Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.O.O.O.[F-].C([Si](C)(C)[O:27][C@H:28]1[CH2:33][C@H:32]([O:34][Si](C(C)(C)C)(C)C)[CH2:31]/[C:30](=[CH:42]/[CH:43]=[CH:44]/[CH2:45][CH2:46][CH2:47][C:48]([CH3:63])([CH3:62])[CH2:49]/[CH:50]=[CH:51]/[C:52]([C:58]([F:61])([F:60])[F:59])([OH:57])[C:53]([F:56])([F:55])[F:54])/[C:29]1=[CH2:64])(C)(C)C>O1CCCC1>[F:54][C:53]([F:55])([F:56])[C:52]([C:58]([F:59])([F:60])[F:61])([OH:57])/[CH:51]=[CH:50]/[CH2:49][C:48]([CH3:63])([CH3:62])[CH2:47][CH2:46][CH2:45]/[CH:44]=[CH:43]/[CH:42]=[C:30]1\[C:29](=[CH2:64])[C@@H:28]([OH:27])[CH2:33][C@H:32]([OH:34])[CH2:31]\1
Reactant: C=C1/C(=C\C=C\CCCC(C)(C)C/C=C/C(O)(C(F)(F)F)C(F)(F)F)C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C=C1/C(=C\C=C\CCCC(C)(C)C/C=C/C(O)(C(F)(F)F)C(F)(F)F)C[C@@H](O)C[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
0.83 g of tetrabutylammoniumfluoride trihydrate (2.60 mmol) in 3.5 ml of tetrahydrofuran was carefully dried by stirring during 2 h at room temperature over 1.05 g of 3 Å molecular sieve. This solution was then added to the above prepared 151 mg of (3E,10E)-12-[(Z)-(3S,5R)-3,5-bis-(tert-butyl-dimethyl-silanyloxy)-2-methylene-cyclohexylidene]-1,1,1-trifluoro-6,6-dimethyl-2-trifluoromethyl-dodeca-3,10-dien-2-ol and kept for 1.5 h at 45°. The reaction mixture was then poured onto crushed ice, extracted twice with ether, washed with water, dried over sodium sulfate and evaporated to dryness. Flash chromatography (SiO2, hexane/ethylacetate=4/6) yielded 76 mg of the title compound as colourless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[C:16]1(=O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[N:10]1[CH:9]=[CH:8][C:7]([C:5]2[S:4][C:3]3[C:13](=[O:14])[NH:15][C:16]4([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)[NH:1][C:2]=3[CH:6]=2)=[CH:12][CH:11]=1
Reactant: O=C1CCCCCC1
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1NC2(CCCCCC2)Nc2cc(-c3ccncc3)sc21
Temperature: 110 °C
Reaction time: 2 h
Yield: 14 %

Procedure:
A mixture of 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (0.108 g, 0.500 mmol), cycloheptanone (1.0 mL), p-toluenesulfonic acid monohydrate (0.0095 g, 0.050 mmol) and acetic acid (2.0 mL) was stirred for 2 h at 110° C. in a sealed tube. Then, this mixture was poured into sat. aqueous sodium hydrogen carbonate. Extraction with ethyl acetate, washing with brine, drying over magnesium sulfate, filtration and concentration at reduced pressure were carried out. This residue was purified by column chromatography (Combiflash, 12 g silica gel, dichloromethane to 90:10 dichloromethane/methanol), then recrystallized from methanol-ethyl acetate and the crystals were collected by filtration to afford the title compound (0.0226 g, 14%) as a yellow solid:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:23](OC)(OC)(OC)[CH2:24][CH2:25][CH3:26]>C1(C)C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[CH2:24]([C:23]1[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH2:25][CH3:26]
Reactant: CCCC(OC)(OC)OC
Reactant: CCOC(=O)CCCCCNc1c(N)cnc2ccccc12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: CCCc1nc2cnc3ccccc3c2n1CCCCCC(=O)OCC
Temperature: 25 °C
Yield: 73.6 %

