Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([CH3:25])=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[C:5]2[N:6]([N:8]=[C:9]([NH:11][C:12](=[O:14])[CH3:13])[N:10]=2)[CH:7]=1.C([Sn](CCCC)(CCCC)[C:31]1[N:35]([C:36]2[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[CH:38][CH:37]=2)[N:34]=[CH:33][CH:32]=1)CCC>>[C:40]([C:39]1[CH:38]=[CH:37][C:36]([N:35]2[C:31]([C:2]3[C:3]([CH3:25])=[C:4]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:24])[F:23])[CH:16]=4)[C:5]4[N:6]([N:8]=[C:9]([NH:11][C:12](=[O:14])[CH3:13])[N:10]=4)[CH:7]=3)=[CH:32][CH:33]=[N:34]2)=[CH:43][CH:42]=1)#[N:41]
Reactant: CC(=O)Nc1nc2c(-c3cccc(C(F)(F)F)c3)c(C)c(Br)cn2n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1-c1ccc(C#N)cc1
Product: CC(=O)Nc1nc2c(-c3cccc(C(F)(F)F)c3)c(C)c(-c3ccnn3-c3ccc(C#N)cc3)cn2n1

Procedure:
The title compound was prepared from the N-[6-bromo-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-acetamide (Int. 18, 65 mg, 0.157 mmol) and 4-(5-tributylstannanyl-pyrazol-1-yl)-benzonitrile (Int. 3, 79 mg, 0.173 mmol) using a similar method to that used in Example 1 (Step 4) (26 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][C@@H:27]([OH:31])[CH2:26]1>>[N:20]1([C:18]([C:15]2[CH:16]=[CH:17][C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:25]4[CH2:30][CH2:29][CH2:28][C@@H:27]([OH:31])[CH2:26]4)=[CH:7][CH:8]=3)=[CH:13][CH:14]=2)=[O:19])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(c1ccc(-c2ccc(OCCCCl)cc2)cc1)N1CCCC1
Reactant: O[C@@H]1CCCNC1
Product: O=C(c1ccc(-c2ccc(OCCCN3CCC[C@@H](O)C3)cc2)cc1)N1CCCC1

Procedure:
The product from Example 11A and (3R)-3-piperidinol were processed as described in Example 10F to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7](N)=[CH:6][C:5]=1[NH:11][C:12](=[O:23])[C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1.N([O-])=[O:26].[Na+].OS(O)(=O)=O>FC(F)(F)C(O)=O.O>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([OH:26])=[CH:6][C:5]=1[NH:11][C:12](=[O:23])[C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1
Reactant: O=N[O-]
Reactant: COC(=O)c1ccc(N)cc1NC(=O)c1ccc(C(C)(C)C)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(O)cc1NC(=O)c1ccc(C(C)(C)C)cc1
Reaction time: 0.08 h
Yield: 71 %

Procedure:
To a solution of afford 4-amino-2-(4-tert-butyl-benzoylamino)-benzoic acid methyl ester (0.711 g, 2.18 mmol) in trifluoroacetic acid cooled to 0° C. was added NaNO2 (0.182 g, 2.64 mmol, 1.21 eq) as a solution in water (4 mL) and the reaction was stirred 5 minutes. It was then added dropwise to 30% solution of H2SO4 (50 mL) at 65° C. and stirred for 15 minutes. It was extracted with ethyl acetate, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography using ethyl acetate/hexanes (20/80) to afford 2-(4-tert-butyl-benzoylamino)-4-hydroxy-benzoic acid methyl ester (0.508, 71%) as a white solid. mp=146.0-148.4° C.; mass spectrum (−ES, M−H) m/z 326. 1H NMR (400 MHz, DMSO-d6); δ 11.95 (bs, 1H), 10.60 (bs, 1H), 8.26 (d, 1H), 7.88 (m, 3H), 7.62 (d, 2H), 6.58 (dd, 1H), 3.85 (s, 3H), 1.32 (s, 9H). Elemental analysis: Calcd. for C19H21NO4: C, 69.71; H, 6.47; N, 4.28. Found: C, 69.20; H, 6.54; N, 4.17.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)[N:15]=[CH:14]3)=[N:8][CH:9]=1)([O-])=O.C(OCC)(=O)C>CO.[Pt](=O)=O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)[N:15]=[CH:14]3)=[N:8][CH:9]=1
Reactant: N#Cc1ccc(-n2ncc3cc(Oc4ccc([N+](=O)[O-])cn4)ccc32)cc1
Agent: O=[Pt]=O
Solvent: CO
Solvent: CCOC(C)=O
Product: N#Cc1ccc(-n2ncc3cc(Oc4ccc(N)cn4)ccc32)cc1
Reaction time: 3 h
Yield: 96.7 %

