Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)/[C:27]([OH:29])=O)[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:62][C@@H:63]1[C:81](=[O:82])[N:65]2[C:66]([C:78]([OH:80])=[O:79])=[C:67]([CH2:70][S:71][C:72]3[N:76]([NH2:77])[N:75]=[N:74][N:73]=3)[CH2:68][S:69][C@H:64]12.C(N(CC)CC)C.NC1C(CSC2N(NC(C)C)N=NN=2)=C(C(O)=O)N2C(=O)C[C@H]2S1>CC(N(C)C)=O.O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH:32]2[CH2:33][CH2:34][CH2:35][CH2:36]2)/[C:27]([NH:62][C@@H:63]2[C:81](=[O:82])[N:65]3[C:66]([C:78]([OH:80])=[O:79])=[C:67]([CH2:70][S:71][C:72]4[N:76]([NH2:77])[N:75]=[N:74][N:73]=4)[CH2:68][S:69][C@H:64]23)=[O:29])[N:25]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3N)CS[C@H]12
Reactant: O=C(O)/C(=N\OC1CCCC1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)Nn1nnnc1SCC1=C(C(=O)O)N2C(=O)C[C@H]2SC1N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: Nn1nnnc1SCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\OC3CCCC3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 50.8 %

Procedure:
A solution of 2-(2-tritylaminothiazol-4-yl)-(Z)-2-cyclopentyloxyiminoacetic acid (3.23 g, 6.5 mmol), 1-hydroxybenzotriazole (1.01 g, 7.47 mmol) and N,N'-dicyclohexylcarbodiimide (1.47 g, 7.15 mmol) in dimethylacetamide (36 ml) was stirred at room temperature for 2.5 hours. To the solution was added a solution of 7β-amino-3-[(1-amino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (2.35 g, 7.15 mmol) and triethylamine (1.44 g, 13 mmol) in dimethylacetamide (18 ml) and water (2.4 ml) and the mixture was stirred at room temperature for 17 hours. Then the mixture was treated in a manner to that described in Example 6, (c) to give pale brown powder of 7β-[2-(2-tritylaminothiazol-4-yl)-(Z)-2-cyclopentyloxyiminoacetamido]-3-[(1-amino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (2.67 g, 51%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH2:12]Cl.[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.[K]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH2:12][N:18]1[C:14](=[O:24])[C:15]2[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:17]1=[O:19]
Reactant: COc1cc(Br)c(CCl)cc1OC
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Br)c(CN2C(=O)c3ccccc3C2=O)cc1OC
Temperature: 80 °C
Reaction time: 4.5 h

Procedure:
A solution of 1-bromo-2-chloromethyl-4,5-dimethoxy-benzene (26.01 g, 0.09796 mol) in dry DMF (100 mL) was treated with potassium phthalimide (19.05 g, 0.1029 mol). The resulting slurry was heated to 80° C. while stirring under nitrogen for 4.5 h. The resulting mixture was then cooled to room temperature and allowed to stir 16 h. The resulting mixture solidified, was diluted with water (400 mL) and stirred 1 h. The resulting white precipitate was collected via filtration and washed with water (1 L). The white solid was dissolved in boiling methanol (2 L). The resulting solution was reduced to about 1 L, at which time a precipitate began to form. The resulting slurry was allowed to cool to room temperature then placed on an ice bath. The precipitate was collected via filtration to yield 2-(2-bromo-4,5-dimethoxy-benzyl)-isoindole-1,3-dione as a white solid.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][C:10]1[N:11]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][N:13]=2.O>CC#N>[Br:8][C:18]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[N:11]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:20])=[O:21])[C:10]=1[CH3:9]
Reactant: Cc1cc2cccnc2n1S(=O)(=O)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: O
Product: Cc1c(Br)c2cccnc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 72.1 %

