Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[CH3:27][NH:28][C:29](=[O:46])[C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][C:31]=1[CH3:45]>>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH:7]([CH3:26])[CH2:6][C:5]3[C:10](=[CH:11][C:2]([C:33]4[CH:34]=[CH:35][C:30]([C:29]([NH:28][CH3:27])=[O:46])=[C:31]([CH3:45])[CH:32]=4)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]2)[N:15]=1
Reactant: CNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1C
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Product: CNC(=O)c1ccc(-c2ccc3c(c2)CN(c2cc(N4CCN(C)CC4)nc(N)n2)C(C)C3)cc1C

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 129, Step 4 starting from 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine and N,2-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide. LCMS (M+H)+: m/z=486.298.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][C:11]2=[O:19])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:20][N:21]1[CH2:25][CH2:24][CH2:23][C:22]1=O>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[C:22]3[CH2:23][CH2:24][CH2:25][N:21]3[CH3:20])[C:11]2=[O:19])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CN1CCCC1=O
Reactant: COc1ccc(N2C(=O)Cc3ccccc32)cc1F
Solvent: CCOC(C)=O
Product: COc1ccc(N2C(=O)C(=C3CCCN3C)c3ccccc32)cc1F

Procedure:
By the procedure of Example B5, except to use ethyl acetate as eluant, 1-(3-fluoro-4-methoxyphenyl)-2(1H,3H)-indolone (2.0 g, 7.8 mmoles) and 1-methyl-2-pyrrolidone (1.5 ml, 15.6 mmole) were converted to title product, 0.32 g, m.p. 68°-71°.
Reaction SMILES: FC(F)(F)C(O)=O.[Si:8]([O:25][C@H:26]([CH3:45])[C@H:27]([NH:37]C(=O)OC(C)(C)C)[C:28]1[CH:33]=[C:32]([F:34])[C:31]([F:35])=[C:30]([F:36])[CH:29]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Si:8]([O:25][C@H:26]([CH3:45])[C@H:27]([NH2:37])[C:28]1[CH:33]=[C:32]([F:34])[C:31]([F:35])=[C:30]([F:36])[CH:29]=1)([C:21]([CH3:22])([CH3:23])[CH3:24])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: C[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@H](NC(=O)OC(C)(C)C)c1cc(F)c(F)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@H](N)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 11 h
Yield: 91.1 %

