Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][N:7]([CH:9]2[CH2:12][O:11][CH2:10]2)[CH2:6][CH2:5][N:4]1[C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]2[C:21](=[O:36])[N:22]([CH3:35])[CH:23]=[C:24](B3OC(C)(C)C(C)(C)O3)[CH:25]=2)=[N:17][CH:18]=1)[CH3:2].Cl[C:38]1[C:43]([CH:44]=[O:45])=[C:42]([N:46]2[CH2:58][CH2:57][C:56]3[N:55]4[C:50]([CH2:51][CH2:52][CH2:53][CH2:54]4)=[CH:49][C:48]=3[C:47]2=[O:59])[N:41]=[CH:40][CH:39]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[CH2:1]([CH:3]1[CH2:8][N:7]([CH:9]2[CH2:10][O:11][CH2:12]2)[CH2:6][CH2:5][N:4]1[C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]2[C:21](=[O:36])[N:22]([CH3:35])[CH:23]=[C:24]([C:38]3[C:43]([CH:44]=[O:45])=[C:42]([N:46]4[CH2:58][CH2:57][C:56]5[N:55]6[C:50]([CH2:51][CH2:52][CH2:53][CH2:54]6)=[CH:49][C:48]=5[C:47]4=[O:59])[N:41]=[CH:40][CH:39]=3)[CH:25]=2)=[N:17][CH:18]=1)[CH3:2]
Reactant: CC[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)nc1
Reactant: O=Cc1c(Cl)ccnc1N1CCc2c(cc3n2CCCC3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: CCC1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(N4CCc5c(cc6n5CCCC6)C4=O)c3C=O)cn(C)c2=O)nc1
Temperature: 100 °C
Yield: 56.6 %

Procedure:
A 50-mL round-bottomed flask equipped with a reflux condenser was charged with 161f (200 mg, 0.40 mmol), 4-chloro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrido[3,4-b]indolizin-2(1H)-yl)nicotinaldehyde 139a (132 mg, 0.40 mmol), K3PO4 3 water (213 mg, 0.80 mmol), sodium acetate (66 mg, 0.80 mmol), 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (16 mg, 0.020 mmol), and acetonitrile (20 mL). After three cycles of vacuum/N2 flush, the mixture was heated at 100° C. under N2 protection for 2 h. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was diluted with dichloromethane (50 mL) and water (50 mL). The aqueous layer was separated and extracted with dichloromethane (3×20 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The dark residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (80/1 to 30/1) to afford 161g (150 mg, 57%) as yellow solid. MS-ESI: [M+H]+ 663
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]#[N:15])[CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[SH2:24]>CN(C)C=O>[CH3:16][N:2]([CH3:1])[CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14](=[S:24])[NH2:15])[CH:12]=2)[NH:7][CH:6]=1
Reactant: S
Reactant: CN(C)CCc1c[nH]c2ccc(C#N)cc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)CCc1c[nH]c2ccc(C(N)=S)cc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 3-[2-(dimethylamino)ethyl]-1H-indole-5-carbonitrile (13.0 g) and triethylamine (50 ml) in dimethylformamide (300 ml) was stirred for 2 h whilst gaseous hydrogen sulphide was bubbled through it. More triethylamine (10 ml) was added and the solution was stirred at room temperature for 2 days, then evaporated in vacuo to give an oil (15 g) which was partitioned between ethyl acetate (500 ml) and water (3×250 ml). The organic layer was dried (MgSO4) pre-absorbed onto silica and purified by flash chromatography (A). The appropriate fractions were combined, concentrated in vacuo and triturated with ether (250 ml) to give the title compound (12.0 g) as a solid, m.p. 155°.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]1[CH:13]=[N:14][NH:15][CH:16]=1)[CH:8]=[CH:7][CH:6]=2.[H-].[Na+].Br[CH2:20][CH2:21][O:22][CH3:23]>CN(C=O)C.[Cl-].[Na+].O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]1[CH:16]=[N:15][N:14]([CH2:20][CH2:21][O:22][CH3:23])[CH:13]=1)[CH:8]=[CH:7][CH:6]=2
Reactant: Clc1cc2c(-c3cn[nH]c3)cccc2cn1
Reactant: COCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCn1cc(-c2cccc3cnc(Cl)cc23)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-chloro-5-(1H-pyrazol-4-yl)isoquinoline (Preparation 3, 10 mg, 0.42 mmol) in DMF (3 mL) was added NaH (60%, 28 mg, 0.122 mmol). After stirring at room temperature for 15 minutes, 1-bromo-2-methoxyethane (25.4 mg, 0.183 mmol) was added and the reaction mixture was stirred at 80° C. for 60 minutes. The reaction was diluted with brine and extracted with EtOAc, the organic layers were dried with Na2SO4 and concentrated in vacuo to afford the title compound that was used in the next step without further purification (15 mg).
Reaction SMILES: [NH2:1][C:2]1[C:6]2[N:7]=[C:8]([C:10](=[O:21])[NH:11][C:12]([CH3:20])([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH3:13])[S:9][C:5]=2[N:4]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[N:3]=1.Cl.Cl.[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=2)[CH2:34][CH2:33]1.[Cl-].[Na+]>N1C=CC=CC=1>[CH3:13][C:12]([NH:11][C:10]([C:8]1[S:9][C:5]2[N:4]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[N:3]=[C:2]([NH:1][C:42](=[O:43])[C:41]3[CH:40]=[CH:39][C:38]([N:35]4[CH2:34][CH2:33][N:32]([CH3:31])[CH2:37][CH2:36]4)=[CH:46][CH:45]=3)[C:6]=2[N:7]=1)=[O:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:20]
Reactant: CC(C)(C)OC(=O)n1nc(N)c2nc(C(=O)NC(C)(C)c3ccccc3)sc21
Reactant: CN1CCN(c2ccc(C(=O)Cl)cc2)CC1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CN1CCN(c2ccc(C(=O)Nc3nn(C(=O)OC(C)(C)C)c4sc(C(=O)NC(C)(C)c5ccccc5)nc34)cc2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 43.7 %

