Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.[NH2:10][C:11]1[C:20]2[N:21]=[C:22]([CH2:32][CH3:33])[N:23]([CH2:24][C:25]3([OH:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:19]=2[C:18]2[N:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1.[N:34]1([C:40](Cl)=[O:41])[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>ClCCl>[NH2:10][C:11]1[C:20]2[N:21]=[C:22]([CH2:32][CH3:33])[N:23]([CH2:24][C:25]3([OH:31])[CH2:30][CH2:29][N:28]([C:40]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[O:41])[CH2:27][CH2:26]3)[C:19]=2[C:18]2[N:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: CCc1nc2c(N)nc3cccnc3c2n1CC1(O)CCNCC1
Reactant: O=C(Cl)N1CCOCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2c(N)nc3cccnc3c2n1CC1(O)CCN(C(=O)N2CCOCC2)CC1
Temperature: -5 °C
Reaction time: 48 h
Yield: 88.3 %

Procedure:
Under a nitrogen atmosphere triethylamine (1.39 mL, 10.0 mmol) was added to a suspension of 4-[(4-amino-2-ethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]piperidin-4-ol dihydrochloride (1.00 g, 2.50 mmol) in dichloromethane (25 mL). The mixture was cooled to −5° C. 4-Morpholinecarbonyl chloride (292 μL, 2.50 mmol) was added and the reaction mixture was allowed to slowly warm to ambient temperature. The reaction mixture was stirred at ambient temperature for 2 days and then at 30° C. for 2 days. More 4-morpholinecarbonyl chloride (30 μL) was added and the reaction mixture was stirred at 30° C. for 5 days. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between chloroform (150 mL) and saturated aqueous sodium carbonate (30 mL). The organic was washed with saturated aqueous sodium carbonate (20 mL) and brine (20 mL), dried over sodium sulfate, filtered, and then concentrated under reduced pressure to provide an off white solid. This material was triturated with acetonitrile, recrystallized from chloroform/hexanes, isolated by filtration, washed with hexanes, and dried under high vacuum at 130° C. to provide 0.97 g of 4-[(4-amino-2-ethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]-1-(morpholin-4-ylcarbonyl)piperidin-4-ol as a white powder, mp>255.0° C. Anal. Calcd for C22H29N7O3.0.25H2O C, 59.51; H, 6.70; N, 22.08. Found: C, 59.32; H, 6.36; N, 22.00.
Reaction SMILES: CO[C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[C:12]([CH3:15])[O:13][CH:14]=2)[CH:5]=1.[C:17]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])[CH3:18].[Li]>>[C:21]([O:20][C:17](=[O:19])[CH2:18][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[C:12]([CH3:15])[O:13][CH:14]=2)[CH:5]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)c1cccc(-c2coc(C)n2)c1
Agent: [Li]
Product: Cc1nc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)co1

Procedure:
3-(2-Methyl-oxazol-4-yl)-benzoic acid methyl ester (1.02 g) was treated with lithium tert.-butyl acetate according to the general procedure K (method b) to give crude 3-oxo-3-(3-(2-methyl-oxazol-4-yl)-phenyl]-propionic acid tert -butyl ester (1.50 g) as a pale-yellow oil.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1)=[CH2:2].S(Cl)([Cl:14])=O.C(O)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl.[N+](C1C=CC=CC=1)([O-])=O>[CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:14])=[O:8])=[CH:5][CH:4]=1)=[CH2:2]
Reactant: O=S(Cl)Cl
Reactant: C=Cc1ccc(C(=O)O)cc1
Agent: O=C(O)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O=[N+]([O-])c1ccccc1
Product: C=Cc1ccc(C(=O)Cl)cc1
Temperature: 50 °C
Yield: 91 %

