Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]([CH3:9])(C)[C:3]([N:5]([CH3:7])[CH3:6])=[O:4].[CH3:10][C:11]1[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:13][NH:14][CH:15]=1.C1(C2C=CNN=2)C=CC=CC=1>>[Br:1][CH:2]([CH2:9][N:14]1[CH:15]=[C:11]([CH3:10])[C:12]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[N:13]1)[C:3]([N:5]([CH3:7])[CH3:6])=[O:4]
Reactant: Cc1c[nH]nc1-c1ccccc1
Reactant: CN(C)C(=O)C(C)(C)Br
Agent: c1ccc(-c2cc[nH]n2)cc1
Product: Cc1cn(CC(Br)C(=O)N(C)C)nc1-c1ccccc1

Procedure:
Following the procedure of Example 121, but substituting 2,3-dibromo-N,N-dimethylpropionamide for 2-bromo-N,N,2-trimethylpropionamide and 4-methyl-3-phenylpyrazole for 3-phenylpyrazole there was obtained α-bromo-N,N,4-trimethyl-3-phenylpyrazole-1-propionamide having a melting point of 104°-107° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[F:10][C:11]([F:26])([F:25])[CH2:12]OC1C=C(S([O-])(=O)=O)C=CC=1C.[H-].[Na+]>CN(C)C=O.O>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:12][C:11]([F:26])([F:25])[F:10]
Reactant: Oc1ccc(F)cc1Br
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(OCC(F)(F)F)c(Br)c1
Temperature: 110 °C

Procedure:
To a solution of 2-bromo-4-fluorophenol (4 g) and 2,2,2-trifluoroethoxy-p-toluene sulphonate (5 g) in dimethylformamide (40 ml) was slowly added sodium hydride (1 g, 60% in oil) and the mixture then heated at 110° C. for 12 h. The solution was cooled, diluted with water (500 ml) and the product extracted into ethyl acetate (2×150 ml). The organic phase was washed with saturated NaHCO3 solution, water, saturated brine and dried (MgSO4). The solvent was removed in vacuo and the residue was chromatographed on silica gel (eluting with diethyl ether/hexane (1:5)) to give the title compound as a colourless oil. 1H NMR (250 MHz, CDCl3) δ4.36 (2H, q, J 8 Hz), 6.91-7.05 (2H, m), and 7.33 (1H, dd, J 8, 3 Hz).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]3[CH:24]=[CH:23]C=[CH:21][C:13]3=[C:14]([CH:19]=[O:20])[CH:15]=2)[N:10]=[CH:9]1.[NH2:25]C1C2C(=CC=CC=2)C(Br)=CC=1C(OC)=O>>[OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]3[CH:24]=[CH:23][N:25]=[CH:21][C:13]3=[C:14]([CH:19]=[O:20])[CH:15]=2)[N:10]=[CH:9]1
Reactant: COC(=O)c1cc(Br)c2ccccc2c1N
Reactant: O=Cc1cc2c(=O)n([C@H]3CCCC[C@@H]3O)cnc2c2ccccc12
Product: O=Cc1cc2c(=O)n([C@H]3CCCC[C@@H]3O)cnc2c2ccncc12

Procedure:
3-[(1S,2S)-2-Hydroxycyclohexyl]-4-oxo-3,4-dihydropyrido[3,4-h]quinazoline-6-carbaldehyde was prepared by the procedure described for the synthesis of 3-[(1S,2S)-2-hydroxycyclohexyl]-4-oxo-3,4-dihydrobenzo[h]quinazoline-6-carbaldehyde in Example 2, substituting methyl 5-amino-8-bromoisoquinoline-6-carboxylate for methyl 1-amino-4-bromo-2-naphthoate.
Reaction SMILES: C(O)[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[CH2:13]([O:15][P:16]([O:43][CH2:44][CH3:45])([CH:18]([F:42])[C@@H:19]1[O:39][C@H:38]([CH2:40][OH:41])[C@@H:29]([O:30]CC2C=CC=CC=2)[C@@H:20]1[O:21]CC1C=CC=CC=1)=[O:17])[CH3:14].C(O)[C@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.P([O-])(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.[H][H]>CO.[OH-].[Pd+2].[OH-]>[CH2:13]([O:15][P:16]([O:43][CH2:44][CH3:45])([CH:18]([F:42])[C@H:19]1[O:39][C@H:38]([CH2:40][OH:41])[C@@H:29]([OH:30])[C@@H:20]1[OH:21])=[O:17])[CH3:14]
Reactant: CCOP(=O)(OCC)C(F)[C@@H]1O[C@H](CO)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: O=P([O-])(Oc1ccccc1)Oc1ccccc1
Agent: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Solvent: CO
Product: CCOP(=O)(OCC)C(F)[C@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Yield: 90 %