Procedure:
A solution of ethyl 6-[(3-aminoquinolin-4-yl)amino]hexanoate (44.0 g, 146 mmol) in toluene (500 mL) was heated at reflux under a Dean-Stark trap for 1.5 hours and then allowed to cool to ambient temperature. Trimethyl orthobutyrate (29.2 mL, 182.5 mmol) and pyridinium p-toluenesulfonate (0.300 g, 1.20 mmol) were sequentially added, and the reaction was heated at reflux for three hours, allowed to cool to ambient temperature, and concentrated under reduced pressure. The residue was dissolved in dichloromethane, and the resulting solution was washed sequentially with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with 97:3 dichloromethane:methanol) to provide 38 g of ethyl 6-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)hexanoate.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:19][CH2:18]1.C([O-])([O-])=O.[K+].[K+].C(O)CC(C)C>C(O)CCC>[N+:11]([C:8]1[CH:9]=[CH:10][C:2]([NH:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])([O-:13])=[O:12]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: NCCN1CCN(c2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: CC(C)CCO
Product: O=C(O)c1cc([N+](=O)[O-])ccc1NCCN1CCN(c2ccccc2)CC1
Yield: 66.9 %

Procedure:
2-Chloro-5-nitrobenzoic acid (179 g), 182.5 g 1-(2-aminoethyl)-4-phenylpiperazine, 138 g K2CO3, 900 ml isoamyl alcohol and CuO catalyst were refluxed for 8 hours adding a pinch of CuO periodically. The mixture was cooled overnight, diluted with butanol and filtered. The solid was dissolved in water and neutralized to pH 4-4.5 with 3N HCl to give 247 g crude product. This was recrystallized from 3.5 liters dimethylformamide and 1 liter of water to give 220 g product, m.243-6°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:8]=[C:9]([N+:11]([O-])=O)[CH:10]=1)=[O:5])[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[N:7]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:8]=[C:9]([NH2:11])[CH:10]=1)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])cn1S(C)(=O)=O
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc(N)cn1S(C)(=O)=O
Yield: 98.8 %

Procedure:
To a solution of 1-methanesulfonyl-4-nitro-1H-pyrrole-2-carboxylic acid ethyl ester (2.4 g, 9.15 mmol) in ethanol (30 mL) was added Pd/C (10%) (120 mg) under nitrogen atmosphere. The reaction flask was charged with hydrogen at 50 psi for 2 hours. The catalyst was removed by filtration through celite. The solvent was evaporated under reduced pressure to afford a sticky syrup that was purified by flash column eluting with 50% EtOAc in hexanes to give the product as sticky oil (2.1 g, 99%). MS (ES+): m/e=233.1 (M+H); LC/Method A/2.36 min.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[N:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.OC1C=[CH:18][C:19]([C:22]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=O)=NC=1>C1COCC1>[NH3:1].[N:1]1([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:18][CH2:19][CH2:22][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:12][N:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccc(O)cn1)N1CCCCC1
Reactant: Oc1ccc(CN2CCCCC2)nc1
Solvent: C1CCOC1
Product: N
Product: c1cc(CN2CCCCC2)ncc1OCCCN1CCCCC1
Temperature: 60 °C
Yield: 4 %
Yield: 17 %

Procedure:
6-Piperidin-1-ylmethyl-Pyridin-3-ol. To a solution of (5-hydroxy-pyridin-2-yl)-piperidin-1-yl-methanone (1.30 g, 6.31 mmol) in THF (100 mL) was added borane-dimethylsulfide complex (1.75 mL, 18.9 mmol). After 18 h the solvent was removed and the residue was diluted with MeOH (50 mL) and heated to 60° C. After 2 h the solvent was evaporated and chromatography of the residue (SiO2: 4-8% 2 M NH3 in MeOH/DCM) gave the title compound as an oil (0.225 g, 17%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[CH:11][CH:10]=1)#[N:2].[O:27]1[C:31]2([CH2:36][CH2:35][CH:34]([NH:37][C:38]3[NH:42][CH:41]=[N:40][N:39]=3)[CH2:33][CH2:32]2)[O:30][CH2:29][CH2:28]1>>[O:27]1[C:31]2([CH2:32][CH2:33][CH:34]([N:37]3[C:17](=[O:18])[C:16]([CH2:15][C:12]4[CH:13]=[CH:14][C:9]([C:4]5[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=5)=[CH:10][CH:11]=4)=[C:22]([CH2:23][CH2:24][CH3:25])[N:39]4[N:40]=[CH:41][N:42]=[C:38]34)[CH2:35][CH2:36]2)[O:30][CH2:29][CH2:28]1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Reactant: c1nnc(NC2CCC3(CC2)OCCO3)[nH]1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCCO3)c2ncnn12
Temperature: 250 °C
Reaction time: 0.33 h
Yield: 57.2 %

