Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[F:23])[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16](C)(C)[CH3:17])=[O:14])[CH2:9][CH2:8]1)#[N:2].CCN(CC)CC.ClC(OCC)=O>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[F:23])[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(F)c(C#N)c2)CC1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1CCN(Cc2ccc(F)c(C#N)c2)CC1
Temperature: 0 °C

Procedure:
The tert-butyl 4-(3-cyano-4-fluorobenzyl)piperazine-1-carboxylate from the previous step (15.0 g, 47.0 mmol, 1.0 equiv.) was dissolved in CH2Cl2 (150 mL), to which TFA (150 mL) was slowly added and the resultant mixture stirred for 10 minutes. CH2Cl2 and TFA were removed by concentration in vacuo. The resulting residue was dissolved in THF (170 mL) and Et3N (Aldrich, redistilled, 16.6 mL, 188.1 mmol, 4.0 equiv.). The reaction vessel was cooled to 0° C. and ethyl chloroformate (Aldrich, 4.7 mL, 49.4 mmol, 1.05 equiv.) was added dropwise via syringe under a nitrogen atmosphere. After 30 minutes the reaction was concentrated under reduced pressure, diluted with EtOAc, washed with sat. aq. NaHCO3 and brine, and dried over Na2SO4. The organic layer was removed in vacuo to yield 5.9 g of ethyl 4-(3-cyano-4-fluorobenzyl)piperazine-1-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[C:12]#[N:13])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[C:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([OH:21])=[O:20].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:25]2[CH:26]=[CH:27][C:22]([C:19]([OH:21])=[O:20])=[CH:23][CH:24]=2)=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: N#Cc1ccccc1COc1cc(Br)cnc1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccccc1COc1cc(-c2ccc(C(=O)O)cc2)cnc1N
Temperature: 85.5 °C
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
2-(2-Amino-5-bromo-pyridin-3-yloxymethyl)-benzonitrile (9.0 g, 29.6 mmol), 4-carboxybenzeneboronic acid (5.4 g, 32.5 mmol), tetrakis(triphenylphosphine)palladium(0) (1.1 g, 1.0 mmol), anhydrous potassium carbonate (13.8 g, 70.0 mmol), dimethylformamide (72 mL) and water (36 mL) were charged to a 250 mL three neck round bottom flask equipped with a thermometer, a reflux condenser and magnetic stirring. The mixture was purged with nitrogen and gradually heated from 81 to 90° C. over a period of 2 hr. Thin layer chromatography (ethyl acetate:hexane:acetic acid 4:6:0.5) showed a trace of starting material at Rf 0.7, product at Rf 0.4 and an impurity at Rf 0.5. The mixture was cooled to 45° C. The sticky solids were collected by vacuum filtration, washed with 30 mL of ethanol:water 1:1 and discarded. The filtrate was diluted with 432 mL of water and 8 mL of 9 N potassium hydroxide solution (to pH 12–13), cooled in an ice bath and stirred for 30 minutes. The solids were collected by vacuum filtration and washed with 20 mL of water. The solids were discarded. The filtrate was cooled in an ice bath acidified with acetic acid to pH 7.5 using a pH meter. The solids were collected by vacuum filtration, washed with 20 mL water and dried under vacuum to give 8.5 g (83% yield) of 4-[6-amino-5-(2-cyano-benzyloxy)-pyridin-3-yl]-benzoic acid as a very dark solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][C:11]([CH3:20])([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:10][C:9]2=[O:21])[N:3]=1.[Cl:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[Cl:22][C:23]1[CH:28]=[C:27]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([N:8]3[CH2:13][CH2:12][C:11]([CH3:20])([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[O:10][C:9]3=[O:21])[N:3]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: CC1(c2ccccc2)CCN(c2nccc(Cl)n2)C(=O)O1
Reactant: OB(O)c1cccc(Cl)c1
Product: CC1(c2ccccc2)CCN(c2nccc(-c3cccc(Cl)c3)n2)C(=O)O1