Procedure:
2.0 g (5.0 mmol) of tert-butyl 3-amino-5-(1-methyl-1-phenylethylcarbamoyl)-1H-pyrazolo[4,3-d]thiazole-1-carboxylate dissolved in 40 ml of pyridine are placed in a 250 ml round-bottomed flask under argon. 1.56 g (5.0 mmol) of 4-(4-methylpiperazin-1-yl)benzoyl chloride dihydrochloride (prepared according to WO 2005/113494) are then gradually added and the mixture is stirred for 15 hours at 25° C. The reaction medium is then concentrated to dryness under reduced pressure (40° C.) and the residue is taken up in 50 ml of dichloromethane and 50 ml of water, and basified with 0.1N sodium hydroxide solution. The emulsion obtained is resorbed by saturation with sodium chloride. After separation of the phases by settling, the organic phase is dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue is purified by flash chromatography (msilica=30 g; eluent: 95/5 dichloromethane/methanol). 1.32 g of tert-butyl 5-(1-methyl-1-phenylethylcarbamoyl)-3-[4-(4-methylpiperazin-1-yl)benzoylamino]-1H-pyrazolo[4,3-d]thiazole-1-carboxylate are thus obtained in the form of a yellow foam. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.62 (s, 9H); 1.70 (s, 6H); 2.22 (s, 3H); 2.44 (m, 4H); 3.32 (m, 4H); 7.02 (d, J=8.5 Hz, 2H); 7.20 (t, J=7.5 Hz, 1H); 7.30 (t, J=7.5 Hz, 2H); 7.40 (d, J=7.5 Hz, 2H); 7.95 (d, J=8.5 Hz, 2H); 8.71 (s, 1H); 11.05 (s, 1H). LC-MS-DAD-ELSD: 602(−)=(M−H)(−); 604(+)=(M+H)(+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.[C:18]([C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C:22]1[CH:23]=[CH:24][C:25]([S:28][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)=[CH:26][CH:27]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: O=C1CCc2cc(OCCCCBr)ccc2N1
Reactant: CC(C)(C)c1ccc(S)cc1
Product: CC(C)(C)c1ccc(SCCCCOc2ccc3c(c2)CCC(=O)N3)cc1

Procedure:
Prepared analogous to Example 122 from 6-(4-bromo-butoxy)-3,4-dihydro-carbostyril (m.p. 142°-147° C.) and 4-tert. butyl-thiophenol.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[CH2:20](Cl)[O:21][CH3:22].[NH4+].[OH-].O>C1COCC1>[CH3:20][O:21][CH2:22][O:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1
Reactant: COCCl
Reactant: N#Cc1ccc(CO)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCOCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.8 %

