Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:33][C:34]1[CH:43]=[CH:42][C:37]2[O:38][CH2:39][CH2:40][O:41][C:36]=2[CH:35]=1)[CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=3)[C:20]([C:29]([OH:31])=O)=[CH:19][C:18]2=[O:32])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)OCC.[NH2:50][CH2:51][CH2:52][OH:53].C(OC(C)C)(C)C>C(OCC)C.O.C(OCC)(=O)C.C(N(CC)CC)C.O1CCCC1>[O:38]1[C:37]2[CH:42]=[CH:43][C:34]([CH2:33][N:8]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][N:17]4[C:26]5[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=5)[C:20]([C:29]([NH:50][CH2:51][CH2:52][OH:53])=[O:31])=[CH:19][C:18]4=[O:32])[CH2:13][CH2:14]3)[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:35][C:36]=2[O:41][CH2:40][CH2:39]1
Reactant: COc1ccc2c(C(=O)O)cc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Reactant: NCCO
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Solvent: CCOCC
Product: COc1ccc2c(C(=O)NCCO)cc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Reaction time: 2 h

Procedure:
To 3.0 mL of tetrahydrofuran suspension containing 0.15 g of 1-(2-(4-((tert-butoxycarbonyl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinoline-4-carboxylic acid, 39 μL of triethylamine was added at room temperature, 25 μL of ethyl chlorocarbonate was added dropwise under ice-cooling, and the reaction mixture was stirred at the same temperature for 2 hours. Then, 15 μL of 2-aminoethanol was added dropwise. After stirred at the same temperature for 3 hours, 15 μL of 2-aminoethanol was added dropwise and stirred for 1.5 hours. Further, 15 μL of 2-aminoethanol was added dropwise and stirred at room temperature for 40 min. To the reaction mixture, ethyl acetate and water were added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and extracts were combined, washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. To the residue thus obtained, diethyl ether and diisopropyl ether were added, and the resulting solid was filtered to give 84 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(4-(((2-hydroxyethyl)amino)carbonyl)-7-methoxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a slight yellow solid.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[NH2:8][C:9]1[N:10]=[C:11]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:12]([C:16]2[CH:17]=[CH:18][C:19](=[O:25])[N:20]([CH:22]([CH3:24])[CH3:23])[N:21]=2)=[N:13][C:14]=1Br.O>O1CCOCC1.C(Cl)(Cl)Cl>[NH2:8][C:9]1[N:10]=[C:11]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:12]([C:16]2[CH:17]=[CH:18][C:19](=[O:25])[N:20]([CH:22]([CH3:24])[CH3:23])[N:21]=2)=[N:13][C:14]=1[N:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1
Reactant: c1cc[nH]c1
Reactant: CC(C)n1nc(-c2nc(Br)c(N)nc2-c2ccccc2)ccc1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: CC(C)n1nc(-c2nc(-n3cccc3)c(N)nc2-c2ccccc2)ccc1=O
Temperature: 27.5 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (60% in oil suspension) (77.7 mg) in dioxane (0.6 ml) was added 1H-pyrrole (0.161 ml) and the mixture was stirred at 25-30° C. for 30 minutes. After addition of 6-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (150 mg), the mixture was heated at 100-105° C. for 2 hours. A mixture of water and chloroform was added to the reaction mixture. An organic layer was collected, dried over MgSO4, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (75:25 v/v) to give a solid. The solid was crystallized from a mixture of IPE and n-hexane to give 6-[5-amino-3-phenyl-6-(1H-pyrrol-1-yl)-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone (38 mg).
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].O.O[N:19]1[C:24](=[O:25])[CH2:23][CH2:22][C:20]1=[O:21].C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[NH:1]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[C@H:2]([C:7]([O:9][N:19]1[C:24](=[O:25])[CH2:23][CH2:22][C:20]1=[O:21])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: O=C1CCC(=O)N1O
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
Boc-Leu-OH.H2O (49.9 g, 0.2 M) and HOSu (23.0 g, 0.2 M) were dissolved in THF (300 ml) in a 1 lit. round flask. DCC (41.3 g, 0.2 M) in THF (200 ml) solution was added dropwise at -10° C. for about 10 minutes and the mixture was stirred at room temperature overnight. Precipitated DCU was filtered off and the filtrate was concentrated. The residue was dissolved in ethyl acetate (300 ml), washed with 1 N-HCl, NaCl solution and a small amount of water and dried with anhydrous sodium sulfate. After removal of the drying agent, the solution was concentrated, and n-hexane was added thereto to obtain Boc-Leu-OSu as a colorless powder (m.p. 106°-110° C., 59.11 g, yield: 90%).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][C:4]1=[O:9])[CH3:2].C(N(CC)C(C)C)(C)C.[F:19][C:20]1[CH:21]=[C:22]([N+:27]([O-:29])=[O:28])[CH:23]=[CH:24][C:25]=1F.FC(F)(F)C(O)=O.C(N(CC)C(C)C)(C)C>C(#N)C>[F:19][C:20]1[CH:21]=[C:22]([N+:27]([O-:29])=[O:28])[CH:23]=[CH:24][C:25]=1[N:6]1[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[C:4](=[O:9])[CH2:5]1
Reactant: CCN1CCNCC1=O
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCN(c2ccc([N+](=O)[O-])cc2F)CC1=O