Procedure:
72 mg of NBS in 2 ml of CH3CN are added to a solution of 100 mg of 2-methyl-1-(benzenesulfonyl)-7-azaindole in 3 ml of CH3CN. The mixture is stirred at room temperature for 20 h, poured into water, the precipitate which has precipitated out is separated off and dried, giving 93 mg of 3-bromo-2-methyl-1-(benzenesulfonyl)-7-azaindole, M˜351.22 g/mol, M+H found 351.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[C:12](=[O:15])[CH2:13]Br.[S-:16][C:17]#[N:18].[NH4+].C(=O)(O)[O-].[Na+]>C(#N)C>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[C:12](=[O:15])[CH2:13][S:16][C:17]#[N:18]
Reactant: O=C(CBr)c1c(F)c(F)c(F)c(F)c1F
Reactant: N#C[S-]
Agent: O=C([O-])O
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Product: N#CSCC(=O)c1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1-(2,3,4,5,6-pentafluorophenyl)-2-bromo-1-ethanone 5.00 g, ammonium thiocyanate 1.58 g and acetonitrile 100 mL was stirred at 25° C. for one hour. To the reaction mixtures was added aqueous saturated sodium bicarbonate solution and the mixtures were extracted with ethyl acetate. The organic layers were washed with aqueous saturated sodium bicarbonate solution and were dried over anhydrous sodium sulfate. The resulting mixtures were concentrated under reduced pressure to give 1-(2,3,4,5,6-pentafluorophenyl)-2-thiocyanato-1-ethanone.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]1([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH:35](=O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(O)(=O)C>ClCCl.O>[CH2:35]([NH:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][N:24]2[CH2:23][CH2:22][N:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:26][CH2:25]2)=[CH:33][CH:32]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1ccc(CN2CCN(c3ccccc3)CC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: c1ccc(CNc2ccc(CN3CCN(c4ccccc4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
Sodium triacetoxyborohydride (282 mg, 1.34 mmol) was added in one portion to a stirred solution of 4-(4-phenyl-piperazin-1-yl methyl)-phenylamine, benzaldehyde (75 μl, 0.73 mmol) and acetic acid (43 μl, 0.73 mmol) in dry dichloromethane (6 ml) and the reaction was stirred for 16 hours at room temperature. Water was added and the organic layer separated then washed with brine and dried over magnesium sulfate. The solution was concentrated in vacuo and the crude residue purified by column chromatography (hexanes/ethyl acetate 1:1) to afford the title compound as a colourless solid (175 mg, 72%). HPLC retention time 7.53 min. Mass spectrum (ES+) m/z 358 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:16][C@H:17]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])[C:18](O)=[O:19])[CH:5]=[CH:6][C:7]=1[CH:8]1[S:12](=[O:14])(=[O:13])[NH:11][C:10](=[O:15])[CH2:9]1.F[P-](F)(F)(F)(F)F.[N:38]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[N:40]=N1.C(N(CC)C(C)C)(C)C.C1(N)C(N)=CC=CC=1>CN(C=O)C>[NH2:38][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=1[NH:40][C:18](=[O:19])[CH:17]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:23])=[O:24])[CH2:16][C:4]1[CH:5]=[CH:6][C:7]([CH:8]2[S:12](=[O:13])(=[O:14])[NH:11][C:10](=[O:15])[CH2:9]2)=[C:2]([Br:1])[CH:3]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: O=C1CC(c2ccc(C[C@H](NS(=O)(=O)c3ccccc3)C(=O)O)cc2Br)S(=O)(=O)N1
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1ccccc1N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccccc1NC(=O)C(Cc1ccc(C2CC(=O)NS2(=O)=O)c(Br)c1)NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
(2S)-3-[3-Bromo-4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)phenyl]-2-[(phenylsulfonyl)-amino]propanoic acid (20.7 mg, 0.040 mmol) in DMF (1 mL) was treated with benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (21.2 mg, 0.0480 mmol). After stirring 5 minutes at rt a solution of N,N-diisopropylethylamine (34.8 μL, 0.200 mmol) and 1,2-benzenediamine (6.49 mg, 0.0600 mmol) in DMF (1.0 mL) was added. The solution stirred at rt for 2 h. Purification by preparative LCMS afforded product as a white solid (18.1 mg, 75%).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[CH3:17][C:18](C)=[O:19].C(=O)([O-])[O-].[K+].[K+]>O>[C:18]([N:11]1[CH2:16][CH2:15][N:14]([CH2:1][CH:2]=[CH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:13][CH2:12]1)(=[O:19])[CH3:17]
Reactant: C1CNCCN1
Reactant: CC(C)=O
Reactant: BrCC=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(=O)N1CCN(CC=Cc2ccccc2)CC1

