Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S([O:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])(C(F)(F)F)(=O)=O.[F:16][CH:17]([F:20])[CH2:18]O.C([O-])(O)=O.[Na+]>>[F:15][C:12]([F:13])([F:14])[S:9]([O:8][CH2:18][CH:17]([F:20])[F:16])(=[O:10])=[O:11]
Reactant: OCC(F)F
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Product: O=S(=O)(OCC(F)F)C(F)(F)F
Temperature: 84 °C
Yield: 64.1 %

Procedure:
Triflic anhydride (27.9 g, 99.1 mmol) was placed in a flask and cooled with an ice bath. 2,2-Difluoroethanol (8.1 g, 99.1 mmol) was added and the reaction was heated to 84° C. for 1 hour. The reaction was cooled in an ice bath and poured into 100 ml cold 5% NaHCO3 solution. The mixture was extracted with diethyl ether, dried over MgSO4, and concentrated under reduced pressure to remove the ether. The residue was vaccuum distilled to give 2,2-difluoroethyl trifluoromethanesulfonate as a clear liquid (13.6 g, 64%, bp˜55° C.). 1H NMR (400 MHz, CDCl3) δ ppm 6.17-5.88 (1H), 4.61-4.13 (2H)
Reaction SMILES: [F:1][C:2]1[C:3]([C:24]([F:27])([F:26])[F:25])=[N:4][N:5]([C:14]2[CH:15]=[CH:16][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[N:18][CH:19]=2)[C:6]=1[C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1.BrC1C=CC(C2(CC)N([C:40]3C=C[C:43]([S:46](N)(=O)=O)=[N:44][CH:45]=3)NC(C(F)(F)F)=C2)=CC=1>>[F:1][C:2]1[C:3]([C:24]([F:27])([F:26])[F:25])=[N:4][N:5]([C:14]2[CH:15]=[CH:16][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[N:18][CH:19]=2)[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:40]2[S:46][CH:43]=[N:44][CH:45]=2)=[CH:9][CH:8]=1
Reactant: CCC1(c2ccc(Br)cc2)C=C(C(F)(F)F)NN1c1ccc(S(N)(=O)=O)nc1
Reactant: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(F)c2-c2ccc(Br)cc2)cn1
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(F)c2-c2ccc(-c3cncs3)cc2)cn1

Procedure:
The title compound was prepared according to the procedure of step 1 in the Example 10 using 5-[4-fluoro-5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide (Example 8, step 1), instead of 5-[5-(4-bromophenyl)-5-ethyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH:10]([O:11][C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])[CH2:9][CH2:8][C:5]2([O:7][CH2:6]2)[CH:4]1[C:20]1([CH3:28])[CH:22]([CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[O:21]1>C(OCC)(=O)C.[Pt]=O>[CH3:1][O:2][CH:3]1[CH:10]([O:11][C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[O:13])[CH2:9][CH2:8][C:5]2([O:7][CH2:6]2)[CH:4]1[C:20]1([CH3:28])[CH:22]([CH2:23][CH2:24][CH:25]([CH3:26])[CH3:27])[O:21]1
Reactant: COC1C(OC(=O)N2CCOCC2)CCC2(CO2)C1C1(C)OC1CC=C(C)C
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: COC1C(OC(=O)N2CCOCC2)CCC2(CO2)C1C1(C)OC1CCC(C)C
Yield: 80.6 %

