Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]([C:5]1C=[CH:9][C:8]([Br:11])=[CH:7][N:6]=1)=[O:4].BrC1C=[N:16]C(C(O)=O)=NC=1>>[CH3:12][N:2]([CH3:1])[C:3]([C:5]1[N:6]=[CH:7][C:8]([Br:11])=[CH:9][N:16]=1)=[O:4]
Reactant: O=C(O)c1ncc(Br)cn1
Reactant: CN(C)C(=O)c1ccc(Br)cn1
Product: CN(C)C(=O)c1ncc(Br)cn1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 161a, from 5-bromopyrimidine-2-caboxylic acid (1.03 g, 5.074 mmol) to give a yellow oil (308 mg, 26% yield). 1H NMR (400 MHz, CDCl3) δ 8.50 (s, 2 H) 3.17 (s, 3 H) 3.00 (s, 3 H); LCMS for C7H8BrN3O m/z 230.00 and 232.00 (M+H+).
Reaction SMILES: Br[CH2:2][CH2:3][CH3:4].[CH2:5]([O:7][C:8]([C:10]1[S:27][C:13]2[N:14]=[C:15]([NH2:26])[N:16]=[C:17]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=3[CH3:25])[C:12]=2[CH:11]=1)=[O:9])[CH3:6].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:5]([O:7][C:8]([C:10]1[S:27][C:13]2[N:14]=[C:15]([NH2:26])[N:16]=[C:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:2][CH2:3][CH3:4])=[CH:20][C:19]=3[CH3:25])[C:12]=2[CH:11]=1)=[O:9])[CH3:6]
Reactant: CCCBr
Reactant: CCOC(=O)c1cc2c(-c3ccc(O)cc3C)nc(N)nc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1ccc(-c2nc(N)nc3sc(C(=O)OCC)cc23)c(C)c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 79.7 %

Procedure:
1-Bromopropane (15 uL; 0.17 mmol) was added to a solution of 2-Amino-4-(4-hydroxy-2-methyl-phenyl)-thieno[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (50 mg: 0.152 mmol) and potassium carbonate (25 mg; 0.18 mmol) in DMF (15 mL). Reaction mixture was heated to 50 degrees C. for 18 hours. Reaction mixture was allowed to cool and solvent removed in vacuo. Residue was partitioned between saturated aqueous sodium bicarbonate solution (10 mL) and ethyl acetate (20 mL). Organic phase was dried over Na2SO4 and filtered, filtrate solvents removed in vacuo to afford a yellow solid purified by flash chromatography on silica gel (eluting ethyl acetate in hexane) to afford product as yellow solid (45 mg; 80%)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:24]([O:27][CH2:28][C:29]1[C:30]([N:38]2[CH2:49][CH2:48][N:47]3[C:40](=[CH:41][C:42]4[CH2:43][C:44]([CH3:51])([CH3:50])[CH2:45][C:46]=43)[C:39]2=[O:52])=[N:31][CH:32]=[CH:33][C:34]=1B(O)O)(=[O:26])[CH3:25].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O.O.O.C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C.O>[C:24]([O:27][CH2:28][C:29]1[C:30]([N:38]2[CH2:49][CH2:48][N:47]3[C:40](=[CH:41][C:42]4[CH2:43][C:44]([CH3:51])([CH3:50])[CH2:45][C:46]=43)[C:39]2=[O:52])=[N:31][CH:32]=[CH:33][C:34]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)OCc1c(B(O)O)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: CN1CCC(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C4CCN(C)CC4)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 100 °C
Yield: 57.7 %

Procedure:
A 50-mL round-bottomed flask equipped with a reflux condenser was charged with 5-bromo-1-methyl-3-(5-(1-methylpiperidin-4-yl)pyridin-2-ylamino)pyridin-2(1H)-one 232d (160 mg, 0.40 mmol), {3-[(acetoxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (240 mg, 0.60 mmol), Pd(dppf)Cl2 (20 mg, 0.020 mmol), K3PO4 (180 mg, 0.80 mmol), sodium acetate trihydrate (120 mg, 0.80 mmol), water (0.5 mL), and acetonitrile (10 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 2 h. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified on silica-gel column chromatography eluting with 25:1 dichloromethane/methanol to afford 236a as a yellow solid (150 mg, 38%). MS-ESI: [M+H]+ 650.3
