Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[OH:19])[CH:14]=O>>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:14]([C:13]3[CH:16]=[CH:17][C:18]([OH:19])=[C:11]([Cl:10])[CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1N
Reactant: O=Cc1ccc(O)c(Cl)c1
Product: Oc1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1Cl

Procedure:
The title compound was prepared from 5-bromo-2,3-diaminopyridine and 3-chloro-4-hydroxybenzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:17])=[CH:4][C:5]2[O:15][C:14](=[O:16])[C:9]3[CH2:10][NH:11][CH2:12][CH2:13][C:8]=3[C:6]=2[CH:7]=1.C(N(CC)CC)C.Cl[CH2:26][C:27](=[O:29])[CH3:28]>>[Cl:1][C:2]1[C:3]([CH3:17])=[CH:4][C:5]2[O:15][C:14](=[O:16])[C:9]3[CH2:10][N:11]([CH2:26][C:27](=[O:29])[CH3:28])[CH2:12][CH2:13][C:8]=3[C:6]=2[CH:7]=1
Reactant: CC(=O)CCl
Reactant: Cc1cc2oc(=O)c3c(c2cc1Cl)CCNC3
Solvent: CCN(CC)CC
Product: CC(=O)CN1CCc2c(c(=O)oc3cc(C)c(Cl)cc23)C1
Yield: 27.3 %

Procedure:
Prepared by the method described for example 26 from 9-chloro-1,2,3,4-tetrahydro-8-methyl-5H-[1]benzopyrano[3,4-c]pyridin-5-one (1.6 g, 0.006 moles), triethylamine (1 ml, 0.007 moles) and 1-chloro-2-propanone (0.57 g, 0.006 moles). Recrystallization from isopropanol gave the product (0.5 g), mp 172°-175° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([C:20]2[CH:21]=[CH:22][C:23]3[O:27][C:26]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)=[C:25]([C:35](=[O:38])[NH:36][CH3:37])[C:24]=3[CH:39]=2)[C:18]=1[CH3:19])[C:12]([O:14]C)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([C:20]2[CH:21]=[CH:22][C:23]3[O:27][C:26]([C:28]4[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=4)=[C:25]([C:35](=[O:38])[NH:36][CH3:37])[C:24]=3[CH:39]=2)[C:18]=1[CH3:19])[C:12]([OH:14])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)OC)cc(OCc4ccccc4)c3C)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)cc(OCc4ccccc4)c3C)cc12
Temperature: 60 °C

Procedure:
To a mixture of methyl 3-(benzyloxy)-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoate (0.3 g, 0.57 mmol, 1 eq) in a 1:1 mixture of MeOH/THF at ambient temperature was added 5 eq. of NaOH, and the resulting mixture was heated to 60° C. for 5 h. The mixture was cooled to ambient temperature and then cooled in ice-water bath. The reaction mixture was acidified with 1.5 N HCl and then concentrated. The mixture with white precipitates was diluted with water and filtered to get the solid. It is further washed with water and dried in vacuum. Yield: 0.2 g (70%). 1H NMR (400 MHz, DMSO-d6): δ 2.19 (s, 3H), 2.82-2.83 (d, 3H, J=4.56 Hz), 5.27 (s, 2H), 7.34-7.46 (m, 6H), 7.50-7.55 (m, 4H), 7.60 (s, 1H), 7.75-7.77 (d, 1H, J=8.44 Hz), 7.99-8.03 (m, 2H), 8.49-8.50 (d, 1H), 13.0 (s, 1H). LCMS: (ES+) m/z=510 (M+H). Ascentis Express C18 (5.0×2.1-2.7 μm) Mphase A: 2% MeCN-98% H2O-10 mM NH4COOH Mphase B: 98% MeCN-2% H2O-10 mM NH4COOH
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH:15]1[CH2:20][CH2:19][S:18][CH2:17][CH2:16]1>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:15]2[CH2:20][CH2:19][S:18][CH2:17][CH2:16]2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: C1CSCCN1
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1Br
Solvent: ClCCl
Product: O=C(O)c1cc(S(=O)(=O)N2CCSCC2)ccc1Br