Procedure:
4-vinyl benzoyl chloride was synthesized from 4-vinyl benzoic acid (obtained from Trans World Chemicals). The 4-vinyl benzoic acid was dissolved in chloroform with a small (0.16 mole/mole 4-vinyl benzoic acid) amount of nitrobenzene added as an inhibitor to prevent cross-linking. A large excess of thionyl chloride (six times the moles of benzoic acid) was added dropwise while stirring and gently heating to 50° C. Once the thionyl chloride was completely added, and the solution was at a temperature of 50° C., it was allowed to stir for one hour. The solution was then distilled (rotary evaporator) to remove the bulk of the chloroform and unreacted thionyl chloride. The impure 4-vinylbenzoyl chloride was then vacuum distilled to further purify it. At <1 mm mercury the 4-vinylbenzoyl chloride distills at around 70° C. The composition of the product was checked by NMR and was confirmed to be 4-vinylbenzoyl chloride. The yield was 91%.
Reaction SMILES: I[C:2]1[C:3]([CH3:14])=[N:4][N:5]([C@H:7]2[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]2)[CH:6]=1.C1COCC1.C([Mg]Cl)(C)C.CO[B:27]1[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]1>>[CH3:14][C:3]1[C:2]([B:27]2[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]2)=[CH:6][N:5]([C@H:7]2[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]2)[N:4]=1
Reactant: COB1OC(C)(C)C(C)(C)O1
Reactant: Cc1nn([C@H]2CC[C@H](O)CC2)cc1I
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1nn([C@H]2CC[C@H](O)CC2)cc1B1OC(C)(C)C(C)(C)O1
Reaction time: 0.5 h

Procedure:
To a solution of trans-4-(4-iodo-3-methyl-1H-pyrazol-1-yl)cyclohexanol (150.0 mg, 0.4900 mmol) in THF (9 mL, 100 mmol) was added 2 M isopropylmagnesium chloride in THF (0.7349 mL, 1.470 mmol) at rt, and the mixture was stirred for 30 min. 2-Methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.3212 mL, 1.960 mmol) was added, and the mixture stirred at rt for 2 h. The reaction was quenched with sat. NH4Cl, and the organic solvent was removed in vacuo. The material was extracted with DCM and water, and the organic layer was concentrated in vacuo to afford the title compound as a clear oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[C:20](=[O:21])[C:19]4=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]4[C:17]3=[O:26])[CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[S:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[S:39](Cl)(=[O:41])=[O:40]>ClCCl>[C:20]1(=[O:21])[N:16]([CH2:15][CH2:14][CH2:13][CH2:12][N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:2]([O:1][S:39]([C:35]4[S:34][CH:38]=[CH:37][CH:36]=4)(=[O:41])=[O:40])=[CH:3][CH:4]=3)[CH2:9]2)[C:17](=[O:26])[C:18]2=[CH:25][CH:24]=[CH:23][CH:22]=[C:19]12
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: O=C1c2ccccc2C(=O)N1CCCCN1CCc2ccc(O)cc2C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCCCN1CCc2ccc(OS(=O)(=O)c3cccs3)cc2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.7 %

Procedure:
A stirred mixture of 7-hydroxy-2-(4-phthalimidobutyl)-1,2,3,4-tetrahydroisoquinoline (2.94 g, 8.4 mmol) and triethylamine (1.4 ml, 10 mmol) in dichloromethane (75 ml) was treated with 2-thiophenesulfonyl chloride (1.69 g, 9.2 mmol). After stirring at room temperature for 18 h the mixture was washed with saturated aqueous sodium bicarbonate (100 ml). The aqueous layer was separated and extracted with dichloromethane (2×50 ml). The combined extracts were washed with brine, dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed on silica using 30-100% ethyl acetate-pentane gradient elution to afford the title compound as a pale yellow oil (3.45 g, 83%).
Reaction SMILES: [CH:1]1([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:20]N1C(=O)CCC1=O>C(#N)C>[Br:20][C:13]1[CH:12]=[C:11]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:10]=[CH:9][C:8]=1[O:7][CH2:6][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)CCc1ccc(OCC2CCCC2)cc1
Solvent: CC#N
Product: COC(=O)CCc1ccc(OCC2CCCC2)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of Intermediate 2 (1.31 g) in acetonitrile (50 ml) was added with N-bromosuccinimide (hereinafter abbreviated as “NBS”, 979 mg, KANTO), stirred at room temperature for 2 hours, then warmed to 40° C., and stirred for 3 hours. The reaction mixture was concentrated under reduced pressure, then added with ethyl acetate (200 ml) and washed successively with saturated aqueous ammonium chloride, 5% aqueous sodium sulfite, saturated aqueous sodium hydrogencarbonate and saturated brine. The organic layer was dried, and then the solvent was evaporated under reduced pressure to obtain the title compound (Compound No. A-1, 1.69 g).
Reaction SMILES: [CH3:1][CH:2]([CH3:32])[CH2:3][CH2:4][O:5][C:6]1[C:11]2[C:12](=[O:28])[CH:13]=[C:14]([C:16]3[N:20](CC4C=CC=CC=4)[N:19]=[N:18][N:17]=3)[O:15][C:10]=2[C:9]([CH2:29][CH2:30][CH3:31])=[CH:8][CH:7]=1.[H][H]>[Pd].C(O)C>[CH3:1][CH:2]([CH3:32])[CH2:3][CH2:4][O:5][C:6]1[C:11]2[C:12](=[O:28])[CH:13]=[C:14]([C:16]3[NH:20][N:19]=[N:18][N:17]=3)[O:15][C:10]=2[C:9]([CH2:29][CH2:30][CH3:31])=[CH:8][CH:7]=1
Reactant: [H][H]
Reactant: CCCc1ccc(OCCC(C)C)c2c(=O)cc(-c3nnnn3Cc3ccccc3)oc12
Agent: [Pd]
Solvent: CCO
Product: CCCc1ccc(OCCC(C)C)c2c(=O)cc(-c3nnn[nH]3)oc12