Reaction SMILES: Br.[NH2:2][CH:3]1[CH2:8][CH2:7][O:6][C:4]1=[O:5].CN1CCOCC1.[C:16]1([C:22](Cl)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[C:16]1([C:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:2][CH:3]2[CH2:8][CH2:7][O:6][C:4]2=[O:5])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NC1CCOC1=O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Br
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C1OCCC1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
α-Aminobutyrolactone hydrobromide (10.0 g, 54.9 mmol), N-methylmorpholine (11.2 g, 110.0 mmol) and triphenylmethyl chloride (15.4 g, 55.2 mmol) were dissolved in N,N-dimethylformamide (DMF) (200 ml) (distilled from calcium hydride) and stirred at ambient temperature for 16 hours. The mixture was filtered, and water (200 ml) was added to the DMF-solution. The resulting slurry was stirred for 2 hours, the precipitate was filtered off and washed with a mixture of DMF and water (1:1, 50 ml). The solid was resuspended in water (100 ml), filtered and dried at 50° C. in vacuo. N-triphenylmethyl-α-aminobutyrolactone was isolated as a white solid. Yield 17.55 g (93.2%), mp 164.5°-165.5° C. (uncorrected).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[CH:21][C:20]=3[O:31][CH3:32])=[N:16]2)=[CH:11][CH:10]=1.[O:33]1[CH2:36][C:35](=O)[CH2:34]1.C([BH3-])#N.[Na+].N1N2C=CC=C2C=NC=1>CN(C)C=O.C(O)(=O)C.CO>[CH3:32][O:31][C:20]1[CH:21]=[C:22]([CH:25]2[CH2:30][CH2:29][N:28]([CH:35]3[CH2:36][O:33][CH2:34]3)[CH2:27][CH2:26]2)[CH:23]=[CH:24][C:19]=1[NH:18][C:15]1[N:14]=[CH:13][C:12]2=[CH:11][CH:10]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[N:17]2[N:16]=1
Reactant: O=C1COC1
Reactant: COc1cc(C2CCNCC2)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: c1cc2cncnn2c1
Solvent: CO
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1cc(C2CCN(C3COC3)CC2)ccc1Nc1ncc2ccc(-c3ccccc3OC)n2n1
Temperature: 0 °C
Reaction time: 10 h
Yield: 58.8 %

Procedure:
To [7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(2-methoxy-4-piperidin-4-yl-phenyl)-amine (60.00 mg, 0.140 mmol) in N,N-dimethylformamide (0.52 mL)/Methanol (2.00 mL)/Acetic acid (0.26 mL) was added oxetan-3-one (30.06 mg, 0.417 mmol) and the reaction mixture was cooled to 0° C. Sodium cyanoborohydride (43.64 mg, 0.695 mmol) was added and the reaction was heated at 60° C. overnight, and then at room temperature in air for 10 h to re-aromatize the pyrrolo[2,1-f][1,2,4]triazine core, which underwent partial reduction. The reaction mixture was concentrated, and the residue was partitioned between dichloromethane/1N sodium carbonate, washed with brine, dried over sodium sulfate, and concentrated. The product was isolated by flash chromatography (ISCO, SIlicagel, MeOH/DCM 0-10%) to afford [2-methoxy-4-(1-oxetan-3-yl-piperidin-4-yl)-phenyl]-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-amine as a yellow solid (40 mg, 59%). MP: 78-85° C.; 1H-NMR (CDCl3) δ 8.69 (s, 1H), 8.30 (d, J=8.7 Hz, 1H), 7.99 (dd, J=7.6 ; 1.4 Hz, 1H), 7.42 (m, 2H), 7.12 (m, 1H), 7.07 (d, J=8.4 Hz, 1H), 7.02 (d, J=4.6 Hz, 1H), 6.83 (d, J=4.6 Hz, 1H), 6.74 (m, 2H), 4.68 (m, 4H), 3.88 (s, 3H), 3.84 (s, 3H), 3.51 (m, 1H), 2.88 (m, 2H), 2.47 (m, 1H), 1.90 (m, 6H); LC/MS (ESI+): 485.9 (M+H).