Procedure:
This product is prepared by the reaction of 2-bromo-5-chlorosulfonyl benzoic acid with excess thiomorpholine in methylene chloride. The product, m.p. 195°-197.5° C., is purified by solution in aqueous sodium hydroxide, crystallization by acidifying the basic solution, and recrystallization from acetone-hexane.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH2:24]([NH:26][C:27](=[O:45])[C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30][C:29]=1[NH:43][CH3:44])[CH3:25]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:31]=[N:30][C:29]([NH:43][CH3:44])=[C:28]([CH:33]=5)[C:27]([NH:26][CH2:24][CH3:25])=[O:45])[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: CCNC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cnc1NC
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: CCNC(=O)c1cc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cnc1NC

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and N-ethyl-2-methylamino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-nicotinamide (Stage 242.1.1) to give the title compound as a yellowish foam. (HPLC: tR 2.17 min (Method A); M+H=471 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.92 (s, 1H), 8.58 (t, 1H), 8.25-8.20 (m, 2H), 8.11-8.06 (m, 2H), 8.05-8.02 (m, 1H), 7.96-7.92 (m, 1H), 7.47-7.44 (m, 1H), 3.89 (s, 3H), 3.57 (s, 3H), 3.40-3.19 (m, 2H), 2.93 (d, 3H), 1.97 (s, 3H), 1.15 (t, 3H))
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([NH:12][C:13](=[O:22])[CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:4]([Br:23])[CH:3]=1.[Cl:24][C:25]1[S:29][C:28]([CH:30]=O)=[CH:27][CH:26]=1.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO>[Br:23][C:4]1[CH:3]=[C:2]([NH:1][CH2:30][C:28]2[S:29][C:25]([Cl:24])=[CH:26][CH:27]=2)[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[C:5]=1[NH:12][C:13](=[O:22])[CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=Cc1ccc(Cl)s1
Reactant: Nc1cc(Br)c(NC(=O)CCC2CCCCC2)c(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=C(CCC1CCCCC1)Nc1c(Br)cc(NCc2ccc(Cl)s2)cc1C(F)(F)F
Temperature: 130 °C
Yield: 33 %

Procedure:
N-(4-Amino-2-bromo-6-trifluoromethyl-phenyl)-3-cyclohexyl-propionamide (1.03 g) and 5-chloro-thiophene-2-carbaldehyde (310 uL) were dissolved in methanol (16 mL) and heated to 130° C. for 8 minutes in a sealed microwave process vial. Sodium cyanoborohydride (800 mg) was added and the reaction mixture was heated to 130° C. for 5 minutes in a sealed microwave process vial. Saturated aqueous sodium bicarbonate (100 mL) was added, the product was extracted with ethyl acetate (3×50 mL) and the combined organic phases were washed with water (2×100 mL) and brine (100 mL), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography to furnish 517 mg (33% yield) of the title compound as a yellow solid. LC-MS (m/z) 524 (MH+); tR=4.09, (UV, ELSD) 99%, 99%. 1H NMR (500 MHz, DMSO-d6): 0.86 (q, 2H), 1.15 (m, 3H), 1.26 (m, 1H), 1.46 (q, 2H), 1.65 (m, 5H), 2.24 (t, 2H), 4.89 (d, 2H), 6.94 (d, 1H), 6.95 (d, 1H), 6.98 (d, 1H), 7.04 (t, 1H), 7.13 (d, 1H), 9.32 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]([OH:13])[C:10]([NH2:12])=[O:11].[C:14](=O)(OC)[O:15]C.CC(C)([O-])C.[K+]>C(O)(C)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]1[O:13][C:14](=[O:15])[NH:12][C:10]1=[O:11]
Reactant: COC(=O)OC
Reactant: NC(=O)C(O)c1c(F)cccc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: O=C1NC(=O)C(c2c(F)cccc2Cl)O1
Temperature: 25 °C
Yield: 101.6 %

