Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:14])=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6](O)=O.O=S(Cl)Cl.[C:19]([O:27]C)(=[O:26])[CH2:20][CH2:21][C:22]([O:24][CH3:25])=O>[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[CH3:25][O:24][C:22]1[C:9]2[C:5](=[C:4]([CH3:14])[C:3]([O:2][CH3:1])=[C:11]([O:12][CH3:13])[CH:10]=2)[CH:6]=[C:20]([C:19]([OH:27])=[O:26])[CH:21]=1
Reactant: COc1ccc(C(=O)O)c(C)c1OC
Reactant: COC(=O)CCC(=O)OC
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: O=S(Cl)Cl
Product: COc1cc2c(OC)cc(C(=O)O)cc2c(C)c1OC

Procedure:
4,6,7-Trimethoxy-8-methyl-2-naphthoic acid (7) is prepared in six steps according to the following reaction diagram. Reduction of 3,4-dimethoxy-2-methylbenzoic acid (1) to aldehyde (2) can be carried out by the Rosenmund reaction (SOCl2 then H2, Pd/BaSO4) (see reference 27). The aldehyde (2) is then reacted with dimethyl succinate (Stobbe reaction) (see reference 28). The coupling product (3) is not isolated but is treated directly with sodium acetate in the presence of acetic anhydride and acetic acid (AcOH/Ac2O 1:1) to give 4. After saponification, 4-hydroxy-6,7-dimethoxy-8-methyl-2-naphthoic acid (5) is obtained with a yield of 70% (3 steps). After esterification under the conditions described above (90%), compound 6 is hydrolysed to give 4,6,7-trimethoxy-8-methyl-2-naphthoic acid (7) (92%).
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:5]=2[CH:4]=[CH:3][C:2]=1[OH:12].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.O>CN(C=O)C>[CH:21]1([CH2:20][O:12][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[CH:1]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: BrCC1CCCCC1
Reactant: Oc1ccc2c(c1)CCCCC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: c1cc2c(cc1OCC1CCCCC1)CCCCC2
Temperature: 60 °C

Procedure:
To a mixture of 6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ol (Helvetica Chimica Acta 1947, 1883.) (9.9 g, 61.0 mmol) and Cs2CO3 (26.3 g, 73.2 mmol) in DMF (100 ML) was added (bromomethyl)cyclohexane (10.2 mL, 73.2 mmol). The mixture was heated to 60° C. for 18 h, dumped into water and extracted with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate and concentrated to a solid. The solid was recrystallized from ethanol (13.0 g, 83%). m.p. 62-63° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[C@@H:25](Cl)[CH3:26]>CN1CCCC1=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[C@@H:25]([C:19]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=2[Cl:17])[CH3:26])=[CH:4][CH:3]=1
Reactant: C[C@H](Cl)c1ccc(Cl)cc1Cl
Reactant: Brc1ccc2cn[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: C[C@H](c1ccc(Cl)cc1Cl)n1ncc2ccc(Br)cc21
Temperature: 25 °C
Yield: 39 %

Procedure:
To a solution of 6-bromoindazole (3.4 g, 17.0 mmol) and Cs2CO3 (15.8 g, 48.5 mmol) in 1-methyl-2-pyrrolidinone (NMP, 11 mL) at 85° C. was added crude (S)-2,4-dichloro-1-(1-chloroethyl)benzene (3.2 g, 15.4 mmol) dropwise. The reaction mixture was heated for 10 min, and cooled to room temperature. The mixture was diluted with ethyl acetate (20 mL), washed with deionized water and brine, dried (Na2SO4), and concentrated in vacuo. The resulting crude material was purified by flash chromatography (SiO2, 5% ethyl acetate in hexanes) to afford (R)-6-bromo-1-(1-(2,4-dichlorophenyl)ethyl)-1H-indazole (2.2 g, 6.0 mmol, 39%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[C:4]([F:11])[CH:3]=1.Br[C:13]1[N:18]=[CH:17][CH:16]=[CH:15][N:14]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]2[N:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[C:4]([F:11])[CH:3]=1
Reactant: Brc1ncccn1
Reactant: OB(O)c1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Fc1cc(Br)ccc1-c1ncccn1
Reaction time: 8 h

