Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:45]=[CH:44][CH:43]=[CH:42][C:7]=1[C:8]([NH:10][C:11]1[CH:41]=[CH:40][C:14]([C:15]([N:17]([CH3:39])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)=[O:31])=[O:16])=[CH:13][CH:12]=1)=[O:9].C(N(CC)CC)C.[C:53](OC(=O)C)(=[O:55])[CH3:54]>ClCCl>[C:53]([NH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:45]=[CH:44][CH:43]=[CH:42][C:7]=1[C:8]([NH:10][C:11]1[CH:41]=[CH:40][C:14]([C:15]([N:17]([CH3:39])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([N:32]2[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]2)=[O:31])=[O:16])=[CH:13][CH:12]=1)=[O:9])(=[O:55])[CH3:54]
Reactant: CN1CCN(C(=O)CCCCCOc2ccccc2N(C)C(=O)c2ccc(NC(=O)c3ccccc3OCCCN)cc2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCCOc1ccccc1C(=O)Nc1ccc(C(=O)N(C)c2ccccc2OCCCCCC(=O)N2CCN(C)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.1 %

Procedure:
To an ice bath cooled solution of 4-[2-[(3-aminoprop-1-yl)oxy]benzoyl]amino-N-methyl-N-[2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (200 mg) in dichloromethane (10 ml) were added triethylamine (36.2 mg) and acetic anhydride (36.5 mg) and the mixture was stirred at ambient temperature for 4 hours. The reaction mixture was washed successively with water (10 ml), saturated aqueous sodium hydrogen carbonate solution (10 ml) and brine (10 ml), and dried over magnesium sulfate. The solvent was evaporated to give 4-[2-[(3-acetylaminoprop-1-yl)oxy]benzoyl]amino-N-methyl-N-[2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (201 mg) as a colorless amorphous.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH2:9][CH2:10][CH:11]([OH:17])[C:12]1[S:13][CH:14]=[CH:15][N:16]=1)([CH3:4])[CH3:3].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1O>>[CH3:4][C:2]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH2:9][CH2:10][CH:11]([O:17][C:21]1[CH:22]=[C:23]([C:26]([F:28])([F:29])[F:27])[CH:24]=[CH:25][C:20]=1[Cl:19])[C:12]1[S:13][CH:14]=[CH:15][N:16]=1)([CH3:1])[CH3:3]
Reactant: Oc1cc(C(F)(F)F)ccc1Cl
Reactant: CC(C)(C)OC(=O)NCCCC(O)c1nccs1
Product: CC(C)(C)OC(=O)NCCCC(Oc1cc(C(F)(F)F)ccc1Cl)c1nccs1

Procedure:
The subtitle compound was prepared according to the method of Example 19 step (b) using the product of Example 43 step (c) and 2-chloro-5-trifluoromethylphenol.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:3]1.[CH:23]([C:25]([CH3:27])=[O:26])=[CH2:24].C(Cl)(Cl)Cl>C(OCC)(=O)C>[CH3:9][C:6]1([CH3:8])[CH2:7][C:2]([CH3:22])([CH3:1])[CH2:3][CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[CH2:17][CH2:18][N:19]([CH2:24][CH2:23][C:25](=[O:26])[CH3:27])[CH2:20][CH2:21]2)[CH2:5]1
Reactant: CC1(C)CC(c2ccccc2N2CCNCC2)CC(C)(C)C1
Reactant: C=CC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(=O)CCN1CCN(c2ccccc2C2CC(C)(C)CC(C)(C)C2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
A mixture of 1-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (160 mg, 0.532 mmol) produced in Example (8b), methyl vinyl ketone (0.058 mL, 0.692 mmol) and chloroform (0.7 mL) was stirred for 21 hours and 30 minutes at an external temperature of room temperature. The reaction mixture was diluted with ethyl acetate and then washed with aqueous solution of sodium hydrogencarbonate. The separated organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/heptane) to give 155 mg of the title compound as a light brown oil.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[NH:26])[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(C1C=C(C[F:38])C=CC=1CBr)#N>>[CH:1]1([CH2:7][CH:8]([N:17]2[CH2:25][C:24]3[C:19](=[CH:20][C:21]([F:38])=[CH:22][CH:23]=3)[C:18]2=[NH:26])[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1cc(CF)ccc1CBr
Reactant: N=C1c2ccccc2CN1C(CC1CCCCC1)C(=O)Nc1nccs1
Product: N=C1c2cc(F)ccc2CN1C(CC1CCCCC1)C(=O)Nc1nccs1

