Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:9])[C:5](O)=[N:6][CH:7]=1.P(Br)(Br)[Br:11]>>[Cl:9][C:4]1[C:5]([Br:11])=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: Oc1ncc(Br)cc1Cl
Reactant: BrP(Br)Br
Product: Clc1cc(Br)cnc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
36.0 g (172.7 mmol) of 5-bromo-3-chloro-2-hydroxypyridine are stirred at 160° C. for 6 hours in 320 ml of phosphorus tribromide. The reaction mixture is cooled to room temperature and poured carefully into ice water. After 2 hours, the mixture is extracted three times with 500 ml of dichloromethane in each case. The combined organic phases are washed with sodium bicarbonate solution until neutral, dried over Na2SO4 and filtered, and the filtrate is evaporated to dryness. Chromatographic purification (silica gel/dichloromethane) gives 20.53 g of 3-chloro-2,5-dibromopyridine. ##STR14## m.p.: 40°-41° C.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[F:5][C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=1)[NH2:9]>>[F:5][C:6]1[CH:12]=[CH:11][CH:10]=[C:8]([N:9]=[C:1]=[S:2])[CH:7]=1
Reactant: Nc1cccc(F)c1
Reactant: S=C(Cl)Cl
Product: Fc1cccc(N=C=S)c1

Procedure:
A solution of thiophosgene and 3-fluoroaniline were processed as described in Example 55A to provide the desired product.
Reaction SMILES: C(O[C:6](=O)[N:7]([C@@H:9]([C:18](=[O:21])[NH:19][CH3:20])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)C)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+].C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl>[F:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][C@@H:9]([NH:7][CH3:6])[C:18]([NH:19][CH3:20])=[O:21])=[CH:16][CH:15]=1
Reactant: CNC(=O)[C@@H](Cc1ccc(F)cc1)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)[C@@H](Cc1ccc(F)cc1)NC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
((1R)-2-(4Fluorophenyl)-1-(methylcarbamoyl)ethyl)-methylcarbamic acid tert-butylester (1.0 g; 3.22 mmol) was dissolved in methylene chloride (5 mL). Trifluoroacetic acid (5 mL) was added and the reaction mixture was stirred for 30 min at room temperature. Methylene chloride (30 mL), an aqueous solution of sodium hydrogen carbonate/sodium carbonate (pH 9; 30 mL) and sodium hydrogen carbonate (solid), were added to the reaction mixture, until pH 9. The organic phase was dried (magnesium sulfate) and evaporated in vacuo to afford 0.62 g of (2R)-3-(4-fluorophenyl)-N-methyl-2-methylaminopropionamide.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[NH:19][C:18]3=[O:26])[CH2:13][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[H-].[Na+].Br[CH2:30][CH2:31][O:32][C:33](=[O:35])[CH3:34]>O1CCCC1>[CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[N:19]([CH2:30][CH2:31][O:32][C:33](=[O:35])[CH3:34])[C:18]3=[O:26])[CH2:13][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: CC(=O)OCCBr
Reactant: COC(=O)N1CCC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)N1CCC(N2CCC(n3c(=O)n(CCOC(C)=O)c4ccccc43)CC2)CC1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
Three-hundred (300) mg of 1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one was dissolved in 15 ml of tetrahydrofuran, and to which 33 mg of 60% sodium hydride was added. After evolution of a gas ceased, 93 μl of (2-bromoethyl)acetate was added, heated to 40° C. and stirred for 2 hours. The reaction liquid was concentrated and the remaining matter was distributed between water and chloroform. The chloroform layer was separated, dried over anhydrous sodium sulfate, concentrated and the residue was purified by silica gel column chromatography (chloroform/methanol=19/1). Thus 354 mg of 1-[1-(1-methoxycarbonylpiperidin-4-yl)-piperidin-4-yl]-3-(2-acetoxy-ethyl)-1,3-dihydro-2H-benzimidazol-2-one was obtained. The product was dissolved in 10 ml of methanol, to which 35 mg of sodium borohydride was added and stirred for 7 hours at room temperature. The reaction liquid was concentrated, to which water was added and extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and then concentrated. The residue was purified by silica gel column chromatography (chloroform/methanol=19/1), to provide 246 mg of the title compound as a colorless, amorphous substance.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[CH2:13]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH:29]([OH:31])[CH3:30])[CH2:25][CH2:24]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl>[S:2]([O:31][CH:29]([CH:26]1[CH2:27][CH2:28][N:23]([C:21]([O:20][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:22])[CH2:24][CH2:25]1)[CH3:30])(=[O:4])(=[O:3])[CH3:1]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(OS(C)(=O)=O)C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 3 h