Procedure:
1-Ethyl-2-oxopiperazine (3TFA salt, 10.5 g) was dissolved in acetonitrile (200 ml), and N,N-diisopropylethylamine (19.5 ml) followed by 3,4-difluoronitrobenzene (2.25 ml) were added. The mixture was heated to reflux for 18 hours. Solvent was evaporated, and the residue chromatographed on silica using as eluant a gradient increasing in polarity from 0 to 4% methanol in dichloromethane. Relevant fractions were combined and evaporated to give a solid containing some N,N-diisopropylethylamine trifluoroacetate. The solid was purified by dissolving in ethyl acetate and washing well with water. Evaporation of the organic layer gave 3-fluoro-4-(4-ethyl-3-oxopiperazin-1-yl)nitrobenzene as a solid (3.44 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])=[CH:11][N:10]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[O:32][C:33]=4[CH3:34])=[CH:23][CH:22]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].C(O)C.Cl>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:11][N:10]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=5)[O:32][C:33]=4[CH3:34])=[CH:23][CH:22]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1-c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(CCC(=O)O)c(-c3ccc(F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
A mixture of ethyl 3-[3-(4-fluorophenyl)-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (500 mg), 1N aqueous sodium hydroxide solution (2 ml), ethanol (3 ml), and tetrahydrofuran (5 ml) was stirred at room temperature for 1 hour. The reaction mixture was acidified with 1N hydrochloric acid, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The colorless crystals obtained were collected by filtration to yield 3-[3-(4-fluorophenyl)-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (330 mg, yield: 69%). This was recrystallized from ethyl acetate-hexane. Melting point: 139–140° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][NH:4][N:3]=1.Cl[C:12]1[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][N:13]=1>>[Cl:18][C:17]1[C:12]([N:4]2[CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:2]([CH3:1])=[N:3]2)=[N:13][CH:14]=[C:15]([C:19]([F:21])([F:20])[F:22])[CH:16]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: COC(=O)c1c[nH]nc1C
Product: COC(=O)c1cn(-c2ncc(C(F)(F)F)cc2Cl)nc1C
Yield: 81.5 %

Procedure:
Using methyl 3-methyl-1H-pyrazole-4-carboxylate (3.8 g) synthesized in Example 1(3) and 2,3-dichloro-5-trifluoromethylpyridine (5.8 g) and in the same manner as in Example 1(4), the title object compound (7.0 g, 78%) was obtained as a pale-yellow solid.
Reaction SMILES: C([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([CH:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=2)[CH3:22])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[Cl:20][C:15]1[CH:14]=[C:13]([CH:11]2[CH2:12][NH:8][CH2:9][CH:10]2[CH:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][N:25]=2)[CH3:22])[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: CC(Oc1ccc(C(F)(F)F)cn1)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Agent: CC(Cl)OC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(Oc1ccc(C(F)(F)F)cn1)C1CNCC1c1ccc(Cl)c(Cl)c1
Temperature: 100 °C
Yield: 86.8 %