Procedure:
5 Grams of cinnamyl bromide, 5 g of anhydrous piperazine and 50 ml of acetone solution containing 8.4 g of anhydrous potassium carbonate were refluxed for 6 hours. To the reaction mixture was added water and the whole mixture was extracted with chloroform. The chloroform layer was washed with water, dried and the solvent was removed by evaporation. 2.2 Grams of 1-acetyl-4-cinnamylpiperazine thus obtained was dissolved in 80% of methanol, and 2 g of potassium hydroxide was added thereto, then the mixture was refluxed for 8 hours. To the reaction mixture was added water, and the whole mixture was extracted with chloroform, washed with water, dried, and chloroform was removed by evaporation. The residue thus obtained was purified by means of a silica gel column chromatography (eluent: chloroform and chloroform:methanol=30:1) to yield 1.2 g of N-cinnamylpiperazine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:22])[C:6]=1[N:7]1[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:9][CH2:8]1.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:65]([O:69][C:70]([NH:72][C:73]1[S:77][C:76]([C:78]2[C:83]([F:84])=[CH:82][CH:81]=[CH:80][C:79]=2[F:85])=[N:75][C:74]=1[C:86](O)=[O:87])=[O:71])([CH3:68])([CH3:67])[CH3:66]>C(Cl)Cl>[F:85][C:79]1[CH:80]=[CH:81][CH:82]=[C:83]([F:84])[C:78]=1[C:76]1[S:77][C:73]([NH:72][C:70](=[O:71])[O:69][C:65]([CH3:67])([CH3:66])[CH3:68])=[C:74]([C:86](=[O:87])[NH:1][C:2]2[CH:3]=[N:4][N:5]([CH3:22])[C:6]=2[N:7]2[CH2:8][CH2:9][CH:10]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH:11]([OH:14])[CH2:12][CH2:13]2)[N:75]=1
Reactant: Cn1ncc(N)c1N1CCC(O)C(NC(=O)C(F)(F)F)CC1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1N1CCC(O)C(NC(=O)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.2 %

Procedure:
To a solution of N-(1-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-hydroxyazepan-4-yl)-2,2,2-trifluoroacetamide (504 mg, 1.57 mmol) in DCM (20 mL) was added DIPEA (1.65 mL, 9.42 mmol), PyBOP (1.17 mg, 2.20 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)-thiazole-4-carboxylic acid (559 mg, 1.57 mmol) and the mixture was stirred at room temperature for 18 hr. The mixture was diluted with DCM (100 mL) and washed with water (20 mL). The organic layer was separated, dried over MgSO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0 to 100% EtOAc/heptane) gave tert-butyl 2-(2,6-difluorophenyl)-4-(5-(4-hydroxy-5-(2,2,2-trifluoroacetamido)azepan-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as an off-white solid (240 mg, 23%). This solid (240 mg, 0.36 mmol) was stirred with HCl in 1,4-dioxane (4 M, 6 mL, 24 mmol) in MeOH (5 mL) at room temperature for 18 h. The solvent was removed under reduced pressure, basified with saturated NaHCO3, and extracted with ethyl acetate (3×). The combined organic layers were dried over MgSO4 and the solvent removed under reduced pressure and the residue purified by preparative HPLC to afford 333. LCMS (ES+) m/z 464 (M+1)
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.C(O)(=O)[CH2:10][C:11]([OH:13])=[O:12].O.Cl>N1CCCCC1.N1C=CC=CC=1>[Cl:1][C:2]1[S:6][C:5](/[CH:7]=[CH:10]/[C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)s1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)/C=C/c1ccc(Cl)s1
Yield: 81.7 %

Procedure:
The solution of 1 g (6.62 mmol) of 5-chloro-2-thiophenecarboxaldehyde and 1.38 g (13.23 mmol) of malonic acid in 0.07 ml of piperidine and 5 ml of pyridine is refluxed for 2 hours. The reaction solution is subsequently allowed to cool, then poured into 20 ml of water and acidified to pH 1 using 2N hydrochloric acid. The product which precipitates in the process is filtered off with suction and dried in a drying cabinet at 80° C., giving 1.02 g of (E)-3-(5-chlorothiophen-2-yl)acrylic acid as brown crystals, ESI 189. Analogously to Example 7.1, reaction between the compound of Example 7.2 and (E)-3-(5-chlorothiophen-2-yl)acrylic acid gives the compound N-[4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-1-[(E)-3-(5-chlorothiophen-2-yl)acryloyl]-4-hydroxypyrrolidine-2-carboxamide as colourless crystals, ESI 476, m.p. 151°.
Reaction SMILES: [C:1]1(C=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:13](O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1.Cl>N1C=CC=CC=1>[C:9]1([C:14](=[CH2:13])[C:15]([OH:17])=[O:16])[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cccc2ccccc12
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: C=C(C(=O)O)c1cccc2ccccc12
Temperature: 25 °C

