Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.Cl[C:25]1[C:30]([Cl:31])=[CH:29][N:28]=[C:27]([NH2:32])[C:26]=1[N+:33]([O-:35])=[O:34]>CC(O)C>[Cl:31][C:30]1[C:25]([N:12]2[CH2:11][CH2:10][N:9]([CH2:1][CH2:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:14][CH2:13]2)=[C:26]([N+:33]([O-:35])=[O:34])[C:27]([NH2:32])=[N:28][CH:29]=1
Reactant: c1ccc(CCN2CCNCC2)cc1
Reactant: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Nc1ncc(Cl)c(N2CCN(CCc3ccccc3)CC2)c1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
1-Phenethylpiperazine (0.100 g, 0.52 mmol, 1.1 eq) was suspended in iPrOH (1 mL). DIPEA (0.13 mL, 0.79 mmol, 1.5 eq) was added followed by 4,5-dichloro-3-nitropyridin-2-amine (0.099 g, 0.48 mmol, 1 eq). The mixture was heated and stirred at 65° C. overnight. The mixture was cooled to room temperature and filtered. The bright yellow solid was washed with iPrOH (3×2 mL), Et2O (2×2 mL) and dried to give the title compound as a bright yellow solid (0.112 g, 64%); 1H-NMR (500 MHz, DMSO-d6): δ 2.53-2.63 (m, 6H), 2.71-2.78 (m, 2H), 3.06 (m, 4H, piperazine N(CH2)2), 6.95 (s, 2H, NH2), 7.15-7.21 (m, 1H), 7.22-7.31 (m, 4H), 8.06 (s, 1H, pyridine 6-H); LC (Method B)-MS (ESI, m/z): Rt=2.31 min—362/364 [(M+H)+, Cl isotopic pattern].
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:6][N:5]=[C:4]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)[N:3]=1.[NH:30]1[CH:34]=[CH:33][CH:32]=[N:31]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN1CCCC1=O.C(OCC)(=O)C>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:4]2[N:3]=[C:2]([N:30]3[CH:34]=[CH:33][CH:32]=[N:31]3)[C:7]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:6][N:5]=2)=[CH:23][CH:24]=1)#[N:29]
Reactant: c1cn[nH]c1
Reactant: CC(C)(C)OC(=O)NCCCC#Cc1cnc(Nc2ccc(C#N)cc2)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCCC#Cc1cnc(Nc2ccc(C#N)cc2)nc1-n1cccn1
Temperature: 60 °C
Reaction time: 3 h
Yield: 61.9 %

Procedure:
To a solution of tert-butyl (5-(4-chloro-2-((4-cyanophenyl)amino)pyrimidin-5-yl)-4-pentyn-1-yl)carbamate (T5, 30 mg) and pyrazole (7 mg) in N-methylpyrrolidone (1 mL), cesium carbonate (71 mg) was added at room temperature, and the mixture was stirred at 60° C. for 3 hours. The reaction mixture was cooled to room temperature, and then water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 90 to 40% hexane in ethyl acetate) to obtain tert-butyl (5-(2-((4-cyanophenyl)amino)-4-(1H-pyrazol-1-yl)pyrimidin-5-yl)-4-pentyn-1-yl)carbamate (T7, 20 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(O[C:41](=[O:47])[O:42][C:43](Cl)(Cl)Cl)Cl.[Cl:49][C:50]1[CH:60]=[CH:59][CH:58]=[CH:57][C:51]=1[O:52][CH2:53][CH2:54]CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:41](=[O:47])[O:42][CH2:43][CH2:54][CH2:53][O:52][C:51]2[CH:57]=[CH:58][CH:59]=[CH:60][C:50]=2[Cl:49])=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: OCCCOc1ccccc1Cl
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCCCOc4ccccc4Cl)cc3)c2cc1OC
Temperature: 25 °C
Yield: 73.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (61 mg) was added to toluene/triethylamine=10/1 (6 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (91 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-(2-chlorophenoxy)-1-propanol (57 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (77 mg, yield 69%).
Reaction SMILES: CO[C:3](=[C:14]([C:17]#[N:18])[C:15]#[N:16])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=[O:12])[CH:6]=1.[OH2:19].[NH2:20][NH2:21]>CCO>[N+:11]([C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[CH2:4][C:3]1[C:14]([C:15]#[N:16])=[C:17]([NH2:18])[NH:21][N:20]=1)([O-:12])=[O:19]
Reactant: NN
Reactant: COC(Cc1cccc([N+](=O)[O-])c1)=C(C#N)C#N
Reactant: O
Solvent: CCO
Product: N#Cc1c(Cc2cccc([N+](=O)[O-])c2)n[nH]c1N
Yield: 100 %