Procedure:
The title compound was prepared following procedures analogous to those in Example 56 using 3-(4-chloropyrimidin-2-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one and 3-chlorophenylboronic acid. LC-MS Method 3, tR=1.354 min, m/z=781.1. 1H NMR (CDCl3) 1.80 (s, 3H), 2.48-2.53 (m, 1H), 2.62-2.71 (m, 1H), 3.55-3.67 (m, 1H), 4.30-4.40 (m, 1H), 7.30-7.60 (m, 8H), 7.90-7.95 (m, 1H), 8.05 (s, 1H), 8.80-8.85 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([N:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[N:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[NH:29][CH:28]=1.Cl>O1CCOCC1>[N:27]1([C:2]2[N:3]=[C:4]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:13][CH2:14][CH:15]([N:18]([CH3:20])[CH3:19])[CH2:16][CH2:17]4)=[CH:8][C:6]=3[N:7]=2)[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[CH:28]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: CN(C)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CN(C)C1CCN(Cc2cc3nc(-n4cnc5ccccc54)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C
Yield: 61.2 %

Procedure:
A mixture of [1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]dimethylamine (50 mg, 0.13 mmol), benzimidazole (32 mg, 0.27 mmol) and concentrated HCl (53 μL, 0.64 mmol) in 1,4-dioxane (1 mL) was subjected to microwave irradiation at 150° C. for 40 min. The reaction mixture was cooled to ambient temperature and loaded onto an Isolute® SCX-2 cartridge (2 g). The cartridge was then washed with MeOH and the desired product was subsequently eluted using 2 M NH3 in MeOH. The eluent was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM: 2 M NH3 in MeOH 100:0 to 98:2 to 95:5 to 90:10) to afford 110 as a white solid (38 mg, 63%). LCMS (Method F): RT=5.12 min, [M+H]+ 478.2. 1H NMR (CDCl3, 400 MHz): δ 9.04 (s, 1 H); 8.61-8.57 (m, 1 H); 7.86-7.82 (m, 1 H); 7.43-7.31 (m, 2 H); 7.27 (s, 1 H); 4.07 (t, J=4.8 Hz, 4 H); 3.92 (t, J=4.8 Hz, 4 H); 3.82 (s, 2 H); 3.08-2.99 (m, 2 H); 2.30 (s, 6 H); 2.20-2.10 (m, 3 H); 1.88-1.78 (m, 2 H); 1.66-1.54 (m, 2 H)
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[S:11][N:10]=2)[CH2:5][CH2:4]1)#[N:2].[C-]#N.[K+].[CH3:21][OH:22]>>[CH3:21][O:22][C:1]([N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[S:11][N:10]=2)[CH2:5][CH2:4]1)=[NH:2]
Reactant: N#CN1CCC(c2nsc3ccccc23)CC1
Reactant: CO
Agent: [C-]#N
Agent: [K+]
Product: COC(=N)N1CCC(c2nsc3ccccc23)CC1

Procedure:
A mixture of 3-(1-cyano-4-piperidinyl)-1,2-benzisothiazole (11.7 g, 0.048 mole), KCN (3.1 g) and MeOH (145 ml) was stirred and refluxed for 4 hours, and then stirred at ambient temperature for 14 hours. The MeOH was removed in vacuo and the residue diluted with water. The aqueous suspension was extracted with chloroform and the chloroform extract was washed with water and dried over MgSO4. Thereafter, the chloroform was evaporated in vacuo to yield 12.4 g of a solid. Recrystallization from EtOAc yielded 6.0 g (45.2%) of a solid. An analytical sample was obtained by a second recrystallization of a 3.5 g sample. The resultant solid (2.6 g) had a melting point of 144°-146° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.[NH2:28][C@H:29]([C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=1)[CH3:30]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:26])[F:25])[CH:18]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([NH:28][C@H:29]([C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=1)[CH3:30])=[O:8]
Reactant: O=C(O)c1cc(Cl)cnc1N1CCC(Oc2cccc(C(F)(F)F)c2)C1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2N2CCC(Oc3cccc(C(F)(F)F)c3)C2)cc1
Yield: 38.3 %