Procedure:
A solution of 5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-6-morpholinocarbonyloxy-1-oxaspiro[2,5]octane (1.23 g) in ethyl acetate (12 ml) was hydrogenated under hydrogen (1 atm) in the presence of platinum oxide (120 mg) for 1 hour. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel eluted with a mixture of diethyl ether and n-hexane (1:1, V/V) to give 5-methoxy-4-[2-methyl-3-(3-methylbutyl)oxiranyl]-6-morpholinocarbonyloxy-1-oxaspiro-[2,5]octane (996 mg) as an oil, which was standing on to give crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:34][C:35]1[CH:36]=[C:37]([S:41](Cl)(=[O:43])=[O:42])[CH:38]=[CH:39][CH:40]=1.O>ClCCl>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([S:41]([C:37]4[CH:36]=[C:35]([CH3:34])[CH:40]=[CH:39][CH:38]=4)(=[O:43])=[O:42])[C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:25])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Cl)cc4c32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cccc(S(=O)(=O)n2c(=O)n(-c3ccc(C(C)(C)C#N)cc3)c3c4cc(Cl)ccc4ncc32)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-(8-chloro-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 2, 50 mg, 0.14 mmol) and triethylamine (28 mg, 0.28 mmol) in dichloromethane (6 ml) was added 3-methylbenzene-1-sulfonyl chloride (40 mg, 0.21 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound. Yield: 29 mg (40%); 1H NMR (CDCl3, 300 MHz): δ 9.605 (s, 1H), 8.023-8.093 (m, 3H), 7.72-7.748 (dd, 2H, J=6.6 Hz, 1.8 Hz), 7.44-7.551 (m, 5H), 6.855-6.862 (d, 1H, J=2.1 Hz), 2.44 (s, 3H), 1.82 (s, 6H); MS: m/z 517 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH2:4][N:5]=[N+:6]=[N-:7].[C:12]([C:15]([OH:17])=[O:16])#[C:13]C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH2:4][N:5]1[CH:13]=[C:12]([C:15]([OH:17])=[O:16])[N:7]=[N:6]1
Reactant: [N-]=[N+]=NCc1ccccc1Cl
Reactant: CC#CC(=O)O
Solvent: Cc1ccccc1
Product: O=C(O)c1cn(Cc2ccccc2Cl)nn1
Temperature: 25 °C

Procedure:
A solution of 16.75 g (100 mmol) of o-chlorobenzyl azide, 7.35 g (100 mmol) of propynecarboxylic acid and 200 ml of toluene is stirred for 24 hours at 50°. After being cooled to room temperature, the precipitated product is filtered off with suction and washed first with toluene and then with diethyl ether. In this manner there is obtained 1-(o-chlorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid having a melting point of 175° (with decomposition). After concentration of the filtrates by evaporation and washing the residue with a little toluene, 1-(o-chlorobenzyl)-1H-1,2,3-triazole-5-carboxylic acid having a melting point of 120° (with decomposition) remains.
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1.CCN(C(C)C)C(C)C>CS(C)=O.O>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:3]2[C:2]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=3)[N:4]=2)=[CH:17][CH:18]=1
Reactant: C1CCNC1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCC3)nc2c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
To a solution of methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (130 mg, 0.41 mmol) in DMSO (2 mL) was added pyrrolidine (58 mg, 0.82 mmol) and DIEA (106 mg, 0.82 mmol). After stirring 2 h at 70° C., the reaction mixture was dissolved in water (100 mL), extracted with dichloromethane (3×30 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified via silica gel column chromatography (2% dichloromethane in petroleum ether) to afford methyl 2-(4-fluorophenyl)-3-(pyrrolidin-1-yl)quinoxaline-6-carboxylate as a light yellow solid (72 mg, 50%).
Reaction SMILES: [C:1]([CH:4]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[CH:5]([CH3:12])[CH2:6][C:7](OCC)=[O:8])(=O)[CH3:2].C([O-])(=O)C.[NH4+:23]>C(O)C>[CH3:12][CH:5]1[C:4]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:1]([CH3:2])[NH:23][C:7](=[O:8])[CH2:6]1
Reactant: CCOC(=O)CC(C)C(C(C)=O)c1ccncc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Product: CC1=C(c2ccncc2)C(C)CC(=O)N1
Yield: 9.8 %

