Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:29]=[CH:28][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:14][C@H:13]2[CH2:25][CH:26]=O)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:30][N:31]([CH3:33])[NH2:32].C(OCC)(=O)C>C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15]([O:17][Si:18]([C:21]([CH3:23])([CH3:22])[CH3:24])([CH3:19])[CH3:20])[CH2:14][C@H:13]2[CH2:25][CH2:26][NH:32][N:31]([CH3:33])[CH3:30])=[O:11])=[CH:28][CH:29]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CC=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: CN(C)N
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(C)NCC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(2S,4R)-1-p-Nitrobenzyloxycarbonyl-2-formylmethyl-4-t-butyldimethylsilyloxypyrrolidine (423 mg) was dissolved in 2 ml of ethanol, and 65 mg of N,N-dimethylhydrazine was added thereto, followed by stirring at room temperature for 15 minutes. To the reaction mixture was added ethyl acetate, and the mixture was washed with water, dried over anhydrous sodium sulfate and distilled to remove the solvent. The residue was purified by silica gel thin layer chromatography to obtain (2R,4R)-1-p-nitrobenzyloxycarbonyl-2-(2-dimethylhydrazinoethyl)-4-t-butyldimethylsilyloxypyrrolidine.
Reaction SMILES: Br[C:2]1[O:3][C:4]2[C:24]([O:25]C(=O)C)=[C:23]([O:29][CH3:30])[CH:22]=[CH:21][C:5]=2[C:6]=1[C:7](=[O:20])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=1.C[Si]([C:35]#[CH:36])(C)C>ClCCl.C(N(CC)CC)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.[Cu]I>[C:35]([C:2]1[O:3][C:4]2[C:24]([OH:25])=[C:23]([O:29][CH3:30])[CH:22]=[CH:21][C:5]=2[C:6]=1[C:7](=[O:20])[C:8]1[CH:9]=[C:10]([O:18][CH3:19])[C:11]([O:16][CH3:17])=[C:12]([O:14][CH3:15])[CH:13]=1)#[CH:36]
Reactant: COc1cc(C(=O)c2c(Br)oc3c(OC(C)=O)c(OC)ccc23)cc(OC)c1OC
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#Cc1oc2c(O)c(OC)ccc2c1C(=O)c1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.2 %

Procedure:
To a stirred solution of 2-Bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxybenzofuran (50 mg, 0.10 mmol) in dichloromethane (1 ml) and triethylamine (0.5 ml) was added Pd(Ph3P)2Cl2 (3.5 mg, 5 mol %) and the reaction vessel was evacuated and backfilled with nitrogen three times. Trimethylsilylacetylene (30 mg, 0.30 mmol) and copper (I) iodide (3 mg, 15 mol %) were added sequentially and the resulting dark mixture was stirred for two hours at room temperature. After this time the reaction was concentrated under vacuum and treated with methanol (1 ml) and potassium hydroxide (30 mg, excess). Stirring was continued for 0.5 hours then the crude mixture was concentrated onto silica and chromatographed (silica gel, gradient elution—2:1 hexanes:ethyl acetate, 1:1 hexanes:ethyl acetate) to afford the product as a tan solid (10 mg, 26%); 1H NMR (CDCl3) δ 7.26 (d, J=8.6 Hz, 1H), 7.20 (s, 2H), 6.98 (d, J=8.6 Hz, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.87 (s, 6H), 3.51 (s, 1H); LRMS (ESI) m/z=383 (M+H+).
Reaction SMILES: O=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([O:15]CC3C=CC=CC=3)=[C:11]([CH2:12][CH2:13][CH3:14])[C:6]=2[O:5][C:4]([CH:23]=[CH:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:3]1>C(O)(=O)C.[Pd]>[OH:15][C:10]1[CH:9]=[CH:8][C:7]2[CH2:2][CH2:3][CH:4]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[O:5][C:6]=2[C:11]=1[CH2:12][CH2:13][CH3:14]
Reactant: CCCc1c(OCc2ccccc2)ccc2c(=O)cc(C=CC(=O)OCC)oc12
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCc1c(O)ccc2c1OC(CCC(=O)OCC)CC2
Yield: 87.2 %

