Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9]/[N:10]=[C:11](/[C:15]1[N:16]=[C:17]([NH:20][C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[S:18][CH:19]=1)\[C:12](O)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)Cl.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.Cl.[NH2:59][CH:60]1[C:85](=[O:86])[N:62]2[C:63]([C:69]([O:71][CH:72]([C:79]3[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=3)[C:73]3[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=3)=[O:70])=[C:64]([CH2:67][Cl:68])[CH2:65][S:66][C@H:61]12>C(Cl)Cl.C(OCC)(=O)C>[C:1]([O:5][C:6]([CH2:8][O:9]/[N:10]=[C:11](/[C:15]1[N:16]=[C:17]([NH:20][C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[S:18][CH:19]=1)\[C:12]([NH:59][CH:60]1[C:85](=[O:86])[N:62]2[C:63]([C:69]([O:71][CH:72]([C:73]3[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=3)[C:79]3[CH:80]=[CH:81][CH:82]=[CH:83][CH:84]=3)=[O:70])=[C:64]([CH2:67][Cl:68])[CH2:65][S:66][C@H:61]12)=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Reactant: CC(C)(C)OC(=O)CO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 67 %

Procedure:
To an ice-cooled solution of (Z)-2-t-butoxycarbonylmethoxyimino-2-(tritylaminothiazol-4-yl)acetic acid (IVg') (2.71 g, 5 mmoles) in CH2Cl2 (20 ml) was added PCl5 (1.24 g, 6 mmoles), and the solution was stirred for 20 minutes at room temperature. The acid chloride solution was added under ice-cooling to a solution of the silylated 7-ACA ester, which was prepared by adding bis(trimethylsilyl)acetamide (BSA, 3.7 ml, 15 mmoles) to a stirred suspension of benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate hydrochloride (V) (2.25 g, 5 mmoles) in CH2Cl2 (20 ml). The reaction mixture was stirred at room temperature for 30 minutes, diluted with ethyl acetate (200 ml) and washed with an aqueous NaHCO3 solution and water. After drying over Na2SO4, the solution was evaporated and the residue was purified by silica gel chromatography (Wako gel C-200, 60 g). The desired fractions, eluted by CHCl3, were combined and concentrated to give 3.16 g (67%) of the title compound VIg'.
Reaction SMILES: [CH3:1][C:2]1([C:11]([O:13]CC)=[O:12])[CH:4]([CH:5]=[C:6]([Cl:8])[Cl:7])[C:3]1([CH3:10])[CH3:9].[OH-].[Na+]>CO>[CH3:1][C:2]1([C:11]([OH:13])=[O:12])[CH:4]([CH:5]=[C:6]([Cl:8])[Cl:7])[C:3]1([CH3:9])[CH3:10]
Reactant: CCOC(=O)C1(C)C(C=C(Cl)Cl)C1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)C(C=C(Cl)Cl)C1(C)C(=O)O

Procedure:
0.72 Part of the above ester was agitated at 40° - 50° C. for 3 hours in the presence of 3.26 parts of a 10% aqueous solution of sodium hydroxide and methyl alcohol to effect hydrolysis of the ester and obtain 0.60 part of 1,2,2-trimethyl-3-(2',2'-dichlorovinyl)-cyclopropanecarboxylic acid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]([NH:22][C:23]3[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=3)[CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[C:11]([CH3:32])[CH:10]=2)=[N:7][CH:8]=1)[CH3:2].[NH:33]1[CH2:38][CH2:37][CH2:36][C@@H:35]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:34]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)CC)(C)C>CN(C)C=O.O>[CH2:1]([C:3]1[CH:8]=[N:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([C:27]([N:33]4[CH2:38][CH2:37][CH2:36][C@@H:35]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:34]4)=[O:28])=[CH:30][CH:31]=3)[CH2:16][CH2:17][C:18]([F:20])([F:21])[F:19])=[C:11]([CH3:32])[CH:10]=2)=[N:5][CH:4]=1)[CH3:2]
Reactant: CCOC(=O)[C@@H]1CCCNC1
Reactant: CCc1cnc(-c2ccc(C(CCC(F)(F)F)Nc3ccc(C(=O)O)cc3)c(C)c2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@@H]1CCCN(C(=O)c2ccc(NC(CCC(F)(F)F)c3ccc(-c4ncc(CC)cn4)cc3C)cc2)C1