Procedure:
A solution of methanesulphonyl chloride (0.85 ml) in dichloromethane (20 ml) was added dropwise to a stirred, ice-cooled solution of triethylamine (1.55 ml) and the product of step (i) (2.64 g) in dichloromethane (50 ml). After stirring for 3 hours the reaction mixture was washed with water (3×) and brine, dried (PS paper) and evaporated in vacuo to yield N-benzyloxycarbonylpiperidin-4-ylethanol mesylate as a colourless paste (3.4 g) NMR (d6DMSO) : δ 0.9-1.2 (2H,m); 1.5-1.8 (5H,m);2.6-2.9 (2H,m); 4.0 (2H,d);4.25 (2H,t);4.4 (3H,s); 5.1 (2H,s); 7.35 (5H,m); m/e 342 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]([P:21](=[O:24])([OH:23])[OH:22])[CH:10]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:11][CH2:12][CH2:13]Br)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[C:25]([O-:28])(=[S:27])[CH3:26].[Na+]>CC(C)=O>[CH2:1]([O:3][P:4]([CH:9]([P:21](=[O:24])([OH:23])[OH:22])[CH:10]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:11][CH2:12][CH2:13][S:27][C:25](=[O:28])[CH3:26])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CC([O-])=S
Reactant: CCOP(=O)(OCC)C(C(CCCBr)c1cccnc1)P(=O)(O)O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOP(=O)(OCC)C(C(CCCSC(C)=O)c1cccnc1)P(=O)(O)O
Temperature: 50 °C
Reaction time: 12 h

Procedure:
A solution of [5-bromo-2-(3-pyridinyl)pentylidene]bis [phosphonic acid] diethyl ester (5.0 mmol) is stirred in dry acetone (35 ml) and sodium thioacetate (5.2 mmol) is added. The mixture is stirred at 50° C. for 12 hours. After cooling to room temperature the solvent is removed under reduced pressure. The crude residue is dissolved in methylene chloride and washed with water. The organic layer is then dried and concentrated under reduced pressure. The desired product is purified by flash chromatography using a 5-10% isopropanol in methylene chloride gradient on silica gel.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]2[N:16]([CH:17]=1)[CH2:15][CH2:14][O:13][C:12]1[C:7]2=[CH:8][C:9]([C:19]#[C:20][C:21]([OH:27])([CH3:26])[C:22](OC)=[O:23])=[C:10]([F:18])[CH:11]=1)(=[O:3])[NH2:2].[NH3:28].CO>>[C:22]([C:21]([OH:27])([CH3:26])[C:20]#[C:19][C:9]1[C:10]([F:18])=[CH:11][C:12]2[O:13][CH2:14][CH2:15][N:16]3[C:6](=[N:5][C:4]([C:1]([NH2:2])=[O:3])=[CH:17]3)[C:7]=2[CH:8]=1)(=[O:23])[NH2:28]
Reactant: N
Reactant: COC(=O)C(C)(O)C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2
Solvent: CO
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)C(N)=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of methyl 4-[4-carbamoyl-12-fluoro-9-oxa-3,6-diazatricyclo[8.4.0.0[2,6]]tetradeca-1(14),2,4,10,12-pentaen-13-yl]-2-hydroxy-2-methylbut-3-ynoate (300 mg, 0.80 mmol, 1.00 equiv) in NH3/MeOH (30 w/w %, 40 mL). The resulting solution was stirred for 12 h at 25° C. The resulting mixture was concentrated under vacuum. The resulting mixture was washed with 3×10 mL of methanol and 2×5 mL of CH3CN. The trace solvents were removed under reduced pressure. This resulted in 43 mg (15%) of 9-(3-Carbamoyl-3-hydroxy-but-1-ynyl)-8-fluoro-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid amide as a brown solid. LC-MS: (ES, m/z): 359[M+H]+; 1H-NMR: (400 MHz, DMSO-d6, ppm): δ 8.579 (d, 1H), 7.786 (s, 1H), 7.589 (br s, 1H), 7.378 (br s, 2H), 7.128 (br s, 1H), 7.029 (d, 1H), 6.423 (s, 1H), 4.600-4.410 (m, 4H), 1.612 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH:11](=[O:13])[CH3:12]>>[Br:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6]([CH2:8][CH:11]([OH:13])[CH3:12])[CH:7]=1
Reactant: CC=O
Reactant: Cc1cnc(C#N)c(Br)c1
Product: CC(O)Cc1cnc(C#N)c(Br)c1