Procedure:
4-Bromo-2-fluorophenyl boronic acid (2AB) (3.0 g, 13.71 mmol, 1 equiv), 2-bromopyrimidine (1AB) (6.54 g, 41.13 mmol, 3 equiv), and 2M sodium carbonate (34 mL) were added in a pressure vessel (350 mL) and a (1v:1v) mixture of toluene and ethanol (45 mL: 45 mL) was added. The mixture was then bubbled with nitrogen gas for about 10 minutes. Tetrakistriphenylphosphine palladium (0) (793 mg, 0.686 mmol, 0.05 equiv) was added to the mixture. The reaction vessel was tightly capped, placed in an oil bath at 90° C. and stirred overnight.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].Br[CH2:19][C:20]1([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[O:24][CH2:23][CH2:22][O:21]1.O>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:19][C:20]3([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)[O:21][CH2:22][CH2:23][O:24]3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: Clc1ccc(C2(CBr)OCCO2)cc1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CN1CCc2c(c3cc(Cl)ccc3n2CC2(c3ccc(Cl)cc3)OCCO2)C1
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1 g, 4.4 mmol) was dissolved in 10 mL of NMP. KOH (1.77 g, 31.78 mmol) was added at RT under nitrogen atmosphere and the reaction mixture was stirred for 5 min. 2-Bromomethyl-2-(4-chlorophenyl)-1,3-dioxolane (1.68 mg, 6.81 mmol) was added and the reaction mixture was heated at 100° C. for 3 h. Water was added and the product was extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-2% MeOH:DCM.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6](O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32][C:33]([NH2:35])=[O:34])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1>C(O)(=O)C>[F:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32][C:33]([NH:35][C:1]3[C:11]4[CH:10]=[CH:9][C:8]5[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=5[CH2:6][C:5]=4[CH:4]=[CH:3][CH:2]=3)=[O:34])[CH2:26][CH2:25]2)=[CH:22][CH:23]=1
Reactant: OC1c2ccccc2C=Cc2ccccc21
Reactant: NC(=O)CCCN1CCN(c2ccc(F)cc2)CC1
Solvent: CC(=O)O
Product: O=C(CCCN1CCN(c2ccc(F)cc2)CC1)Nc1cccc2c1C=Cc1ccccc1C2
Temperature: 70 °C
Reaction time: 20 h
Yield: 57.1 %

Procedure:
A mixture of 200 mg of 5H-dibenzo[a,d]cyclohepten-5-ol, 300 mg of 4-[4-(4-fluorophenyl)-1-piperazinyl]butyramide and 8 ml of acetic acid is stirred at 70° C. for 20 hours. The acetic acid is distilled off under reduced pressure and 100 ml of chloroform is added to the residue. The solution is washed successively with 10% aqueous potassium carbonate solution, water and saturated aqueous sodium chloride solution, and dried over magnesium sulfate, and the chrloroform is distilled off. The residue is chromatographed on silica gel with chloroform-methanol (100:3) to give 250 mg of the title compound. m.p. 233°-235° C. (recrystallized from chloroform-n-hexane);
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[C:13](=[O:15])[CH3:14])=[O:4].[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17].[ClH:21]>C1(C)C=CC=CC=1.CCOCC>[ClH:21].[CH2:16]([N:18]([CH2:19][CH3:20])[CH2:2][C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[C:13](=[O:15])[CH3:14])=[O:4])[CH3:17]
Reactant: CCNCC
Reactant: CC(=O)c1cccc(C)c1NC(=O)CBr
Agent: Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCN(CC)CC(=O)Nc1c(C)cccc1C(C)=O

