Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1COCC1.[NH2:6][C:7]1[C:12]2=[C:13]([C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:32][C:33]4[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][C:34]=4[F:43])=[O:31])=[CH:25][CH:24]=3)[C:14]([CH2:16][CH2:17][C:18](OCC)=[O:19])=[CH:15][N:11]2[N:10]=[CH:9][N:8]=1.CC(C[AlH]CC(C)C)C>CCOC(C)=O>[NH2:6][C:7]1[C:12]2=[C:13]([C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:32][C:33]4[CH:38]=[C:37]([C:39]([F:40])([F:41])[F:42])[CH:36]=[CH:35][C:34]=4[F:43])=[O:31])=[CH:25][CH:24]=3)[C:14]([CH2:16][CH2:17][CH2:18][OH:19])=[CH:15][N:11]2[N:10]=[CH:9][N:8]=1
Reactant: CCOC(=O)CCc1cn2ncnc(N)c2c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ncnn2cc(CCCO)c(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
To a solution of THF (6 mL) was added ethyl 3-(4-amino-5-{4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino }carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-6-yl)propanoate (62 mg, 0.12 mmol) followed by DIBAL (0.6 mL, 0.6 mmol, 1.0M solution in toluene). The reaction was stirred at rt for 1 h. Additional DIBAL (1.2 mL, 1.2 mmol, 1.0M solution in toluene) was added and stirred at rt for an additional 1 h. The reaction was diluted with EtOAc and quenched with saturated aqueous Rochelle's salt. Reaction was extracted with EtOAc (4×). The combined organic layers were dried (Na2SO4), filtered, and evaporated to dryness to afford a crude yellow solid (56 mg, 98%) that was used directly in the next step without further purification. 1H-NMR (CD3OD) δ 8.62 (d, J=7.6 Hz, 1H), 7.74 (s, 1H), 7.61 (d, J=7.6 Hz, 2H), 7.52 (s, 1H), 7.38 to 7.31 (m, 4H), 3.50 (t, J=7.1 Hz, 2H), 2.61 (t, J=7.8 Hz, 2H), 1.77 to 1.65 (m, 2H); MS [M+H]+=489; LCMS RT=2.50 min.
Reaction SMILES: COC(=O)C1C=CC(OCC2C=CC3C(=CC=CC=3)N=2)=CC=1.[CH3:23][N:24]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[C:26]([C:35]2[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=2)=[N:25]1.[Cl:42][C:43]1[CH:52]=[C:51]2[C:46]([CH:47]=[CH:48][C:49]([CH2:53]Cl)=[N:50]2)=[CH:45][CH:44]=1>>[ClH:42].[Cl:42][C:43]1[CH:52]=[C:51]2[C:46]([CH:47]=[CH:48][C:49]([CH2:53][O:41][C:38]3[CH:39]=[CH:40][C:35]([C:26]4[C:27]([C:29]5[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=5)=[CH:28][N:24]([CH3:23])[N:25]=4)=[CH:36][CH:37]=3)=[N:50]2)=[CH:45][CH:44]=1
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(O)cc2)n1
Reactant: ClCc1ccc2ccc(Cl)cc2n1
Agent: COC(=O)c1ccc(OCc2ccc3ccccc3n2)cc1
Product: Cl
Product: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccc(Cl)cc4n3)cc2)n1

Procedure:
Following the procedure for the preparation of 4-(Quinolin-2-ylmethoxy)-benzoic acid methyl ester but substituting 4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenol and 7-chloro-2-chloromethyl-quinoline provided the title compound. 1H NMR (400 MHz, DMSO) δ 8.66 (d, J=6.6 Hz, 2H), 8.54 (s, 1 H), 8.47 (d, J=8.3, 2H), 8.04 (m, 2H), 7.70 (m, 2H), 7.65 (m, 1H), 7.36 (d, J=8.7 Hz, 2H), 7.12 (d, J=8.7, 2H), 5.38 (s, 2H), 3.90 (s, 3 H); MS: (M+H m/z=427.1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].ON1C2C=CC=CC=2N=N1.[F:33][C:34]([F:47])([F:46])[C:35]1[N:39]2[CH2:40][CH2:41][NH:42][CH2:43][C:38]2=[C:37]([CH2:44][OH:45])[N:36]=1.C(N(CC)CC)C>CN(C)C=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:42]1[CH2:41][CH2:40][N:39]2[C:35]([C:34]([F:47])([F:33])[F:46])=[N:36][C:37]([CH2:44][OH:45])=[C:38]2[CH2:43]1)=[O:5]
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: OCc1nc(C(F)(F)F)n2c1CNCC2
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCn2c(C(F)(F)F)nc(CO)c2C1
Reaction time: 12 h
Yield: 63.8 %