Procedure:
Trifluoroacetic acid (0.5 ml) was added to a solution of tert-butyl [(1R,2R)-2-tert-butyldiphenylsilanyloxy-1-(3,4,5-trifluorophenyl)propyl]carbamate (370 mg) in methylene chloride (2 ml), and the reaction solution was stirred at room temperature for 11 hours. A saturated sodium bicarbonate solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium bicarbonate solution and brine, and then the solvent was evaporated under reduced pressure to obtain 275 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:23][C:24]([OH:26])=O)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[C:7]2[CH3:21].Cl.CN(C)CCCN=C=NCC.[CH3:39][S:40]([NH2:43])(=[O:42])=[O:41]>CN(C1C=CN=CC=1)C.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:23][C:24]([NH:43][S:40]([CH3:39])(=[O:42])=[O:41])=[O:26])=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[C:8]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=1)=[C:7]2[CH3:21]
Reactant: CS(N)(=O)=O
Reactant: Cc1nc2c(Cl)ccc(OCC(=O)O)c2c(C)c1Cc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1nc2c(Cl)ccc(OCC(=O)NS(C)(=O)=O)c2c(C)c1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of [8-chloro-3-(4-chlorobenzyl)-2,4-dimethylquinolin-5-yloxy]acetic acid (0.050 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.037 g), methanesulfonamide (0.020 g), and 4-(N,N-dimethylamino)pyridine (0.005 g) in dichloromethane (5.0 mL) was stirred at room temperature 1 hour. The mixture was diluted with dichloromethane and this solution was washed with water and then dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by preparative reverse-phase HPLC using a gradient over 30 minutes of acetonitrile in water (40% to 95% of organic modifier) gave title compound as a yellow solid, 0.010 g
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:4][CH:3]=1.Cl[S:35]([C:38]1[CH:46]=[CH:45][C:41]([C:42]([OH:44])=[O:43])=[CH:40][CH:39]=1)(=[O:37])=[O:36].C(N(CC)CC)C.ClCCl>>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:22][CH2:23][N:24]([S:35]([C:38]3[CH:39]=[CH:40][C:41]([C:42]([OH:44])=[O:43])=[CH:45][CH:46]=3)(=[O:37])=[O:36])[CH2:25][CH2:26]2)=[CH:32][CH:31]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: O=c1cc(NC2CCNCC2)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2[nH]1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)c1ccc(S(=O)(=O)N2CCC(Nc3cc(=O)[nH]c4ccc(C(c5ccc(Cl)cc5)c5ccc(Cl)cc5)cc34)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 25-mL round-bottom flask, was placed 6-[bis(4-chlorophenyl)methyl]-4-[(piperidin-4-yl)amino]-1,2-dihydroquinolin-2-one (150 mg, 0.31 mmol, 1.00 equip, 98%), 4-(chlorosulfonyl)benzoic acid (103.77 mg, 0.47 mmol, 1.50 equip), triethylamine (98.28 mg, 0.95 mmol, 3.00 equip, 98%), dichloromethane (3 g, 35.32 mmol, 114.96 equip). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The resulting residue was purified by Prep-HPLC with the following conditions: Column, Sunfire Prep C18 OBD 5 um, 19×150 mm; mobile phase, Phase A: water (0.05% NH4HCO3), Phase B:CH3CN (20% CH3CN up to 65% in 8 min, up to 100% in 0.1 min, hold 100% for 1.9 min, down to 20% in 0.1 min, hold 20% for 1.9 min); Detector, UV 220 & 254 nm to yield 4-[4-([6-[bis(4-chlorophenyl)methyl]-2-oxo-1,2-dihydroquinolin-4-yl]amino)piperidine-1-sulfonyl]benzoic acid as an off-white solid.
Reaction SMILES: [CH2:1]([S:4]([NH:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](O)=[O:12])(=[O:6])=[O:5])[CH2:2][CH3:3].S(Cl)([Cl:19])=O>>[CH2:1]([S:4]([NH:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([Cl:19])=[O:12])(=[O:6])=[O:5])[CH2:2][CH3:3]
Reactant: CCCS(=O)(=O)Nc1cccc(C(=O)O)c1
Reactant: O=S(Cl)Cl
Product: CCCS(=O)(=O)Nc1cccc(C(=O)Cl)c1

Procedure:
A solution of 3-(propane-1-sulfonylamino)-benzoic acid (76, 1.20 g, 4.93 mmol) in thionyl chloride was heated to reflux for 3.0 hours. Evaporation of the solvent gave compound 77 as white solid that was used for the next step.
Reaction SMILES: [K].[C:2]1([C:8]2[CH:16]=[C:12]3[CH:13]=[CH:14][CH:15]=[C:11]3[O:10][C:9]=2[CH2:17][C:18]([OH:20])=[O:19])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:22][O:23][CH3:24]>CN(C)C=O>[C:2]1([C:8]2[CH:16]=[C:12]3[CH:13]=[CH:14][CH:15]=[C:11]3[O:10][C:9]=2[CH2:17][C:18]([O:20][CH2:22][O:23][CH3:24])=[O:19])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCl
Reactant: O=C(O)Cc1oc2cccc-2cc1-c1ccccc1
Agent: [K]
Solvent: CN(C)C=O
Product: COCOC(=O)Cc1oc2cccc-2cc1-c1ccccc1