Procedure:
A solution of 4-((1-(4-(5-ethylpyrimidin-2-yl)-2-methylphenyl)-4,4,4-trifluorobutyl)amino)benzoic acid obtained in step B, ethyl (3R)-piperidine-3-carboxylate (5.08 mL), 1-hydroxybenzotriazole (4.46 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.32 g) and diisopropylethylamine (5.76 mL) in dimethylformamide (79 mL) was stirred at room temperature overnight. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (15.9 g).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1C1C=NN(C)C=1)=[O:11].CC1C([N:35]2[N:39]=[CH:38][CH:37]=[N:36]2)=C(C=CC=1)C(O)=O>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([CH3:18])[C:17]=1[N:35]1[N:39]=[CH:38][CH:37]=[N:36]1)=[O:11]
Reactant: Cc1cccc(C(=O)O)c1-n1nccn1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1cccc(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1-n1nccn1

Procedure:
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1 using 3-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI) 314(M+H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](Cl)[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[CH3:27][N:28]([CH2:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1)[CH3:29].[OH-].[Na+]>CN(C=O)C.CO>[CH3:29][N:28]([CH2:30][C:31]1[CH:32]=[CH:33][C:34]([NH:35]/[C:16](=[C:6]2\[C:5](=[O:26])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:36][CH:37]=1)[CH3:27]
Reactant: COc1ccc(C(Cl)=C2C(=O)N(C(C)=O)c3ccc([N+](=O)[O-])cc32)cc1
Reactant: CN(C)Cc1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc(/C(Nc2ccc(CN(C)C)cc2)=C2/C(=O)Nc3ccc([N+](=O)[O-])cc32)cc1

Procedure:
Prepared analogously to Example 2 from 1-acetyl-3-[1-chloro-1-(4-methoxyphenyl)-methylidene)-5-nitro-2-indolinone and 4-dimethylaminomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].[CH3:13][Mg+].[Br-]>C(Cl)(Cl)Cl>[CH3:13][C:5]1[C:6]2[S:10][CH:9]=[N:8][C:7]=2[CH:11]=[CH:12][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2ncsc2c1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: ClC(Cl)Cl
Product: Cc1c([N+](=O)[O-])ccc2ncsc12
Reaction time: 2 h
Yield: 45.5 %

Procedure:
To a solution of 6-nitrobenzothiazole (1.4 g, 7.7 mmol) in 50 mL of TMF was added 5.1 mL of MeMgBr (15.3 mmol) dropwise in 0.5 h period at 0° C. The reaction mixture was then stirred for additional 2 h. It was quenched by adding THF solution of 2,3-dichloro-5,6-dicyanobenzoquinone until the color of the solution turns to dark green. The reaction mixture was concentrated in vacuo to yield a dark solid which was subjected to column chromatography (CHCl3, neat) to provide 0.68 g (3.5 mmol, 46%) of the desired product.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:25][CH2:24][CH:23]([N:26]([CH3:28])[CH3:27])[CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([C:31]([F:42])([F:41])[F:30])[CH:37]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:25][CH2:24][CH:23]([N:26]([CH3:27])[CH3:28])[CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CN(C)C1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)C1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(C)C1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2cccc(C(F)(F)F)c2)C1
Yield: 60 %

Procedure:
The title compound was synthesized in analogy to example 66, from (RS)-(4,4-difluoro-piperidin-1-yl)-[5-(3-dimethylamino-pyrrolidine-1-carbonyl)-1H-indol-2-yl]-methanone (example 42, intermediate a)), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light brown foam (60%).
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH3:4].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][N:8]=1>C(O)C>[CH3:4][C:3]1[N:6]=[C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][N:8]2[CH:2]=1
Reactant: COc1ccc(N)nc1
Reactant: CC(=O)CCl
Solvent: CCO
Product: COc1ccc2nc(C)cn2c1
Yield: 54 %