Procedure:
A solution of 2.0 g (5.1 mmole) ethyl 3-(4-oxo-7-phenylmethoxy-8-propyl-4H-1-benzopyran-2-yl)-2-propenoate in 40 ml of acetic acid was hydrogenated at 50 psi and 70° over 5% palladium on carbon catalyst. The catalyst was removed by filtration and the filtrate was evaporated to dryness to give 1.3 g of the title compound as an oil. Structure assignment was supported by nmr and infrared spectra.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[OH:33].CN1C=CN=C1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: Oc1ccccc1Cl
Reactant: CN1CCN(c2cc(N3CCc4ccc(Br)cc4C3)nc(N)n2)CC1
Agent: Cn1ccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CN1CCN(c2cc(N3CCc4ccc(Oc5ccccc5Cl)cc4C3)nc(N)n2)CC1
Temperature: 25 °C

Procedure:
A mixture of 4-(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (20.0 mg, 0.0496 mmol), 2-chlorophenol (0.00765 g, 0.0595 mmol, Aldrich, Cat. No. 185779), 1-methylimidazole (2.04 mg, 0.0248 mmol, Aldrich, Cat. No. M50834), Cuprous monochloride (0.245 mg, 0.00248 mmol, Aldrich, Cat. No. 229628), and potassium carbonate (13.7 mg, 0.0992 mmol) in 1,4-dioxane (0.8 mL) was heated at 140° C. overnight. The reaction mixture was cooled to r.t. and concentrated. Then the reaction mixture was dissolved in MeOH and filtered, the filtration was purified by RP-HPLC (pH=10) to afford the desired compound. LCMS(M+H)+: m/z=451.3.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[C:12]([NH2:19])[CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]=O)[CH:23]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH:19][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:11]=2[N:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:20])[F:21])[CH:4]=2)[CH:18]=[CH:17]3)[CH:23]=1
Reactant: O=Cc1cccnc1
Reactant: Nc1cccc2ccc(-c3cccc(C(F)(F)F)c3)nc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: FC(F)(F)c1cccc(-c2ccc3cccc(NCc4cccnc4)c3n2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.8 %

Procedure:
To a mixture of 2-(3-(trifluoromethyl)phenyl)quinolin-8-amine (200 mg, 0.7 mmol), 3-pyridinecarbaldehyde (150 mg, 1.4 mmol) and acetic acid (84 mg, 1.4 mmol) in methanol (10 mL) was added NaCNBH3 (88 mg, 1.4 mmol) in portions at room temperature, then the reaction was stirred at room temperature for 5 h. The reaction was concentrated in vacuo, the residue was taken up in DCM, The solution was washed with water (1×50 mL), treated with active carbon and Na2SO4, filtered through a silica gel pad, and the pad was washed with CH2Cl2. The organic solutions were combined and concentrated in vacuo, triturated with a mixture of ethyl acetate/pentane and filtered to give N-(pyridin-3-ylmethyl)-2-(3-(trifluoromethyl)phenyl)quinolin-8-amine as a yellow solid (220 mg, yield 83%) MS (ESI) calcd for C22H16F3N3 (m/z): 379.13. found: 380 [M+1].
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([C:14]4[CH:15]=[C:16]5[C:21](=[CH:22][CH:23]=4)[CH2:20][N:19]([CH2:24][CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])[CH2:18][CH2:17]5)=[CH:11][C:10]=3[CH:33]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([C:14]4[CH:15]=[C:16]5[C:21](=[CH:22][CH:23]=4)[CH2:20][N:19]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])[CH2:18][CH2:17]5)=[CH:11][C:10]=3[CH:33]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)CCN1CCc2cc(-c3cc4cc(C5CCCC5)ccc4o3)ccc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCN1CCc2cc(-c3cc4cc(C5CCCC5)ccc4o3)ccc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.1 %

Procedure:
To a stirring solution of tert-butyl 3-(6-(5-cyclopentylbenzofuran-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)propanoate (25 mg, 0.056 mmole) in CH2Cl2 (0.5 ml) was added TFA (0.5 ml). The mixture was stirred at room temperature for 3 hours. Under reduced pressure, solvents and excess of TFA were removed affording a yellow oil which was rinsed with a mixture of CH2Cl2/Hexane (1:4) followed by ether. The solvents were removed under vacuum to give the title compound (19 mg, 90%). 1H NMR (400 MHz, CD3OD) δ 7.82 (m, 2H), 7.47 (s, 1H), 7.40 (d, 1H), 7.30 (d, 1H), 7.20 (d, 1H), 7.19 (s, 1H), 4.54 (br, 2H), 3.69 (br, 2H), 3.60 (dd, 2H), 3.28 (m, 2H), 3.10 (m, 1H), 2.96(dd, 2H), 2.10 (m, 2H), 1.85 (m, 2H), 1.74 (m, 2H), 1.65 (m, 2H). MS (ESI) m/z: Calculated: 389.2; Observed: 390.20 (M++1).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@@H:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[CH:15]=2)[C@@H:11]([NH2:13])[CH3:12])=[CH:5][CH:4]=1.[CH3:22][S:23]([CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=O)(=[O:25])=[O:24]>>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@@H:10]([C:14]2[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=2)[C:20]#[N:21])[C@@H:11]([NH:13][CH:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:26][S:23]([CH3:22])(=[O:24])=[O:25])[CH3:12])=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)CC(=O)c1ccccc1
Reactant: C[C@H](N)[C@@H](Cc1ccc(Cl)cc1)c1cccc(C#N)c1
Agent: Cl
Product: C[C@H](NC(CS(C)(=O)=O)c1ccccc1)[C@@H](Cc1ccc(Cl)cc1)c1cccc(C#N)c1

