Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:11]1[CH2:15][C@H:14]([O:16][CH3:17])[CH2:13][C@H:12]1[CH2:18][OH:19])=O)C1C=CC=CC=1>CO>[CH3:17][O:16][C@H:14]1[CH2:15][NH:11][C@H:12]([CH2:18][OH:19])[CH2:13]1
Reactant: CO[C@@H]1C[C@@H](CO)N(C(=O)OCc2ccccc2)C1
Solvent: CO
Product: CO[C@H]1CN[C@H](CO)C1
Reaction time: 12 h
Yield: 59.7 %

Procedure:
To 1.00 g (5.62 mmol) of (2S,4R)-2-Hydroxymethyl-4-methoxy-pyrrolidine-1-carboxylic acid benzyl ester in 3 mL of MeOH was added 0.1 g of 10% Pd(C) under 1 atmosphere of H2 while stirring for 12 h. The mixture was filtered through 0.22 μM Teflon filter concentrated and put under high vacuum for 2 h to give 0.44 g (96%) of ((2S,4R)-4-Methoxy-pyrrolidin-2-yl)-methanol as clear oil. LCMS (APCI) (M+H+) m/z: 266.2.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:3]=1[CH2:4][O:5][C:6]1[CH:18]=[CH:17][C:9]2[C:10]([CH2:13][C:14]([NH2:16])=[O:15])=[CH:11][S:12][C:8]=2[CH:7]=1.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:39][S:40](Cl)(=[O:42])=[O:41]>O>[Cl:1][C:2]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:3]=1[CH2:4][O:5][C:6]1[CH:18]=[CH:17][C:9]2[C:10]([CH2:13][C:14]([NH:16][S:40]([CH3:39])(=[O:42])=[O:41])=[O:15])=[CH:11][S:12][C:8]=2[CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: NC(=O)Cc1csc2cc(OCc3ccc(Cl)cc3Cl)ccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)NC(=O)Cc1csc2cc(OCc3ccc(Cl)cc3Cl)ccc12
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 12.4 %

Procedure:
To a mixture of 2-(6-((2,4-dichlorobenzyl)oxy)-1-benzothiophen-3-yl)acetamide (73.3 mg) and THF (dry) (10 mL) was added sodium bis(trimethylsilyl)amide (0.158 ml, 1.9 M in toluene) at −78° C. The mixture was stirred at −40° C. under argon atmosphere for 30 min. And then methanesulfonyl chloride (34.4 mg) was added thereto. The resulting mixture was stirred at room temperature under argon atmosphere overnight. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (11.00 mg).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH3:13])=[CH:7]2.[CH3:14][CH:15]1[CH2:17][O:16]1.O>O1CCCC1.CCOCC>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:14][CH:15]([OH:16])[CH3:17])[C:8]([CH3:13])=[CH:7]2
Reactant: CC1CO1
Reactant: Cc1cc2cc(Cl)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc2cc(Cl)ccc2n1CC(C)O
Reaction time: 1 h
Yield: 61.7 %

Procedure:
A suspension of 75 ml of sodium hydride dispersion in 15 ml of tetrahydrofuran was treated with 0.33 g of 5-chloro-2-methylindole at 0° and stirred at this temperature for 1 hour. After the addition of 0.28 ml of (RS)-methyloxirane the reaction mixture was stirred at room temperature for 48 hours and subsequently treated with water. The mixture was diluted with ether, washed with water and with saturated sodium chloride solution and the organic phase was dried over sodium sulfate. After removal of the solvent the residue was chromatographed over 13 g of silica gel with toluene-ethyl acetate (19:1). There was obtained 0.27 g (61.7%) of (RS)-1-(5-chloro-2-methyl-indol-1-yl)-propan-2-ol as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([O:11][C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:15]=[CH:16][CH:17]=3)[CH:9]=[CH:10][C:4]=2[N:3]=1.[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1.CO.[OH-].[Na+]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH:26]1([C:29]([NH:1][C:2]2[NH:6][C:5]3[CH:7]=[C:8]([O:11][C:12]4[CH:13]=[C:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])[CH:15]=[CH:16][CH:17]=4)[CH:9]=[CH:10][C:4]=3[N:3]=2)=[O:30])[CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc3nc(N)[nH]c3c2)c1
Reactant: O=C(Cl)C1CC1
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)[nH]c3c2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.1 %

