Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C1(=O)[O:11][CH:9]([CH3:10])[CH2:8]O1>>[OH:11][CH:9]([CH3:10])[CH2:8][C:2]1[NH:1][CH:5]=[CH:4][N:3]=1
Reactant: c1c[nH]cn1
Reactant: CC1COC(=O)O1
Product: CC(O)Cc1ncc[nH]1
Temperature: 140 °C

Procedure:
Mix 6.8 g imidazole and 15.3 g propylene carbonate and heat at 140° C. for 1 hour. Chromatograph the resultant residue on silica gel, eluting with methylene chloride:ethyl acetate (1:1), then with 5→10% methanol in methylene chloride to obtain the title compound of step A.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:23])[NH:11][C:12]([C:15]1[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=1[F:22])([CH3:14])[CH3:13])[CH2:2]2.[CH3:24][CH:25]([CH3:30])[CH2:26]B(O)O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:22][C:16]1[CH:17]=[CH:18][C:19]([CH2:24][CH:25]([CH3:30])[CH3:26])=[CH:20][C:15]=1[C:12]([NH:11][C:10](=[O:23])[O:9][CH:3]1[CH:4]2[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]2)[CH2:2]1)([CH3:14])[CH3:13]
Reactant: CC(C)(NC(=O)OC1CN2CCC1CC2)c1cc(Br)ccc1F
Reactant: CC(C)CB(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: CC(C)Cc1ccc(F)c(C(C)(C)NC(=O)OC2CN3CCC2CC3)c1
Yield: 32.7 %

Procedure:
Using general procedure E, 1-azabicyclo[2.2.2]oct-3-yl[2-(5-bromo-2-fluorophenyl)propan-2-yl]carbamate (120 mg, 0.312 mmol), 2-methylpropylboronic acid (79.4 mg, 0.779 mmol) and palladium (II) acetate gave the title as a white solid compound (37 mg, 33%). 1H NMR (400 MHz, CDCl3) δ 7.08 (dd, J=2.0, 8.2 Hz, 1H), 6.95 (d, J=4.9 Hz, 1H), 6.93-6.85 (m, 1H), 5.23 (s, 1H), 4.72-4.52 (m, 1H), 3.20-2.47 (m, 6H), 2.41 (d, J=7.1 Hz, 2H), 1.89-1.76 (m, 1H), 2.02-1.26 (m, 5H), 1.70 (d, J=7.6 Hz, 6H), 0.88 (d, J=6.6 Hz, 6H) ppm. 13C NMR (100 MHz, CDCl3) δ 160.4, 158.0, 137.1, 137.1, 129.2, 129.1, 128.1, 116.2, 116.0, 71.2, 55.8, 54.2, 47.6, 46.7, 45.1, 30.5, 29.9, 28.6, 27.0, 25.6, 24.8, 22.5, 19.8, 19.5 ppm. Purity: 95.0% UPLCMS (210 nm); retention time 1.02 min; (M+1) 363.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:37])=[C:21]([NH:25][S:26]([C:29]3[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[CH3:38][S:39]([N:42]1[CH2:47][CH2:46][CH:45]([NH2:48])[CH2:44][CH2:43]1)(=[O:41])=[O:40]>FC(F)(F)CO>[F:36][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]([F:35])[C:29]=1[S:26]([NH:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:9]2[N:10]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:48][CH:45]3[CH2:46][CH2:47][N:42]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:43][CH2:44]3)[N:7]=2)[C:20]=1[F:37])(=[O:28])=[O:27]
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1c(F)cccc1F
Reactant: CS(=O)(=O)N1CCC(N)CC1
Solvent: OCC(F)(F)F
Product: CS(=O)(=O)N1CCC(Nc2nccc(-c3sc(N4CCOCC4)nc3-c3cccc(NS(=O)(=O)c4c(F)cccc4F)c3F)n2)CC1
Yield: 15 %

