Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[CH:10]=[C:9](F)[C:8]([F:12])=[CH:7][C:6]=1[N+:13]([O-:15])=[O:14]>CO>[Cl:4][C:5]1[CH:10]=[C:9]([O:2][CH3:1])[C:8]([F:12])=[CH:7][C:6]=1[N+:13]([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(Cl)c([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To sodium methoxide (100 mL of a 0.5 M solution in methanol, 50.1 mmol) cooled to 0° C. was added a solution of 1-chloro-4,5-difluoro-2-nitro-benzene (9.7 g, 50.1 mmol) in methanol (10 mL) dropwise over 15 min. The solution was warmed to room temperature and stirred for 2 h, then poured slowly over ice. The yellow precipitate was collected by filtration and washed with cold water. The crystals were air dried to give 8.2 g (79%) of 1-chloro-4-fluoro-5-methoxy-2-nitro-benzene: Crude 1H NMR (400 MHz, CDCl3): δ 7.85 (d, J=10.5 Hz, 1H), 7.06 (d, J=7.3 Hz, 1H), 3.98 (s, 3H). The crude material was pure enough to carry on to the next step.
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=[O:10])[CH3:9])=[C:6]([NH:11][C:12]2[CH:13]=[N:14][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:16][CH:17]=2)[N:5]=[CH:4][N:3]=1.Cl.[CH:23]([C:26]1[N:30]=[C:29]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[O:28][N:27]=1)([CH3:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:23]([C:26]1[N:30]=[C:29]([CH:31]2[CH2:36][CH2:35][N:34]([C:2]3[C:7]([C:8](=[O:10])[CH3:9])=[C:6]([NH:11][C:12]4[CH:13]=[N:14][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:16][CH:17]=4)[N:5]=[CH:4][N:3]=3)[CH2:33][CH2:32]2)[O:28][N:27]=1)([CH3:25])[CH3:24]
Reactant: CC(C)c1noc(C2CCNCC2)n1
Reactant: CC(=O)c1c(Cl)ncnc1Nc1ccc(S(C)(=O)=O)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1c(Nc2ccc(S(C)(=O)=O)nc2)ncnc1N1CCC(c2nc(C(C)C)no2)CC1
Yield: 30.4 %

Procedure:
To a solution of 1-[4-chloro-6-(6-methanesulfonyl-pyridin-3-ylamino)-pyrimidin-5-yl]-ethanone (0.21 mmol, 70 mg) and 4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidine hydrochloride (0.21 mmol, 49 mg) in N,N-dimethyl formamide (500 uL) was added potassium carbonate (0.21 mmol, 29 mg). The mixture was microwaved at 100° C. for 150 seconds. Its progress was monitored by thin layer chromatography and LCMS. The reaction was treated with water and the desired compound was extracted in ethyl acetate. Organic layer was evaporated in vacuo. Purification by HPLC provided Compound B139 as a white solid (31 mg, 31%). 1H-NMR (400 MHz, CDCl3) δ(ppm): 10.9 (s, 1H); 8.90 (d, 1H); 8.58 (d, 1H); 8.32 (s, 1H); 8.05 (d, 1H); 4.09 (m, 2H); 3.41 (m, 2H); 3.29 (h, 1H); 3.23 (s, 3H); 3.09 (h, 1H); 2.48 (s, 3H), 2.18 (m, 2H), 2.02 (m, 2H), 1.35 (d, 6H) LCMS (ESI), m/z 486.3 (M+H+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[CH:20]=2)[NH:10][CH2:11][CH2:12][C:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=2)=[CH:5][CH:4]=1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:10][CH2:11][CH2:12][C:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=2)[C:19]2[CH:20]=[C:21]([NH2:25])[CH:22]=[CH:23][CH:24]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(NCCC2=CCCCC2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(C(NCCC2=CCCCC2)c2cccc(N)c2)cc1