Procedure:
1-Naphthyl acrylic acid was prepared by reaction of 1-naphthaldehyde and malonic acid. 1-Naphthaldehyde (46.8 g.), malonic acid (60.0 g.), pyridine (120 ml.), and piperidine (3 ml.) were charged into a 500 ml. round bottom flask and refluxed on a water bath for 4 hours. The reaction solution was cooled to room temperature and poured onto a mixture of 175 ml. concentrated hydrochloric acid and 300 g. of crushed ice. A white precipitate formed and the slurry was stirred until all the ice had melted. The precipitate was separated from the slurry by filtration and washed with one portion of 10% hydrochloric acid (75 ml.) and two portions of deionized water (each 75 ml.). The 1-naphthyl acrylic acid precipitate was fully dewatered by continued application of suction on the filter, and then vacuum dried at 40°C. for 24 hours.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH2:11][S:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[CH:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1.C(Cl)CCl>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:10][CH2:11][S:12][CH3:13])[C:14]([O:16][CH:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1)=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCC(O)CC1
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CSCCC(NC(=O)OC(C)(C)C)C(=O)OC1CCN(C)CC1
Yield: 56 %

Procedure:
A solution of tert-butoxycarbonyl-L-methionine (5 g; 20 mmol), 4-hydroxy-1-methylpiperidine (3.3 g; 20 mmol); DMAP (2.44 g; 20 mmol) and EDC (4.6 g; 2.4 mmol) in dichloromethane (200 ml) was stirred at ambient temperature overnight. The mixture was extracted with dichloromethane. The organic phase was evaporated and purified by flash chromatography, eluting with dichloromethane/ethanol (97/3) to give 1-methylpiperidin-4-yl 2-tert-butoxycarbonylamino-4-methylsulfanylbutyrate. Yield 56%.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].[CH2:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][C:13]=1[C:22]1[NH:27][C:26](=[O:28])[N:25]2[C:29]([CH3:35])=[N:30][C:31]([CH2:32][CH2:33][CH3:34])=[C:24]2[N:23]=1)[CH3:10]>ClCCl>[CH2:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:6]2[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5]2)(=[O:20])=[O:19])=[CH:14][C:13]=1[C:22]1[NH:27][C:26](=[O:28])[N:25]2[C:29]([CH3:35])=[N:30][C:31]([CH2:32][CH2:33][CH3:34])=[C:24]2[N:23]=1)[CH3:10]
Reactant: CCN1CCNCC1
Reactant: CCCc1nc(C)n2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nc12
Solvent: ClCCl
Product: CCCc1nc(C)n2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(CC)CC4)ccc3OCC)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
83 mg (0.73 mmol) of N-ethylpiperazine are added to a solution of 100 mg (0.24 mmol) of 4-ethoxy-3-(6-methyl-4-oxo-8-propyl-3,4-dihydro-imidazo[1,5-α]-[1,3,5]triazin-2-yl)-benzenesulfonyl chloride (example VI) in 5 ml of dichloromethane and the reaction mixture is stirred at room temperature for 2 hours. After chromatographic purification (dichloromethane/methanol=95:5), 104 mg (87%) of 2-[2-ethoxy-5-(4-ethyl-piperazine-1-sulfonyl)-phenyl]-6-methyl-8-propyl-3H-imidazo[1,5-α][1,3,5]triazin-4-one are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:27])=[C:12]3[CH:18]=[C:17]([C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[O:20])[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[C:30](=O)([O-])[O-].[K+].[K+].IC.O>CN(C=O)C>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:27])[C:12]3[CH:18]=[C:17]([C:19]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)=[O:20])[S:16][C:13]=3[N:14]([CH3:30])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(C(=O)N3CCOCC3)cc2c1O
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C(=O)N3CCOCC3)sc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
To a solution of N-(4-chlorobenzyl)-4-hydroxy-2-(4-morpholinylcarbonyl)thieno[2,3-b]pyridine-5-carboxamide (0.527 g) from Example No. 47 in DMF (10 mL) is added potassium carbonate (0.337 g) followed by iodomethane (0.11 mL). The reaction mixture is stirred at room temperature for 1 h. The reaction mixture is then poured into water (25 mL). The resulting off-white solid is filtered off and recrystallized from acetonitrile to yield 0.448 g (82%) of the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[C:21]([N+:22]([O-])=O)=[CH:20][NH:19][N:18]=2)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.CN(C=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[C:21]([NH2:22])=[CH:20][NH:19][N:18]=2)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2n[nH]cc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2n[nH]cc2N)CC1
Yield: 73.8 %

