Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1CCNCC1)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].C(C1C=CC(C(Cl)=O)=CC=1)CCC.[OH-].[Na+].[CH2:35]([C:39]1[CH:52]=[CH:51][C:42]([C:43]([N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)=O)=[CH:41][CH:40]=1)[CH2:36][CH2:37][CH3:38].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(=O)([O-])[O-].[Na+].[Na+]>O.O1CCCC1>[CH2:35]([C:39]1[CH:52]=[CH:51][C:42]([CH2:43][N:45]2[CH2:46][CH2:47][NH:48][CH2:49][CH2:50]2)=[CH:41][CH:40]=1)[CH2:36][CH2:37][CH3:38]
Reactant: CCCCc1ccc(C(=O)N2CCNCC2)cc1
Agent: CCCCc1ccc(C(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Al+3]
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1ccc(CN2CCNCC2)cc1
Reaction time: 18 h

Procedure:
A 26.4 g. portion of 1-benzylpiperazine, 25 g. of potassium carbonate and 200 ml. of dry tetrahydrofuran were stirred and cooled. A 31.5 g. portion of 4-n-butyl benzoyl chloride and 100 ml. of tetrahydrofuran were added and the mixture stirred 18 hours. A 100 ml. portion of 1 N sodium hydroxide was added and the mixture stirred for one hour. The phases were separated. The aqueous phase was extracted with 100 ml. of chloroform. The extract was combined with the tetrahydrofuran layer, dried and evaporated to an oil. This oil was suspended in a mixture of 100 ml. of glacial acetic acid and 10 ml. of water, 4 g. of 10% palladium on carbon catalyst were added and the mixture reduced. The reaction mixture was filtered. The filtrate was washed with ethanol, evaporated to a syrup and triturated with ether, giving 17.5 g. of colorless crystals. A 17.0 g. portion of these crystals were dissolved in water and 10 N sodium hydroxide added to a pH>10. This mixture was extracted with two 200 ml. portions of chloroform. The extracts were combined, dried and evaporated to give 12.3 g. of 1-(p-n-butylbenzoyl)-piperazine as a viscous syrup. This was dissolved in 250 ml. of dry tetrahydrofuran, 2 g. of lithium aluminum hydride was added, and the mixture was stirred and refluxed for 20 hours. The reaction mixture was cooled, treated with aqueous sodium carbonate solution, and the tetrahydrofuran was removed in vacuo. The aqueous solution was extracted with chloroform followed by concentration of the extract in vacuo giving the title compound as a colorless oil, b.p. 127°-130° C./0.05 mm.
Reaction SMILES: [CH2:1]([C:11]1[CH:16]=[C:15]([O:17][CH3:18])[N:14]=[C:13]([N:19]([CH3:21])[CH3:20])[N:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Br:22]N1C(=O)CCC1=O>C(#N)C>[Br:22][C:16]1[C:11]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[N:12][C:13]([N:19]([CH3:20])[CH3:21])=[N:14][C:15]=1[O:17][CH3:18]
Reactant: CCCCCCCCCCc1cc(OC)nc(N(C)C)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CCCCCCCCCCc1nc(N(C)C)nc(OC)c1Br
Temperature: 23 °C
Reaction time: 5 h