Procedure:
In a similar manner to that described in Example (1b), a solution of N-[(4-methoxyphenyl)-(3-nitrophenyl)methyl]-N-[2-(cyclohexen-1-yl)ethyl]amine (2.80 g) [prepared as described in step (a) above] in methanol (60 m), nickel chloride hexahydrate (3.61 g) and sodium borohydride (1.15 g) were reacted, to afford a mixture (2.15 g) of the title compound and the reduction product of the title compound, that is 3-[(4-methoxyphenyl)-(2-cyclohexylethylamino)methyl]phenylamine, as a yellow oil.
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].[Cl:7][C:8]1[CH:31]=[CH:30][C:11]([NH:12][C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27]SC)=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][N:14]=2)=[C:10]([F:32])[CH:9]=1.[CH3:33]O>O.C(Cl)Cl>[Cl:7][C:8]1[CH:31]=[CH:30][C:11]([NH:12][C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][S:3]([CH3:33])(=[O:5])=[O:2])=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][N:14]=2)=[C:10]([F:32])[CH:9]=1
Reactant: CO
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCSC
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCS(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
A solution of OXONE, (trade mark of E.I. du Pont de Nemours & Co., Inc), (652 mg) in water (1.6 ml) was added to a solution of 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-methylthioethoxy)quinazoline (200 mg, 0.5 mmol), (prepared as described in Example 29), in methanol (10 ml) and the mixture was stirred for 18 hours at ambient temperature. The mixture was diluted with methylene chloride, was washed with aqueous sodium hydrogen carbonate solution, dried (MgSO4) and the solvent was removed by evaporation. The residue was triturated with ethyl acetate/hexane, collected by filtration and dried to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-methylsulphonylethoxy)quinazoline (172 mg, 80%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:13]OC(OC)(C)C>CO.CC1C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:12])[C:9]([O:11][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(C)(C)OC
Reactant: O=C(O)C(O)c1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)C(O)c1ccc(Br)cc1
Temperature: 55 °C
Reaction time: 8 h
Yield: 75.6 %

Procedure:
To a solution of 2-(4-bromophenyl)-2-hydroxyacetic acid (5.00 g, 21.6 mmol) in MeOH (10 mL) was added 2,2-dimethoxypropane (3.39 g, 32.6 mmol) and 4-methylbenzene-1-sulfonic acid (2.00 mg, 0.0100 mmol). The resulting solution was stirred at 55° C. overnight. The reaction mixture was concentrated under reduced pressure, and H2O (100 mL) was added. The resulting solids were collected by filtration and washed with hexane to obtain compound 9a as a gray solid (4.00 g, 72% yield). 1H-NMR (300 MHz, CDCl3) δ (ppm): 7.54-7.51 (m, 2H), 7.35-7.28 (m, 2H), 5.18-5.16 (m, 1H), 3.793 (s, 3H), 3.51-3.49 (m, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3](=[O:25])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:13])[CH:6]=1.Cl[C:28]1[C:29]2[C:36]([CH3:37])=[CH:35][NH:34][C:30]=2[N:31]=[CH:32][N:33]=1.C(N(CC)C(C)C)(C)C>C(O)C(C)C>[CH3:26][N:2]([CH3:1])[C:3](=[O:25])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[CH2:19][CH2:18][N:17]([C:28]3[C:29]4[C:36]([CH3:37])=[CH:35][NH:34][C:30]=4[N:31]=[CH:32][N:33]=3)[CH2:16][CH2:15]2)=[O:13])[CH:6]=1
Reactant: CN(C)CCC1(C(=O)Nc2cccc(OC(=O)N(C)C)c2)CCNCC1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)CO
Product: Cc1c[nH]c2ncnc(N3CCC(CCN(C)C)(C(=O)Nc4cccc(OC(=O)N(C)C)c4)CC3)c12
Temperature: 110 °C
Yield: 40.5 %

Procedure:
Impure 3-(4-(2-(dimethylamino)ethyl)piperidine-4-carboxamido)phenyl dimethylcarbamate from step D (173 mg) was combined with 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (50 mg, 0.30 mmol) and N,N-diisopropylethylamine (0.174 mL, 5 mmol) in isobutanol (0.4 mL) and heated at 110° C. for 7 hours. The reaction was cooled to room temperature and concentrated under vacuum. The residue was purified by prep HPLC (30×100 mm C18 column, 10-70% MeCN:H2O (10 mM NH4OAc), 12 min, 45 mL/min) and lyophilized to give the title compound (60 mg) as the di-acetate salt.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][CH:10]2[NH:13][C:14](=[O:35])/[C:15](=[CH:20]/[C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]3)=[C:23]([O:33][CH3:34])[CH:22]=2)/[CH2:16][CH2:17][CH2:18]Cl)=[CH:6][C:5]=1[N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.O.C(OCC)(=O)C>CN(C=O)C>[F:3][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][CH:10]2[N:13]2[CH2:18][CH2:17][CH2:16]/[C:15](=[CH:20]\[C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]4)=[C:23]([O:33][CH3:34])[CH:22]=3)/[C:14]2=[O:35])=[CH:6][C:5]=1[N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1
Reactant: COc1cc(/C=C(\CCCCl)C(=O)NC2CCc3cc(N4CCOCC4)c(F)cc32)ccc1-n1cnc(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(/C=C2\CCCN(C3CCc4cc(N5CCOCC5)c(F)cc43)C2=O)ccc1-n1cnc(C)c1
Reaction time: 0.25 h
Yield: 74 %