Reaction SMILES: Cl.[CH:2]([NH2:4])=[NH:3].CC[O-].[Na+].[CH3:9][CH:10]1[CH:14]([C:15](OC)=[O:16])[C:13](=O)[CH2:12][S:11]1>C(O)C>[CH3:9][CH:10]1[C:14]2[C:15]([OH:16])=[N:4][CH:2]=[N:3][C:13]=2[CH2:12][S:11]1
Reactant: N=CN
Reactant: COC(=O)C1C(=O)CSC1C
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC1SCc2ncnc(O)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.2 %

Procedure:
To a solution of formamidine HCl salt (37.3 g, 463 mmol) in ethanol (300 mL) was slowly added NaOEt (21%, 169 mL, 453 mmol). The mixture was stirred at room temperature for 1 hour and then filtered. To the filtrate was added methyl 2-methyl-4-oxo-tetrahydrothiophene-3-carboxylate (79 g, 453 mmol). The mixture was stirred at room temperature for 1 hour and then refluxed overnight. After cooling, the solvent was removed and the residue was purified by silica gel chromatography, eluted with Hexane/ethyl acetate (2:1-0:1)-DCM/MeOH (20:1) to afford 5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-ol (36 g, 47%). 1H NMR (CDCl3, 400 MHz) δ 12.83 (s, 1H), 4.68 (m, 1H), 4.32-4.08 (m, 2H), 1.66 (m, 3H). MS (APCI+) [M+H]+ 169.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:4]=1[CH:5]=O.O.NN.[OH-].[K+].Cl>OCCOCCO.O>[CH3:5][C:4]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(Cl)cc1C=O
Agent: Cl
Agent: NN
Agent: [K+]
Solvent: O
Solvent: OCCOCCO
Product: COc1ccc(Cl)cc1C
Temperature: 125 °C

Procedure:
To a suspension of 2-methoxy-5-chlorobenzaldehyde (34.5 g, 0.202 mole) in bis-(2-hydroxyethyl)ether (225 ml) was added hydrazine hydrate (17.7 g, 0.353 mole) and the mixture heated on a 125° C. oil bath for 15 minutes. It was then cooled to 50° C. and powdered potassium hydroxide (15.5 g of 85%, 0.24 mole) added. The mixture was heated on a 165° C. oil bath for 30 minutes. After it had cooled to room temperature it was poured into water (600 ml) and the aqueous solution acidified by addition of 6N HCl. Carbon tetrachloride (4×100 ml) extractions of the acid solution, followed by washing the pooled extracts with brine (1×100 ml), drying (MgSO4) and concentration in vacuo gave a clear viscous oil which crystallized upon addition of a small volume of petroleum ether and chilling in an ice bath. The white crystals were filtered and dried in vacuo. Yield=24.7 g (78 %); m.p. 35°-37° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@@H:11]([O:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)=[O:17])[C@H:10]([NH:30][C:31](=[O:46])[C:32]2[CH:37]=[CH:36][C:35]([O:38][Si](C(C)(C)C)(C)C)=[CH:34][CH:33]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.O.O.O.[F-].[Cl-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@@H:11]([O:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)=[O:17])[C@H:10]([NH:30][C:31](=[O:46])[C:32]2[CH:33]=[CH:34][C:35]([OH:38])=[CH:36][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](OC(=O)c2ccc(-c3ccccc3)cc2)[C@H](NC(=O)c2ccc(O[Si](C)(C)C(C)(C)C)cc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](OC(=O)c2ccc(-c3ccccc3)cc2)[C@H](NC(=O)c2ccc(O)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