Procedure:
To a solution of tert-butyl {3-[(2-amino-1H-benzimidazol-6-yl)oxy]phenyl}carbamate (1.30 g, 3.82 mmol) in pyridine (50 mL) were added cyclopropanecarbonyl chloride (1 mL, 11.0 mmol) and N,N-dimethylpyridine-4-amine (21.3 mg, 174 μmol), and the mixture was stirred at room temperature for 16 hr. To the reaction mixture were added methanol (30 mL) and 8N aqueous sodium hydroxide solution (3 mL), and the mixture was stirred at the same temperature for 2.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methanol (5 mL) and ethyl acetate (50 mL). This solution was washed with 0.1N hydrochloric acid (50 mL) and saturated aqueous sodium hydrogencarbonate solution (50 mL), successively, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate and diisopropyl ether to give the title compound (1.53 g, 98%) as colorless crystals.
Reaction SMILES: [N:1]1([S:5]([NH2:8])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].ClC1C=C(OC2COC(C3C=CC=CC=3)OC2)N=C(SCC2C=CC=C(F)C=2F)N=1.Cl[C:80]1[CH:85]=[C:84]([O:86][C@@H:87]([C@@H:89]2[CH2:93][O:92][C:91]([CH3:95])([CH3:94])[O:90]2)[CH3:88])[N:83]=[C:82]([S:96][CH2:97][C:98]2[CH:103]=[CH:102][CH:101]=[C:100]([F:104])[C:99]=2[F:105])[N:81]=1.[Cl-].[NH4+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:105][C:99]1[C:100]([F:104])=[CH:101][CH:102]=[CH:103][C:98]=1[CH2:97][S:96][C:82]1[N:81]=[C:80]([NH:8][S:5]([N:1]2[CH2:4][CH2:3][CH2:2]2)(=[O:7])=[O:6])[CH:85]=[C:84]([O:86][C@@H:87]([C@@H:89]2[CH2:93][O:92][C:91]([CH3:94])([CH3:95])[O:90]2)[CH3:88])[N:83]=1
Reactant: C[C@@H](Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1)[C@@H]1COC(C)(C)O1
Reactant: NS(=O)(=O)N1CCC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: Fc1cccc(CSc2nc(Cl)cc(OC3COC(c4ccccc4)OC3)n2)c1F
Solvent: C1COCCO1
Product: C[C@@H](Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1)[C@@H]1COC(C)(C)O1
Temperature: 100 °C

Procedure:
A mixture of azetidine-1-sulphonamide (prepared according to patent WO 2004/011443, 0.16 g), tris(dibenzylideneacetone)-dipalladium (0) (33 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (17 mg), cesium carbonate (0.28 g) and 4-chloro-2-[[(2,3-difluorophenyl)-methyl]thio]-6-[(2-phenyl-1,3-dioxan-5-yl)oxy]-pyrimidine (the product of step i) (0.25 g) in dioxane (10 mL) was heated at reflux in a microwave at 100° C., 300 W, open vessel with cooling for 20 min. Saturated ammonium chloride was added and the resulting mixture extracted with EtOAc. The combined organic extracts were washed with saturated aqueous sodium chloride, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography on silica gel using EtOAc/isohexane (3:7) as eluent to give the subtitle compound as a yellow oil. Yield: 0.13 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1F.BrC1C=CC=C([N+]([O-])=O)C=1[NH:22][CH2:23][CH2:24][OH:25]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[NH:22][CH2:23][CH2:24][OH:25]
Reactant: O=[N+]([O-])c1cccc(F)c1F
Reactant: O=[N+]([O-])c1cccc(Br)c1NCCO
Product: O=[N+]([O-])c1cccc(F)c1NCCO

