Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:16])=[C:12]([F:15])[CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:17].[NH:18]1[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][O:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:20][CH2:19]1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[F:16][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][C:12]=1[F:15])[N:5]([CH2:4][CH2:3][CH2:2][N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][O:26][C:27](=[O:32])[C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:20][CH2:19]1)[C:6](=[O:17])[CH2:7][CH2:8]2
Reactant: CC(C)(C)C(=O)OCCC1CCNCC1
Reactant: O=C1CCc2cc(F)c(F)cc2N1CCCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C(=O)OCCC1CCN(CCCN2C(=O)CCc3cc(F)c(F)cc32)CC1
Temperature: 80 °C
Reaction time: 72 h
Yield: 24 %

Procedure:
A 4 ml vial was charged with 1-(3-chloropropyl)-6,7-difluoro-3,4-dihydro-1H-quinolin-2-one (52 mg, 0.20 mmol), 2,2-dimethyl-propionic acid 2-piperidin-4-yl-ethyl ester, and Cs2CO3 (200 mg, 0.60 mmol) in dry DMF (1 ml). The reaction was shaken at 80° C. for 3 days and the reaction was poured into water and extracted with EtOAc. The organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The oily residue was purified by ion-exchange column chromatography to yield the title product as an oil (21 mg, 48 μmol, 24%). 1H NMR (CD3OD) d 7.23-7.12 (m, 2H), 4.11 (t, J=6.0 Hz, 2H), 3.96 (t, J=7.2 Hz, 2H), 3.18-3.06 (m, 2H), 2.88 (br t, 6.8 Hz, 2H), 2.66-2.58 (m, 4H), 2.29 (dt, J=2.0, 12.0 Hz, 2H), 1.94-1.85 (m, 2H), 1.81 (br d, J=13.6 Hz, 2H), 1.64-1.57 (m, 2H), 1.57-1.45 (m, 1H), 1.42-1.31 (m, 2H), 1.18 (s, 9H); 13C NMR (CD3OD) d 178.9, 171.1, 149.2 (dd, J=13, 241 Hz) 145.8 (dd, J=13, 230 Hz), 135.0 (br), 123.8 (dd, J=4, 6 Hz), 116.5 (d, J=19 Hz), 105.1 (d, J=23 Hz), 62.2, 55.0 53.2, 40.2, 38.6, 34.7, 31.1, 30.8, 26.4, 24.3, 23.5; HPLC-MS (ammonium acetate) [M+H]+=437.22.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:37])=[C:21]([NH:25][S:26]([C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.C([O-])=O.[NH4+]>>[F:36][C:30]1[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:29]=1[S:26]([NH:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:9]2[N:10]=[C:11]([CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[CH:2][N:7]=2)[C:20]=1[F:37])(=[O:27])=[O:28]
Reactant: O=S(=O)(Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1cc(F)ccc1F
Agent: O=C[O-]
Agent: [NH4+]
Product: O=S(=O)(Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccncn2)c1F)c1cc(F)ccc1F

Procedure:
Following a procedure analogous to the procedure described in Example 26 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (150 mg, 0.265 mmol) and ammonium formate (89 mg, 2.65 mmol), the title compound was obtained as a light yellow solid (89 mg, 63% yield). MS (ESI): 533.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=1.[OH-].[Na+].Cl>CO>[CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1
Reactant: COC(=O)c1ccc(OCCN(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C)CCOc1ccc(C(=O)O)cc1
Yield: 100 %