Procedure:
To a solution of 4.0 g of 2-bromo-2'-acetyl-6'-methylacetanilide in 60 ml of toluene was added 2.5 g of diethylamine at room temperature. The resultant mixture was stirred at room temperature overnight. The reaction mixture was washed with water, dried over anhydrous sodium sulfate and evaporated to give an oily residue. The residue was dissolved in ether and hydrogen chloride was added to the solution to give crystals. Recrystallization from ethanol-ether gave 2-(diethylamino)-2'-acetyl-6'-methylacetanilide hydrochloride having a melting point of 141° to 143° C.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=1)[C:8]#[N:9])([O-])=O.[CH3:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][OH:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=1)[C:8]#[N:9]
Reactant: COCCOCCOCCO
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOCCOCCOc1ccc(C#N)c(C#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
A mixture of 4-nitrophthalonitrile (1.73 g, 10 mmol), triethylene glycol monomethyl ether (1.52 g, 10 mmol) and dried potassium carbonate (2.76 g, 20 mmol) in anhydrous DMF (15 mL) was stirred overnight at ambient temperature under argon. The solvents were removed in vacuo, and the crude product was purified by column chromatography on silica gel using dichloromethane/methanol mixture (97:3) as an eluent to give the product in 45% yield. [1H NMR (δ, ppm, CDCl3): 7.70 (d, 1H, J=8.7 Hz), 7.31 (d, 1H, J=2.5 Hz), 7.23 (dd, 1H, J=8.7 Hz, J=2.5 Hz), 4.22 (m, 2H), 3.88 (m, 2H), 3.6-3.75 (m, 6H), 3.53 (m, 2H), 3.37 (s, 3H).]
Reaction SMILES: [CH2:1]([NH:8][NH2:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]1([N:16]=[C:17]=[S:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)(C)C>[CH2:1]([N:8]([C:17]([NH:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[S:18])[NH2:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNCc1ccccc1
Reactant: S=C=Nc1ccccc1
Solvent: CC(C)O
Product: NN(Cc1ccccc1)C(=S)Nc1ccccc1
Reaction time: 1 h

Procedure:
Benzylhydrazine (30 g, 0.0245 mole) and phenyl isothiocyanate (33.1 g, 0.0245 mole) were dissolved in 200 ml of isopropanol and cooled to 0°-5° C. The phenyl isothiocyanate was then added dropwise in 50 ml of petroleum ether. The title compound precipitated from solution during this phase of the operation. After addition, the reaction mixture was stirred at 40°-45° C. for one hour. The title product was filtered off as a white solid, m.p. 121°-3° C., yield 43 g.
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[CH:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[F:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][N:14]=3)[C:10]([C:7]3[CH2:8][CH:9]4[N:4]([CH2:3][CH2:2][CH2:1]4)[CH2:5][CH:6]=3)=[CH:11]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: C1=C(c2c[nH]c3ncccc23)CC2CCCN2C1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(F)cc1)n1cc(C2=CCN3CCCC3C2)c2cccnc21

Procedure:
1-(4-Chlorobenzenesulfonyl)-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl-7-azaindole (10.2 mg, 58.9%); from 3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-7-Azaindole (10 mg, 0.0418 mmol), 4-fluorobenzenesulfonyl chloride (20 mg, 0.095 mmol) and 1M NaN(TMS)2 (100 μL, 0.10 mmol) in THF (0.5 mL) at RT.
Reaction SMILES: [ClH:1].CO[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[NH:5].[NH3:19]>CO>[ClH:1].[ClH:1].[CH2:12]([N:9]1[CH2:10][CH2:11][CH:6]([C:4]([NH2:19])=[NH:5])[CH2:7][CH2:8]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=N)C1CCN(Cc2ccccc2)CC1
Reactant: N
Agent: Cl
Solvent: CO
Product: N=C(N)C1CCN(Cc2ccccc2)CC1
Reaction time: 18 h
Yield: 97 %

Procedure:
Dissolve 1-benzyl-piperidine-4-carboximidic acid methyl ester hydrochloride (17.47 g 1.00 equiv; 65 mmoles) in 2M ammonia in methanol (˜350 mL). Saturate with ammonia gas for 15 min. Stir for 18 hours and evaporate. Co-evaporate with dry methanol. Dry under high vacuum to give 18.29 g (63.03 mmol, 97%) of 1-benzyl-piperidine-4-carboxamidine dihydrochloride as a light yellow solid.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[CH3:16][C:17]1[CH:18]=[C:19]([CH2:28][NH2:29])[CH:20]=[N:21][C:22]=1[N:23]1[CH:27]=[CH:26][CH:25]=[N:24]1>>[Cl:14][C:13]1[C:3]2[CH2:2][N:29]([CH2:28][C:19]3[CH:20]=[N:21][C:22]([N:23]4[CH:27]=[CH:26][CH:25]=[N:24]4)=[C:17]([CH3:16])[CH:18]=3)[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: Cc1cc(CN)cnc1-n1cccn1
Agent: Cl
Product: Cc1cc(CN2Cc3c(ccnc3Cl)C2=O)cnc1-n1cccn1
Yield: 71 %

