Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].O.CC1C=CC=CC=1C>[CH3:13][O:12][C:11]1[C:2]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[C:3]2[C:8](=[CH:9][CH:10]=1)[N:7]=[CH:6][CH:5]=[CH:4]2
Reactant: C1CNCCN1
Reactant: COc1ccc2ncccc2c1Br
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1C
Solvent: O
Product: COc1ccc2ncccc2c1N1CCNCC1
Temperature: 120 °C
Yield: 5.5 %

Procedure:
To an oven-dried 100 mL flask under N2 atmosphere was added 5-bromo-6-methoxyquinoline (3 g, 12.6 mmol), piperazine (6.5 g. 75.6 mmol), Pd(dba)2 (570 mg, 5 mol %), P(t-Bu)3 (0.628 mL, 5 mol %) and sodium t-butoxide (1.82 g, 18.9 mmol). 50 mL dry o-xylene was added and the reaction mixture stirred and heated at 120° C. for 3 hours, then at room temperature overnight. The reaction mixture was poured into H2O (100 mL) and extracted into EtOAc (3×100 mL). The organic fractions were combined, dried over Na2SO4, concentrated and purified by column chromatography (10% MeOH/CH2Cl2+NH1OH) affording 170 mg (6%) of 6-methoxy-5-piperazin-1-yl-quinoline. This material was used without further purification (combined with another batch) in the next step. (Ref: Tet Lett. 1998, 39, p. 617-620).
Reaction SMILES: [C:1]1([N:7]2[C:15]3[CH2:14][CH2:13][NH:12][CH:11]([C:16](OCC)=[O:17])[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:1]1([N:7]2[C:15]3[CH2:14][CH2:13][NH:12][CH:11]([CH2:16][OH:17])[C:10]=3[N:9]=[CH:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1NCCc2c1ncn2-c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1NCCc2c1ncn2-c1ccccc1
Yield: 70.7 %

Procedure:
To a solution of ethyl 1-phenyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-4-carboxylate (0.10 g, 0.37 mmol) in THF (10 mL) at −78° C. was added LiAlH4 (1M in THF) (1.1 mL, 1.10 mmol). After 14 h the reaction was quenched with 1 N NaOH, Rochelle's salt, and extracted with DCM (3×25 mL). The organic layers were combined, dried (Na2SO4), and concentrated. Chromatography of the resulting residue (SiO2; MeOH(NH3):DCM) gave the title compound (0.06 g, 71%). MS (ESI): mass calculated for C13H15N3O, 229.12. m/z found 230.1 [M+H]+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:20]([F:21])=[C:19]([F:22])[C:10]([CH2:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)=[C:9]([F:23])[C:8]=1[F:24].[Cl:25]/[CH:26]=[CH:27]\[CH2:28]I.[Cl-].[NH4+]>O1CCCC1>[Cl:25][CH:26]=[CH:27][CH2:28][C:7]1[C:20]([F:21])=[C:19]([F:22])[C:10]([CH2:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)=[C:9]([F:23])[C:8]=1[F:24]
Reactant: Cl/C=C\CI
Reactant: Fc1c(F)c(COC2CCCCO2)c(F)c(F)c1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Fc1c(F)c(COC2CCCCO2)c(F)c(F)c1CC=CCl
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
n-Butyl lithium (2.5M in hexane, 3 cm3) was added portionwise to a solution of 2-[4-bromo-2,3,5,6-tetrafluorobenzyloxy]-tetrahydropyran (1.7 g) in dry tetrahydrofuran (10 cm3) under an atmosphere of dry nitrogen, whilst the reaction temperature was maintained at -70° C. After 30 minutes, copper (I) bromide - dimethyl sulphide complex (1.54 g) was added in one portion and the reaction temperature allowed to warm to 0° C., for a period of 15 minutes. After cooling to -70° C., a solution of Z-1-chloro-3-iodoprop-1-ene (2.03 g) in dry tetrahydrofuran (3 cm3) was added portionwise, and the reaction mixture stirred for a further hour at -70° C. After warming to the ambient temperature, (ca. 25° C.), aqueous ammonium chloride was added to the reaction mixture, which was then extracted with ethyl acetate. After drying, the solvent was evaporated under reduced pressure to give an orange oil. The residue was then subjected to medium pressure column chromatography on a silica gel column using a Gilson apparatus, eluting with petroleum ether (boiling range 40°-60° C.) containing diethyl ether (5% by volume) to give 2-[4-(3-chloroprop-2-en-1-yl)-2,3,5,6-tetrafluorobenzyloxy]-tetrahydropyran, as a mixture consisting predominantly of the Z isomer.
Reaction SMILES: [CH:1]1([NH:4][CH2:5][C:6]2[CH:15]=[C:14]3[C:9]([NH:10][C:11](=[O:19])[C:12]4[N:13]3[CH:16]=[CH:17][CH:18]=4)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>O1CCOCC1>[CH:1]1([N:4]([CH2:5][C:6]2[CH:15]=[C:14]3[C:9]([NH:10][C:11](=[O:19])[C:12]4[N:13]3[CH:16]=[CH:17][CH:18]=4)=[CH:8][CH:7]=2)[S:28]([CH3:27])(=[O:30])=[O:29])[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: O=c1[nH]c2ccc(CNC3CC3)cc2n2cccc12
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N(Cc1ccc2[nH]c(=O)c3cccn3c2c1)C1CC1
Reaction time: 24 h

