Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:12]2[CH2:15][CH2:14][CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7](Cl)[C:6]=12.[NH3:16].O>CC(O)C>[Br:1][C:2]1[N:3]=[C:4]([CH:12]2[CH2:15][CH2:14][CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH2:16])[C:6]=12
Reactant: N
Reactant: Clc1nccn2c(C3CCC3)nc(Br)c12
Solvent: O
Solvent: CC(C)O
Product: Nc1nccn2c(C3CCC3)nc(Br)c12
Temperature: 100 °C

Procedure:
A suspension of 1-bromo-8-chloro-3-cyclobutylimidazo[1,5-a]pyrazine (341 mg, 1.2 mmol) in IPA (3 mL) was saturated with NH3(g) at 0° C. for 3 min. The tube was sealed and heated at 100° C. for 17 h. H2O (10 mL) was added and the mixture was extracted with EtOAc (3×30 mL). The organic phase was washed with brine and concentrated under reduced pressure to provide the title compound as a white solid; 1H NMR (400 MHz, CDCl3) δ 7.30 (d, J=4.8 Hz, 1H), 6.97 (d, J=5.2 Hz, 1H), 5.65 (br, 2H), 3.70 (qud, J=0.8 Hz, 8.4 Hz, 1H), 2.55-2.35 (m, 4H), 2.18-1.93 (m, 2H); MS (ES+): m/z 267.1 (100), 269.1 (100) [MH+]; HPLC: tR=1.70 min (OpenLynx, polar—5 min).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:13][C:14]([C@@H:16]1[CH2:21][C@@H:20]2[C@@H:18]([CH2:19]2)[N:17]1[C:22](=[O:44])[CH2:23][N:24]1[C:32]2[C:27](=[CH:28][C:29]([O:33]CC3C=CC=CC=3)=[CH:30][CH:31]=2)[C:26]([C:41](=[O:43])[CH3:42])=[N:25]1)=[O:15]>CO.[Pd]>[F:1][C:2]1[C:7]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:13][C:14]([C@@H:16]1[CH2:21][C@@H:20]2[C@@H:18]([CH2:19]2)[N:17]1[C:22](=[O:44])[CH2:23][N:24]1[C:32]2[C:27](=[CH:28][C:29]([OH:33])=[CH:30][CH:31]=2)[C:26]([C:41](=[O:43])[CH3:42])=[N:25]1)=[O:15]
Reactant: CC(=O)c1nn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)Nc2cccc(OC(F)(F)F)c2F)c2ccc(OCc3ccccc3)cc12
Agent: [Pd]
Solvent: CO
Product: CC(=O)c1nn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)Nc2cccc(OC(F)(F)F)c2F)c2ccc(O)cc12
Reaction time: 1 h

Procedure:
A mixture of (1R,3S,5R)-2-[2-(3-acetyl-5-benzyloxy-indazol-1-yl)-acetyl]-2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid (2-fluoro-3-trifluoromethoxy-phenyl)-amide (2.0 g, 3.28 mmol) and Pd/C (10%, 165 mg) in MeOH (40 mL) was stirred under a H2 atmosphere for 1 h. The mixture was filtered through a celite pad and concentrated. The product was used in the next step without further purification. MS (UPLC-MS): 521 [M+H]+; tR (HPLC conditions f): 2.02 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C@@H:11]1/[CH:17]=[CH:18]/[CH:19]([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[H][H]>[Pd].CO>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C@@H:11]1[CH2:17][CH2:18][CH:19]([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCC(O)/C=C/[C@H]1CCCC(=O)N1CCCCCCC(=O)OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCCCC(O)CC[C@H]1CCCC(=O)N1CCCCCCC(=O)OC
Reaction time: 18.5 h
Yield: 8.4 %

Procedure:
Palladium on carbon (10 wt. %, 7 mg) was added to a solution of 7-[(R)-2-((E)-3-hydroxy-oct-1-enyl)-6-oxo-piperidin-1-yl]-heptanoic acid methyl ester (33 mg, 0.90 mmol) in MeOH (3.0 mL). A hydrogen atmosphere was established by evacuating and refilling with hydrogen (3×) and the reaction mixture was stirred under a balloon of hydrogen for 18.5 h. The reaction mixture was filtered through celite, washing with MeOH, and the filtrate was concentrated in vacuo to afford 28 mg (84%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:16]=[CH:17][C:18]([C:19]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:21])=[CH:22][CH:23]=1
Reactant: C1CCNC1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N2CCCC2)cn1
Yield: 98 %