Procedure:
To a stirred solution containing 1.22 g (4.16 mmol) of 4-decyl-6-methoxy-N,N-dimethylpyrimidin-2-amine in 20 mL of acetonitrile were added 808 mg (4.54 mmol) of N-bromosuccinimide. The reaction mixture was stirred at 23° C. and protected from light for 5 h. The reaction mixture was concentrated under diminished pressure and the residue was dissolved into 100 mL of ethyl acetate. The organic solution was washed with a 100-mL portion of brine, dried (MgSO4) and concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column. Elution with 9:1 hexanes-ethyl ether afforded the expected product as white solid: yield 1.27 g (82%); mp: 45-46° C.; silica gel TLC Rf 0.75 (9:1 hexanes-ethyl ether); 1H-NMR (CDCl3) δ 0.86 (t, 3H, J=6.8 Hz), 1.33-1.24 (br m, 14H), 1.65 (quint, 2H, J=7.2 Hz), 2.68 (dd, 2H, J=7.6, 7.6 Hz), 3.12 (s, 6H) and 3.92 (s, 3H); 13C NMR (CDCl3) δ 14.09, 22.67, 27.62, 29.32, 29.37, 29.45, 29.57, 29.60, 31.89, 36.70, 36.94, 36.94, 53.97, 91.17, 160.07, 165.06 and 169.05.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:20]([O:22]CC)=[O:21])[C:7]3[C:12]([CH3:13])=[N:11][N:10]([C:14]4[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=4)[C:8]=3[N:9]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([C:4]2[CH:5]=[C:6]([C:20]([OH:22])=[O:21])[C:7]3[C:12]([CH3:13])=[N:11][N:10]([C:14]4[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=4)[C:8]=3[N:9]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cc(C2CC2)nc2c1c(C)nn2-c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nn(-c2ccncc2)c2nc(C3CC3)cc(C(=O)O)c12
Reaction time: 1 h

Procedure:
The title compound was prepared in the same manner as described for intermediate 46 using ethyl 6-cyclopropyl-1-(4-pyridinyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (240 mg, 0.796 mmol), sodium hydroxide (4 mL, 4.00 mmol), and ethanol (30 mL), wherein the stir time was 1 h. The final product was collected as 0.210 g (89%). LCMS E-S (M+H)=295.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH3:27])=[C:11]([CH:13]3[C:17](=[O:18])/[C:16](=[CH:19]/[CH:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)/[CH2:15][C:14]3=[O:26])[N:12]=2)=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH3:27])=[C:11]([CH:13]3[C:17](=[O:18])[CH:16]([CH2:19][CH:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH2:15][C:14]3=[O:26])[N:12]=2)=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: Cc1sc(-c2ccc(Cl)cc2)nc1C1C(=O)C/C(=C\C2CCOCC2)C1=O
Agent: [Pd]
Solvent: CCO
Product: Cc1sc(-c2ccc(Cl)cc2)nc1C1C(=O)CC(CC2CCOCC2)C1=O
Yield: 23.2 %