Procedure:
Sodium hydride (containing mineral oil at 40%, 19.0 mg) was added to a solution of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid (6-fluoro-5-morpholin-4-ylindan-1-yl)amide (123 mg) in DMF (3.0 mL) at 0° C., and the reaction solution was stirred for 15 minutes. After confirming that the raw materials disappeared, water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (elution solvent:heptane-ethyl acetate system, ethyl acetate-methanol system) to obtain 85 mg of (E)-1-(6-fluoro-5-morpholin-4-ylindan-1-yl)-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)piperidin-2-one as a racemate. Next, the compound (12.0 mg) was fractionated using CHIRALCEL™ OD-H manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm: mobile phase: hexane:ethanol=70:30) to obtain the title optically active substance with a retention time of 13 minutes (Example 973, 4.60 mg; >99% ee) and the title optically active substance with a retention time of 15 minutes (Example 974, 4.70 mg; >99% ee). The physical properties of the optically active substances are as follows.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]([OH:6])=O.C1N(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)C1.[OH:35][C:36]([CH2:38][CH2:39][CH2:40][CH2:41][C@H:42]1[C@@H:50]2[C@@H:45]([NH:46][C:47]([NH:49]2)=[O:48])[CH2:44][S:43]1)=[O:37]>CN(C=O)C.C(N(CC)CC)C>[CH3:1][NH:2][CH2:3][C:4]([CH:38]([CH2:39][CH2:40][CH2:41][C@H:42]1[C@@H:50]2[C@@H:45]([NH:46][C:47]([NH:49]2)=[O:48])[CH2:44][S:43]1)[C:36](=[O:35])[OH:37])=[O:6]
Reactant: CNCC(=O)O
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Agent: O=C(O)CN1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNCC(=O)C(CCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)C(=O)O

Procedure:
The N-methyl glycine-linked DOTA-biotin conjugate was prepared by an analogous method to that used to prepare D-analine-linked DOTA-biotin conjugates. N-methyl-glycine (trivial name carcosine, available from Sigma Chemical Co.) was condensed with biotin-NHS ester in DMF and triethylamine to obtain N-methyl glycyl-biotin. N-methyl-glycyl biotin was then activated with EDCI and NHS. The resultant NHS ester was not isolated and was condensed in situ with DOTA-aniline and excess pyridine. The reaction solution was heated at 60° C. for 10 minutes and then evaporated. The residue was purified by preparative HPLC to give [N-methyl-N-biotinyl)-N-glycyl]-aminobenzyl-DOTA.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16]S(C3C=CC(C)=CC=3)(=O)=O)=[C:12]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:37][C:38]([OH:42])([CH3:41])[CH2:39]O>>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:37][C:38]([OH:42])([CH3:41])[CH3:39])=[C:12]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:29][CH:28]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(O)CO
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3ccc(F)c(F)c3)c2=O)cc1
Product: CC(C)(O)COc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 178, substituting 2-(3,4-difluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 2-methyl-1,2-propanediol in place of 2-ethyl-1-hexanol (yield: 55 mg, 31%. 1H NMR (300 MHz, DMSO-d6) δ 0.97 (s, 6H), 3.30 (s, 3H), 4.20 (s, 2H), 4.54 (s, 1H), 7.52 (m, 1H), 7.62 (m, 1H), 7.81 (m, 1H), 7.98 (d, J=9 Hz, 2H), 8.05 (d, J=9 Hz, 2H), 8.21 (s, 1H); MS (APCI+) m/z 451 (M+H)+; (APCI−) m/z 485 (M+Cl)−; Anal. calc. for C21H20F2N2O5S: C, 55.99; H, 4.47; N, 6.21. Found: C, 56.00; H, 4.48; N, 5.87.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[CH:31]=[CH:32][C:33]([C:36]([NH:38][CH2:39][CH2:40][C:41]([O:43]C(C)(C)C)=[O:42])=[O:37])=[N:34][CH:35]=3)=[CH:18][CH:17]=2)[CH:12]=[CH:13][C:14]=1[Cl:15]>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[CH:31]=[CH:32][C:33]([C:36]([NH:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[O:37])=[N:34][CH:35]=3)=[CH:18][CH:17]=2)[CH:12]=[CH:13][C:14]=1[Cl:15]
Reactant: CC(C)(C)OC(=O)CCNC(=O)c1ccc(-c2ccccc2CNc2ccc(-c3ccc(Cl)c(Cl)c3)cc2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCNC(=O)c1ccc(-c2ccccc2CNc2ccc(-c3ccc(Cl)c(Cl)c3)cc2)cn1