Procedure:
Reagent 2-(1-methoxy-2-(3-nitrophenyl)ethylidene)malononitrile (0.3 g; 1.3 mmol) was combined with hydrazine monohydrate (0.07 mL; 1.4 mmol; Sigma-Aldrich) in 5 mL EtOH for 1 hour at RT. The reaction was concentrated in vacuo to yield 3-(3-nitrobenzyl)-5-amino-1H-pyrazole-4-carbonitrile (0.3 g; 1.3 mmol; ESI-MS m/z [M+H]+ found 244.5, calculated 244.1, 1H NMR (400 MHz, DMSO): δ 11.77 (s, 1H), 8.09 (d, J=8 Hz, 1H), 8.08 (s, 1H), 7.69 (d, J=8 Hz, 1H), 7.60 (m, 1H), 6.33 (s, 2H), 3.96 (s, 2H)), which was subsequently combined with formamide (6 mL) and heated to 180° C. overnight. H20 was added to the cooled reaction and the precipitate was filtered and dried to yield 3-(3-nitrobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.26 g; 0.96 mmol; ESI-MS m/z [M+H]+ found 271.4, calculated 271.09; 1H NMR (400 MHz, DMSO): δ 8.18 (s, 1H), 8.10 (s, 1H), 8.06 (d, J=8 Hz, 1H), 7.69 (d, J=8 Hz, 1H), 7.58 (m, 1H), 7.22 (br, 2H), 4.51 (s, 2H)). The recovered intermediate (0.05 g; 0.18 mmol) was combined with bromocyclopentane (0.1 mL; 0.38 mmol), 0.125 g K2CO3, in 1 mL DMF and refluxed under argon for 2 hours. The reaction was filtered to remove solid K2CO3, and the filtrate was combined with brine and the organic product was extracted in CH2Cl2 to yield 3-(3-nitrobenzyl)-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (ESI-MS m/z [M+H]+ found 339.5, calculated 339.15; 1H NMR (400 MHz, CDCl3): δ 8.30 (s, 1H), 8.12 (m, 2H), 7.51 (m, 2H), 5.25 (pen, 8 Hz, 1H), 5.06 (br, 2H), 4.42 (s, 2H), 2.14 (m, 4H), 1.97 (m, 2H), 1.73 (m, 2H)). Reduction of this material was carried out as per Cmpd 1 to yield 3-(3-aminobenzyl)-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (ESI-MS m/z [M+H]+ found 309.5, calculated 309.17). The reduced precursor was coupled to 3-(trifluoromethyl)phenyl isocyanate and purified as described for Cmpd 1 to yield Cmpd 3 1-(3-((4-amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)methyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea (ESI-MS m/z [M+H]+ found 496.4, calculated 496.2; 1H NMR (400 MHz, DMSO): δ 9.22 (s, 1H), 8.93 (s, 1H), 8.34 (s, 1H), 8.06 (s, 1H), 7.50-7.60, (m, 2H), 7.43 (s, 1H), 7.18-7.22 (m, 3H), 6.90 (d, J=8 Hz, 1H), 5.20 (pentet, J=7 Hz, 1H), 4.40 (s, 2H), 1.98-2.13 (m, 4H), 1.85-1.95 (m, 2H), 1.62-1.73 (m, 2H); 13C NMR (400 MHz, DMSO): δ 24.76, 32.33, 33.48, 57.62, 98.34, 114.48, 117.01, 118.17, 118.46, 118.89, 122.13, 122.34, 122.66, 129.97 (q), 139.53, 140.11, 141.16, 145.37, 150.60, 152.32, 152.94, 154.38, 159.00 (q)).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:10]([CH3:12])[CH3:11])[C:7]([OH:9])=O)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:37]1[C:41]2([CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[CH2:40][CH:39]([C:47]([O:49][CH2:50][CH3:51])=[O:48])[NH:38]1.CCN(C(C)C)C(C)C>O.CN(C=O)C>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:10]([CH3:12])[CH3:11])[C:7]([N:38]1[C@H:39]([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:40][C:41]2([CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[CH2:37]1)=[O:9])=[O:4]
Reactant: CCOC(=O)C1CC2(CCOCC2)CN1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@@H]1CC2(CCOCC2)CN1C(=O)[C@@H](NC(=O)OC)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83.2 %