Procedure:
To a solution of 2-{(SR)-1-[(3RS,4SR)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethoxy}-5-trifluoromethyl-pyridine 0.45 g (0.91 mmol) dissolved in toluene (5 mL) were added 0.30 mL (2.7 mmol) of 1-chloroethyl chloroformate and 0.46 mL of Hunig's base. The reaction mixture was heated at 100° C. for one hour. After cooling down to RT, volatiles were removed under vacuo and the crude was dissolved in MeOH (5 mL). The reaction mixture was heated at 85° C. for 30 minutes and after cooling down to RT, volatiles were removed under vacuo and the residue was directly purified on column chromatography (SiO2, CH2Cl2/MeOH 9:1) yielded 0.32 g (87%) of the title compound as a light yellow oil. ES-MS m/e: 405.9 (M+H+).
Reaction SMILES: [H-].[K+].N#N.[CH2:5]([N:12]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:13][CH2:14][C:15]([CH3:18])([OH:17])[CH3:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:26]I>C1COCC1>[CH2:19]([N:12]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:13][CH2:14][C:15]([O:17][CH3:26])([CH3:18])[CH3:16])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CI
Reactant: CC(C)(O)CCN(Cc1ccccc1)Cc1ccccc1
Agent: N#N
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(C)(C)CCN(Cc1ccccc1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57.3 %

Procedure:
Add potassium hydride (30%, 2.6 g, 19.4 mmol) portion wise under N2 to a cooled solution (0° C.) of 4-(dibenzylamino)-2-methylbutan-2-ol (5 g, 17.6 mmol) in THF (50 mL). Stir the mixture at 0° C. for 0.5 h, treat with MeI (2.76 g, 19.4 mmol) dropwise, allow the mixture to warm to RT and stir for 3 h. Re-cool the mixture to 0° C., treat with saturated. NH4Cl, and remove the organics under reduced pressure. Extract the residue with EtOAc (3×), wash the combined organics with brine, dry over Na2SO4, concentrate and purify via silica gel chromatography (Pet ether/EtOAc, 50:1) to afford the title compound (3.0 g, 57% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.29 (m, 10H), 3.58 (s, 4H), 3.05 (s, 3H), 2.50 (m, 2H), 1.73 (m, 2H), 1.07 (s, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=2)=[C:8]([CH:14]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])([O-])=O.NC1C=CC=CC=1>C(O)C.C1COCC1>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:15][C:16]2[CH:17]=[C:18]([F:23])[CH:19]=[C:20]([F:22])[CH:21]=2)=[C:8]([CH:14]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])ccc1Oc1cc(F)cc(F)c1
Solvent: CCO
Solvent: C1CCOC1
Solvent: Nc1ccccc1
Product: CCOC(=O)c1cc(N)ccc1Oc1cc(F)cc(F)c1
Yield: 100.9 %