Procedure:
The potassium salt of 3-phenyl-7-benzofuranacetic acid is reacted with chloromethoxymethane in dimethylformamide to provide methoxymethyl 3-phenyl-7-benzofuranacetate.
Reaction SMILES: C([O:5]C1C=CC(SC(C2C=CC(Cl)=CC=2)C(NO)=O)=CC=1)C#CC.[CH2:25]([O:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([CH:38]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=2)[C:39]([NH:41][OH:42])=[O:40])=[O:37])=[CH:32][CH:31]=1)[C:26]#[C:27][CH3:28]>>[CH2:25]([O:29][C:30]1[CH:31]=[CH:32][C:33]([S:36]([CH:38]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=2)[C:39]([NH:41][OH:42])=[O:40])(=[O:5])=[O:37])=[CH:34][CH:35]=1)[C:26]#[C:27][CH3:28]
Reactant: CC#CCOc1ccc(SC(C(=O)NO)c2ccc(Cl)cc2)cc1
Reactant: CC#CCOc1ccc(S(=O)C(C(=O)NO)c2ccc(Cl)cc2)cc1
Product: CC#CCOc1ccc(S(=O)(=O)C(C(=O)NO)c2ccc(Cl)cc2)cc1
Yield: 29 %

Procedure:
Starting from a mixture of 2-{[4-(2-butynyloxy)phenyl]sulfanyl}-2-(4-chlorophenyl)-N-hydroxyacetamide (from example 80) and 2-{[4-(2-butynyloxy) phenyl]sulfinyl}-2-(4-chlorophenyl) N-hydroxyacetamide (750 mg, 1.99 mmol), and following the procedure as outlined in Example 75, 228 mg of 2-{[4-(2-butynyloxy)phenyl]sulfonyl}-2-(4-chlorophenyl)-N-hydroxyacetamide was isolated as a white solid. mp: 140° C.; Yield: 29%; MS: 394.2 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ 1.85 (t, J=2.19 Hz, 3H), 4.86 (d, J=2.28 Hz, 2H), 5.05 (s, 1H), 7.1 (d, 2H), 7.4 (m, 4H), 7.5 (d, 2H), 9.33 (s, 1H), 10.8 (s, 1H).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:7]=1[NH2:8])([O-:5])=[O:4].F[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>CC(N(C)C)=O>[N+:3]([C:6]1[CH:12]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:10]=[CH:9][C:7]=1[NH:8][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)([O-:5])=[O:4]
Reactant: Fc1ccccn1
Reactant: Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Nc1ccccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 23.9 %

Procedure:
To a stirred suspension of sodium hydride (2.40 g, 60 mmol) in dimethylacetamide (60 ml) at room temperature under a nitrogen atmosphere was added a solution of 2-nitro-4-trifluoromethylaniline (10.31 g, 50 mmol) in dimethylacetamide (20 ml) during 30 min. After stirring the mixture at room temperature for 15 min., a solution of 2-fluoropyridine (5.83 g, 60 mmol) in dimethylacetamide (20 ml) was added during 5 min. The resulting mixture was heated to reflux for about 8 h. Volatiles were removed by evaporation under reduced pressure. The residue was dissolved into ethyl acetate (200 ml) and washed with water (3×100 ml). The organic layer was dried (magnesium sulfate) and concentrated to dryness. Column chromatography (silica gel, 250 g; n-hexane/ethyl acetate (17/3)) yielded 3.38 g (23%) of the titled compound as yellow solids.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH:10][C:11](=[O:13])[CH3:12].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=O)CC(OCC)=O)=[CH:17][CH:16]=1.P(Cl)(Cl)Cl>ClCCCl>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[NH:10][C:11](=[O:13])[CH:12]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)CC(=O)c1ccc(Cl)cc1
Reactant: COc1ccccc1NNC(C)=O
Solvent: ClCCCl
Solvent: ClP(Cl)Cl
Product: COc1ccccc1-n1[nH]c(=O)cc1-c1ccc(Cl)cc1
Temperature: 50 °C
Yield: 51.7 %

