Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:11]2[NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:10]=2[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH:6]=1)=[O:4].[OH-].[Na+]>CO.O>[CH2:9]1[C:10]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[NH:12][C:11]=2[C:5]([C:3]([OH:4])=[O:2])=[CH:6][NH:7][CH2:8]1
Reactant: COC(=O)C1=CN(C(=O)OC(C)(C)C)CCc2c1[nH]c1ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1=CNCCc2c1[nH]c1ccccc21
Yield: 49.5 %

Procedure:
To a solution of 1,6-dihydro-2H-azepino[4,5-b]indole-3,5-dicarboxylic acid 3-tert-butyl ester 5-methyl ester (0.293 g, 0.62 mmol) in MeOH (4 mL) was added 4 N NaOH (2 mL) and the mixture was heated for 5 hours under nitrogen. After cooling, the reaction mixture was diluted with water and extracted with EtOAc. The aqueous layer was acidified with AcOH. Precipitate was collected by filtration and washed with water and ether and dried under high vacuum to give the title compound (70 mg); 1H-NMR (DMSO-d6): δ 11.40 (1H, s), 10.73 (1H, br s), 7.83 (1H, m), 7.73 (2H, d), 7.38 (1H, m), 7.25 (1H, m), 6.88 (2H, m), 3.45 (2H, t), 3.87 (3H, s), 3.2.98 (2H, t), MS (ES): 229 (MH+).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:17])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([O:15][CH3:16])([CH3:14])[CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].CS(C)=O.[CH2:28](Cl)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O>[CH2:28]([O:1][C:2]1[C:3]([CH3:17])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([O:15][CH3:16])([CH3:14])[CH2:6][CH2:5]2)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC1(C)CCc2c(C)c(OCc3ccccc3)c(C)c(C)c2O1

Procedure:
A mixture of 70.8 g. of (±)-6-hydroxy-2-methoxy-2,5,7,8-tetramethylchroman, 90.9 g. of anhydrous potassium carbonate, 300 ml. of dimethylsulfoxide and 69 ml. of benzyl chloride was stirred at 23° under N2 for 24 hours. The suspension was poured into water and extracted with ether. The ether solutions were washed with brine, dried over sodium sulfate and stripped of solvent to give (±)-6-benzyloxy-2-methoxy-2,5,7,8-tetramethylchroman as an oil which solidified to a light yellow mass, m.p. 70°-72.5°.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([N:10]3[CH2:14][CH2:13][C@@H:12]([N:15]4[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]4)[CH2:11]3)=[N:7][C:6]=2[CH:21]=1.[N:22]1[NH:23][C:24](=[O:28])[CH:25]=[CH:26][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].CNCCNC>[Cu].[Cu]I.C(OCC)C.C1(C)C=CC=CC=1.N1C=CC=CC=1>[N:15]1([C@@H:12]2[CH2:13][CH2:14][N:10]([C:8]3[S:9][C:5]4[CH:4]=[CH:3][C:2]([N:23]5[C:24](=[O:28])[CH:25]=[CH:26][CH:27]=[N:22]5)=[CH:21][C:6]=4[N:7]=3)[CH2:11]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Brc1ccc2sc(N3CC[C@@H](N4CCCCC4)C3)nc2c1
Reactant: O=c1cccn[nH]1
Agent: [Cu]
Agent: [Cu]I
Agent: CNCCNC
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=c1cccnn1-c1ccc2sc(N3CC[C@@H](N4CCCCC4)C3)nc2c1
Temperature: 117 °C