Procedure:
A mixture containing 24 g of ethyl 4-acetyl-3-methyl-4-(4-pyridinyl)butanoate, 7 g of ammonium acetate and 50 ml of ethanol was refluxed for 8 hours with stirring. The reaction mixture was then concentrated to dryness in vacuo and the remaining white solid was collected, washed with ethanol and dried to produce 1.8 g of 3,4-dihydro-4,6-dimethyl-5-(4-pyridinyl)-2(1H)-pyridinone, m.p. 184°-185° C. It's nmr and mass spectrum were consistent with the assigned structure.
Reaction SMILES: [O:1]=[C:2]([CH:6]=[CH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[C:3]([OH:5])=[O:4].O1[CH2:18][CH2:17][CH2:16]C1.Cl.[OH-].[Na+].[CH3:22]COCC>>[O:1]=[C:2]([CH:6]=[CH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[C:3]([O:5][C:17]([CH3:16])([CH3:18])[CH3:22])=[O:4]
Reactant: CCOCC
Reactant: O=C(O)C(=O)C=Cc1cccnc1
Reactant: C1CCOC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)C(=O)C=Cc1cccnc1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
A mixture of 1.41 g of the acid of Step A, 4.5 g of 0-tert.-butyl-N,N-diisopropyl-isourea and 32 ml of tetrahydrofuran was stirred at 20° C. under nitrogen for 15 hours and then 8 ml of aqueous N hydrochloric acid were added with stirring. 8 ml of aqueous N sodium hydroxide solution and 10 ml of ether were added with stirring and the mixture was filtered. The decanted aqueous phase was extracted with ether and the combined organic phases were washed and evaporated to dryness under reduced pressure. The residue was chromatographed over silica and was eluted with a 93-7 methylene chloride-acetone mixture to obtain 1.35 g of 1,1-dimethyl-ethyl 2-oxo-4-{pyridin-3-yl)-3-butenoate melting at 51°-52° C.
Reaction SMILES: [N:1]1(S(O)(=O)=O)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[Na].C1[S:21](=[O:23])(=[O:22])CCC1.P(Cl)(Cl)([Cl:26])=O>O>[Cl:26][S:21]([C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[NH:1][C:2](=[O:3])[C:4]2=[O:5])(=[O:23])=[O:22]
Reactant: O=S1(=O)CCCC1
Reactant: O=C1C(=O)N(S(=O)(=O)O)c2ccccc21
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na]
Solvent: O
Product: O=C1Nc2ccc(S(=O)(=O)Cl)cc2C1=O
Temperature: 60 °C
Yield: 60.5 %

Procedure:
To a mixture of isatinsulfonic acid, sodium salt dihydrate (10 g, 35.1 mmol) and 50 mL tetramethylene sulfone was added phosphorus oxychloride (16.5 mL, 177 mmol). The resulting mixture was heated at 60° C. for 3 hours. The mixture was cooled to 0° C. and 120 mL of water was cautiously added. The resulting green solid was filtered and washed with water. The solid was dissolved in 100 mL EtOAc and washed thrice with 50 mL of water. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to give a yellow solid. The solid was recrystallized from EtOAc/Hexanes to give the title compound as an orange solid (5.2 g, 60.5%). ES (−) MS m/e=344 (M−H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([CH3:10])[C:4]=1[N+:11]([O-:13])=O.BrC[C:16]1C=CC=C(C(F)(F)F)[C:17]=1[N+:26]([O-])=O.ClC1C=C(C)C([N+]([O-])=[O:38])=C(C)C=1>>[NH2:26][CH:17]1[CH2:2][C:3]2[C:4](=[C:5]([CH3:10])[CH:6]=[C:7]([Cl:9])[CH:8]=2)[N:11]([OH:13])[C:16]1=[O:38]
Reactant: O=[N+]([O-])c1c(CBr)cccc1C(F)(F)F
Reactant: Cc1cc(Cl)cc(CBr)c1[N+](=O)[O-]
Reactant: Cc1cc(Cl)cc(C)c1[N+](=O)[O-]
Product: Cc1cc(Cl)cc2c1N(O)C(=O)C(N)C2
Yield: 50 %

Procedure:
1-(Bromomethyl)-5-chloro-3-methyl-2-nitrobenzene (38) Following the procedure for the preparation of 1-(bromomethyl)-2-nitro-3-(trifluoromethyl)benzene (17) in Example 3, reaction of 5-chloro-1,3-dimethyl-2-nitrobenzene (37) provided the title compound as a solid (50%). 1H NMR (400 MHz, CDCl3) δ 2.36 (m, 3H), 4.43 (s, 2H), 7.28 (m, 1H), 7.37 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21](O)[CH2:22][OH:23].C(OCC)(OCC)OCC.C(=O)([O-])O.[Na+]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][CH2:9][C:10]1([CH2:12][O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[O:23][CH2:22][CH2:21][O:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(COCc1ccccc1)COCc1ccccc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(OCC)OCC
Solvent: O
Solvent: CCOC(C)=O
Product: c1ccc(COCC2(COCc3ccccc3)OCCO2)cc1
Temperature: 50 °C
Reaction time: 14 h
Yield: 81.6 %