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (0.107 g, 0.188 mmol) and 1-(methylsulfonyl)-4-piperidinamine (0.3 g, 1.68 mmol) in 2,2,2-trifluoroethanol (2 mL) the title compound was obtained (0.020 g, 0.028 mmol, 15% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.83 (s, 1H), 7.85 (d, J=5.1 Hz, 2H), 7.70-7.57 (m, 2H), 7.42-7.33 (m, 2H), 7.30-7.03 (m, 4H), 5.47-5.86 (m, 1H) 3.72-3.31 (m, 11H), 2.91-2.73 (m, 5H), 1.92-1.77 (m, 2H), 1.58-1.40 (m, 2H). MS (ESI): 710 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([CH2:17]O)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.O=S(Cl)[Cl:21]>C(Cl)Cl>[Cl:21][CH2:17][C:10]1[CH:11]=[C:12]([C:13]([O:15][CH3:16])=[O:14])[N:8]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[N:9]=1
Reactant: COC(=O)c1cc(CO)nn1-c1ncccc1Cl
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1cc(CCl)nn1-c1ncccc1Cl
Temperature: 5 °C
Reaction time: 4 h

Procedure:
Methyl 1-(3-chloropyridin-2-yl)-3-(hydroxymethyl)-1H-pyrazole-5-carboxylate (26.7 g, 0.1 mol) was dissolved in 150 ml of CH2Cl2, and the solution was cooled to 5° C. SOCl2 (0.12 mol) in 30 ml of CH2Cl2 was slowly added dropwise at this temperature. The mixture was stirred at 40° C. for a further 4 h and concentrated under reduced pressure. The product can be used further without purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][C:8]=2[O:14][CH3:15])[CH:6]=1.[C:16](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:17]>ClCCl>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:13]=[CH:12][C:10]([N:11]=[C:16]=[S:17])=[CH:9][C:8]=2[O:14][CH3:15])[CH:6]=1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: COc1cc(N)ccc1-n1cnc(Cl)c1
Solvent: ClCCl
Product: COc1cc(N=C=S)ccc1-n1cnc(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.3 %

Procedure:
Step A (3): Dichloromethane (125 mL) was added to a flask charged with 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (4.55 g, 20.3 mmol) and 1,1′-thiocarbonyldipyridin-2(1H)-one (4.72 g, 20.3 mmol). The resulting mixture was stirred for 24 h at rt. The crude reaction mixture was concentrated and the crude products were purified using silica gel chromatography to afford 4-chloro-1-(4-isothiocyanato-2-methoxy-phenyl)-1H-imidazole (4.28 g, 79% yield) as a white solid. LC-MS (M+H)+ 266.0. 1H NMR (500 MHz, chloroform-d) δ ppm 7.60 (d, J=1.53 Hz, 1 H) 7.24 (d, J=8.24 Hz, 1 H) 7.09 (d, J=1.83 Hz, 1 H) 6.93 (dd, J=8.24, 2.14 Hz, 1 H) 6.89 (d, J=2.14 Hz, 1 H) 3.88 (s, 3 H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:13]=[C:14]([CH:23]([CH3:25])[CH3:24])[C:15]3[O:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:16]=3[CH:22]=2)=[CH:7][CH:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].IC.CN(C)[C:37](=O)[CH3:38]>>[CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH2:37][CH3:38])[C:12]2[CH:13]=[C:14]([CH:23]([CH3:25])[CH3:24])[C:15]3[O:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:16]=3[CH:22]=2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CC(=O)N(C)C
Reactant: CCOC(=O)c1ccc(Nc2cc(C(C)C)c3c(c2)C(C)(C)CO3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: CCOC(=O)c1ccc(N(CC)c2cc(C(C)C)c3c(c2)C(C)(C)CO3)cc1
Yield: 75 %

