Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([OH:17])=[O:16])=[C:13]([Cl:18])[N:12]=[C:11]([Cl:19])[C:10]=1[C:20]([O:22]C(C)(C)C)=[O:21]>ClCCl>[NH2:8][C:9]1[C:14]([C:15]([OH:17])=[O:16])=[C:13]([Cl:18])[N:12]=[C:11]([Cl:19])[C:10]=1[C:20]([OH:22])=[O:21]
Reactant: CC(C)(C)OC(=O)c1c(Cl)nc(Cl)c(C(=O)O)c1N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1c(C(=O)O)c(Cl)nc(Cl)c1C(=O)O

Procedure:
In scheme (V), 5-(tert-butoxycarbonyl)-4-(tert-butoxycarbonylamino)-2,6-dichloronicotinic acid (4) is first treated with 25% trifluoracetic acid (TFA) in dichloromethane (DCM) at room temperature (25° C.) for 2 hours, removing one of the two Boc groups and forming 4-amino-5-(tert-butoxycarbonyl)-2,6-dichloronicotinic acid (5). A stronger condition (reflux at 60° C., 25% TFA in DCM, 2 h) is then used to maximize hydrolysis of the tert-butyl ester of 4-amino-5-(tert-butoxycarbonyl)-2,6-dichloronicotinic acid (5) and obtain 4-amino-2,6-dichloropyridine-3,5-dicarboxylic acid (6).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1.C([Li])CCC.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1)[CH:22]=[O:23].CC(O)C>C1COCC1.O>[O:6]1[C:5]2[CH:10]=[CH:11][C:2]([CH:22]([C:21]3[CH:24]=[C:25]([O:27][CH3:28])[CH:26]=[C:19]([O:18][CH3:17])[CH:20]=3)[OH:23])=[CH:3][C:4]=2[O:9][CH2:8][CH2:7]1
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: Brc1ccc2c(c1)OCCO2
Agent: [Li]CCCC
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(O)c2ccc3c(c2)OCCO3)c1
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
A solution of 6-bromo-2,3-dihydrobenzo[1,4]dioxine (1.09 g, 5.07 mmol) in anhydrous THF (10 ml) was cooled to −78° C., evacuated and refilled with nitrogen for ten cycles. To this clear solution was slowly added n-butyl lithium (2.03 ml, 5.07 mmol) and stirred for 30 min. Then a solution of 3,5-dimethoxybenzaldehyde (0.77 g, 4.61 mmol) in anhydrous THF (10 ml) was added via a syringe. The mixture was stirred at −78° C. under nitrogen for 4 h then quenched with 2-propanol (2.10 ml, 27.65 mmol) and stirred overnight. To the orange colored mixture was added 30 ml of water and extracted with ether (3×60 ml). The combined ether extracts was washed with water (2×60 ml), dried over MgSO4, filtered and concentrated in vacuo to an oil, which was purified via flash column chromatography (10% EtOAc in hexane gradient to 40% EtOAc in hexane in about 40 min.) to give (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(3,5-dimethoxy-phenyl)-methanol as a light brown oil (1.27 g, 91%), HPLC purity was 93.4% at 3.45 min. (50/50 ACN/0.1% H3PO4): 1HNMR (CDCl3) δ 6.88-6.79 (m, 3H, Ar), 6.54 (d, J=2 Hz, 2H, Ar), 6.35 (t, J=2 Hz, 1H, Ar), 5.65 (d, J=3 Hz, 1H, CH), 4.22 (m, 4H, 2CH2), 3.77 (s, 6H, OCH3), 2.25 (d, J=3 Hz, 1H, OH). The product was carried over to the next step.
Reaction SMILES: FC1N(C)CCN(C2C=CC(N[C:16]3[N:21]=[C:20]([C:22]4[CH:23]=[C:24]([NH:28][C:29](=[O:32])[CH:30]=[CH2:31])[CH:25]=[CH:26][CH:27]=4)[C:19]([NH:33][C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=4)=[CH:18][N:17]=3)=CC=2)C1.[Cl:41]C1N=C(Cl)C(NC2C=CC=C(F)C=2)=CN=1.C(NC1C=C(B(O)O)C=CC=1)(=O)C=C>[Pd]>[Cl:41][C:16]1[N:21]=[C:20]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:32])[CH:30]=[CH2:31])[CH:25]=[CH:26][CH:27]=2)[C:19]([NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=2)=[CH:18][N:17]=1
Reactant: Fc1cccc(Nc2cnc(Cl)nc2Cl)c1
Reactant: C=CC(=O)Nc1cccc(-c2nc(Nc3ccc(N4CCN(C)C(F)C4)cc3)ncc2Nc2cccc(F)c2)c1
Agent: [Pd]
Agent: C=CC(=O)Nc1cccc(B(O)O)c1
Product: C=CC(=O)Nc1cccc(-c2nc(Cl)ncc2Nc2cccc(F)c2)c1