Procedure:
2-[(2-Fluoro-6-nitrophenyl)amino]ethanol was prepared starting from 1,2-difluoro-3-nitrobenzene (0.66 g) according to the procedure described for the synthesis of 2-[(2-bromo-6-nitrophenyl)amino]ethanol. Yield 0.78 g (95%). MS (ESI) m/z 201.1 [M+H]. 1H NMR (400 MHz, DMSO-D6) δ ppm: 3.56 (m, 4 H), 4.91 (m, 1H), 6.70 (m, 1H), 7.46 (m, 1H), 7.85 (bs, 1H), 7.89 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[C:14]([N+:17]([O-])=O)[CH:15]=[CH:16][C:9]=3[S:8][C:7]=2[CH:20]=1)#[N:2].O1CCCC1.Cl.[OH-].[Na+]>O>[NH2:17][C:14]1[CH:15]=[CH:16][C:9]2[S:8][C:7]3[CH:20]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=3[CH:12]=[CH:11][C:10]=2[CH:13]=1
Reactant: N#Cc1ccc2c(c1)Sc1ccc([N+](=O)[O-])cc1C=C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc2c(c1)Sc1ccc(N)cc1C=C2
Reaction time: 24 h

Procedure:
5.6 G. 3-cyano-8-nitrodibenzo[b,f]thiepin is dissolved in 600 cc. tetrahydrofuran and 27 g. stannous chloride dihydrate in 40 cc. water is added, followed by 100 cc. concentrated hydrochloric acid. The mixture is stirred for 24 hours, poured onto ice, and shaken with 300 cc. 20% sodium hydroxide. The organic layer is separated and the aqueous basic layer shaken once more with tetrahydrofuran. The combined organic extracts are dried and the solvent evaporated to dryness and the residue chromatographed on silica gel and eluted with 20% ethyl acetate in benzene to yield 2.45 g. of the pure amine, m.p. 188°-190° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:19])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=2[NH2:18])=[N:6][CH:7]=1.[Cl:20]N1C(=O)CCC1=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:19])[C:10]2[CH:15]=[C:14]([Cl:20])[CH:13]=[C:12]([O:16][CH3:17])[C:11]=2[NH2:18])=[N:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1cccc(C(=O)Nc2ccc(Cl)cn2)c1N
Solvent: c1ccccc1
Product: COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cn2)c1N
Temperature: 52.5 °C
Yield: 91.5 %