Procedure:
The title compound is prepared in 71% yield (520 mg, pale brown solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (600 mg, 2.2 mmol, Step-1 of Intermediate-1) and (5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)methanamine hydrochloride (480 mg, 2.2 mmol, Amine-53) in a similar manner to Intermediate-2.
Reaction SMILES: CN1C=CN=C1.[Cl:7][C:8]1[S:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=1.CS(Cl)(=O)=O.[NH2:21][CH2:22][CH:23]1[O:27][C:26](=[O:28])[N:25]([C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][C:36]3=[O:41])=[CH:31][CH:30]=2)[CH2:24]1>ClCCl.O>[Cl:7][C:8]1[S:12][C:11]([C:13]([NH:21][CH2:22][CH:23]2[O:27][C:26](=[O:28])[N:25]([C:29]3[CH:34]=[CH:33][C:32]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][C:36]4=[O:41])=[CH:31][CH:30]=3)[CH2:24]2)=[O:15])=[CH:10][CH:9]=1
Reactant: NCC1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Reactant: O=C(O)c1ccc(Cl)s1
Agent: CS(=O)(=O)Cl
Agent: Cn1ccnc1
Solvent: O
Solvent: ClCCl
Product: O=C(NCC1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)c1ccc(Cl)s1
Reaction time: 0.17 h
Yield: 89.7 %

Procedure:
1-Methylimidazole (24.6 g, 0.3 mol) was added to a stirred suspension of 5-chlorothiophene-2-carboxylic acid (16.25 g, 0.1 mol) in dichloromethane (162 ml) at 0-5° C. and the resulting solution was stirred for 10 minutes. A solution of methanesulfonyl chloride (12 g, 0.105 mol) in dichloromethane (40 ml) was added to the above solution at −5° C. The resulting solution was stirred for 1 hour at −5° C. to produce a reaction mass containing the sulfonyl ester intermediate, followed by portion wise addition of racemic 4-[4-[5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (29.1 g, 0.1 mol). The reaction mixture was stirred for 2 hours at 25-30° C., followed by the addition of water (162 ml) and then stirring for 15 minutes. The separated solid was filtered, washed with dichloromethane (50 ml) and water (100 ml), and the resulting wet material was dried at 80-85° C. for 3 to 4 hours to produce 39.1 g of pure racemic 5-chloro-N-[[2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]oxazolidin-5-yl]methyl]thiophene-2-carboxamide as a white crystalline solid (Theoretical Yield: 90%; Purity by HPLC: 99.9%).
Reaction SMILES: [NH2:1][C:2]1[C:16]([NH2:17])=[CH:15][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=3)[NH:8][C:4]=2[CH:3]=1.[N:18]#[C:19]Br.C>>[NH2:18][C:19]1[NH:17][C:16]2[CH:15]=[C:5]3[N:6]=[C:7]([C:9]4[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=4)[NH:8][C:4]3=[CH:3][C:2]=2[N:1]=1
Reactant: Nc1cc2nc(-c3ccncc3)[nH]c2cc1N
Reactant: N#CBr
Product: Nc1nc2cc3[nH]c(-c4ccncc4)nc3cc2[nH]1
Temperature: 25 °C

Procedure:
2.9 g. 5,6-diamino-2-(4-pyridyl)-benzimidazole and 1.3 g. cyanogen bromide are stirred for 2 hours at 85° C. with the exclusion of moisture. After cooling to ambient temperature, the reaction mixture is treated with active charcoal, filtered and the filtrate evaporated to dryness. The residue is suspended in water, the pH value is adjusted to 8.5 with aqueous ammonia solution and filtered off with suction. The 1.47 g. of residue obtained is applied to 15 g. silica gel 60 and eluted with a mixture of methylene chloride and ammoniacal methanol (95:5 v/v to 92:8 v/v). The appropriate fractions are evaporated to dryness and the residue is dissolved in methanol. Isopropanol is added thereto until turbid and then left to crystallise. There is obtained 0.52 g. of the desired compound; m.p. >320° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[C:4]([CH3:15])[CH:3]=1.C1C(=O)N([Br:23])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[C:4]([CH2:15][Br:23])[CH:3]=1
Reactant: Cc1cc(Br)ccc1-c1cccc(Cl)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cccc(-c2ccc(Br)cc2CBr)c1
Temperature: 25 °C
Yield: 60 %