Procedure:
To a solution of 4-[5-(5-Nitro-pyridin-2-yloxy)-indazol-1-yl]-benzonitrile (0.79 mmol) in 10 mL of methanol was added 10 mL of ethyl acetate and 30 mg of platinum (IV) oxide. After shaking under 50 psi of H2 for 3 h, the mixture was filtered through a pad of Celite and concentrated in vacuo, affording 0.25 g of 4-[5-(5-Amino-pyridin-2-yloxy)-indazol-1-yl]-benzonitrile.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[Br:24][CH2:25][C:26](Cl)=[O:27].C(N(CC)C(C)C)(C)C>ClCCl>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:26](=[O:27])[CH2:25][Br:24])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: O=C(Cl)CBr
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(NC(=O)CBr)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Acylation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (130 mg) with bromoacetyl chloride (69 l) and N,N-diisopropylethylamine (121 l) in dichloromethane (10 ml) was performed according to the method described in example 6.
Reaction SMILES: O[Li].O.C[O:5][C:6](=[O:46])[CH2:7][C:8]1[CH:45]=[CH:44][CH:43]=[CH:42][C:9]=1[CH2:10][CH2:11][C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:15]=[C:14]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([CH:29]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]3)=[N:27][CH:28]=2)[N:13]=1>O.C1COCC1>[C:38]([O:37][C:35]([N:32]1[CH2:31][CH2:30][CH:29]([C:26]2[N:27]=[CH:28][C:23]([NH:22][C:14]3[N:13]=[C:12]([CH2:11][CH2:10][C:9]4[CH:42]=[CH:43][CH:44]=[CH:45][C:8]=4[CH2:7][C:6]([OH:46])=[O:5])[C:17]([C:18]([F:19])([F:20])[F:21])=[CH:16][N:15]=3)=[CH:24][CH:25]=2)[CH2:34][CH2:33]1)=[O:36])([CH3:41])([CH3:39])[CH3:40]
Reactant: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)nc2)ncc1C(F)(F)F
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(=O)O)n3)cn2)CC1
Temperature: 40 °C

Procedure:
LiOH.H2O (297 mg, 7.1 mmol) was added to a stirred solution of tert-butyl 4-(5-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate (A45) (85 mg, 0.14 mmol) in H2O (2 mL) and THF (20 mL) and the resulting mixture heated at 40° C. for 18 hours. The volatiles were removed in vacuo and the residue was partitioned between EtOAc (100 mL), and aqueous 2 M HCl (50 mL). The layers were separated and the organics washed with water (100 mL), brine (50 mL) and dried over MgSO4. The volatiles were removed in vacuo to give the title compound A46 as an orange foam (74 mg, 89%); 1H NMR (400 MHz, d4-MeOH) δ 9.00 (d, J=1.8 Hz, 1H), 8.66 (s, 1H), 8.36 (dd, J=8.7, 2.6 Hz, 1H), 7.54 (d, J=8.7 Hz, 1H), 7.28-7.10 (m, 4H), 4.25 (d, J=13.4 Hz, 2H), 3.72 (s, 2H), 3.19-3.09 (m, 4H), 3.07-2.83 (m, 3H), 1.94 (d, J=12.7 Hz, 2H), 1.72 (m, 2H), 1.48 (s, 9H). LCMS-A: rt 5.707 min; m/z 586 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([CH3:15])[CH:13]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.O>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([CH3:15])=[CH:13][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: CC(C=O)Cc1ccc(C(C)(C)C)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=CN1CCCCC1)Cc1ccc(C(C)(C)C)cc1