Procedure:
0.69 g (3.09 mmol) of methyl 4-(2-dimethylaminoethoxy)benzoate was dissolved in 15 ml of methanol. 4.64 ml of a 1N sodium hydroxide aqueous solution was added thereto and the mixture was refluxed under heating for 3 hours. After cooling, 4.64 ml of 1N hydrochloric acid was added and the mixture was concentrated to dryness. A chloroform-methanol mixed solution (1:1 (v/v)) was added to the residue. The solution was stirred for a while and filtered with Celite. The solvent was distilled off under reduced pressure to obtain 0.65 g (3.09 mmol) of 4-(2-dimethylaminoethoxy)benzoic acid shown below as a pale yellow solid. ##STR17## Its spectroscopic data are as follows: 1H-NMR (DMSO-d6) δ (ppm): 2.27 (6H, s), 2.71 (2H, t, J=5.6 Hz), 4.14 (2H, t, J=5.8 Hz), 7.01 (2H, d, J=8.8 Hz), 7.88 (2H, d, J=9.2 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Cl)[CH:16]=1.[CH:24]1([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.[I-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH:30][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:16]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CCl)c1
Reactant: NC1CCCCC1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CNC2CCCCC2)c1
Yield: 59.3 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-3-((cyclohexylamino)methyl)benzamide was prepared following Method C starting from N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(chloromethyl)benzamide (0.050 g; 0.144 mmol), cyclohexanamine (0.057 mL; 0.5 mmol), and sodium iodide (0.015 g; 0.1 mmol) in THF (3 mL), under a microwave irradiation at 150° C. for 5 minutes. Flash chromatography on silica gel (eluent 0 to 10% methanol in dichloromethane) furnished 0.035 g (58%) of the title compound as a white solid.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10](=[O:45])[CH2:11][C@H:12]([O:37][Si](C(C)(C)C)(C)C)[CH2:13][C:14](=[O:36])/[CH:15]=[CH:16]/[C:17]2[N:18]([CH:33]([CH3:35])[CH3:34])[C:19]3[C:24]([C:25]=2[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C1([C@@H](NC(=O)C[C@H](O)CC(=O)/C=C/C2C(C3CC3)=NC3C(C=2C2C=CC(F)=CC=2)=CC=CC=3)C)C=CC=CC=1>C(O)C>[C:1]1([C@@H:7]([NH:9][C:10](=[O:45])[CH2:11][C@H:12]([OH:37])[CH2:13][C:14](=[O:36])/[CH:15]=[CH:16]/[C:17]2[N:18]([CH:33]([CH3:34])[CH3:35])[C:19]3[C:24]([C:25]=2[C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)n1c(/C=C/C(=O)C[C@H](CC(=O)N[C@@H](C)c2ccccc2)O[Si](C)(C)C(C)(C)C)c(-c2ccc(F)cc2)c2ccccc21
Agent: C[C@H](NC(=O)C[C@H](O)CC(=O)/C=C/c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1)c1ccccc1
Agent: Cl
Solvent: CCO
Product: CC(C)n1c(/C=C/C(=O)C[C@@H](O)CC(=O)N[C@@H](C)c2ccccc2)c(-c2ccc(F)cc2)c2ccccc21

Procedure:
can be prepared from (E)-(R)-3-(tert-Butyl-dimethyl-silanyloxy)-7-[3-(4-fluoro-phenyl)-1-isopropyl-1H-indol-2-yl]-5-oxo-hept-6-enoic acid ((S)-1-phenyl-ethyl)-amide by deprotection with HCl in ethanol according to the procedure described above for the preparation of (E)-(R)-7-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3-hydroxy-5-oxo-hept-6-enoic acid ((S)-1-phenyl-ethyl)-amide. Chromatography on silicagel with ethyl acetate/n-hexanes (9:1) as eluent affords (E)-(R)-7-[3-(4-Fluoro-phenyl)-1-isopropyl-1H-indol-2-yl]-3-hydroxy-5-oxo-hept-6-enoic acid ((S)-1-phenyl-ethyl)-amide as a yellow foam. Rf=0.30 (TLC on silicagel, ethyl acetate/hexanes 9:1 as eluent). [α]D20=−35.5° (CH3OH, c=1) MS (ES+, m/z): 535 ([MNa]+, 100%); IR (KBr): 3307 (broad), 3061, 2973, 2932, 1645, 1590, 1539, 1495, 1452, 1421, 1371, 1339, 1273, 1221, 1155, 1138, 1105, 1095, 1048, 1016, 973, 910, 839, 815, 744, 719, 700 cm−1. Microanalysis: calculated (found) for C32H33FN2O3: 74.98 (74.20) % C, 6.49 (6.49) % H, 5.46 (5.49) % N, 3.71 (3.58) % F.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:26])[O:5][C:6]2[C:11]([C:12]=1[OH:13])=[CH:10][CH:9]=[C:8]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22]C=1)[CH:7]=2)#[N:2].C(C1C=CC(OC(C)CCOC2C=CC=C3C=2C(O)=C(C#N)C(=O)O3)=C(CCC)C=1O)(=O)C>>[C:1]([C:3]1[C:4](=[O:26])[O:5][C:6]2[C:11]([C:12]=1[OH:13])=[CH:10][CH:9]=[C:8]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:20]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:7]=2)#[N:2]
Reactant: N#Cc1c(O)c2ccc(OCCCCCc3ccccc3)cc2oc1=O
Agent: CCCc1c(OC(C)CCOc2cccc3oc(=O)c(C#N)c(O)c23)ccc(C(C)=O)c1O
Product: N#Cc1c(O)c2ccc(OCCCCc3ccccc3)cc2oc1=O