Procedure:
A solution of 2.96 parts of 5-[5-(3-methyl-n-butoxy)-8-n-propyl-4-oxo-4H-1-benzopyran-2-yl]-N-benzyltetrazole in 500 parts of ethanol was stirred at 60°C, with 0.096 parts of 5% palladium on charcoal, in an atmosphere of hydrogen for 111/2 hours. The reaction mixture was cooled, was filtered and the solvent removed by evaporation to give a residue which was chromatographed on silica gel. Careful elution with chloroform and chloroform/acetone gave 0.16 parts of 5-[5-(3-methyl-n-butoxy)-8-n-propyl-4-oxo-4H-1-benzopyran-2-yl]tetrazole, m.p. 199°-200°C (after recrystallisation from ethanol).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[C:11]3[C:17]#[N:18])=[CH:4][CH:3]=1.[OH:19]O.[OH-].[Na+]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[C:11]3[C:17]([NH2:18])=[O:19])=[CH:4][CH:3]=1
Reactant: OO
Reactant: N#Cc1c[nH]c2ccc(-c3ccc(Br)cc3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1c[nH]c2ccc(-c3ccc(Br)cc3)cc12

Procedure:
A solution of 4 (1.00 g, 3.38 mmol) in ethanol was treated with hydrogen peroxide (30%) and 1N NaOH. On completion of reaction solvent was removed and the resultant solid was washed with organic solvents to give pure 5 as a beige colored solid.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[C:19]([CH2:21][C:22](OCC)=[O:23])=O.O>S(=O)(=O)(O)O>[OH:2][C:1]1[CH:3]=[C:4]2[C:6]([C:19]([C:10]3[CH:11]=[CH:12][C:13]4[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH:9]=3)=[CH:21][C:22](=[O:23])[O:5]2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)CC(=O)c1ccc2ccccc2c1
Reactant: Oc1cccc(O)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=c1cc(-c2ccc3ccccc3c2)c2ccc(O)cc2o1
Temperature: 25 °C
Reaction time: 120 h
Yield: 26 %

Procedure:
A mixture of resorcinol (11.0 g, 0.1 mole) and ethyl 2-naphthoylacetate (24.2 g, 0.1 mole) in concentrated sulphuric acid (50 ml) was stirred at room temperature for 5 days then poured into water to give a yellow gum. The gum was washed several times with water then dissolved in ethanol and diluted with water to give 7-hydroxy-4-(2-naphthyl)coumarin as a fine pale brown precipitate in 26% yield.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:14][NH:15][O:16][CH3:17].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl>[CH3:17][O:16][N:15]([CH3:14])[C:10](=[O:12])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)CNC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 70.7 %