Procedure:
To a mixture of N′-(2-methoxyphenyl)acetohydrazide (2.90 g, 16.09 mmol) and ethyl 3-(4-chlorophenyl)-3-oxopropanoate (3.65 g, 16.09 mmol) in 10 mL of DCE was added drop wise phosphorus trichloride (1.41 mL, 16.09 mmol). The mixture was heated to 50° C. and all solids dissolved. After 2 hrs at 50° C. the mixture was cooled to RT and the ppt was collected by filtration and washed with water and EtOAc and dried to give 2.50 g (49%) of a white solid.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=2)[NH:4][CH:3]=1.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-].[Na+]>C(Cl)Cl>[C:18]1([S:24]([N:4]2[C:5]3=[N:6][CH:7]=[C:8]([S:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:9]=[C:10]3[C:2]([I:1])=[CH:3]2)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Ic1c[nH]c2ncc(Sc3ccccc3)cc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)n1cc(I)c2cc(Sc3ccccc3)cnc21
Reaction time: 0.5 h

Procedure:
A mixture of 3 (200 mg, 0.57 mmol), benzenesulfonyl chloride (109 μL, 0.85 mmol), n-BuNHSO4 (25 mg, 0.074 mmol) and 50% aqueous NaOH (108 μL) in CH2Cl2 (3.5 mL) were stirred for 0.5 h. The mixture was partitioned between sat. aq. NaHCO3/CH2Cl2. The organic layer was separated and the aqueous phase extracted with CH2Cl2. The combined organic solutions were dried (MgSO4) and concentrated to give 4 as an orange oil (336 mg, 120
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[C:8](=[O:12])[NH:9][CH2:10][CH2:11][C:6]=2[CH:5]=[CH:4]1)[CH3:2].I[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH3:20].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH2:1]([N:3]1[C:7]2[C:8](=[O:12])[N:9]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:19]=3[CH3:20])[CH2:10][CH2:11][C:6]=2[CH:5]=[CH:4]1)[CH3:2]
Reactant: CCn1ccc2c1C(=O)NCC2
Reactant: Cc1ccncc1I
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCn1ccc2c1C(=O)N(c1cnccc1C)CC2
Yield: 47.4 %

Procedure:
Using similar reaction conditions as described in Example 5, 1-ethyl-1H-3-pyrrole-3-carbaldehyde was converted to 1-ethyl-1,4,5,6-tetrahydro-pyrrolo[2,3-c]pyridin-7-one. By employing analogous reaction conditions as described in Example 1, 1-ethyl-1,4,5,6-tetrahydro-pyrrolo[2,3-c]pyridin-7-one (75 mg, 0.4571 mmol) was reacted with 3-iodo-4-methyl-pyridine (100 mg, 0.457 mmol), 1,4-dioxane (5 mL), copper iodide (8.5 mg, 0.0457 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (0.021 mL, 0.137 mmol) and potassium phosphate (290 mg, 1.371 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% methanol in CHCl3) afforded 55 mg of the product (47.4% yield).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[CH2:21][CH2:20]N(C5C=CC=CC=5)C4=O)[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[Cl:31][C:32]1[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=1[N:39]=[C:40]=[O:41].Cl>>[F:1][C:2]1[CH:30]=[CH:29][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[CH2:21][CH2:20][N:39]([C:33]5[CH:34]=[CH:35][CH:36]=[C:37]([Cl:38])[C:32]=5[Cl:31])[C:40]4=[O:41])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C1N(CCN2CCC(c3noc4cc(F)ccc34)CC2)CCN1c1ccccc1
Reactant: O=C=Nc1cccc(Cl)c1Cl
Agent: Cl
Product: O=C1N(CCN2CCC(c3noc4cc(F)ccc34)CC2)CCN1c1cccc(Cl)c1Cl

Procedure:
This product is obtained in the same manner as the compound of Example 5, but with replacement of the phenyl isocyanate by 2,3-dichlorophenyl isocyanate in Step 1 of the synthesis. The hydrochloride of the title compound melts at 218°-222° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[CH:20]([CH:22]1[NH:27][CH2:26][CH2:25][NH:24][CH2:23]1)=[CH2:21]>N1C=CC=CC=1>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:24]4[CH2:25][CH2:26][NH:27][CH:22]([CH:20]=[CH2:21])[CH2:23]4)[CH:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Reactant: C=CC1CNCCN1
Solvent: c1ccncc1
Product: C=CC1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CCN1
Temperature: 140 °C
Yield: 12.7 %