Procedure:
A solution of 330 mg of 2,5-anhydro-1-deoxy-1-(diethoxyphosphinyl)-1-fluoro-3,4-bis-O-(phenylmethyl)-D-glucitol D-glucitol and D-mannitol, diphenyl phosphate mixture in 20 ml of methanol was hydrogenated over palladium hydroxide catalyst until hydrogen uptake ceased. Filtration and removal of the solvent gave a yellow oil. This oil was purified by flash chromatography taking 20 ml fractions Fractions 1-26 were eluted with 3% methanol in dichloromethane and after evaporation gave 135 mg of 2,5-anhydro-1-deoxy-1-(diethoxyphosphinyl)-1-fluoro-D-mannitol, 6-(diphenyl phosphate).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2[S:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[N:12][C:11]=2[CH3:25])[CH:5]=[CH:4][C:3]=1[OH:26].Br[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2[S:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[N:12][C:11]=2[CH3:25])[CH:5]=[CH:4][C:3]=1[O:26][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32]
Reactant: COC(=O)CCCBr
Reactant: Cc1cc(CCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)CCCOc1ccc(CCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-methyl-4-(2-{4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}ethyl)phenol (intermediate 7, 0.08 g ) in acetonitrile (2 ml) was added methyl 4-bromobutyrate (0.090 g) and cesium carbonate (0.194 g). The mixture was stirred at room temperature for 24 hours then partitioned between water and ethyl acetate. The organic layer was dried, the solvent removed and the resulting oil was purified by SPE(Si cartridge). Elution with cyclohexane:ethyl acetate (20:1) gave the title compound as an oil which crystallised on standing.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH2:20][C:21]12[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2>CN(C=O)C>[C:21]12([CH2:20][CH2:19][NH:4][C:3]3[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:2]=3[F:1])[CH2:22][CH:23]3[CH2:29][CH:27]([CH2:26][CH:25]([CH2:24]3)[CH2:30]1)[CH2:28]2
Reactant: BrCCC12CC3CC(CC(C3)C1)C2
Reactant: Nc1ccc([N+](=O)[O-])cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(NCCC23CC4CC(CC(C4)C2)C3)c(F)c1
Temperature: 140 °C
Reaction time: 12 h
Yield: 10 %

Procedure:
To a solution of 2-fluoro-4-nitroaniline (2.34 g, 15.0 mmol) in DMF (30 mL) were added K2CO3 (4.2 g, 30.4 mmol), KI (0.5 g, 3.01 mmol) and 1-(2-bromoethyl)adamantane (3.65 g, 15.0 mmol) and the mixture was stirred at 140° C. for 12 h. The mixture was then cooled to rt and filtered. The filtrate was diluted with 150 mL of DCM and washed with water (50 mL×3), brine (150 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=8:1) to give the title compound as a yellow solid (477 mg, 10%).
Reaction SMILES: [N:1]([C@H:4]1[C@@H:16]2[C:17](=[O:20])[O:18][CH2:19][C@H:15]2[C@H:14]([C:21]2[CH:26]=[C:25]([O:27][CH3:28])[C:24]([OH:29])=[C:23]([O:30][CH3:31])[CH:22]=2)[C:13]2[C:5]1=[CH:6][C:7]1[O:11][CH2:10][O:9][C:8]=1[CH:12]=2)=[N+]=[N-]>C(OCC)(=O)C.[Pd]>[NH2:1][C@H:4]1[C@@H:16]2[C:17](=[O:20])[O:18][CH2:19][C@H:15]2[C@H:14]([C:21]2[CH:26]=[C:25]([O:27][CH3:28])[C:24]([OH:29])=[C:23]([O:30][CH3:31])[CH:22]=2)[C:13]2[C:5]1=[CH:6][C:7]1[O:11][CH2:10][O:9][C:8]=1[CH:12]=2
Reactant: COc1cc([C@@H]2c3cc4c(cc3[C@@H](N=[N+]=[N-])[C@@H]3C(=O)OC[C@@H]23)OCO4)cc(OC)c1O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc([C@@H]2c3cc4c(cc3[C@@H](N)[C@@H]3C(=O)OC[C@@H]23)OCO4)cc(OC)c1O
Reaction time: 16 h