Procedure:
2-(2-Chloro-6-fluorophenyl)-2-hydroxyacetamide (3 g., 15 mmoles) was taken into 40 ml. of tert-butanol and dimethyl carbonate (2.7 g., 2.5 ml. 30 mmoles). Potassium tert-butoxide (3.4 g., 30 mmoles) was added portionwise and the reaction mixture heated to reflux for 65 minutes, cooled to room temperature, quenched by the portionwise addition of 60 ml. of 1 N hydrochloric acid, poured into 200 ml. of water and extracted with three portions of ethyl acetate. The combined organic extracts were washed with water, washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated to yield 5-(2-chloro-6-fluorophenyl)oxazolidine-2,4-dione (3.5 g.). Purified product was obtained by recrystallization from toluene (3.0 g., m.p. 156°-158° C.).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=2)=[C:8]([CH:11]=1)[C:9]#[N:10].CS[C:25]1[NH:26][CH:27]=[C:28]([CH2:32][C:33]2[CH:34]=[N:35][CH:36]=[N:37][CH:38]=2)[C:29](=[O:31])[N:30]=1>C(O)C>[O:31]=[C:29]1[C:28]([CH2:32][C:33]2[CH:38]=[N:37][CH:36]=[N:35][CH:34]=2)=[CH:27][NH:26][C:25]([NH:1][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([O:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][N:14]=3)=[C:8]([CH:11]=2)[C:9]#[N:10])=[N:30]1
Reactant: N#Cc1cc(CCN)ccc1Oc1ccc(C(F)(F)F)cn1
Reactant: CSc1nc(=O)c(Cc2cncnc2)c[nH]1
Solvent: CCO
Product: N#Cc1cc(CCNc2nc(=O)c(Cc3cncnc3)c[nH]2)ccc1Oc1ccc(C(F)(F)F)cn1
Temperature: 125 °C
Reaction time: 8 h
Yield: 43.1 %

Procedure:
5-(2-amino-ethyl)-2-(5-trifluoromethyl-pyridin-2-yloxy)benzonitrile (0.163 mmol, 1 eq) and 2-methylsulfanyl-5-pyrimidin-5-ylmethyl-1H-pyrimidin-4-one (0.065 mmol, 0.4 eq) were dissolved in dry ethanol (200 μL) and stirred at 125° C. overnight. Solvent was evaporated and crude product was purified on Biotage SP1 Snap Si 10; 15 ml/min in the gradient of MeOH in DCM: 0-15% in 20CV. The appropriate fractions were combined and evaporated in vacuo to give the required product 5-[2-(4-oxo-5-pyrimidin-5-ylmethyl-1.4-dihydro-pyrimidin-2-ylamino)-ethyl]-2-(5-trifluoromethyl-pyridin-2-yloxy)benzonitrile (0.028 mmol, yield: 17%, HPLC-MS/UV: [M+H]+=494.17; rt: 9.91 mins; purity: 91%). 1H NMR (300 MHz; CDCl3) δ/ppm 2.98 (t, J=6.57, 2H), 3.52-3.75 (m, 4H), 5.31 (br.s., 1H), 7.12-7.30 (m, 3H), 7.48-7.56 (m, 1H), 7.57-7.62 (m, 1H), 7.71 (s, 1H), 7.98 (dd, J=8.40, J=2.55, 1H), 8.57-5.69 (m, 2H), 9.04 (s, 1H), 11.80 (br.s., 1H)
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1/[CH:11]=[C:12](/[C:15](=O)[CH3:16])\[C:13]#[N:14].[NH2:18][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:20][C:21]#[N:22]>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[CH:11]1[C:20]([C:21]#[N:22])=[C:19]([C:23]([F:26])([F:25])[F:24])[NH:18][C:15]([CH3:16])=[C:12]1[C:13]#[N:14]
Reactant: CC(=O)/C(C#N)=C/c1cc2cn[nH]c2cc1F
Reactant: N#CC=C(N)C(F)(F)F
Product: CC1=C(C#N)C(c2cc3cn[nH]c3cc2F)C(C#N)=C(C(F)(F)F)N1