Procedure:
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (372 mg, 1.25 mmol) was dissolved in 5 mL of N,N-dimethylformamide, followed by addition of N-hydroxybenzotriazole (85 mg, 0.63 mmol), [3-(trifluoromethyl)-5,6,7,8-tetrahydro imidazo[1,5-a]pyrazin-1-yl]methanol 6a (277 mg, 1.25 mmol), 1-ethyl-(3-dimethyl-aminopropyl) carbodiimide hydrochloride (359 mg, 1.88 mmol) and triethylamine (0.3 mL, 2.5 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 4-[[4-fluoro-3-[1-(hydroxymethyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one 6 (400 mg, yield 64.0%) as a white solid.
Reaction SMILES: CO.[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[C:8]([O:17][CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]2)[CH:7]=1)([O-:5])=[O:4].[BH4-].[Na+].Cl>O1CCCC1>[OH:24][CH:21]1[CH2:22][CH2:23][CH:18]([O:17][C:8]2[CH:7]=[C:6]([N+:3]([O-:5])=[O:4])[CH:11]=[CH:10][C:9]=2[NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:19][CH2:20]1
Reactant: CS(=O)(=O)Nc1ccc([N+](=O)[O-])cc1OC1CCC(=O)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)Nc1ccc([N+](=O)[O-])cc1OC1CCC(O)CC1
Reaction time: 0.33 h
Yield: 73.5 %

Procedure:
To 8 ml of a mixture of methanol and tetrahydrofuran (1:2) containing 0.23 g of N-[4-nitro-2-(4-oxocyclohexyloxy)phenyl]methanesulfonamide obtained in Example 5 (2) was added 0.01 g of sodium borohydride under ice cooling, and the mixture was stirred for 20 minutes. To the reaction solution was a dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed, in turn, with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (eluent; n-hexane:dichloromethane:ethyl acetate=1:1:1) and then by recrystallization from dichloromethane-n-hexane to give 0.17 g of N-[2-(4-hydroxycyclohexyloxy)-4-nitrophenyl]methanesulfonamide.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH2:4][CH2:3]1.Br[C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=1[C:28]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:29]=1[CH2:30][CH2:31][N:32]([S:38]([NH:41][C:42]1[S:43][C:44]([F:47])=[CH:45][N:46]=1)(=[O:40])=[O:39])[CH2:33]2.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O>[F:47][C:44]1[S:43][C:42]([NH:41][S:38]([N:32]2[CH2:31][CH2:30][C:29]3[C:34](=[CH:35][CH:36]=[CH:37][C:28]=3[C:19]3[CH:20]=[C:21]([C:24]([F:26])([F:25])[F:27])[CH:22]=[CH:23][C:18]=3[C:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH:6]=3)[CH2:33]2)(=[O:39])=[O:40])=[N:46][CH:45]=1
Reactant: CN1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O=S(=O)(Nc1ncc(F)s1)N1CCc2c(cccc2-c2cc(C(F)(F)F)ccc2Br)C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CN1CC=C(c2ccc(C(F)(F)F)cc2-c2cccc3c2CCN(S(=O)(=O)Nc2ncc(F)s2)C3)CC1
Temperature: 25 °C
Yield: 10.3 %