Procedure:
0.6 g of 10% Pd/C is added to a solution of 7 mmol of the compound obtained in Step 1 in 160 ml of ethyl acetate. The reaction mixture is then stirred under hydrogen for 16 hours and subsequently filtered over Celite. After concentration of the fil trate under reduced pressure, the residue is chromatographed on silica gel (dichloromethane/ethyl acetate: 90/10), enabling the expected product to be isolated.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:15])=[C:6]([CH:8]([OH:14])[C:9]([F:13])([F:12])[CH2:10][OH:11])[CH:7]=1.N1C=CN=C1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:15])=[C:6]([CH:8]([OH:14])[C:9]([F:13])([F:12])[CH2:10][O:11][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH:7]=1
Reactant: OCC(F)(F)C(O)c1cc(Br)ccc1F
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC(F)(F)C(O)c1cc(Br)ccc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To an ice cooled solution of 1-(5-bromo-2-fluorophenyl)-2,2-difluoropropane-1,3-diol (17.0 g, 59.8 mmol) in dry DCM (200 mL) was added imidazole (12.2 g, 179.2 mmol) at 0° C. and stirred for 15 min. tert-butyldimethylsilylchloride (13.5 g, 89.5 mmol) was added to the resultant reaction mixture portion wise for a period of 30 min. and stirring continued for 2 h. Reaction was monitored by TLC analysis. The solids formed in the reaction mixture were separated by filtration and filtrate was concentrated under reduced pressure to obtain crude product which was purified by column chromatography on silica gel with 2% Ethylacetate in Hexane as eluent to furnish title compound as a colorless liquid. Yield=19 g (80%). TLC (20% ethyl acetate in Hexane): Rf=0.75),
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([Cl:14])=[C:8]2[C:3]=1[C:4](=[O:27])[C:5]([C:24]([OH:26])=[O:25])=[CH:6][N:7]2[C:15]1[C:20]([F:21])=[CH:19][C:18]([F:22])=[C:17]([NH2:23])[N:16]=1.Cl.Cl.[NH2:30][CH:31]1[CH2:34][NH:33][CH2:32]1.CN1CCCC1>N1C=CC=CC=1>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:33]2[CH2:34][CH:31]([NH2:30])[CH2:32]2)[C:9]([Cl:14])=[C:8]2[C:3]=1[C:4](=[O:27])[C:5]([C:24]([OH:26])=[O:25])=[CH:6][N:7]2[C:15]1[C:20]([F:21])=[CH:19][C:18]([F:22])=[C:17]([NH2:23])[N:16]=1
Reactant: NC1CNC1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3c(N)c(F)c(F)c(Cl)c32)c(F)cc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: c1ccncc1
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3c(N)c(F)c(N4CC(N)C4)c(Cl)c32)c(F)cc1F
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 23 %

Procedure:
To 550 mg of pyridine were added 185 mg of 5-amino-1-(6-amino-3 , 5-difluoropyridine-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 110 mg of 3-aminoazetidine dihydrochloride, and 200 mg of N-methylpyrrolidine, and the mixture was stirred at 100° C. for 30 minutes, and concentrated under reduced pressure. After adding 2 ml of ethanol, the mixture was stirred, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 48 mg of the title compound as a yellow powder.
Reaction SMILES: [Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl:26][CH:27]=[C:28]1[CH:34]=[CH:33][C:32]2[CH:35]=[C:36]([C:39](O)=[O:40])[CH:37]=[CH:38][C:31]=2[O:30][CH2:29]1>CO>[Cl:26][CH:27]=[C:28]1[CH:34]=[CH:33][C:32]2[CH:35]=[C:36]([C:39]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:40])[CH:37]=[CH:38][C:31]=2[O:30][CH2:29]1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1ccc2c(c1)C=CC(=CCl)CO2
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Product: O=C(Nc1ccccc1)c1ccc2c(c1)C=CC(=CCl)CO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 15.3 %