Procedure:
A mixture of 1.3 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.9 g of 3-ethenylpiperazine and 15 ml of pyridine is heated at 140° C. in a pressure bottle for 18 hours and then purified as described in Example 101, giving 210 mg of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[C:20](=[O:21])[N:19]([CH3:22])[C:12]3[N:13]=[C:14](SC)[N:15]=[CH:16][C:11]=3[CH:10]=2)=[CH:4][C:3]=1[NH:23][C:24]([NH:26][C:27]1[O:31][N:30]=[C:29]([C:32]([F:35])([F:34])[F:33])[CH:28]=1)=[O:25].[CH3:36][NH2:37].C1COCC1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[C:20](=[O:21])[N:19]([CH3:22])[C:12]3[N:13]=[C:14]([NH:37][CH3:36])[N:15]=[CH:16][C:11]=3[CH:10]=2)=[CH:4][C:3]=1[NH:23][C:24]([NH:26][C:27]1[O:31][N:30]=[C:29]([C:32]([F:35])([F:34])[F:33])[CH:28]=1)=[O:25]
Reactant: CN
Reactant: CSc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(F)(F)F)no4)c(F)cc3F)c(=O)n(C)c2n1
Solvent: C1CCOC1
Product: CNc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(F)(F)F)no4)c(F)cc3F)c(=O)n(C)c2n1
Yield: 13 %

Procedure:
Using a procedure analogous to Example A1, 1-(2,4-difluoro-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3-(trifluoromethyl)isoxazol-5-yl)urea (65 mg, 0.130 mmol) and 2.0N methylamine in THF (0.63 mL, 1.3 mmol) were combined to afford 1-(2,4-difluoro-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3-(trifluoromethyl)isoxazol-5-yl)urea (8 mg, 13% yield). MS (ESI) m/z: 496.0 (M+H+).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[NH:16][CH:15]=[CH:14]4)[CH:9]=[N:10][C:5]2=[N:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH:16]1[C:17]2[C:13](=[CH:12][C:11]([N:8]3[C:6]4=[N:7][C:2]([C:24]5[CH:25]=[C:26]([O:30][CH3:31])[C:27]([O:28][CH3:29])=[C:22]([O:21][CH3:20])[CH:23]=5)=[CH:3][N:4]=[C:5]4[N:10]=[CH:9]3)=[CH:19][CH:18]=2)[CH:14]=[CH:15]1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Reactant: Brc1cnc2ncn(-c3ccc4[nH]ccc4c3)c2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1cc(-c2cnc3ncn(-c4ccc5[nH]ccc5c4)c3n2)cc(OC)c1OC
Temperature: 150 °C

Procedure:
Following a method described in Pteridines, 2002, Vol. 13, 65-72, Intermediate BB was heated in anhydrous DMF at 175° C. for 15 min in a Personal Chemistry Optimizer. To the resulting 6-bromo-1-(1H-indol-5-yl)-1H-imidazo[4,5-b]pyrazine 1 in CH3CN (1 mL) in a microwave reaction vial was added 3,4,5-trimethoxyphenylboronic acid (30 mg, 0.14 mmol), bis(triphenylphosphine)-palladium(II) dichloride (7.0 mg, 0.010 mmol), and 1 M Na2CO3 (1 mL). The resulting mixture was de-gassed with Ar for 10 min, after which it was heated at 150° C. for 10 min in a Personal Chemistry Optimizer. The resulting mixture was partitioned between EtOAc and 1 M NaOH. The organic layer was separated, dried over MgSO4, filtered, and stripped to give a residue that was purified via preparatory HPLC to give 4.7 mg of the title compound. HPLC retention time: 2.43 minutes; MS ESI (m/z): 402.8 (M+1)+, calc. 401.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]>CN(C=O)C>[CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][CH2:18][CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(N)cc1
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(CNc1ccc(C(C)C)cc1)OCC