Procedure:
6.54 kg of 3-(p-tert.butyl-phenyl)-2-methyl-propionaldehyde and 3 kg of piperidine are heated at reflux overnight in 4.54 liters of toluene in a water-separator under nitrogen gasification and the toluene is distilled in vacuo. The residue is distilled in vacuo. There is obtained pure 1-[3-(p-tert.butyl-phenyl)-2-methyl-1-propenyl]-piperidine of boiling point 118°-120° C./0.026 Torr.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH:15]1([C:18]2[C:19]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])=[CH:20][C:21]3[O:25][C:24]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[C:23]([C:33]([NH:35][CH3:36])=[O:34])[C:22]=3[CH:37]=2)[CH2:17][CH2:16]1.C([O-])([O-])=O.[K+].[K+]>CN(C)P(N(C)C)(N(C)C)=O.CCOC(C)=O>[CH:15]1([C:18]2[C:19]([N:38]([C:2]3[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=3)[C:7]([O:9][CH3:10])=[O:8])[S:39]([CH3:42])(=[O:41])=[O:40])=[CH:20][C:21]3[O:25][C:24]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[C:23]([C:33](=[O:34])[NH:35][CH3:36])[C:22]=3[CH:37]=2)[CH2:17][CH2:16]1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(C3CC3)cc12
Reactant: COC(=O)c1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 60 °C
Reaction time: 72 h
Yield: 55.4 %

Procedure:
A mixture of methyl 5-fluoro-2-nitrobenzoate (2.138 g, 10.73 mmol), 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (4.0 g, 9.94 mmol) and K2CO3 (4.12 g, 29.8 mmol) in hexamethylphosphoramide (25 mL) in a seal tube was stirred at 60° C. for 3 days. Cooled down to room temperature, the mixture was diluted with EtOAc and then filtered through a pad of Celite. The filtrate was washed with water and brine and dried over Na2SO4. Concentrated under reduced pressure, the residue was purified by flashing chromatography on silica gel eluted with 0-50% EtOAc in hexane to give the product (3.2 g, 55%) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.00 (d, J=9.17 Hz, 1H) 7.89 (dd, J=8.78, 5.27 Hz, 2H) 7.55 (d, J=9.37 Hz, 2H) 7.50 (dd, J=9.07, 2.63 Hz, 1H) 7.44 (d, J=2.73 Hz, 1H) 7.23 (t, J=8.68 Hz, 2H) 5.81 (d, J=4.49 Hz, 1H) 3.91 (s, 3H) 3.35 (s, 3H) 3.02 (d, J=4.88 Hz, 3H) 1.86-1.96 (m, 1H) 0.97-1.05 (m, 1H) 0.89 (br. s., 2H) 0.59 (br. s., 1H). LCMS (m/z, ES+)=582 (M+H+).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([C:12]#[C:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([C:12]#[C:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19]
Reactant: O=P(Cl)(Cl)Cl
Reactant: C[Si](C)(C)C#Cc1cc2c(O)c(C#N)cnc2cn1
Product: C[Si](C)(C)C#Cc1cc2c(Cl)c(C#N)cnc2cn1

Procedure:
To 500 mg of 4-hydroxy-6-trimethylsilanylethynyl-[1,7]naphthyridine-3-carbonitrile under an inert atmosphere was added 10 mL of phosphorous oxychloride. After two hours at reflux, the excess phosphorous oxychloride was removed in vacuo and ice-water, chloroform, a tract of methanol, and aqueous saturated sodium bicarbonate were added. The chloroform layer was washed with brine, dried with sodium sulfate, and evaporated to give 626 mg of crude 4-chloro-6-trimethylsilanylethynyl-[1,7]naphthyridine-3-carbonitrile as a yellowish solid, which was used in the following step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[N:7]([C@H:10]1[C@H:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[CH2:13][NH:12][CH2:11]1)[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.[CH3:33][S:34]([N:37]1[CH2:42][CH2:41][N:40]([C:43](Cl)=[O:44])[CH2:39][CH2:38]1)(=[O:36])=[O:35]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:23])[N:7]([C@H:10]1[C@H:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[CH2:13][N:12]([C:43]([N:40]2[CH2:39][CH2:38][N:37]([S:34]([CH3:33])(=[O:36])=[O:35])[CH2:42][CH2:41]2)=[O:44])[CH2:11]1)[CH2:8][CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN(C(=O)OC(C)(C)C)[C@@H]1CNC[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: CS(=O)(=O)N1CCN(C(=O)Cl)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(C(=O)OC(C)(C)C)[C@@H]1CN(C(=O)N2CCN(S(C)(=O)=O)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Yield: 97.6 %