Procedure:
A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (1.9 g) and N-(1,4-dioxaspiro[4.5]dec-8-yl)-4H-1,2,4-triazol-3-amine (0.6 g) was stirred at 250° C. for 20 min under microwave irradiation. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (0.78 g, 56%).
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[Br:13])[NH:4][C:3]1=O.[CH:15]1([C:18]2[N:22]=[C:21]([CH2:23][N+:24]#[C-:25])[O:20][N:19]=2)[CH2:17][CH2:16]1>>[CH:15]1([C:18]2[N:22]=[C:21]([C:23]3[N:24]=[CH:25][N:4]4[C:5]5[C:10](=[C:9]([Br:13])[CH:8]=[CH:7][CH:6]=5)[C:11](=[O:12])[N:2]([CH3:1])[C:3]=34)[O:20][N:19]=2)[CH2:17][CH2:16]1
Reactant: [C-]#[N+]Cc1nc(C2CC2)no1
Reactant: Cn1c(=O)[nH]c2cccc(Br)c2c1=O
Product: Cn1c(=O)c2c(Br)cccc2n2cnc(-c3nc(C4CC4)no3)c12

Procedure:
M.p. 246°-247° C. by reaction between 3-methyl-5-bromo-1,2,3,4-tetrahydro-2,4-dioxo-quinazoline and 3-cyclopropyl-5-isocyanomethyl-1,2,4-oxadiazole.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[NH:10][CH:11]=[C:12]([I:13])[C:5]=12.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C.O>[Cl:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[N:10]([S:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:22])=[O:21])[CH:11]=[C:12]([I:13])[C:5]=12
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Clc1ccnc2[nH]cc(I)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(c1ccccc1)n1cc(I)c2c(Cl)ccnc21
Reaction time: 2.5 h
Yield: 83 %

Procedure:
To a mixture of 95% sodium hydride (28 mg, 1.1 mmol) and 4-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine (278 mg, 1.0 mmol) in 10 mL DMF was added benzenesulfonyl chloride (194 mg, 1.1 mmol) and the reaction mixture stirred for 2.5 hours then diluted with water and the resulting precipitate collected by filtration to give the title compound in 83% yield. MS (ESI+) m/z 418.9 (M+H)+
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:7]=[C:8]2[CH:17]=[CH:16][CH:15]=[CH:14][N:9]2[C:10](=[O:13])[C:11]=1[Br:12])(=O)C.Cl.O1CCOCC1.[OH-].[NH4+]>O>[Br:12][C:11]1[C:10](=[O:13])[N:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]2=[N:7][C:6]=1[CH2:5][OH:4]
Reactant: CC(=O)OCc1nc2ccccn2c(=O)c1Br
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=c1c(Br)c(CO)nc2ccccn12
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A heterogeneous mixture of the (3-bromo-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)methyl acetate (4.24 g, 1.0 equiv.), conc. HCl (8.0 equiv.) and 1,4-dioxane (39 mL) was heated with stirring at 70° C. for 3 h. LCMS showed the completion of reaction. The residue was diluted with water (100 mL) and treated with 28% ammonium hydroxide (10 mL) to pH 10. The precipitate was filtered, washed with water (200 mL) and dried under high vacuum to give 3-bromo-2-(hydroxylmethyl)-4H-pyrido[1,2-a]pyrimidin-4-one as tan solid. Used without further purification: 1HNMR (400 MHz, DMSO-d6): δ 8.96-8.98 (dd, 1H), 8.03-8.08 (m,1H), 7.74-7.76 (dd, 1H), 7.43-7.48 (m,1H), 5.3 (t,1H), 4.6 (d,2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H]4CCCNC4)[C:14]([F:24])=[CH:13][N:12]=3)=[CH:9][N:8]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:5]2=[N:6][CH:7]=1.[CH3:35][O:36][CH2:37][CH:38]1[CH2:40][O:39]1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:5]4[CH2:4][CH2:3][CH2:2][CH2:7][N:6]4[CH:37]([O:36][CH3:35])[C@@H:38]([OH:39])[CH3:40])[C:14]([F:24])=[CH:13][N:12]=3)=[CH:9][N:8]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)(=[O:26])=[O:27])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCNC4)n3)c3cc(Cl)cnc32)cc1
Reactant: COCC1CO1
Solvent: CCO
Product: COC([C@H](C)O)N1CCCCC1Nc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(Cl)cc23)ncc1F
Temperature: 140 °C