Procedure:
Using the method of Example 17.3, ethyl 5-nitro-2-(3,5-difluorophenoxy)benzoate (0.76 g) in ethanol (7 mL) and THF (3 mL) was converted to the corresponding aniline derivative which was obtained as an oil (0.696 g).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:21](=[O:47])[N:22]([CH:26]([C:36]1[NH:37][CH:38]=[C:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:40]=1)[CH2:27][O:28]CC1C=CC=CC=1)[CH:23]([CH3:25])[CH3:24])[CH2:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([C:17](=[O:19])[NH2:18])=[CH:12][C:11]=1[CH3:20])(C)(C)C.I[Si](C)(C)C.CO.O.C(#N)C>C(Cl)(Cl)Cl>[NH2:7][CH:8]([C:21](=[O:47])[N:22]([CH:26]([C:36]1[NH:37][CH:38]=[C:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:40]=1)[CH2:27][OH:28])[CH:23]([CH3:25])[CH3:24])[CH2:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([C:17]([NH2:18])=[O:19])=[CH:12][C:11]=1[CH3:20]
Reactant: Cc1cc(C(N)=O)cc(C)c1CC(NC(=O)OC(C)(C)C)C(=O)N(C(C)C)C(COCc1ccccc1)c1nc(-c2ccccc2)c[nH]1
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: Cc1cc(C(N)=O)cc(C)c1CC(N)C(=O)N(C(C)C)C(CO)c1nc(-c2ccccc2)c[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of [1-{[2-benzyloxy-1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-isopropyl-carbamoyl}-2-(4-carbamoyl-2,6-dimethyl-phenyl)-ethyl]-carbamic acid tert-butyl ester, (0.287 g, 0.439 mmol), in chloroform (10 mL) was cooled in an ice bath and treated with 0.62 mL (4.4 mmol) of iodotrimethylsilane. The reaction, which immediately clouded, was warmed slowly to room temperature while stirring. After 16 h, the reaction was cooled in an ice bath to 5-10° C. and treated with 100 mL of MeOH. The quenched mixture was stirred at 5-10° C. for 30 min, removed from the ice bath and stirred for an additional 30 min, and concentrated in vacuo to yield an orange residue that was subjected to reverse phase HPLC (water/acetonitrile/0.1% TFA). The fractions of interest were combined and the sample was lyophilized to yield 4-(2-amino-2-{[2-hydroxy-1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-isopropyl-carbamoyl}-ethyl)-3,5-dimethyl-benzamide (TFA salt) as a white powder (HPLC: 99% @ 254 nm and 100% @ 214 nm)
Reaction SMILES: CN1[C@@H](CC2C3C=C(CCS(C4C=CC=CC=4)(=O)=O)C=CC=3NC=2)CCC1.C1(S(C=CC2C=C3C(=CC=2)NC=C3C[C@H]2CCCN2C)(=O)=O)C=CC=CC=1.BrC1C=C2C(=CC=1)NC=C2.C(O[C:73]([N:75]1[CH2:79][CH2:78][CH2:77][C@@H:76]1[C:80]([C:82]1[C:90]2[C:85](=[CH:86][CH:87]=[C:88]([Br:91])[CH:89]=2)[NH:84][CH:83]=1)=O)=O)C1C=CC=CC=1>>[Br:91][C:88]1[CH:89]=[C:90]2[C:85](=[CH:86][CH:87]=1)[NH:84][CH:83]=[C:82]2[CH2:80][C@H:76]1[CH2:77][CH2:78][CH2:79][N:75]1[CH3:73]
Reactant: O=C(c1c[nH]c2ccc(Br)cc12)[C@H]1CCCN1C(=O)OCc1ccccc1
Agent: Brc1ccc2[nH]ccc2c1
Agent: CN1CCC[C@@H]1Cc1c[nH]c2ccc(C=CS(=O)(=O)c3ccccc3)cc12
Agent: CN1CCC[C@@H]1Cc1c[nH]c2ccc(CCS(=O)(=O)c3ccccc3)cc12
Product: CN1CCC[C@@H]1Cc1c[nH]c2ccc(Br)cc12

Procedure:
European Patent No. 0592438 describes the preparation of eletriptan by the catalytic reduction of (R)-5-(2-benzenesulphonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1 H-indole, which compound is prepared by (i) reacting N-benzyloxycarbonyl-D-proline acid chloride with 5-bromoindole in the presence of a Grignard reagent, (ii) reducing the resulting (R)-3-(N-benzyloxycarbonylpyrrolidin-2-ylcarbonyl)-5-bromo-1H-indole to give (R)-5-bromo-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole and (iii) reacting same with phenyl vinyl sulphone in the presence of a palladium catalyst, a triarylphosphine and a base.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([NH2:21])=[CH:17][CH:16]=1.[CH:22]1([C:25](Cl)=[O:26])[CH2:24][CH2:23]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([NH:21][C:25]([CH:22]2[CH2:24][CH2:23]2)=[O:26])=[CH:17][CH:16]=1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(N)nn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(NC(=O)C2CC2)nn1
Yield: 75 %