Procedure:
Following the procedure described for Example 4, 200 mg (0.87 mmol) (2E)-2-[(6-fluoro-1H-indazol-5-yl)methylidene]-3-oxobutanenitrile (Example 6A) were treated with 3-amino-4,4,4-trifluorobut-2-enenitrile. The crude product was purified by preparative RP-HPLC (acetonitrile/water gradient, final mixture 90:10 v/v) to yield 115 mg (40% of th.) of the racemic title compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[CH:5]=[C:4]([CH3:11])[N:3]=1.[CH3:12][O-:13].[Na+]>CO.O>[C:8]([C:7]1[C:2]([O:13][CH3:12])=[N:3][C:4]([CH3:11])=[CH:5][C:6]=1[CH3:10])#[N:9]
Reactant: Cc1cc(C)c(C#N)c(Cl)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1nc(C)cc(C)c1C#N
Temperature: 60 °C
Yield: 64.6 %

Procedure:
A solution of 2-chloro-3-cyano-4,6-dimethylpyridine (4.60 g, 27.7 mmol) in methanol (30 mL) is added to a stirred solution of sodium methoxide (2.09 g, 38.78 mmol) in methanol (20 mL) and the reaction mixture is heated at 60° C. for 4 hr. After cooling, the reaction is diluted with water (150 mL) and the solids are collected by filtration, washed with water and dried to yield 3-cyano-4,6-dimethyl-2-methoxypyridine (2.90 g, 65%) as an off-white solid containing the same impurity as the starting material. LC/MS: MS m/e=163 (M+H); RT 3.29 min; 1H NMR (CDCl3, δ ppm) 6.69, (1H, s), 4.00 (3H, s), 2.43 (6H, s).
Reaction SMILES: [N+](=[CH2:3])=[N-].[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]([CH2:17][C:18]([NH:21][S:22]([C:25]([F:28])([F:27])[F:26])(=[O:24])=[O:23])([CH3:20])[CH3:19])=[O:16])([CH3:7])([CH3:6])[CH3:5]>CCOCC>[CH3:3][N:21]([C:18]([CH3:20])([CH3:19])[CH2:17][C:15]([O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:4]([CH3:5])([CH3:6])[CH3:7])=[O:16])[S:22]([C:25]([F:28])([F:26])[F:27])(=[O:24])=[O:23]
Reactant: C=[N+]=[N-]
Reactant: CC(C)(CC(=O)Oc1ccccc1C(C)(C)C)NS(=O)(=O)C(F)(F)F
Solvent: CCOCC
Product: CN(C(C)(C)CC(=O)Oc1ccccc1C(C)(C)C)S(=O)(=O)C(F)(F)F
Reaction time: 8 h
Yield: 96 %

Procedure:
A freshly prepared solution of diazomethane in anhydrous ether was added in excess to a solution of N-[2-(2-tert-butylphenylcarboxy)-1,1-dimethylethyl]trifluoromethanesulfonamide (13.1 g) in ether. The resulting yellow solution was allowed to stand at RT overnight, then was washed with 10% HCl followed by 2.5N aq NaOH. The organic solution was dried (MgSO4), and concentrated to afford 13.0 g of pure N-methyl-N-[2-(2-tert-butylphenylcarboxy)-1,1-dimethylethyl]trifluoromethanesulfonamide as a white solid, a 96% yield. m.p. 42-44° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([Cl:10])[C:3]=1[N:11]=[C:12]=[O:13].[CH3:14][NH:15][C:16]1[CH:21]=[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[CH:25][CH:24]=2)[N:19]=[CH:18][N:17]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([Cl:10])[C:3]=1[NH:11][C:12](=[O:13])[N:15]([CH3:14])[C:16]1[CH:21]=[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[CH:25][CH:24]=2)[N:19]=[CH:18][N:17]=1
Reactant: COc1ccc(Cl)c(N=C=O)c1Cl
Reactant: CNc1cc(Nc2ccc(N3CCN(C)CC3)cc2)ncn1
Solvent: Cc1ccccc1
Product: COc1ccc(Cl)c(NC(=O)N(C)c2cc(Nc3ccc(N4CCN(C)CC4)cc3)ncn2)c1Cl
Temperature: 110 °C
Reaction time: 17 h