Procedure:
To a solution of 2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[5,4-b]pyridin-3-yl]-5-fluoro-N-[(3S)-3-piperidyl]pyrimidin-4-amine, 1c, (0.20 g, 0.40 mmol) in ethanol was added 2-(methoxymethyl)oxirane (0.04 mL, 0.40 mmol). The reaction mixture was heated in a microwave reactor at 140° C. for 5 minutes. The reaction was evaporated to dryness and the resulting residue was purified via silica gel chromatography (0-10% MeOH: CH2Cl2) to afford the desired product (1d).
Reaction SMILES: [CH3:1][N:2]1[C:11]([OH:12])=[C:5]2[N:6]=[CH:7][N:8]=[C:9]([SH:10])[C:4]2=[N:3]1.[CH2:13](Br)[CH2:14][CH2:15][CH3:16]>N>[CH3:1][N:2]1[C:11]([OH:12])=[C:5]2[N:6]=[CH:7][N:8]=[C:9]([S:10][CH2:13][CH2:14][CH2:15][CH3:16])[C:4]2=[N:3]1
Reactant: Cn1nc2c(S)ncnc2c1O
Reactant: CCCCBr
Agent: N
Product: CCCCSc1ncnc2c(O)n(C)nc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1.2 g of 2-methyl-3-hydroxy-7-mercapto-pyrazolo [4,3-d]pyrimidine was dissolved in 50 ml of aqueous ammonia, and after an addition of 1.08 g of n-butyl bromide, the mixture was stirred at room temperature for 5 hours. By means of a rotary evaporator, ammonia gas was distilled off at room temperature. Then, the aqueous solution was acidified with hydrochloric acid and extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate, and then evaporated to dryness. The remaining solid was recrystallized from acetone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=3[CH2:8][C:7](=O)[C:6]=2[CH:18]=1.[N:19]1([CH2:25][CH2:26][N:27]2[CH2:31][CH2:30][O:29][C:28]2=[O:32])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(=O)(O)[O-].[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=3[CH:8]=[C:7]([N:22]3[CH2:23][CH2:24][N:19]([CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][O:29][C:28]4=[O:32])[CH2:20][CH2:21]3)[C:6]=2[CH:18]=1
Reactant: Cc1ccc2c(c1)CC(=O)c1cc(Cl)ccc1S2
Reactant: O=C1OCCN1CCN1CCNCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: Cc1ccc2c(c1)C=C(N1CCN(CCN3CCOC3=O)CC1)c1cc(Cl)ccc1S2
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
27.4 G. of 8-chloro-2-methyl-dibenzo[b,f]thiepin-10(11H)one, 400 ml. of absolute benzene and 40 g. of 3-[2-(1-piperazinyl)ethyl]-2-oxazolidinone are stirred under an atmosphere of argon at 20° C. To the mixture, there are added dropwise over a period of 60 minutes, 9.3 ml. of titanium tetrachloride in 200 ml. of absolute benzene. The mixture is subsequently heated at reflux for 3.5 hours and, after cooling to about 40° C., poured on to a saturated, aqueous sodium bicarbonate solution and stirred for an additional 30 minutes. The suspension obtained is filtered and the benzene phase separated. The aqueous phase is back extracted with 100 ml. of benzene. The combined benzene extracts are washed with water, dried over magnesium sulfate, filtered and evaporated. By recrystallization from acetonitrile, there is recovered from the residue still unchanged 8-chloro-2-methyl-dibenzo[b,f]thiepin-10(11H)-one. The mother liquor is evaporated and the residue recrystallized from benzene, whereby there is obtained 3-[2-[4-(8-chloro-2-methyl-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl]-2-oxazolidinone which melts at 194°-196° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[C:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:26]2[CH2:31][CH2:30][S:29][C:28]([CH3:33])([CH3:32])[C@@H:27]2[C:34]([O:36]C)=[O:35])(=[O:25])=[O:24])=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-].[Li+]>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[C:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:26]2[CH2:31][CH2:30][S:29][C:28]([CH3:33])([CH3:32])[C@@H:27]2[C:34]([OH:36])=[O:35])(=[O:25])=[O:24])=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H]1N(S(=O)(=O)c2ccc(OCC#CCCCCNC(=O)OC(C)(C)C)cc2)CCSC1(C)C
Agent: [I-]
Agent: [Li+]
Product: CC(C)(C)OC(=O)NCCCCC#CCOc1ccc(S(=O)(=O)N2CCSC(C)(C)[C@@H]2C(=O)O)cc1