Procedure:
The title compound was synthesized according to the method described in connection with Compound 11, except that 2-cyano-4-fluoromethylbenzyl bromide was used. 1H NMR (400 MHz, MeOH-d4) δ: 7.99 (dd, J=2.4, 8.0 Hz, 1H), 7.76-7.82 (m, 1H), 7.58-7.66 (m, 1H), 7.44 (d, J=0.6 Hz, 1H), 7.13 (d, J=0.6 Hz, 1H), 5.11-5.21 (m, 2H), 4.96 (d, J=20.0 Hz, 1H), 2.03-2.24 (m, 2H), 1.70-1.90 (m, 5H), 1.0-138 (m, 6H). [M+H] calc'd for C20H23FN4OS, 387; found, 387.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:22]=[CH:21][C:20]([C:23]([OH:25])=O)=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[N:18]2.[CH2:26]([N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([NH2:41])=[N:39][CH:40]=2)[CH2:30][CH2:29]1)[CH3:27]>C(Cl)Cl.CO>[CH2:26]([N:28]1[CH2:29][CH2:30][N:31]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([NH:41][C:23]([C:20]3[CH:21]=[CH:22][C:13]([C:3]4[C:4]([Cl:12])=[C:5]([O:10][CH3:11])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=4[Cl:1])=[C:14]4[C:19]=3[N:18]=[CH:17][CH:16]=[CH:15]4)=[O:25])=[N:39][CH:40]=2)[CH2:32][CH2:33]1)[CH3:27]
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)O)c3ncccc23)c1Cl
Reactant: CCN1CCN(Cc2ccc(N)nc2)CC1
Solvent: CO
Solvent: ClCCl
Product: CCN1CCN(Cc2ccc(NC(=O)c3ccc(-c4c(Cl)c(OC)cc(OC)c4Cl)c4cccnc34)nc2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 5-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid (Step 159.1), 5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Step 26.1; purified by silica gel column chromatography), and stirring the reaction mixture for 20 h at rt. Title compound: ESI-MS: 580.1 [M+H]+; tR=3.80 min (System 1); TLC: Rf=0.27 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:19][C:9]2=[CH:10][N:11]=[C:12]([O:14][CH2:15][CH2:16][O:17][CH3:18])[CH:13]=[C:8]2[CH:7]=1)=[O:5])C.[Li+].[OH-]>C1COCC1.CO>[CH3:18][O:17][CH2:16][CH2:15][O:14][C:12]1[CH:13]=[C:8]2[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[NH:19][C:9]2=[CH:10][N:11]=1
Reactant: CCOC(=O)c1cc2cc(OCCOC)ncc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COCCOc1cc2cc(C(=O)O)[nH]c2cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1 g (3.784 mmol) 5-(2-Methoxy-ethoxy)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester (example 10 (iii)) in 50 mL THF and 25 mL MeOH 15.14 mL of a 1M LiOH solution were added. The mixture was stirred for 2 h at room temperature. The organic solvents were removed in vacuo, the solution acidified and concentrated in vacuo. The residue was purified by flash chromatography over silica gel using H2Cl2/MeOH/HOAc/H2O=90/10/1/1 as eluent. The product fractions were combined, concentrated in vacuo and lyophilized.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[C:4]([Cl:10])[C:3]=1[OH:11].[C:12](=O)([O-])[O-:13].[K+].[K+].C(Cl)(Cl)=O>C1(C)C=CC=CC=1>[Cl:8][C:6]1[C:5]([Cl:9])=[C:4]([Cl:10])[C:3]2[O:11][C:12](=[O:13])[NH:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Cl)c(Cl)c(Cl)c1O
Reactant: O=C([O-])[O-]
Agent: O=C(Cl)Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=c1[nH]c2cc(Cl)c(Cl)c(Cl)c2o1
Yield: 95 %

Procedure:
21.3 g of 2-amino-4,5,6-trichlorophenol, 27.6 g of anhydrous potassium carbonate and 150 ml of toluene were placed in a 300 ml round-bottom flask and 9.9 g of phosgen was slowly added to the mixture with stirring under cooling an ice-water bath. The resulting mixture was heated at reflux temperature for one hour and the reaction solution was then cooled and transferred to a 500 ml separating funnel. 150 ml of tetrahydrofuran and 150 ml of water were added into the funnel and the organic layer was separated, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to remove the solvent, leaving yellowish white crystals. The crystals were recrystallized from a mixed solvent of methanol and acetone to give 22.7 g of 5,6,7-trichlorobenzoxazolone as white crystals having a melting point of 253°-254° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](I)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=1)[CH:9]=2)=[O:4].[C:28]([Cu])#[N:29].C(Cl)Cl>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:28]#[N:29])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=1)[CH:9]=2)=[O:4]
Reactant: N#C[Cu]
Reactant: COC(=O)c1nc(I)c2cc(Oc3ccc4ccccc4c3)ccc2c1O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1nc(C#N)c2cc(Oc3ccc4ccccc4c3)ccc2c1O
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
4-Hydroxy-1-iodo-7-(naphthalen-2-yloxy)-isoquinoline-3-carboxylic acid methyl ester (130 mg, 0.28 mmol) and CuCN (49 mg, 0.55 mmol) were suspended in DMF (1.1 mL). The resulting mixture was heated at 120° C. for 7 minutes and then cooled to room temperature. The reaction crude was poured into CH2Cl2 (30 mL) and stirred vigorously for 10 minutes at room temperature. The resulting suspension was filtered through a pad of celite and the filtrate was washed with H2O and brine sequentially. The organic layer was dried over MgSO4, concentrated, and purified by flash chromatography (0-50% EtOAc/hexanes) to give the title compound in 75 mg. MS: (−) m/z 369.24 (M−1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([OH:10])=[N:2]1.[CH:11]([N:14]1C(=O)O[C:17](=[O:18])[C:16]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:15]12)([CH3:13])[CH3:12]>>[CH:11]([NH:14][C:15]1[CH:25]=[CH:24][CH:23]=[CH:22][C:16]=1[C:17]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([OH:10])=[N:2]1)=[O:18])([CH3:13])[CH3:12]
Reactant: CC(C)n1c(=O)oc(=O)c2ccccc21
Reactant: Oc1n[nH]c2ccccc12
Product: CC(C)Nc1ccccc1C(=O)n1nc(O)c2ccccc21
Yield: 71.3 %

Procedure:
1H-Indazol-3-ol was reacted with N-isopropylisatoic anhydride according to the general procedure A above and afforded the desired amine as a yellow solid in 71.3% yield; m.p. 190°-192° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:12]=[CH:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[CH:8]=[C:7]([OH:17])[C:6]=2[CH:18]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(OCC)C>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:12]=[CH:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[CH2:8][C:7](=[O:17])[C:6]=2[CH:18]=1
Reactant: OC1=Cc2ccccc2C=Cc2ccc(Br)cc21
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=C1Cc2ccccc2C=Cc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 93.3 %

Procedure:
To a solution of 3-bromo-5-hydroxy-dibenzo[a,e]cyclooctene (0.75 g) in dry dichloromethane (60 ml) was added pyridinium dichromate (2.1 g) and crushed 4 A molecular sieves (1.3 g). After stirring at room temperature for 14 h, diethyl ether (150 ml) Was added and the reaction mixture was filtered through a plug of celite. The solvent was removed and the residue purified by chromatography on flash silica with 5% ethyl acetate in hexane as eluent to give, as a colorless solid, the title compound (0.7 g). δ(360 MHz, CDCl3) 4.04 (2H, s, CH2 --C=O), 6.95 (1H, d, J=12.8 Hz, CHA =CHB), 7.09 (1H, d, J=12.8 Hz, CHA =CHB), 7.22-7.59 (6H, m, ArH), 8.36 (1H, d, J=2.2 Hz, C(O)--C=CH--CBr).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[CH:4]=1.[CH2:10]([O:12][P:13]([O:17]CC)[O:14][CH2:15][CH3:16])[CH3:11]>>[F:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH2:2][P:13](=[O:17])([O:14][CH2:15][CH3:16])[O:12][CH2:10][CH3:11]
Reactant: Fc1cccc(CBr)c1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1cccc(F)c1)OCC
Temperature: 150 °C
Reaction time: 2 h

Procedure:
A flask was charged with 1-(bromomethyl)-3-fluorobenzene (7.5 mL, 61.1 mmol) and treated with triethylphosphite (21.39 mL, 122 mmol) dropwise with stirring. Upon completion of the addition, the reaction was fitted with a reflux condensor (no cooling) and a slow stream of nitrogen was passed over the reaction mixture. The reaction was slowly warmed to 150° C. and held there for 2 h. The reaction was cooled to room temperature and concentrated under high vacuum to remove most of the excess triethylphosphite. The resulting residue was purified by column chromatography (50%-->100% EtOAc/Hex) to give 15.13 g (quant.) as a colorless oil. 1H-NMR (CDCl3, 500 MHz) δ 7.29 (m, 1H), 7.10 (m, 1H), 7.05 (m, 1H), 6.97 (m, 1H), 4.06 (m, 4H), 3.16 (d, J=21.7, 2H), 1.28 (t, J=7.0, 6H). 13C-NMR (CDCl3, 126 MHz) δ 162.85 (dd, J=246, 3.8), 134.2 (t, J=8.6), 130.0 (dd, J=7.7, 2.9), 125.6 (dd, J=6.7, 2.9), 116.9 (dd, J=22, 6.7, 114.0 (dd, J=21, 2.9), 62.3 (d, J=6.7), 33.7 (dd, J=138, 1.9, 16.5 (d, J=5.8).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:12]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:13](=[O:20])[C@H:14]([CH2:16][C:17]([OH:19])=O)[CH2:15][C:4]=2[CH:3]=1.[NH:26]1[C:30]2([CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[C:29](=[O:36])[NH:28][C:27]1=[O:37].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:12]([CH2:21][C:22]([F:24])([F:23])[F:25])[C:13](=[O:20])[C@H:14]([CH2:16][C:17]([N:33]3[CH2:32][CH2:31][C:30]4([NH:26][C:27](=[O:37])[NH:28][C:29]4=[O:36])[CH2:35][CH2:34]3)=[O:19])[CH2:15][C:4]=2[CH:3]=1
Reactant: O=C1NC(=O)C2(CCNCC2)N1
Reactant: O=C(O)C[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(CC(F)(F)F)C1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1NC(=O)C2(CCN(C(=O)C[C@@H]3Cc4cc(Cl)c5[nH]ncc5c4CN(CC(F)(F)F)C3=O)CC2)N1
Reaction time: 2 h
Yield: 45.7 %

Procedure:
To a solution of (S)-2-(4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetic acid (50 mg, 0.133 mmol) in DMF (2.0 mL) were added 1,3,8-triazaspiro[4.5]decane-2,4-dione (34 mg, 0.2 mmol) followed by 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (47 mg, 0.15 mmol) and triethylamine (1.0 mL). After 2 h, the solvent was removed under reduced pressure and the crude product was purified by PrepHPLC to give (S)-8-(2-(4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione (32 mg) in 46% yield. MS (ESI) 527 (M+H); Rf=1.66.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[O:9])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[OH:9])=[CH:4][CH:3]=1
Reactant: COc1ccccc1C(=O)c1ccc(N)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1C(O)c1ccc(N)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (6-amino-pyridin-3-yl)-(2-methoxy-phenyl)-methanone (14 g, 61.4 mol) in CH3OH (150 mL) was added NaBH4 (3.48 g, 92.1 mmol) portion-wise at 0° C. After the addition was completed, the reaction was warmed to room temperature and stirred at room temperature for 1 hr. The solvent was removed in vacuo and water (100 mL) was added to the residue. The mixture was extracted with dichloromethane (100 mL×3). The combined organic layers were washed with saturated solution of NaHCO3 and brine, dried over Na2SO4, filtered and concentrated in vacuo to give a crude product that was used directly in the next step with no further purification.
Reaction SMILES: Cl[C:2]1[C:3]([CH2:14][C:15]2[N:16]=[CH:17][NH:18][CH:19]=2)=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1>CO.[Pd]>[C:4]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=[CH:2][C:3]=1[CH2:14][C:15]1[N:16]=[CH:17][NH:18][CH:19]=1
Reactant: Clc1cccc(-c2ccccc2)c1Cc1c[nH]cn1
Agent: [Pd]
Solvent: CO
Product: c1ccc(-c2ccccc2Cc2c[nH]cn2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.2 %

Procedure:
To a stirred solution of 50 mg (0.19 mmol) 4-(3-chloro-biphenyl-2-ylmethyl)-1H-imidazole in 40 ml methanol was added 40 mg of 10% palladium on charcoal and the mixture was then stirred for 16 h at room temperature under hydrogen at 0.6 bar excess pressure. The mixture was then filtered and the filtrate concentrated in vacuo to afford 25 mg (57%) of the title compound as a white crystalline solid. MS (ISP): 235.1 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([CH:24]=O)[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.[CH3:28][NH:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C([BH3-])#N.[Na+].C(O)(=O)C>CCO>[CH2:30]([N:29]([CH2:24][CH:21]1[CH2:22][CH2:23][N:18]([C:16]([C:8]2[N:7]([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([F:1])=[CH:3][CH:4]=3)[C:15]3[C:10]([CH:9]=2)=[CH:11][CH:12]=[CH:13][CH:14]=3)=[O:17])[CH2:19][CH2:20]1)[CH3:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CNCc1ccccc1
Reactant: O=CC1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CN(Cc1ccccc1)CC1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(F)cc2)CC1
Reaction time: 14 h

Procedure:
1-(1-(4-fluorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carbaldehyde (86 mg, 0.236 mmol) was dissolved in EtOH (5 mL) and N-methylbenzylamine (0.027 mL, 0.283 mmol), sodium cyanoborohydride (30 mg, 0.472 mmol), and a catalytic drop of glacial acetic acid were added. Stirring was permitted for 14 h, at which time the solvent was removed in vacuo, the residue was taken up in EtOAc. The organic phase was washed with 10% aq. sodium carbonate, dried over magnesium sulfate, and concentrated. Purification was accomplished via silica gel flash chromatography (30 g silica gel, 100% EtOAc.) The title compound was obtained as an oil. (Yield: 23 mg, 0.049 mmol, 20%) 1H NMR (400 MHz, CDCl3) 7.62, 7.37-7.23, 7.14, 7.08-7.02, 6.82, 6.57, 5.45, 4.60, 4.04, 3.44, 2.75, 2.16, 2.10, 1.83-1.59, 0.91, 0.51
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][C@H:34]5[CH2:38][CH2:37][NH:36][CH2:35]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.FC(F)(F)S(O[CH2:54][CH:55]([F:57])[F:56])(=O)=O>C(Cl)Cl>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][C@H:34]5[CH2:38][CH2:37][N:36]([CH2:54][CH:55]([F:57])[F:56])[CH2:35]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1O[C@H]1CCNC1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1O[C@H]1CCN(CC(F)F)C1
Temperature: 40 °C
Reaction time: 1 h
Yield: 44.3 %

Procedure:
To a solution of (S)-1-(5-tert-butylisoxazol-3-yl)-3-{3-[6-methoxy-7-(pyrrolidin-3-yloxy)quinazolin-4-yloxy]phenyl}urea (0.198 g, 0.38 mmol) and N,N-diisopropylethylamine (0.5 mL) in CH2Cl2 (10 mL) was added 2,2-difluoroethyl trifluoromethanesulfonate (0.128 g. 0.6 mmol) and it was stirred at 40° C. for 1 hour. It was quenched with saturated NaHCO3 and extracted with CH2Cl2. Extracts were dried over MgSO4 and concentrated under reduced pressure. It was purified by silica gel chromatography with 70-85% EtOAc/hexane as eluants to afford (S)-1-(5-tert-Butylisoxazol-3-yl)-3-(3-{7-[1-(2,2-difluoroethyl)pyrrolidin-3-yloxy]-6-methoxyquinazolin-4-yloxy}phenyl)urea as solid (0.098 g, 44%). 1H NMR (300 MHz, CDCl3) δ 9.4 (s, 1H), 8.62 (s, 1H), 7.81 (s, 1H), 7.65 (t, 1H), 7.54 (s, 1H), 7.40 (t, 1H), 7.33 (m, 1H), 7.19 (s, 1H), 7.00 (d, 1H), 5.93 (tt, 1H), 5.87 (s, 1H), 5.05 (m, 1H), 4.03 (s, 3H), 3.20 (m, 1H), 3.89-3.09 (m, 4H), 2.8 (m, 1H), 2.5 (m, 1H), 2.15 (m, 1H), 1.33 (s, 9H); LC-MS (ESI) m/z 583 (M+1-1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](O)=O)=[CH:5][CH:4]=1.[NH2:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=2)=[CH:5][CH:4]=1
Reactant: Cc1ccnc(N)c1
Reactant: COc1ccc(CC(=O)O)cc1
Product: COc1ccc(CCNc2cc(C)ccn2)cc1