Procedure:
3-Bromo-5-(2-hydroxypropyl)picolinonitrile was prepared from 3-bromo-5-methylpicolinonitrile (from the previous step) and acetaldehyde following the procedures described for Example 53/Step 3.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([C:9](=[O:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Br:18]Br>CCOCC>[Br:18][CH2:10][C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=1)=[O:11]
Reactant: BrBr
Reactant: CC(=O)c1cccc(C(F)(F)F)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: O=C(CBr)c1cccc(C(F)(F)F)c1

Procedure:
To a solution of 24.8 g. (0.127 mol.) of m-trifluoromethylacetophenone in 20 ml. of anhydrous ether is added with cooling and stirring 0.15 g. of anhydrous aluminum chloride and 20.2 g. (0.127 mol.) of bromine. The reaction mixture is concentrated and the residue is distilled to give α-bromo-m-trifluoromethylacetophenone, b.p. 135°-140° (20 mm.).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1.Cl>O>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:2]2[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[N:5]=[C:4]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=3)[N:3]=2)=[CH:22][CH:21]=1
Reactant: COCc1cc(Cl)nc(-c2cccc(C)c2)n1
Reactant: COc1ccc(N)cc1
Agent: Cl
Solvent: O
Product: COCc1cc(Nc2ccc(OC)cc2)nc(-c2cccc(C)c2)n1
Yield: 40.8 %

Procedure:
A mixture of 4-chloro-6-(methoxymethyl)-2-(3-methylphenyl)pyrimidine (100 mg, 0.402 mmol), p-anisidine (50 mg, 0.402 mmol), water (5 ml) and 2N HCl (300 μl) was refluxed overnight. The resulting yellow solid was collected by filtration, washed with water and then dried under vacuum to give the title compound (55 mg, 41%). 1H NMR (CDCl3): 8.28 (d, J=8.7 Hz, 2H), 7.43-7.35 (m, 4H), 6.96 (d, J=9.0 Hz, 2H), 6.83 (s, 1H), 4.64 (s, 2H), 3.85 (s, 3H), 3.45 (s, 3H), 2.44 (s, 3H).
Reaction SMILES: [CH2:1]([NH:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[C:12](SC)=[NH:13])[CH2:2][CH2:3][CH2:4][CH3:5].[F:16][C:17]([F:23])([F:22])[C:18]([NH:20][NH2:21])=O>C(O)C>[CH2:1]([NH:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[C:12]1[NH:21][N:20]=[C:18]([C:17]([F:23])([F:22])[F:16])[N:13]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCNc1nc[nH]c1C(=N)SC
Reactant: NNC(=O)C(F)(F)F
Solvent: CCO
Product: CCCCCNc1nc[nH]c1-c1nc(C(F)(F)F)n[nH]1

Procedure:
The mixture of methyl 4-(pentylamino)-1H-imidazole-5-carbimidothioate (0.53 g, 2.4 mmol) and trifluoroacetic acid hydrazide (0.45 g, 3.5 mmol) in ethanol (10 mL) was refluxed overnight. The reaction mixture was concentrated to yield the product as slightly green viscous oil. LCMS calculated for C11H16F3N6(M+H): 289.1. found: 289.1.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1.[NH2:15][C:16]1[CH:17]=[C:18]([C:22]2[C:26]([Br:27])=[CH:25][N:24]([CH3:28])[N:23]=2)[CH:19]=[CH:20][CH:21]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:27][C:26]1[C:22]([C:18]2[CH:17]=[C:16]([NH:15][C:8]([C:7]3[CH:11]=[CH:12][C:4]([O:3][C:2]([F:14])([F:13])[F:1])=[CH:5][CH:6]=3)=[O:9])[CH:21]=[CH:20][CH:19]=2)=[N:23][N:24]([CH3:28])[CH:25]=1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: Cn1cc(Br)c(-c2cccc(N)c2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(Br)c(-c2cccc(NC(=O)c3ccc(OC(F)(F)F)cc3)c2)n1
Reaction time: 16 h
Yield: 75.7 %