Procedure:
The methyl ester of methyl(3S)-4-{[4-({7-[(tert-butoxycarbonyl)amino]-2-heptynyl}oxy)phenyl]sulfonyl}-2,2-dimethyl-3-thiomorpholine carboxylate was converted into the analogous carboxylic acid using lithium iodide according to the procedure of Example 250 to provide (3S)-4-{[4-({7-[(tert-butoxycarbonyl)amino]-2-heptynyl}oxy)phenyl]sulfonyl)-2,2-dimethyl-3-thiomorpholine carboxylic acid as a white solid. Electrospray Mass Spec: 541.2 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:11][C:10]=1[C:20]([O-:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].[CH:24]1([C:27](Cl)=[O:28])[CH2:26][CH2:25]1.O1CCOCC1>O>[CH2:1]([N:8]([C:27]([CH:24]1[CH2:26][CH2:25]1)=[O:28])[C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:11][C:10]=1[C:20]([OH:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])c1sc(-c2ccccc2)cc1NCc1ccccc1
Reactant: O=C(Cl)C1CC1
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1sc(-c2ccccc2)cc1N(Cc1ccccc1)C(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.5 %

Procedure:
To a solution of sodium 3-benzylamino-5-phenyl-thiophene-2-carboxylate (41.1 mg, 0.1 mmol) was added 32 mg (0.3 mmol) of cyclopropanecarbonyl chloride, 1.5 ml of dioxane and 0.5 ml of water. The mixture was stirred overnight at room temperature and concentrated in vacuo. A 4N hydrogen chloride solution in dioxane (1 ml) was added and the mixture was stirred for one hour at room temperature. The mixture was again concentrated and the crude material was purified by reverse phase HPLC giving access to 11.9 mg (31.5%) of 3-(benzyl-cyclopropanecarbonyl-amino)-5-phenyl-thiophene-2-carboxylic acid as a pale yellow solid. NMR 1H (DMSO D6, 400 MHz): 7.56-7.54 ppm (m, 2H, Haro); 7.39-7.13 ppm (m, 10H, Haro, Hazole and COOH); 5.27 ppm (d, 1H, J=15.2 Hz); 4.48 ppm (d, 1H, J=15.2 Hz); 1.49 ppm (m, 1H); 0.77 ppm (m, 2H); 0.61 ppm (m, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]=1[OH:14])[N:10]=[C:9]([C:18]([OH:20])=[O:19])[CH:8]=[C:7]2[N:21]([CH3:23])[CH3:22])(=[O:3])[CH3:2].[CH2:24](O)[CH3:25]>>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]=1[OH:14])[N:10]=[C:9]([C:18]([O:20][CH2:24][CH3:25])=[O:19])[CH:8]=[C:7]2[N:21]([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CCO
Reactant: CCCc1c(O)c(C(C)=O)cc2c(N(C)C)cc(C(=O)O)nc12
Product: CCCc1c(O)c(C(C)=O)cc2c(N(C)C)cc(C(=O)OCC)nc12
Yield: 76 %