Procedure:
To a solution of rac-[(3S,4R)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid tert-butyl ester (0.25 g, 0.69 mmol) in CH2Cl2 (5 ml) was added ethyl-diisopropyl-amine (0.20 ml, 1.1 mmol) and 4-methanesulfonyl-piperazine-1-carbonyl chloride (189 mg, 0.83 mmol). Stirring was continued over night at RT, concentrated under vacuo and purification by flash chromatography (SiO2, EtOAc) afforded 0.37 g (97%) of the title compound as a white solid. ES-MS m/e: 549.3 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:9]([CH3:10])=[C:8]([F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15]>>[F:1][C:2]1[C:9]([CH3:10])=[C:8]([F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[CH:13][C:14]([OH:16])=[O:15]
Reactant: O=C(O)CC(=O)O
Reactant: Cc1c(F)ccc(C=O)c1F
Product: Cc1c(F)ccc(C=CC(=O)O)c1F

Procedure:
According to the previously described general procedure (GP1), Knoevenagel condensation (75° C.; 3h30) between 2,4-difluoro-3-methyl-benzaldehyde (1.560 g; 9.744 mmol) and malonic acid (1.926 g; 18.515 mmol) gave the product 3-(2,4-difluoro-3-methyl-phenyl)-acrylic acid as a pale yellow solid (1.600 g; 83%). LC-MS: tR=0.86 min; [M+H]+: no ionisation.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[CH:16][C:15]([O:23]CC1C=CC=CC=1)=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[CH:16][C:15]([OH:23])=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2]
Reactant: COCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc(OCc4ccccc4)cc3c12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc(O)cc3c12
Yield: 84.8 %

Procedure:
At room temperature and under normal pressure, 7 g (18 mmol) of 6-benzyloxy-4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester is hydrogenated in 600 ml of ethanol with 7 g of palladium/carbon (10%) as well as hydrogen for 8.5 hours. After the mixture has been removed from the catalyst by filtration, it is concentrated, thus obtaining 4.8 g (90% yield) of 6-hydroxy-4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester which is further reacted without any additional purification.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:3][CH2:2]1.[NH2:20][C@@H:21]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:22][OH:23]>>[OH:23][CH2:22][C@@H:21]([NH:20][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[CH2:24][CH:25]([CH3:27])[CH3:26]
Reactant: O=C(O)c1ccc(N2CCCC2)c(OCC2CC2)n1
Reactant: CC(C)C[C@H](N)CO
Product: CC(C)C[C@@H](CO)NC(=O)c1ccc(N2CCCC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid and (2S)-2-amino-4-methyl-1-pentanol (CAN 7533-40-6) as starting materials, MS (LC/MS): 362.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:5]([O:14][CH3:15])=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Br[CH2:32][C:33]#[N:34]>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:5]([O:14][CH3:15])=[C:6]([N:8]2[CH2:9][CH2:10][N:11]([CH2:32][C:33]#[N:34])[CH2:12][CH2:13]2)[CH:7]=1
Reactant: COc1c(N2CCNCC2)cc(Br)cc1C(C)(C)C
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1c(N2CCN(CC#N)CC2)cc(Br)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
1-[5-bromo-3-(tert-butyl)-2-methoxyphenyl]piperazine (550 mg), potassium carbonate (302 mg), dimethylformamide (7 ml) and bromoacetonitrile (0.12 ml) were combined and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate, the insoluble portion was filtered off, and the concentrated residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (480 mg) as colorless crystals (78%).
Reaction SMILES: [OH:1][CH:2]([CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:3][NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:31]1(=[O:36])[O:35][CH2:34][CH2:33][CH2:32]1>>[CH2:19]([N:18]([CH2:17][CH:2]([OH:1])[CH2:3][N:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:34](=[O:35])[CH2:33][CH2:32][CH2:31][OH:36])[C:31](=[O:36])[CH2:32][CH2:33][CH2:34][OH:35])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCCCCNCC(O)CNCCCCCCCCCCCC
Reactant: O=C1CCCO1
Product: CCCCCCCCCCCCN(CC(O)CN(CCCCCCCCCCCC)C(=O)CCCO)C(=O)CCCO
Temperature: 160 °C
Reaction time: 5 h
Yield: 50.1 %