Procedure:
To a solution of EXAMPLE 12 (26 mg) and triethylamine (25 μL) in 1 mL dioxane was added methanesulfonyl chloride (5.53 μL). The mixture was stirred for 24 hours and concentrated. The title compound was purified by RP-HPLC using a gradient elution of 10/90 to 70/30 acetonitrile/0.1% TFA in water at 254 nm over 30 minutes. The free base was isolated after eluting from an ion exchange column (10 g). 1H NMR (500 MHz, DMSO-d6) δ 11.28 (s, 1H), 8.14 (m, 1H), 7.95 (s, 1H), 7.29 (s, 2H), 7.03 (m, 1H), 6.70 (m, 1H), 4.41 (s, 2H), 2.96 (s, 3H), 2.46 (m, 1H), 0.68 (d, 4H).
Reaction SMILES: O.[OH-].[Li+].[Br:4][C:5]1[CH:6]=[CH:7][C:8]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[C:27]([F:32])[CH:26]=2)=[C:9]([CH:22]=1)[C:10]([O:12]CC1C=CC(F)=C(F)C=1)=[O:11].Cl>O1CCCC1.C(OCC)(=O)C>[Br:4][C:5]1[CH:6]=[CH:7][C:8]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[C:27]([F:32])[CH:26]=2)=[C:9]([CH:22]=1)[C:10]([OH:12])=[O:11]
Reactant: O=C(OCc1ccc(F)c(F)c1)c1cc(Br)ccc1OCc1ccc(F)c(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(Br)ccc1OCc1ccc(F)c(F)c1

Procedure:
Water (50 ml) and lithium hydroxide (0.60 g, 24.93 mmol) were added to a solution of (3,4-difluorophenyl)methyl 5-bromo-2-{[(3,4-difluorophenyl)methyl]oxy}benzoate (may be prepared by Description 88; 3.9 g, 8.31 mmol) in tetrahydrofuran (150 ml). The mixture was heated to reflux for 2 hours. The mixture was allowed to cool and diluted with ethyl acetate (200 ml) and this mixture was then acidified to pH=1 using 2M aqueous HCl. The organics were separated and the aqueous layer was extracted with ethyl acetate (100 ml). The organics were combined, dried (MgSO4) and evaporated under reduced pressure to yield the title compound as a white solid. 2.9 g. The residue contains some benzyl alcohol.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1.Cl.[Cl:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.O>CN1CCCC1=O.CO.C(OCC)(=O)C>[ClH:16].[F:13][C:11]([F:14])([F:12])[C:9]1[CH:8]=[CH:7][C:4]2[S:5][CH:6]=[C:2]([NH:1][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:3]=2[CH:10]=1
Reactant: Clc1ccncc1
Reactant: Nc1csc2ccc(C(F)(F)F)cc12
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: FC(F)(F)c1ccc2scc(Nc3ccncc3)c2c1
Yield: 95.3 %