Procedure:
A solution of Cl2Pd(AmPhos) (Sigma-Aldrich, St. Louis, Mo., 0.014 g, 0.019 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (0.054 g, 0.242 mmol), 5-(2-bromo-5-(trifluoromethyl)phenyl)-N-(5-fluorothiazol-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (0.104 g, 0.194 mmol), and potassium phosphate (0.165 g, 0.776 mmol) in 2 mL dioxane and 1 mL water, was heated to 110° C. 2 hours. The reaction mixture was allowed to cool to room temperature, was diluted with EtOAc and washed with 1N citric acid. The organic layer was then concentrated. Purification of the resulting residue by reverse phase column chromatography [RediSep Gold C18 50 g, 10 to 100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] gave N-(5-fluorothiazol-2-yl)-5-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (0.011 g, 0.020 mmol). [M+H]+=553.0 1H NMR (400 mHz, Acetone-d6) δ ppm: 7.70-7.77 (m, 1H), 7.50 (d, J=8.1 Hz, 1H), 7.42 (s, 1H), 7.05-7.14 (m, 2H), 6.93 (d, J=6.7 Hz, 1H), 6.62 (d, J=0.9 Hz, 1H), 5.87-5.93 (m, 1H), 4.48-4.56 (d, J=17.4 Hz, 1H), 4.19 (d, J=17.4 Hz, 1H), 3.70-3.84 (m, 2H), 3.32-3.43 (m, 1H), 3.12-3.32 (m, 3H), 2.87-2.98 (m, 1H), 2.76-2.82 (m, 1H), 2.57 (s, 3H), 1.98-2.04 (m, 2H)
Reaction SMILES: [CH3:1][CH:2]([C:4]1[S:20][C:7]2[N:8]=[C:9]3[CH:16]=[CH:15][C:14]([C:17](O)=[O:18])=[CH:13][N:10]3[C:11](=[O:12])[C:6]=2[CH:5]=1)[CH3:3].C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:34][C:35]1[NH:39][N:38]=[N:37][N:36]=1>CN(C)C=O>[CH3:3][CH:2]([C:4]1[S:20][C:7]2[N:8]=[C:9]3[CH:16]=[CH:15][C:14]([C:17]([NH:34][C:35]4[NH:39][N:38]=[N:37][N:36]=4)=[O:18])=[CH:13][N:10]3[C:11](=[O:12])[C:6]=2[CH:5]=1)[CH3:1]
Reactant: Nc1nnn[nH]1
Reactant: CC(C)c1cc2c(=O)n3cc(C(=O)O)ccc3nc2s1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1cc2c(=O)n3cc(C(=O)Nc4nnn[nH]4)ccc3nc2s1
Temperature: 105 °C
Reaction time: 8 h
Yield: 50.7 %

Procedure:
2.88 g (0.01 mol) of 2-(1-methylethyl)-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidin-7-carboxylic acid (Example 18) and 3.31 g (0.02 mol) of 1,1' carbonyldiimidazole (Aldrich Chemical Company) in 100 ml of dimethylformamide are stirred and heated in a wax bath at 105° C. for ninety minutes under nitrogen. The mixture is cooled and stirred at room temperature for thirty minutes and 1.03 g (0.01 mol) of 5-aminotetrazole monohydrate (Aldrich Chemical Company) is added and the resulting mixture is stirred and heated at 105° C. for one hundred thirty-five minutes under nitrogen. The mixture is allowed to stand overnight at room temperature, the precipitate is filtered and the filtrate is evaporated in vacuo. The residue is slurried in boiling methanol, the mixture cooled and filtered. This precipitate is combined with the previous precipitate to give 1.8 g of 2-(1-methylethyl)-4-oxo-N-1H-tetrazol-5-yl-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7 -carboxamide; mp 307° C. (dec) after recrystallization from pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:11].N(/C(C)(C)C#N)=N\C(C)(C)C#N.[Br:24]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:24][CH:4]1[C:3]2[C:7](=[CH:8][CH:9]=[CH:10][C:2]=2[Cl:1])[C:6](=[O:11])[O:5]1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1OCc2c(Cl)cccc21
Agent: CC(C)(C#N)/N=N/C(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1OC(Br)c2c(Cl)cccc21
Yield: 96.7 %