Procedure:
To 4-(trifluoromethoxy)benzoyl chloride (19 μL, 0.12 mmol) in CH2Cl2 (1 mL) was added dropwise a solution of 3-(3-aminophenyl)-4-bromo-1-methylpyrazole (30 mg, 0.12 mmol) and triethylamine (17 μL, 0.12 mmol) in CH2Cl2 (0.5 mL). The reaction mixture was stirred for 16 h and concentrated. Chromatography on flash silica (50% EtOAc/hexane) gave the title compound as a colourless solid (40 mg, 76%), m.p. 138.6-139.6° C. (EtOAc/hexane).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[CH3:25][O:26][C:27]1[N:32]=[C:31](B(O)O)[CH:30]=[CH:29][CH:28]=1>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:31]4[CH:30]=[CH:29][CH:28]=[C:27]([O:26][CH3:25])[N:32]=4)=[C:4]([CH:9]=3)[C:3]([OH:24])=[O:2])[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: COc1cccc(B(O)O)n1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: COc1cccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)n1
Yield: 25.1 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with and 6-methoxypyridine-2-boronic acid (available from Combi-Blocks Inc.; 61 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-2-(6-methoxy-pyridin-2-yl)-benzoic acid (23 mg, 25%). 1H NMR (400 MHz, DMSO-d6) δ 12.95 (br s, 3H), 8.48 (s, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.21 (dd, J=4.3, 2.3 Hz, 2H), 8.10 (dd, J=8.3, 2.0 Hz, 1H), 7.73-7.94 (m, 3H), 7.39 (d, J=7.3 Hz, 1H), 6.83 (d, J=8.0 Hz, 1H), 3.88 (s, 3H), 2.54 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]([CH:15]1[CH:19]=[CH:18][C:17](=[O:20])[O:16]1)[CH2:9][CH:10]([CH3:14])[CH2:11][CH:12]=[CH2:13])([CH3:4])([CH3:3])[CH3:2].[C:22]1(C)C=CC=CC=1>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu].[Cu].[Cu].[Cu].[Cu].[Cu]>[C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]([CH:15]1[CH2:19][CH:18]([CH3:22])[C:17](=[O:20])[O:16]1)[CH2:9][CH:10]([CH3:14])[CH2:11][CH:12]=[CH2:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccccc1
Reactant: C=CCC(C)C[C@@H](NC(=O)OC(C)(C)C)C1C=CC(=O)O1
Agent: [Cu]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: C=CCC(C)C[C@@H](NC(=O)OC(C)(C)C)C1CC(C)C(=O)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under nitrogen atmosphere to 20 ml thoroughly degassed toluene are subsequently added 0.63 g (0.31 mmol) hydrido(triphenylphosphine)copper(I) hexamer, 2.9 ml polymethylhydrosiloxane and a (degassed) solution of 5.7 g (19.3 mmol) [(R)-3-methyl-1-(5-oxo-2,5-dihydro-furan-2-yl)hex-5-enyl]-carbamic acid tert-butyl ester in toluene. After stirring for 2 h at 25° C. 6 mg (0.01 mmol) of R(+)-2,2′-bis-(diphenylphosphino)-6,6′-dimethoxy-1,1-biphenyl are added as an accelerating ligand for the copper complex. After 12 h the mixture is diluted with ethyl acetate and washed with water, 5% aqueous citric acid and 5% aqueous NaHCO3. Chromatography on silica gel (EtOAc/hexane 1:9, then 1:3) provides the title compound as a diastereomeric mixture.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][C:13]([S:19]([OH:22])(=[O:21])=[O:20])=[CH:14]2)=O)(C)(C)C.[Cl:23]N1C(=O)CCC1=O>>[NH2:8][C:9]1[CH:18]=[CH:17][C:16]([Cl:23])=[C:15]2[C:10]=1[CH:11]=[CH:12][C:13]([S:19]([OH:22])(=[O:21])=[O:20])=[CH:14]2
Reactant: CC(C)(C)OC(=O)Nc1cccc2cc(S(=O)(=O)O)ccc12
Reactant: O=C1CCC(=O)N1Cl
Product: Nc1ccc(Cl)c2cc(S(=O)(=O)O)ccc12
Yield: 100.1 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 31B, 5-(tert-butoxycarbonylamino)naphthalene-2-sulfonic acid (Intermediate 31A, 3.70 g, 11.44 mmol) and N-chlorosuccinimide (1.60 g, 12.01 mmol) were converted to the title compound (2.95 g, 90%). MS(ESI+) m/z 275.1 (M+NH4)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:13][C:12]3[CH:14]=[CH:15][C:16]([CH:18]([CH3:22])[C:19]([OH:21])=[O:20])=[CH:17][C:11]=3[C:10](=[O:23])[CH2:9][C:8]=2[CH:24]=1)([O-:3])=[O:2].CO.[C:27](=O)([O-])O.[Na+]>C(O)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:13][C:12]3[CH:14]=[CH:15][C:16]([CH:18]([CH3:22])[C:19]([O:21][CH3:27])=[O:20])=[CH:17][C:11]=3[C:10](=[O:23])[CH2:9][C:8]=2[CH:24]=1)([O-:3])=[O:2]
Reactant: O=C([O-])O
Reactant: CC(C(=O)O)c1ccc2c(c1)C(=O)Cc1cc([N+](=O)[O-])ccc1S2
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)C(C)c1ccc2c(c1)C(=O)Cc1cc([N+](=O)[O-])ccc1S2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
To 72 mg of 2-(10,11-dihydro-8-nitro-11-oxodibenzo[b,f]-thiepin-2-yl)-propionic acid were added 10 ml of a diazomethaneether solution and 1 ml of methanol, and the mixture was stirred at room temperature for 30 minutes. To this was added acetic acid, and the mixture was made alkaline with a saturated sodium hydrogen carbonate solution and then extracted with benzene. The extract was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed by distillation to obtain a yellow oil, which was chromatographed over 2 g of silica gel and eluted with chloroform, thereby obtaining 44 mg (yield: 57%) of methyl 2-(10,11-dihydro-8-nitro-11-oxodibenzo[b,f]thiepin-2-yl)-propionate as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]([O:16][CH3:17])=[O:15])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2.CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>>[CH3:20][N:21](/[CH:23]=[N:1]/[C:2]1[C:3]([C:14]([O:16][CH3:17])=[O:15])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2)[CH3:22]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)c1cc2cc(OC)ccc2cc1N
Product: COC(=O)c1cc2cc(OC)ccc2cc1/N=C/N(C)C
Temperature: 25 °C