Procedure:
A mixture of (R)-5-bromo-2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazole (Example 51, 0.792 g, 2.16 mmol), pyridazin-3(2H)-one (0.415 g, 4.32 mmol), copper powder (0.137 g, 2.16 mmol), copper(I) iodide (57.6 mg, 0.303 mmol), and potassium carbonate (0.896 g, 6.49 mmol) is weighed into a large Biotage microwave vial equipped with a magnetic stirbar. The vial is crimp capped with a septum. Pyridine (17.3 mL) is introduced via syringe. The reaction mixture is purged (vacuum/nitrogen) three times, then N1,N2-dimethylethane-1,2-diamine (0.065 mL, 0.605 mmol) is added via syringe and the reaction mixture is stirred with heating at 117° C. for 24 hours. The reaction mixture is allowed to cool to room temperature, then the vial is uncapped and the contents are transferred to a 100 mL round bottom flask (methanol rinse). Volatiles are removed under reduced pressure and the residue is partitioned between CHCl3 and aqueous ammonium hydroxide. The organic layer is washed with brine then dried (MgSO4) and filtered The filtrate is concentrated under reduced pressure to give a residue that is treated with toluene and returned to the rotary evaporator in an attempt to remove residual pyridine. This residue is purified by column chromatography on an Analogix IntelliFlash-280 (Analogix SF65-220g, 100% CHCl3 to 97:3 CHCl3/methanol). Fractions containing product are combined and concentrated under reduced pressure to give a solid that is stirred with diethyl ether. The solid is collected by filtration and rinsed once with ethyl acetate and several times with hexane. This solid is crystallized from hot ethyl acetate. The first crystal batch is collected by filtration and dried in a vacuum oven at 84° C. for 5 hours. The filtrate is concentrated under reduced pressure and the solid residue is dissolved in hot ethyl acetate in a second crystallization attempt. The second crystal batch is collected by filtration and dried in the vacuum oven along with the first batch at 88° C. overnight. The two dried crystal batches combined give (R)-2-(2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazol-5-yl)pyridazin-3(2H)-one.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][CH:12]=2)[C@@H:7]([O:19][C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)[CH2:6][C@@H:5]1[CH3:27])(=[O:3])[CH3:2].C(N(CC)C(C)C)(C)C.Br[CH2:38][CH2:39][O:40][CH2:41][CH2:42]Br.O>C1(C)C=CC=CC=1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][CH:12]=2)[C@@H:7]([O:19][C:20]2[CH:21]=[CH:22][C:23]([N:26]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[CH:24][CH:25]=2)[CH2:6][C@@H:5]1[CH3:27])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)[C@@H](Oc1ccc(N)cc1)C[C@H](C)N2C(C)=O
Reactant: BrCCOCCBr
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccc2c(c1)[C@@H](Oc1ccc(N3CCOCC3)cc1)C[C@H](C)N2C(C)=O
Yield: 75.7 %

Procedure:
(Step 6) 66.1 mg of ethyl (2S,4S)-1-acetyl-4-(4-aminophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate was dissolved in 2 mL of toluene, and 312 μL of N,N-diisopropylethylamine and 113 μL of 2-bromoethyl ether were added to the solution at 0° C. The mixture was heated to reflux for 14 hours. After completion of the reaction, the reaction liquid was cooled, water was added thereto, and the mixture was extracted three times with chloroform. The extraction product was washed with saturated brine, dehydrated over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by using silica gel chromatography (hexane:ethyl acetate=1:1), and thus 59.4 mg (75.7%) of ethyl (2S,4S)-1-acetyl-2-methyl-4-(4-morpholinophenoxy)-1,2,3,4-tetrahydroquinoline-6-carboxylate was obtained as a pale yellow oily substance.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:31][CH2:32][CH:33]4[CH2:35][CH2:34]4)[C:15]=3[NH:14][C:13]=2[CH3:36])=[O:11])[CH2:5][CH2:4]1.[C:37](Cl)(=[O:39])[CH3:38]>>[C:37]([NH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:31][CH2:32][CH:33]4[CH2:34][CH2:35]4)[C:15]=3[NH:14][C:13]=2[CH3:36])=[O:11])[CH2:5][CH2:4]1)(=[O:39])[CH3:38]
Reactant: Cc1[nH]c2c(-c3cc(C(F)(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)(F)F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-(trifluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f33) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][O:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[C:9](Cl)[N:8]=1)[CH3:2].C(N(CC)CC)C.[CH3:25][O:26][C:27]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:28]=1[CH2:29][NH2:30]>CC#N>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][O:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[C:9]([NH:30][CH2:29][C:28]2[CH:31]=[CH:32][C:33]([O:35][CH3:36])=[CH:34][C:27]=2[O:26][CH3:25])[N:8]=1)[CH3:2]
Reactant: CCOC(=O)COc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)COc1nc(NCc2ccc(OC)cc2OC)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.1 %

Procedure:
To a cooled (˜10° C.) solution of (6-chloro-3-nitro-pyridin-2-yloxy)-acetic acid ethyl ester (8.0 g, 30.8 mmol) in MeCN (80 mL) was added a solution of triethylamine (6.4 mL, 46 mmol) and 2,4-dimethoxybenzylamine (5.5 mL, 37 mmol). The mixture was then stirred for 16 hours at ambient temperature and then concentrated in vacuo. The residue was partitioned between EtOAc and aqueous potassium hydrogenphosphate solution. The EtOAc layer was then washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified using SiO2 chromatography (10-50% EtOAc/Petrol) to give [6-(2,4-dimethoxy-benzylamino)-3-nitro-pyridin-2-yloxy]acetic acid ethyl ester (9.53 g) as a yellow solid. MS: [M+H]+ 392
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][C:6]([OH:8])=O)[CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH2:45]([O:47][C:48]([C:50]1([CH2:56][CH2:57][O:58][CH3:59])[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)=[O:49])[CH3:46]>>[CH2:45]([O:47][C:48]([C:50]1([CH2:56][CH2:57][O:58][CH3:59])[CH2:51][CH2:52][N:53]([C:6](=[O:8])[CH2:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[CH2:54][CH2:55]1)=[O:49])[CH3:46]
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: O=C(O)CCC1CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(CCOC)CCN(C(=O)CCC2CC2)CC1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 36.4 %