Procedure:
To a solution of 2-[2-(4-Chloro-phenyl)-5-methyl-thiazol-4-yl]-4-[1-(tetrahydro-pyran-4-yl)-meth-(E)-ylidene]-cyclopentane-1,3-dione (130 mg, 0.32 mmol) in ethanol (2 ml) was added 5% palladium on carbon (13 mg), and the reaction stirred under an atmosphere hydrogen at a pressure of 2 bar for 4 hours. The crude reaction mixture was filtered through a pad of Celite and purified by preparative mass-directed HPLC to give 2-[2-(4-Chloro-phenyl)-5-methyl-thiazol-4-yl]-4-(tetrahydro-pyran-4-ylmethyl)-cyclopentane-1,3-dione (30 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[C:20](=[O:21])[C:19]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[C:7]=3[N:8]([CH3:13])[C:9]2=[O:12])=[CH:4][CH:3]=1.ClC(=O)[C:24]([O:26]C)=[O:25].CN1C2C3C=CC=CC=3C(=O)C=2C2C(=CC(NC(=O)C(OC)=O)=CC=2)C1=O.[OH-].[Na+]>O1CCCC1.O.C(O)C.C(N(CC)CC)C>[CH3:13][N:8]1[C:7]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:20](=[O:21])[C:6]=2[C:5]2[C:10](=[CH:11][C:2]([NH:1][C:24](=[O:25])[OH:26])=[CH:3][CH:4]=2)[C:9]1=[O:12]
Reactant: COC(=O)C(=O)Cl
Reactant: Cn1c2c(c3ccc(N)cc3c1=O)C(=O)c1ccccc1-2
Agent: COC(=O)C(=O)Nc1ccc2c3c(n(C)c(=O)c2c1)-c1ccccc1C3=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c2c(c3ccc(NC(=O)O)cc3c1=O)C(=O)c1ccccc1-2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-Amino-6-methyl-5H-indeno[1,2-c]isoquinoline-5,11(6H)-dione (3, 201 mg, 0.72 mmol) was dissolved in tetrahydrofuran (30 mL) and cooled to 0° C. Methyl oxalyl chloride (4, 0.1 mL, 1.16 mmol) and triethylamine (0.2 mL) were added dropwise and the reaction mixture was stirred for 2 h at 0° C. The reaction mixture was diluted with water (100 mL) and extracted with chloroform (4×50 mL). The solvent was removed under vacuum and the compound passed through a short silica gel column chromatography, eluting with chloroform-methanol, 9:1. The impure solid, compound 9, was dissolved in a solution of sodium hydroxide (0.1 g, 2.5 mmol) in ethanol (50 mL) and water (1 mL) and the reaction mixture was stirred overnight at room temperature. The solvent was removed under vacuum and the residue purified by silica gel column chromatography, eluting with chloroform-methanol-acetic acid, 90:9:1. Compound 14 was obtained as a reddish-brown solid (103 mg, 44.7%, after 2 steps): mp 360° C. (dec). IR (Film) 3325, 2928, 1692, 1657, 1600, 1580, 1533, 1435, 1319, 1197, 903, 701 cm−1; 1H NMR (300 MHz, DMSO-d6) δ 10.9 (s, 1H), 8.70 (s, 1H), 8.35 (d, J=8.2 Hz, 1H), 8.02 (s, 1H), 7.90 (br s, 1H), 7.45 (m, 3H), 3.89 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 190.1, 162.4, 162.2, 157.9, 156.3, 137.5, 136.9, 134.6, 134.0, 131.4, 128.4, 126.9, 124.4, 123.5, 123.4, 122.8, 118.5, 106.9; ESIMS m/z (rel intensity) 347 [(M-H+)−]; negative ion; HRESIMS calcd for C19H12N2O5 347.0668 [(M-H+)−]. found 347.0664 [(M-H+)−]; HPLC purity: 95.2% (MeOH—H2O, 85:15), 95.7% (MeOH—H2O, 75:25).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[N:8][O:10][N+:9]=2[O-:11])[N:7]=1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Solvent: CC(C)=O
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Product: [O-][n+]1onc2nc(Cl)ccc21
Temperature: 80 °C
Reaction time: 6 h

Procedure:
6-Chloro-3-nitropyridin-2-amine (1.25 g, 7.06 mmol) and iodobenzene diacetate (5.80 g, 17.65 mmol) were taken-up in acetone (70.6 ml) and stirred at 80° C. for 6 hours. The reaction was then concentrated directly, and the resulting crude product was purified by silica gel chromatography (0-100% ethyl acetate/hexanes) to afford 5-chloro[1,2,5]oxadiazolo[3,4-b]pyridine 1-oxide. LRMS (APCI) calc'd for (C5H3ClN3O2) [M+H]+, 172. found 172.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[NH2:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][N:23]=1)[C:18]([NH2:20])=[O:19].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CO>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([NH:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][N:23]=1)[C:18]([NH2:20])=[O:19])=[O:8]
Reactant: O=C(O)COc1ccc(Cl)cc1Cl
Reactant: NC(=O)c1ccnc(N)c1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CO
Product: NC(=O)c1ccnc(NC(=O)COc2ccc(Cl)cc2Cl)c1
Temperature: 25 °C
Yield: 76.7 %