Procedure:
As described for example 18, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazin-3-ylamine (200 mg, 0.7 mmol) was converted, using cyclopropanecarbonyl chloride instead of methoxyacetyl chloride, to the title compound (185 mg, 75%) which was obtained as a white solid. MS: m/e=351.3 [M+H]+.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Cl[CH2:15][C:16]1[N:17]=[C:18]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=2)[O:19][CH:20]=1.[I-].[Na+]>CN(C)C=O.O>[F:27][C:25]1[CH:24]=[C:23]([C:28]([F:29])([F:30])[F:31])[CH:22]=[C:21]([C:18]2[O:19][CH:20]=[C:16]([CH2:15][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[N:17]=2)[CH:26]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Fc1cc(-c2nc(CCl)co2)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(Cc1coc(-c2cc(F)cc(C(F)(F)F)c2)n1)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a 50 mL round bottomed flask was placed diethyl malonate (3.72 g, 23.25 mmol, 5 equiv.) and N,N-dimethylformamide (10 mL). To the solution was added sodium hydride (60% suspension in mineral oil, 744.0 mg, 18.6 mmol, 4.0 equiv.) at room temperature portionwise over 10 minutes. After stirring for 30 minutes a solution of 4-(chloromethyl)-2-[5-fluoro-3-(trifluoromethyl)phenyl]-1,3-oxazole (1.30 g, 4.65 mmol) in N,N-dimethylformamide (10 mL) was added at 0° C. over 15 minutes, and the reaction mixture allowed to warm up to ambient temperature. To the mixture was added sodium iodide (697.0 mg, 4.65 mmol, 1 equiv) at room temperature. The reaction mixture was stirred at the same temperature for 2 hours. Water was then added to the reaction mixture (30 mL) and the whole was extracted with ethyl acetate (30 mL×3). The organic layers were combined, washed with brine (30 mL) and dried with sodium sulfate. After removal of the solvent under reduced pressure the crude mixture was purified by a silica-gel column chromatography (SiO2=80 g, hexane:EtOAc=7:1) repeatedly. The desired product, diethyl 2-({2-[5-fluoro-3-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}methyl)propane-1,3-dioate, was obtained as colorless powder (1.75 g).
Reaction SMILES: [CH2:1]1[CH2:43][O:42][C:4]2=[CH:5][C:6]3[C:11]4[C:12]5[C:37](=[O:38])[N:36](CO)[C:35](=[O:41])[C:13]=5[C:14]5[C:15]6[C:20]([N:21]([C@@H:23]7[O:31][C@H:30]([CH2:32][OH:33])[C@@H:28]([OH:29])[C@H:26]([OH:27])[C@H:24]7[OH:25])[C:22]=5[C:10]=4[NH:9][C:7]=3[CH:8]=[C:3]2[O:2]1)=[CH:19][CH:18]=[C:17]([OH:34])[CH:16]=6.[NH4+].[OH-]>CO>[CH2:1]1[CH2:43][O:42][C:4]2=[CH:5][C:6]3[C:11]4[C:12]5[C:37](=[O:38])[NH:36][C:35](=[O:41])[C:13]=5[C:14]5[C:15]6[C:20]([N:21]([C@@H:23]7[O:31][C@H:30]([CH2:32][OH:33])[C@@H:28]([OH:29])[C@H:26]([OH:27])[C@H:24]7[OH:25])[C:22]=5[C:10]=4[NH:9][C:7]=3[CH:8]=[C:3]2[O:2]1)=[CH:19][CH:18]=[C:17]([OH:34])[CH:16]=6
Reactant: O=C1c2c(c3c4cc(O)ccc4n([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)c3c3[nH]c4cc5c(cc4c23)OCCO5)C(=O)N1CO
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: O=C1NC(=O)c2c1c1c3cc4c(cc3[nH]c1c1c2c2cc(O)ccc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)OCCO4
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 9 (5.0 mg, 0.00845 mmol) in MeOH (0.5 mL) was added NH4OH (1.5 mL). The mixture was stirred at ambient temperature for 3 hours, then concentrated in vacuo to give a crude solid. Recrystallization with MeOH/hexane/CHCl3 afforded 4.3 mg (90.5%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].CC(C[AlH]CC(C)C)C>C1COCC1>[Br:1][C:2]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:3]=1[CH:4]=[O:5]
Reactant: CON(C)C(=O)c1cc(C)ccc1Br
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: Cc1ccc(Br)c(C=O)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
Step AI (2): 2-Bromo-N-methoxy-N,5-dimethylbenzamide (656 mg, 2.54 mmol) was dissolved in THF (20 mL). The reaction mixture was cooled down to −78° C. and a 1.0M solution of DIBAL-H (7.62 mL, 7.62 mmol) was added. The reaction mixture was stirred at −78° C. for 1 h. The reaction was quenched with acetone and stirred at rt with Rochelle's salt. The mixture was extracted with DCM. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuum to yield 2-bromo-5-methylbenzaldehyde (500 mg, 99%) as a colorless oil. LC-MS (M+H)+=199.21.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([OH:14])=[O:13])[CH:2]=[CH2:3].[OH-].[Na+].I[CH2:18][CH:19]([OH:22])[CH2:20][OH:21].CN(C)P(N(C)C)(N(C)C)=O>O.CCOCC>[CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([O:14][CH2:18][CH:19]([OH:22])[CH2:20][OH:21])=[O:13])[CH:2]=[CH2:3]
Reactant: C=CCNc1ccccc1CC(=O)O
Reactant: OCC(O)CI
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=CCNc1ccccc1CC(=O)OCC(O)CO