Procedure:
Neat TFA (0.09 mL, 1.15 mmol) was added to a DCM solution (1 mL) of tert-butyl 3-(5-(2-(((3′,4′-dichloro-[1,1′-biphenyl]-4-yl)amino)methyl)phenyl)picolinamido)propanoate (44 mg, 0.08 mmol). After 16 h the resulting mixture was concentrated in vacuo, dissolved in DCM and 1 N HCl in diethyl ether was added. The resulting solution was concentrated in vacuo and the DCM/HCl process was repeated 2×. The resulting solid was characterized as the corresponding HCl salt of the title compound.
Reaction SMILES: [NH3:1].[C:2]([OH:10])(=[O:9])[C:3]([CH2:5][C:6]([OH:8])=[O:7])=[CH2:4]>CS(C)=O>[C:5](#[N:1])[CH:3]=[CH2:2].[C:2]([OH:10])(=[O:9])[C:3]([CH3:5])=[CH2:4].[C:2]([OH:10])(=[O:9])[C:3]([CH2:5][C:6]([OH:8])=[O:7])=[CH2:4]
Reactant: N
Agent: C=C(CC(=O)O)C(=O)O
Solvent: CS(C)=O
Product: C=C(C)C(=O)O
Product: C=CC#N

Procedure:
95 mol % of acrylonitrile, 3 mol % of methacrylic acid and 2 mol % of itaconic acid were polymerized by solution polymerization using dimethylsulfoxide as a solvent, and then ammonia was added thereto in an amount equivalent to that of itaconic acid to neutralize the reaction product to prepare a polyacrylontrile-based copolymer in the form of an ammonium salt, thereby obtaining a spinning solution including 22 wt % of the polyacrylontrile-based copolymer.
Reaction SMILES: O1CCCC1.C(#N)C.[CH2:9]([O:16][C:17]([C:19]1([C:22](=[O:39])[NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][N:34]=[C:33]([NH2:37])[CH:32]=3)=[CH:26][C:25]=2[F:38])[CH2:21][CH2:20]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl[C:41]([O:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:42]>N1C=CC=CC=1>[CH2:9]([O:16][C:17]([C:19]1([C:22](=[O:39])[NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][N:34]=[C:33]([NH:37][C:41]([O:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[O:42])[CH:32]=3)=[CH:26][C:25]=2[F:38])[CH2:20][CH2:21]1)=[O:18])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cc(Oc2ccc(NC(=O)C3(C(=O)OCc4ccccc4)CC3)c(F)c2)ccn1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CC#N
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)OCc4ccccc4)CC3)c(F)c2)ccn1)Oc1ccccc1
Reaction time: 3 h
Yield: 82.9 %