Procedure:
To solution of (2,4-dichloro-phenoxy)-acetic acid (51 mg, 0.23 mmol), 2-amino isonicotinamide (47.66 mg, 0.34 mmol) and DMAP (56.6 mg, 0.46 mmol) in DMF 4 ml was added PyBOP (236 mg, 0.46 mmol), and stirred room temperature. Reaction mixture was poured onto ice cold water, diluted by methanol/MC mixture (10%). The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The residue was purified by PLC (EtoAC:Hexane:MeOH=3:6:1-2:4:1) to afford 2-[2-(2,4-dichloro-phenoxy)-acetylamino]-isonicotinamide as a colorless solid (0.06 g, 77% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:55][CH3:56])=[C:6]([CH:54]=1)[CH2:7][C@@H:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][C@@H:19]([C:23]2[CH:35]=[CH:34][C:26]([C:27]([O:29]C(C)(C)C)=[O:28])=[C:25]([N+:36]([O-:38])=[O:37])[CH:24]=2)[CH2:20][CH2:21][CH3:22])=[O:17])[CH2:12][C:11](=[N:39][OH:40])[N:10](CC2C(OC)=CC(OC)=CC=2OC)[CH2:9]1.Cl>C(OCC)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:55][CH3:56])=[C:6]([CH:54]=1)[CH2:7][C@@H:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][C@@H:19]([C:23]2[CH:35]=[CH:34][C:26]([C:27]([OH:29])=[O:28])=[C:25]([N+:36]([O-:38])=[O:37])[CH:24]=2)[CH2:20][CH2:21][CH3:22])=[O:17])[CH2:12][C:11](=[N:39][OH:40])[NH:10][CH2:9]1
Reactant: CCC[C@@H](NC(=O)N1CC(=NO)N(Cc2c(OC)cc(OC)cc2OC)C[C@H](Cc2cc(Cl)ccc2OC)C1=O)c1ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCC[C@@H](NC(=O)N1CC(=NO)NC[C@H](Cc2cc(Cl)ccc2OC)C1=O)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
To the compound 97a crude product obtained at Step (1) (10.7 g), a 4M hydrochloric acid in ethyl acetate solution (100 ml) was added, and the mixture was stirred at room temperature for 5.5 hours. The reaction mixture was concentrated until the crystals were precipitated, and the precipitated crystals were collected by filtration to obtain the title compound (1.74 g).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:29]=[CH:28][C:8]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH:19]=[C:20]4[S:24][C:23](SC)=[N:22][C:21]4=[O:27])=[CH:16][CH:17]=3)[CH:12]=[N:11]2)=[C:7]([C:30]([F:33])([F:32])[F:31])[CH:6]=1)(=[O:4])=[O:3].[N:34]1([CH2:40][CH2:41][OH:42])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[OH:42][CH2:41][CH2:40][N:34]1[CH2:39][CH2:38][N:37]([C:23]2[S:24][C:20](=[CH:19][C:15]3[CH:14]=[C:13]4[C:18](=[CH:17][CH:16]=3)[N:10]([CH2:9][C:8]3[CH:28]=[CH:29][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][C:7]=3[C:30]([F:33])([F:31])[F:32])[N:11]=[CH:12]4)[C:21](=[O:27])[N:22]=2)[CH2:36][CH2:35]1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(S(C)(=O)=O)cc3C(F)(F)F)c2)S1
Reactant: OCCN1CCNCC1
Product: CS(=O)(=O)c1ccc(Cn2ncc3cc(C=C4SC(N5CCN(CCO)CC5)=NC4=O)ccc32)c(C(F)(F)F)c1

Procedure:
2-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-5-[1-(4-methanesulfonyl-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one was prepared from 5-[1-(4-methanesulfonyl-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 2-piperazin-1-yl-ethanol following General Procedure C.
Reaction SMILES: CCOCC.O[CH:7]([CH2:17][C:18]([CH2:21][Si](C)(C)C)=[C:19]=[CH2:20])[CH2:8][CH:9]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:16].[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.O>CCOC(C)=O>[CH2:21]=[C:18]1[C:19](=[CH2:20])[C:10]23[O:16][CH:7]([CH2:8][CH:9]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[CH2:17]1
Reactant: C=C=C(CC(O)CC1CCCCCC1=O)C[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCOCC
Product: C=C1CC2CC3CCCCCC3(O2)C1=C
Temperature: -78 °C
Yield: 90.2 %