Procedure:
Following general procedure G and using 4-[(3,3-dimethyl-7-isopropyl-2,3-dihydro-benzofuran-5-yl)-amino]-benzoic acid ethyl ester (Compound 17, 0.064 g, 0.19 mmol), potassium carbonate (0.105×2 g, 0.76×2 mmol) and iodomethane (0.24×2 g, 0.76×2 mmol) in 2 mL of anhydrous N,N-dimethylacetamide, the title compound (0.05 g, 75%) was obtained as a pale yellow oil. This reaction was performed in a sealed tube for 96 hours, with addition of a second equivalent of potassium carbonate and iodomethane to the reaction mixture after 48 hours. 1H NMR (300 MHz, CDCl3): δ 7.75 (d, 2H, J=9.0 Hz), 6.74 (d, 1H, J=2.1 Hz), 6.67 (d, 1H, J=2.1 Hz), 6.49 (d, 2H, J=9.0 Hz), 4.23 (q, 2H, J=7.1 Hz), 4.20 (s, 2H), 3.66 (q, 2H, J=7.1 Hz), 3.01 (heptet, 1H J=6.8 Hz), 1.27 (t, 3H, J=7.1 Hz), 1.25 (s, 6H), 1.19-1.13 (m, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9](=O)/[C:10](/[CH3:18])=[C:11](\[O-])/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:7][CH:8]=1)#[N:2].[Li+].Cl.[NH2:22][NH2:23]>C(O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[NH:23][N:22]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]=2[CH3:18])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)/C([O-])=C(\C)C(=O)c1cccc(C#N)c1
Reactant: NN
Agent: Cl
Agent: [Li+]
Solvent: CCO
Product: CCOC(=O)c1n[nH]c(-c2cccc(C#N)c2)c1C
Reaction time: 8 h
Yield: 29.6 %

Procedure:
To a solution of lithium (Z)-4-(3-cyanophenyl)-1-ethoxy-3-methyl-1,4-dioxobut-2-en-2-olate (400 mg, 1.51 mmol, Eq: 1.00) in Ethanol (10 ml) was added Hydrazine hydrochloride (113 mg, 1.65 mmol, Eq: 1.093) at rt to give an orange solution. The resulting mixture was stirred overnight at the same temperature. After 1 day the solvent was removed under reduce pressure and to the mixture was added brine. The solution was extracted two times with AcOEt, and the combined organic layers were dried over MgSO4, filtered and concentrated to give the desired compound as a yellow gum (114 mg, 26.6%). MS (ISP): 256.0 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([NH:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:50][O:51][C:52]1[CH:57]=[CH:56][C:55]([CH2:58]Br)=[CH:54][CH:53]=1.O>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([N:30]([CH2:58][C:55]3[CH:56]=[CH:57][C:52]([O:51][CH3:50])=[CH:53][CH:54]=3)[CH2:31][C:32]3[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=3)=[N:9][N:10]([C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:4]=2[CH:3]=1
Reactant: COc1ccc(CBr)cc1
Reactant: COc1ccc(CNc2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3cc(Cl)ncc23)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3cc(Cl)ncc23)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40.6 %

Procedure:
At 0° C., to a solution of 6-chloro-N-(4-methoxybenzyl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-amine (2.0 g, 3.78 mmol) in anhydrous THF (30 mL) was added LiHMDS (1.0 M solution in Toluene, 7.56 mL, 7.56 mmol) and the contents were stirred at the same temperature. After 15 min, PMBBr (0.92 g, 4.53 mmol) was added at the same temperature and the contents were allowed to warm to ambient temperature. After 3 h, H2O (10 mL) was added and stirred for 5 min. The organic contents were extracted with EtOAc (3×40 mL) and the EtOAc layer washed with brine (1×20 mL), dried over anhydrous Na2SO4 and the solvents were removed under reduced pressure. The residue thus obtained was purified by a filter column to afford the title compound (1.0 g, 41% yield). MS ES calc'd. for C41H35ClN4O2 [M+H]+ 651. Found 651.
Reaction SMILES: [CH3:1][NH:2][CH3:3].CCN(C(C)C)C(C)C.[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)([O-:15])=[O:14]>C(Cl)Cl>[CH3:1][N:2]([CH3:3])[S:22]([C:19]1[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:21][CH:20]=1)(=[O:23])=[O:24]
Reactant: CNC
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
To the solution of dimethylamine (284 mg, 6.3 mmol, 1.5 equiv.) and DIPEA (1 mL) in DCM (15 mL) was added dropwise a solution of 4-nitrobenzene-1-sulfonyl chloride (800 mg, 4.2 mmol, 1.0 equiv.) in DCM (5 mL). The reaction mixture was stirred at room temperature for 2 h. Then, the reaction mixture was washed with water and brine. The organic layers was dried (Na2SO4) and concentrated to get the residue, which was washed with isopropyl ether to afford compound N,N-dimethyl-4-nitrobenzenesulfonamide (879 mg, 91%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[CH2:3]1.C(OCC)C.N.[Li]>C(O)C>[NH2:1][CH:2]1[CH2:8][CH2:7][CH2:6][C:5]2[CH2:9][CH:10]=[CH:11][CH2:12][C:4]=2[CH2:3]1
Reactant: NC1CCCc2ccccc2C1
Agent: N
Agent: [Li]
Solvent: CCOCC
Solvent: CCO
Product: NC1CCCC2=C(CC=CC2)C1
Reaction time: 0.17 h