Procedure:
As an example, N-(3-(2-((4-(3-fluoro-4-methylpiperazin-1-yl)phenyl)amino)-5-((3-fluorophenyl)amino)pyrimidin-4-yl)phenyl)acrylamide can be prepared according to Route I. Beginning with 2,4-dichloro-N-(3-fluorophenyl)pyrimidin-5-amine, a palladium catalyzed coupling reaction with (3-acrylamidophenyl)boronic acid provides N-(3-(2-chloro-5-((3-fluorophenyl)amino)pyrimidin-4-yl)phenyl)acrylamide under mild conditions. Reaction of this product with 4-(3-fluoro-4-methylpiperazin-1-yl)aniline under palladium catalyzed aminolysis conditions yields N-(3-(2-((4-(3-fluoro-4-methylpiperazin-1-yl)phenyl)amino)-5-((3-fluorophenyl)amino)pyrimidin-4-yl)phenyl)acrylamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]#[C:11][C:12]2[C:13]([CH3:24])=[N:14][CH:15]=[N:16][C:17]=2[N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:5][N:4]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.N1C=CC=CC=1.O>C(Cl)Cl>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:9][C:8]2[C:3]([O:2][CH3:1])=[N:4][CH:5]=[C:6]([C:10]#[C:11][C:12]3[C:13]([CH3:24])=[N:14][CH:15]=[N:16][C:17]=3[N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[CH:7]=2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COc1ncc(C#Cc2c(C)ncnc2N2CCOCC2)cc1N
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ncc(C#Cc2c(C)ncnc2N2CCOCC2)cc1NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To 100 mg (0.31 mmol) 2-Methoxy-5-(4-methyl-6-morpholin-4-yl-pyrimidin-5-ylethynyl)-pyridin-3-ylamine (E-9) in 5 mL DCM is added 130 mg (0.61 mmol) 4-chlorobenzenesulfonyl chloride and 72 μL (0.97 mmol) pyridine and the reaction mixture is stirred over night at RT. Water (2 mL) is added, the mixture is shaken for five minutes, the aqueous phase is separated and is extracted three times with 4 mL DCM. The combined organic phases are dried over MgSO4 and concentrated under reduced pressure. The crude product is purified by RP chromatography (C18, 20-80% ACN in water containing 1% formic acid). Yield: 105 mg (76%). HPLC-MS: M+H=500; tR=0.91 min.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].C(Cl)CCl.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[N:20][C:21]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([OH:35])=O)=[CH:27][CH:26]=3)=[N:22][CH:23]=2)=[CH:14][CH:13]=1.[NH4+].[Cl-]>CN(C1C=CN=CC=1)C.ClCCl.CN1C(=O)CCC1>[CH2:1]([N:3]([CH2:4][CH3:5])[C:33](=[O:35])[CH2:32][CH2:31][C:28]1[CH:27]=[CH:26][C:25]([NH:24][C:21]2[N:22]=[CH:23][C:18]([C:15]3[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=3)=[CH:19][N:20]=2)=[CH:30][CH:29]=1)[CH3:2]
Reactant: CCNCC
Reactant: COc1ccc(-c2cnc(Nc3ccc(CCC(=O)O)cc3)nc2)cc1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CN1CCCC1=O
Solvent: ClCCCl
Product: CCN(CC)C(=O)CCc1ccc(Nc2ncc(-c3ccc(OC)cc3)cn2)cc1
Reaction time: 3 h