Procedure:
A solution of 3-amino-5-trifluoromethylbenzo[b]thiophene (27 g, 124 mmol) and 4-chloropyridine hydrochloride (20.5 g, 137 mmol) in 250 mL of 1-methyl-2-pyrrolidinone was stirred at 70°-80° C. for 1.5 hours. After cooling, the reaction mixture was stirred with water, washed with ether and separated. The aqueous layer was basified with a saturated sodium carbonate solution and the product which precipitated was collected. The reaction was repeated as above with an additional sample of 3-amino-5-trifluoromethylbenzo[b]thiophene (25.6 g, 118 mmol) and 4-chloropyridine hydrochloride (22 g, 148 mmol) in 225 mL of 1-methyl-2-pyrrolidinone. After a similar work-up, the two products were combined and dissolved in 10% methanol in ethyl acetate. The solution was dried (anhydrous magnesium sulfate), filtered and concentrated, yielding a yellow solid. This solid product was washed with ether and filtered to afford 39.1 g of a golden solid. Elution of a portion (3.5 g) of the residue through silica with ethyl acetate via flash column chromatography afforded 3.2 g of a white solid. Conversion of 2.4 g to the hydrochloride salt in 10% methanol in ether afforded 2.6 g of white crystals, mp 318°-319° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:6]=[C:5]([C:13]2[N:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[N:4]=1.C(N(CC)CC)C.[Cl:27][CH2:28][C:29](Cl)=[O:30]>C1COCC1>[Cl:27][CH2:28][C:29]([NH:19][C:16]1[CH:17]=[N:18][C:13]([C:5]2[N:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:6]=2)=[CH:14][CH:15]=1)=[O:30]
Reactant: COc1cc(C(F)(F)F)nc(-c2ccc(N)cn2)n1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(C(F)(F)F)nc(-c2ccc(NC(=O)CCl)cn2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cool (0° C.) solution of compound of example 59 (0.08 g, 0.296 mmol) in THF (5 mL) was added triethylamine (0.044 g, 0.44 mmol) and chloroacetylchloride (0.050 g, 0.44 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. THF was removed under reduced pressure, and reaction mixture was quenched with water and extracted with ethyl acetate (3×10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography (silica gel, 50% ethyl acetate in petroleum ether as an eluent) to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2C2CCCCO2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)[N:3]=1
Reactant: Clc1nc(N2CCOCC2)c2ncn(C3CCCCO3)c2n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: Clc1nc(N2CCOCC2)c2nc[nH]c2n1
Reaction time: 0.5 h

Procedure:
To 4-(2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)morpholine (100 g) in methanol (500 mL) at 50° C. was added p-toluenesulfonic acid monohydrate (6 g). The reaction was stirred for 30 mins, whereupon white solid has crashed fully out of solution. The solid is filtered and collected thru Buchner funnel, rinsed with Methanol and dried under vacuum to get 4-(2-chloro-9H-purin-6-yl)morpholine. Cesium carbonate (200 g) and iodomethane (30 mL) were subsequently added to a stirring solution of 4-(2-chloro-9H-purin-6-yl)morpholine in DMF at 50° C. The reaction was monitored by lc-ms until complete, about 30 minutes, whereupon the solvent was concentrated to dryness. Subsequent suspension of the crude reaction in water precipitated 4-(2-chloro-9-methyl-9H-purin-6-yl)morpholine (72 g) as a white solid, which was filtered and dried under vacuum overnight.
Reaction SMILES: Cl.Cl.Cl.[CH:4]1([N:10]2[CH2:27][CH2:26][C:13]3([CH2:17][N:16]([CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:15][CH2:14]3)[CH2:12][CH2:11]2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[NH:28]1[CH:32]=[CH:31][N:30]=[C:29]1[CH:33]=O>>[CH:4]1([N:10]2[CH2:27][CH2:26][C:13]3([CH2:17][N:16]([CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([N:25]([CH2:33][C:29]5[NH:28][CH:32]=[CH:31][N:30]=5)[CH2:33][C:29]5[NH:30][CH:31]=[CH:32][N:28]=5)[CH2:23][CH2:24]4)[CH2:15][CH2:14]3)[CH2:12][CH2:11]2)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: N[C@H]1CC[C@H](CN2CCC3(CCN(C4CCCCC4)CC3)C2)CC1
Reactant: O=Cc1ncc[nH]1
Agent: Cl
Product: c1c[nH]c(CN(Cc2ncc[nH]2)[C@H]2CC[C@H](CN3CCC4(CCN(C5CCCCC5)CC4)C3)CC2)n1