Procedure:
To N-(5-chloropyridin-2-yl)-2-amino-3-methoxybenzamide (39 g, 140 mmol) in benzene (2 L) was added N-chlorosuccinimide (20 g, 148 mmol) and the reaction heated at 50-55° C. After 24 hours the reaction was cooled to ambient temperature and concentrated of all volatiles in vacuo. The resulting solid was dissolved in ethyl acetate (1 L), washed with water (3×100 mL), dried over sodium sulfate, and concentrated. Recrystallization from benzene afforded 40 g (90% yield) of N-(5-chloropyridin-2-yl)-2-amino-3-methoxy-5-chlorobenzamide as off-white needles; NMR (CDCl3) 8.6 (br, 1), 8.3 (m, 2), 7.7 (dd, 1), 7.1 (d, 1), 6.8 (d, 1), 5.9 (br, 1), 3.9 (s, 3) ppm.
Reaction SMILES: [BH4-].[Na+].[Cl-].[Ca+2].[Cl-].C(O[C:9]([C:11]1[CH:12]=[CH:13][C:14]([C:17]([OH:19])=[O:18])=[N:15][CH:16]=1)=[O:10])C.S(=O)(=O)(O)O.[CH2:25](O)[CH3:26]>>[OH:10][CH2:9][C:11]1[CH:12]=[CH:13][C:14]([C:17]([O:19][CH2:25][CH3:26])=[O:18])=[N:15][CH:16]=1
Reactant: CCO
Reactant: CCOC(=O)c1ccc(C(=O)O)nc1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Ca+2]
Product: CCOC(=O)c1ccc(CO)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.636 g of sodium borohydride was added to 22 mL of ice-cooled ethanol, to which a solution of 1.09 g of calcium chloride in 14 mL of ethanol was added dropwise, followed by addition of 1.20 g of 5-(ethoxycarbonyl)-2-pyridinecarboxylic acid ½ calcium salt, and this mixture was stirred for one hour at room temperature. The reaction mixture, to which 2.8 mL of concentrated sulfuric acid was added, was stirred for 6 hours while heating it under reflux. The reaction mixture was cooled to room temperature and concentrated under reduced pressure followed by successive addition of a saturated aqueous solution of sodium hydrogen carbonate and chloroform, and then the organic phase was separated therefrom. The resultant organic phase was washed with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure to yield 0.34 g of ethyl 5-(hydroxymethyl)-2-pyridinecarboxylate as light yellow solid.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[N:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]2[NH:12][CH:13]=[CH:14][N:15]=2)[CH:5]=1.Br[CH2:17][CH2:18]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:3][C:4]1[N:9]=[CH:8][C:7]2[O:10][CH2:18][CH2:17][N:15]3[CH:14]=[CH:13][N:12]=[C:11]3[C:6]=2[CH:5]=1
Reactant: BrCCBr
Reactant: Oc1cnc(Cl)cc1-c1ncc[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Clc1cc2c(cn1)OCCn1ccnc1-2
Temperature: 90 °C

Procedure:
A mixture of 2.30 g (8.55 mmol) of 6-chloro-4-(1H-imidazol-2-yl)pyridin-3-ol dihydrochloride, 1,2-dibromoethane (1.842 mL, 21.37 mmol) and Cesium Carbonate (19.46 g, 59.74 mmol) in 120 ml of N,N-Dimethylformamide was heated for 3 hours at 90° C. The mixture was filtered and concentrated in high vacuum to give 10-Chloro-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine. Weight 1.88 g (99%) MS (ESI+): 222.2. 1H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 8.17 (s, 1H), 7.24 (d, J=1.0, 1H), 7.10 (d, J=0.9, 1H), 4.51-4.45 (m, 4H).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[C:10]([C:12]([NH2:14])=O)[CH:9]=[CH:8][N:7]3[C:15]=2[CH2:16][C:17]2[CH:40]=[CH:39][C:20]3/[C:21](=[C:31](\[C:33]4[NH:37][C:36](=[O:38])[O:35][N:34]=4)/[CH3:32])/[C:22]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:23]=4[O:24][CH2:25][C:19]=3[CH:18]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])O.[Na+]>C1COCC1>[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[C:10]([C:12]#[N:14])[CH:9]=[CH:8][N:7]3[C:15]=2[CH2:16][C:17]2[CH:40]=[CH:39][C:20]3/[C:21](=[C:31](\[C:33]4[NH:37][C:36](=[O:38])[O:35][N:34]=4)/[CH3:32])/[C:22]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:23]=4[O:24][CH2:25][C:19]=3[CH:18]=2)[CH2:3][CH2:2]1
Reactant: C/C(=C1/c2ccc(Cc3c(C4CC4)nc4cc(C(N)=O)ccn34)cc2COc2cc(F)ccc21)c1noc(=O)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C/C(=C1/c2ccc(Cc3c(C4CC4)nc4cc(C#N)ccn34)cc2COc2cc(F)ccc21)c1noc(=O)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.6 %