Procedure:
To a solution of 2,6-dichloro-3-methoxyphenylisocyanate (preparation 1, 52.3 mg, 0.24 mmol, 1.2 eq.) in toluene (2.5 ml) is added N-methyl-N′-[4-(4-methyl-piperazin-1-yl)-phenyl]-pyrimidine-4,6-diamine (59.7 mg, 0.2 mmol, 1.0 eq.). The obtained suspension is stirred under argon at 110° C. for 17 h. After cooling the crude product is filtered off und purified by flash chromatography (100% DCM to 5% MeOH in DCM within 35 min). Fractions containing the product are pooled and evaporated to dryness. The residue is triturated with ether (2 ml) and treated with ultra sound until a homogeneous suspension is obtained. The precipitate is filtered off and vacuum dried at 60° C. over night to afford the title compound as a colorless powder: m.p. 161.5-163° C., HPLC: tR=5.07 min (purity: >99%, gradient A), ESI-MS: 516.6/518.5/520.4 [MH]+.
Reaction SMILES: O.[NH2:2][NH2:3].[CH:4]1([C:7]([C:9]2[C:10](Cl)=[N:11][CH:12]=[N:13][C:14]=2[Cl:15])=O)[CH2:6][CH2:5]1>C1COCC1>[Cl:15][C:14]1[N:13]=[CH:12][N:11]=[C:10]2[NH:2][N:3]=[C:7]([CH:4]3[CH2:6][CH2:5]3)[C:9]=12
Reactant: NN
Reactant: O=C(c1c(Cl)ncnc1Cl)C1CC1
Solvent: O
Solvent: C1CCOC1
Product: Clc1ncnc2[nH]nc(C3CC3)c12
Reaction time: 4 h

Procedure:
Add hydrazine hydrate (2.67 g, 53.4 mmol) slowly to cyclopropyl-(4,6-dichloro pyrimidin-5-yl)-methanone (9.66 g, 44.5 mmol) dissolved in 300 mL THF at room temperature and stir for 4 hours. Upon completion, partition the reaction mixture between water and ethyl acetate, collect the organic layer, wash with saturated aqueous sodium chloride, dry over anhydrous sodium sulfate, and concentrate under vacuum. Purify the resultant title compound by passing through a short silica gel (60-120 mesh) pad using Chloroform/methanol (97:3) as eluent.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1.CC(C)([O-])C.[K+].Br[CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CN(C=O)C>[O:16]=[C:5]1[C:4]2[CH:3]=[C:2]([O:1][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:15]=[CH:14][C:13]=2[O:12][C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: O=c1c2ccccc2oc2ccc(O)cc12
Reactant: CCOC(=O)CCCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCOc1ccc2oc3ccccc3c(=O)c2c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2-hydroxyxanthone (7.7 g, 36 mmol) prepared as described in Example 1, was dissolved in DMF (50 mL), and potassium tert-butoxide (4.6 g, 41 mmol) was added in one portion. The mixture was stirred under N2 at 25° C. for 1.5 hours, and then ethyl 5-bromovalerate (8.74 g, 42 mmol) in DMF (20 mL) was added dropwise over 20 minutes. The reaction mixture was heated at 115° C. for 11 hours, then cooled, filtered, and washed with EtOAc (2×10 mL). The filtrate was concentrated to provide a light-brown oily residue, which slowly solidified at room temperature. Light-beige crystals were collected and washed with n-hexane (3×10 mL). TLC pure, Rf =0.79 benzene-EtOH 10:9. Yield: 9.70 g (79%). A small amount of the product was recrystallized from n-hexane-EtOH (10:1) for elemental analysis. White needles, 1H-NMR (CDCl3 δ: 8.34 (dd, J=1.6 and 8.0 Hz, 1H), 7.66-7.76 (m, 2H, 7.3-7.5 (m, 4H), 4.14 (q, J=7.1 Hz, 2H), 2.40 [t,J=6.9 Hz, 2H, CH2 (C=0)] 1.85 (m, 4H), 1.26 (t,J=7.1 Hz, 3H-CH3).
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:12]3[C:13]=2[C:14](=[O:26])[N:15]([C:17]2[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=2)[N:16]=3)[CH2:3][CH2:2]1.[CH3:27][N:28]([CH3:33])[CH2:29][CH2:30][CH2:31][NH2:32]>O1CCCC1>[CH3:27][N:28]([CH3:33])[CH2:29][CH2:30][CH2:31][NH:32][C:21](=[O:22])[C:20]1[CH:19]=[CH:18][C:17]([N:15]2[C:14](=[O:26])[C:13]3=[C:4]([CH:1]4[CH2:3][CH2:2]4)[NH:5][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:12]3=[N:16]2)=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccc(-n2nc3c4ccccc4[nH]c(C4CC4)c-3c2=O)cc1
Reactant: CN(C)CCCN
Solvent: C1CCOC1
Product: CN(C)CCCNC(=O)c1ccc(-n2nc3c4ccccc4[nH]c(C4CC4)c-3c2=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.4 %