Procedure:
3-cyano-4-hydroxy-7-(5-phenylpentoxy) coumarin and 5-(3-[4-acetyl-3-hydroxy-2-n-propylphenoxy]butoxy)-3-cyano-4-hydroxy coumarin
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:28])[C:4]([C:6]1[C:11]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=2)(=[O:15])=[O:14])=[CH:10][C:9]([CH3:27])=[CH:8][N:7]=1)=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH3:35][O:36][CH2:37]Cl>C1COCC1>[CH3:1][O:2][N:3]([CH3:28])[C:4]([C:6]1[C:11]([N:12]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([C:23]([F:26])([F:24])[F:25])[CH:17]=2)(=[O:15])=[O:14])[CH2:35][O:36][CH3:37])=[CH:10][C:9]([CH3:27])=[CH:8][N:7]=1)=[O:5]
Reactant: CON(C)C(=O)c1ncc(C)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCN(c1cc(C)cnc1C(=O)N(C)OC)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
Prepared from 223 mg (0.51 mmol) of 3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-5-methyl-pyridine-2-carboxylic acid methoxy-methyl-amide, 352 mg of potassium carbonate and 116 μL of methoxymethyl chloride in 1 mL THF using procedure x. Yield: 200 mg of a white solid. LC-MSD, m/z for C18H19ClF3N3O5S [M+H]+=482.0, 484.0; HPLC retention time: 2.5 min.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=3)[CH:9]=[C:10]([NH:11][CH:12]3[CH2:14][CH2:13]3)[C:5]2=[N:4][CH:3]=1.B(O)(O)[C:27]1[S:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[S:35]1[C:27]([C:2]2[N:6]3[N:7]=[C:8]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=4)[CH:9]=[C:10]([NH:11][CH:12]4[CH2:14][CH2:13]4)[C:5]3=[N:4][CH:3]=2)=[CH:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:34]1=2
Reactant: COc1ccc(Nc2cc(NC3CC3)c3ncc(Br)n3n2)cc1OC
Reactant: OB(O)c1cc2ccccc2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(Nc2cc(NC3CC3)c3ncc(-c4cc5ccccc5s4)n3n2)cc1OC
Yield: 34.9 %