Procedure:
The product of step (a) (2 g; 6.3291 mmole) was dissolved in ethanol and hydrogen chloride was bubbled through the solution. When the heat of soluation subsided, the solution was heated to reflux on a steambath for 2 hours. The mixture was cooled, treated with water and concentrated, followed by basification with NH3 solution (pH about 6). The solution was extracted into chloroform and this was washed with water, dried and evaporated to give a brown solid (1.6 g, 76%). NMR and mass spectra were consistent with required structure.
Reaction SMILES: [N+]([C:4]1[CH:5]=C2C(=C[CH:13]=1)C(=O)NN=C2Br)([O-])=O.[N+:16]([C:19]1[CH:28]=[C:27]2[C:22]([C:23]([Br:30])=[N:24][NH:25][C:26]2=[O:29])=[CH:21][CH:20]=1)([O-:18])=[O:17].[H-].[Na+].BrC(C)C>CN(C=O)C>[N+:16]([C:19]1[CH:28]=[C:27]2[C:22]([C:23]([Br:30])=[N:24][N:25]([CH:4]([CH3:5])[CH3:13])[C:26]2=[O:29])=[CH:21][CH:20]=1)([O-:18])=[O:17]
Reactant: O=c1[nH]nc(Br)c2cc([N+](=O)[O-])ccc12
Reactant: O=c1[nH]nc(Br)c2ccc([N+](=O)[O-])cc12
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)Br
Solvent: CN(C)C=O
Product: CC(C)n1nc(Br)c2ccc([N+](=O)[O-])cc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
A mixture of 6-nitro-4-bromo-2H-phthalazin-1-one and 7-nitro-4-bromo-2H-phthalazin-1-one (84 g, 0.31 mol) was dissolved in DMF (400 ml). To this was added NaH (60%, 7.5 g, 0.31 mol) as a DMF suspension (200 ml). The mixture was stirred at RT for 30 min then 2-bromo-propane (7.7 g, 62 mmol) was added in one portion as a solution in DMF (250 ml). The reaction mixture was stirred for 24 hours whereupon LC-MS showed 40% starting material remaining. To this was added NaH (3.75 g, 0.15 mol) and the reaction stirred for a further 24 hours. The DMF was removed under vacuum and the resulting crude material purified by successive column chromatography (elution: 92% heptane, 8% EtOAc) to give the title compound (38.8 g, 40% yield) as a light yellow solid. δH (400 MHz, DMSO), 8.88 (1H, d), 8.87 (1H, dd), 8.16 (1 H, d), 5.19 (1H, m), 1.13 (6H, d).
Reaction SMILES: [N:1]([C@@H:4]1[CH2:8][N:7]([C:9](=[O:24])[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C@H:6]([CH3:25])[CH2:5]1)=[N+]=[N-]>C(O)C.[Pd]>[NH2:1][C@@H:4]1[CH2:8][N:7]([C:9](=[O:24])[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:21])([F:22])[F:20])[CH:14]=2)[C@H:6]([CH3:25])[CH2:5]1
Reactant: C[C@@H]1C[C@H](N=[N+]=[N-])CN1C(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CCO
Product: C[C@@H]1C[C@H](N)CN1C(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Reaction time: 4 h

Procedure:
N-{2-[(2R,4S)-4-Azido-2-methylpyrrolidin-1-yl]-2-oxoethyl}-3-(trifluoromethyl)benzamide (1.33 g, 3.74 mmol) was dissolved in ethanol (50 mL) and then 10% Pd—C (130 mg) was added to the solution. The flask was purged with hydrogen and then stirred under an atmosphere of hydrogen using a balloon for four hours at which point, TLC indicated complete consumption of starting material. The reaction was then flushed with nitrogen and filtered through Celite on a glass frit and washed with methanol. The filtrate was concentrated to give the desired amine as a dark brown oil, 1.21 g (98%). LC/MS (M+H)+ m/z=330.1. 1H NMR (CDCl3) δ 8.12 (s, 1H), 8.02 (d, 1H), 7.77 (d, 1H), 7.58 (t, 1H), 7.37 (bs, 1H), 4.16 (m, 3H), 3.72 (m, 1H), 3.61 (m, 1H), 3.15 (m, 1H), 2.44 (m, 1H), 1.70-1.20 (m, 3H), 1.43 (d, 3H); 19F NMR (CDCl3) δ −63.12 (s).
Reaction SMILES: N#N.[H-].[Na+].[F:5][C:6]1([F:20])[C:11](=O)[CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7]1.[OH2:21].[CH2:22]1[CH2:26][O:25][CH2:24][CH2:23]1>>[CH2:24]([O:25][C:26](=[O:21])[CH:22]=[C:11]1[CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]1([F:20])[F:5])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(F)(F)C1
Reactant: O
Reactant: C1CCOC1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C=C1CCN(C(=O)OC(C)(C)C)CC1(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to NaH (45 mg, 1.12 mmol, 60% dispersion in oil washed with heptane) was added a solution of triethyl phosphonoacetate (262 mg, 1.17 mmol) in dry THF (10 mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 min. Molecular sieves were then added followed by a solution of tert-butyl 3,3-difluoro-4-oxopiperidine-1-carboxylate (220 mg, 0.93 mmol) in THF (5 mL). The reaction mixture was stirred at 0° C. for 30 min and at rt for 1 h. Water was then added and the mixture extracted with EA (3×). The combined org. extracts were dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound as a yellow oil (mixture of E and Z isomers). LC-MS-conditions 08: tR=0.88 and 0.93 min; [M-CH3+H]+=291.27.