Procedure:
To a partial solution of 4-(4-cyclopropyl-3-oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl)-benzoyl chloride (0.1 g, 0.28 mmol) in tetrahydrofurane (6 ml) under nitrogen was added a solution of 3-dimethylamino-propyl amine (0.03 g, 0.3 mmol) in tetrahydrofurane (3 ml). The mixture was stirred at RT for 3 h. The solvent was removed under reduced pressure and the yellow solid was washed with a little saturated sodium bicarbonate, water and dried under vacuo to yield N-(3-Dimethylamino propyl)-4-(4-cyclopropyl-3-oxo-3,5-dihydro-pyrazolo[4,3-c]-quinolin-2-yl]-benzamide (57 mg, 47%) as a yellow solid. LCMS m/z 430.11 [M+H]+ @ RT 0.99 min: 100% purity.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15](O)=[O:16])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:11]2=[O:25])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[N:27]1([C:33]2[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=3[S:35][N:34]=2)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]([N:30]3[CH2:31][CH2:32][N:27]([C:33]4[C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=5[S:35][N:34]=4)[CH2:28][CH2:29]3)=[O:16])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:11]2=[O:25])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C1CN(S(=O)(=O)c2ccccc2)C(=O)N1c1ccccc1Cl
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: Cl
Product: O=C(C1CN(S(=O)(=O)c2ccccc2)C(=O)N1c1ccccc1Cl)N1CCN(c2nsc3ccccc23)CC1

Procedure:
In analogy to example 1, (RS)-1-benzenesulfonyl-3-(2-chloro-phenyl)-2-oxo-imidazolidine-4-carboxylic acid (example 49, step 2) was coupled with 3-piperazin-1-yl-benzo[d]isothiazole hydrochloride to give the title compound as a colorless solid. MS: 581.6 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][C:3]=1[S:11][CH3:12].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N:19]=[C:20]=[O:21])[CH:14]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:20](=[O:21])[NH:19][C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)=[CH:4][C:3]=1[S:11][CH3:12]
Reactant: CSc1cc2c(cc1Cl)NCC2
Reactant: O=C=Nc1cccnc1
Product: CSc1cc2c(cc1Cl)N(C(=O)Nc1cccnc1)CC2
Yield: 81 %