Procedure:
A solution of 7.34 g. of 2-(allylamino)phenylacetic acid, 4.80 g. of 25% aqueous sodium hydroxide, and 12.6 g. of 3-iodo-1,2-propanediol in 50 ml. of hexamethylphosphoramide is stirred for 24 hours at ambient temperature, diluted with 100 ml. of ether and stirred for 5 days at ambient temperature. The mixture is treated with water and extracted with ether. The dried extracts are evaporated to yield 2,3-dihydroxypropyl 2-(allylamino)phenylacetate.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:4]([NH2:19])=[N:5][CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:8]=1.C([O-])(O)=O.[Na+].Cl[CH2:28][CH:29]=O.O>CCO>[F:21][C:2]([F:1])([F:20])[C:3]1[C:4]2[N:5]([CH:28]=[CH:29][N:19]=2)[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:8]=1
Reactant: Nc1ncc(-c2ccc(C(F)(F)F)cc2)cc1C(F)(F)F
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)c3nccn3c2)cc1
Yield: 69 %

Procedure:
To a mixture of 3-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyridin-2-ylamine (12.77 g, 42 mmol) and NaHCO3 (5.96 g, 71 mmol) in EtOH (300 mL) was added chloracetaldehyde solution 55% in water (22 mL, 188 mmol), then refluxed overnight. The reaction mixture was concentrated and purified by column chromatography (CH2Cl2/Et2O 1:1) to give the product as a white crystalline solid (9.6 g, 69%). MS (ISP) 331.1 [(M+H)+].
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:16]=[C:17]([C:21]([NH:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:52])=[C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][N:38]5[CH2:43][CH2:42][N:41](C(OC(C)(C)C)=O)[C@@H:40]([CH3:51])[CH2:39]5)[CH:32]=4)[CH:30]=3)=[O:22])[CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=O)(C)C.[H-].[Na+].[C:55]1([O:61][CH2:62][CH2:63][CH2:64]Br)[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>CN(C=O)C>[F:52][C:28]1[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][N:38]3[CH2:43][CH2:42][NH:41][C@@H:40]([CH3:51])[CH2:39]3)[CH:32]=2)=[CH:30][C:25]([CH2:24][N:23]([CH2:64][CH2:63][CH2:62][O:61][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:21](=[O:22])[C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([CH2:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:16]=2)=[CH:26][CH:27]=1
Reactant: BrCCCOc1ccccc1
Reactant: C[C@H]1CN(Cc2cccc(-c3cc(CNC(=O)c4cccc(CC5CCN(C(=O)OC(C)(C)C)CC5)c4)ccc3F)c2)CCN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H]1CN(Cc2cccc(-c3cc(CN(CCCOc4ccccc4)C(=O)c4cccc(CC5CCNCC5)c4)ccc3F)c2)CCN1
Yield: 24.1 %

Procedure:
Following the general procedure outlined in Example 66, 1,1-dimethylethyl (2S)-4-[(5′-{[({3-[(1-{[(1,1-dimethylethyl)oxy]carbonyl}-4-piperidinyl)methyl]phenyl}carbonyl)amino]methyl)-2′-fluoro-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate (75.4 mg, 0.105 mmol), NaH (5.37 mg, 0.243 mmol) and 3-bromopropyl phenyl ether (0.020 mL, 0.127 mmol) in DMF (0.5 mL) were reacted to give the desired product (16.4 mg, 24.0%). EI-MS m/z 649(M−H)+.