754 mg of (3R,4R)-4-(Biphenyl-4-ylcarbonyloxy)-3-[4-(tert-butyl-dimethyl-silanyloxy)-benzoylamino]-azepane-1-carboxylic acid tert-butyl ester were dissolved in 10 ml tetrahydrofuran and 147 mg of tetrabutylammoniumfluoride trihydrate were added at 0° C. and the reaction mixture was stirred for two hours at room temperature. 2.5 ml of a saturated solution of sodium chloride and 2.5 ml of an aqueous 1 molar solution of citric acid were added. The organic layer was concentrated under vacuo diluted with ethyl acetate then washed with 5 ml of a saturated solution of sodium chloride dried over magnesium sulfate and evaporated. The crude compound was purified on silica gel (dichloromethane:ethylacetate 1:1) to yield 551 mg (89% yield) of (3R,4R)-4-(Biphenyl-4-ylcarbonyloxy)-3-(4-hydroxy-benzoylamino)-azepane-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [C:1]([C:7]1[CH:8]=[C:9]([C:13]2[NH:14][CH:15]=[CH:16][N:17]=2)[CH:10]=[CH:11][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH3:6]>CO.[Pd]>[CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[NH:17][CH:16]=[CH:15][N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC#Cc1cccc(-c2ncc[nH]2)c1
Agent: [Pd]
Solvent: CO
Product: CCCCCCc1cccc(-c2ncc[nH]2)c1
Yield: 94.6 %

Procedure:
A solution of 6.15 g (27.4 mmol) of 2-(3-hex-1-ynyl-phenyl)-1H-imidazole in 140 ml of MeOH was treated with 1.46 g (1.4 mmol) of Pd—C (10%) and hydrogenated with H2 (1 bar) at RT for 1 hour. After removal the catalyst by filtration, the solvent was evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 98:2) to give 5.92 g (95%) of the title compound as light brown solid. MS: 229.2 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([CH:19]([OH:27])[CH2:20][O:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+].[ClH:41].C(O)C>N1C=CC=CC=1.O.C(OCC)(=O)C>[ClH:41].[C:28]([O:27][CH:19]([C:14]1[CH:13]=[CH:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:10]=2)[CH:15]=1)[CH2:20][O:21][CH2:22][CH2:23][N:24]([CH3:25])[CH3:26])(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: CN(C)CCOCC(O)c1ccc2cc(OCc3ccccc3)ccc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CCO
Product: CC(=O)OC(COCCN(C)C)c1ccc2cc(OCc3ccccc3)ccc2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In 12 ml of pyridine was suspended 3.0 g of 1-(6-benzyloxy-2-naphthyl)-2-[2-(N,N-dimethylamino)ethoxy]ethanol. To the suspension was added 1.6 ml of acetic anhydride. The resulting mixture was stirred at room temperature for 24 hours. After the completion of the reaction, the solvent was removed by distillation under reduced pressure. To the residue thus obtained were added 60 ml of ethyl acetate and 60 ml of water. The mixture was adjusted to pH 10.5 with potassium carbonate. The organic layer was separated. The aqueous layer was extracted with 30 ml of ethyl acetate. The extract was combined with the previously separated organic layer. The combined organic-layer was washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was added 1.5 ml of a 5N dry hydrogen chloride-ethanol solution. The resulting mixture was stirred at room temperature for 1 hour. The resulting crystals were collected by filtration and dried to obtain 2.6 g of 1-acetoxy-1-(6-benzyloxy-2-naphthyl)-2-[2-(N,N-dimethylamino)ethoxy]ethane hydrochloride (compound No. 286).