Procedure:
As described for example 191, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.64 mmol) was converted, using pyrrolidine instead of 2-aminoethyl isopropylether, to the title compound (229 mg, 98%) which was obtained as a colourless. MS: m/e=364.3 [M+H]′.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=O)=[CH:8][CH:7]=2.CCN(C(C)C)C(C)C.[C:28]1([C:34]2[N:39]=[N:38][C:37]([NH:40][NH2:41])=[CH:36][CH:35]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([C:13]([CH3:18])([CH3:17])[C:14]([NH:41][NH:40][C:37]1[N:38]=[N:39][C:34]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:35][CH:36]=1)=[O:16])=[CH:8][CH:7]=2
Reactant: NNc1ccc(-c2ccccc2)nn1
Reactant: COc1cnc2ccc(C(C)(C)C(=O)O)cc2c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cnc2ccc(C(C)(C)C(=O)NNc3ccc(-c4ccccc4)nn3)cc2c1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
A suspension of 2-(3-methoxyquinolin-6-yl)-2-methylpropanoic acid (92 mg, 375 μmol), DIEA (66 μl, 375 μmol), and o-(7-azabenzotriazol-1-yl)-n,n,n′,n-tetramethyl uronium hexafluorophosphate (143 mg, 375 μmol) in DMF was stirred for 2 h at 23° C. To the solution was added 1-(6-phenylpyridazin-3-yl)hydrazine (70 mg, 375 μmol) and stirred for 72 h at 23° C. Reaction partitioned between 9:1 CHCl3/IPA (25 mL) and 1M NaOH (5 mL). Organic dried over MgSO4 the concentrated to a solid from toluene under reduced pressure. Solid triturated with ACN (2 mL) and collected by filtration. 2-(3-methoxyquinolin-6-yl)-2-methyl-N′-(6-phenylpyridazin-3-yl)propanehydrazide isolated as a white solid. MS (ESI pos. ion) m/z: 414 (MH+). Calc'd exact mass for C24H23N5O2: 413.
Reaction SMILES: [N+:1]([C:4]1[CH:39]=[CH:38][C:7]([C:8]([NH:10][C:11]2[C:12](=[O:37])[N:13]([CH2:23][C:24]([NH:26][CH:27]([CH:34]([CH3:36])[CH3:35])[C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])=[O:25])[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][CH:16]=2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.O.O.[Sn](Cl)Cl.O.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][C:11]2[C:12](=[O:37])[N:13]([CH2:23][C:24]([NH:26][CH:27]([CH:34]([CH3:36])[CH3:35])[C:28](=[O:33])[C:29]([F:32])([F:30])[F:31])=[O:25])[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)=[O:9])=[CH:38][CH:39]=1
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(NC(=O)c2ccc([N+](=O)[O-])cc2)c1=O)C(=O)C(F)(F)F
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(NC(=O)c2ccc(N)cc2)c1=O)C(=O)C(F)(F)F
Temperature: 25 °C

Procedure:
To a suspension of 2-[3-(4-nitrobenzoylamino)-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl]-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide (0.38 g) in ethanol (20 mL), was added tin(II) chloride dihydrate (0.79 g). This mixture was heated to reflux for 1 h then cooled to ambient temperature. The reaction mixture was poured into water and the pH adjusted to 7-8 with saturated sodium bicarbonate. The aqueous layer was extracted with ethyl acetate, and the organic extract washed (water, brine), dried (magnesium sulfate), and evaporated. The crude solid was triturated with diethyl ether:hexane (1:1), then further purified by chromatography, eluting with dichloromethane:methanol (gradient, 99.5:0.5, 99:1, 98.5:1.5), to give the title compound as a pale yellow solid; TLC: Rf =0.32, dichloromethane:methanol (98:2); MS: m/z=515(M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[N:6][CH:7]=1.OS(O)(=O)=O.C([O-])(O)=O.[Na+].[CH2:22](O)[CH3:23]>>[CH2:22]([O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:7][N:6]=1)[CH3:23]
Reactant: Nc1ccc(CC(=O)O)nc1
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)Cc1ccc(N)cn1
Temperature: 25 °C
Reaction time: 16.5 h