Procedure:
127 mg (0.46 mmol) of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride and then 39 mg (0.42 mmol) of aniline are added to 100 mg (0.42 mmol) of 3-(chloromethylene)-2,3-dihydro-1-benzoxepin-7-carboxylic acid, prepared according to example 63, in solution in 4 ml of methanol, and the medium is stirred at ambient temperature for 3 hours. The methanol is evaporated and the crude reaction product is purified by chromatography on silica gel (ethyl acetate/heptane 40/60) to give 20 mg (15%) of 3-(chloromethylene)-N-phenyl-2,3-dihydro-1-benzoxepin-7-carboxamide in the form of a pink solid comprising two Z/E isomers as a mixture in an 85/15 ratio; mass (APCI) M+1=312.
Reaction SMILES: [ClH:1].Cl.[C:3]1([C:9]2[O:13][N:12]=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:10]=2)[CH:8]=[CH:7]C=[CH:5][CH:4]=1.C(O)(=O)C1C=C[N:24]=CC=1>>[ClH:1].[ClH:1].[N:24]1[CH:7]=[CH:8][C:3]([C:9]2[O:13][N:12]=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:10]=2)=[CH:4][CH:5]=1
Reactant: O=C(O)c1ccncc1
Reactant: c1ccc(-c2nc(N3CCNCC3)no2)cc1
Agent: Cl
Product: c1cc(-c2nc(N3CCNCC3)no2)ccn1

Procedure:
The title product was prepared following the procedure of Intermediate 11 (step a to d) but using isonicotinic acid in step c). The title compound was obtained as a solid. TLC—Chloroform/methanol (8/2): Rf=0.2. HPLC purity: 97%.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:16])[CH3:15])[CH2:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)CO)C2=CC=1C.C(O)(=O)C>C1COCC1.[OH-].[Pd+2].[OH-]>[F:1][C:2]1[C:7]([CH:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:16])[CH3:15])[CH2:12][CH2:13]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)N1CC=C(c2cccnc2F)CC1
Agent: [Pd+2]
Agent: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)CO)c2cc1C
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)N1CCC(c2cccnc2F)CC1
Reaction time: 5 h

Procedure:
1-(4-(2-fluoropyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone (0.14 g, 0.65 mmol), palladium hydroxide, 20 wt % pd (dry basis) on carbon, wet, degussa type e101 ne/w (91 mg, 0.13 mmol) and acetic acid, glacial (19 uL, 0.32 mmol) were suspended in THF (13 mL) in a pressure tube. The reaction mixture was hydrogenated at 50 psi for 5 h then filtered through a pad of celite and washed with THF. The filtrate was concentrated to give 1-(4-(2-fluoropyridin-3-yl)piperidin-1-yl)ethanone as clear oil.
Reaction SMILES: Br[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[S:9][C:4]=2[C:3]=1[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.CC1(C)C(C)(C)OB([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[NH2:34])O1.C(=O)([O-])O.[Na+].C(OCC)(=O)C>O.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[S:9][C:4]=2[C:3]=1[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)c1cc2[nH]c(Br)c(C3CCCCC3)c2s1
Reactant: CC1(C)OB(c2ccccc2N)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cc2[nH]c(-c3ccccc3N)c(C3CCCCC3)c2s1
Temperature: 25 °C