Procedure:
In a 50 ml round-bottomed flask, (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (813 mg, 4.64 mmol) was combined with DMF (10 ml) to give a colorless solution. HATU (1.76 g, 4.64 mmol) was added and stirred at room temperature for 10 min. Ethyl 8-oxa-2-azaspiro[4.5]decane-3-carboxylate (prepared according to the patent procedure described in WO 199808850) (900 mg, 4.22 mmol) and DIPEA (1.91 g, 2.58 ml, 14.8 mmol) were added and stirred overnight. It was diluted with H2O and extracted with EtOAc (2×100 ml). The organic layer was washed with brine and H2O, dried with MgSO4, filtered and concentrated in vacuo to afford (S)-ethyl 2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-8-oxa-2-azaspiro[4.5]decane-3-carboxylate as a viscous oil (1.3 g, 83.2%). ESI-LRMS m/e calcd for C18H30N2O6 [M+] 370. found 371 [M+H+].
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1/[CH:12]=[CH:13]/[NH:14][CH:15]=[O:16].[C:17](OC(=O)C)(=[O:19])[CH3:18]>N1C=CC=CC=1>[CH:15]([NH:14]/[CH:13]=[CH:12]/[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[O:1][C:17](=[O:19])[CH3:18])=[O:16]
Reactant: O=CN/C=C/c1c(O)ccc2ccccc12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2ccccc2c1/C=C/NC=O
Yield: 90 %

Procedure:
To a cooled solution of (E)-N-[2-(2-hydroxynaphth-1-yl) ethenyl] formamide (2133 mg, 10 mmol) in dry pyridine (5 ml) is added acetic anhydride (2042 mg, 20 mmol) and the mixture maintained at 0°-5° overnight. Thereupon the mixture is concentrated under vacuum, the residue dissolved in dichloromethane, the organic layer washed with water and then evaporated under reduced pressure. The crude product is crystallized from chloroform/methanol to yield pure title compound in 90% yield (2300 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([NH:13][NH2:14])=[O:12])[NH:8][C:5]2=[CH:6][N:7]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[C:45](O)(=[O:55])[C:46]1[CH:54]=[CH:53][C:52]2[O:51][CH2:50][O:49][C:48]=2[CH:47]=1>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([NH:13][NH:14][C:45]([C:46]3[CH:54]=[CH:53][C:52]4[O:51][CH2:50][O:49][C:48]=4[CH:47]=3)=[O:55])=[O:12])[NH:8][C:5]2=[CH:6][N:7]=1
Reactant: NNC(=O)c1cc2cc(Cl)ncc2[nH]1
Reactant: O=C(O)c1ccc2c(c1)OCO2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NNC(=O)c1cc2cc(Cl)ncc2[nH]1)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid hydrazide (Preparation 10—route 2, 0.100 g, 0.48 mmol) in DMF (4 mL) was added HOBt (0.064 g, 0.48 mmol), EDCI (0.110 g, 0.58 mmol), DIPEA (200 μL, 0.96 mmol) and piperonylic acid (0.079 g, 0.48 mmol). The reaction mixture was stirred at rt for 16 h. The reaction mixture was poured into water (75 mL) and extracted with ethyl acetate (2×150 mL). The combined organic extract was washed with saturated sodium chloride (75 mL), dried (MgSO4) and concentrated in vacuo to give a solid. The solid obtained was purified by recrystallisation from methanol to give the title compound. m/z (ES+)=359 [M+H]+; RT=2.92 min.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[Br:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[C:36](=O)[CH2:35][CH2:34]2>C1COCC1>[Br:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)/[C:36](=[CH:2]/[O:3][CH3:4])/[CH2:35][CH2:34]2
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCc2cc(Br)ccc21
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CO/C=C1\CCc2cc(Br)ccc21
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 93.2 %