Procedure:
To a 2-(tert-butoxycarbonylamino)acetic acid (800 mg, 4.57 mmol), N,O-dimethylhydroxylamine hydrochloride (535 mg, 5.48 mmol), EDCI (1.05 g, 5.48 mmol), HOBt (740 mg, 5.48 mmol) in DCM (25 mL) was added NMM (2.77 g, 27.42 mmol) at rt. The reaction mixture was stirred overnight. After the reaction was completed, DCM was evaporated in vacuo. The residue was dissolved in MeOH, filtered through a syringe filter, and then purified by reverse-phase prep HPLC to provide the desired product (705 mg, 71%) as white solid
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].[H][H]>[Pd]>[F:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: [H][H]
Reactant: O=C(O)C=Cc1ccc(F)cc1F
Agent: [Pd]
Product: O=C(O)CCc1ccc(F)cc1F
Temperature: 100 °C
Yield: 90 %

Procedure:
The procedure was as in Example 5, but the 2,4-difluorocinnamic acid obtained was not isolated. The aqueous-acidic product suspension obtained was treated with 2 g of Pd/C (5% strength) at 50° C. with further stirring and heated to 100° C. It was then pressurized to 5 bar of hydrogen. After constant pressure had been achieved, it was cooled to room temperature, the pressure was released and the solid was filtered off. The filter cake was taken up in methylene chloride, the palladium catalyst was filtered off and the solvent was removed. After drying in vacuo, 100.5 g of 3-(2,4-difluorophenyl)propionic acid (90% of theory; melting point: 100° C.) were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:27])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[C:10]=1[N+:28]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+].O>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:27])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[C:10]=1[NH2:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)c([N+](=O)[O-])c4CC[C@H]3[C@@H]1CCC2=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)c(N)c4CC[C@H]3[C@@H]1CCC2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
To a suspension of 3-benzyloxy4-nitroestra-1,3,5(10)-trien-17-one (84, 3.24 g, 8.0 mmol) in acetone (400 mL) were added 0.5 N aqueous NaOH (100 mL, 50 mmol) and sodium hydrosulfite (85%, 10 g) at 80° C.; the mixture was then stirred for 1 h. After the reaction mixture was cooled to room temperature, H2O (300 mL) was added; Acetone was then removed at reduced pressure, and the mixture allowed to stand for 3 h at 0° C. The precipitate was collected by filtration and washed with H2O to afford 2.29 g of 85 (76% yield) mp: 219-221° C.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N12CCCN=C1CCCCC2.[NH2:20][CH2:21][CH2:22][CH2:23][OH:24]>ClCCl>[O:24]([CH2:23][CH2:22][CH2:21][NH2:20])[Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: NCCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCN
Temperature: 25 °C
Reaction time: 6 h