Procedure:
1.30 mL of ether was added to 2-(2-hydroxy-4-trimethylsilanylmethyl-hexa-4,5-dienyl)-cycloheptanone (95 mg, 0.32 mmol) under nitrogen atmosphere. While stirring at −78° C., TMSOTf (58.4 μL, 0.32 mmol) was added. While stirring the reaction mixture, the reaction temperature was slowly increased to room temperature for 3 hours. The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was completed, H2O was added. After stirring for about 5 minutes, the reaction mixture was diluted with EtOAc and washed with water and saturated brine. The organic layer was separated from the reaction mixture and dried with anhydrous MgSO4. The solvent was removed under reduced pressure and the remaining material was purified with column chromatography (EtOAc/n-hexane=1/6) to obtain 59 mg of the product (90%).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[C:18]([O:19][CH2:20][C:21]#[CH:22])=[CH:17][C:16]([C:23]2[C:27]([CH3:28])=[C:26]([S:29][CH3:30])[N:25]([CH3:31])[N:24]=2)=[C:15]([F:32])[CH:14]=1>ClCCl>[Cl:12][C:13]1[C:18]([O:19][CH2:20][C:21]#[CH:22])=[CH:17][C:16]([C:23]2[C:27]([CH3:28])=[C:26]([S:29]([CH3:30])=[O:9])[N:25]([CH3:31])[N:24]=2)=[C:15]([F:32])[CH:14]=1
Reactant: C#CCOc1cc(-c2nn(C)c(SC)c2C)c(F)cc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: C#CCOc1cc(-c2nn(C)c(S(C)=O)c2C)c(F)cc1Cl
Temperature: 22 °C
Reaction time: 8 h

Procedure:
A solution of 1.57 g (0.005 mol) of 50-60% 3-chloroperbenzoic acid in 30 ml of dichloromethane is added dropwise at 0-5° C. to a solution of 1.7 g (0.005 mol) of 3-(4-chloro-2-fluoro-5-propargyloxyphenyl)-4-methyl-5-(methylthio)-1-methyl-[1H]-pyrazole (Example P12) in 20 ml of dichloromethane. After being stirred overnight at 22° C., the reaction mixture is washed with a dilute sodium hydrogen carbonate solution, then with water and concentrated by evaporation, and the resulting residue is recrystallised in petroleum ether/diethyl ether. 1.5 g (88.2% of the theoretical yield) of the desired compound are isolated in the form of crystals having a melting point of 93-96° C.
Reaction SMILES: Br.Br[CH2:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)=[N:8][C:7]=1[CH3:18])=O.C(N(CC)CC)C.[C:26]([CH2:28][C:29]([NH2:31])=[S:30])#[N:27]>CCO>[CH3:18][C:7]1[N:8]=[C:9]([NH:11][C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[S:10][C:6]=1[C:4]1[N:31]=[C:29]([CH2:28][C:26]#[N:27])[S:30][CH:3]=1
Reactant: N#CCC(N)=S
Reactant: Cc1nc(Nc2cnccn2)sc1C(=O)CBr
Agent: Br
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1nc(Nc2cnccn2)sc1-c1csc(CC#N)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-bromo- 1-[4-methyl-2-(pyrazin-2-ylamino)-1,3 -thiazol-5-yl]lethanone, (Intermediate 3) (75 mg; 0.19 mmol; 1 eq.) in EtOH (2 ml), is added triethylamine (66 μl; 0.48 mmol; 2.50 eq.) and 2-cyanothioacetamide (19.0 mg; 0.19 mmol; 1 eq.). The mixture is stirred overnight at rt. The reaction mixture is filtered and rinsed -with ethanol affording Compound (53) as brown solid (35.4 mg; 59%). 1H NMR (DMSO-d6) δ2.49 (s, 3H), 4.62 (s, 2H), 7.67 (s, 1H), 8.13 (m, 1H), 8.36 (m, 1H), 8.44 (m, 1H), 11.79 (br s, 1H). M31 (ESI): 312.88; M+(ESI): 314.95. HPLC (method A), Rt: 2.47 min (purity: 93.5%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]2[C:15](=O)[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][OH:18]>C(O)C.O>[CH2:1]([N:8]1[CH2:14][CH:13]2[C:15](=[N:17][OH:18])[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C1C2CCC1CN(Cc1ccccc1)C2
Solvent: O
Solvent: CCO
Product: ON=C1C2CCC1CN(Cc1ccccc1)C2
Yield: 68 %