Procedure:
To a suspension of (methoxymethyl)triphenylphosphonium chloride (39.7 g, 116 mmol) in THF (210 ml) at −20° C. was added dropwise 1M potassium t-butoxide (95 ml, 95 mmol) and the solution stirred at −20° C. for 20 min. To this solution was added dropwise a solution of 5-bromo-2,3-dihydro-1H-inden-1-one (10.0 g, 47.4 mmol) in THF (230 ml) and stirring was continued at −20° C. for 30 min then warmed to room temperature and stirred for 2 h. The solution was filtered through Celite and the filtrate was concentrated in vacuo to give crude product which was purified by chromatography on a silica gel cartridge eluting with CH2Cl2/hexane to give the title compound (10.56 g, 93%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([S:19][CH3:20])[C:3]=1[C:21](=[O:35])[C:22]1[CH:27]=[C:26]([CH2:28][CH2:29][C:30](OC)=[O:31])[CH:25]=[CH:24][C:23]=1[CH3:34].CC(C[AlH]CC(C)C)C>C1COCC1>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:15])[F:16])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([S:19][CH3:20])[C:3]=1[C:21](=[O:35])[C:22]1[CH:27]=[C:26]([CH2:28][CH2:29][CH2:30][OH:31])[CH:25]=[CH:24][C:23]=1[CH3:34]
Reactant: COC(=O)CCc1ccc(C)c(C(=O)c2c(SC)nn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)c2N)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: CSc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C(=O)c1cc(CCCO)ccc1C
Temperature: 25 °C

Procedure:
A solution of 0.530 g (1.0 mmol) of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(5- [β-methoxycarbonylethyl]-2-methylbenzoyl)-3-methylthiopyrazole in 10 mL of THF was cooled in an ice bath while 1.33 mL of a 1.5 M solution of DIBAL in THF was added. The reaction mixture was warmed to room temperature and then quenched with water. The product was extracted into EtOAc, dried and concentrated. The residues were chromatographed on silica gel using mixtures of hexane/EtOAc to elute the title product which was isolated as an amorphous foam, 174 mg (34%). Anal. Calcd. for C22H20O2N3SCl2F3 : C, 50.97; H, 3.88; N, 8.10. Found, C, 51.10; H, 3.96; N, 7.60.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Br:15][CH2:16][CH2:17]Br.O>CN(C=O)C>[Br:15][CH2:16][CH2:17][O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(I)cc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: BrCCOc1ccc(I)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 30.9 %

Procedure:
To a stirring solution of 4-iodophenol (25 g, 110 mmol) and K2CO3 (31 g, 220 mmol) in DMF (250 mL) was added 1,2-dibromoethane (5 mL, 55 mmol) over a period of 1 hr. The solution was heated at 50° C. and stirred overnight under Ar. In order to complete the reaction additional reagents were added: 1,2-dibromoethane (20 mL, 220 mmol) and K2CO3 (6 g, 43 mmol) and the mixture was heated at 50° C. an additional 12 hours under Ar. Water was added and the reaction mixture was extracted with dichloromethane, dried over Na2SO4, filtered and the solvent evaporated under reduced pressure. The crude mixture was purified by silica gel chromatography eluted with 10% ethyl acetate in hexanes to give the title compound as a white solid (5.5 g, 17 mmol).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)=O.[C:14]([NH2:22])(=[S:21])[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=1>C(O)C>[BrH:1].[N+:11]([C:7]1[CH:6]=[C:5]([C:3]2[N:22]=[C:14]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[S:21][CH:2]=2)[CH:10]=[CH:9][CH:8]=1)([O-:13])=[O:12]
Reactant: O=C(CBr)c1cccc([N+](=O)[O-])c1
Reactant: NC(=S)c1cccnc1
Solvent: CCO
Product: Br
Product: O=[N+]([O-])c1cccc(-c2csc(-c3cccnc3)n2)c1
Yield: 92 %