Procedure:
4-chloroisobenzofuran-1(3H)-one (10 g, 59.32 mmol), (E)-2,2′-(diazene-1,2-diyl)bis(2-methylpropanenitrile) (0.974 g, 5.93 mmol) and 1-bromopyrrolidine-2,5-dione (11.61 g, 65.25 mmol) were dissolved CCl4 (100 mL) and heated at reflux for 2 hours. The reaction was cooled and filtered, the filtrate was evaporated to the desired compound as a yellow gum (14.20 g, 97% yield); 1H NMR (400.132 MHz, CDCl3) δ 7.32 (1H, s), 7.61 (1H, t), 7.73 (1H, d), 7.88 (1H, d); m/z (LC-MS, ESI+), RT=2.28 (M+H not detected).
Reaction SMILES: ClS(O)(=O)=O.[NH2:6][C:7]1[N:11]=[CH:10][NH:9][N:8]=1.[C:12]([CH:16]([CH2:19][CH:20]=[CH2:21])[C:17]#[N:18])(=O)[CH2:13][CH3:14]>O.CC1C=CC=CC=1C>[CH2:19]([C:16]1[C:12]([CH2:13][CH3:14])=[N:6][C:7]2[N:8]([N:9]=[CH:10][N:11]=2)[C:17]=1[NH2:18])[CH:20]=[CH2:21]
Reactant: Nc1nc[nH]n1
Reactant: C=CCC(C#N)C(=O)CC
Agent: O=S(=O)(O)Cl
Solvent: O
Solvent: Cc1ccccc1C
Product: C=CCc1c(CC)nc2ncnn2c1N
Temperature: 130 °C
Yield: 84 %

Procedure:
In a 20 l jacketed vessel fitted with reflux condenser and water separator, 14650 g of o-xylene were initially charged, and 411 g of chlorosulfonic acid were added. 2074 g of 3-amino-1,2,4-triazole and 3690 g of a solution of 2-propionylpent-4-enenitrile (87.4% in o-xylene) were added, and the mixture was heated to reflux. The mixture was stirred under reflux for 14 hours, and the water of reaction formed was removed via a phase separator. Once no more water separated off, the mixture was cooled to 130° C. and 634 g of triethylamine were added. On further cooling, the product precipitated in the form of colorless crystals. At a temperature of 100° C., 2350 g of isopropanol were added. The mixture was cooled further to 20° C., and the solid formed was separated off. The filtercake was washed with 1500 ml of a 1:1 mixture of isopropanol and water and then dried under reduced pressure. This gives 4057 g of a colorless powder. Melting point: 258° C. (decomposition), 1H-NMR: 1.35 (t, 3H); 2.88 (q, 2H); 3.45 (d, 2H); 5.09 (d, 2H); 5.20 (d, 2H); 5.6 (s, broad, 2H); 5.8-6.0 (m, 1H); 8.30 (s, 1H). Yield: 84.0%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[CH2:11][C:10](=[O:15])[CH2:9]1.[C:16](O)(=[O:18])[CH3:17].CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[OH:18][C:16](=[C:11]1[C:12](=[O:14])[CH2:13][CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH2:9][C:10]1=[O:15])[CH3:17]
Reactant: CC(=O)O
Reactant: O=C1CC(=O)CC(c2ccccc2Cl)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: CN(C)C=O
Product: CC(O)=C1C(=O)CC(c2ccccc2Cl)CC1=O
Temperature: 25 °C
Reaction time: 13 h
Yield: 78.5 %

Procedure:
To a solution of 5-(2-chlorophenyl)cyclohexane-1,3-dione (1.5 g), acetic acid (0.73 g) and dimethylaminopyridine (0.12 g) in dimethylformamide (65 ml) was added dicyclohexylcarbodiimide (1.5 g), and the mixture was stirred at room temperature for 13 hours. Under reduced pressure, the solvent was evaporated, and to the residue was ethyl acetate. The solution was washed with sodium hydrogen carbonate solution, water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate-hexane to give colorless crystals of 2-(1-hydroxyethylidene)-5-(2-chlorophenyl)cyclohexane-1,3-dione (1.4 g).
Reaction SMILES: Cl.Cl.[CH2:3]1[C:11]2[C:6](=[C:7]([N:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[CH2:27]([N:29]([CH2:32][CH3:33])[CH2:30]C)[CH3:28].ClC(Cl)([O:37]C(=O)OC(Cl)(Cl)Cl)Cl.C(NCC)C>ClCCl>[CH2:3]1[C:11]2[C:6](=[C:7]([N:12]3[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:30]([N:29]([CH2:32][CH3:33])[CH2:27][CH3:28])=[O:37])[CH2:24][CH2:25]4)[CH2:16][CH2:17]3)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3CCC4)CC2)CC1
Reactant: CCN(CC)CC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: CCNCC
Solvent: ClCCl
Product: CCN(CC)C(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3CCC4)CC2)CC1
Reaction time: 20 h