Procedure:
A solution of 16.1 g. (0.10 mole) of 6-amino-6,7,8,9-tetrahydro-5H-benzocycloheptene in 100 ml. of diethyl ether and 500 ml. of liquid NH3 is treated portionwise with 15 g. of lithium in small pieces. After 10 minutes, the mixture is treated dropwise with absolute ethanol to completely discharge the color. After removal of NH3, the residue is cooled and treated with water. Further extraction with ether and removal of organic solvent leaves crude 6-amino-1,4,6,7,8,9-hexahydro-5H-benzocycloheptene which is converted to its N-benzoyl derivative with benzoyl chloride-pyridine and thence to the tetrol as described previously.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.I[C:10]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].C([O-])([O-])=O.[Cs+].[Cs+]>CCOC(C)=O.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:11]=2[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: O=C(O)c1cc(I)ccc1I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(I)ccc1Oc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 108 %

Procedure:
A RBF equipped with a reflux condenser was charged with 4-bromophenol (15.5 g, 89.4 mmol), 2,5-diiodobenzoic acid (25.700 g, 68.7 mmol), EtOAc (0.337 ml, 3.44 mmol), and toluene (100 mL). Cs2CO3 (44.8 g, 137 mmol) was carefully added portionwise. After stirring at RT for 1 min, the mixture was heated to 50° C. for 40 min and then heated to 100° C. for 20 hrs. The reaction mixture was allowed to cool to RT. The mixture was filtered through Celite and the solids were washed with EtOAc. The filtrate was diluted with water (200 mL), acidified with 2N HCl (300 mL), and extracted with EtOAc (4×500 mL). The organic extract was washed with brine and dried over sodium sulfate. The organic fraction was concentrated under reduced pressure to afford crude 2-(4-bromophenoxy)-5-iodobenzoic acid (31.1 g) as a tan oil that solidified upon standing.
Reaction SMILES: C([O:3][C:4](=[O:43])[C:5]([CH3:42])([CH3:41])[CH2:6][NH:7][C:8]([C:10]1[C:11]([OH:40])=[C:12]2[C:17](=[C:18]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[N:19]=1)[N:16]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:15](=[O:33])[C:14]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[CH:13]2)=[O:9])C.[OH-].[Na+].CO.C1COCC1>C([O-])(O)=O.[Na+]>[CH2:26]([N:16]1[C:17]2[C:12](=[C:11]([OH:40])[C:10]([C:8]([NH:7][CH2:6][C:5]([CH3:42])([CH3:41])[C:4]([OH:43])=[O:3])=[O:9])=[N:19][C:18]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:13]=[C:14]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:15]1=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)C(C)(C)CNC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(CNC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 29.4 %

Procedure:
A mixture of 3-[(1-benzyl-5-hydroxy-2-oxo-3-phenyl-8-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carbonyl)-amino]-2,2-dimethyl-propionic acid ethyl ester (30 mg, 0.052 mmol), 2 M NaOH (3 mL), MeOH (3 mL) and THF (3 mL) was stirred at r.t. for 16 h, then concentrated to approximately one-third of its original volume. 1 M HCl was added to acidify the mixture, and the resulting suspension was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-60% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4, and the resulting precipitate was isolated by filtration to give 8.4 mg of the title compound as a light yellow solid. MS: (+) m/z 549.56 (M+1).
Reaction SMILES: CN([CH:4]=[C:5]1[C:13](=O)[C:12]2[N:11]([CH3:15])[N:10]=[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]=2[C:7]([CH3:22])([CH3:21])[CH2:6]1)C.[Cl:23][C:24]1[CH:25]=[C:26]([NH:37][C:38]([NH2:40])=[NH:39])[CH:27]=[CH:28][C:29]=1[N:30]1[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]1>CN(C)C=O.O>[Cl:23][C:24]1[CH:25]=[C:26]([NH:37][C:38]2[N:40]=[CH:4][C:5]3[CH2:6][C:7]([CH3:21])([CH3:22])[C:8]4[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:10][N:11]([CH3:15])[C:12]=4[C:13]=3[N:39]=2)[CH:27]=[CH:28][C:29]=1[N:30]1[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]1
Reactant: CCOC(=O)c1nn(C)c2c1C(C)(C)CC(=CN(C)C)C2=O
Reactant: CN1CCN(c2ccc(NC(=N)N)cc2Cl)CC1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1nn(C)c2c1C(C)(C)Cc1cnc(Nc3ccc(N4CCN(C)CC4)c(Cl)c3)nc1-2
Reaction time: 37 h
Yield: 88.2 %