Procedure:
4-Hydroxymethyl-benzonitrile (3.1 g, 23.3 mmoles) was combined with N,N-diisopropylethylamine (4.9 mL, 28 mmoles) in 100 mL of anhydrous THF. To this solution was added MOMCl (3.5 mL, 46.1 mmoles) and the mixture was stirred at room temperature for 16 hours. After this period a solution of NH4OH/H2O (1:1, 20 mL) was added (-MOMCl) and the solution was stirred for 15 minutes. After this period the reaction mixture was evaporated in vacuo (-THF) and the resulting mixture was extracted with DCM (3×30 mL). The combined DCM layer was dried over anhydrous Na2SO4, evaporated in vacuo, and the resulting crude product was purified using flash silica chromatography (0-20% EtOAc/Hexane) to yield 1.6 g (39% yield) of 4-Methoxymethoxymethylbenzonitrile as a colorless liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.Cl[C:19]([O:21][CH2:22][CH2:23][CH3:24])=[O:20]>>[CH2:22]([O:21][C:19]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:20])[CH2:23][CH3:24]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: CCCOC(=O)Cl
Product: CCCOC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 81.3 %

Procedure:
Beginning with 10 mg (0.0437 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 5.62 mg (0.0458 mMol) propyl chloroformate, 11.2 mg (81%) of the title compound were recovered.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)(=[O:3])[CH3:2].C(N(CC)CC)C.C(OC(Cl)=O)C.[Cl:27][C:28]1[CH:41]=[CH:40][C:31]([CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[CH:30][CH:29]=1>CN(C=O)C.C(Cl)Cl>[Cl:27][C:28]1[CH:41]=[CH:40][C:31]([CH2:32][CH2:33][N:34]2[CH2:35][CH2:36][N:37]([C:8](=[O:10])[C:7]3[CH:11]=[CH:12][CH:13]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=3)[CH2:38][CH2:39]2)=[CH:30][CH:29]=1
Reactant: Clc1ccc(CCN2CCNCC2)cc1
Reactant: CC(=O)Nc1cccc(C(=O)O)c1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)c1

Procedure:
10 g of 3-acetamidobenzoic acid are dissolved in 100 ml of DMF. At a temperature of from -5° to 0° there are added dropwise, while stirring, firstly 5.65 g of triethylamine and then 6.05 g of chloroformic acid ethyl ester dissolved in 40 ml of CH2Cl2. The whole is stirred for a further 30 minutes at from 0° to +5° and then, at the same temperature, 12.54 g of 1-(p-chlorophenethyl)piperazine in 75 ml of DMF are added dropwise. The whole is stirred overnight at room temperature and then concentrated to dryness by evaporation. The residue is taken up in 350 ml of CH2Cl2 and the whole is washed with 150 ml of 2N NaOH and with 50 ml of H2O and dried over Na2SO4. After filtration and concentration by evaporation, a brown oil is obtained, which is caused to crystallise with ether. Recrystallisation is effected from ethanol/ether. 1-[2-(p-chlorophenyl)-ethyl]-4-(3-acetamidobenzoyl)-piperazine having a melting point of 101°-107° is thus obtained.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[NH:12][C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=3)=[C:14]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[N:22]=[CH:21][CH:20]=[CH:19]4)[N:15]=2)=[CH:6][C:3]=1[C:4]#[N:5].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[NH:12][C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=3)=[C:14]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[N:22]=[CH:21][CH:20]=[CH:19]4)[N:15]=2)=[CH:6][C:3]=1[CH2:4][NH2:5]
Reactant: Cc1cccc(-c2[nH]c(Cc3ccc(F)c(C#N)c3)nc2-c2ccc3ncccc3c2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cccc(-c2[nH]c(Cc3ccc(F)c(CN)c3)nc2-c2ccc3ncccc3c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.8 %