Procedure:
The biphenyl (0.235 mg, 1.0 equiv) was dissolved in CCl4 (5 mL), NBS added, and the solution was irradiated until starting material was consumed. The mixture was allowed to cool to room temperature and then filtered through celite. The filtrate was concentrated and the residue purified by column chromatography (SiO2, hexane) to give the desired product (0.258 g, 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][N:14]([CH:17]([CH3:19])[CH3:18])[CH2:13][CH2:12]1.C([O-])=O.[NH4+]>CO.[Zn]>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:12][CH2:13][N:14]([CH:17]([CH3:18])[CH3:19])[CH2:15][CH2:16]1
Reactant: CC(C)N1CCN(c2ccc([N+](=O)[O-])cc2Cl)CC1
Agent: O=C[O-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: CC(C)N1CCN(c2ccc(N)cc2Cl)CC1
Temperature: 25 °C

Procedure:
To a solution of 1-(2-chloro-4-nitro-phenyl)-4-isopropyl-piperazine (1.500 g, 5.30 mmol), prepared according to example 5, in MeOH (20 mL) is added zinc dust (1.039 g, 15.90 mmol) followed by ammonium formate (1.002 g, 15.90 mmol). The reaction is stirred at room temperature. Once the reaction is finished, the reaction mixture is filtrated and concentrated. The mixture is taken up in dichloromethane and washed with water. The combined organic layers are dried (MgSO4) and the solvent is removed under reduced pressure to yield the title compound, which is used as such for the next step.
Reaction SMILES: [P:1]([O:5][CH2:6][C@H:7]1[O:11][C@@H:10]([N:12]2[C:21]3[N:20]=[CH:19][N:18]=[C:16]([NH2:17])[C:15]=3[N:14]=[C:13]2Br)[C@H:9]([OH:23])[C@@H:8]1[OH:24])([OH:4])([OH:3])=[O:2].[CH2:25]([NH2:28])[CH2:26][NH2:27].[OH-].[Na+].C(=O)(O)[O-]>O>[P:1]([O:5][CH2:6][C@H:7]1[O:11][C@@H:10]([N:12]2[C:21]3[N:20]=[CH:19][N:18]=[C:16]([NH2:17])[C:15]=3[N:14]=[C:13]2[NH:27][CH2:26][CH2:25][NH2:28])[C@H:9]([OH:23])[C@@H:8]1[OH:24])([OH:4])([OH:3])=[O:2]
Reactant: Nc1ncnc2c1nc(Br)n2[C@@H]1O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]1O
Reactant: NCCN
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NCCNc1nc2c(N)ncnc2n1[C@@H]1O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]1O

Procedure:
A reaction mixture consisting of 2.2 mmol 8-bromoadenosine-5'-monophosphate, prepared according to the method described in Arch. Biochem. Biophys. 163: 561-9(1974), 66 mmol ethylenediamine and 25 ml water was heated in an oil bath at 140° for 2 hr. The cooled mixture was adjusted to pH 11.5 with sodium hydroxide and passed into a 2.5×55 cm column of Dowex 1×8 (200-400 mesh, bicarbonate form). The column was washed with 300 ml water and then with a linear gradient generated with 3 liters water and 3 liters 0.5M ammonium bicarbonate. The absorbance of the effluent at 254 nm was monitored and a major peak of absorbing material eluted between 4.6 and 5.8 liters of the gradient.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[CH2:6][CH2:7][CH:8]3[C:13]([C:4]=2[CH:3]=1)=[N:12][N:11]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=1)[C:10](=[O:23])[CH2:9]3.Cl>C(O)C.O.[Fe]>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[C:10](=[O:23])[CH2:9][CH:8]3[C:13]([C:4]4[CH:3]=[C:2]([Cl:1])[CH:25]=[CH:24][C:5]=4[CH2:6][CH2:7]3)=[N:12]2)=[CH:15][CH:16]=1
Reactant: O=C1CC2CCc3ccc(Cl)cc3C2=NN1c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc(N2N=C3c4cc(Cl)ccc4CCC3CC2=O)cc1
Temperature: 25 °C