Procedure:
To a solution of (5-amino-2-pyridinyl)acetic acid (1.46 g, 9.6 mmol, Daisley; R. W.; Hanbali, J. R., Synthetic Communications., 1981, 11(9), 743.) in ethanol was added conc. H2SO4 and stirred for 16.5 h under hydrogen atmosphere at room temperature. The mixture was neutralized with saturated NaHCO3 aqueous solution and the solvent was removed. The mixture was diluted with water and extracted with ethyl acetate (5×20 ml). The organic layer was washed with brine, dried (MgSO4) and concentrated to give 1.2 g of title compound as brown oil.
Reaction SMILES: [NH:1]([C:8]1[S:12][N:11]=[C:10]([C:13]([Cl:16])([Cl:15])[Cl:14])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17][C:18]([Cl:23])([Cl:22])[C:19](Cl)=[O:20]>C1(C)C=CC=CC=1>[C:2]1([N:1]([C:8]2[S:12][N:11]=[C:10]([C:13]([Cl:16])([Cl:15])[Cl:14])[N:9]=2)[C:19](=[O:20])[C:18]([Cl:23])([Cl:22])[Cl:17])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: ClC(Cl)(Cl)c1nsc(Nc2ccccc2)n1
Solvent: Cc1ccccc1
Product: O=C(N(c1ccccc1)c1nc(C(Cl)(Cl)Cl)ns1)C(Cl)(Cl)Cl
Yield: 90.9 %

Procedure:
A solution of 14.7 grams (0.05 mole) 5-anilino-3-trichloromethyl-1,2,4-thiadiazole and 18.0 grams (0.1 mole) trichloroacetyl chloride in 200 milliliters toluene was refluxed at about 110° C. for 20 hours. After removal of the low boiling material in vacuo, the resulting residue was recrystallized from benzene to give 20.0 grams (91% yield) pure product; m.p. 158° C.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([OH:66])[CH2:21][NH:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32]([C:34]3[CH:35]=[C:36]([S:40]([C:43]4[CH:44]=[C:45]5[C:50](=[C:51]([CH3:53])[CH:52]=4)[N:49]=[CH:48][C:47]([C:54]([NH2:56])=[O:55])=[C:46]5[NH:57][C:58]4[CH:63]=[CH:62][CH:61]=[C:60]([O:64][CH3:65])[CH:59]=4)(=[O:42])=[O:41])[CH:37]=[CH:38][CH:39]=3)=[O:33])=[CH:27][CH:26]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)C1C=CC=CC=1>CCO.C1COCC1.[Pd]>[OH:66][C@H:20]([C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16](=[O:19])[NH:17]2)[CH2:21][NH:22][CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]([NH:31][C:32]([C:34]2[CH:35]=[C:36]([S:40]([C:43]3[CH:44]=[C:45]4[C:50](=[C:51]([CH3:53])[CH:52]=3)[N:49]=[CH:48][C:47]([C:54]([NH2:56])=[O:55])=[C:46]4[NH:57][C:58]3[CH:63]=[CH:62][CH:61]=[C:60]([O:64][CH3:65])[CH:59]=3)(=[O:41])=[O:42])[CH:37]=[CH:38][CH:39]=2)=[O:33])=[CH:29][CH:30]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(CCNC[C@H](O)c6ccc(OCc7ccccc7)c7[nH]c(=O)ccc67)cc5)c4)cc23)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(CCNC[C@H](O)c6ccc(O)c7[nH]c(=O)ccc67)cc5)c4)cc23)c1
Yield: 60.7 %

Procedure:
Intermediate 144 (119 mg) was dissolved in a mixture of EtOH (2 mL) and THF (3.5 mL) and hydrogenated in the presence of 10% Pd/C at rt and ambient pressure. After completion, the reaction was filtered and the filtrate purified by reverse-phase preparatory-LC to give the title compound as a yellow solid (65 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6](=O)[CH2:5]2.B.CO.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][CH2:6][CH2:5]2
Reactant: O=C1Cc2cc(F)c(F)cc2N1
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Fc1cc2c(cc1F)NCC2
Temperature: 70 °C