Procedure:
To a suspension of 2-Fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)benzonitrile (Example 76) (100 mg, 0.238 mmol) in THF (1.5 mL) was added LAH (1M solution in THF, 476 uL, 0.476 mmol) and the mixture was stirred at room temperature for 2 hours. The reaction was quenched by addition of ethyl acetate (1 mL) and H2O (3 drops), and the mixture was stirred for 30 min. The mixture was dried over Na2SO4, filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by MPLC (MeOH:CH2Cl2=1:50 (v/v) to 1:20 (v/v)) to afford the title compound (53.2 mg, 53%). (300 MHz, CDCl3+CD3OD) δ 2.49 (3H, s), 3.87 (2H, s), 4.17 (2H, s), 6.95-7.01 (2H, m), 7.17-7.33 (3H, m), 7.35-7.43 (2H, m), 7.96 (1H, d), 8.08-8.17 (3H, m), 8.91 (1H, dd), 10.40 (1H, bs), MS (ESI) m/z 424 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:14]3[N:10]([CH2:11][CH2:12][CH2:13]3)[CH:9]=2)=[CH:4][CH:3]=1.[Cl:22]N1C(=O)CCC1=O>C1COCC1>[Cl:22][C:9]1[N:10]2[C:14](=[C:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH2:13][CH2:12][CH2:11]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: Fc1ccc(-c2cn3c(c2-c2ccccc2)CCC3)cc1
Solvent: C1CCOC1
Product: Fc1ccc(-c2c(-c3ccccc3)c3n(c2Cl)CCC3)cc1
Reaction time: 0.17 h

Procedure:
The clear solution of 6-(4-fluorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine (Example 8 d, 2.77 g, 10 mmol) in THF (20 ml) is treated at RT with N-chlorosuccinimide (NCS, 1.34 g, 10 mmol). The solution, immediately turning from yellow to black-coloured with spontaneous heating, is stirred for a further 10 min, then adsorbed on an Al2O3 column (100 g, TSC-ICI), and the substance sought is eluted with ethyl acetate-n-hexane 1:9 (Rf=0.8, starting material Rf=0.6). The eluate fractions are concentrated in vacuo and the residue is crystallized from diisopropyl ether: 1.63 g (52%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16]Cl)[N:9]=[CH:8][NH:7][C:6]2=[O:18].[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[OH-].[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[N:9]=[CH:8][NH:7][C:6]2=[O:18]
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCCCl
Reactant: C1CCNCC1
Agent: [Na+]
Agent: [OH-]
Product: COc1cc2c(=O)[nH]cnc2cc1OCCCN1CCCCC1
Temperature: 50 °C
Reaction time: 5 h
Yield: 84.6 %

Procedure:
In a 5 mL volume glass vessel equipped with a stirrer and a thermometer were placed 0.5 g (1.9 mmol) of 6-methoxy-7-(3-chloropropoxy)quinazolin-4-one prepared by procedures similar to those of Reference Example V-1, 0.81 g (9.5 mmol) of piperidine, and 4.8 mL (19 mmol) of aqueous sodium hydroxide solution (4.0 mol/L). The resulting mixture was stirred at 50° C. for 5 hours. After the reaction was complete, the reaction mixture was analyzed by high performance liquid chromatography (absolute quantitative analysis). There was produced 0.51 g (reaction yield: 85%) of 6-methoxy-7-(3-piperidinopropoxy)-quinazolin-4-one.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([I:8])=[CH:6][CH:7]=1.Br[CH2:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13].P([O-])([O-])(O)=O.[Na+].[Na+]>CN(C)C(=O)C>[I:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:1]=2)[N:4]=1
Reactant: Nc1ccc(I)nn1
Reactant: CCOC(=O)C(=O)CBr
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cn2nc(I)ccc2n1
Yield: 41.8 %

Procedure:
Using 3-amino-6-iodopyridazine (2.0 g, 9.05 mmol), N,N-dimethylacetamide (20 mL), ethyl 3-bromo-2-oxopropanate (1.82 mL, 14.5 mmol) and disodium hydrogenphosphate (3.21 g, 22.6 mmol), and in the same manner as in Reference Example 3, the title compound (1.2 g, 44%) was obtained as a green powder.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH3:9][C:10]1([S:13][CH2:12]1)[CH3:11]>CCOCC>[NH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH:8][CH2:9][C:10]([SH:13])([CH3:12])[CH3:11]
Reactant: CC1(C)CS1
Reactant: Nc1ccccc1N
Solvent: CCOCC
Product: CC(C)(S)CNc1ccccc1N
Temperature: 80 °C
Yield: 26.4 %