Procedure:
A mixture of 2-bromo-3'-nitroacetophenone (5 g, 20 mmol) and thionicotinamide (2.76 g, 20 mmol) in ethanol (25 ml) was heated to reflux for 1 h, during which time extensive precipitation occurred. Filtration and drying afforded the product as a yellow solid (6.7 g, 92%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]=[CH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2.[I-].[Na+].[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.[OH-].[Na+]>CN(C)C=O.CCOCC.C(N(CC)CC)C>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=1[N:27]1[CH2:28][CH2:29][N:30]([CH2:2][CH2:3][CH:4]=[CH:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]3)[CH2:31][CH2:32]1
Reactant: Cc1cccc(Cl)c1N1CCNCC1
Reactant: O=C1CCc2cc(C=CCCCl)ccc2N1
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cccc(Cl)c1N1CCN(CCC=Cc2ccc3c(c2)CCC(=O)N3)CC1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
2.8 Grams of 6-(4-chloro-1-butenyl)-3,4- dihydrocarbostyril and 2.1 g of sodium iodide were dissolved in 40 ml of dimethylformamide and stirred at 50° C. for 1 hour. To this solution were added 2.7 g of 4-(2-chloro-6-methlphenyl)piperazine and 1.5 g of triethylamine and the mixture was further stirred at 50° C. for 5 hours. The reaction mixture was concentrated under a reduced pressure to dryness to obtain a residue. To the residue were added 10N-NaOH and ether and stirred at a room temperature for 30 minutes to precipitate crystals. The crystals were separated by a silica-gel chromatography and recrystallized from ethanol-acetone-chloroform to obtain 6-{4-[4-(2-chloro-6-methlphenyl)-1-piperazinyl]-1-butenyl}-3,4-dihydrocarbostyril in colorless prism-like crystals. Yield: 2.7 g. Melting point: 179°-180° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11]([NH2:14])(=[O:13])=[O:12])[CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.C[Al](C)C.[CH3:26][O:27][C:28]1[CH:33]=[C:32]([CH3:34])[N:31]=[C:30]([NH:35][C:36](=O)[O:37]C)[N:29]=1>C(Cl)Cl>[CH3:26][O:27][C:28]1[CH:33]=[C:32]([CH3:34])[N:31]=[C:30]([NH:35][C:36]([NH:14][S:11]([C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[N:1]=[CH:2][CH:3]=[CH:4]3)(=[O:12])=[O:13])=[O:37])[N:29]=1
Reactant: NS(=O)(=O)c1cccc2cccnc12
Reactant: COC(=O)Nc1nc(C)cc(OC)n1
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2cccc3cccnc23)n1
Reaction time: 0.75 h
Yield: 47.8 %

Procedure:
To a stirred mixture of 8-quinolinesulfonamide (4.2 g) in 100 ml methylene chloride is added a 2 M toluene solution of trimethylaluminum (15 ml). The resulting solution is stirred under N2 for 45 min. Solid methyl (4-methoxy-6-methylpyrimidin-2-yl)carbamate (4.0 g) is added and the mixture is heated at reflux for 60 hrs. The reaction is quenched sequentially with acetic acid (2 ml) 6 N HCl (5 ml) and water (25 ml). The organic solution is retained, dried with MgSO4, filtered, and is concentrated in vacuo to a crude solid. Washing with methyl acetate afforded 3.6 g of a pale yellow powder m.p. 181°-185° C. The infrared spectrum showed characteristic absorption bands at 3100 and 1700 cm-1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:6]=[CH:5]2.C(N(CC)CC)C.[C:27](Cl)(Cl)=[S:28]>CN(C)C(=O)C.C(#N)C>[N:1]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH:12]=[CH:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH:6]=[CH:5]2)=[C:27]=[S:28]
Reactant: Nc1ccc2nc(C=Cc3ccccc3)ccc2c1
Reactant: S=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CC(=O)N(C)C
Product: S=C=Nc1ccc2nc(C=Cc3ccccc3)ccc2c1
Reaction time: 5 h

