ClC1C=C(C2ON=C(C3C=CC(OC(C)C)=C(I)C=3)N=2)C=CC=1OCCC>>[I:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH3:26])=[C:19]([N+:27]([O-:29])=[O:28])[CH:18]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CCCOc1ccc(-c2nc(-c3ccc(OC(C)C)c(I)c3)no2)cc1[N+](=O)[O-]
Agent: CCCOc1ccc(-c2nc(-c3ccc(OC(C)C)c(I)c3)no2)cc1Cl
Product: CCCOc1ccc(-c2nc(-c3ccc(O)c(I)c3)no2)cc1[N+](=O)[O-]
Yield: 77 %

Procedure:
When the product of Step B was substituted for 5-(3-chloro-4-propoxyphenyl)-3-(3-iodo-4-isopropoxyphenyl)-1,2,4-oxadiazole in Example 36, Step C, the similar procedure afforded the title compound in 77% yield, as creamy solid. 1H NMR (CDCl3) 8.65 (d, 1H, J=2.16 Hz); 8.47 (d, 1H, J=1.95 Hz); 8.3 (dd, 1H, J=8.82, 2.19 Hz); 8.03 (dd, 1H, J=8.49, 2.01 Hz); 7.21 (d, 1H, J=8.88 Hz); 7.08 (d, 1H, J=8.49 Hz); 4.17 (t, 2H, J=6.39 Hz); 1.96-1.84 (m, 2H); 1.09 (t, 3H, J=7.38 Hz).
Reaction SMILES: CCCCCC.C([Li])CCC.[CH2:12]([C:19]1[S:20][CH:21]=[CH:22][C:23]=1[C:24]#[CH:25])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[N:26]12[CH2:33][CH2:32][CH:29]([CH2:30][CH2:31]1)[C:28](=[O:34])[CH2:27]2>O.O1CCCC1>[CH2:12]([C:19]1[S:20][CH:21]=[CH:22][C:23]=1[C:24]#[C:25][C:28]1([OH:34])[CH:29]2[CH2:32][CH2:33][N:26]([CH2:31][CH2:30]2)[CH2:27]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C1CN2CCC1CC2
Reactant: C#Cc1ccsc1Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: OC1(C#Cc2ccsc2Cc2ccccc2)CN2CCC1CC2
Reaction time: 20 h

Procedure:
0.200 ml of a hexane solution containing 1.8 mol of butyl lithium was added dropwise to a mixture of 45.2 mg of 2-benzyl-3-ethynyl-thiophene and 1 ml of tetrahydrofuran at −78° C., followed by stirring at the same temperature for 20 hours. A solution of 0.5 ml of tetrahydrofuran containing 39.9 mg of 3-quinuclidinone was added dropwise to the reaction solution at the same temperature, followed by stirring and then at room temperature for 4 hours. 0.5 ml of water and NH-silica gel were added to the reaction solution, and the solvent was removed. The residue was subjected to NH-silica gel column chromatography using ethyl acetate, to give 39.5 mg of the target compound.