Procedure:
The title compound (D192) (64 mg) was prepared according to the experimental procedure described in Description 146 starting from 5-chloro-2-(3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)nicotinic acid (D137) (120 mg, 0.305 mmol) and (S)-methyl 4-(1-aminoethyl)benzoate (D3) (65.7 mg, 0.305 mmol)
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[CH:4][CH:3]=1.[C:24]1([NH:30][C:31]([C:33]2([C:36](O)=[O:37])[CH2:35][CH2:34]2)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:36]([C:33]5([C:31]([NH:30][C:24]6[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=6)=[O:32])[CH2:35][CH2:34]5)=[O:37])=[CH:3][CH:4]=4)=[CH:12][N:11]3[CH:13]=2)=[O:18])[CH2:20][CH2:21]1
Reactant: O=C(O)C1(C(=O)Nc2ccccc2)CC1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cn2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccccc5)CC4)cc3)ccc2n1)C1CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.9 %

Procedure:
To a solution of N-[6-(4-aminophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (142 mg, 0.461 mmol) in N,N-dimethylacetamide (2.8 mL) were added 1-(phenylcarbamoyl)cyclopropanecarboxylic acid (142 mg, 0.691 mmol), HATU (263 mg, 0.691 mmol) and N,N-diisopropylethylamine (120 μL, 0.691 mmol), and the mixture was stirred at room temperature for 4 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=40/60→0/100), washed with hexane/ethyl acetate and collected by filtration to give the title compound (130 mg, 57%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:11]2[CH:20]=[CH:19][C:14]3[O:15][CH2:16][CH2:17][O:18][C:13]=3[CH:12]=2)=[C:5]([CH3:10])[C:6]=1[C:7]([NH2:9])=[O:8].ClC(Cl)(Cl)[C:23]([N:25]=C=O)=[O:24].N>O1CCCC1.CO>[NH2:25][C:23]([NH:1][C:2]1[S:3][C:4]([C:11]2[CH:20]=[CH:19][C:14]3[O:15][CH2:16][CH2:17][O:18][C:13]=3[CH:12]=2)=[C:5]([CH3:10])[C:6]=1[C:7]([NH2:9])=[O:8])=[O:24]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: Cc1c(-c2ccc3c(c2)OCCO3)sc(N)c1C(N)=O
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(-c2ccc3c(c2)OCCO3)sc(NC(N)=O)c1C(N)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-Amino-4-methyl-5-(1,4-benzodioxan-6-yl)-3-thiophencarboxamide (0.44 g) was dissolved in tetrahydrofuran (10 ml), cooled to 0° C. and trichloroacetylisocyanate (0.11 ml) added dropwise with stirring. Stirring was continued for a further 30 minutes at room temperature and then a solution of ammonia in methanol (8 ml of a 10% solution) was added and stirring was continued for a further 3 h. The solvent was evaporated and the residue treated with ethyl acetate and the product filtered off.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:12][NH:11][CH2:10][CH2:9][C:7]=2[N:8]=1.[CH3:13][O:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[C:18](Br)[CH:17]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:13][O:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([N:11]2[CH2:10][CH2:9][C:7]3[N:8]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=3[CH2:12]2)[CH:17]=1
Reactant: CSc1ncc2c(n1)CCNC2
Reactant: COC(=O)c1ccc(C)c(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C)c(N2CCc3nc(SC)ncc3C2)c1
Temperature: 100 °C