Procedure:
o-Phenylenediamine (15.31 g, 1.42×10-1 mol, 100M %) and 12.46 g (1.42×10-1 mol, 100M %) isobutylene sulfide (Snyder et al, J Am Chem Soc 69: 2672-2674, 1947) were mixed in a Parr bomb and heated in an oven at 80° C. for 18 hr. The bomb was cooled to room temperature and then opened. The crude brown oil contained some solid. The mixture was dissolved in 150 ml ether (some white solid did not dissolve), washed with saturated aqueous NaCl solution, and the solvent was removed on the rotary evaporator. The oily residue was placed on flash silica in a 600 ml sintered glass funnel and eluted with 500 ml portions of hexane, 90% hexane/ether, twice with 80% hexane/ether and twice with 50% hexane/ether. Evaporation of the first 50:50 hexane/ether fraction gave 7.36 g (26.5%) of 2-amino-1-(2-mercapto-2-methylpropylamino)benzene as a waxy crystalline product, mp 38°-40° C.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([C:8]1[N:13]2[N:14]=[C:15]([NH:17]C(NCC)=O)[N:16]=[C:12]2[CH:11]=[C:10]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[CH:9]=1)=[O:7])(=O)[CH3:2].C(=O)(O)[O-].[Na+]>>[CH3:2][C:1]1[O:7][C:6]([C:8]2[N:13]3[N:14]=[C:15]([NH2:17])[N:16]=[C:12]3[CH:11]=[C:10]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[CH:9]=2)=[N:5][N:4]=1
Reactant: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(C(=O)NNC(C)=O)n2n1
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1nnc(-c2cc(-c3cccnc3)cc3nc(N)nn23)o1
Temperature: 120 °C
Yield: 57.3 %

Procedure:
A mixture of the product of Step 2 (0.419 g, 1.10 mmol) in polyphosphoric acid (10 mL) was heated to 120° C. for 2 h. The viscous mixture was poured onto ice and made basic with saturated aqueous sodium bicarbonate, then extracted with dichloromethane (4×250 mL). Removal of the solvent in vacuo gave a solid which was triturated with methanol then filtered to give 5-(5-methyl-[1,3,4]oxadiazol-2-yl)-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (0.185 g, 58%) as a solid. ACPI-MS Found: [M+H]+=294.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[O:16][C:15](=[O:17])[CH:14]=[C:13]2[CH3:18])=[CH:8][CH:7]=1>C(OCC)(=O)C.O=[Pt]=O>[Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C@H:12]2[O:16][C:15](=[O:17])[CH2:14][C@H:13]2[CH3:18])=[CH:8][CH:7]=1
Reactant: CC1=CC(=O)OC1c1ccc(OCCCBr)cc1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: C[C@@H]1CC(=O)O[C@@H]1c1ccc(OCCCBr)cc1
Reaction time: 0.5 h

Procedure:
The lactone from Example 10 (26 g) was hydrogenated in ethyl acetate (200 ml) over PtO2 (1 g) at 20 p.s.i. H2 pressure for 30 minutes. The mixture was filtered, concentrated and the residue was purified by chromatography on silica gel to Provide the title compound as an oil, contaminated with 7% of the (5S, 4S), (5R, 4R) diastereomer as determined by NMR spectroscopy.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([CH3:11])=[N:9][N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[C:5]2=[CH:6][N:7]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[N:23][CH:24]=1.C(#N)C.C([O-])(=O)C.[K+]>O.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:18][C:19]1[CH:20]=[C:21]([C:2]2[CH:3]=[C:4]3[C:10]([CH3:11])=[N:9][N:8]([CH:12]4[CH2:17][CH2:16][CH2:15][CH2:14][O:13]4)[C:5]3=[CH:6][N:7]=2)[CH:22]=[N:23][CH:24]=1
Reactant: Cc1nn(C2CCCCO2)c2cnc(Br)cc12
Reactant: OB(O)c1cncc(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: Cc1nn(C2CCCCO2)c2cnc(-c3cncc(F)c3)cc12