Procedure:
A solution of ethyl 6-[(dimethylamino)methylene]-1,4,4-trimethyl-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate (0.50 g, 1.6 mmol) and N-[3-chloro-4-(4-methylpiperazin-1-yl)-phenyl]-guanidine (0.48 g, 1.8 mmol) in anhydrous dimethylformamide was heated to 100° C. and kept at this temperature for 37 hours. After cooling, the mixture was diluted with water (50 mL) and the resulting precipitate was collected by filtration and dried to give the title compound (0.72 g, 85% yield) as a yellow solid.
Reaction SMILES: [Cl-].[C:2]1([N+:8]#[N:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C=CC=CC=1.[NH2:17][C:18]1[N:19]=[C:20]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[NH:21][C:22](=[O:24])[CH:23]=1.[OH-].[Na+]>O>[NH2:17][C:18]1[N:19]=[C:20]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[NH:21][C:22](=[O:24])[C:23]=1[N:9]=[N:8][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cc(=O)[nH]c(Cc2ccccc2)n1
Reactant: N#[N+]c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Nc1ccccc1
Product: Nc1nc(Cc2ccccc2)[nH]c(=O)c1N=Nc1ccccc1
Reaction time: 1 h

Procedure:
A cold solution of benzenediazonium chloride (prepared by the method well known in the art, from 2 g. aniline) was added dropwise with stirring to a solution of 4-amino-2-benzylpyrimid-6-one (4 g.) and sodium hydroxide (1.6 g.) in water (50 ml.) at 5° C. After stirring for a further 1 hour, the solid was filtered off and recrystallised from a mixture of dimethylformamide and water (4:1 v/v) to give 4-amino-2-benzyl-5-phenylazopyrimid-6-one (3.8 g.) in the form of orange needles, which decomposed at 256°-257° C.
Reaction SMILES: N12CCCN=C1CCCCC2.Br[C:13]1[CH:20]([CH:21]([OH:26])[C:22]([O:24]C)=[O:23])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=1.Cl>CS(C)=O>[C:18]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH:20]([CH:21]([OH:26])[C:22]([OH:24])=[O:23])[C:19]#1
Reactant: COC(=O)C(O)C1CCCCCC=C1Br
Agent: Cl
Solvent: CS(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)C(O)C1C#CCCCCC1
Reaction time: 0.25 h
Yield: 55 %

Procedure:
150 μl of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 1 mmol) are added to a solution of methyl 2-bromocyclooctene-3-glycolate 17 (0.5 mmol) in anhydrous DMSO at 60° C. After stirring for 15 min, an additional 600 μl of DBU (4 mmol) are added and then the combined mixture is stirred overnight at 60° C. The mixture is acidified with 1M HCl and extracted with AcOEt. The organic phase is filtered through a separating filter and is concentrated under vacuum. The cyclooct-1-yn-3-glycolic acid 18 is purified on a preparative plate (CH2Cl2/MeOH 9/1) and is obtained with a yield of 55% (w=50 mg).
Reaction SMILES: Cl[C:2]1[C:3]([C:9]([NH2:11])=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:12]([NH2:15])([CH3:14])[CH3:13]>ClCCl>[Cl:8][C:6]1[CH:7]=[C:2]([NH:15][CH:12]([CH3:14])[CH3:13])[C:3]([C:9]([NH2:11])=[O:10])=[N:4][CH:5]=1
Reactant: CC(C)N
Reactant: NC(=O)c1ncc(Cl)cc1Cl
Solvent: ClCCl
Product: CC(C)Nc1cc(Cl)cnc1C(N)=O
Temperature: 200 °C
Yield: 55.8 %