Procedure:
With the compound produced in Example 25 and 1H-imidazole-2-carbaldehyde, the same operation as in Example 2 was performed to obtain the title compound having the following physical properties.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:18][CH3:19])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:20][CH:21]=[C:22]([C:23]#[N:24])[N:4]2[N:3]=1.[NH2:25][C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([N:35]2[CH2:44][CH2:43][C@@H:42]3[C@H:37]([O:38][CH2:39][C:40](=[O:45])[NH:41]3)[CH2:36]2)[C:33]=1[Cl:34])[C:29]#[N:30].C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>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.[Fe+2].C([O-])(=O)C.[Pd+].O1CCOCC1>[Cl:34][C:33]1[C:32]([N:35]2[CH2:44][CH2:43][C@@H:42]3[C@H:37]([O:38][CH2:39][C:40](=[O:45])[NH:41]3)[CH2:36]2)=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=1[NH:25][C:2]1[N:7]=[C:6]([N:8]([CH2:18][CH3:19])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:20][CH:21]=[C:22]([C:23]#[N:24])[N:4]2[N:3]=1
Reactant: N#Cc1cc(N)c(Cl)c(N2CC[C@H]3NC(=O)CO[C@@H]3C2)c1
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(Cl)nn2c(C#N)cnc12
Agent: [Fe+2]
Agent: [Pd+]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: CCN(Cc1ccc(OC)cc1)c1nc(Nc2cc(C#N)cc(N3CC[C@H]4NC(=O)CO[C@@H]4C3)c2Cl)nn2c(C#N)cnc12
Temperature: 100 °C
Reaction time: 3 h

Procedure:
2-chloro-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (33.5 mg, 0.098 mmol), (Intermediate 10), (+/−)-3-amino-4-chloro-5-((4aR,8aR)-2-oxohexahydro-1H-pyrido[3,4-b][1,4]oxazin-6(7H)-yl)benzonitrile (30 mg, 0.098 mmol), DPPF (3.8 mg, 6.85 mol), Cs2CO3 (65.4 mg, 0.201 mmol), Xantphos (5.66 mg, 9.78 μmol), palladium(I)Acetate (6.83 mg, 0.029 mmol) and 1,4-dioxane (2 ml) were combined in a microwave vial. The vial was evacuated and backfilled with Nitrogen 3×. The reaction stirred at 100° C. for 3 hr. The reaction mixture cooled to 25° C., diluted with EtOAc and washed with brine and dried (Na2SO4). The solvents were removed and the material purified on silica gel 5% MeOH in DCM to afford (+/−)-2-((2-chloro-5-cyano-3-((4aR,8aR)-2-oxohexahydro-1H-pyrido[3,4-b][1,4]oxazin-6(7H)-yl)phenyl)amino)-4-(ethyl(4 methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:5])[CH3:4].[CH3:6][N:7]1[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]1>>[CH3:4][CH:3]1[CH2:2][NH:1][C:10]2([CH2:11][CH2:12][N:7]([CH3:6])[CH2:8][CH2:9]2)[O:5]1
Reactant: CC(O)CN
Reactant: CN1CCC(=O)CC1
Product: CC1CNC2(CCN(C)CC2)O1
Reaction time: 8 h

Procedure:
A mixture of 1-amino-2-propanol (9.2 ml, 1.2 mmol) and 1-methyl-4-piperidone (11.5 ml, 1.0 mmol) was heated under reflux for 2 h and left overnight at room temperature. The reaction mixture was distilled under reduced pressure (˜15 mm Hg). The title compound was collected at 82-95° C. 1H NMR (CDCl3, 300 MHz) δ 4.02 (m, 1H, OCH), 3.25 (dd, J=11.9, 6.3 Hz, 1H, CHH), 2.68 (dd, J=11.9, 6.6 Hz, 1H, CHH), 2.4-2.6 (m, 4H-piperidine), 2.1 (s, 3H, NCH3), 1.65-1.81 (m, 4H-piperidine), 1.21 (d, J=6.1 Hz, 3H, CH3CH) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)[C:7]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:5])[CH3:2].Cl[C:34]1[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][N:35]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:34]3[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][N:35]=3)[CH:13]=2)[N:8]([C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23]([F:26])([F:24])[F:25])=[CH:20][CH:21]=2)[C:7]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(OC(F)(F)F)cc1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(C(F)(F)F)cn3)ccc2n1-c1ccc(OC(F)(F)F)cc1