Procedure:
Under an argon atmosphere 0.30 g (1.8 mmol) 5,6-difluoroxindole were dissolved in 10 mL THF and 3.0 mL of a 1 molar borane solution in THF were added dropwise. Then the reaction mixture was heated to 70° C. for 2 h and then cooled. After mixing with 3 mL MeOH another 5 mL of a 4N aqueous hydrochloric acid solution were added and the mixture was refluxed for 1 h. The organic phase was evaporated down, the aqueous phase was washed with DCM and then made alkaline with a 4N aqueous sodium hydroxide solution and extracted several times with EtOAc. The combined organic phases were dried on sodium sulphate, filtered and evaporated down.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH:5]([CH2:15][O:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[CH2:6][S:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)C.[OH-].[Na+].O>C(O)C>[CH2:8]([S:7][CH2:6][CH:5]([CH2:15][O:16][CH:17]1[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1)[C:4]([OH:23])=[O:3])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)C(COC1CCOCC1)CSCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C(COC1CCOCC1)CSCc1ccccc1

Procedure:
A solution of 3-benzylsulfanyl-2-(tetrahydro-pyran-4-yloxymethyl)-propionic acid ethyl ester (1.27 g) in ethanol (30 ml) was treated with 2N NaOH (9.4 ml) overnight. Usual water work up gave the title compound as white solid; MS: 333 (M+Na), 311 (M+1); LCMS retention time 3.7 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:15]([C:16]([OH:18])=[O:17])[CH:14]3[N:9]([CH2:10][CH2:11][C:12]4[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=43)[C:8](=[O:23])[C:7]=2[CH:24]=1.S(Cl)(Cl)=O.[CH3:29]O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C@@H:15]([C:16]([O:18][CH3:29])=[O:17])[C@@H:14]3[N:9]([CH2:10][CH2:11][C:12]4[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=43)[C:8](=[O:23])[C:7]=2[CH:24]=1
Reactant: CO
Reactant: COc1ccc2c(c1)C(=O)N1CCc3ccccc3C1C2C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H]1c2ccc(OC)cc2C(=O)N2CCc3ccccc3[C@H]12

Procedure:
A suspension of 14 g (43.3 mmol ) of 10-methoxy-8-oxo-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine-13-carboxylic acid in 100 ml of methanol is prepared in a 500 ml three-necked round-bottomed flask, 3.2 ml (44.11 mmol) of thionyl chloride are added dropwise and the mixture is heated to reflux for 4 h.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:29])[C:8]2[CH:13]=[N:12][C:11](S(C)(=O)=O)=[N:10][C:9]=2[N:18]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[CH2:25][CH2:24][CH2:23]3)[CH:19]=1)=[O:5])[CH3:2].[CH3:30][N:31]([CH2:33][C:34]1[CH:35]=[C:36]([NH2:40])[CH:37]=[CH:38][CH:39]=1)[CH3:32]>CC(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:29])[C:8]2[CH:13]=[N:12][C:11]([NH:40][C:36]3[CH:37]=[CH:38][CH:39]=[C:34]([CH2:33][N:31]([CH3:32])[CH3:30])[CH:35]=3)=[N:10][C:9]=2[N:18]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[CH2:25][CH2:24][CH2:23]3)[CH:19]=1)=[O:5])[CH3:2]
Reactant: CN(C)Cc1cccc(N)c1
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Solvent: CC(C)O
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3cccc(CN(C)C)c3)ncc2c1=O
Temperature: 90 °C
Reaction time: 3 h
Yield: 46.3 %

Procedure:
8-Indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (105 mg, 0.25 mmol) and 3-dimethylaminomethyl-phenylamine (38 mg, 0.25 mmol) were combined in iPrOH (2 mL) and heated to 90° C. After 3 h, the reaction mixture was concentrated and purified by preparative HPLC (30 mL/min 5-100% MeCN/H2O gradient over 10 min) and lyophilized to provide 56 mg of 2-(3-Dimethylaminomethyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.31 (br s, 1H), 8.98 (br s, 1H), 8.51 (s, 1H), 8.39 (s, 1H), 7.00-7.53 (m, 7H), 4.28-4.40 (m, 2H), 3.64 (br s, 2H), 2.88-3.09 (m, 4H), 2.40 (s, 6H), 2.05-2.25 (m, 2H), 1.32-1.40 (m, 3H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:30])[CH2:22][CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:30])[CH2:22][CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(CCc1cccnc1)NCCCCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CCc1cccnc1)NCCCCC1CCN(C(=O)c2ccccc2)CC1