Procedure:
To a solution of the title compound of Step A (6.6 g, 30.7 mmol) in ethanol (80 ml) was added hydroxylamine (3.6 ml of a 50% Wt solution in water, 42.9 mmol) and the resulting mixture heated at reflux for 4 h. The cooled reaction mixture was evaporated and the residue triturated with hexanes, filtered and dried to afford the title compound 4.8 g (68%) as a white solid. 1H NMR (CDCl3): 1.76 (m, 2H), 1.97 (m, 2H), 2.40 (d, J 10.1 Hz, 2H), 2.56 (s, 1H), 2.84 (dd, J 10.3 and 3.7 Hz, 1H), 2.91 (dd, J 10.1 and 3.0 Hz, 1H), 3.35 (s, 1H), 3.57 (s, 2H), 7.29 (m, 1H), 7.35 (m, 4H), 8.49 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:8][C:9]=1[NH2:10])=[O:4].CO[CH:20]([N:23]([CH3:25])[CH3:24])OC>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:8][C:9]=1[N:10]=[CH:20][N:23]([CH3:25])[CH3:24])=[O:4]
Reactant: COC(=O)c1sc(C(=O)C2CCCC2)cc1N
Reactant: COC(OC)N(C)C
Product: COC(=O)c1sc(C(=O)C2CCCC2)cc1N=CN(C)C

Procedure:
3-Amino-5-cyclopentanecarbonylthiophene-2-carboxylic acid methyl ester and dimethoxymethyldimethylamine were reacted by method B. The product with the molecular weight of 308.40 (C15H20N2O3S) was obtained in this way; MS (ESI): 309 (M+H+).
Reaction SMILES: [Mg].Cl[CH:3]1[CH2:12][N:11]2[CH:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)[CH2:5][CH2:4]1.[Cl:13][C:14]1[CH:27]=[CH:26][C:25]2[S:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:28])[C:16]=2[CH:15]=1.[Cl-].[NH4+]>C(Br)C.O1CCCC1>[Cl:13][C:14]1[CH:27]=[CH:26][C:25]2[S:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH:3]3[CH2:12][N:11]4[CH:6]([CH2:7][CH2:8][CH2:9][CH2:10]4)[CH2:5][CH2:4]3)([OH:28])[C:16]=2[CH:15]=1
Reactant: ClC1CCC2CCCCN2C1
Reactant: O=c1c2ccccc2sc2ccc(Cl)cc12
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCBr
Product: OC1(C2CCC3CCCCN3C2)c2ccccc2Sc2ccc(Cl)cc21
Temperature: 0 °C