Reaction SMILES: [N:1]1([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:9]2[CH:8]=[CH:7][N+:6]([O-])=[CH:5][C:4]=2[CH:3]=[CH:2]1.[CH3:21][C:22]([NH2:29])([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:23].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl.ClCCl>[CH3:21][C:22]([NH:29][C:5]1[C:4]2[CH:3]=[CH:2][N:1]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[C:9]=2[CH:8]=[CH:7][N:6]=1)([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:23]
Reactant: CC(C)(C)CC(C)(C)N
Reactant: O=C(OCc1ccccc1)n1ccc2c[n+]([O-])ccc21
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)CC(C)(C)Nc1nccc2c1ccn2C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 54.1 %

Procedure:
A solution of benzyl 1H-pyrrolo[3,2-c]pyridine-1-carboxylate 5-oxide (500 mg, 1.9 mmol, Step b) in chloroform was treated dropwise with 2,4,4-trimethylpentan-2-amine (1.57 mL, 8.5 mmol) and stirred for about 15 minutes. The mixture was cooled to 0° C. followed by the portion wise addition of p-toluenesulphonyl chloride (745 mg, 4.2 mmol). The reaction mixture was then stirred at room temperature for 1 hour, diluted with dichloromethane and washed with saturated sodium bicarbonate solution. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under vacuum to yield viscous oil. The crude product was purified by silica gel (100-200 mesh) column chromatography using ethyl acetate in hexane (1.5%) as eluent to yield benzyl 4-[(2,4,4-trimethylpentan-2-yl)amino]-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (390 mg, 43%) as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]=1)=[N:7]2.[NH2:19][C:20]1[N:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1.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.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:18][C:17]1[C:12]([C:6]2[N:7]=[C:8]3[C:3]([C:2]([NH:19][C:20]4[N:21]=[CH:22][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:24][N:25]=4)=[CH:11][CH:10]=[N:9]3)=[CH:4][CH:5]=2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1cccnc1-c1ccc2c(Cl)ccnc2n1
Reactant: Nc1ncc(C(F)(F)F)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cccnc1-c1ccc2c(Nc3ncc(C(F)(F)F)cn3)ccnc2n1

Procedure:
Heat a mixture of 5-chloro-2-(3-methylpyridin-2-yl)-[1,8]naphthyridine (51 mg, 0.2 mmol), 2-amino-5-trifluoromethylpyrimidine (42.0 mg, 0.25 mmol), xantphos (11.6 mg, 0.02 mmol), Pd2(dba)3 (18.3 mg, 0.02 mmol) and Cs2CO3 (130 mg, 0.4 mmol) in dioxane (2.0 mL) at 100° C. for 20 hours. Cool the mixture, concentrate under vacuum, dilute with EtOAc/water (5.0 mL each), filter through celite, wash celite with EtOAc (2×5 mL) and dry the combined organic layers with MgSO4. Filter the dried extract and concentrate under vacuum to afford the crude product. Purify by column chromatography using EtOAc as eluent to afford the title compound as a yellow solid. 1H NMR (400 MHZ, DMSO-D6) δ 10.92 (s, 1H), 9.0 (m, 3H), 8.92 (d, 1H, J=1.8 Hz), 8.58 (d, 1H, J=1.0 Hz), 8.12 (m, 2H), 7.80(d, 1H, J=2.1 Hz), 7.41 (dd, 1H), 2.65 (s, 3H). MS=383.3 (M+H).
Reaction SMILES: [CH3:1][C:2]([CH3:18])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH2:3].Br[C:20]1[C:21](=[O:38])[N:22]([C:27]2[CH:28]=[C:29]([CH:34]=[CH:35][C:36]=2[CH3:37])[C:30]([O:32][CH3:33])=[O:31])[CH:23]=[C:24]([Br:26])[N:25]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1.O>[CH3:33][O:32][C:30](=[O:31])[C:29]1[CH:34]=[CH:35][C:36]([CH3:37])=[C:27]([N:22]2[CH:23]=[C:24]([Br:26])[N:25]=[C:20]([NH:3][C:2]([CH3:18])([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH3:1])[C:21]2=[O:38])[CH:28]=1
Reactant: COC(=O)c1ccc(C)c(-n2cc(Br)nc(Br)c2=O)c1
Reactant: CC(C)(N)c1ccccc1OCc1ccccc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C)c(-n2cc(Br)nc(NC(C)(C)c3ccccc3OCc3ccccc3)c2=O)c1
Temperature: 100 °C
Reaction time: 10 h
Yield: 68.8 %

Procedure:
A solution of α,α-dimethyl-2-(phenylmethoxy)-benzenemethanamine (Example 198d, 1.5 g) dissolved in dioxane (52.2 mL) was treated with methyl 3-(3,5-dibromo-2-oxopyrazin-1(2H)-yl)-4-methylbenzoate (Example 1b, 2.499 g) and N-ethyldiisopropylamine (1.083 mL) under nitrogen. The resulting solution was stirred at 100° C. for 10 h. After cooling to room temperature, the reaction mixture was diluted with water (50 mL), and extracted with ethyl acetate (100 mL×2). The organic was dried (MgSO4), filtered and evaporated. The crude product was trituated with 50% diethyl ether in iso-hexane for 3 h. The solid was filtered off to afford the subtitle compound (2.405 g).