Procedure:
tert-Butyldimethylsilyl chloride (14.7 g, 97.5 mmol), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (14.6 ml, 97.5 mmol) was added to a solution 3-amino-1-propanol (7.45 ml, 97.5 mmol) in dichloromethane (100 ml) at 0° C. under argon. After 6 hours stirring at room temperature, the mixture was quenched with water and washed successively with 10% hydrochloric acid, saturated sodium bicarbonate solution and brine. Evaporation of the dried (magnesium sulfate) organic phase gave the title amine. 1 (HNMR(CDCl3): -0.03 (s, 6H), 0.81 (s, 9H), 1.61 (p, 2H, J=6.1 Hz), 2.20 (br, 2H), 2.75 (t, 2H, J=6.8 Hz) and 3.63 (t, 2H, J=6.12 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:11])=[N:4][C:5]([CH2:9][CH3:10])=[CH:6][C:7]=1[Cl:8].[C:12]([O-])(=[O:14])[CH3:13].[Na+]>C(OC(=O)C)(=O)C>[C:12]([NH:1][C:2]1[C:3]([Cl:11])=[N:4][C:5]([CH2:9][CH3:10])=[CH:6][C:7]=1[Cl:8])(=[O:14])[CH3:13]
Reactant: CC(=O)[O-]
Reactant: CCc1cc(Cl)c(N)c(Cl)n1
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CCc1cc(Cl)c(NC(C)=O)c(Cl)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7.8 g (40.8 mmol) of 3-amino-2,4-dichloro-6-ethyl-pyridine are heated under reflux for two hours in a mixture of 40 ml of acetic anhydride and 4 g (49 mmol) of anhydrous sodium acetate. The mixture is subsequently evaporated in vacuo, the residue is partitioned between dilute NH3 solution and CHCl3, and the organic phase is separated off, dried using Na2SO4 and evaporated. The residue (11.2 g) consists of a mixture of mono- and diacetylated amine. It is dissolved in 50 ml of methanol, 10 g of powdered K2CO3 are added and the mixture is stirred for one hour at room temperature. It is subsequently evaporated and partitioned between water and CHCl3, and the organic phase is separated off and washed with 5% strength aqueous NaH2PO4 solution. After drying using Na2SO4, the organic phase is evaporated. The residue is stirred with ether and filtered off with suction. Yield 7.7 g (80.9% of theory) melting point: 142° C.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[Na].[Cl:6][C:7]1[CH:8]=[N:9][N:10]([C:12]([CH3:16])([CH3:15])[C:13]#[N:14])[CH:11]=1>C(O)C>[Cl:6][C:7]1[CH:8]=[N:9][N:10]([C:12]([CH3:16])([CH3:15])[C:13](=[NH:14])[O:1][CH2:2][CH3:3])[CH:11]=1
Reactant: CC[O-]
Reactant: CC(C)(C#N)n1cc(Cl)cn1
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=N)C(C)(C)n1cc(Cl)cn1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To a sodium ethoxide solution, prepared from sodium (20 mg, 1 mmol) and ethanol (4 mL), was added a solution of 2-(4-chloro-1H-pyrazol-1-yl)-2-methylpropanenitrile (225 mg, 1.33 mmol) in ethanol (1 mL). The reaction mixture was stirred at 70° C. for 30 min. The solvent was removed under a stream of nitrogen and the residue was dried under high vacuum to afford the crude title compound as a colorless solid, which was used without further purification.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[O:16][CH:15]([CH3:18])[CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][C:11]=2[S:10][CH:9]=1.[C:26](OCC)(=[O:28])C.Cl>>[CH3:26][O:28][C:5]1[CH:4]=[C:3]([C:8]2[C:17]3[O:16][CH:15]([CH3:18])[CH2:14][NH:13][CH2:12][C:11]=3[S:10][CH:9]=2)[CH:2]=[CH:7][CH:6]=1
Reactant: CC1CN(C(=O)OC(C)(C)C)Cc2scc(-c3ccccc3F)c2O1
Reactant: CCOC(C)=O
Agent: Cl
Product: COc1cccc(-c2csc3c2OC(C)CNC3)c1
Yield: 95 %

Procedure:
tert-Butyl 8-(2-fluorophenyl)-2-methyl-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (168 mg) was stirred in 4 N hydrogen chloride-ethyl acetate solution (5 mL) for 30 min. The reaction solution was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to give 8-(2-fluorophenyl)-2-methyl-2,3,4,5-tetrahydrothieno[2,3-f][1,4]oxazepine 1 hydrochloride (132 mg, 95%) as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][NH:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2].[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[Cl:27])[C:21](Cl)=[O:22].C(N(CC)CC)C>O1CCCC1.[Pd]>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][C:26]([Cl:27])=[C:18]([Cl:17])[CH:19]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)CNc1ncccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CNc1ncccc1NC(=O)c1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 7.2 %

Procedure:
A solution of N-(3-nitro-2-pyridinyl)glycine ethyl ester (22.5 g, 0.1 mole) in 250 ml of tetrahydrofuran was hydrogenated in a small Parr bottle over 5% palladium on carbon (2.5 g) at room temperature for 1 hr. The reaction mixture was dried over magnesium sulfate and filtered through a Celite pad. Under nitrogen atmosphere, 3,4-dichlorobenzoyl chloride (20.95 g, 0.1 mole) and triethylamine (11.1 g, 0.11 mole) were added dropwise simultaneously to the above stirred filtrate at room temperature. After stirring overnight, the reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was treated with acetone and water to obtain a crystalline solid, which was refrigerated overnight. The solid was collected by filtration, washed with water, and dried under high vacuum at 50° C. overnight (37.1 g). A 4-g sample was recrystallized from acetone/water and dried under high vacuum at 50° C. for 2 days to give 2.66 g of title compound, mp 137°-38° C.
Reaction SMILES: [CH:1]1[N:9]2[C:4]([CH2:5][O:6][C:7]3[CH:13]=[C:12]([CH:14]=O)[CH:11]=[CH:10][C:8]=32)=[N:3][CH:2]=1.[C:16](=O)([O-])[O-].[K+].[K+].CO>C(Cl)Cl>[C:14]([C:12]1[CH:11]=[CH:10][C:8]2[N:9]3[CH:1]=[CH:2][N:3]=[C:4]3[CH2:5][O:6][C:7]=2[CH:13]=1)#[CH:16]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc2c(c1)OCc1nccn1-2
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: C#Cc1ccc2c(c1)OCc1nccn1-2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43.6 %