Procedure:
4-(3-Diethylamino-propyl)-phenyl]-[S-(4-methoxy-phenyl)-pyrimidin-2-yl]-amine can be prepared by the following procedure. Diethylamine (10 mmol), EDC (25 mmol) and DMAP (0.1 mmol) are dissolved in dichloromethane (3 mL) and added to the crude 3-{4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-phenyl}-propionic acid dissolved in NMP (from example 5ao) at rt. After 3 h, sat. aq NH4Cl is added and the mixture is extracted with EtOAc. The combined extracts are dryed over anhydrous Na2SO4 and solvent is removed. Purification by preparative HPLC yields N,N-diethyl-3-{4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-phenyl}-propionamide.
Reaction SMILES: [Mg].II.Br[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[C:15]([F:22])[C:14]=2[F:23])=[C:9]([F:24])[C:8]=1[F:25].C([CH:29]1[O:34][C:33](=O)[CH:32]([C:36]2[CH:41]=[CH:40][C:39]([C:42]3C=CC(C4CCC(CCCCC)OC4)=[C:44](F)[C:43]=3F)=[C:38](F)[C:37]=2F)[CH2:31][CH2:30]1)CC.C1C[O:66]CC1>>[CH2:20]([O:19][C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][C:29]3([OH:66])[CH2:30][CH2:31][CH:32]([CH:36]4[CH2:41][CH2:40][CH:39]([CH2:42][CH2:43][CH3:44])[CH2:38][CH2:37]4)[CH2:33][O:34]3)=[C:8]([F:25])[C:9]=2[F:24])=[C:14]([F:23])[C:15]=1[F:22])[CH3:21]
Reactant: C1CCOC1
Reactant: CCOc1ccc(-c2ccc(CCBr)c(F)c2F)c(F)c1F
Reactant: CCCCCC1CCC(c2ccc(-c3ccc(C4CCC(CCC)OC4=O)c(F)c3F)c(F)c2F)CO1
Agent: II
Agent: [Mg]
Product: CCCC1CCC(C2CCC(O)(CCc3ccc(-c4ccc(OCC)c(F)c4F)c(F)c3F)OC2)CC1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 47.1 %

Procedure:
THF (5 ml) was added to magnesium turnings (0.30 g) in a reaction vessel under an atmosphere of nitrogen, and a minute amount of iodine was added. 4-(2-Bromoethyl)-4′-ethoxy-2,2′,3,3′-tetrafluorobiphenyl (29) (4.60 g) in a THF (5 ml) solution was slowly added dropwise at a temperature 50° C. or lower. After the addition had been completed, the stirring was continued at room temperature for 30 minutes. The reaction mixture was then cooled to −30° C. or lower, and 5-(4-propylcyclohexyl)tetrahydro-2H-pyran-2-one (20) (2.46 g) in a THF (5 ml) solution was added dropwise. After the reaction mixture had been stirred at room temperature for 5 hours, it was quenched with a saturated aqueous solution of ammonium chloride, and water (20 ml) was added to give two layers. The water layer was extracted with toluene (10 ml) twice, and the combined organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (silica gel: 20 g, eluent: toluene/ethyl acetate=70/30 by volume) to give 2-(2-(4′-ethoxy-2,2′,3,3′-tetrafluorobiphenyl-4-yl)ethyl)-5-(4-propylcyclohexyl)tetrahydro-2H-pyran-2-ol (30) (2.7 g) in 47.1% yield.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:4][CH:3]=1.[C:19]([N:26]1C=CN=C1)(N1C=CN=C1)=[O:20].[C:31]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])(=[O:34])[NH:32]N>O1CCCC1>[NH:26]([C:19]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:4][CH:3]=1)=[O:20])[NH:32][C:31]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)NN
Reactant: CC(=O)Nc1nc(CCc2ccc(O)cc2)cs1
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(CCc2ccc(OC(=O)NNC(=O)OC(C)(C)C)cc2)cs1
Temperature: 45 °C
Reaction time: 1 h
Yield: 50.1 %