Procedure:
A mixture of 2-(methylsulfanyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (100 mg, 0.552 mmol), methyl-3-bromo-4-methylbenzoate (126 mg, 0.552 mmol), palladium(II)acetate (12.4 mg, 0.0552 mmol), rac-BINAP (34.4 mg, 0.0552 mmol), and cesium carbonate (252 mg, 0.773 mmol) in toluene (10 ml) was heated at 100° C. for 18 hours. Upon cooling, the reaction mixture was diluted with ethyl acetate and the insolubles were filtered off (celite). The filtrate was concentrated and the residue was eluted through a flash column (silica gel 60, 230-400 mesh, 4:1 hexanes:EtOAc to 7:3 hexanes:EtOAc) to obtain the title compound as a light yellow, viscous oil which crystallized on standing (143 mg, 79%).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]([N:16]([CH2:18][C:19]4[N:24]=[C:23]5[CH:25]=[CH:26][N:27](COCC[Si](C)(C)C)[C:22]5=[CH:21][C:20]=4[F:36])[CH3:17])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.[NH4+].[OH-]>C1COCC1>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]([N:16]([CH2:18][C:19]4[N:24]=[C:23]5[CH:25]=[CH:26][NH:27][C:22]5=[CH:21][C:20]=4[F:36])[CH3:17])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CN(Cc1nc2ccn(COCC[Si](C)(C)C)c2cc1F)c1nccc(Nc2cc(C3CC3)[nH]n2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1nc2cc[nH]c2cc1F)c1nccc(Nc2cc(C3CC3)[nH]n2)n1
Temperature: 63 °C
Yield: 20 %

Procedure:
A mixture of N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-((6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-5-yl)methyl)-N2-methylpyrimidine-2,4-diamine (40 mg, 0.1 mmol) and tetrabutyl ammonium fluoride (260 mg, 1 mmol) in THF (5 mL) was heated at 63° C. for 18 h. The reaction mixture was poured into water (10 mL) and the pH was adjusted to 10 by addition of an NH4OH solution. The mixture was extracted with EtOAc (50 mL×3) and the combined extracts dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC to afford 8 mg, (20%) of N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-((6-fluoro-1H-pyrrolo[3,2-b]pyridin-5-yl)methyl)-N2-methylpyrimidine-2,4-diamine as a white solid. 1H NMR (500 MHz, DMSO) δ 11.8 (brs, 1H), 11.3 (brs, 1H), 9.33 (brs, 1H), 7.85 (d, J=5 Hz, 1H), 7.65 (d, 0.1=10 Hz, 1H), 7.58 (d, J=3 Hz, 1H), 6.51 (s, 1H), 6.00-6.20 (brs, 2H), 5.06 (s, 2H), 3.16 (s, 3H), 1.81 (s, 1H), 0.85 (s, 2H), 0.59 (s, 2H); MS (ESI): m/z=379.3 [M+1]+.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4]([OH:14])=[CH:3][CH:2]=1.[H-].[Na+].[CH2:17](I)[CH3:18]>CN(C=O)C>[CH2:17]([O:14][C:4]1[C:5]2[O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[C:9]=2[CH:1]=[CH:2][CH:3]=1)[CH3:18]
Reactant: Oc1cccc2c1oc1ccccc12
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cccc2c1oc1ccccc12
Yield: 82.4 %

Procedure:
A solution of Dibenzo[b,d]furan-4-ol (1 g, 5.43 mmol) in DMF (5 ml) was added to a stirred and cooled (0° C.) suspension of 60% sodium hydride (326 mg, 8.12 mmol) in DMF (20 ml). The mixture was stirred at 0° C. for 5 min and ethyl iodide (1.18 g, 10.86 mmol) in DMF (5 ml) was added dropwise over a period of 10 min. The cooling bath was removed and the mixture was stirred for 1 h at room temperature. The reaction mixture was diluted with ice-cold water (100 ml) and extracted with EtOAc (3×50 ml). The combined organic extracts were washed with water (2×100 ml), brine (100 ml) and dried (Na2SO4), to give 0.95 g (82%) of the product as viscous liquid,
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[C:12](Br)[CH:13]=[CH:14][CH:15]=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][O:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][N:30]=1>>[CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[C:12]([C:32]3[CH:31]=[N:30][C:29]([O:28][CH3:27])=[N:34][CH:33]=3)[CH:13]=[CH:14][CH:15]=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc2c1C[C@@H](N(Cc1ccccc1)Cc1ccccc1)CC2
Reactant: COc1ncc(B(O)O)cn1
Product: COc1ncc(-c2cccc3c2C[C@@H](N(Cc2ccccc2)Cc2ccccc2)CC3)cn1
Yield: 80 %