Procedure:
0.74 g (8.04 mW of chloroacetone is added to a solution of 0.5 g (mM) of 2-amino-5-methoxypyridine in 17 ml of ethanol. The mixture is refluxed for 20 hours and then concentrated under reduced pressure. Ethyl acetate is added to the evaporation residue and the organic phase is washed with a saturated aqueous solution of sodium bicarbonate and then with a saturated solution of sodium chloride. The organic phase is subsequently dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The evaporation residue is purified by NH2 (amino group)-grafted silica gel chromatography, elution being carried out with a toluene/isopropyl alcohol mixture (99/1; v/v). The expected product is obtained in the form of an orange oil with a yield of 54%.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:10]=[C:9]([N:11]2[CH:15]([CH3:16])[C:14](=[O:17])[C:13]([CH3:19])([CH3:18])[C:12]2=[O:20])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].C1COCC1.O>C1COCC1>[OH:17][C@H:14]1[C@@H:15]([CH3:16])[N:11]([C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:10]=2)[C:12](=[O:20])[C:13]1([CH3:18])[CH3:19]
Reactant: CC1C(=O)C(C)(C)C(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1[C@H](O)C(C)(C)C(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
A solution of 2-(trifluoromethyl)-4-(3,3,5-trimethyl-2,4-dioxopyrrolidin-1-yl)benzonitrile (50 mg) in THF (5 mL) was cooled to −78° C., lithium tri(sec-butyl)borohydride-THF solution (0.242 mL, 1 mol/L) was added, and the mixture was stirred at −78° C. for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the obtained solid was recrystallized from hexane-ethyl acetate to give the title compound as a colorless solid (yield: 32.2 mg, 64%).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11](=[O:24])[C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH2:25]([O:27][C:28]([C:30]1[CH:31]=[CH:32][C:33](Cl)=[N:34][CH:35]=1)=[O:29])[CH3:26].C(N(C(C)C)CC)(C)C>C1COCC1>[CH2:25]([O:27][C:28](=[O:29])[C:30]1[CH:31]=[CH:32][C:33]([N:21]2[CH2:22][CH2:23][N:18]([C:15]3[CH:14]=[CH:13][C:12]([C:11](=[O:24])[NH:10][C:6]4[CH:5]=[C:4]5[C:9](=[CH:8][CH:7]=4)[CH2:1][CH2:2][CH2:3]5)=[CH:17][CH:16]=3)[CH2:19][CH2:20]2)=[N:34][CH:35]=1)[CH3:26]
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: O=C(Nc1ccc2c(c1)CCC2)c1ccc(N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(N2CCN(c3ccc(C(=O)Nc4ccc5c(c4)CCC5)cc3)CC2)nc1
Temperature: 170 °C
Yield: 52.9 %

Procedure:
To a solution of N-indan-5-yl-4-piperazin-1-yl-benzamide (80 mg) and 2-chloropyridine-5-carboxylic acid ethyl ester (220 mg) in THF (4 mL) was added diisopropylethylamine (0.1 mL). The solution was heated in a microwave at 170° C. for 2 hrs. The crystalline precipitate was filtered and washed with THF to give 6-{4-[4-(indan-5-ylcarbamoyl)-phenyl]-piperazin-1-yl}-nicotinic acid ethyl ester (62 mg, Yield: 53%). LCMS calc for C28H30N4O3 (m/e) 470, obsd 471 (M+H).
Reaction SMILES: CS([C:4]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:6][N:5]=1)=O.CS(C1N=C(C2C=CC=CC=2)SN=1)(=O)=O.[CH2:30]([OH:33])[C:31]#[CH:32].[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[C:9]1([C:7]2[S:6][N:5]=[C:4]([O:33][CH2:30][C:31]#[CH:32])[N:8]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CS(=O)c1nsc(-c2ccccc2)n1
Reactant: C#CCO
Agent: CS(=O)(=O)c1nsc(-c2ccccc2)n1
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Product: C#CCOc1nsc(-c2ccccc2)n1
Reaction time: 0.33 h