Procedure:
To a solution of 3-cyclopropyl-propionic acid (0.342 g) in acetronitril (15 ml) were added under an argon atmosphere N-ethyldiisopropylamine (0.775 g, 1.03 ml) and BOP (1.328 g and the mixture was stirred for 50 minutes at RT. Then 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (0.646 g) were added and the mixture was stirred for 12 h at RT. The reaction mixture was partitioned between ethyl acetate and aqueous 1M HCl, the layers were separated and the aqueous layer washed with 2M aqueous KHCO3 then dried over Na2SO4. The solvent was evaporated off, the residue purified by flash chromatography (methylene chloride/AcOEt, gradient from 0 to 30%) to give 1-(3-cyclopropyl-propionyl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester, (0.34 g) as a yellow oil that was used in the next step without further purification.
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4CCN(C(OCC)=O)C[CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[C:45]([C:47]1[CH:53]=CC(N)=[CH:49][CH:48]=1)#[N:46].NC1C=CC=CC=1>>[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:30]=[CH:53][C:47]([C:45]#[N:46])=[CH:48][CH:49]=4)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH2:34][CH3:35])[N:32]=[CH:33][C:14]=13)[CH2:6]2
Reactant: N#Cc1ccc(N)cc1
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: CCn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)Nc4ccc(C#N)cc4)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 4-cyanoaniline as the aniline component. (9%, MS=495.2 (M+H))
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13](/[CH:16]=[CH:17]/[C:18]([O:20]CC)=[O:19])[CH:14]=2)[C:9](=[O:23])[N:8]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:7]=1[CH2:29][NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.Cl>O1CCCC1.C(O)C>[CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])[CH:14]=2)[C:9](=[O:23])[N:8]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:7]=1[CH2:29][NH:30][C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)(C)C)c(=O)c2ccc(/C=C/C(=O)OCC)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)(C)C)c(=O)c2ccc(/C=C/C(=O)O)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
To a solution of ethyl (E)-3-[4-butoxy-3[[(tert-butoxycarbonyl)amino]methyl]-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenate (0.67 g, 1.3 mmol) in tetrahydrofuran (5 mL) and ethanol (5 mL) as added 1N sodium hydroxide (3 mL). The obtained mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water, acidified with 1N hydrochloric acid and extracted with ethyl-acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-n-hexane to give (E)-3-[4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-neopentyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenic acid (0.53 g, 84.1%) as crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH2:13][C:14]1[C:30]([CH3:31])=[CH:29][C:17]([O:18][CH2:19][CH2:20][CH2:21][C:22]([CH3:28])([CH3:27])[C:23]([O:25][CH3:26])=[O:24])=[C:16]([CH3:32])[CH:15]=1.C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:13][C:14]2[C:30]([CH3:31])=[CH:29][C:17]([O:18][CH2:19][CH2:20][CH2:21][C:22]([CH3:27])([CH3:28])[C:23]([O:25][CH3:26])=[O:24])=[C:16]([CH3:32])[CH:15]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)C(C)(C)CCCOc1cc(C)c(N)cc1C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)CCCOc1cc(C)c(NS(=O)(=O)c2ccc(OC)cc2)cc1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
A solution of 2.2 g (12.5 mmol) of para-methoxybenzenesulfonyl chloride in 10 mL of tetrahydrofuran is added over 10 minutes at 0° C. to a solution of 3.5 g (12.5 mmol) of 5-(4-amino-2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid, methyl ester as the free base (Example 2) and 2.5 g (2×12.5 mmol) of triethylamine in 40 mL of tetrahydrofuran. The ice bath is removed and the solution is permitted to stir at ambient temperature for 24 hours. The triethylammonium chloride is removed by filtration, the solvent is removed; the residue is taken up in diethyl ether, and the solution washed with 2×25 mL of 2N hydrochloric acid solution, brine, dried (magnesium sulfate), and evaporated leaving 5.0 g of a colored oil which crystallizes on standing. Recrystallization from 35 mL of isopropyl ether in the presence of charcoal affords 3.3 g of the title compound as off-white crystals; mp 90°-92° C.
Reaction SMILES: N12CCCN=C1CCCCC2.[Br:12][C:13]1[N:18]([CH3:19])[C:17](=[O:20])[NH:16][C:15](=[O:21])[C:14]=1[CH3:22].Cl[CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(#N)C>[CH2:26]([O:25][CH2:24][N:16]1[C:15](=[O:21])[C:14]([CH3:22])=[C:13]([Br:12])[N:18]([CH3:19])[C:17]1=[O:20])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: ClCOCc1ccccc1
Reactant: Cc1c(Br)n(C)c(=O)[nH]c1=O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1c(Br)n(C)c(=O)n(COCc2ccccc2)c1=O
Reaction time: 90 h