Procedure:
A reactor was charged with 9.5 g (0.02 mole) of 15-hydroxy-13,17-diazanonacosan and 11.7 g (0.13 mole) of γ-butyrolactone, and the contents were heated to 160° C. and kept for 5 hours at this temperature, thereby reacting them. After completion of the reaction, the product was purified by column chromatography (on 500 g of silica gel, developing solvent: chloroform/methanol=97/3), thereby obtaining 6 g (yield: 45%) of the title compound as a viscous liquid.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH2:15])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3.C(N(CC)CC)C.Cl[C:26]([O:28][CH2:29][CH2:30][Cl:31])=[O:27]>ClCCl>[CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH:15][C:26]([O:28][CH2:29][CH2:30][Cl:31])=[O:27])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3
Reactant: CC1(C)Oc2cc3nonc3cc2C(N)C1O
Reactant: O=C(Cl)OCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)Oc2cc3nonc3cc2C(NC(=O)OCCCl)C1O
Reaction time: 21 h
Yield: 87.3 %

Procedure:
400 mg (1.70 mmol) of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazole, 260 μl (1.87 mmol) of triethylamine and 40 mg of dichloromethane were stirred at room temperature, and 193 μl (1.87 mmol) of 2-chloroethyl chloroformate were added thereto and stirred for 21 hours. The reaction liquid was washed thrice with water and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was recrystallized from chloroform to obtain 507 mg of the intended compound as pale yellow crystals. (yield: 87%)
Reaction SMILES: [OH:1][N:2]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[Cl:23][C:24]1[CH:50]=[CH:49][CH:48]=[CH:47][C:25]=1[CH2:26][N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([C:36](O)=[O:37])[CH:34]=2)[C:29]([C:39](=[O:43])[CH:40]([CH3:42])[CH3:41])=[C:28]1[CH2:44][CH2:45][CH3:46].Cl.NO.C(N(C(C)C)CC)(C)C>CN(C)C=O>[Cl:23][C:24]1[CH:50]=[CH:49][CH:48]=[CH:47][C:25]=1[CH2:26][N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([C:36]([NH:2][OH:1])=[O:37])[CH:34]=2)[C:29]([C:39](=[O:43])[CH:40]([CH3:42])[CH3:41])=[C:28]1[CH2:44][CH2:45][CH3:46]
Reactant: CCCc1c(C(=O)C(C)C)c2ccc(C(=O)O)cc2n1Cc1ccccc1Cl
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCc1c(C(=O)C(C)C)c2ccc(C(=O)NO)cc2n1Cc1ccccc1Cl
Temperature: 20 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
1-Hydroxybenzotriazole (68 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (72 mg) were added to a solution of 1-(2-chlorobenzyl)-3-isobutyryl-2-propylindole-6-carboxylic acid (100 mg) in dimethylformamide (3 ml), and the mixture was stirred at 20° C. overnight, then hydroxylamine hydrochloride (35 mg) and diisopropylethylamine (0.088 ml) were added. After stirred at 20° C. for 2 hours, the reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with 1N hydrochloric acid and brine, dried over sodium sulfate, and evaporated in vacuo. The residue was purified by preparative thin layer chromatography with 10% methanol in chloroform and recrystallization from ethyl acetate to give 1-(2-chlorobenzyl)-3-isobutyryl-2-propylindole-6-carbohydroxamic acid (67 mg) as pale red crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][S:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:5].[C:21](N1C=CN=C1)(N1C=CN=C1)=[S:22]>O1CCCC1>[N:14]1[CH:15]=[CH:16][C:11]([S:10][CH2:9][CH2:8][CH2:7][N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:1][C:21]2=[S:22])=[CH:12][CH:13]=1
Reactant: Nc1ccccc1C(=O)NCCCSc1ccncc1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=c1c2ccccc2[nH]c(=S)n1CCCSc1ccncc1
Temperature: 25 °C
Reaction time: 64 h
Yield: 68.4 %