Procedure:
The title compound was synthesized as described for Intermediate example I-4 in 80% yield starting from (S)-N,N-dibenzyl-8-bromo-1,2,3,4-tetrahydronaphthalen-2-amine and 2-methoxypyrimidine-5-boronic acid (1.9 equiv) and. The reaction mixture was irradiated in a microwave under an atmosphere of argon at 140° C. for 1 h; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.59 (s, 2 H), 7.22-7.32 (m, 8 H), 7.09-7.20 (m, 4 H), 7.00-7.04 (m, 1 H), 4.00 (s, 3 H), 3.53-3.70 (m, 4 H), 2.87-3.00 (m, 2 H), 2.64-2.85 (m, 2 H), 2.45-2.54 (m, 1 H, obscured by DMSO), 2.05-2.14 (m, 1 H), 1.62-1.78 (m, 1 H); MS (ESI) m/z 436[M+H+].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]=[CH:6][C:7]1[C:8](Cl)=[N:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=1)[CH3:2].[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]=[CH:6][C:7]1[C:8]([C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([F:19])[CH:25]=2)=[N:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=1)[CH3:2]
Reactant: OB(O)c1cccc(F)c1
Reactant: CCOC(=O)C=Cc1ccc(C(F)(F)F)nc1Cl
Product: CCOC(=O)C=Cc1ccc(C(F)(F)F)nc1-c1cccc(F)c1
Yield: 53 %

Procedure:
3-(2-Chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid ethyl ester (110 mg, 0.393 mmol) was reacted with 3-fluorophenyl boronic acid (2 eq) to give 3-[2-(3-fluoro-phenyl)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid ethyl ester (70 mg, 53%).
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]4[CH:20]=[CH:21][C:22]5[O:26][C:25]([C:27]([O:29]C)=O)=[CH:24][C:23]=5[CH:31]=4)[C:15]([F:32])=[CH:14][N:13]=3)=[CH:4][C:3]=2[O:2]1.Cl.[CH3:34][NH2:35]>>[CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]4[CH:20]=[CH:21][C:22]5[O:26][C:25]([C:27]([NH:35][CH3:34])=[O:29])=[CH:24][C:23]=5[CH:31]=4)[C:15]([F:32])=[CH:14][N:13]=3)=[CH:4][C:3]=2[O:2]1
Reactant: CN
Reactant: COC(=O)c1cc2cc(Nc3nc(Nc4ccc5c(c4)OCCO5)ncc3F)ccc2o1
Agent: Cl
Product: CNC(=O)c1cc2cc(Nc3nc(Nc4ccc5c(c4)OCCO5)ncc3F)ccc2o1

Procedure:
In like manner to the preparation of N4-(ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine, the reaction of N2-(3,4-ethylenedioxyphenyl)-N4-(2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine with methylamine hydrochloride gave N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[2-(N-methylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 8.10 (s, 1H), 7.94 (d, 1H, J=5.1 Hz), 7.59 (s, 2H), 7.44 (s, 1H), 6.96 (d, 1H, J=2.4 Hz), 6.82 (d, 1H, J=8.4 Hz), 6.76 (dd, 1H, J=3.6 and 8.1 Hz), 4.22 (s, 2H), 4.21 (s, 2H), 2.95 (s, 3H); LCMS: ret. time: 17.76 min.; purity: 97%; MS (m/e): 436 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:29])[N:4]([C:18]2[CH:23]=[C:22]([C:24](=O)[C:25]#[CH:26])[CH:21]=[CH:20][C:19]=2[CH3:28])[C:5]([CH3:17])=[N:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1.Cl.[OH:31][C:32]([CH3:37])([CH3:36])[C:33]([NH2:35])=[NH:34].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[C:3](=[O:29])[N:4]([C:18]2[CH:23]=[C:22]([C:24]3[CH:25]=[CH:26][N:35]=[C:33]([C:32]([OH:31])([CH3:37])[CH3:36])[N:34]=3)[CH:21]=[CH:20][C:19]=2[CH3:28])[C:5]([CH3:17])=[N:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1
Reactant: C#CC(=O)c1ccc(C)c(-n2c(C)nc(OCc3ccc(F)cc3)c(Cl)c2=O)c1
Reactant: CC(C)(O)C(=N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(-c2ccnc(C(C)(C)O)n2)cc1-n1c(C)nc(OCc2ccc(F)cc2)c(Cl)c1=O
Temperature: 75 °C
Yield: 29.3 %