Procedure:
The sub-title compound was prepared in accordance with step (a) Example 21 from 1-(4-trifluoromethoxyphenyl)-2-ethoxycarbonylmethyl-5-hydroxyindole-3′-carboxylic acid ethyl ester (140 mg, 0.31 mmol, see step (b) Example 9) and 2-chloro-5-(trifluoromethyl)pyridine (112 mg, 0.62 mmol). Yield 87 mg (47%).
Reaction SMILES: ClC1C=CC(C2SC(C(OCC)=O)=C(C)N=2)=CC=1[N+]([O-])=O.[CH3:22][C:23]1[N:24]=[C:25]([C:33]2[CH:38]=[CH:37][C:36]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[C:35]([N+:45]([O-:47])=[O:46])[CH:34]=2)[S:26][C:27]=1[C:28]([O:30]CC)=[O:29]>N1CCOCC1>[CH3:22][C:23]1[N:24]=[C:25]([C:33]2[CH:38]=[CH:37][C:36]([N:39]3[CH2:40][CH2:41][O:42][CH2:43][CH2:44]3)=[C:35]([N+:45]([O-:47])=[O:46])[CH:34]=2)[S:26][C:27]=1[C:28]([OH:30])=[O:29]
Reactant: CCOC(=O)c1sc(-c2ccc(N3CCOCC3)c([N+](=O)[O-])c2)nc1C
Agent: CCOC(=O)c1sc(-c2ccc(Cl)c([N+](=O)[O-])c2)nc1C
Solvent: C1COCCN1
Product: Cc1nc(-c2ccc(N3CCOCC3)c([N+](=O)[O-])c2)sc1C(=O)O
Yield: 71 %

Procedure:
As described in Example 37, ethyl 2-(4-chloro-3-nitrophenyl)-4-methyl-5-thiazolecarboxylate was reacted in morpholine, and the resulting ethyl 4-methyl-2-(4-morpholino-3-nitrophenyl)-5-thiazolecarboxylate was hydrolyzed by a conventional process to give 4-methyl-2(4-morpholino-3-nitrophenyl)-5-thiazolecarboxylic acid (yield: 71%).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[N:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[C:19](O)=[O:20].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(CC)CC)C.[Li+].[OH-]>C(Cl)Cl.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:19]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][N:13]=3)=[O:20])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(O)c1cnccn1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1cnccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (0.200 g, 0.869 mmol, Example 1, Step H), pyrazine-2-carboxylic acid (0.227 g, 1.83 mmol), BOP-Cl (0.465 g, 1.83 mmol), and triethylamine (0.606 ml, 4.35 mmol) were placed in DCM (5 mL) and stirred at room temperature for 30 minutes. 3M LiOH (3 mL) was then added, and the reaction was stirred for an additional 10 minutes and then poured into water. The mixture was then filtered, washed with DCM, and then washed with 10:1 DCM:MeOH and dried to give N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrazine-2-carboxamide (0.180 g, 61% yield) as a solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2.C([Li])CCC.[Br:26][C:27]1[CH:41]=[CH:40][C:30]([C:31]([C:33]2[CH:38]=[CH:37][C:36]([Br:39])=[CH:35][CH:34]=2)=O)=[CH:29][CH:28]=1>O1CCCC1.C(O)(=O)C.S(=O)(=O)(O)O>[Br:26][C:27]1[CH:41]=[CH:40][C:30]([C:31]2([C:33]3[CH:38]=[CH:37][C:36]([Br:39])=[CH:35][CH:34]=3)[C:19]3[C:20]4=[C:15]([C:14]5[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=5[N:8]4[C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]2=4)[CH:16]=[CH:17][CH:18]=3)=[CH:29][CH:28]=1
Reactant: Brc1ccccc1-n1c2ccccc2c2ccccc21
Reactant: O=C(c1ccc(Br)cc1)c1ccc(Br)cc1
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Brc1ccc(C2(c3ccc(Br)cc3)c3ccccc3-n3c4ccccc4c4cccc2c43)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
6.96 g of 9-(2-bromophenyl)-9H-carbazole as the intermediate of Preparation Example 8 was dissolved in 10 mL of purified tetrahydrofuran, and the resulting solution was cooled to −78° C. and 8.64 mL of butyllithium was slowly added dropwise. The mixture was stirred at the same temperature for 30 min, and 6.12 g of 4,4′-dibromobenzophenone was added. The mixture was stirred at the same temperature for 40 min and then further stirred at room temperature for an additional 3 hours. The reaction was terminated with aqueous ammonium chloride, and the reaction mixture was extracted with ethyl ether. The organic layer was dewatered using anhydrous magnesium sulfate, and the organic solvent was then removed. The resulting solid was dispersed in ethanol, stirred for one day, filtered, and vacuum dried, thus obtaining an intermediate material. The solid thus obtained was dispersed in 10 mL of acetic acid, and 10 drops of concentrated sulfuric acid were added, after which the mixture was refluxed for 4 hours. The resulting solid was filtered, washed with ethanol, and vacuum dried, yielding a 8,8-bis(4-bromophenyl)-8H-indolo[3,2,1-de]acridine compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:17]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[C:16]3[C:11](=[CH:12][C:13]([O:25][CH3:26])=[CH:14][CH:15]=3)[O:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Cl.Cl[CH2:37][CH2:38][N:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:37][CH2:38][N:39]4[CH2:43][CH2:42][CH2:41][CH2:40]4)=[CH:20][CH:19]=3)[C:16]3[C:11](=[CH:12][C:13]([O:25][CH3:26])=[CH:14][CH:15]=3)[O:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)OC[C@@H](c1ccc(F)cc1)[C@H]2c1ccc(O)cc1
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: COc1ccc2c(c1)OC[C@@H](c1ccc(F)cc1)[C@H]2c1ccc(OCCN2CCCC2)cc1
Temperature: 60 °C