Procedure:
To a solution of 3-bromo-N8-cyclopropyl-N6-(3,4-dimethoxyphenyl)imidazo[1,2-b]pyridazine-6,8-diamine (66 mg, 0.163 mmol, 1.0 equiv) in acetonitrile (1.63 mL), was added benzo[b]thiophen-2-yl-2-boronic acid (58 mg, 0.327 mmol, 2.0 equiv), bis(triphenylphosphine)palladium(II) chloride (11 mg, 0.0163 mmol, 0.1 equiv), then sodium carbonate (1.63 mL, 1.0 M aqueous solution, 10 equiv). The reaction mixture was irradiated at 150° C. for 10 min. Purification by column chromatography gave 26 mg of the brown solid, 34%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[C:21]1([CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[Na+]>C(Cl)Cl.CN(C)C=O>[C:34]1([CH:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:28]2[CH2:29][CH2:30][N:31]([C:14]([C:10]3[CH:9]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=4)[CH:13]=[CH:12][CH:11]=3)=[O:16])[CH2:32][CH2:33]2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: Cc1ccc(-c2cccc(C(=O)O)c2)cc1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: Cc1ccc(-c2cccc(C(=O)N3CCN(C(c4ccccc4)c4ccccc4)CC3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
To a suspension of 4'-methylbiphenyl-3-carboxylic acid (2.2 g) in a mixture of methylene chloride (20 ml) and dimethylformamide (0.5 ml) was added thionyl chloride (1.48 g). The mixture was refluxed until the suspension dissolved, after which the temperature was allowed to cool to room temperature. To this solution was added 1-(diphenylmethyl)piperazine (3.94 g) in methylene chloride dropwise, and the reaction mixture allowed to stand overnight. Sodium hydroxide (30 ml of 1N) and 50 ml of methylene chloride was added, the organic layer separated, washed with brine, dried over sodium sulfate, and solvent removed under reduced pressure. The residue was chromatographed on silica gel, eluting with 25% ethyl acetate in heptane, to yield 3.8 g of 1-diphenylmethyl-4-(4'-methylbiphenyl-3-carbonyl)piperazine. The dihydrochloride salt was prepared and recrystallized from ethanol, m.p. 226° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl:65][C:66]1[CH:67]=[C:68]([CH:70]=[CH:71][C:72]=1[C:73]1[NH:77][N:76]=[N:75][N:74]=1)[NH2:69]>C(Cl)Cl>[Cl:65][C:66]1[CH:67]=[C:68]([NH:69][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[NH:10]2)=[O:30])[CH:70]=[CH:71][C:72]=1[C:73]1[NH:77][N:76]=[N:75][N:74]=1
Reactant: Nc1ccc(-c2nnn[nH]2)c(Cl)c1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(-c3nnn[nH]3)c(Cl)c2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.17 mmol) in methylene chloride (10 mL), HATU (Aldrich, 98 mg, 0.26 mmol) was added followed by the addition of DIPEA (0.150 mL, 0.855 mmol) and 3-chloro-4-(1H-tetrazol-5-yl) aniline (made below, 67 mg, 0.34 mmol). The mixture was stirred at rt for 1.5 hr. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on a reverse phase HPLC to give a white solid. 52 mg.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[O:17]COCC[Si](C)(C)C)[OH:10])=[CH:5][CH:4]=1)[CH3:2].O1CCCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>O>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[OH:17])[OH:10])=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(C(O)c2ccncc2OCOCC[Si](C)(C)C)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1ccc(C(O)c2ccncc2O)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 85.5 %

Procedure:
Next, to a mixture of (4-ethylphenyl)-[3-[2-(trimethylsilyl)ethoxymethoxy]pyridin-4-yl]-methanol (20 g, 55.6 mmol), tetrahydrofuran (500 ml) and water (20 ml), p-toluenesulfonic acid monohydrate (26.3 g, 138 mmol) was added. After stirring at 50° C. for 4 hours, at room temperature for 15.5 hours and at 50° C. for 3 hours, the reaction mixture was neutralized with saturated aqueous sodium bicarbonate and extracted three times with chloroform. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to give (4-ethylphenyl)-(3-hydroxypyridin-4-yl)-methanol (10.9 g, 86%) as a light-yellow amorphous substance.
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH:5]([OH:36])[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:35]=[CH:34][C:14]([C:15]([N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27][CH2:26][C:24]3=[O:25])[CH2:19][CH2:18]2)=[O:16])=[CH:13][CH:12]=1)[CH3:2].[CH3:39][N:40]=[C:41]=[O:42]>C(#N)C>[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4][CH:5]([O:36][C:41]([NH:40][CH3:39])=[O:42])[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([N:17]2[CH2:18][CH2:19][CH:20]([N:23]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27][CH2:26][C:24]3=[O:25])[CH2:21][CH2:22]2)=[O:16])=[CH:34][CH:35]=1)[CH3:38]
Reactant: CCN(CC)CC(O)CCCCOc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Reactant: CN=C=O
Solvent: CC#N
Product: CCN(CC)CC(CCCCOc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1)OC(=O)NC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-{1-[4-(6-Diethylamino-5-hydroxyhexyloxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (0.7 g) and methyl isocyanate (0.24 ml) are dissolved in acetonitril (20 ml), and thereto is added trifluroboran ethyl ether complex (0.35 ml) under ice-cooling, and the mixture is stirred at room temperature overnight. The reaction mixture is concentrated and purified by silica gel column chromatography (eluent; dichloromethane: methanol=20:1) to give 1-{1-[4-(6-diethylamino-5-methylaminocarbonyloxyhexyloxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (314 mg) as colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C@@H](C2C=CC=CC=2)C)[C@@H:10]([CH3:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[Pd+2].[OH-]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH2:14])[C@@H:10]([CH3:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H](N[C@H]1CCN(C(=O)OC(C)(C)C)C[C@@H]1C)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Reaction time: 8 h