Procedure:
To a solution of N-{4-[2-(4-hydroxyphenyl)ethyl]-1,3-thiazol-2-yl}acetamide (655.8 mg, 2.50 mmol) in anhydrous tetrahydrofuran (12 ml) was added 1,1′-carbonyldiimidazole (608.1 mg, 3.75 mmol). After stirring at 45° C. for 1 hr, the mixture was cooled to room temperature. tert-Butyl carbazate (495.6 mg, 3.75 mmol) was added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (FUJI SILYSIA CHEMICAL LTD. BW-300SP 80 g, ethyl acetate:hexane=1:1→3:2) and chemically modified silica gel column chromatography (FUJI SILYSIA CHEMICAL LTD. DM-2035 45 g, dichloromethane:methanol=50:1→20:1) to give 4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}phenyl tert-butyl hydrazine-1,2-dicarboxylate (526.4 mg, 1.252 mmol, yield 50.0%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])=[C:4]([F:21])[CH:3]=1.[N+:22]([O-])([OH:24])=[O:23]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:7]([N+:22]([O-:24])=[O:23])=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[N:10]([CH3:19])[C:9]2=[O:20])=[C:4]([F:21])[CH:3]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)cc2F)c1=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc([N+](=O)[O-])c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 3.0 grams (9.4 mmole) of 3-(4-chloro-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)pyrimidinedione in 30 mL of concentrated sulfuric acid was stirred and cooled in an ice bath. During 15 minutes, 0.75 mL (12 mmole) of aqueous 70% nitric acid was added dropwise, after which the reaction mixture was allowed to warm to ambient temperature, where it stirred for two hours. The reaction mixture was then poured into 150 mL of ice-water. The resulting precipitate was collected by filtration, washed with water, and dried under reduced pressure, yielding 3.0 grams of 3-(4-chloro-2-fluoro-5-nitrophenyl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([O:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][NH2:18])[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](O)=[O:25]>>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([O:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][NH:18][C:24]([C:20]3[NH:19][CH:23]=[CH:22][CH:21]=3)=[O:25])[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC/C=C\COc1cc(CN2CCCC2)ccn1
Reactant: O=C(O)c1ccc[nH]1
Product: O=C(NC/C=C\COc1cc(CN2CCCC2)ccn1)c1ccc[nH]1
Yield: 64 %

Procedure:
Following a procedure similar to that described in Example 13, but using 4-[4-(1-pyrrolidinylmethyl)-2-pyridyloxy]-cis-2-butenylamine and 2-pyrrolecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 124°-127° C., in a 64% yield.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Cl[C:23]1[CH:28]=[N:27][CH:26]=[CH:25][N:24]=1.C(N(CC)CC)C>CS(C)=O>[N:24]1[CH:25]=[CH:26][N:27]=[CH:28][C:23]=1[N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: Clc1cnccn1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(c3cnccn3)CC1)O2
Temperature: 100 °C
Reaction time: 3 h
Yield: 7.4 %

Procedure:
A mixture of spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione (0.150 g, 0.50 mmol), 2-chloropyrazine (0.57 g, 1.67 mmol), triethylamine (0.1 ml, 0.72 mmol), and DMSO (50 ml) was stirred for three hours at 100° C. The crude reaction mixture was purified directly by reverse phase HPLC to give the product as a purple solid (0.014 g, 0.7%) MP=255-256° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.41 (s, 1H), 8.10-8.07 (m, 1H), 7.91-7.81 (m, 3H), 7.76-7.70 (m, 1H), 7.58-7.52 (m, 1H), 4.28-4.22 (m, 2H), 3.39-3.28 (m, 2H), 3.12 (s, 2H), 2.11-2.04 (m, 2H), 1.88-1.79 (m, 2H); LCMS: 380 [M+H].
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][O:7][C:8]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].[CH3:19]O>>[CH3:6][O:7][C:8]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:9]=1[C:10]([O:12][CH3:19])=[O:11]
Reactant: CO
Reactant: COc1ccc(C(=O)O)c(OC)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(OC)cc1OC

Procedure:
2.1 1 ml of conc. sulfuric acid is added to a solution of 100 g of 2,4-dimethoxybenzoic acid in 500 ml of methanol, and the mixture is refluxed for 14 hours. The mixture is cooled, the solvent is removed, the residue is dissolved in 1 litre of MTB, the solution is washed three times with 200 ml of water each time and dried, and the solvent is removed, giving 105.5 g of methyl 2,4-dimethoxybenzoate.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:18])[CH:8]=2)[N:3]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C>CN1C(=O)CCC1>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([NH:32][C:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([Cl:18])[CH:8]=3)[N:3]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Clc1ccc2nc(Cl)nc(N3CCOCC3)c2c1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(Nc2nc(N3CCOCC3)c3cc(Cl)ccc3n2)CC1
Yield: 42 %

Procedure:
A mixture of 2,6-dichloro-4-morpholin-4-yl-quinazoline (0.9 g, 3.17 mmol, 1.0 equiv) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.27 g, 6.33 mmol, 2.0 equiv; commercially available) in anhydrous NMP (8 mL) and triethylamine (2 mL) was heated by microwave irradiation to 170° C. for 1 h. The organic phase was concentrated under reduced pressure and the residue extracted with dichloromethane (3×50 mL) from a sat. solution of sodium bicarbonate (100 mL). The combined organic phases were dried over MgSO4 and the product purified by column chromatography on silica eluting with a gradient of toluene/ethyl acetate (4:1→2:1) providing 0.6 g (42%) of the title compound. MS (ISP): 448.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=[CH:9][C:8]([O:26][CH3:27])=[CH:7][CH:6]=2.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:37][CH2:38][S:39][CH:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1>C(#N)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][CH2:19][N:18]([CH2:37][CH2:38][S:39][CH:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)[CH2:17][CH2:16]1)=[CH:9][C:8]([O:26][CH3:27])=[CH:7][CH:6]=2
Reactant: ClCCSC1CCCC1
Reactant: CCOC(=O)C1(CCCc2c(Cl)cnc3ccc(OC)cc23)CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C1(CCCc2c(Cl)cnc3ccc(OC)cc23)CCN(CCSC2CCCC2)CC1
Temperature: 80 °C
Yield: 56.5 %