Procedure:
A mixture of (±)-cis-3-(4-fluorophenyl)-4-(4-hydroxyphenyl)-7-methoxy-chromane, (0.53 g, 1.51 mmol) potassium carbonate, (2.10 g, 15.2 mmol) sodium iodide, (0.01 g, 0.07 mmol) 1-(2-chloroethyl)pyrrolidine hydrochloride, (0.28 g, 1.65 mmol) and acetone, (35 ml) was stirred at 60° C., under reflux, for 24 h. The resulting mixture was filtered and the solvent evaporated to give a colourless gum, which solidified on cooling. The crude solid was recrystallised from aqueous ethanol to give the product as colourless needles, which were vacuum dried.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[C:5]([C:7]1[C:8]([NH:18][CH2:19][CH3:20])=[N:9][C:10]([CH:13]([O:16]C)OC)=[CH:11][CH:12]=1)=O.[H-].[Na+].Cl[CH:27]([CH2:33][CH2:34][C:35]([O-])=[O:36])[C:28]([O:30][CH2:31]C)=[O:29]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[C:7]3[C:8](=[N:9][C:10]([CH:13]=[O:16])=[CH:11][CH:12]=3)[N:18]([CH2:19][CH3:20])[C:35](=[O:36])[C:34]=2[CH2:33][CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)C(Cl)CCC(=O)[O-]
Reactant: CCNc1nc(C(OC)OC)ccc1C(=O)c1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(=O)c(CCC(=O)OC)c(-c2cccc(Cl)c2)c2ccc(C=O)nc21

Procedure:
In DMF was treated 3-(3-chlorobenzoyl)-2-ethylamino-6-dimethoxymethylpyridine with 60% sodium hydride, followed by the reaction with monoethyl chloroglutarate. Thereafter, the reaction mixture was worked up and purified in a usual manner. The resulting compound was reacted in ethanol in the presence of sodium methoxide under heating, and the reaction mixture was worked up and purified in a usual manner. Then, the resulting compound was reacted in a solution of 6M hydrochloric acid-dioxane (1:1) under heating, and then the reaction mixture was worked up and purified in a usual manner. The resulting compound was further reacted with methyl iodide in DMF in the presence of potassium carbonate, and then the reaction mixture was worked up and purified in a usual manner to obtain methyl 3-[4-(3-chlorophenyl)-1-ethyl-7-formyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl]propanoate. NMR1: 10.11 (1H, d, J=0.6 Hz), 2.45-2.95 (4H, m), 1.43 (3H, t, J=7.1 Hz).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O:15][C:16]([C:18]1[O:19][C:20]([CH2:23]Cl)=[CH:21][CH:22]=1)=[O:17]>>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:23][C:20]2[O:19][C:18]([C:16]([OH:17])=[O:15])=[CH:22][CH:21]=2)[CH:8]=1
Reactant: COC(=O)c1ccc(CCl)o1
Reactant: Oc1cccc(-c2ccccc2)c1
Product: O=C(O)c1ccc(COc2cccc(-c3ccccc3)c2)o1

Procedure:
5-(Biphenyl-3-yloxymethyl)-furan-2-carboxylic acid was prepared using general procedure A from 3-phenylphenol (available from Aldrich, Milwaukee, Wis.) and 5-chloromethylfuran-2-carboxylic acid methyl ester (available from Aldrich, Milwaukee, Wis., or from Maybridge plc, Tintagel, UK). Yield: 67 mg. Mass spectrum (ES) MH+=295.