Procedure:
(3S, 4S)-3-Methyl-4-(1-(R)-phenyl-ethylamino)-piperidine-1-carboxylic acid tert-butyl ester (510 mg, 1.60 mmol) was dissolved in methanol (15 mL). Palladium hydroxide (20%, 100 mg) was added and the mixture was shaken under a hydrogen atmosphere overnight at 55 psi. The reaction was filtered and concentrated in vacuo to provide the title compound as a clear oil. Wt.: 320 mg (88%). NMR (300 MHz, CDCl3) δ 4.06 (m, 1H), 3.96 (m, 1H), 2.73 (m, 1H), 2.34 (m, 2H), 1.77 (m, 1H), 1.43 (s, 9H), 1.27 (m, 2H), 0.94 (d, 3H); LC/MS m/z 215 (M+H)+.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[CH3:5][O:6][C:7]([NH:9][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH2:18][CH2:19][S:20][CH3:21])=[O:8]>C1(C)C=CC=CC=1>[CH3:5][O:6][C:7]([NH:9][N:10]([C:1]([Cl:4])=[O:2])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH2:18][CH2:19][S:20][CH3:21])=[O:8]
Reactant: O=C(Cl)Cl
Reactant: COC(=O)NNc1ccccc1OCCSC
Solvent: Cc1ccccc1
Product: COC(=O)NN(C(=O)Cl)c1ccccc1OCCSC
Temperature: 90 °C

Procedure:
80 ml of a 20% solution of phosgene in toluene are added at 20° C. to 14.1 g of 2-[2-(2-methylthioethoxy)-phenyl]-hydrazinecarboxylic acid methyl ester in 130 ml of toluene. The reaction mixture is subsequently heated for 3 hours at 90° C., and the solvent is then removed. Recrystallisation of the residue in ethyl alcohol yields the compound No. 1.1 of the formula ##STR63## having a melting point of 55°-57° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:6]=1[C:7](O)=[O:8])(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:21])=O>C(Cl)Cl.CN(C=O)C>[Cl:21][C:7]([C:6]1[CH:10]=[CH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:5]=1[O:4][C:1](=[O:3])[CH3:2])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)Oc1cc(C(F)(F)F)ccc1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)Oc1cc(C(F)(F)F)ccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2-acetoxy-4-trifluoromethyl-benzoic acid (180 mg, 0.73 mmol) in CH2Cl2 (6 mL) were added oxalyl chloride (0.08 mL, 0.91 mmol) and DMF (1 drop). The reaction mixture was stirred at room temperature for 1 hour. CH2Cl2 and excess oxalyl chloride were removed in vacuo. Acetic acid 2-chlorocarbonyl-5-trifluoromethylphenyl ester was obtained as a colorless oil (190 mg) and used in the following step without further purification. To a stirred solution of [1-Methyl-6-(5-methylaminopyridin-2-yloxy)-1H-indol-2-yl]{4-[4-(2,2,2-tri-fluoroethoxy)benzyl]piperazin-1-yl}methanone (340 mg, 0.6 mmol) in AcOEt (4 mL) were added triethylamine (0.13 mL, 0.91 mmol) and acetic acid 2-chlorocarbonyl-5-trifluoromethyl-phenyl ester (190 mg, 0.73 mmol) in AcOEt (3 mL) under ice cooling. The reaction mixture was stirred for 10 minutes at 0° C. Water was added to the reaction mixture, and the aqueous layer was extracted with AcOEt. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH=50:1) to afford 0.46 g of the title compound as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH2:12])[C:5]([O:7][CH3:8])=[O:6].[CH2:13]([O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>[N+](C1C=CC=CC=1)([O-])=O>[CH3:8][O:7][C:5]([C:4]1[CH:9]=[CH:10][C:11]2[N:12]=[C:24]([C:23]3[CH:26]=[CH:27][C:20]([O:19][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:21][CH:22]=3)[NH:1][C:2]=2[CH:3]=1)=[O:6]
Reactant: CCCCCCOc1ccc(C=O)cc1
Reactant: COC(=O)c1ccc(N)c(N)c1
Solvent: O=[N+]([O-])c1ccccc1
Product: CCCCCCOc1ccc(-c2nc3ccc(C(=O)OC)cc3[nH]2)cc1
Temperature: 145 °C
Reaction time: 48 h
Yield: 48.9 %