Procedure:
4-[(4-Nitro-1H-pyrazole-3-carbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (13.05 g) was dissolved in ethanol/DMF (300 ml/75 ml), treated with 10% palladium on carbon (500 mg) then hydrogenated at room temperature and pressure overnight. The catalyst was removed by filtration through Celite and the filtrate evaporated and re-evaporated with toluene. The crude material was purified by flash column chromatography eluting with EtOAc then 2% MeOH I EtOAc then 5% MeOH/EtOAc. Product containing fractions were combined and evaporated to give 8.78 g of 4-[(4-amino-1H-pyrazole-3-carbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a brown foam. (LC/MS: Rt 1.91, [M+H]+ 310).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH3:11][N:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1.N1CCCC1>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:15]1[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH:14]=1
Reactant: CN1CCC(=O)CC1
Reactant: Brc1ccc2[nH]ccc2c1
Solvent: C1CCNC1
Solvent: CCO
Product: CN1CC=C(c2c[nH]c3ccc(Br)cc23)CC1
Temperature: 25 °C
Yield: 75.6 %

Procedure:
5-Bromo-1H-indole (4.31 g, 22 mmol), 1-methyl-4-piperidone (2.46 mL, 20 mmol) and pyrrolidine (17 mL, 200 mmol) were mixed in ethanol (30 mL) and refluxed for 72 hours. The mixture was cooled to room temperature and the resulting solid, collected by filtration, washed with methanol and dried to provide the title compound as a white solid (4.40 g, 76%). mp>230° C., dec.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].C1O[CH2:23][CH2:22]OCCOCCOCCOCCOC1.O.[C:26]1([CH3:32])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[OH:5][CH2:4][CH2:3][CH2:2][CH2:1][O:6][CH2:32][C:26]1[CH:31]=[CH:30][C:29]([CH:22]=[CH2:23])=[CH:28][CH:27]=1
Reactant: OCCCCO
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: Cc1ccccc1
Solvent: O
Product: C=Cc1ccc(COCCCCO)cc1

Procedure:
1,4-Butanediol (50.00 g) was dissolved in dry toluene (60 ml), para-choloromethylstyrene (15.62 g; 0.1 mol) was then added with stirring. A catalytic quantity of 18-crown-6 (0.3 g) was then added. The flask was stoppered, stirred at room temperature for 18 hours and for a further 4 hours at 45-60°. The resulting solution was then poured in to water (500 ml) and extracted with dichloromethane (3×75 ml). The combined extracts were dried (MgSO4) and evaporated (20°/21 mm) to give a yellow oil, which was distilled to give a yellow oil (14.33 g; 69.6%).b.pt. 152-157°/1 mbar.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH2:8])=[O:6].CN1CCCC1=O.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[C:19]([NH:8][NH:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NNC(=O)c1cccc(Br)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(NNC(=O)c1cccc(Br)c1)c1ccccc1
Yield: 96 %

Procedure:
Subsequently, 5.0 g (23 mmol) of 3-bromobenzohydrazine obtained in (i) above was put in a 300-mL three-neck flask, 10 mL of N-methyl-2-pyrrolidone was added therein, and the mixture was stirred. Thereafter, a mixed solution of 10 mL of N-methyl-2-pyrrolidone and 3.2 mL (28 mmol) of benzoyl chloride was dripped to the above mixture through a 50-mL dropping funnel. After the dripping, the mixture was heated and stirred at 80° C. for 3 hours so as to be reacted. After the reaction, water was added to the reaction solution, and a solid was precipitated. The precipitated solid was collected by suction filtration to obtain another solid. The obtained solid was washed with approximately 1 L of water and collected by suction filtration. The collected solid was washed with methanol and collected by suction filtration; thus, 7.1 g of a white solid that was an object was obtained (yield: 96%).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-])=O)[CH:24]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[H][H].CCCCCC.C(OCC)(=O)C>CO.[Pd]>[NH2:29][C:25]1[CH:24]=[C:23]([NH:22][C:3]2[C:2]([F:1])=[CH:7][N:6]=[C:5]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:11][CH:10]=3)[N:4]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: COCCOCOc1ccc(Nc2ncc(F)c(Nc3cccc([N+](=O)[O-])c3)n2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COCCOCOc1ccc(Nc2ncc(F)c(Nc3cccc(N)c3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
To a suspension of Pd/C (0.2 g) in methanol (20 mL), 5-fluoro-N2-(4-((2-methoxyethoxy)methoxy)phenyl)-N4-(3-nitrophenyl)pyrimidine-2,4-diamine (0.40 g) was added under nitrogen atmosphere into the autoclave at room temperature. Hydrogen pressure (70 psi) was applied and the reaction mixture was stirred overnight at room temperature. The reaction was monitored on TLC using hexane:ethyl acetate (4:6) as mobile phase. After completion, the reaction mixture was filtered using Celite and the filter cake was washed with methanol. The combined filtrate was concentrated under reduced pressure at 40° C. to give 0.3 g of N4-(3-aminophenyl)-5-fluoro-N2-(4-((2-methoxyethoxy)methoxy)phenyl)pyrimidine-2,4-diamine as a solid.