Reaction SMILES: [CH2:1]([O:3][CH:4]=[CH:5][C:6](=[O:8])[CH3:7])[CH3:2].[Si:9](OS(C(F)(F)F)(=O)=O)([CH3:12])([CH3:11])[CH3:10]>C1COCC1>[CH2:1]([O:3][CH:4]=[CH:5][C:6](=[CH2:7])[O:8][Si:9]([CH3:12])([CH3:11])[CH3:10])[CH3:2]
Reactant: CCOC=CC(C)=O
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: C1CCOC1
Product: C=C(C=COCC)O[Si](C)(C)C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
In a 250 mL three-necked flask under N2 atomosphere, to a solution of 7.2 g of 4-ethoxy-but-3-en-2-one (63 mmol, 1 eq) and 12.7 g of TEA (126 mmol, 2 eq) in THF at −78° C., was added 21 g of TMSOTf (95 mmol, 1.5 eq) dropwise in 40 mins. Stirring was continued for 60 mins at 0˜−30° C. After the conversion was complete (check by NMR), the reaction was quenched with 5% NaHCO3, extract with Hexane and dried over Na2SO4. After remove the solvent the crude product was purified with redistillation (oil pump, <<1 mmbar: Bp, 40° C., Toluene; Bp, 115° C., product) to give 9.1 g pure product. Yield: 72.2%.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[CH:7]=1.[NH:16]1[CH:20]=[CH:19][N:18]=[C:17]1[CH:21]=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:15][C:10]1[CH:9]=[C:8]([N:6]2[CH:7]=[C:3]([CH2:2][N:16]3[CH:20]=[CH:19][N:18]=[C:17]3[CH:21]=[O:22])[N:4]=[CH:5]2)[CH:13]=[CH:12][C:11]=1[Cl:14]
Reactant: O=Cc1ncc[nH]1
Reactant: ClCc1cn(-c2ccc(Cl)c(Cl)c2)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=Cc1nccn1Cc1cn(-c2ccc(Cl)c(Cl)c2)cn1
Temperature: 60 °C
Reaction time: 12 h
Yield: 61 %

Procedure:
4-Chloromethyl-1-(3,4-dichloro-phenyl)-1H-imidazole (1.31 g, 5.0 mmol) was dissolved in DMF (10 ml), 2-imidazolecarboxaldehyde (0.48 g, 5.0 mmol) and cesium carbonate (0.82 g, 2.5 mmol) was added and the resulting mixture was stirred at 60° C. for 12 h. After evaporation of the solvent the residue was dissolved in AcOEt and washed with H2O. The organic phase was dried (Na2SO4), concentrated and chromatographed [silica, elution with gradient CH2Cl2 to 100% (CH2Cl2/MeOH=9:1)] to obtain 0.98 g (61%) of the title compound as an off-white solid. Mp. 130-131° C. (CH2Cl2/iPr2O), MS: m/e=320 (M+).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5](B2OC(C)(C)C(C)(C)O2)[C:4]([CH3:17])=[N:3]1.Br[C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([F:28])[CH:26]=2)[N:21]([CH2:29][CH2:30][CH2:31][O:32][C:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=[CH:35][CH:34]=2)[C:20]=1[C:43]([O:45]CC)=[O:44].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1>[F:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:29][CH2:30][CH2:31][O:32][C:33]1[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=[CH:35][CH:34]=1)[C:20]([C:43]([OH:45])=[O:44])=[C:19]2[C:5]1[C:4]([CH3:17])=[N:3][N:2]([CH3:1])[C:6]=1[CH3:7]
Reactant: Cc1nn(C)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: CCOC(=O)c1c(Br)c2cc(F)ccc2n1CCCOc1cccc2ccccc12
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1nn(C)c(C)c1-c1c(C(=O)O)n(CCCOc2cccc3ccccc23)c2ccc(F)cc12
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A mixture of 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (43.2 mg), ethyl 3-bromo-5-fluoro-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate (The synthesis of this compound was described in EXAMPLE 134B as an intermediate) (43 mg), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (15.01 mg) and K3PO4 (58.2 mg) in toluene (2.1 ml) was heated in a microwave reactor (CEM Discover) at 110° C. for 2 hours. The reaction was directly loaded into a silica cartridge, and eluted with 0%-25% ethyl acetate in dichloromethane. The collected desired ester was hydrolyzed with NaOH in tetrahydrofuran-methanol-H2O at 50° C. overnight to provide the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 8.15 (d, J=8.90 Hz, 1H), 7.86 (d, J=7.36 Hz, 1H), 7.71 (dd, J=9.21, 4.30 Hz, 1H), 7.42-7.56 (m, 3H), 7.32-7.41 (m, 1H), 7.05-7.16 (m, 1H), 6.92 (dd, J=9.36, 2.61 Hz, 1H), 6.86 (d, J=7.36 Hz, 1H), 4.69-5.00 (m, 2H), 4.17 (t, J=5.83 Hz, 2H), 3.72 (s, 3H), 2.27-2.43 (m, 2H), 1.99 (s, 3H), 1.90 (s, 3H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C:3]1=[O:8].O.[C:10](OC(=O)C)(=[O:12])[CH3:11]>N1C=CC=CC=1>[C:10]([O:1][C@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C:3]1=[O:8])(=[O:12])[CH3:11]
Reactant: O=C1NCCC[C@@H]1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)O[C@H]1CCCNC1=O
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of 460 mg of (S)-(-)-3-hydroxy-2-piperidone [A. Hunter, Biochemical Journal, 35, 1298 (1941); mp. 170°-171° C., [α]D26 =-3.0°±0.1° (c=7.027, H2O)] in 6 ml of pyridine is added 2 ml of acetic anhydride, and the mixture is allowed to stand at room temperature overnight and concentrated under reduced pressure. The residue is crystallized from ether and then recrystallized from ether to give 560 mg of (S)-(-)-3-acetoxy-2-piperidone as pillar crystals in 89% yield.