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (6.00 mL, 40.2 mmol) was added to a suspension of C2 (8.00 g, 36.5 mmol) and benzyl chloromethyl ether (95%, 5.86 mL, 40.2 mmol) in acetonitrile (100 mL). After 90 hours at room temperature, the reaction mixture was concentrated in vacuo, diluted with water, and extracted several times with ethyl acetate. The combined organic layers were washed sequentially with water and with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Silica gel chromatography (Gradient: 10% to 25% ethyl acetate in heptane) afforded the product as a white solid. Yield: 10.1 g, 29.8 mmol, 82%. 1H NMR (400 MHz, CDCl3) δ 7.24-7.39 (m, 5H), 5.52 (s, 2H), 4.71 (s, 2H), 3.63 (s, 3H), 2.11 (s, 3H).
Reaction SMILES: [CH2:1]([OH:9])[CH:2]([OH:8])[CH:3]([OH:7])[CH2:4][CH:5]=[CH2:6].N1C=CN=C1.[Si:15](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl.CN(C)C=O.C(OCC)C>[CH3:31][C:28]([Si:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[O:9][CH2:1][CH:2]([OH:8])[CH:3]([OH:7])[CH2:4][CH:5]=[CH2:6])([CH3:29])[CH3:30]
Reactant: C=CCC(O)C(O)CO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOCC
Product: C=CCC(O)C(O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
A 0° C. solution of 7.33 g of product from Example 273 in 120 ml of 5:1 dry methylene chloride/N,N-dimethylformamide is treated with 5.29 g of imidazole and 16.77 g of t-butyl diphenylsilyl chloride. The reaction mixture is warmed to room temperature and stirred vigorously for 16 hours, diluted with diethyl ether and filtered. The filtrate is concentrated and purified by chromatography (Silica Gel: 0-50% ethyl acetate/hexane) to give 15 g of the desired product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[CH:5]=[CH:4][N:3]=1.[F:17][C:18]1[CH:26]=[C:25]2[C:21]([CH:22]=[N:23][N:24]2C2CCCCO2)=[C:20]([CH2:33][NH:34][CH2:35][CH2:36][N:37](C)[C:38](=O)OC(C)(C)C)[CH:19]=1.CCN(C(C)C)C(C)C.Cl.O1CCOCC1>CCCCO>[CH:14]1([C:12]2[NH:11][N:10]=[C:9]([NH:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([N:34]([CH2:33][C:20]4[CH:19]=[C:18]([F:17])[CH:26]=[C:25]5[C:21]=4[CH:22]=[N:23][NH:24]5)[CH2:35][CH2:36][NH:37][CH3:38])[N:7]=3)[CH:13]=2)[CH2:16][CH2:15]1
Reactant: CN(CCNCc1cc(F)cc2c1cnn2C1CCCCO1)C(=O)OC(C)(C)C
Reactant: Clc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Agent: Cl
Solvent: CCCCO
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CNCCN(Cc1cc(F)cc2[nH]ncc12)c1nccc(Nc2cc(C3CC3)[nH]n2)n1
Temperature: 115 °C
Reaction time: 16 h
Yield: 12.7 %

Procedure:
A vial was charged with 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (100 mg, 0.42 mmol), tert-butyl (2-(((6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)methyl)amino)ethyl)(methyl)carbamate (207 mg, 0.51 mmol), DIPEA (0.22 mL, 1.27 mmol) and n-BuOH (0.9 mL), sealed and heated at 115° C. for 4 d. The reaction mixture was then cooled to RT and 4N HCl/dioxane (1.06 mL, 4.24 mmol) was added. The reaction mixture was stirred at RT for 16 h then concentrated nvacuo. The crude mixture was purified by preparative HPLC to afford 22.4 mg (13%) of N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-((6-fluoro-1H-indazol-4-yl)methyl)-N2-(2-(methylamino)ethyl)pyrimidine-2,4-diamine (II-47).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[CH:11][C:12]([CH2:15][Br:18])=[CH:13][CH:14]=3)[O:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc(-c2nc3ccc(Br)cc3o2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(-c2nc3ccc(Br)cc3o2)cc1