Procedure:
To a mixture of 4-isopropylaniline (4.05 g, 30.0 mmol) and potassium carbonate (6.21 g, 45 mmol) in DMF (100 mL) at room temperature was added 2-bromo-1,1-diethoxyethane (6.50 g, 33.0 mmol). The mixture was then stirred at 80-90° C. until all of the 4-isopropylaniline was consumed (24 h). The solvent was removed in vacuo and the residue was treated with dichloromethane (150 mL), washed with water and brine, dried over anhydrous MgSO4, and then concentrated. Chromatography (silica gel, hexanes:ethyl acetate, 9:1) of the crude product, furnished the pure intermediate, N-(4-isopropylphenyl)-2,2-diethoxyethylamine, as a colorless oil (5.71 g, 75.8%). 1H NMR (CDCl3, 300 MHz) δ (ppm) 1.18-1.32 (m, 12H), 2.75-2.91 (m, 1H), 3.24 (d, 2H), 3.52-3.62 (m, 2H), 3.67-3.79 (m, 2H), 3.87 (s, br, 1H), 4.70 (t, 1H), 6.60 (d, 2H), 7.05 (d, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([OH:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2].Cl[CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH:30]2[CH2:33][O:34][CH2:35][CH:29]2[CH2:28]1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([O:20][CH2:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][CH:30]5[CH2:33][O:34][CH2:35][CH:29]5[CH2:28]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2]
Reactant: C#Cc1cccc(Nc2ncnc3cc(OC)c(O)cc23)c1
Reactant: ClCCCN1CCC2COCC2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C#Cc1cccc(Nc2ncnc3cc(OC)c(OCCCN4CCC5COCC5C4)cc23)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 44.9 %

Procedure:
A mixture of 4-((3-ethynylphenyl)amino)-7-methoxyquinazolin-6-ol (250 mg, 0.68 mmol, 1 eq), 5-(3-chloropropyl)octahydrofuro[3,4-c]pyridine (280 mg, 0.82 mmol, 1.2 eq) and K2CO3 (188 mg, 1.36 mmol, 2 eq) in DMF (10 mL) was stirred at 80° C. overnight and cooled to room temperature. To this, CH2Cl2 (50 mL) was added. The mixture was washed with brine (20 mL×3) and water (20 mL×2), then dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (eluting agent: 20:1 (v/v) CH2Cl2/CH3OH) to give the title compound as a yellow solid (140 mg, 45.50%), HPLC: 98.47%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 459.2 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.73-1.75 (2H, m), 2.35-2.46 (3H, m), 2.54-2.68 (2H, m), 2.65-2.70 (3H, m), 2.72-2.76 (2H, m), 2.96-3.03 (3H, m), 3.05-3.10 (2H, m), 3.71-3.90 (2H, m), 4.03 (1H, s), 4.22-4.27 (2H, m), 7.06-7.12 (1H, m), 7.13 (1H, s), 7.76-7.82 (2H, m), 7.85 (1H, s), 8.06-8.11 (1H, m), 8.55 (1H, s) ppm.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=[CH:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2.[CH3:18][O:19]C=O>>[CH:18]([NH:1][CH2:2][CH:3]1[C:4]2[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=2[CH:6]=[CH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2)=[O:19]
Reactant: COC=O
Reactant: NCC1c2ccccc2C=Cc2ccccc21
Product: O=CNCC1c2ccccc2C=Cc2ccccc21
Temperature: 110 °C

Procedure:
5-Aminomethyl-5H-dibenzo[a,d]cycloheptene (4.82 g., 0.0218 mole) and methylformate, 200 ml. are heated to 110° C. for 161/2 hours in an autoclave. The yellow solution is evaporated to dryness on a film evaporator under reduced pressure. The residue is dissolved in benzene, the solution extracted with dilute hydrochloric acid, then with water and dried over anhydrous sodium sulfate. The benzene is evaporated and the residue dried to constant weight in a film evaporator under reduced pressure. The yellow solid residue weighs 5.49 g. and melts at 115°-117.5° C. to a cloudy melt, clearing at 119° C. Recrystallization from mixtures of benzene and hexane, followed by recrystallization from mixtures of ethanol and water gives a product melting at 120.3°-121° C. (clears 121.8° C.).