Procedure:
To a solution of 5-chloro-6-(4-fluoro-benzyloxy)-2-methyl-3-(2-methyl-5-propynoyl-phenyl)-3H-pyrimidin-4-one of Step C (10 mg, 0.02 mmol) in acetonitrile (1 mL) was added 2-hydroxy-2-methylpropionamidine HCl (5 mg, 0.03 mmol) and potassium carbonate (10 mg, 0.08 mmol) and the slurry was heated at 75° C. for eighteen hours. After cooling to room temperature the reaction was filtered to remove excess salts. The filtrate was concentrated and purified via normal phase chromatography (ethyl acetate/heptane) to provide the title compound as a yellow oil (2.9 mg, 24% yield). MS (M+H): 495
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H:13]2O)=[N:5][C:6]([CH2:9]C)=[CH:7][N:8]=1)C.[CH:22]1(N)C2C(=CC=CC=2)CCC1.ClC1C(C)=NC=C(C)N=1>>[CH3:1][C:3]1[C:4]([NH:11][CH:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13][CH2:22]2)=[N:5][C:6]([CH3:9])=[CH:7][N:8]=1
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Reactant: NC1CCCc2ccccc21
Agent: Cc1cnc(C)c(Cl)n1
Product: Cc1cnc(C)c(NC2CCCc3ccccc32)n1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 1,2,3,4-tetrahydronaphthalen-1-amine and 3-chloro-2,5-dimethylpyrazine, and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 1.91, 2.11, 2.31, 2.40, 2.87, 4.50, 5.16, 7.21, 7.35, 7.62; MS (ESI+) for C16H19N3 m/z 254.4 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH2:9][CH2:10][CH2:11]C)[CH:6]=[CH:5][C:3]=1[NH2:4].[N+:13]([C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14]>>[N+:13]([C:16]1[CH:21]=[C:20]([C:2]2[CH:8]=[C:7]([CH2:9][CH2:10][CH3:11])[CH:6]=[CH:5][C:3]=2[NH2:4])[CH:19]=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: CCCCc1ccc(N)c(Br)c1
Product: CCCc1ccc(N)c(-c2cccc([N+](=O)[O-])c2)c1

Procedure:
2-bromo-4-(n-butyl)aniline and 3-nitrobenzene boronic acid can be combined to form 2-(3-nitrophenyl)-4-propylaniline,
Reaction SMILES: [CH2:1]([N:8]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:9][CH2:10][C:11]([CH3:14])(O)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(S(F)(F)[F:28])CC)C.N#N.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([N:8]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:9][CH2:10][C:11]([F:28])([CH3:14])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(O)CCN(Cc1ccccc1)Cc1ccccc1
Reactant: CCN(CC)S(F)(F)F
Agent: N#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(F)CCN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.5 %

Procedure:
In a cooled solution (−78° C.) of 4-(dibenzylamino)-2-methylbutan-2-ol (110.0 g, 0.39 mol) in DCM (1 L), add diethylaminosulfur trifluoride (75 g, 0.47 mol) dropwise under N2, allow it to warm to RT and stir overnight. Re-cool the mixture to −78° C., add dropwise with saturated NaHCO3 (300 mL), warm to RT, extract with EtOAc (3×), wash the combined organics with brine, dry over Na2SO4, concentrate to dryness and purify via silica gel chromatography (0.1-0.2% EtOAc/pet ether) to afford the title compound (44.0 g, 40% yield). MS (m/z): 286.2 (M+1).