Procedure:
[step 2] (E)-2-cyclopropyl-3-({3-fluoro-11(6H)-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethylidene]dibenzo[b,e]oxepin-8-yl}methyl)imidazo[1,2-a]pyridine-7-carboxamide (83 mg, 0.15 mmol) obtained in step 1 was suspended in THF (0.77 mL), and triethylamine (0.11 mL, 0.77 mmol) was added. Under ice-cooling, trifluoroacetic anhydride (0.11 mL, 0.77 mmol) was added, and the mixture was stirred at room temperature for 4 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the mixture was extracted 3 times with chloroform-methanol mixed solvent. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=100/0 v/v-90/10 v/v) to give the title compound (compound 14b) (41 mg, 51%).
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[CH:4][N:3]=[CH:2]1.[Li]CCCC.[C:17](Cl)(=[O:20])[CH2:18][CH3:19]>C1COCC1.CCOC(C)=O.[Cl-].[Cl-].[Zn+2]>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:5]1[O:1][C:2]([C:17](=[O:20])[CH2:18][CH3:19])=[N:3][CH:4]=1
Reactant: c1ccc(-c2cnco2)nc1
Reactant: CCC(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(=O)c1ncc(-c2ccccn2)o1
Reaction time: 0.33 h
Yield: 65.7 %

Procedure:
(194) A solution of 2-(oxazol-5-yl)pyridine (98 mg, 0.67 mmol) in anhydrous THF (5 mL) cooled to −75° C. under N2 was treated with n-BuLi (2.5 M in hexanes, 1.1 equiv, 0.74 mmol, 0.3 mL), and stirred for 20 min. ZnCl2 (0.5 M in THF, 2.0 equiv, 1.34 mmol, 2.7 mL) was added at −75° C., and stirred for 45 min at 0° C. Cul (1.0 equiv, 0.67 mmol, 128 mg) was added, and the solution was stirred for 10 min at 0° C. Propionyl chloride (2.0 equiv, 1.34 mmol, 124 mg, 0.12 mL) was added and the solution was stirred for 1 h at 0° C. The reaction was diluted with EtOAc (10 mL), and washed with 15% aqueous NH4OH (1×10 mL), H2O (1×10 mL), and saturated aqueous NaCl (1×10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. Flash chromatography (SiO2, 2.5 cm×17.5 cm, 20% EtOAc-hexanes) afforded 1-[5-(pyridin-2-yl)oxazol-2-yl]propan-1-one (194) (89 mg, 0.44 mmol, 65% yield) as a light brown powder: mp 65-67° C.; 1H NMR (CDCl3, 250 MHz) d 8.65-8.62 (m, 1H), 7.86-7.75 (m, 3H), 7.31-7.26 (m, 1H), 3.18-3.08 (m, 2H), 1.29-1.21 (m, 3H); 13C NMR (CDCl3, 62.5 MHz) d 188.8, 161.9, 157.2, 150.1, 146.3, 136.9, 126.8, 124.0, 120.3, 32.5, 7.8; IR (KBr) u. 2935, 2862, 1699, 1471, 1426, 1377 cm−1; MALDI-FTMS (DHB) m/z 203.0818 (C11H10N2O2+H+ requires 203.0815).
Reaction SMILES: [NH2:1]N.[N:3]1([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]C2C=CC=C3C(NC(=O)C=23)=O)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1>CO>[N:3]1([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:1])[CH2:4][CH2:5][O:6][CH2:7][CH2:8]1
Reactant: O=C1NC(=O)c2c(CCCCCCCN3CCOCC3)cccc21
Reactant: NN
Solvent: CO
Product: NCCCCCCCN1CCOCC1