Procedure:
1.2 g of ethyl 4-[3-(3-chloro-6-methoxy-quinolin-4-yl)propyl]piperidine-4-carboxylate, 0.51 g of potassium carbonate and 0.61 g of potassium iodide were added, at a temperature in the region of 20° C., with stirring and under an inert atmosphere, to a solution of 0.607 g of (2-chloroethylthio)cyclopentane in 50 cm3 of acetonitrile. After heating for 20 hours at a temperature in the region of 80° C., the reaction mixture was cooled to about 20° C., filtered and concentrated under reduced pressure (1 kPa) at a temperature in the region of 50° C. The residue obtained was purified by chromatography under a nitrogen pressure of 100 kPa, on a column of silica gel (particle size 40-60μ; diameter 3.5 cm), eluting with a mixture of dichloromethane/methanol (98/2 by volume) and collecting 35-cm3 fractions. Fractions 25 to 31 were combined and then concentrated as above. 0.9 g of ethyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopentylthio)ethyl]piperidine-4-carboxylate was obtained.
Reaction SMILES: BrC1C=CC([C:8]2[CH:21]=[CH:20][C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]=[CH:11][C:10]=3[CH:9]=2)=CC=1.Br[C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([Br:33])[CH:29]=2)[CH:24]=1>>[Br:33][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([C:8]1[CH:21]=[CH:20][C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]=[CH:11][C:10]=3[CH:9]=1)[CH:32]=[CH:31]2
Reactant: Brc1ccc(-c2ccc3c(ccc4ccccc43)c2)cc1
Reactant: Brc1ccc2cc(Br)ccc2c1
Product: Brc1ccc2cc(-c3ccc4c(ccc5ccccc54)c3)ccc2c1

Procedure:
Synthesis was performed in the same manner as in the synthesis of 2-(4-bromophenyl)phenanthrene except that 2,6-dibromo naphthalene was used instead of 4-bromoiodobenzene.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]([NH:11][C:12](=[NH:16])[CH2:13][CH2:14][CH3:15])[CH:8]=[CH:9][CH:10]=1)=[O:5])C.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCOCC1>[CH2:23]([N:16]1[C:4](=[O:5])[C:6]2=[CH:10][CH:9]=[CH:8][N:7]2[N:11]=[C:12]1[CH2:13][CH2:14][CH3:15])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: CCCC(=N)Nn1cccc1C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCCc1nn2cccc2c(=O)n1Cc1ccccc1
Temperature: 85 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
To a solution of 1-butyrimidoylamino-1H-pyrrole-2-carboxylic acid ethyl ester (7.6 g, 34 mmol) in dioxane (70 mL) at room temperature was added cesium carbonate (21.7 g, 66.7 mmol). The mixture was heated at 85° C. for 45 min and then benzyl bromide (4.2 mL, 35 mmol) was added. The reaction was stirred at 85° C. for 1 h. After cooling to room temperature, the reaction was filtered through a plug of silica gel and concentrated in vacuo. Purification of the crude product by flash column chromatography (SiO2, EtOAc/Hexane 1:4) gave the title compound as a white solid (8.9 g, 99%): 1H NMR (CDCl3) δ 7.22 (m, 6H), 6.96 (m, 1H), 6.43 (m, 1H), 5.17 (s, 2H), 2.47 (q, 2H, J=7.44 Hz), 1.63 (m, 2H), 0.88 (t, 3H, J=7.4 Hz); 13C NMR (CDCl3) δ 155.7, 149.7, 136.9, 129.3, 128.0, 126.8, 121.0, 118.4, 110.9, 108.8, 45.2, 34.6, 20.5, 14.1; MS (ESI+) 268.12 (M++H).
Reaction SMILES: C([C@H]1C[C@H:6]2[C@@H:7]([C:16]3[CH:21]=[CH:20][C:19](O)=[CH:18][CH:17]=3)[O:8][C:9]3C=CC(O)=CC=3[C@H]2C1)C.C[Si]([N-][Si](C)(C)C)(C)C.[K+].CN(C)P(N(C)C)(N(C)C)=O.COC1CC2[CH:51]([C:63]3[CH:68]=[CH:67][C:66](OCOC)=[CH:65][CH:64]=3)[O:52][C:53]3[CH:54]=[CH:55][C:56]([O:59][CH2:60][O:61]C)=[CH:57][C:58]=3C2C1.C1C[O:77][CH2:76]C1>>[CH2:19]([CH:20]1[C:57]2[C:56](=[CH:55][CH:54]=[C:53]([O:52][CH2:51][C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[CH:58]=2)[O:59][C:60](=[O:61])[CH:21]1[CH2:16][C:7]([O:8][CH2:9][O:77][CH3:76])=[CH2:6])[CH:18]=[CH2:17]
Reactant: C1CCOC1
Reactant: CC[C@H]1C[C@@H]2[C@H](C1)c1cc(O)ccc1O[C@@H]2c1ccc(O)cc1
Reactant: COCOc1ccc(C2Oc3ccc(OCOC)cc3C3CC(OC)CC32)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=CCC1c2cc(OCc3ccccc3)ccc2OC(=O)C1CC(=C)OCOC
Reaction time: 1.5 h