Procedure:
To a mixture of 5-bromo-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine (90.0 mg, 0.304 mmol), 5-fluoropyridin-3-ylboronic acid (128.6 mg, 0.9124 mmol) and 1,1′-Bis(diphenylphosphino)ferrocenepalladium (II) chloride (37.2 mg, 0.0456 mmol) in Acetonitrile (2.86 mL, 54.7 mmol) was added 1.0 M of Potassium acetate in Water (0.456 mL) and 1.0 M of Sodium carbonate in Water (0.456 mL). The reaction mixture was irradiated in microwave at 125° C. for 20 min. The reaction was filtered thru celite and concentrated. The crude product was purified by silica gel column using ethyl acetate/heptane to give 5-(5-fluoropyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine which was dissolved in 12M HCl (1.30 mL, 15.6 mmol) and Methanol (13.0 mL). The reaction mixture was stirred at RT (room temperature) for 18 h. The reaction was concentrated and then submitted for rHPLC to give 123 (27.9 mg, 40.2% yield). ESI MS m/z=229.1 (M+1). 1H NMR (400 MHz, DMSO) δ 9.25 (s, 1H), 9.08 (s, 1H), 8.62-8.49 (m, 2H), 8.47-8.30 (m, 1H), 2.60 (s, 3H)
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11](I)[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[CH2:40]([N:43]1[CH:47]=[CH:46][N:45]=[CH:44]1)[CH:41]=[CH2:42]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:12]=[C:11]([CH:42]=[CH:41][CH2:40][N:43]2[CH:47]=[CH:46][N:45]=[CH:44]2)[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1ccc(I)cc1Cl
Reactant: C=CCn1ccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1ccc(C=CCn2ccnc2)cc1Cl

Procedure:
A mixture of ethyl 2-chloro-4-iodobenzoate (0.92 g, 2.96 mmol), triphenylphosphine (0.014 g, 0.0534 mmol), triethylamine (0.58 g, 5.73 mmol), 1-allylimidazole (1.2 g, 11.1 mmol), and palladium acetate (0.007 g) in acetonitrile (0.6 ml) was stirred and heated at 120° for 6 h in a steel bomb. The reaction mixture was cooled and concentrated to give an oily solid. The solid was purified by `flash` chromatography to give 1-[3-(3-chloro-4-ethoxycarbonylphenyl)prop-2-enyl]imidazole as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[CH:17][O:18]C)=[C:12]([F:20])[C:11]=2[F:21])=[C:6]([F:22])[C:5]=1[F:23])[CH3:2].Cl.O>CC(C)=O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH:17]=[O:18])=[C:12]([F:20])[C:11]=2[F:21])=[C:6]([F:22])[C:5]=1[F:23])[CH3:2]
Reactant: CCOc1ccc(-c2ccc(C=COC)c(F)c2F)c(F)c1F
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: CCOc1ccc(-c2ccc(CC=O)c(F)c2F)c(F)c1F
Reaction time: 1 h
Yield: 97.1 %

Procedure:
4-Ethoxy-2,2′,3,3′-tetrafluoro-4′-(2-methoxyvinyl)biphenyl (8) (18.5 g) prepared in the sixth step was dissolved in acetone (200 ml) and hydrochloric acid (6M; 200 ml) was added, and the stirring was continued at room temperature for 1 hour. Water (200 ml) was added, and the water layer was extracted with toluene (100 ml) three times. The combined organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to leave 2-(4′-ethoxy-2,2′,3,3′-tetrafluorobiphenyl-4-yl)acetoaldehyde (9) (17.2 g) in 97.2% yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:16])=[C:4]([C:11]([O:13]CC)=O)[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[CH3:8].[NH2:17][C:18]1[NH:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1.BrC1C=CC=CC=1>CCCCCC>[N:19]1[C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[NH:22][C:18]=1[NH:17][C:11]([C:4]1[C:5](=[O:10])[N:6]([CH3:9])[C:7]([CH3:8])=[C:2]([Cl:1])[C:3]=1[OH:16])=[O:13]
Reactant: Nc1nc2ccccc2[nH]1
Reactant: CCOC(=O)c1c(O)c(Cl)c(C)n(C)c1=O
Solvent: Brc1ccccc1
Solvent: CCCCCC
Product: Cc1c(Cl)c(O)c(C(=O)Nc2nc3ccccc3[nH]2)c(=O)n1C
Temperature: 25 °C
Reaction time: 9.5 h
Yield: 82.5 %

Procedure:
199 mg of ethyl 5-chloro-1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylate and 98 mg of 2-amino-benzimidazole were added to 2 ml of bromobenzene, then, the mixture was stirred for 9.5 hours under heat refluxing condition. The reaction mixture was cooled to room temperature, then, hexane was added to this and the resultant mixture was allowed to stand still. The resulting solid was collected by filtration, and washed with a mixture of t-butyl methyl ether and n-hexane and dried to obtain 202 mg of N-(2-benzimidazolyl)-5-chloro-1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxamide (hereinafter, referred to as present compound 28) represented by the formula: