Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[Si](Cl)(Cl)Cl.[N-:6]=[N+:7]=[N-:8].[Na+].[CH2:10]([O:12][C:13]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31](=O)[NH:32][CH3:33])[CH:26]=1)[CH2:19][C:18]2([CH3:36])[CH3:35])=[O:14])[CH3:11]>C(#N)C>[CH2:10]([O:12][C:13]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]3[N:32]([CH3:33])[N:8]=[N:7][N:6]=3)[CH:26]=1)[CH2:19][C:18]2([CH3:35])[CH3:36])=[O:14])[CH3:11]
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(C(=O)NC)c1)N2
Reactant: [N-]=[N+]=[N-]
Agent: Cl[Si](Cl)(Cl)Cl
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(-c3nnnn3C)c1)N2
Temperature: 25 °C
Yield: 65.9 %

Procedure:
To a stirred solution of tetrachlorosilane (5.3 mL, 46.3 mmol), sodium azide (5.6 g, 87 mmol) in dry acetonitrile (20 mL) was added 4,4-dimethyl-2-(3-methylcarbamoyl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.23 g, 3.3 mmol) at room temperature. Then the mixture solution was stirred at room temperature for over night. LC/MS showed that reaction finished completely. The reaction mixture was poured into ice-cold saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (150 mL×2), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (30% ethyl acetate/hexanes) afforded 4,4-dimethyl-2-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (851.6 mg, 66%) as a white solid: MS (ESI) M+1=392.1.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][N:9]=[C:10]2[NH2:13])=[CH:5][CH:4]=1.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].CN1CCOCC1>C(Cl)Cl>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][N:9]=[C:10]2[NH:13][C:17](=[O:18])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:5][CH:4]=1
Reactant: Nc1nccc2ccc(C(F)(F)F)cc12
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(Nc1nccc2ccc(C(F)(F)F)cc12)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 7-(trifluoromethyl)isoquinolin-1-amine (410 mg, 1.9 mmol), from above step E, and benzyl chloroformate (0.33 mL, 2.3 mmol) in DCM was treated with N-methylmorpholine (0.23 mL, 2.1 mmol) and stirred at room temperature for 18 h. Reaction mixture was diluted with DCM and washed with water and dried over Na2SO4. DCM was removed under vacuum and the residue was purified by silica column chromatography to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH3:14])[CH:11]=[CH:12][CH:13]=2)[N:5]=[CH:4][N:3]=1.[C:15]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)([OH:17])=[O:16].C([O-])([O-])=O.[Na+].[Na+].Cl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[C:10]1([CH3:14])[CH:11]=[CH:12][CH:13]=[C:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([C:21]3[CH:22]=[CH:23][C:18]([C:15]([OH:17])=[O:16])=[CH:19][CH:20]=3)[CH:7]=2)[CH:9]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Cc1cccc(-c2cc(Cl)ncn2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Product: Cc1cccc(-c2cc(-c3ccc(C(=O)O)cc3)ncn2)c1
Temperature: 150 °C

Procedure:
Part B. A 10 mL microwave tube is charged with 4-chloro-6-m-tolyl-pyrimidine (45.7 mg, 0.22 mmol), 4-carboxyphenylboronic acid (39.2 mg, 0.23 mmol), (235.3 mg, 2.22 mmol), Na2CO3 (70.6 mg, 0.67 mmol), tetrabutylammonium iodide (83.0 mg, 0.22 mmol), palladium acetate (0.5 mg, 2.2×mmol) and 2 mL of water. The reaction mixture is heated to 150° C. at 60 w, 250 psi in a microwave reactor for 10 min. The reaction mixture is added to 5 mLl of 6 N HCl and extracted with ethyl acetate (10 mL). The organic portion is washed with saturated NaHCO3 and brine, dried (MgSO4), and concentrated on a rotary evaporator. The oily residue is suspended in ethyl acetate/hexanes (1:1) to provide 9.8 mg (15.1% yield) of white powder as the desired product, m.p. 211-213° C. 1H NMR (300 MHz, DMSO-d6): δ 9.31 (1H, s), 8.66 (1H, s), 8.46 (2H, d, J=8.3 Hz), 8.20 (1H, s), 8.15 (1H, dd, J=8.0, 1.2 Hz), 8.09 (2H, d, J=8.3 Hz), 7.45 (1H, t, J=7.7 Hz), 7.38 (111, dd, J=7.7, 1.0 Hz). MS (ES+): m/e 291.58.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH3:9])[CH2:4]1.[CH3:10][NH2:11]>C(O)C>[CH3:10][NH:11][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH3:9])[CH2:4]1
Reactant: CN1CCCC(CCl)C1
Reactant: CN
Solvent: CCO
Product: CNCC1CCCN(C)C1

Procedure:
A solution of 3-(chloromethyl)-1-methylpiperidine (9.2 g, 50 mmol) (U.S. Pat. No. 6,184,338, example 5) and 33% methylamine in ethanol (60 mL) in ethanol (30 mL) was heated in a sealed vessel at 100° C. for 17 hours. The reaction mixture was concentrated in vacuo and diluted with water before being extracted into dichloromethane and dried over magnesium sulphate. The reaction mixture was filtered and concentrated in vacuo to yield the title product, 8.2 g.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][O:9][C:10]1[CH:41]=[CH:40][C:13]([C:14]([C:16]2[CH:39]=[CH:38][C:19]([O:20][CH2:21][CH2:22][CH2:23][O:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][C@H:32]([O:36][CH3:37])[C:33]([OH:35])=[O:34])=[CH:27][CH:26]=3)=[CH:18][CH:17]=2)=[O:15])=[CH:12][CH:11]=1)(C)(C)C>C(O)(=O)C.C1COCC1.O>[OH:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([C:16]2[CH:39]=[CH:38][C:19]([O:20][CH2:21][CH2:22][CH2:23][O:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][C@H:32]([O:36][CH3:37])[C:33]([OH:35])=[O:34])=[CH:27][CH:26]=3)=[CH:18][CH:17]=2)=[O:15])=[CH:40][CH:41]=1
Reactant: CO[C@@H](Cc1ccc(OCCCOc2ccc(C(=O)c3ccc(OCCO[Si](C)(C)C(C)(C)C)cc3)cc2)cc1)C(=O)O
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(C(=O)c3ccc(OCCO)cc3)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound of (2S)-3-{4-[3-(4-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-benzoyl}-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acid (Example 253, Step C) (0.05 mmol, 30 mg) was dissolved in 5 mL of a mixture of acetic acid, THF and H2O (3:1:1) and stirred at room temperature for 2 hours. The mixture was diluted with H2O and extracted with ethyl acetate (4×20 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under vacuum to afford the title compound. MS(ES) for C28H30O8 [M+H]+: 495.1
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[C:43]1([CH2:49][C:50]([N:52]=[C:53]=[S:54])=[O:51])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(O)C.C1(C)C=CC=CC=1>[CH3:25][N:23]([CH2:22][CH:19]1[CH2:20][CH2:21][N:16]([C:14]([NH:13][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:26]=[CH:27][C:2]([NH:1][C:53]([NH:52][C:50](=[O:51])[CH2:49][C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)=[S:54])=[CH:3][CH:4]=3)[CH:12]=[CH:11][N:10]=2)=[O:15])[CH2:17][CH2:18]1)[CH3:24]
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3)ccn2)CC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Solvent: Cc1ccccc1
Product: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3)ccn2)CC1
Reaction time: 1 h
Yield: 46 %

Procedure:
To a solution of 4-(4-aminophenoxy)-2-{[4-(dimethylaminomethyl)piperidin-1-yl]carbonylamino}pyridine (105.6 mg) and (+)-10-camphorsulfonic acid (62 mg) in ethanol (2.5 ml) was added a solution of 2-phenylacetyl isothiocyanate in toluene (0.25 M, 2.5 ml) at room temperature, followed by stirring for 1 hour. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine in this order, dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate:heptane=1:1 to 4:1) to provide the titled compound (70.2 mg, 46%) as white powder.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]2[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=2[O:32][CH3:33])=[CH:11][C:10]=1[C:34]1[N:38]([CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:37]=[N:36][N:35]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH:29]([C:27]1[CH:26]=[CH:25][C:24]([O:32][CH3:33])=[C:23]([C:12]2[C:13]([OH:15])=[CH:14][C:9]([OH:8])=[C:10]([C:34]3[N:38]([CH2:39][CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[N:37]=[N:36][N:35]=3)[CH:11]=2)[CH:28]=1)([CH3:31])[CH3:30]
Reactant: [H][H]
Reactant: COc1ccc(C(C)C)cc1-c1cc(-c2nnnn2CCc2ccccc2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(C(C)C)cc1-c1cc(-c2nnnn2CCc2ccccc2)c(O)cc1O
Reaction time: 8 h
Yield: 63.9 %

Procedure:
5% Pd/C (30 mg) was wetted carefully with methanol under nitrogen in a 25 ml round flask, then a solution of 5-(4,6-bis-benzyloxy-5′-isopropyl-2′-methoxy-biphenyl-3-yl)-1-phenethyl-1H-tetrazole (100 mg, 0.16 mmol) in methanol (10 ml) was added. The reaction flask was vacuumed and filled with hydrogen three times. The reaction was then stiffed under hydrogen at r.t. overnight. After filtering the catalyst over celite, the filtrate was concentrated to give 5′-isopropyl-2′-methoxy-5-(1-phenethyl-1H-tetrazol-5-yl)-biphenyl-2,4-diol (44 mg, 63%). M.p.: 206-209° C.; 400 MHz 1H NMR (DMSO-d) δ: 10.22 (s, 1H), 9.64 (s, 1H), 7.19-7.08 (m, 4H), 7.02-6.97 (m, 3H), 6.94 (d, J=8.4 Hz, 1H), 6.75 (s, 1H), 6.61 (s, 1H), 4.55 (t, J=7.2 Hz, 2H), 3.66 (s, 3H), 3.11 (t, J=7.2 Hz, 2H), 2.90-2.81 (m, 1H), 1.20 (d, J=7.2 Hz, 6H); LCMS: 431 [M+H].
Reaction SMILES: [N+]([O-])(O)=[O:2].[CH2:5]([O:7][C:8](=[O:18])[CH:9]([CH:15]([CH3:17])[CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:6]>>[CH2:5]([O:7][C:8](=[O:18])[C:9]([CH:15]([CH3:16])[CH3:17])([C:10]([O:12][CH2:13][CH3:14])=[O:11])[OH:2])[CH3:6]
Reactant: CCOC(=O)C(C(=O)OCC)C(C)C
Reactant: O=[N+]([O-])O
Product: CCOC(=O)C(O)(C(=O)OCC)C(C)C
Reaction time: 48 h

Procedure:
400 g (6.3 mols) of 98 % to 100 % nitric acid are placed in a sulphonating flask, and 10 g (0.05 mols) of isopropyl-malonic acid diethyl ester are added dropwise within 15 minutes at room temperature while stirring. The clear solution is allowed to stand at room temperature for 48 hours. Most of the nitric acid is then carefully removed by evaporation on a rotary evaporator under a water pump vacuum, the residue is distributed between an aqueous potassium hydrogen carbonate solution and a sufficient amount of methylene chloride and is worked up in the usual manner. The methylene chloride phases are again extracted with a small amount of water, dried over sodium sulphate, and the solvent is carefully removed by evaporation in a vacuum. The resulting crude product is distilled in a high vacuum and yields isopropyl-tartronic acid diethyl ester having a B.P. of 65°-67° (0.05 mm of Hg), nD20 = 1.4289.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=[O:2].[CH3:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27]Br>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:10][CH2:11][C:4]([C:1]([O:3][CH2:24][C:25]4[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=4[CH3:27])=[O:2])([CH2:9][CH2:8]2)[CH2:5][CH2:6]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: Cc1ccccc1CBr
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: Cc1ccccc1COC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)CC2
Yield: 86 %

Procedure:
In a similar manner to Example 8, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (30.0 mg) and 2-methylbenzyl bromide (18.9 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-(2-methylbenzyl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (34.1 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:9]([CH3:17])([CH2:11][CH2:12][C:13]([CH3:16])(Cl)[CH3:14])[CH3:10].[Al+3].[Cl-].[Cl-].[Cl-].Cl>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:13]([CH3:16])([CH3:14])[CH2:12][CH2:11][C:9]([CH3:17])([CH3:10])[C:4]=2[CH:3]=1
Reactant: Brc1ccccc1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.4 %

Procedure:
To a solution of 2-bromobenzene (40 g, 255 mmol) and 2,5-dichloro-dimethyl hexane (52.7 g, 280 mmol) in 600 mL anhydrous CH2Cl2 at 5° C. was added, portionwise, AlCl3 (10.2 g, 76 mmol). Upon addition of AlCl3, HCl gas evolution was observed. The solution changed from yellow to reddish orange. The reaction solution was kept at 5-20° C. for two hours and then allowed to stir at room temperature overnight. The reaction mixture was poured into 600 g of ice and extracted with CHCl3 (2×700 mL). The organic phase was washed with water, aqueous saturated NaHCO3, saturated NaCl and dried (Na2SO4). The organic solution was then concentrated in vacuo and chromatographed (hexane) to provide 50 g of 2-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene as a yellow gummy solid in 73% yield. 1H NMR (400 MHz, CDCl3) δ7.41 (d, J=2.0 Hz, 1H, aromatic), 7.22 (dd, J=8.0 and 1.9 Hz, 1H, aromatic), 7.18 (d, J=8.0 Hz, 1H, aromatic), 1.68 (s, 4H, 2CH2), 1.27 (s, 6H, 2CH3), 1.24 (s, 6H, 2CH3).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH:15]1([NH2:18])[CH2:17][CH2:16]1>>[CH:15]1([NH:18][CH:11]2[CH2:12][CH2:13][N:8]([C:5]3[N:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=3)[CH2:9][CH2:10]2)[CH2:17][CH2:16]1
Reactant: NC1CC1
Reactant: Cc1cnc(N2CCC(=O)CC2)nc1
Product: Cc1cnc(N2CCC(NC3CC3)CC2)nc1

Procedure:
The title compound is prepared from 1-(5-methyl-pyrimidin-2-yl)-piperidin-4-one and cyclopropylamine following a procedure analogous to that described in Intermediate 4. LC (method 7): tR=0.55 min; Mass spectrum (ESI+): m/z=233 [M+H]+.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:19]C)[N:12]2[CH2:15][CH2:16][CH2:17]Cl)=[C:8]([NH2:21])[N:7]=1)[CH2:2][CH2:3][CH3:4].[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.[I-].[Na+]>C1COCC1>[NH2:21][C:8]1[N:7]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:19])[N:12]2[CH2:15][CH2:16][CH2:17][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C1CCNCC1
Reactant: CCCCNc1nc(N)c2nc(OC)n(CCCCl)c2n1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCNc1nc(N)c2[nH]c(=O)n(CCCN3CCCCC3)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 5.8 %

Procedure:
A mixture of N2-butyl-9-(3-chloropropyl)-8-(methyloxy)-9H-purine-2,6-diamine (250 mg, 0.8 mmole), piperidine (340 mg, 4 mmole) and sodium iodide (360 mg, 2.4 mmole) in THF (8 ml) was heated under reflux for 48 hours. The solvent was evaporated and the residue purified by preparative TLC then dissolved in methanol (5 ml). Hydrogen chloride in methanol (0.5 ml) was added and the mixture stirred at room temperature for 16 hours. The solvent was then evaporated and the pH of the residue was adjusted to 7-8 by addition of sodium bicarbonate solution. The product was extracted into ethyl acetate and the extract was evaporated and the residue purified by preparative HPLC to give the title compound (16 mg).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[N:8][CH:7]=[C:6]2[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:11]=[CH:12][C:5]=12.Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:33]=[C:32]([CH:34]3[CH2:36][CH2:35]3)[NH:31][N:30]=2)[CH:25]=[CH:24][N:23]=1.CCN(C(C)C)C(C)C>CC(C(O)C(C)C)C>[CH:34]1([C:32]2[NH:31][N:30]=[C:29]([NH:28][C:26]3[CH:25]=[CH:24][N:23]=[C:22]([N:2]([CH3:1])[CH2:3][C:4]4[CH:9]=[N:8][CH:7]=[C:6]5[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:11]=[CH:12][C:5]=45)[N:27]=3)[CH:33]=2)[CH2:36][CH2:35]1
Reactant: Clc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Reactant: CNCc1cncc2c1ccn2COCC[Si](C)(C)C
Agent: CC(C)C(O)C(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1cncc2c1ccn2COCC[Si](C)(C)C)c1nccc(Nc2cc(C3CC3)[nH]n2)n1
Temperature: 140 °C
Yield: 57.9 %

Procedure:
A mixture of N-methyl(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)methanamine (110 mg, 0.38 mmol), 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (107 mg, 0.454 mmol), DIPEA (146 mg, 1.134 mmol) in 2,4-dimethylpentan-3-ol (2.0 mL) in a sealed tube was heated at 140° C. overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified by SiO2 chromatography eluting with DCM/MeOH (10:1) to afford 108 mg of N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-methyl-N2-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)methyl)pyrimidine-2,4-diamine as a yellow solid. MS (ESI): m/z=491.2 [M+1]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:7]=[O:8])[CH3:2].Br[CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])[CH:7]=[O:8])[CH3:2]
Reactant: CCOc1cc(C=O)ccc1O
Reactant: CC(C)=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(C=O)ccc1OCC=C(C)C

Procedure:
The title compound was prepared analogously to intermediate 2 (4-methoxy-3-propoxy-benzaldehyde) by reaction of 3-ethoxy-4-hydroxy-benzaldehyde with 1-bromo-3-methyl-2-butene in DMF using K2CO3 as base. MS (ISN): 233.1 [M−H]−.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)N2C=NC(SCCOC3C=C(C#N)C=CN=3)=N2)C=CC=CC=1.[C:37]1([C:43]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[N:44]2[CH:48]=[N:47][C:46]([CH2:49][CH2:50][CH2:51][O:52][C:53]3[CH:58]=[C:57]([C:59]#[N:60])[CH:56]=[CH:55][N:54]=3)=[N:45]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[C:67]1([C:43]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)([C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)[N:44]2[CH:48]=[N:47][C:46]([CH2:49][CH2:50][CH2:51][O:52][C:53]3[CH:58]=[C:57]([CH2:59][NH2:60])[CH:56]=[CH:55][N:54]=3)=[N:45]2)[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1
Reactant: N#Cc1ccnc(OCCCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Agent: N#Cc1ccnc(OCCSc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Product: NCc1ccnc(OCCCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1

Procedure:
By a method similar to that in Reference Example 20 and using, instead of 2-[(2-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]thio}ethyl)oxy]pyridine-4-carbonitrile, 2-({3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propyl}oxy)pyridine-4-carbonitrile obtained in Reference Example 27, the title compound was obtained as a yellow oil (67 mg, 27%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C@H:10]([NH:14][C:15]([NH:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=1[CH:20]=[N:21][N:22]3[C:27]([O:29][CH2:30][CH2:31][NH:32]C(OCC1C=CC=CC=1)=O)=[O:28])=[O:16])[CH2:9][CH2:8]2)([CH3:4])([CH3:3])[CH3:2].[ClH:43].[H][H]>CO.[Pd]>[ClH:43].[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C@H:10]([NH:14][C:15]([NH:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=1[CH:20]=[N:21][N:22]3[C:27]([O:29][CH2:30][CH2:31][NH2:32])=[O:28])=[O:16])[CH2:9][CH2:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)c1ccc2c(c1)CC[C@H]2NC(=O)Nc1cccc2c1cnn2C(=O)OCCNC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)(C)c1ccc2c(c1)CC[C@H]2NC(=O)Nc1cccc2c1cnn2C(=O)OCCN
Yield: 107.1 %

Procedure:
A mixture of the product from Example 28B (0.53 g, 0.93 mmol) and 10% Pd/C (0.053 g, 0.047 mmol) in methanol (50 mL) and conc. HCl (86 μL, 1.02 mmol) was hydrogenated under 60 psi of hydrogen gas at ambient temperature for 1 h. The resulting mixture was filtered and concentrated to obtain title compound (0.47 g, quantitative yield). 1H NMR (DMSO-d6) δ: 1.28 (s, 9H), 1.84 (m, 1H), 2.46 (m, 1H), 2.85 (m, 1H), 2.94 (m, 1H), 4.65 (dd, 2H), 5.18 (q, 1H), 6.96 (d, 1H), 7.26 (s, 2H), 7.31 (s, 1H), 7.51 (t, 1H), 7.69 (d, 1H), 7.91 (d, 1H), 8.02 (br s, 2H), 8.59 (s, 1H), 9.19 (s, 1H). 1H NMR (methanol-d4) δ: 1.32 (s, 9H), 1.91 (m, 1H), 2.59 (m, 1H), 2.90 (m, 1H), 3.00 (m, 1H), 3.45 (dd, 2H), 4.71 (dd, 21H), 5.30 (t, 1H), 7.28 (s, 2H), 7.32 (s, 1H), 7.57 (t, 1H), 7.67 (d, 1H), 7.90 (d, 1H), 8.48 (s, 1H). MS (ESI) m/z: 436.2 [M+H]+ Anal Calcd for C24H29N5O3.HCl.1.8 H2O: C, 57.15; H, 6.71; N, 13.88. Found: C, 57.21; H, 6.55; N, 13.60.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.C([O:13][C:14]([C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[C:23]([C:26]1([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:28][CH2:27]1)[N:22]=[CH:21]2)=[CH2:15])CCC.O>C1COCC1>[Br:8][CH2:13][C:14]([C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[C:23]([C:26]1([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:28][CH2:27]1)[N:22]=[CH:21]2)=[O:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(OCCCC)c1cccc2cnc(C3(c4ccccc4)CC3)nc12
Solvent: O
Solvent: C1CCOC1
Product: O=C(CBr)c1cccc2cnc(C3(c4ccccc4)CC3)nc12
Temperature: 0 °C
Reaction time: 0.03 h
Yield: 117.2 %

Procedure:
NBS (51.7 mg, 0.290 mmol) was added to a solution 8-(1-butoxyvinyl)-2-(1-phenylcyclopropyl)quinazoline (100.0 mg, 0.290 mmol) in THF (2.2 mL) and water (0.084 mL, 4.65 mmol) at 0° C. and the resulting solution was stirred at 0° C. for 2 min. The mixture was partitioned between Et2O (50 mL) and water (30 mL). The organic layer was separated, sequentially washed with saturated aq. NaHCO3 (20 mL), water (20 mL), and brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to provide crude 2-bromo-1-(2-(1-phenylcyclopropyl)quinazolin-8-yl)ethanone (124.8 mg) as a light-yellow oil. NH4OAc (90 mg, 1.161 mmol) and piperidine-2,4-dione (39.4 mg, 0.348 mmol) were added to the resulting oil, and the mixture was taken up in EtOH (2.2 mL) and stirred under argon in a sealed flask at 50° C. for 15.5 h. The reaction was cooled to 25° C. and concentrated in vacuo. The residue was partitioned between DCM (50 mL) and saturated aq. NaHCO3 (30 mL). The aq. layer was extracted with DCM (2×30 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-10% MeOH/DCM) furnished 2-(2-(1-phenylcyclopropyl)quinazolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (35.3 mg, 0.093 mmol, 32% yield) as a yellow-orange solid: 1H NMR (400 MHz, CDCl3) δ ppm 11.24 (1H, br. s.), 9.28 (1H, s), 8.16 (1H, d, J=7.6 Hz), 7.66 (1H, d, J=7.8 Hz), 7.52-7.58 (3H, m), 7.46 (2H, t, J=7.3 Hz), 7.39 (1H, t, J=7.2 Hz), 7.11 (1H, d, J=2.2 Hz), 5.45 (1H, br. s.), 3.51 (2H, td, J=7.0, 2.1 Hz), 2.49 (2H, t, J=6.9 Hz), 1.95 (2H, q, J=3.6 Hz), 1.51 (2H, q, J=3.6 Hz). m/z (ESI, +ve) 381.2 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7]2)([O-:3])=[O:2].[OH-].[K+].[CH3:15]I.O>CC(C)=O>[CH3:15][N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH2:7][CH2:8]1
Reactant: CI
Reactant: O=[N+]([O-])c1ccc2c(c1)CCN2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CN1CCc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
To a solution of 5-nitro-2,3-dihydro-1H-indole (1 g, 6.09 mmol) in acetone (12 ml) was added powdered potassium hydroxide (1.7 g, 30.45 mmol), followed by methyl iodide (1.2 g, 9.14 mmol) and stirred overnight at ambient temperature. The solvent was evaporated under vacuum to give a residue, to which water was added and the product extracted with ethyl acetate. Drying and concentration of the organic layer yielded 1-methyl-5-nitro-2,3-dihydro-1H-indole (1 g, 92%) as solid.