Procedure:
Similarly prepared from 4-methoxyphenyl acetic acid and 2-amino-4-picoline.
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[C:6](=[O:31])[N:5]([CH3:32])[C:4]=2[N:3]=1.[CH2:33]([NH2:36])[CH2:34][CH3:35]>C(O)C.O>[Si:24]([O:23][CH2:22][CH2:21][CH2:20][N:7]1[C:8](=[O:19])[C:9]2[N:10]([CH2:11][C:12]3[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=3)[C:2]([NH:36][CH2:33][CH2:34][CH3:35])=[N:3][C:4]=2[N:5]([CH3:32])[C:6]1=[O:31])([C:27]([CH3:29])([CH3:28])[CH3:30])([CH3:25])[CH3:26]
Reactant: CCCN
Reactant: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Solvent: O
Solvent: CCO
Product: CCCNc1nc2c(c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)n2C)n1Cc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 62.7 %

Procedure:
Step 1 8-Bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.25 g, 0.46 mmol, intermediate 77) and propan-1-amine (1.44 mL, 9.2 mmol) were combined in ethanol (5 mL) and heated at reflux for 24 h. The reaction was cooled to room temperature, diluted with water (75 mL) and extracted with ethyl acetate (3×75 mL). The combined organic extracts were dried with magnesium sulfate, filtered and the solvent evaporated under reduced pressure to yield a light golden oil. The oil was purified using a 25 g silica gel column eluted with 20% ethyl acetate/hexanes to give 1-(3-((tert-butyldimethylsilyl)oxy)propyl-7-(4-chlorobenzyl)-3-methyl-8-(propylamino)-1H-purine-2,6(3H,7H)-dione (0.15 g, 63% yield) as a white solid. LCMS retention time=5.013 min and 97% purity, LCMS MH+ 520.
Reaction SMILES: [CH2:1]([CH:3]1[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[O:14])[N:6]([CH3:15])[C:5]2[CH:16]=[CH:17][C:18](OS(C(F)(F)F)(=O)=O)=[N:19][C:4]1=2)[CH3:2].C([Sn](CCCC)(CCCC)[C:33]1[CH:34]=[N:35][NH:36][CH:37]=1)CCC.[Cl-].[Li+]>CN(C)C=O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([CH:3]1[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[O:14])[N:6]([CH3:15])[C:5]2[CH:16]=[CH:17][C:18]([C:33]3[CH:34]=[N:35][NH:36][CH:37]=3)=[N:19][C:4]1=2)[CH3:2]
Reactant: CCC1c2ncccc2C(=O)N(C)c2ccc(OS(=O)(=O)C(F)(F)F)nc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn[nH]c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC1c2ncccc2C(=O)N(C)c2ccc(-c3cn[nH]c3)nc21
Temperature: 120 °C
Yield: 15 %

Procedure:
A mixture of 5,11-dihydro-11-ethyl-2-trifluoromethanesulfonyloxy-5-methyl-dipyrido[3,2-b:2',3'-e]azepine-6-one (0.084 g), 4-tributylstannylpyrazole (0.096 g), lithium chloride (0.052 g) and Pd(Ph3P)2Cl2 (0.009 g) in dimethylformamide (1 mL) was heated at 120° C. in a sealed tube 16 hours. The mixture was diluted with ethyl acetate, washed with water, dried, filtered and evaporated. Chromatography of the residue over silica gel (ethyl acetate/hexane) gave 5,11-dihydro-11-ethyl-2-(4-pyrazolyl)-5-methyl-dipyrido[3,2-b:2',3'-e]azepine-6-one (0.010 g).