Reaction SMILES: [Li]CCCC.CCN(C(C)C)C(C)C.[Cl:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][C:20]([C:26]([F:29])([F:28])[F:27])=[CH:21][CH:22]=2)[N:17]=1.[C:30](=[O:32])=[O:31]>C1COCC1>[Cl:15][C:16]1[C:25]([C:30]([OH:32])=[O:31])=[CH:24][C:23]2[C:18](=[CH:19][C:20]([C:26]([F:28])([F:27])[F:29])=[CH:21][CH:22]=2)[N:17]=1
Reactant: O=C=O
Reactant: FC(F)(F)c1ccc2ccc(Cl)nc2c1
Agent: [Li]CCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(O)c1cc2ccc(C(F)(F)F)cc2nc1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
11 ml of BuLi (1M in hexane) were added dropwise at −78° C. to a solution of 1.9 ml (11 mmol) of DIPEA in THF (77 ml). After stirring for 30 min at −78° C., a solution of 2.31 g (10 mmol) of 2-chloro-7-(trifluoromethyl)quinoline in THF (30 ml) was added and stirring was carried out for a further 30 min at −78° C. The reaction solution was then poured onto finely divided, solid CO2. After heating to RT, most of the THF was removed in vacuo. A 1M aq. NaOH soln. was then added and the phases were separated. The aqueous phase was acidified with 10% hydrochloric acid and extracted with EA. The organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. There were obtained as residue 2.12 g (7.7 mmol, 71%) of 2-chloro-7-(trifluoromethyl)quinoline-3-carboxylic acid, which was reacted further without additional purification.
Reaction SMILES: [Cl-].[Cl-].[CH2:3]([Ga+2:5])[CH3:4].[CH3:6][N-:7][CH2:8][CH2:9][N-:10][CH3:11].[Li+].[Li+]>CCCCCC>[CH3:6][N:7]1[CH2:8][CH2:9][N:10]([CH3:11])[Ga:5]1[CH2:3][CH3:4]
Reactant: CC[Ga+2]
Reactant: C[N-]CC[N-]C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCCCCC
Product: CC[Ga]1N(C)CCN1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
25.5 g (0.15 mol) of ethylgallium dichloride in 100 ml of n-hexane are added, at -20°, to 14.6 g (0.15 mol) of dilithium N,N'-dimethylethylenediamide in 300 ml of n-hexane. The mixture is stirred at room temperature for 2 hours and filtered, and the filtrate is concentrated. Sublimation at a bath temperature of 220° and a vacuum of 10-1 mbar gives 2,5-dimethyl-1-ethyl-2,5-diaza-1-gallacyclopentane as a colourless solid, stable in air. ##STR8##
Reaction SMILES: [NH2:1][C:2]1[C:10]([NH2:11])=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].COC(C1C2N=C(N)[NH:23][C:22]=2C=CC=1)=O.BrC#N>CO>[NH2:23][C:22]1[NH:11][C:10]2[C:9]([O:12][CH3:13])=[CH:8][CH:7]=[C:3]([C:4]([OH:6])=[O:5])[C:2]=2[N:1]=1
Reactant: COc1ccc(C(=O)O)c(N)c1N
Reactant: COC(=O)c1cccc2[nH]c(N)nc12
Agent: N#CBr
Solvent: CO
Product: COc1ccc(C(=O)O)c2nc(N)[nH]c12

Procedure:
0.9 g (4.9 mmol) of 2,3-diamino-4-methoxy-benzoic acid was subjected to a similar cyclization condition as illustrated in intermediate A by using 2.6 g (24.5 mmol) of BrCN in methanol to produce 2-amino-7-methoxy-1H-benzoimidazole-4-carboxylic acid. LCMS: 208 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](CC3C=C(C=CC=3)C(O)=O)[C:11]3[CH:23]=[C:24](F)[C:25](F)=[CH:26][C:10]=3[N:9]=2)=[C:4](OCC2CCCC2)[CH:3]=1.C1(N)C(N)=CC=CC=1.[Br:44]C1C=C(Cl)C=CC=1C(O)=O>>[Br:44][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[C:8]1[NH:12][C:11]2[CH:23]=[CH:24][CH:25]=[CH:26][C:10]=2[N:9]=1
Reactant: O=C(O)c1ccc(Cl)cc1Br
Reactant: O=C(O)c1cccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)c1
Agent: Nc1ccccc1N
Product: Clc1ccc(-c2nc3ccccc3[nH]2)c(Br)c1

Procedure:
The title compound was prepared in analogy to Example 19, intermediate c, from benzene-1,2-diamine (CAS Reg. No. 76179-40-3) and 2-bromo-4-chloro-benzoic acid (CAS Reg. No. 936-08-3). Light yellow solid (92%). MS (Turbo Spray): m/z=308.8 (M+H).
Reaction SMILES: [F:1][C:2]([F:22])([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH2:3][CH2:4][S:5][C:6]1[N:7]=[C:8]([CH3:14])[S:9][C:10]=1[C:11]([OH:13])=O.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.[F:52][C:53]1[CH:60]=[CH:59][C:56]([CH2:57][NH2:58])=[CH:55][CH:54]=1>CN(C=O)C>[F:22][C:2]([F:1])([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH2:3][CH2:4][S:5][C:6]1[N:7]=[C:8]([CH3:14])[S:9][C:10]=1[C:11]([NH:58][CH2:57][C:56]1[CH:59]=[CH:60][C:53]([F:52])=[CH:54][CH:55]=1)=[O:13]
Reactant: Cc1nc(SCCC(F)(F)c2ccc(F)cc2)c(C(=O)O)s1
Reactant: NCc1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1nc(SCCC(F)(F)c2ccc(F)cc2)c(C(=O)NCc2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.3 %

Procedure:
To a solution of 4-[[3,3-difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-2-methyl-thiazole-5-carboxylic acid (0.25 g, 0.72 mmol) in DMF (4 ml) are added O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (347 mg, 1.08 mmol) and N-methylmorpholine (0.16 ml, 1.44 mmol) at 0° C. followed by the addition of 4-fluorobenzyl amine (0.01 ml, 0.86 mmol). The reaction mixture is stirred at RT for 3 h. After completion of the reaction, the mixture is poured onto ice-water, extracted with EtOAc (3×15 ml). The combined organic layers are washed with brine (20 ml), dried over sodium sulfate and evaporated to dryness to yield the crude product, which is purified by column chromatography (silica gel, 5% acetone/hexane) followed by preparative HPLC affording 4-[[3,3-difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-N-[(4-fluorophenyl)-methyl]-2-methyl-thiazole-5-carboxylic acid amide (example 15) (0.2 g, 0.42 mmol, 36%). [M+H]+ 455.1.