Procedure:
3.48 ml (30 mmol) benzoyl chloride, 8.7 g (30 mmol) N-(4-piperidin-4-yl-butyl)-3-(pyridin-3-yl)-propionamide and 16.6 g (120 mmol) potassium carbonate are stirred in 160 ml DMF at RT overnight. Subsequently, this is filtered and the filtrate is concentrated under vacuum to a large extent. The residue is taken up in 400 ml CHCl3 and washed twice, each with 100 ml water. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum. The residue is chromatographically purified over silica gel with CHCl3/CH3OH (95/5) and precipitates as an amorphous solid after drawing off the solvent.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:13]2[O:12][CH:11]([C:14]([O:16][CH2:17]C)=[O:15])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)[C:2]#[CH:3].C1C(=O)N([Br:26])C(=O)C1>CC(C)=O.[N+]([O-])([O-])=O.[Ag+]>[Br:26][C:3]#[C:2][CH2:1][O:4][C:5]1[C:13]2[O:12][CH:11]([C:14]([O:16][CH3:17])=[O:15])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: C#CCOc1cccc2c1OC(C(=O)OCC)C2
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC(C)=O
Product: COC(=O)C1Cc2cccc(OCC#CBr)c2O1

Procedure:
67.98 g (0.293 mol) of the compound from Example 46 and 61 g (0.340 mol) of NBS are stirred at 20° C. for 30 minutes in the presence of 5 g of AgNO3 in 2.5 l of acetone. The mixture is concentrated to about 500 ml, poured onto 2 l of ice/water and shaken twice with 500 ml of ethyl acetate each time. The mixture is filtered, and the ethyl acetate phases are dried over Na2SO4 and evaporated. The residue is flash chromatographed on silica gel (eluent: petroleum ether/acetone 3:1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:5][CH:6]=1.[CH3:12][S:13](Cl)(=[O:15])=[O:14]>N1C=CC=CC=1>[CH3:12][S:13]([NH:1][C:2]1[CH:3]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:5][CH:6]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1cc(N)cs1
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(NS(C)(=O)=O)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 4-aminothiophene-2-carboxylate (Int. 41) (theoretical 1.785 mmol) in pyridine (20 ml), methanesulfonyl chloride (0.239 ml, 3.07 mmol) was added and the mixture was stirred overnight at RT. The solvent was evaporated and the residue was partitioned between 1N HCl and EtOAc; the aqueous phase was extracted with EtOAc and the combined organic layers were dried over sodium sulfate and evaporated to afford ethyl 4-(methylsulfonamido)thiophene-2-carboxylate (Int. 42) which was used without any additional purification (370 mg, 1.484 mmol, MS/ESI+249.8 [MH]+).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[CH:15]1[CH2:24][CH2:23][C:18]2(OCC[O:19]2)[CH2:17][CH2:16]1.Cl.C(=O)(O)[O-].[Na+]>CO>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[CH:15]1[CH2:24][CH2:23][C:18](=[O:19])[CH2:17][CH2:16]1
Reactant: COCOc1ccc(C2CCC3(CC2)OCCO3)c(OCOC)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COCOc1ccc(C2CCC(=O)CC2)c(OCOC)c1
Reaction time: 1.5 h
Yield: 78.9 %

Procedure:
A round bottomed flask equipped with magnetic stirrer was charged with 8-[2,4-bis(methoxymethoxy)phenyl]-1,4-dioxaspiro[4.5]decane (3.20 g 9.47 mmol) and methanol (50 ml). Over a 20 min period, aqueous hydrochloric acid (50 ml, 1.00M) was added to the stirred solution, at room temperature and the reaction mixture stirred for 1.5 hr. Solid sodium bicarbonate was added until the reaction mixture was neutralised and the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate (30 ml) and water (10 ml), and the aqueous layer was extracted with ethyl acetate (3×20 ml). The combined organic layers were washed with brine (10 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified via flash column chromatography (SiO2, ethyl acetate/petroleum ether, 1:4, v/v), affording the title compound (2.20 g, 60%) as a white powder. δH(CDCl3) 1.85-1.96 (2H, m), 2.14-2.22 (2H, m), 2.46-2.59 (4H, m), 3.39 (1H, tt), 3.49 (3H, s), 3.52 (3H, s), 5.16 (2H, s), 5.23 (2H, s), 6.67-6.71 (1H, m), 6.85 (1H, m), 7.08 (1H, d).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][N:4]=1)#[N:2].CCN(CC)CC.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1>[OH:8][CH2:7][C:6]1[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[N:4][CH:5]=1
Reactant: N#Cc1ccc(C(=O)O)cn1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1ccc(CO)cn1
Reaction time: 0.25 h
Yield: 36.8 %