Procedure:
The 1,3-bis(benzyloxy)acetone (30 g, 111 mmol) obtained in the step (4a) was mixed with ethylene glycol (64 ml, 1,148 mmol) and triethyl orthoformate (19 ml, 114 mmol), and p-toluenesulfonic acid monohydrate (591 mg, 3.11 mmol). The mixture was stirred at 50° C. for 14 hours. To the mixture, a saturated aqueous solution of sodium hydrogen carbonate and ethyl acetate were added. The organic layer was washed with water and a saline solution, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (elution solvent: heptane/ethyl acetate=1/0-4/1 gradient) and desired fractions were concentrated to obtain the title compound (28.46 g, yield: 81.6%) as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[C@@H:11]2[CH2:12][CH2:13][CH2:14][C@@H:10]2[C:9](=[O:15])[N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7]2[CH:23]=[CH:24][CH:25]=[CH:26][C:6]1=2)=[O:4].[C:27]1(=[O:33])[O:32][C:30](=[O:31])[CH:29]=[CH:28]1.CCCCCC>C1(C)C(C)=CC=CC=1>[CH2:16]([N:8]1[C:9](=[O:15])[C@H:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[N:5]([C:3](=[O:4])[CH2:2][NH:1][C:27](/[CH:28]=[CH:29]\[C:30]([OH:32])=[O:31])=[O:33])[C:6]2[CH:26]=[CH:25][CH:24]=[CH:23][C:7]1=2)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NCC(=O)N1c2ccccc2N(Cc2ccccc2)C(=O)[C@H]2CCC[C@H]21
Reactant: O=C1C=CC(=O)O1
Solvent: CCCCCC
Solvent: Cc1ccccc1C
Product: O=C(O)/C=C\C(=O)NCC(=O)N1c2ccccc2N(Cc2ccccc2)C(=O)[C@H]2CCC[C@H]21
Temperature: 25 °C
Yield: 78.2 %

Procedure:
A mixture of (3aR*,10aS*)-4-(aminoacetyl)-9-benzyl-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta [e][1,4]diazepin-10(1H)-one (420 mg, 1.2 mmol) and maleic anhydride (118 mg, 1.2 mmol) was stirred for 30 minutes in xylene at 140° C. The reaction mixture was left standing for cooling at room temperature, to which was added hexane (5 mL). The resulting solid was collected by filtration, which was recrystallized from chloroform-ethanol-diethyl ether to give 420 mg (yield 78%) of the titled compound, m.p. 207°-209° C.
Reaction SMILES: [CH2:1]([N:3]([C:5]([NH:7][C:8]1[S:9][C:10]([CH3:13])=[N:11][N:12]=1)=[O:6])[NH2:4])[CH3:2].[CH2:14]=O.[OH-].[K+]>CO>[CH2:1]([N:3]1[C:5](=[O:6])[N:7]([C:8]2[S:9][C:10]([CH3:13])=[N:11][N:12]=2)[CH2:14][NH:4]1)[CH3:2]
Reactant: CCN(N)C(=O)Nc1nnc(C)s1
Reactant: C=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCN1NCN(c2nnc(C)s2)C1=O
Reaction time: 0.33 h