Procedure:
3,5-Dichloropicolinamide (50 mg, 0.26 mmol, 1.0 equiv) and isopropylamine (225 uL, 2.6 mmol, 1.0 equiv) were combined in a microwave vial equipped with a stirbar, sealed and heated to 200° C. for 30 min. The mixture was then dissolved in dichloromethane and loaded onto a Biotage caplet. Purification by silica gel MPLC (13%-68% Et2O/Hexanes) provided the desired compound as a white solid (31 mg, 56%). m/z=214.1 [M+H]+
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li:26])CCC>CCOCC>[C:1]([C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:13]=3)[CH2:8][C:7]=2[C:6]=1[Li:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc2c(c1)Cc1cc(C(C)(C)C)ccc1-2
Reactant: [Li]CCCC
Solvent: CCOCC
Product: [Li]c1c(C(C)(C)C)ccc2c1Cc1cc(C(C)(C)C)ccc1-2
Temperature: -78 °C
Reaction time: 12 h

Procedure:
Preparation 1. A one-liter flask was charged with 2,7-di-tert-butylfluorene (50 g, 179.6 mmol) and a stir bar, capped with a rubber septum, and placed under a nitrogen atmosphere. Diethyl ether (about 300 mL) was added via a cannula, and the resulting mixture was cooled to −78° C. in a dry-ice bath. This mixture was stirred at this temperature as n-butyllithium (21.5 mL of 10 M in hexanes, 215 mmol) was added slowly via syringe. After the addition of n-butyllithium was complete, the reddish solution was slowly warmed to room temperature and stirred overnight (at least about 12 hours), to provide an ether solution of 2,7-di-tert-butylfluorenyl lithium.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.[CH2:12]([NH:14][CH2:15][CH3:16])[CH3:13]>C(#N)C>[CH2:12]([N:14]([CH2:15][CH3:16])[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)[CH3:13]
Reactant: CCNCC
Reactant: O=C(O)c1ccc(CCl)cc1
Solvent: CC#N
Product: CCN(CC)Cc1ccc(C(=O)O)cc1
Yield: 63 %

Procedure:
1 g (1 equivalent) of α-chloroparatoluic acid and 1.22 mL (2 equivalents) of diethylamine are placed in solution in 30 mL of acetonitrile. The reaction mixture is taken to reflux for 48 hours. The solvent is evaporated off under vacuum and the residue is purified by chromatography on silica gel column (CH2Cl2/MeOH 60/40 then pure MeOH). The product is obtained in the form of a white powder after precipitation from hexane. (Yield=63%).
Reaction SMILES: [O:1]=[C:2]([C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:29])[CH2:23][CH2:22]2)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[CH2:8][CH2:7]1.[BH4-].[Na+].Cl>CO>[OH:1][CH:2]([C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:29])[CH2:23][CH2:22]2)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[CH2:10][CH2:11]1
Reactant: O=C1CCc2cc(C(=O)CCCN3CCN(c4cccc(Cl)c4)CC3)ccc2N1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C1CCc2cc(C(O)CCCN3CCN(c4cccc(Cl)c4)CC3)ccc2N1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3.0 Grams of 6-{1-oxo-4-[4-(3-chlorophenyl)-1-piperazinyl]butyl}-3,4-dihydrocarbostyril was added to 100 ml of methanol, under stirring condition 1.2 g of sodium borohydride was added gradually to the solution and stirred at a room temperature for 5 hours. Then 5 ml of concentrated hydrochloric acid was added to the reaction mixture and the mixture was concentrated under a reduced pressure to dryness. Then to this dried matter was added 50 ml of 2%-sodium hydroxide aqueous solution and the organic layer was extracted with dichloromethane. The dichloromethane layer was washed with water, dried and the dichloromethane was removed by distillation. The residue thus obtained was purified by a silica gel column chromatography, and recrystallized from isopropanol to obtain 2.2 g of 6-{1-hydroxy-4-[4-(3-chlorophenyl)-1-piperazinyl]butyl}-3,4-dihydrocarbostyril in colorless needle-like crystals.