Procedure:
To 3 ml of N,N-dimethylformamide were added 160 mg of a mixture of 3-methylsulfinyl-5-phenyl-1,2,4-thiadiazole and 3-methylsulfonyl-5-phenyl-1,2,4-thiadiazole (integration ratio of 1H-NMR sulfonyl form:sulfinyl form=4:1) and 60 mg of propargyl alcohol, and to the resulting mixture was added 43 mg of sodium hydride (60% oily) with ice-cooling. The mixture was stirred for 20 minutes with ice-cooling, and allowed to stand at room temperature for 18 hours. Then, the reaction mixture was poured into an aqueous saturated sodium chloride solution, and the mixture was extracted with t-butyl methyl ether. The organic layer was concentrated, and the resulting residue was subjected to silica gel column chromatography to obtain 100 mg of 5-phenyl-3-propargyloxy-1,2,4-thiadiazole (the compound (1) of the present invention).
Reaction SMILES: N#N.[N+:3]([C:6]1[CH:10]=[N:9][NH:8][N:7]=1)([O-:5])=[O:4].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:18][CH2:19][CH2:20][CH2:21][C:22]1([CH3:27])[O:26][CH2:25][CH2:24][O:23]1>C(C#N)(C)=O.CC(=O)OCC.O>[CH3:27][C:22]1([CH2:21][CH2:20][CH2:19][CH2:18][N:8]2[N:7]=[C:6]([N+:3]([O-:5])=[O:4])[CH:10]=[N:9]2)[O:26][CH2:25][CH2:24][O:23]1
Reactant: O=[N+]([O-])c1cn[nH]n1
Reactant: CC1(CCCCBr)OCCO1
Agent: CC(=O)C#N
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(CCCCn2ncc([N+](=O)[O-])n2)OCCO1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 4-nitro-2H-[1,2,3]triazole (100 mg, 0.88 mmol) and Cs2CO3 (315 mg, 0.96 mmol) in AcCN (1.0 mL) was treated with a solution of 2-(4-bromo-butyl)-2-methyl-[1,3]dioxolane (215 mg, 0.96 mmol) in AcCN (1.0 mL). The reaction mixture was stirred at 80° C. for 16 h. Water (20 mL), followed by EA (30 mL) were added. The aq. layer was extracted with EA (30 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (2:1 hept-EA) gave the title compound: TLC:rf (2:1 hept-EA)=0.33. LC-MS-conditions 02: tR=0.92 min.
Reaction SMILES: I[C:2]1[N:11]=[C:10]2[N:4]([CH2:5][CH2:6][C:7]3[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=3[CH:9]2[O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[CH:3]=1.[C:24]1([C:30]#[CH:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCN(CC)CC.N>C(#N)C.[Cu]I.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.O>[CH3:19][N:16]1[CH2:17][CH2:18][CH:13]([O:12][CH:9]2[C:8]3[CH:20]=[CH:21][CH:22]=[CH:23][C:7]=3[CH2:6][CH2:5][N:4]3[C:10]2=[N:11][CH:2]=[C:3]3[C:31]#[C:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:14][CH2:15]1
Reactant: C#Cc1ccccc1
Reactant: CN1CCC(OC2c3ccccc3CCn3cc(I)nc32)CC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: CN1CCC(OC2c3ccccc3CCn3c(C#Cc4ccccc4)cnc32)CC1
Temperature: 80 °C

Procedure:
To a solution of compound 2-iodo-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene (example 2A) (100 mg, 0.24 mmoles) in ACN (600 μL) in a screw-capped vial under argon are added CuI (9 mg, 0.048 mmole), Pd(PPh3)4 (28 mg, 24 μmoles), phenylacetylene (109 μL, 0.96 mmole) and NEt3 (600 μL). The reaction mixture is heated at 80° C. overnight. Water is added and pH adjusted to 9-10 with concentrated aqueous ammonia solution. The aqueous phase is extracted three times with CH2Cl2. The organic phase is dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is pre-purified by silica gel chromatography using (CH2Cl2:MeOH:NH4OH) as eluent with a gradient from (98:2:0.2) to (95:5:0.5) and the residue is submitted to a preparative thin-layer chromatography eluting with (CH2Cl2:MeOH:NH4OH) (9:1:1) to afford 4-(1-methylpiperidin-4-yloxy)-2-phenylethynyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([CH3:9])[CH:5]=[C:4]([I:10])[C:3]=1[N:11]=[C:12]=[O:13].[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1>ClCCl>[F:1][C:2]1[C:7]([F:8])=[C:6]([CH3:9])[CH:5]=[C:4]([I:10])[C:3]=1[NH:11][C:12]([NH:14][CH:15]1[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]1)=[O:13]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1cc(I)c(N=C=O)c(F)c1F
Solvent: ClCCl
Product: Cc1cc(I)c(NC(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of the crude 2,3-difluoro-6-iodo-4-methylphenyl isocyanate from D20, 4-amino-1-N-Boc piperidine (480 mg), and dichloromethane (5 ml) was stirred at room temperature for 18 h then evaporated and directly purified by chromatography on silica gel 20 g eluting with 10-50% ethyl acetate in hexane to give the title compound, 300 mg. M−−H=494.
Reaction SMILES: [OH:1][CH:2]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24]3[NH:28][C:27](=[O:29])[O:26][N:25]=3)[CH:22]=2)[O:17][C:4]2([CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]2)[CH2:3]1.C[N+]1([O-])CCOCC1>C1COCC1.CC#N.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[O:1]=[C:2]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24]3[NH:28][C:27](=[O:29])[O:26][N:25]=3)[CH:22]=2)[O:17][C:4]2([CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]2)[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(O)c1cc(-c3noc(=O)[nH]3)ccc1O2
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(-c3noc(=O)[nH]3)ccc1O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.0 g of tert-butyl 4-hydroxy-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-spiro[chroman-2,4′-piperidine]-1′-carboxylate in 40 ml of THF-CH3CN (1:1) ar rt were added 2.0 g of MS 4A, 435 mg of NMO, and 88 mg of TPAP, and the reaction mixture was stirred at rt overnight. The mixture was filtered through a Celite pad, washed with CHCl3 and CHCl3-MeOH (9:1), and the filtrate was concentrated in reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of hexane-AcOEt (100/0-0/100) as eluent to give the intended compound as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:17])[C:14]([OH:16])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[N+:20]([C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1)([O-:22])=[O:21]>C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:17])[C:14]([NH:27][C:26]3[CH:28]=[CH:29][C:23]([N+:20]([O-:22])=[O:21])=[CH:24][CH:25]=3)=[O:16])[CH2:11][CH2:12]2)=[CH:18][CH:19]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Solvent: CCOCC
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)C(=O)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from [4-(4-fluoro-benzyl)-piperidine-1-yl]-oxo-acetic acid (Example 1b) and 4-nitro-aniline (Aldrich) according to the method described in Example 1c. Melting Point: 157-159° C. (diethylether)
Reaction SMILES: Cl.C([O:4][C:5]([C@@H:7]([NH:16][C@@H:17]1[C:23](=[O:24])[N:22]([CH2:25][C:26]([OH:28])=[O:27])[C:21]2[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=2[O:19][CH2:18]1)[CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:6])C.C(O)(=O)C>[OH-].[Na+]>[C:5]([C@@H:7]([NH:16][C@@H:17]1[C:23](=[O:24])[N:22]([CH2:25][C:26]([OH:28])=[O:27])[C:21]2[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=2[O:19][CH2:18]1)[CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)([OH:6])=[O:4]
Reactant: CCOC(=O)[C@H](CCC1CCOCC1)N[C@H]1COc2ccccc2N(CC(=O)O)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=C(O)CN1C(=O)[C@@H](N[C@@H](CCC2CCOCC2)C(=O)O)COc2ccccc21
Reaction time: 1 h
Yield: 92.7 %