Procedure:
2-Ethyl-4-(5-methyl-1,3,4-thiadiazol-2-yl)semicarbazide (0.1 mole) dissolved in methanol (100 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. Aqueous formaldehyde (0.2 mole; 37% concentration) is then added to the reaction vessel with stirring. Dilute aqueous potassium hydroxide is added to the reaction mixture to adjust the pH to between 7 and 8 and stirring is continued for a period of about 20 minutes resulting in the formation of a solid precipitate. The precipitate is recovered by filtration, is recrystallized and is dried under vacuum to yield the desired product 2-ethyl-4-(5-methyl-1,3,4-thiadiazol-2-yl)-1,2,4-triazolidin-3-one.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]2[NH:14][C:13]3[CH:15]=[CH:16][C:17]([N:19]4[CH2:24][CH2:23][S:22][CH2:21][CH2:20]4)=[CH:18][C:12]=3[N:11]=2)[CH:7]=[CH:6][C:5]=1[NH2:25])([O-])=O>[Pd].C(OCC)(=O)C.CO>[N:19]1([C:17]2[CH:16]=[CH:15][C:13]3[NH:14][C:10]([C:8]4[CH:9]=[C:4]([NH2:1])[C:5]([NH2:25])=[CH:6][CH:7]=4)=[N:11][C:12]=3[CH:18]=2)[CH2:20][CH2:21][S:22][CH2:23][CH2:24]1
Reactant: Nc1ccc(-c2nc3cc(N4CCSCC4)ccc3[nH]2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc(-c2nc3cc(N4CCSCC4)ccc3[nH]2)cc1N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-nitro-4-(5-thiomorpholin-4-yl-1H-benzoimidazol-2-yl)-phenylamine (1.0 g, 2.8 mmol) in 4:1 ethyl acetate/methanol (80 ml) under nitrogen, was added 5% palladium on carbon (240 mg) and the mixture was first evacuated and then stirred at room temperature under an atmosphere of hydrogen for 1 day. The reaction mixture was then filtered through Celite, washed with 1:1 ethyl acetate/methanol (10 mL), and the combined filtrate and washings were concentrated to give the crude 4-(5-thiomorpholin-4-yl-1H-benzoimidazol-2-yl)-benzene-1,2-diamine as a red oil that was used in the next step without any purification.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]2[C:12]([I:13])=[CH:11][NH:10][C:6]=2[N:7]=[CH:8][N:9]=1.[CH2:14](Br)[CH:15]=[CH2:16].O>CN(C)C=O>[Cl:3][C:4]1[C:5]2[C:12]([I:13])=[CH:11][N:10]([CH2:16][CH:15]=[CH2:14])[C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: Clc1ncnc2[nH]cc(I)c12
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCn1cc(I)c2c(Cl)ncnc21
Temperature: 25 °C

Procedure:
Sodium hydride (0.28 g of 60% dispersion in mineral oil) was added to a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.96 g) in dry N,N-dimethylformamide (40 ml) with stirring under nitrogen at ambient temperature. The mixture was then stirred for 30 minutes and allyl bromide (0.62 ml) was added dropwise. After stirring for 1 hour at ambient temperature more allyl bromide (0.20 ml) was added and the mixture was left stirring at ambient temperature for 18 hours. The mixture was added to water with stirring and the solid which precipitated was collected by filtration and dried to give 4-chloro-5-iodo-7-(prop-1-en-3-yl)-7H-pyrrolo[2,3-d]-pyrimidine which was used directly in b).
Reaction SMILES: [CH2:1]([C:5]([CH2:10][OH:11])([CH2:8][OH:9])[CH2:6][OH:7])[CH2:2][CH:3]=[CH2:4].[C:12]1(C)[CH:17]=CC(S(O)(=O)=O)=C[CH:13]=1>CC(C)=O>[CH2:1]([C:5]1([CH2:6][OH:7])[CH2:8][O:9][C:12]([CH3:17])([CH3:13])[O:11][CH2:10]1)[CH2:2][CH:3]=[CH2:4]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C=CCCC(CO)(CO)CO
Solvent: CC(C)=O
Product: C=CCCC1(CO)COC(C)(C)OC1

Procedure:
A mixture of crude 2-(but-3-enyl)-2-hydroxymethylpropan-1,3-diol (4.5 g), acetone (30 ml) and p-toluenesulphonic acid (0.25 g) was refluxed in a Dean and Stark apparatus for 7 hours. The mixture was cooled and washed with aqueous sodium hydrogen carbonate solution. The organic solution was dried over anhydrous magnesium sulphate and the solvent was removed in vacuo. The residue was chromatographed on silica, eluting with 1:4 diethyl ether: hexane. 5-(But-3-enyl)-2,2-dimethyl-5-hydroxymethyl-1,3-dioxane was obtained as a colourless oil (1.0 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:15]=[CH:14][C:13]3[O:12][CH2:11][CH:10](C(O)=O)[CH2:9][C:8]=3[C:7]=2[CH:19]=1.[CH2:20]([N:22](CC)CC)[CH3:21].ClC(OCC)=[O:29].[N-]=[N+]=[N-].[Na+]>CC(C)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:15]=[CH:14][C:13]3[O:12][CH2:11][CH:10]([NH:22][C:20](=[O:29])[CH3:21])[CH2:9][C:8]=3[C:7]=2[CH:19]=1
Reactant: COc1ccc2ccc3c(c2c1)CC(C(=O)O)CO3
Reactant: CCN(CC)CC
Reactant: CCOC(=O)Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc2ccc3c(c2c1)CC(NC(C)=O)CO3
Reaction time: 0.5 h