Procedure:
To a solution of 6-cyanonicotinic acid (12 g, 0.081 mol; see step (i) above) in THF at 0° C., Et3N (12.4 mL, 0.0892 mol) was added followed by ethyl chloroformate (8.53 mL, 0.0892 mol). The reaction mixture was stirred for 15 min and NaBH4 (6.14 g, 0.162 mol) was added. Then the mixture was stirred at RT overnight, quenched with water and extracted with methylene chloride. The organic layer was concentrated and purified by column chromatography to yield 4 g (20%) of the alcohol.
Reaction SMILES: [Br-].[CH3:2][C:3]1([CH3:35])[C:11]2[C:6](=[CH:7][C:8]([CH:12]([P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH3:13])=[CH:9][CH:10]=2)[C:5]([CH3:34])([CH3:33])[CH2:4]1.[C:36]([C:39]1[CH:46]=[CH:45][C:42]([CH:43]=O)=[CH:41][CH:40]=1)(=[O:38])[CH3:37]>>[CH3:2][C:3]1([CH3:35])[C:11]2[C:6](=[CH:7][C:8](/[C:12](/[CH3:13])=[CH:43]/[C:42]3[CH:45]=[CH:46][C:39]([C:36](=[O:38])[CH3:37])=[CH:40][CH:41]=3)=[CH:9][CH:10]=2)[C:5]([CH3:34])([CH3:33])[CH2:4]1
Reactant: CC(c1ccc2c(c1)C(C)(C)CC2(C)C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)c1ccc(C=O)cc1
Agent: [Br-]
Product: CC(=O)c1ccc(/C=C(\C)c2ccc3c(c2)C(C)(C)CC3(C)C)cc1

Procedure:
In a manner analogous to that described in Example 1, from [1-(1,1,3,3-tetramethyl-5-indanyl)ethyl]-triphenylphosphonium bromide and 4-acetyl-benzaldehyde there can be obtained 4'-[(E)-2-(1,1,3,3-tetramethyl-5-indanyl)propenyl]-acetophenone of melting point 130°-131° C.
Reaction SMILES: [NH2:1][C:2]1[C:22]([Cl:23])=[CH:21][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]#[N:18])[CH2:11][C@H:10]2[O:19][CH3:20])=[O:7])=[C:4]([O:24][CH3:25])[CH:3]=1.N.[H][H]>[Ni].CO>[NH2:1][C:2]1[C:22]([Cl:23])=[CH:21][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][C@H:10]2[O:19][CH3:20])=[O:7])=[C:4]([O:24][CH3:25])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCC#N)C[C@H]1OC
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCN)C[C@H]1OC
Yield: 13 %

Procedure:
A mixture of 3 parts of cis-4-amino-5-chloro-N-[1-(2-cyanoethyl)-3-methoxy-4-piperidinyl]-2-methoxybenzamide and 200 parts of methanol, saturated with ammonia was hydrogenated at normal pressure and at 20° C. with 2 parts of Raney-nickel catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in trichloromethane. The solution was washed with water, dried, filtered and evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried in vacuo at 60° C., yielding 0.4 parts (13%) of cis-4-amino-N-[1-(3-aminopropyl)-3-methoxy-4-piperidinyl]-5-chloro-2-methoxybenzamide; mp. 174.8 (interm. 3).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])[C:5]([OH:7])=[O:6].O[N:14]1[C:18](=[O:19])[CH2:17][CH2:16][C:15]1=[O:20].C1(N=C=NC2CCCCC2)CCCCC1>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])[C:5]([O:7][N:14]1[C:18](=[O:19])[CH2:17][CH2:16][C:15]1=[O:20])=[O:6]
Reactant: Cc1cc(C(=O)O)cc(C)c1O
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: Cc1cc(C(=O)ON2C(=O)CCC2=O)cc(C)c1O

Procedure:
treating 3,5-dimethyl-4-hydroxybenzoic acid with N-hydroxysuccinimide and 1,3-dicyclohexylcarbodiimide to produce succinimidyl 3,5-dimethyl-4-hydroxybenzoate;