Procedure:
A suspension of 1.2 g (5.2 mmol) of methyl 3-amino-7-methoxy-2-naphthoate in 30 mL of dimethylformamide dimethylacetal is refluxed for 2.5 hours. The mixture is cooled to room temperature. The resulting precipitate is collected by filtration and washed with ether. After drying in vacuo, this yields 1.28 g (85.9%) of methyl 3-{[(E)-(dimethylamino)methylidene]amino}-7-methoxy-2-naphthoate as a light yellow solid, mp 160–162° C.,
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]#[N:29].O.[NH2:32][NH2:33]>CN(C=O)C>[C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH2:21][CH2:20][C:19]1[C:3]2[C:4](=[O:18])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:33][N:32]=1)#[N:29]
Reactant: NN
Reactant: N#Cc1ccccc1CCC(=O)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccccc1CCc1n[nH]c2c1c(=O)n(-c1ccccc1)c1ncccc21
Yield: 97 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-3-(2-cyanophenyl)propyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (991 mg, 2.51 mmol, prepared in Synthetic Example 11) in DMF (25 ml) was added hydrazine monohydrate (80%, 371 μl, 9.26 mmol, 3.7 eq.), and the mixture was treated in the same manner as in Example 16 to give 3-[2-(2-cyanophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (953 mg, 97%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[C:12]([CH3:14])[N:11]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([CH:22]=[CH:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:18][CH:17]=3)[C:10]=2[CH:30]=1)=[O:5])[CH3:2]>[C].[Pd].C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[C:12]([CH3:14])[N:11]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:18][CH:17]=3)[C:10]=2[CH:30]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2nc(C)n(Cc3ccc(C=Cc4ccccc4)cc3)c2c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1ccc2nc(C)n(Cc3ccc(CCc4ccccc4)cc3)c2c1
Reaction time: 23 h