Procedure:
A solution of methyl 5-bromo-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate (7 g, 20 mmol), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine (4.8 g, 22 mmol), sodium hydrogen carbonate (6.7 g, 80 mmol) and tetrakis(triphenylphosphine)palladium (230 mg, 0.2 mmol) in water (20 ml) and ethylene glycol dimethyl ether (50 ml) was stirred with heating under reflux for 4 hr. The reaction mixture was cooled to room temperature and ethyl acetate (200 ml) was added. The mixture was washed successively with water (100 ml), saturated aqueous sodium hydrogen carbonate solution (100 ml) and saturated brine (100 ml), and dried over magnesium sulfate. Filtration and concentration under reduced pressure gave a crude product of methyl 5-(2-aminophenyl)-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate. The obtained compound was used for Step 10 without purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:17][N:16]([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[CH2:23][CH2:22][CH2:21]3)[C:9]2[N:10]=[C:11]([S:14][CH3:15])[N:12]=[CH:13][C:8]=2[C:7]1=[O:27])=[O:5])[CH3:2].BrBr.N#N.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:27])[C:8]2[CH:13]=[N:12][C:11]([S:14][CH3:15])=[N:10][C:9]=2[N:16]([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[CH2:23][CH2:22][CH2:21]3)[CH:17]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CN(c2ccc3c(c2)CCC3)c2nc(SC)ncc2C1=O
Agent: BrBr
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(SC)ncc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
To a solution of 8-indan-5-yl-2-methylsulfanyl-5-oxo-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (0.32 g, 0.84 mmol) in 5 mL of methylene chloride (CH2Cl2) was added bromine (43 μL, 0.84 mmol) slowly under N2. The solution was stirred at room temperature for 2 hours (or to completion). The solvent was removed under vacuum without heating. The residue was redissolved in 2 mL of CH2Cl2, and was added triethylamine (234 μL, 1.68 mmol) in 1 mL of CH2Cl2. The solution was stirred at rt for 4 hours. The progress of the reaction was monitored by LC-MS. The solvent was evaporated and the residue was applied onto a silica gel column. The product was eluted with EtOAc/hexanes (1:5-1:2.5, v/v) and obtained as a white solid (0.30 g, 94%). 1H NMR (300 MHz, CDCl3) δ (ppm): 9.42 (s, 1H), 8.59 (s, 1H), 7.37 (d, J=7.8 Hz, 1H), 7.24 (s, 1H), 7.16 (d, J=7.8 Hz, 1H), 4.40 (q, 2H), 3.00 (m, 4H), 2.35 (s, 3H), 2.10 (m, 2H), 1.40 (t, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH3:9])=[N:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])=[C:4]([CH2:20][CH3:21])[N:3]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.CCCCCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:19][O:18][C:11]1[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:10]=1[C:5]1[C:4]([CH2:20][CH3:21])=[N:3][C:2]([C:29]2[CH:28]=[C:27]([F:30])[CH:26]=[CH:25][C:24]=2[O:23][CH3:22])=[C:7]([CH2:8][CH3:9])[N:6]=1
Reactant: CCc1nc(-c2ccc(OC)cc2OC)c(CC)nc1Cl
Reactant: COc1ccc(F)cc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: CCCCCC
Product: CCc1nc(-c2cc(F)ccc2OC)c(CC)nc1-c1ccc(OC)cc1OC
Temperature: 90 °C

Procedure:
Pd(PPh3)4 (8 mg) is added to a solution of 2-chloro-5-(2,4-dimethoxy-phenyl)-3,6-diethyl-pyrazine (70 mg) in DME (2 ml) at room temperature, followed by 2-methoxy-5-fluorophenylboronic acid (45 mg) and Na2CO3 (1M, 0.5 ml). The resulting mixture is heated to 90° C. for 20 hours, then cooled to room temperature. The reaction mixture is diluted with 50% EtOAc in hexane and washed with water and brine, dried, filtered and evaporated. The crude is purified by chromatography (eluted with 15% EtOAc in hexane) to give 2-(2,4-Dimethoxy-phenyl)-3,6-diethyl-5-(5-fluoro-2-methoxy-phenyl)-pyrazine compound 3. MS: 397.3 (M+1).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:12]1([CH3:26])[CH:17]=[CH:16][C:15]([N:18]2[CH:22]=[C:21](B(O)O)[CH:20]=[N:19]2)=[CH:14][CH:13]=1>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([C:21]3[CH:20]=[N:19][N:18]([C:15]4[CH:16]=[CH:17][C:12]([CH3:26])=[CH:13][CH:14]=4)[CH:22]=3)=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: Cc1ccc(-n2cc(B(O)O)cn2)cc1
Reactant: Clc1nc2c(Br)cccn2n1
Product: Cc1ccc(-n2cc(-c3cccn4nc(Cl)nc34)cn2)cc1