Procedure:
Tetrahydrofuran (41 ml), acetonitrile (41 ml) and pyridine (2.07 g) was added to 1-[4-(2-aminopyridin-4-yloxy)-2-fluorophenylcarbamoyl]cyclopropanecarboxylic acid benzyl ester (6.0 g, content 5.51 g), which was dissolved by stirring. Phenyl chloroformate (4.1 g) was added dropwise to this solution with cooling on ice at the internal temperature between 8.8° C. and 14.9° C. The reaction mixture was stirred at the same temperature for 2 hours and 9 minutes, then at room temperature for 3 hours and 5 minutes. The precipitate was collected by filtration, washed with a mixed solvent of tetrahydrofuran and acetonitrile (2:1, 16 ml), and dried under aeration to give the target title compound (6.39 g).
Reaction SMILES: [CH3:1][C:2]([N:6]([CH2:19][CH2:20][CH:21]=[O:22])[C:7]([NH:9][C:10]1[S:11][C:12]([C:15]([F:18])([F:17])[F:16])=[N:13][N:14]=1)=[O:8])([CH3:5])[C:3]#[CH:4].Cl>O>[F:16][C:15]([F:18])([F:17])[C:12]1[S:11][C:10]([N:9]2[CH:21]([OH:22])[CH2:20][CH2:19][N:6]([C:2]([CH3:1])([CH3:5])[C:3]#[CH:4])[C:7]2=[O:8])=[N:14][N:13]=1
Reactant: C#CC(C)(C)N(CCC=O)C(=O)Nc1nnc(C(F)(F)F)s1
Agent: Cl
Solvent: O
Product: C#CC(C)(C)N1CCC(O)N(c2nnc(C(F)(F)F)s2)C1=O

Procedure:
The diethyl acetal of 3-[1-(1,1-dimethylprop-2-ynyl)-3-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)ureido]-propionaldehyde (15 grams), water (400 ml) and hydrochloric acid (4 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. The reaction mixture is then filtered while hot and the filtrate is cooled to form a precipitate. The precipitate is recovered by filtration, is dried and is recrystallized to yield the desired product tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-3-(1,1-dimethylprop-2-ynyl)-6hydroxy-2(1H)-pyrimidinone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=O)=[CH:5][CH:4]=1.[C:14]([CH2:16]C(O)=O)#[N:15].C(O)(=O)CCCCCC.C(N)C1C=CC=CC=1.NC1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]=[C:10]2[CH2:16][C:14]#[N:15])=[CH:5][CH:4]=1
Reactant: N#CCC(=O)O
Reactant: COc1ccc2c(c1)C(=O)CCC2
Agent: CCCCCCC(=O)O
Solvent: Nc1ccccc1
Solvent: Cc1ccccc1
Solvent: NCc1ccccc1
Product: COc1ccc2c(c1)C(CC#N)=CCC2
Yield: 90 %

Procedure:
There are introduced into a 670 litre reactor 85.0 kg of 7-methoxy-1-tetralone, 60.3 kg of cyanoacetic acid and 15.6 kg of heptanoic acid in toluene in the presence of 12.7 kg of benzylamine (or 11.0 kg of aniline). The mixture is heated at reflux. When all the starting substrate has disappeared, the solution is cooled and filtered. The precipitate obtained is washed with toluene and then the filtrate obtained is washed with 2N sodium hydroxide solution and then with water until neutrality. After evaporating off the solvent, the solid obtained is recrystallised from an ethanol/water (80/20) mixture to yield the title product in a yield of 90% and with a chemical purity of more than 99%.
Reaction SMILES: [O:1]=[C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=O.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([NH2:36])[CH:30]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].Cl.CN(C)CCCN=C=NCC.C(Cl)Cl>CN(C)C1C=CN=CC=1.CN(C=O)C.O>[F:35][C:32]1[CH:33]=[CH:34][C:29]([CH:26]2[CH2:27][CH2:28][N:23]([C:21]([O:20][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:22])[CH2:24][CH2:25]2)=[CH:30][C:31]=1[NH:36][C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][C:2](=[O:1])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(F)c(N)c2)CC1
Reactant: O=C(O)CCCCC(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(F)c(NC(=O)CCCCC(=O)c3ccccc3)c2)CC1
Reaction time: 12 h
Yield: 50.8 %