Procedure:
In a nitrogen environment, 5% palladium-carbon is added to an ethanol (910 ml) solution of 6-ethoxycarbonyl-2-methyl-1-[4-(2-phenylethenyl)benzyl]benzimidazole (0.320 g). The solution is stirred for 23 hours under a nitrogen environment. Solids are separated through filtration, the filtrate is concentrated, and thus, 6-ethoxycarbonyl-2-methyl-1-[4-(2-phenylethyl)benzyl]-benzimidazole is obtained. This material is immediately used for the following reaction.
Reaction SMILES: [C:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([NH:11][C@@H:12]([CH3:28])[CH2:13][N:14]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21](Cl)[CH:20]=3)=[N:15]2)=[O:10])[CH:5]=1)(=[O:3])[CH3:2].CN(C=O)C.[CH3:34][S-:35].[Na+]>CC#N>[C:1]([C:4]1[CH:5]=[C:6]([C:9]([NH:11][C@@H:12]([CH3:28])[CH2:13][N:14]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([S:35][CH3:34])[CH:20]=3)=[N:15]2)=[O:10])[NH:7][N:8]=1)(=[O:3])[CH3:2]
Reactant: C[S-]
Reactant: CC(=O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)n[nH]1
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CSc1cc(-c2ccn(C[C@H](C)NC(=O)c3cc(C(C)=O)n[nH]3)n2)ccc1C#N
Temperature: 150 °C
Yield: 13.8 %

Procedure:
(S)—5-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-3-carboxamide (64 mg, 0.16 mmol) was placed into a microwave vial. DMF (1 ml) and sodium thiomethoxide (12.4 mg, 0.18 mmol) were added and the reaction mixture was heated in microwave reactor at 150° C. Sodium thiomethoxide was added after 30, 30 and 20 min of heating (12.4 mg, 5.6 mg and 5.6 mg, respectively). After total of 90 min of heating DMF was evaporated, and the evaporation residual was taken up in DCM and washed with water. Organic phase was dried over Na2SO4, filtered and evaporated. Thus obtained crude product was suspended in MeCN. Suspension was filtered to give 9 mg (14%) of the title compound as a colourless solid. Filtrate was purified by CombiFlash (column: C-18 silica, eluent: 0-100% MeCN in water) to yield 13 mg (20%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.11-1.20 (m, 3H), 2.49 (s, 3H, overlap with DMSO) 2.57-2.64 (m, 3H), 4.20-4.55 (m, 3H), 6.91 (s, 1H), 7.31 (s, 1H), 7.62-7.89 (m, 4H), 8.47 (dd, 1H), 14.2 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[F:19][C:20]1[CH:21]=[CH:22][C:23]2[O:27][CH:26]=[C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[C:24]=2[CH:34]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[F:1][C:2]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][CH:15]([N:31]3[CH2:32][CH2:33][N:28]([C:25]4[C:24]5[CH:34]=[C:20]([F:19])[CH:21]=[CH:22][C:23]=5[O:27][CH:26]=4)[CH2:29][CH2:30]3)[CH2:14][CH2:13]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Fc1ccc2occ(N3CCNCC3)c2c1
Reactant: O=C1CCN(c2ccc(F)c3cccnc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Fc1ccc2occ(N3CCN(C4CCN(c5ccc(F)c6cccnc56)CC4)CC3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.2 %

Procedure:
To a solution of 0.200 g of 1-(5-fluoro-quinolin-8-yl)-piperidin-4-one (Example C, Step 3, 0.20 g) and 5-fluoro-3-piperazino benzofuran (Step 2, 0.20 g) in CH2Cl2 (10 mL) was added sodium triacetoxyborohydride (0.224 g) and 0.02 mL acetic acid. The reaction was stirred at room temperature overnight. It was quenched with 1N NaOH, and the product was extracted with CH2Cl2. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ML of silica gel using 50% Ethyl acetate/Hexanes then 100% Ethyl acetate to give 0.100 g of the desired product. Mp: 187-189° C.; MS (ES) m/z (relative intensity): 449 (M++−H, 100).