Procedure:
4H-Imidazo[2,1-c][1,4]benzoxazine-7-carbaldehyde (44 mg, 0.140 mmol) and anhydrous potassium carbonate (120 mg, 0.868 mmol) were placed in a 25-ml flask and placed on high vacuum for 10 min. Under N2, anhydrous MeOH (5 ml) was added. To the suspension was added dimethyl (1-diazo-2-oxopropyl) phosphonate (0.03 ml, 0.192 mmol). The reaction was stirred at rt for 2 h. The mixture was diluted with DCM, washed with water, dried over sodium sulfate, concentrated to afford desired product (11.9 mg, 0.061 mmol, 43.3% yield).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].C[Si]([CH2:9][N:10]=[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[SH-]C)(C)C>C1COCC1>[C:14]1([C:11]2[CH2:3][CH:2]([C:1]#[N:4])[CH2:9][N:10]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[SH-]C(=NC[Si](C)(C)C)c1ccccc1
Reactant: C=CC#N
Solvent: C1CCOC1
Product: N#CC1CN=C(c2ccccc2)C1
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
A solution of acrylonitrile (0.65 mL; 0.01 mol) and N-(trimethylsilyl)methyl-S-methyl-benzenethioimidate (2.4 g; 0.01 mol) in THF (100 mL) is cooled to -5° C. in an ice-acetone bath. Under a nitrogen purge, a solution of tetrabutylammonium fluoride (1.0 mL of a 1 N solution in THF) and THF (20 mL) is added dropwise over 30 minutes The solution is stirred another 30 minutes at -5° C., and then allowed to warm slowly to ambient. Stirring is continued another 18 hours, and then solvent is removed under reduced pressure. The residue is partitioned between ether/water and the water layer extracted with fresh ether. The combined organic layer is washed with water, then saturated sodium chloride. The solution is dried over MgSO4, and cooling the filtrate causes precipitation of an off-white solid (1.2 g; 70% theoretical yield) whose spectral characteristics are identical to the material described by Tsuge [J. Org. Chem. 52, 2523 (1987)].
Reaction SMILES: Br[C:2]1[C:3]([O:31][CH3:32])=[CH:4][C:5]2[CH2:6][CH2:7][N:8]3[C:14]4[C:15](=[O:25])[N:16]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:17][CH2:18][O:19][CH2:20][C:13]=4[C:12]([C:26]4[S:30][CH:29]=[N:28][CH:27]=4)=[C:9]3[C:10]=2[CH:11]=1.C([Sn](CCCC)(CCCC)[C:38]1[S:42][CH:41]=[N:40][CH:39]=1)CCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:21]([N:16]1[C:15](=[O:25])[C:14]2[N:8]3[CH2:7][CH2:6][C:5]4[CH:4]=[C:3]([O:31][CH3:32])[C:2]([C:38]5[S:42][CH:41]=[N:40][CH:39]=5)=[CH:11][C:10]=4[C:9]3=[C:12]([C:26]3[S:30][CH:29]=[N:28][CH:27]=3)[C:13]=2[CH2:20][O:19][CH2:18][CH2:17]1)([CH3:22])([CH3:24])[CH3:23]
Reactant: COc1cc2c(cc1Br)-c1c(-c3cncs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCOC3
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1-c1cncs1)-c1c(-c3cncs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCOC3
Yield: 76.9 %

Procedure:
A degassed solution of 40 mg of 11i, 45 mg of 5-tributylstannyl thiazole and 15 mg of Pd(PPh3)4 in 3 ml of toluene was heated at 110° C. during 5 hr. The reaction mixture was concentrated and the residue was chromatographed over silica gel, using a gradient of toluene/acetone as eluent. The isolated product was treated with diethyl ether, to provide 31 mg of 11l as white crystalline material; Mp: 254-255° C.; Rf 0.30 (heptane/acetone 1/1).