Procedure:
In 5 ml of 1N sodium hydroxide solution is dissolved 0.2 g of 3(S)-[1(S)-ethoxycarbonyl-3-(3,4,5,6-tetrahydro-2H-pyran-4-yl)propyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid hydrochloride obtained in Example 43, and the solution is allowed to stand at room temperature for 1 hours. The solution is neutralized with 1.5 ml of acetic acid and purified by Amberlite XAD-2 column chromatography (acetone:water=1:1). The eluate is concentrated under reduced pressure and lyophilized to give 0.16 g of 3(S)-[1(S)-carboxy-3-(3,4,5,6-tetrahydro-2H-pyran-4-yl)propyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid as a colorless powder.
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][CH2:11][NH:12][OH:13])(=[O:8])[O:5]CC)C.C([O-])(O)=O.[Na+]>Cl>[OH:13][NH:12][CH2:11][CH2:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5]
Reactant: CCOP(=O)(CCCNO)OCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=P(O)(O)CCCNO
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 61.8 %

Procedure:
12.9 g (0.0608 mol) 3-(N-hydroxylamino)-propylphosphonic acid diethylester and 130 ml concentrated HCl were heated for 6 hours under reflux (oil bath temperature: 150° C.). The resulting yellow/orange solution is concentrated under-reduced pressure. The remaining oil is taken up in 30 ml water, stirred with 3 spoonfuls of activated carbon for 30 minutes, filtered out from the activated carbon and the colourless solution is concentrated in the entire diaphragm pump vacuum. After take-up in 30 ml water a pH of 4.0 to 4.5 is adjusted with approximately 4.7 g (0.056 mol) NaHCO3 (from pH=1.5 the product precipitates). Suction filtering of the white solid resulted in 5.83 g 3-(hydroxyamino)-propylphosphonic acid (melting point: 160° C., decomposition). This corresponds to a yield of 61.8%. (DE-A-27 33 658, Öhler Synthesis 1995, 539-543).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].P(Br)(Br)([Br:26])=O>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Br:26])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1ncc2ccc(OCCCC)cc2c1O
Reactant: O=P(Br)(Br)Br
Product: CCCCOC(=O)c1nc(Br)c2ccc(OCCCC)cc2c1O

Procedure:
0.175 g of 6-butoxy-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester, 1 were allowed to react with phosphorous oxybromide analogously to Example D-46 b) to give 0.073 g of a white solid: Proton NMR (200 MHZ, chloroform-d): δ 11.84 (s, 1H), 8.13 (d, 1H), 7.60 (m, 1H), 7.42-7.35 (m, 1H), 4.48 (t, J=7 Hz, 2H), 4.15 (t, J=7 Hz, 2H), 1.95-1.75 (m, 4H), 1.65-1.40 (m, 4H), 1.05-0.95 (m, 6H).