Procedure:
A solution of 24.6 g of 6-amino-2-styrylquinoline and 22.3 g of triethylamine in 100 ml of N,N-dimethylacetamide was added dropwise to 12.5 g of thiophosgene in 25 ml of acetonitrile with the temperature kept at or below -10° C. using a dry ice bath. After reacting for 5 hours at room temperature, the solid was filtered off and 500 ml of chloroform were added to the filtrate. The deposited solid was filtered off and the filtrate was separated and purified by silica gel column chromatography (the developing solution: chloroform). The obtained solid was recrystallized by using ethyl acetate to yield 19.3 g (67% of the theoretical yield) of 6-isothiocyanato-2-styrylquinoline.
Reaction SMILES: [NH2:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)([CH3:5])[CH2:3][OH:4].C(N(CC)CC)C.[Cl:21][CH2:22][C:23](Cl)=[O:24]>C(#N)C.CO>[Cl:21][CH2:22][C:23]([NH:1][C:2]([C:6]1[CH:7]=[CH:8][C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)([CH3:5])[CH2:3][OH:4])=[O:24]
Reactant: COc1ccc(C(C)(N)CO)cc1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CC#N
Product: COc1ccc(C(C)(CO)NC(=O)CCl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 57.5 mmol of 2-amino-2-(4-methoxyphenyl)propan-1-ol in 190 ml of acetonitrile and 33 ml of methanol is cooled to −10° C., and 69 mmol of triethylamine and, dropwise over the course of 1 hour, 63.3 mmol of chloroacetyl chloride are successively added. The reaction mixture is warmed to room temperature and stirred for 16 hours. The mixture is evaporated, and the title compound is obtained as a colourless oil from the residue by flash chromatography (SiO2 60 F). Rf=0.23 (ethyl acetate-heptane 2:1), Rt=2.88 (gradient I).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][N:15]3[C:19]4=[N:20][C:21]([C:24]5[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=5)=[CH:22][N:23]=[C:18]4[N:17]=[N:16]3)[CH2:9]2)=[N:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].[F:36][C:37]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[CH:41][C:38]=1[CH:39]=[O:40]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[F:36][C:37]1[CH:44]=[C:43]([C:2]2[CH:3]=[N:4][C:5]([N:8]3[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][N:15]4[C:19]5=[N:20][C:21]([C:24]6[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=6)=[CH:22][N:23]=[C:18]5[N:17]=[N:16]4)[CH2:9]3)=[N:6][CH:7]=2)[CH:42]=[CH:41][C:38]=1[CH:39]=[O:40]
Reactant: CC1(C)OB(c2ccc(C=O)c(F)c2)OC1(C)C
Reactant: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(Br)cn5)CCO4)c3n2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(-c6ccc(C=O)c(F)c6)cn5)CCO4)c3n2)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.1 %

Procedure:
In a pressure tube reactor, (S)-4-(5-bromopyrimidin-2-yl)-2-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholine (50 mg, 0.11 mmol) was added, and then 1M Na2CO3 (0.33 mL, 0.33 mmol) was added. Pd(PPh3)4 (6 mg, 0.005 mmol) was further added, and then 1,4-dioxane (1 mL) and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzaldehyde (41 mg, 0.16 mmol) were added. The mixture was stirred at room temperature for 10 minutes under nitrogen gas, and then stirred at 105° C. for 13 hours. When the reaction was completed, the organic layer was extracted with ethyl acetate and water, and the extra water was removed by sodium sulfate, followed by concentration under reduced pressure. Solid was generated using ether and hexane, followed by filtration, to give (S)-2-fluoro-4-(2-(2-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)-methyl)morpholino)pyrimidin-5-yl)benzaldehyde (41 mg, 0.087 mmol) with a yield of 76%.