Procedure:
6-Chloro-5-methylthioindoline (D48) (0.70 g, 3.51 mmol) was treated with 3-pyridylisocyanate as in the procedure described in Example 1. The crude product was recrystallised from ethanol/diethyl ether to give the title compound (0.91 g, 81%) as a white crystalline solid m.p. 241°-242° C.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[Cl:12].C([Li])CCC.CN([CH:21]=[O:22])C>C1COCC1>[Cl:12][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[CH:21]=[O:22])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: CN(C)C=O
Reactant: Clc1cnc2ccccc2c1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1c(Cl)cnc2ccccc12
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A flask was charged with 4-bromo-3-chloroquinoline (A275-2) (1.00 g, 4.12 mmol) and THF (16.5 mL) under nitrogen, and the solution was cooled to −78° C. To the cooled mixture was added n-butyllithium (2.5 M solution in hexane, 1.65 mL, 4.12 mmol) and the mixture was stirred at −78° C. for 1 hour. To the mixture was added DMF (1.60 mL, 20.6 mmol) dropwise, and the mixture was allowed to warm to room temperature. After 4 h, the mixture was quenched with saturated aqueous NH4Cl (20 mL). The mixture was partitioned between water (50 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (1×50 mL). The organic extract was dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude material as a brown syrup. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a REDISEP™ pre-packed silica gel column (80 g), eluting with a gradient of 0% to 20% EtOAc in hexane, and dried under high vacuum to give 3-chloroquinoline-4-carbaldehyde (A275-3) as brown solid. 1H NMR (400 MHz, DMSO-d6) δ 10.74 (1H, s), 9.10 (1H, s), 8.68-8.73 (1H, m), 8.15 (1H, dd, J=8.5, 0.9 Hz), 7.79-7.92 (2H, m); LCMS (ESI) m/z 192.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[N:28]2[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]2)[CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([CH:31]3[CH2:30][CH2:29][N:28]([C:26]4[CH:25]=[CH:24][CH:23]=[C:22]5[C:27]=4[N:18]=[CH:19][CH:20]=[CH:21]5)[CH2:33][CH2:32]3)[CH2:14][CH2:13]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Clc1ccc(N2CCNCC2)c2ncccc12
Reactant: O=C1CCN(c2cccc3cccnc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Clc1ccc(N2CCN(C3CCN(c4cccc5cccnc45)CC3)CC2)c2ncccc12

Procedure:
Using the synthetic methods described in previous examples, 5-chloro-8-(piperazin-1-yl)quinoline (Step 3) and 1-quinolin-8-yl-piperidin-4-one (Example A, Step 5, above) were reacted with sodium triacetoxyborohydride to give the desired product as a beige solid; MP. 201-203° C.; MS (ES) m/z (relative intensity) 459 (M+H)+ (100).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[C:2]#[CH:3].[N+:8]([C:11]1[CH:30]=[CH:29][C:14]([CH2:15][O:16][C:17]([N:19]2[CH2:27][CH2:26][N+:25]3[C-:21](C(=O)O[N:24]=3)[CH2:20]2)=[O:18])=[CH:13][CH:12]=1)([O-:10])=[O:9]>CC1C=CC=CC=1C>[N+:8]([C:11]1[CH:12]=[CH:13][C:14]([CH2:15][O:16][C:17]([N:19]2[CH2:27][CH2:26][N:25]3[N:24]=[C:2]([C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH:3]=[C:21]3[CH2:20]2)=[O:18])=[CH:29][CH:30]=1)([O-:10])=[O:9]
Reactant: C#CC(=O)OCC
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CC[n+]2noc(=O)[c-]2C1
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1cc2n(n1)CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C2

Procedure:
ethyl propiolate (cont. 99%)(8.28 g) was added to the o-xylene (348 mL) solution of 5-(4-nitrobenzyloxycarbonyl)-3-oxo-3a,4,6,7-tetrahydro-3H-2-oxa-1,5-diaza-7a-azoniainden-3a-ide (22.3 g) under a nitrogen atmosphere and refluxed for 16 h. The solution was concentrated under reduced pressure, followed by silica-gel column chromatography 3 times (n-hexane/AcOEt=2/1–1/3). The titled compound was obtained as pale yellow crystals (16.78 g, 64%). Besides, 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-3,5-dicarboxylic acid 3-ethyl ester 5-(4-nitrobenzyl) ester was obtained as pale yellow crystals (6.18 g, 24%).