Procedure:
Hydrazine (aqueous solution at 35% by wt.) (0.15 ml; 1.6 mmoles) was added to 7-morpholinylheptylphthalimide (264 mg; 0.8 mmoles) in methanol (5 ml) and the resulting solution was refluxed. Reaction times and process as per Example 1.
Reaction SMILES: C([O:8][C:9]1[C:14]([F:15])=[CH:13][C:12](/[CH:16]=[C:17](\[O:23][CH2:24][CH3:25])/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:11][C:10]=1[F:26])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[F:15][C:14]1[CH:13]=[C:12]([CH2:16][CH:17]([O:23][CH2:24][CH3:25])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:11]=[C:10]([F:26])[C:9]=1[OH:8]
Reactant: [H][H]
Reactant: CCOC(=O)/C(=C/c1cc(F)c(OCc2ccccc2)c(F)c1)OCC
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(Cc1cc(F)c(O)c(F)c1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
To a solution (Z)-ethyl 3-(4-(benzyloxy)-3,5-difluorophenyl)-2-ethoxyacrylate (680) (1.3 g, 3.59 mmol) in ethanol (25 mL) was added Pd/C (140 mg, 10% Degussa type). A balloon of hydrogen gas was added and the reaction was evacuated and back-filled with hydrogen three times. The reaction was stirred overnight at room temperature, was filtered through a pad of celite and concentrated in vacuo to give ethyl 3-(3,5-difluoro-4-hydroxyphenyl)-2-ethoxypropanoate (0.81 g) (681).
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH:8]([CH3:13])[CH:9]([OH:12])[CH2:10][CH3:11])[C:3](=[O:6])[CH2:4][CH3:5].[C:14](OC(=O)C)(=[O:16])[CH3:15]>N1C=CC=CC=1>[CH3:1][CH:2]([CH2:7][CH:8]([CH3:13])[CH:9]([O:12][C:14](=[O:16])[CH3:15])[CH2:10][CH3:11])[C:3](=[O:6])[CH2:4][CH3:5]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(=O)C(C)CC(C)C(O)CC
Solvent: c1ccncc1
Product: CCC(=O)C(C)CC(C)C(CC)OC(C)=O
Yield: 68.4 %

Procedure:
A solution of 4,6-dimethyl-7-hydroxynonan-3-one (IVa, 10 g, 53.8 mmoles) in acetic anhydride (13.8 g, 135 mmoles) and pyridine (12.8 g, 162 mmoles) was set stirring under a nitrogen atmosphere. After stirring for 20 hours at room temperature, most of the acetic anhydride and pyridine were removed at reduced pressure to leave a clear oil (11 g crude weight). The crude product was then distilled at 60° C. and 0.16 mm to give a 68% yield of 4,6-dimethyl-7-acetoxynonan-3-one (8.4 g, 36.8 mmoles).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([NH:9][C:10]([C:12]2[N:13]=[C:14]([CH3:18])[S:15][C:16]=2Br)=[O:11])[CH:6]=[CH:5][N:4]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.[F:61][C:62]1[CH:63]=[C:64]([CH:66]=[C:67]([F:69])[CH:68]=1)[NH2:65].C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O1CCOCC1>[OH:1][CH2:2][C:3]1[CH:8]=[C:7]([NH:9][C:10]([C:12]2[N:13]=[C:14]([CH3:18])[S:15][C:16]=2[NH:65][C:64]2[CH:63]=[C:62]([F:61])[CH:68]=[C:67]([F:69])[CH:66]=2)=[O:11])[CH:6]=[CH:5][N:4]=1
Reactant: Nc1cc(F)cc(F)c1
Reactant: Cc1nc(C(=O)Nc2ccnc(CO)c2)c(Br)s1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: Cc1nc(C(=O)Nc2ccnc(CO)c2)c(Nc2cc(F)cc(F)c2)s1
Yield: 8.4 %