Procedure:
A 25-mL RB-flask was charged with 6-oxo-6-phenylhexanoic acid (51.0 mg, 0.250 mmol), tert-butyl-4-(3-amino-4-fluorophenyl)-1-piperidinecarboxylate (59.0 mg, 0.200 mmol), 1-[3-(Dimethylamino)propyl]-3-ethylcarbodimide hydrochloride (0.400 mmol, 62.0 mg), 4-dimethylaminopyridine (10 mg) in DMF:DCM (0.2:2.0 mL) at room temperature. The reaction mixture was stirred for 12 h and water (10.0 mL) was added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with CHCl3 (3×10 mL). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified by chromatography (silica gel, hexanes:EtOAc 6:1) to afford tert-butyl 4-{4-fluoro-3-[(6-oxo-6-phenylhexanoyl)amino]phenyl}-1-piperidinecarboxylate (49.0 mg, 51.0%): 1H NMR (400 MHz, CDCl3) δ 8.30-8.14 (m, 1H), 8.04-7.89 (m, 2H), 7.62-7.50 (m, 1H), 7.50-7.37 (m, 3H), 7.09-6.93 (m, 1H), 6.93-6.76 (m, 1H), 4.38-4.01 (br, 2H), 3.13-2.95 (m, 2H), 2.89-2.69 (m, 2H), 2.65-2.54 (m, 1H), 2.54-2.35 (m, 2H), 1.95-1.74 (m, 6H), 1.69-1.48 (m, 2H), 1.47 (s, 9H).
Reaction SMILES: C(OC(=O)[CH2:5][N:6]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:7]([C:9]1([NH:12][C:13](OCC2C=CC=CC=2)=[O:14])[CH2:11][CH2:10]1)=[O:8])C.[H][H]>[C].[Pd].C(O)C>[CH2:23]([N:6]1[C:7](=[O:8])[C:9]2([CH2:11][CH2:10]2)[NH:12][C:13](=[O:14])[CH2:5]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)CN(Cc1ccccc1)C(=O)C1(NC(=O)OCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C1CN(Cc2ccccc2)C(=O)C2(CC2)N1
Yield: 100.4 %

Procedure:
5% Palladium carbon (3.6 g) was added to an ethanol (700 ml) solution of the compound (35.5 g, 86.5 mmol) obtained in Step 1 above and contact reduction was performed for 2 hours in a hydrogen atmosphere. The catalyst was filtrated through celite, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to give the title compound (20 g, 100%) as a colorless solid.
Reaction SMILES: CC1(C)CC(NCC[C:11]([NH:13]N)=[O:12])CC(C)(C)N1.[CH3:18][O:19][CH2:20][N:21]=[C:22]=[O:23].[C:24]1(C)C=CC=CC=1>>[CH3:18][O:19][CH2:20][NH:21][C:22](=[O:23])[NH:13][CH2:11][O:12][CH3:24]
Reactant: COCN=C=O
Reactant: Cc1ccccc1
Reactant: CC1(C)CC(NCCC(=O)NN)CC(C)(C)N1
Product: COCNC(=O)NCOC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
36.3 parts of β-(2,2,6,6-tetramethylpiperidine-4-yl)amino-propionic acid hydrazide are dissolved in 100 parts of toluene, followed by the dropwise addition of 28.2 parts of 93% methoxymethyl isocyanate. After stirring for 1 hour at 25° C., the deposit is filtered off under suction. The filter residue is stirred with 300 parts of petroleum ether and refiltered under suction. 48 parts of colourless crystals melting at 62° to 65° C. are left after drying.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Cl[CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.ClC1C=CC(C2C3CCNCCC=3NN2C2CCOCC2)=CC=1>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: ClC1CCOCC1
Agent: Clc1ccc(C2C3=C(CCNCC3)NN2C2CCOCC2)cc1
Product: Clc1ccc(-c2nn(C3CCOCC3)c3c2CCNCC3)cc1

Procedure:
The title compound was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.40 mmol) using 4-chloro-tetrahydro-pyran (1.5 mmol) in place of chloro-cyclobutane. The title compound was obtained as a 2:1 mixture (10 mg) with 3-(4-chloro-phenyl)-2-(tetrahydro-pyran-4-yl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene. Data for the mixture: MS (ESI): exact mass calculated for C18H22ClN3O, 331.15. found, m/z 332.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.44-7.42 (m, 1H), 7.36-7.30 (m, 4H), 7.20-7.18 (m, 1H), 4.36-4.33 (m, 1H), 3.97-3.94 (m, 3H), 3.87-3.86 (m, 1H), 3.51-3.49 (m, 3H), 3.28-3.25 (m, 1H), 2.90-2.75 (m, 8H), 2.66-2.64 (m, 2H), 2.39-2.37 (m, 1H), 2.19-2.10 (m, 3H), 1.74-1.71 (m, 2H), 1.65-1.62 (m, 1H).