Procedure:
0.48 g (1.2 mmol) trans-4-{2-[4-(indan-4-yl)-piperazin-1-yl]-ethyl}-cyclohexyl-amine dihydrochloride was suspended in dry dichloromethane (50 ml), triethylamine 0.67 ml, 4.8 mmol) was added and 0.14 g (0.48 mmol) triphosgene dissolved in dichloromethane was dropped in. After one hour stirring at room temperature diethylamine (0.62 ml, 6 mmol) was added and the stirring was continued for 20 hours. The solution was extracted with water (2×8 ml), dried and evaporated in vacuo. The residue was purified using flash chromatography giving the title compound (0.3 g, 58%), melting point: 157-9° C.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:12]2[CH:13]=[N:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)=[CH:9]\[CH2:10][OH:11])=[CH:4][CH:3]=1.[CH3:24][C:25]1[CH:35]=[C:34](OC/C=C(/C2C=CC(C#CCN3CCOCC3)=CC=2)\C2C=CC=CC=2)[CH:33]=[CH:32][C:26]=1[O:27][CH2:28][C:29]([OH:31])=[O:30].[C:61]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.O1CCCC1>[I:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:12]2[CH:13]=[N:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)=[CH:9]\[CH2:10][O:11][C:34]2[CH:33]=[CH:32][C:26]([O:27][CH2:28][C:29]([O:31][CH3:61])=[O:30])=[C:25]([CH3:24])[CH:35]=2)=[CH:4][CH:3]=1
Reactant: OC/C=C(\c1ccc(I)cc1)c1ccc(-c2ccccc2)nc1
Reactant: Cc1cc(OC/C=C(\c2ccccc2)c2ccc(C#CCN3CCOCC3)cc2)ccc1OCC(=O)O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(-c3ccccc3)nc2)cc1C
Temperature: 0 °C
Reaction time: 72 h

Procedure:
The above allyl alcohol (238 mg, 0.0.65 mmol), methyl (4-hydroxy-2-methylphenoxy)acetate (140 mg, 0.715 mmol; example 2) and triphenylphosphine (205 mg, 0.78 mmol) were dissolved in a mixture of anhydrous toluene (8 mL) and tetrahydrofuran (6 mL). The mixture was cooled to 0° C., kept under argon and a degassed solution of diisopropyl azodicarboxylate (0.163 mL, 0.78 mmol) in anhydrous tetrahydrofuran (1 mL) was added dropwise during 10 min. The reaction mixture was allowed to warm up to ambient temperature with the bath and then was stirred for 3 days. The solvents were evaporated in vacuo and the residue was submitted to flash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 85:15) affording methyl (E)-[4-[3-(4-iodophenyl)-3-(6-phenylpyridin-3-yl)allyloxy]-2-methylphenoxy]acetate as oil.
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[OH:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=1[O:14][CH3:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][CH2:2][CH2:3][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=1[O:14][CH3:15]
Reactant: BrCCBr
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)ccc1OCCBr
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.3 %

Procedure:
1,2-Dibromoethane (57 mL, 0.66 moles) was added to a mixture of 4-hydroxy-3-methoxybenzaldehyde (10 g, 66 mmoles) and potassium carbonate (45 g, 0.33 moles) in DMF (130 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours. The mixture was poured into water (1.2 L) and extracted with ethyl acetate (500+4×300 mL). The combined organic phases were washed with saturated sodium chloride (500 mL), dried over MgSO4 and evaporated in vacuo to afford 16.3 g (95%) of 4-(2-bromoethoxy)-3-methoxybenzaldehyde. M.p. 61-64° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[H][H]>CO>[Cl:1][C:2]1[C:3]([N+:15]([O-:17])=[O:16])=[CH:4][C:5]([C:11]([CH3:13])([CH3:12])[CH3:14])=[CH:6][C:7]=1[NH2:8]
Reactant: CC(C)(C)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Reactant: [H][H]
Solvent: CO
Product: CC(C)(C)c1cc(N)c(Cl)c([N+](=O)[O-])c1
Yield: 78 %