Procedure:
A mixture of Methyl 3,4-diaminobenzoate (1.84 g) and 4-hexyloxy benzaldehyde (2.30 g) in nitrobenzene (40 ml) was stirred for 48 hours at 145° C. After cooling, the mixture was evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel eluted with (n-hexane:ethyl acetate=2:1) gave 5-Methoxycarbonyl-2-(4-hexyloxyphenyl)benzimidazole (1.91 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:22]#[N:23])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[C:11]([C:18]([F:21])([F:20])[F:19])[CH:10]=2)=[CH:6][C:7]=1[NH2:8].[Cl:24][CH2:25][C:26](OCC)(OCC)OCC>C(#N)C.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[CH2:16]([O:15][C:12]1[CH:13]=[CH:14][C:9]([C:5]2[N:4]=[C:3]([C:22]#[N:23])[C:2]3[N:1]=[C:26]([CH2:25][Cl:24])[NH:8][C:7]=3[CH:6]=2)=[CH:10][C:11]=1[C:18]([F:21])([F:19])[F:20])[CH3:17]
Reactant: CCOC(CCl)(OCC)OCC
Reactant: CCOc1ccc(-c2cc(N)c(N)c(C#N)n2)cc1C(F)(F)F
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Product: CCOc1ccc(-c2cc3[nH]c(CCl)nc3c(C#N)n2)cc1C(F)(F)F
Yield: 54.5 %

Procedure:
To a solution of 3,4-diamino-6-(4-ethoxy-3-trifluoromethyl-phenyl)-pyridine-2-carbonitrile (1.86 g, 5.78 mmol) and 2-chloro-1,1,1-triethoxyethane (3.41 g, 17.3 mmol) in acetonitrile (40 ml) was added ytterbium triflate (180 mg, 5 mol %) and the mixture heated to reflux overnight. The mixture was concentrated under reduced pressure before partitioning between ethyl acetate and water. The organic layer was dried over sodium sulfate and concentrated before addition of diethylether. The precipitate was filtered and dried under a stream of air to afford 6-(4-ethoxy-3-trifluoromethyl-phenyl)-2-(chloromethyl)-1H-imidazo[4,5,c]pyridine-4-carbonitrile (1.2 g). 1H NMR (DMSO): δ 8.42 (s, 1H) 8.38 (d, 1H) 8.34 (s, 1H) 7.40 (d, 1H) 5.05 (s, 2H) 4.26 (q, 2H) 1.38 (t, 3H). MS m/z 381.1 (M+1)
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[C:15]([NH:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27]Cl)[CH:22]=1)([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(#N)C>[C:15]([NH:19][C:20]([C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=1)[CH2:27][N:7]1[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3][C@H:2]1[CH3:1])=[O:29])([CH3:18])([CH3:16])[CH3:17]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: CC(C)(C)NC(=O)c1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1Cc1cccc(C(=O)NC(C)(C)C)c1

Procedure:
(R)-tert-Butyl 3-methylpiperazine-1-carboxylate was added to a solution containing N-tert-butyl-3-(chloromethyl)benzamide (3.38 g, 14.9 mmol), potassium carbonate (4.11 g, 29.8 mmol) and sodium iodide (catalytic amount) in acetonitrile. The reaction was stirred under reflux for 2 hours. The acetonitrile was removed under reduced pressure. The resulting residue was taken up in dichloromethane and filtered. The filtrate was concentrated under vacuum to afford the title compound (5.82 g).