Procedure:
Under nitrogen atmosphere, to a solution of 1.48 g (5.15 mmol) of 4-[3-(2-aminobenzoylamino)propylthio]pyridine in 30 ml of tetrahydrofuran, 1.84 g (10.3 mmol) of 1,1'-thiocarbonyldiimidazole was added, and the mixture was stirred at room temperature for 64 hours. The solvent was distilled off and the residue was washed with chloroform/ether to give 1.16 g of the desired product (68.5% yield, pale brown crystals).
Reaction SMILES: [C:1]([C:6]1[C:15](=O)[C:14]2[C:9](=[C:10]([O:17][CH3:18])[CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].C(=O)(O)[O-].[Na+].P(Cl)(Cl)([Cl:26])=O>>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:26])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCC(=O)c1c[nH]c2c(OC)cccc2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Product: CCCC(=O)c1cnc2c(OC)cccc2c1Cl
Yield: 58.5 %

Procedure:
3-Butyryl-8-methoxy-4(1H)-quinolone (9.0 g, 0.037 mol) and phosphorus oxychloride (100 ml) were heated under reflux for 30 minutes. When cool, the mixture was poured onto ice, adjusted to pH 4 with sodium bicarbonate and extracted with dichloromethane. Evaporation and crystallisation from ethyl acetate-petroleum ether gave 3-butyryl-4-chloro-8-methoxyquinoline (5.5 g, 58.5%), m.p. 114°-116°.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)(=O)=O)=CC=1.[CH2:18]([P:27]([O:32]CC)(=[O:31])[O:28]CC)[P:19]([O:24]CC)(=[O:23])[O:20]CC.C(P([O-])(=O)[O-])CP([O-])(=O)[O-]>>[N:12]1([CH2:11][CH:18]([P:27]([OH:32])(=[O:28])[OH:31])[P:19]([OH:24])(=[O:20])[OH:23])[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: Cc1ccc(S(=O)(=O)OCn2ccnc2)cc1
Agent: O=P([O-])([O-])CCP(=O)([O-])[O-]
Product: O=P(O)(O)C(Cn1ccnc1)P(=O)(O)O

Procedure:
Reaction of (imidazol-1-ylmethyl) p-toluenesulfonate with tetraethyl methanediphosphonate and hydrolysis of the primary ethanediphosphonate in accordance with Example 2 gives 2-(imidazol-1-yl)ethane-1,1-diphosphonic acid of m.p. 255° C. (dec.) and salts thereof, e.g. the disodium salt.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.O[C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][O:8][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[CH:16]=[O:17])=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(CO)cc1
Reactant: O=Cc1cccc(O)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)c1ccc(COc2cccc(C=O)c2)cc1
Temperature: 25 °C

Procedure:
Mix 4-(dimethylamino)benzyl alcohol (3.35 g. 22 mmol), 3-hydroxybenzaldehyde (2.69 g, 22 mmol), triphenylphosphine (5.8 g, 22 mmol) and diethylazadicarboxylate (3.83 g, 22 mmol) in tetrahydrofuran (25 mL). Stir at room temperature under anhydrous atmosphere until the reaction is done. Concentrate the solution in vacuo and dilute with a small quantity of ethyl ether. Filter any precipitate and concentrate the filtrat in vacuo. Purify by silica gel chromatography to give 3-(4-(dimethylamino)-benzyloxy) benzaldehyde.