Procedure:
A microwave vial was charged with 5-bromo-2-methyl-thiazole-4-carboxylic acid (2-hydroxymethyl-pyridin-4-yl)-amide (0.135 g, 0.411 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (0.81 g, 0.140 mmol) and palladium dibenzylideneacetone (Pd2dba3)-chloroform complex (0.044 g, 0.043 mmol). Degassed dioxane (10 ml) was added, followed by 3,5-difluoroaniline (0.064 g, 0.496 mmol) and cesium carbonate (0.271 g, 0.831 mmol) The vial was then irradiated in a microwave oven at 150° C. for 40 min. The mixture was diluted with THF and the solids filtered, washing with THF. The filtrate was evaporated and the residue purified by flash chromatography on silica gel with dichloromethane/methanol 100:0→90:10 gradient to yield the title compound (0.013 g, 8%) as an off-white solid, MS (ISP): m/e=377.4 (M+H+).
Reaction SMILES: C([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)(=O)C.C([C:11]([CH2:24][CH3:25])(P(=O)([O-])[O-])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]#[N:19])C.C[O-].[Na+]>CN(C)C=O>[S:5]1[CH:6]=[CH:7][CH:8]=[C:4]1[C:24]([CH3:25])=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]#[N:19]
Reactant: CC(=O)c1cccs1
Reactant: CCC(CC)(c1ccccc1C#N)P(=O)([O-])[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=Cc1ccccc1C#N)c1cccs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The starting material may be produced as follows: (a) A solution of 10.0 g of 2-acetylthiophene and 21.0 g of diethyl-o-cyanobenzylphosphonate in 70 cc of anhydrous dimethyl formamide is added dropwise at 20°-30° in an atmosphere of nitrogen to a suspension of 4.5 g of pulverized sodium methylate in 100 cc of anhydrous dimethyl formamide, the reaction mixture is stirred at 40° for 2 hours, and at 100° for a further 2 hours, is cooled to room temperature and diluted with 600 cc of ice water. The condensation product is extracted with ether, the extract is washed with water until neutral, is dried over potassium carbonate and concentrated by evaporation. The evaporation residue is chromatographed through 110 g of silica gel with a mixture of benzene/petroleum ether (1:4). The 2-[2-(2-thienyl)-1-propenyl]benzonitrile (nD20 =1.6460, B.P. 165°-175°/0.1 mm Hg), isolated as main fraction, is used for the next reaction without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=2[CH2:24][NH:25][CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)=[O:31]>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:17]=[CH:16][C:15]=2[CH2:24][N:25]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=2)=[O:31])[CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCNCc1ccc(C(F)(F)F)cc1-c1cc(CC(=O)OCC)ccc1OC
Reactant: O=C(Cl)OCc1ccc(Cl)cc1
Product: CCOC(=O)Cc1ccc(OC)c(-c2cc(C(F)(F)F)ccc2CN(CC)C(=O)OCc2ccc(Cl)cc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-5′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and 4-chlorobenzyl chloroformate.
Reaction SMILES: C(OC(=O)N[CH2:8][C:9]([C:12]1[NH:13][C:14]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([O:24]C)[CH:18]=2)[N:16]=1)(C)[CH3:10])(C)(C)C.C(OC([NH:40]C(C)(C)C=O)=O)(C)(C)C>>[NH2:40][C:9]([C:12]1[NH:13][C:14]([C:26]2[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=2)=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([OH:24])[CH:18]=2)[N:16]=1)([CH3:10])[CH3:8]
Reactant: CC(C)(C=O)NC(=O)OC(C)(C)C
Reactant: COc1cc(-c2nc(C(C)(C)CNC(=O)OC(C)(C)C)[nH]c2-c2ccncc2)ccc1Cl
Product: CC(C)(N)c1nc(-c2ccc(Cl)c(O)c2)c(-c2ccncc2)[nH]1

Procedure:
The title compound was prepared from the product of Example 1, Step 3 and 2-tert-butoxycarbonylamino-2-methylpropanal (T. Seki et al., Chem. Pharm. Bull.; 1996, 44, 2061) using the methods described in Example 1 Step 4, followed by those of Example 2 and Example 3; MS(ES+) m/e 329/331 [M+H]+.