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[OH:14][C@@H:15]1[CH2:19][NH:18][C:17](=[O:20])[CH2:16]1.Cl>CN(C)C=O>[C:9]([Si:6]([CH3:8])([CH3:7])[O:14][C@@H:15]1[CH2:19][NH:18][C:17](=[O:20])[CH2:16]1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1C[C@H](O)CN1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CNC(=O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.9 %

Procedure:
Imidazole (93.73 g, 1.26 mol) and tert-butyldimethylsilyl chloride (145.3 g, 0.96 mol) were added to a solution of (S)-4-hydroxy-2-pyrrolidone (92.8 g, 0.92 mol) in dimethylformamide (560 mL). The mixture was then stirred at room temperature for 16 hours, after which time it was poured over ice and an aqueous solution of hydrochloric acid (0.2 M, 300 mL) was added. The mixture was stirred at room temperature for 10 minutes, and then extracted with ethyl acetate (4×500 mL). The combined organic extracts were washed with brine (1000 mL), dried over sodium sulphate, filtered, and evaporated under reduced pressure to give (S)-4-(tert-butyl-dimethyl-silanyloxy)-pyrrolidin-2-one as a solid (200 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[N:11]=[C:10]([NH:13][C:14]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[O:15])[N:9]3[CH2:22][CH2:23][N:24]=[C:8]3[C:7]=2[CH:6]=[CH:5][C:4]=1[O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][NH:31]C(=O)OC(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[NH2:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][O:25][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[N:9]([CH2:22][CH2:23][N:24]=3)[C:10]([NH:13][C:14](=[O:15])[C:16]3[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=3)=[N:11][C:12]=2[C:3]=1[O:2][CH3:1]
Reactant: COc1c(OCCOCCNC(=O)OC(C)(C)C)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1c(OCCOCCN)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl {2-[2-({7-methoxy-5-[(pyridin-3-ylcarbonyl)amino]-2,3-dihydroimidazo[1,2-c]quinazolin-8-yl}oxy)ethoxy]ethyl}carbamate (Step 3, 3.6 g, 6.8 mmol) was diluted in a mixture of trifluoroacetic acid (18 mL) and dichloromethane (70 mL). The mixture was stirred at rt overnight, then was concentrated in vacuo. The resultant orange oil was redissolved in dichloromethane and treated with an excess of triethylamine. After stirring at rt for 0.5 h, the solvent was evaporated under reduced pressure and the residue triturated with ethyl acetate. The title compound was isolated by vacuum filtration and dried in the vacuum oven. This material was contaminated with a small amount of triethylamine, but was suitable for use in the next step as is. HPLC MS RT=1.09 min, MH+=425.2. 1H NMR (DMSO-d6+2 drops TFA-d) δ: 3.01 (2H, m), 3.69 (2H, t), 3.89 (2H, m), 4.02 (3H, s), 4.26 (2H, m), 4.44 (2H, m), 4.57 (2H, m), 7.49 (1H, d), 7.76 (1H, m), 8.05 (1H, d), 8.72 (1H, m), 8.89 (1H, m), 9.44 (1H, m).