Procedure:
After dissolving the acid obtained in Step B (50 mg:0.19 mmol) in acetone (2 ml) under an inert atmosphere, distilled triethylamine (0.07 ml:0.52 mmol:2.7 eq.) and also distilled ethyl chloroformate (0.06 ml:0.68 mmol:3.5 eq.) are slowly introduced in succession at 0° C. After 30 minutes of stirring, sodium azide (57 mg:0.87 mmol:4.5 eq.), dissolved in 1 ml of water, is added. After a similar amount of time has passed, the reaction medium is extracted with dichloromethane. The resulting organic phase is concentrated, taken up in 1 ml of toluene and heated at reflux for 30 minutes. While in the hot state, glacial acetic acid (1 ml) is then introduced; the heating is then continued for 1 hour 30 minutes. At ambient temperature, the products are extracted with ethyl acetate and then purified on a flash silica column CHCl3 /AcOEt 7/3. The title compound is washed with diethyl ether.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[CH:6][CH:7]=1.[CH:9]1([N:13]2[CH2:19][CH2:18][CH2:17][N:16]([C:20]([C@H:22]3[CH2:26][C@H:25]([OH:27])[CH2:24][N:23]3[C:28](=[O:30])[CH3:29])=[O:21])[CH2:15][CH2:14]2)[CH2:12][CH2:11][CH2:10]1>>[CH:9]1([N:13]2[CH2:19][CH2:18][CH2:17][N:16]([C:20]([C@H:22]3[CH2:26][C@H:25]([O:27][C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)[CH2:24][N:23]3[C:28](=[O:30])[CH3:29])=[O:21])[CH2:15][CH2:14]2)[CH2:12][CH2:11][CH2:10]1
Reactant: CC(=O)N1C[C@@H](O)C[C@@H]1C(=O)N1CCCN(C2CCC2)CC1
Reactant: Fc1cccc(I)c1
Product: CC(=O)N1C[C@@H](Oc2cccc(F)c2)C[C@@H]1C(=O)N1CCCN(C2CCC2)CC1

Procedure:
The title compound was prepared by Preparation 1: acylation as described for Example 114; or Preparation 2: reaction of 3-fluoro-iodobenzene and (2R,4S)-1-[2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-hydroxy-pyrrolidin-1-yl]-ethanone as described for Example 48. MS (ESI): mass calcd. for C22H30FN3O3, 403.23; m/z found, 404.3 [M+H]+. 1H NMR (CDCl3): 7.28-7.23 (m, 1H), 6.75-6.69 (m, 1H), 6.69-6.64 (m, 1H), 6.65-6.55 (m, 1H), 5.15-4.90 (m, 1H), 4.07 (dd, J=11.2, 4.9 Hz, 1H), 3.89-3.47 (m, 5H), 3.01-2.83 (m, 1H), 2.74-2.27 (m, 6H), 2.13-2.00 (m, 6H), 1.95-1.65 (m, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([CH2:17][CH:18]=[CH2:19])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH:21]([C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1)([CH3:23])[CH3:22]>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:20])[N:7]([CH2:17][CH:18]=[CH2:19])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:30]([C:27]2[CH:28]=[CH:29][C:24]([CH:21]([CH3:23])[CH3:22])=[CH:25][CH:26]=2)(=[O:32])=[O:31])=[CH:12][CH:11]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: C=CCN(CCc1ccc(N)cc1)C(=O)OC(C)(C)C
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: C=CCN(CCc1ccc(NS(=O)(=O)c2ccc(C(C)C)cc2)cc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 646.9 %

Procedure:
To a solution of allyl-[2-(4-amino-phenyl)ethyl]-carbamic acid tert-butyl ester (1.86 g, 6.74 mmol) in pyridine (25 ml) at 0° C. was added 4-isopropyl-benzenesulfonyl chloride (1.47 g, 6.74 mmol) and the mixture was stirred at 0° C. for 1 h. After concentration in vacuo the residue was partitioned between ethyl acetate and saturated aqueous NaHCO3. The organic layer was washed with water, dried over MgSO4, filtered and the solvent evaporated under reduced pressure. The residue was purified by column chromatography (n-heptane/ethyl acetate, 2/1) to give the product as a yellow resin (1.35 g, 43.6 mmol).