Procedure:
2-Chloro-8-(1-p-tolyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine and 1-p-tolyl-pyrazole-4-boronic acid in a manner analogous to Example 2c (0.40 g, 68%).
Reaction SMILES: [CH3:1][N:2]([CH3:51])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:49][CH3:50])=[C:12]([NH:15][C:16]3[N:17]=[C:18]([NH:35][C:36]4[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:37]=4[C:38]([NH:40][CH:41]([CH3:43])[CH3:42])=[O:39])[C:19]4[CH:24]=[CH:23][N:22](S(C5C=CC(C)=CC=5)(=O)=O)[C:20]=4[N:21]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5].O.[OH-].[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH3:51][N:2]([CH3:1])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:49][CH3:50])=[C:12]([NH:15][C:16]3[NH:21][C:20]4=[N:22][CH:23]=[CH:24][C:19]4=[C:18]([NH:35][C:36]4[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:37]=4[C:38]([NH:40][CH:41]([CH3:43])[CH3:42])=[O:39])[N:17]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: COc1cc2c(cc1Nc1nc(Nc3cccc(F)c3C(=O)NC(C)C)c3ccn(S(=O)(=O)c4ccc(C)cc4)c3n1)N(C(=O)CN(C)C)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: COc1cc2c(cc1Nc1nc(Nc3cccc(F)c3C(=O)NC(C)C)c3ccnc-3[nH]1)N(C(=O)CN(C)C)CC2
Temperature: 120 °C
Yield: 72.8 %

Procedure:
2-({2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluoro-N-(1-methylethyl)benzamide (210 mg, 0.294 mmol) was dissolved in 1,4-dioxane (10 mL) and transferred to a 20 ml microwave vessel. Water (3 mL) and a solution of 6M NaOH (3 ml) was added and reaction heated in microwave at 120° C. for 10 minutes. Resulting brown solution was diluted with ethyl acetate and washed with a saturated sodium bicarbonate solution, water and a saturated brine solution. Organics were dried over sodium sulfate and solvents removed under reduced pressure to afford a brown solid that was purified via chromatography on SiO2 to afford 2-[(2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluoro-N-(1-methylethyl)benzamide (120 mg, 0.214 mmol) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.11 (d, J=6.50 Hz, 6 H), 2.25 (s, 6 H), 3.05-3.22 (m, 4 H), 3.77 (s, 3 H), 4.03-4.13 (m, 1 H), 4.18 (t, J=8.29 Hz, 2 H), 6.26 (br. s., 1 H), 6.84-7.01 (m, 3 H), 7.25-7.38 (m, 1 H), 7.57 (s, 1 H), 8.25 (d, J=8.33 Hz, 1 H), 8.45 (d, J=7.60 Hz, 1 H), 8.64 (s, 1 H), 9.69 (s, 1 H), 11.25 (br. s., 1 H). (ESIMS (M+H)+=561)
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][N:20]3[C:28]([C:31]([NH:33][CH2:34][C:35]4[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=4)=[O:32])=[CH:29][CH:30]=[C:19]3[CH2:18]2)=[O:16])=[CH:11][CH:10]=1)=[O:2].[BH4-].[Na+].Cl>C(O)C>[OH:2][CH2:1][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12]([C:15]([N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][N:20]3[C:28]([C:31]([NH:33][CH2:34][C:35]4[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=4)=[O:32])=[CH:29][CH:30]=[C:19]3[CH2:18]2)=[O:16])=[CH:13][CH:14]=1
Reactant: O=Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(-c3ccccc3CO)cc1)C2
Temperature: 25 °C

Procedure:
A solution of 10-[(2′-formyl-1,1′-biphenyl-4-yl)carbonyl]-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 567, Step B (0.75 mmole), in ethanol (5 mL) at 5° C. was treated with sodium borohydride (4.5 mmole). The mixture was stirred and allowed to warm to room temperature over 6 hours. To the reaction mixture was added 2N hydrochloric acid until a pH of 8.0 was reached. The ethanol was evaporated and the residue extracted with dichloromethane. The organic solutions were combined, dried over anhydrous sodium sulfate, and evaporated. The residue was purified by passing it through a short column of silica gel to give the title compound, m.p. 119-121° C.