Procedure:
To a mixture of 9-chloro-2-(4-nitrophenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one in ethanol and water is added iron powder with stirring at room temperature. To the mixture is added dropwise concentrated hydrochloric acid with stirring and heating up to 60° C. on a water bath. The resulting mixture is further stirred under heating at the same temperature and filtered, then the filtrate is concentrated. After the residue is made alkaline by adding an aqueous solution of sodium hydroxide, the mixture is extracted with chloroform. The extract is washed with water and dried over magnesium sulfate anhydride. The chloroform is distilled off to give 2-(4-aminophenyl)-9-chloro-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.
Reaction SMILES: C1C2C(COC(=O)[NH:17][CH:18]3[CH2:23][CH2:22][CH:21]([C:24]4[N:25]=[C:26]([CH3:29])[S:27][CH:28]=4)[CH2:20][CH2:19]3)C3C(=CC=CC=3)C=2C=CC=1.C(NCC)C>C1COCC1>[CH3:29][C:26]1[S:27][CH:28]=[C:24]([CH:21]2[CH2:22][CH2:23][CH:18]([NH2:17])[CH2:19][CH2:20]2)[N:25]=1
Reactant: Cc1nc(C2CCC(NC(=O)OCC3c4ccccc4-c4ccccc43)CC2)cs1
Solvent: CCNCC
Solvent: C1CCOC1
Product: Cc1nc(C2CCC(N)CC2)cs1

Procedure:
1.10 g (2 mmol) of 9H-fluoren-9-ylmethyl[4-(2-methylthiazol-4-yl)cyclohexyl]carbamate (cis compound) and 15 mL of diethylamine are stirred in 30 mL of THF for 16 hours at ambient temperature. Then the reaction mixture is concentrated by evaporation and the residue is combined with THF and concentrated again by evaporation. The residue is purified by chromatography. Yield: 0.13 g (36%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](Cl)[C:7]=1[N:8]1[C:32](=[O:33])[C:11]2=[CH:12][N:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[CH:30][CH:29]=[N:28]4)=[CH:23][CH:22]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]2=[N:9]1.C([O-])=O.[NH4+]>CO>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[C:32](=[O:33])[C:11]2=[CH:12][N:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[CH:30][CH:29]=[N:28]4)=[CH:23][CH:22]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]2=[N:9]1
Reactant: O=c1c2cn(Cc3ccc(-n4cccn4)cc3)c3ccccc3c-2nn1-c1c(Cl)cncc1Cl
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: O=c1c2cn(Cc3ccc(-n4cccn4)cc3)c3ccccc3c-2nn1-c1ccncc1Cl
Temperature: 70 °C
Reaction time: 5 h

Procedure:
2-(3,5-Dichloropyridin-4-yl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H pyrazolo[4,3-c]quinolin-3-one (Example 493, 15 mg, 0.031 mmol), ammonium formate (2.1 mg, 0.34 mmol, 1.1 equiv) and 1,1-bis(diphenylphosphino)ferrocenedichloro palladium(II) dichloromethane complex (2.2 mg, 0.00031 mmol, 0.1 equiv) were combined in methanol (2 mL) and placed into a preheated oil bath at 60° C. for 5 hours. The mixture was then heated at 70° C. for an additional 18 hours. The mixture was cooled to ambient temperature, concentrated in vacuo and the residue was purified by silica gel gradient chromatography (100:0 to 90:10; dichloromethane:methanol), providing the titled compound: 1H-NMR (400 MHz, d6-DMSO) δ 8.94 (1H, br m), 8.75 (1H, br m), 8.71 (1H, s), 8.42 (1H, dd, J=7.7, 1.9 Hz), 8.21 (1H, br m), 7.74-7.72 (3H, m), 7.65-7.55 (4H, m), 7.35 (2H, d, J=8.7 Hz), 6.50 (1H, m), 5.62 (2H, s) ppm; high resolution mass spectrometry (ES+) m/z 453.1241 [(M+H)+; calculated for C25H18ClN6O: 453.1225].
Reaction SMILES: [CH3:1][C:2]1[C:6](B2OC(C)(C)C(C)(C)O2)=[C:5]([CH3:16])[O:4][N:3]=1.I[C:18]1[CH:19]=[C:20]([NH:24][C:25](=[O:27])[OH:26])[CH:21]=[CH:22][CH:23]=1>>[CH3:1][C:2]1[C:6]([C:18]2[CH:19]=[C:20]([NH:24][C:25](=[O:26])[OH:27])[CH:21]=[CH:22][CH:23]=2)=[C:5]([CH3:16])[O:4][N:3]=1
Reactant: Cc1noc(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(O)Nc1cccc(I)c1
Product: Cc1noc(C)c1-c1cccc(NC(=O)O)c1

Procedure:
Using the same method as in Example 5-(i), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole was reacted with the (3-iodophenyl)carbamic acid.tert-butyl to give [3-(3,5-dimethylisoxazol-4-yl)phenyl]carbamic acid.tert-butyl (yield: 85%).