Procedure:
Several drops of ethyl bromide were added to a stirred suspension of 1.29 g. (0.054 g.-atom) of magnesium turnings in 5 ml. of tetrahydrofuran under a nitrogen atmosphere. After the reaction began 9.3 g. (0.054 mole) of 3-chloroquinolizidine in 100 ml. of tetrahydrofuran was added. After the addition was completed the mixture was stirred and refluxed for one hour and cooled to 0° C. To the chilled suspension of the Grignard reagent was added a solution of 12.55 g. (0.051 mole) of 2-chloro-9-thioxanthone in 300 ml. of tetrahydrofuran. The solution was stirred at 24° C. for two hours, poured into aqueous ammonium chloride and extracted with ether. The extracts were washed with water, dried and evaporated to give 2-chloro-9-(3-quinolizidinyl)-9-hydroxythioxanthene.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[NH:5][C:4](=[O:8])[NH:3]1.[Na].[CH3:10][O:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([CH2:19]Cl)=[CH:15][CH:14]=1>CS(C)=O>[CH3:1][N:2]1[C:6](=[O:7])[N:5]([CH2:19][C:16]2[CH:17]=[CH:18][C:13]([C:12]([O:11][CH3:10])=[O:21])=[CH:14][CH:15]=2)[C:4](=[O:8])[NH:3]1
Reactant: COC(=O)c1ccc(CCl)cc1
Reactant: Cn1[nH]c(=O)[nH]c1=O
Agent: [Na]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(Cn2c(=O)[nH]n(C)c2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
To a solution of 1-methyl-[1,2,4]triazolidine-3,5-dione (1.886 g, 0.0164 mol) and sodium hyhride (200 mg) in DMSO (5 mL) was added 4-chloromethyl-benzoic acid methyl ester (1.0 g, 0.0054 mol). The mixture was stirred at RT for overnight, quenched with H2O (100 mL), and extracted by CH2Cl2. The organic layer was washed with H2O, dried (Na2SO4) and concentrated in vacuo to yield methyl 4-((1-methyl-3,5-dioxo-1,2,4-triazolidin4-yl)methyl)benzoate (1.02 g, 72%). 1H NMR (CDCl3): 7.93 (d, J=8.4 Hz, 2H), 7.27 (d, J=8.4 Hz, 2H), 4.68 (s, 2H), 3.83 (s, 3H), 3.27 (s, 3H). MS (ESI) m/e: 264 (M++1)
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([OH:9])=O.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][CH:43]=1)[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([N:32]=[C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:34]=2)[CH:31]=1>CN(C)C=O.CN(C)C(=O)C>[CH:38]1([C:36]([NH:35][C:33]2[N:34]=[C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]4[CH:23]=[C:22]([NH:21][C:7]([C:6]5[S:5][CH:4]=[N:3][C:2]=5[CH3:1])=[O:9])[CH:43]=[CH:42][CH:41]=4)=[CH:31][N:30]3[N:32]=2)=[O:37])[CH2:39][CH2:40]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Reactant: Cc1ncsc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: Cc1ncsc1C(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Yield: 61 %

Procedure:
In the same manner as in Example 18-4 and using 4-methyl-1,3-thiazole-5-carboxylic acid (531 mg, 3.70 mmol), tetrahydrofuran (10 mL), oxalyl chloride (477 μL, 5.49 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (295 mg, 0.954 mmol), N,N-dimethylformamide (2 drops) and N,N-dimethylacetamide (10 mL) as starting materials, the title compound (253 mg, 61%) was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:20]3[CH2:25][CH2:24][N:23](C(OCC4C=CC=CC=4)=O)[CH2:22][CH2:21]3)=[N:9][C:10]=2[C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:5]=[CH:6][N:7]=1>Cl.O>[NH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:19]=[C:11]1[C:10]1[N:9]=[C:8]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=12
Reactant: Nc1nccn2c(C3CCN(C(=O)OCc4ccccc4)CC3)nc(-c3cc4ccccc4[nH]3)c12
Agent: Cl
Solvent: O
Product: Nc1nccn2c(C3CCNCC3)nc(-c3cc4ccccc4[nH]3)c12
Yield: 101.8 %

Procedure:
A solution of benzyl 4-[8-amino-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl]piperidine-1-carboxylate (3.61 g, 0.00774 mol) in conc. HCl (100 ml) was stirred at rt overnight. The mixture was then diluted with water (200 mL), washed with Et2O (2×30 mL) then the aqueous layer concentrated in vacuo yielding 2.62 g of desired product as the trihydrochloride salt. 1H NMR (400 MHz, MeOD): δ 2.19-2.32 (m, 4H), 3.26-3.30 (m, 2H), 3.53-3.36 (m, 2H), 3.70 (m, 1H), 7.06 (d, J=5.6 Hz, 1H), 7.10-7.14 (m, 1H), 7.23-7.26 (m, 2H), 7.50-7.52 (m, 1H), 7.67 (m, 1H), 7.93 (m, 1H). MS (ES+): m/z 333.27 [MH+].