Procedure:
Cool a solution of Preparation 39 (3.65 g, 12.4 mmol) in THF (90 mL) to −78 C. Add a solution of KHMDS (32 mL, 0.5 M in toluene, 16 mmoL) over 5 min, then allow to stir for 15 in at −78 C. Add hexamethylphosphoramide (HMPA) via syringe (2.8 mL, 16.1 mmoL) quickly, and allow to stir for 20 min at −78 C. Add 2-O-methoxylmethyl allyl iodide (4.24 g) over 2 min, and then allow the solution to warm to −50 C. over 1.5 h. Pour the contents of the reaction into ½ satd. NaHCO3 and extract with Et2O (2×100 mL) and EtOAc (2×100 mL). Wash the combined organic extracts with H2O (2×150 mL) and brine (150 mL) and then dry over Na2SO4. Concentrate the crude product to leave a brown oil, which is purified by MPLC (0% to 12% to 20% EtOAc/hexanes) to afford Preparation 40 (3.72 g, 76%) as a light yellow oil. 1H NMR (CDCl3) δ 7.31-7.44 (m, 5H), 6.98 (d, J=8.8 Hz, 1H), 6.87 (dd, J=8.8, 3.2 Hz, 1H), 6.74 (d, J=3.2 Hz, 1H), 5.66 (m, 1H), 5.01-5.09 (m, 4H), 4.93 (A ob AB, JAB=6.4 Hz, 1H), 4.90 (B of AB, JAB=6.4 Hz, 1H), 4.18 (d, J=2.4 Hz, 1H), 3.87 (d, J=2.4 Hz, 1H), 3.44 (s, 3H), 3.18 (m, 1H), 2.86 (m, 1H), 2.22-2.39 (m, 3H), 2.12 (dd, J=9.4, 14.0 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[O:6][C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15](Cl)=[N:16][OH:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.O1CCCC1.[C:24]([C:26]1[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=1)#[CH:25].C(N(CC)CC)C>O>[Cl:1][C:2]1[O:6][C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[CH:25]=[C:24]([C:26]4[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=4)[O:17][N:16]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: ON=C(Cl)Cc1ccc(Cc2ccc(Cl)o2)cc1
Reactant: C#Cc1ccc(N)nc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(-c2cc(Cc3ccc(Cc4ccc(Cl)o4)cc3)no2)cn1
Temperature: 50 °C
Reaction time: 1 h
Yield: 6.4 %

Procedure:
To a mixture of (4-(5-chloro-furan-2-ylmethyl)-phenyl)-acetohydroximoyl chloride (25 mg, 0.088 mmol) described in Manufacturing Example 62-1-6 and tetrahydrofuran (1 mL) were added 5-ethynyl-pyridin-2-ylamine (8.0 mg, 0.068 mmol) described in Manufacturing Example 28-1-3 and triethylamine (19 μL, 0.14 mmol), which was stirred for 1 hour at 50° C. The reaction mixture was allowed to room temperature, and water was added to the system at the same temperature, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue thus obtained was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (1.6 mg, 4.9%) as a trifluoroacetic acid salt.