Procedure:
A mixture of 100 parts of 2-chloro-5-(1,1-dimethylethyl)-1,3-dinitrobenzene and 800 parts of methanol is hydrogenated at normal pressure and at room temperature with 10 parts of ruthenium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is purified by column-chromatography over silica gel using trichloromethane as eluent. The pure fractions are collected and the eluent is evaporated, yielding 69 parts (78%) of 2-chloro-5-(1,1-dimethylethyl)-3-nitrobenzenamine as a residue.
Reaction SMILES: [C:1]1([NH:7][C:8]2([C:22]([OH:24])=[O:23])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].CN(C)P(=O)(N(C)C)N(C)C.Br[CH:38]([CH3:40])[CH3:39]>O>[C:1]1([NH:7][C:8]2([C:22]([O:24][CH:38]([CH3:40])[CH3:39])=[O:23])[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:12][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)Br
Reactant: O=C(O)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Agent: [Na]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)OC(=O)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Temperature: 110 °C

Procedure:
A mixture of 10.4 parts of 4-(phenylamino)-1-(2-phenylethyl)-4-piperidinecarboxylic acid, sodium salt and 75 parts of hexamethylphosphoric triamide is stirred at 110° C for a while. It is cooled to 20° C and 3.7 parts of 2-bromopropane are added dropwise. After stirring for 4 hours, another 0.37 parts of 2-bromopropane is added dropwise. Upon completion, stirring is continued over week-end at room temperature. The reaction mixture is poured onto 150 parts of water and the product is extracted with methylbenzene. The extract is washed with water, dried, filtered and evaporated. The oily residue is dissolved in 1,1'-oxybisethane. The solution is stirred with activated charcoal. The latter is filtered off and the filtrate is evaporated. The oily residue is crystallized from hexane. The product is filtered off and recrystallized from hexane, yielding 1-methylethyl 4-(phenylamino)-1-(2-phenylethyl)-4-piperidinecarboxylate; mp. 78.5° C.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8](Cl)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[SH-:14].[Na+]>O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([SH:14])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [SH-]
Reactant: CC(C)(C)n1ncc(Cl)c(Cl)c1=O
Agent: [Na+]
Solvent: O
Product: CC(C)(C)n1ncc(S)c(Cl)c1=O
Temperature: 60 °C
Reaction time: 4 h
Yield: 81.5 %

Procedure:
To 560 ml of water were added 66.3 g of 2-tert.-butyl-4,5-dichloro-3(2H)-pyridazinone and 48.0 g of 70% sodium hydrosulfide. After stirring at 60° C. for 4 hours activated carbon was added thereto. The resulting mixture was allowed to cool and then filtered. Concentrated hydrochloric acid was added to the resulting filtrate until the pH thereof was lowered to 2 or less. The resulting solid was filtered off, washed with water, dried and then recrystallized from a mixed solvent of benzene and n-hexane to give the intended product as white needle-like crystals of m.p. 112°-113° C. (yield: 81.5%).
Reaction SMILES: CS[C:3](=[N:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[NH:4][C:5]([C@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)=[O:6].[Cl:30][C:31]1[CH:32]=[C:33]([CH:36]=[C:37]([Cl:46])[C:38]=1[NH:39][C:40](=[O:45])[CH2:41][N:42]([CH3:44])[CH3:43])[CH2:34][NH2:35]>C(N(CC)CC)C>[Cl:30][C:31]1[CH:32]=[C:33]([CH:36]=[C:37]([Cl:46])[C:38]=1[NH:39][C:40](=[O:45])[CH2:41][N:42]([CH3:43])[CH3:44])[CH2:34][NH:35][C:3]([NH:4][C:5]([C@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)=[O:6])=[N:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: CN(C)CC(=O)Nc1c(Cl)cc(CN)cc1Cl
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)[C@H]1CCCN1c1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Product: CN(C)CC(=O)Nc1c(Cl)cc(CNC(=NC(=O)OC(C)(C)C)NC(=O)[C@H]2CCCN2c2ccc(C(F)(F)F)cc2)cc1Cl
Yield: 54.5 %

Procedure:
A solution of (R)-tert-butyl methylthio(1-(4-(trifluoromethyl)-phenyl)pyrrolidine-2-carboxamido)methylenecarbamate (6 mg), 3,5-dichloro-4-(2-(dimethylamino)acetamido)-benzylamine (10 mg) and triethylamine (50 μL) was heated at 56° C. for 12 h. The crude reaction mixture was purified directly by preparative TLC eluting with 10% methanol/89% dichloromethane/1% ammonia hydroxide to give the title compound as a colorless oil (5 mg). retention time: 2.03 min (method A). MS (ESI) (M+Na)+ 659.19.