Procedure:
3.00 g (10.41 mmol) 6-bromo-2-p-tolyl-benzoxazole are stirred together with 1.90 g (10.68 mmol) N-bromosuccinimide, 10.00 mg (0.04 mmol) dibenzoylperoxide and 60 ml carbon tetrachloride for 2 h at 90°. The reaction mixture is filtered through kieselguhr, then the solv. is eliminated by rotary evaporation in vacuo and the residue is recrystallised from petroleum ether.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=1.[As](=O)(O)(O)O.P(=O)(O)(O)O.[Br:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=O)[CH2:37][CH2:38]Cl)=[CH:32][CH:31]=1.[OH-].[K+]>>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([C:7]2[C:6]3[C:11](=[C:2]4[C:3](=[CH:4][CH:5]=3)[C:36]([C:33]3[CH:34]=[CH:35][C:30]([Br:29])=[CH:31][CH:32]=3)=[CH:37][CH:38]=[N:1]4)[N:10]=[CH:9][CH:8]=2)=[CH:13][CH:14]=1
Reactant: O=C(CCCl)c1ccc(Br)cc1
Reactant: Nc1cccc2c(-c3ccc(Br)cc3)ccnc12
Agent: O=P(O)(O)O
Agent: O=[As](O)(O)O
Agent: [K+]
Product: Brc1ccc(-c2ccnc3c2ccc2c(-c4ccc(Br)cc4)ccnc23)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 8-amino-4-(4-bromophenyl)quinoline (2.0 g), arsenic acid (2.3 g) and orthophosphoric acid (6 mL) was added 1-(4-bromophenyl)-3-chloropropan-1-one (2.1 g). Care was taken during the addition that the temperature did not to exceed 120° C. The temperature was then ramped to 140° C. and kept there for 1.5 h. The reaction mixture was cooled to room temperature, poured onto ice and then made alkaline with 30% KOH. The precipitated solid was filtered off, washed with water and extracted with hot toluene. This solution was dried over MgSO4 and evaporated to give 4,7-bis(4-bromophenyl)-1,10-phenanthroline as confirmed by 1H NMR.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:17][C:18](=[O:20])[CH3:19])[CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([F:16])[CH2:12][CH2:11]1.[CH3:21][C:22]([CH3:27])([CH3:26])[C:23](Cl)=O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:22]([C:27]1[N:8]([CH2:9][CH:10]2[CH2:11][CH2:12][CH:13]([F:16])[CH2:14][CH2:15]2)[C:7]2[CH:6]=[CH:5][C:4]([NH:17][C:18](=[O:20])[CH3:19])=[CH:3][C:2]=2[N:1]=1)([CH3:26])([CH3:23])[CH3:21]
Reactant: CC(=O)Nc1ccc(NCC2CCC(F)CC2)c(N)c1
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc2c(c1)nc(C(C)(C)C)n2CC1CCC(F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(3-Amino-4-{[(4-fluorocyclohexyl)methyl]amino}phenyl)acetamide (300 mg, 1.07 mmol) and DMAP (25 mg, 0.214 mmol) were dissolved in 10 mL of DCM. Trimethylacetyl chloride (0.145 mL, 1.18 mmol) was added dropwise and the solution was stirred at rt for 1 h. The solution was washed with aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The residue was dissolved in 5 mL of AcOH and was heated at 150° C. for 2.5 h using a Personal Chemistry microwave apparatus. The solvent was evaporated. The residue was dissolved in EtOAc and washed with aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The crude product was purified by silica gel flash chromatography using 2:1/acetone:hexanes as eluent. Yield: 196 mg (53%). 1HNMR (400 MHz, CHLOROFORM-D) δ 1.14-1.25 (m, 2 H), 1.37-1.45 (m, 1 H), 1.43-1.51 (m, 1 H), 1.54-1.57 (m, 9 H), 1.70-1.78 (m, 2 H), 1.70-1.77 (m, 1 H), 2.02-2.08 (m, 1 H), 2.10-2.17 (m, 1 H), 2.19-2.21 (m, 3 H), 4.12-4.19 (m, 2 H), 4.53 (m, 0.3 H), 4.73 (m, 0.3 H), 4.78 (m, 0.2 H), 4.90 (m, 0.2 H), 7.21-7.29 (m, 1 H), 7.30 (s, 1 H), 7.50-7.57 (m, 1 H), 7.64-7.67 (m, 1 H).