Procedure:
The title compound was prepared from 3-(4-chlorophenyl)-2(S)(3-cyanophenyl)-1(S)-methyl-propylamine hydrochloride and 2-methanesulfonylacetophenone by the procedure of Example 33 as a mixture of two diastereomers. LC-MS: m/e=467 (M+1), 469 (M+3) (3.05 min and 4.05 min).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[O:10][C:11]([CH3:18])=[CH:12][C:13]=1[S:14](Cl)(=[O:16])=[O:15].[F:19][C:20]1[CH:21]=[CH:22][C:23]([O:35][CH3:36])=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]([NH2:34])[CH3:33])=[CH:28][CH:27]=2)[CH:25]=1>ClCCl>[F:19][C:20]1[CH:21]=[CH:22][C:23]([O:35][CH3:36])=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([C@H:32]([NH:34][S:14]([C:13]3[CH:12]=[C:11]([CH3:18])[O:10][C:9]=3[CH3:8])(=[O:16])=[O:15])[CH3:33])=[CH:28][CH:27]=2)[CH:25]=1
Reactant: COc1ccc(F)cc1-c1ccc(C(C)N)cc1
Reactant: Cc1cc(S(=O)(=O)Cl)c(C)o1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(F)cc1-c1ccc([C@@H](C)NS(=O)(=O)c2cc(C)oc2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.8 %

Procedure:
Triethylamine (41.1 μl, 0.295 mmol) then 2,5-dimethyl-3-furansulfonyl chloride (19.1 mg, 0.0982 mmol) were added to a solution of 1-(5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethylamine (20 mg, 0.082 mmol) in dichloromethane (1 ml) and the resulting solution shaken at room temperature overnight. The reaction mixture was washed with saturated sodium bicarbonate solution (500 μl) and the organic phase separated, dried over anhydrous magnesium sulfate and the solvent evaporated. The crude product was purified by preparatory LCMS. The solvent was evaporated under reduced pressure to give the title compound (3.9 mg, 0.0097 mmol, 11.8%). 1H NMR (400 MHz, CDCl3): δ 7.40, 7.23 (a/b, 4H), 7.05-6.88 (m, 3H), 5.99 (s, 1H), 4.67 (m, 1H), 4.55 (m, 1H), 3.78 (s, 3H), 2.35 (s, 3H), 2.17 (s, 3H), 1.52 (d, 3H) ppm; MS (ESI) m/z: 426 [M+Na]+.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([O:25][CH3:26])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][C:22](O)=[O:23])[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([O:25][CH3:26])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][C:22]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[O:23])[N:20]=2)=[CH:12]3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C1COCCN1
Reactant: COc1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](CC(=O)O)CS3)cc2c1
Product: COc1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](CC(=O)N4CCOCC4)CS3)cc2c1
Yield: 24 %

Procedure:
The compound (83 mg, 0.22 mmol) prepared in Example 48 and morpholine instead of methylamine were reacted according to the same procedure as Example 87 to give the title compound (24 mg, Yield 24%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH2:8][C:9]([CH:11]1[C:27]2([CH3:28])[CH:14]([CH:15]3[CH:24]([CH2:25][CH2:26]2)[C:23]2([CH3:29])[C:18](=[CH:19][C:20](=[O:30])[CH2:21][CH2:22]2)[CH2:17][CH2:16]3)[CH2:13][CH2:12]1)=[O:10].[N-:31]=[N+:32]=[N-:33].[Na+]>CN(C)C=O>[N:31]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH2:8][C:9]([CH:11]1[C:27]2([CH3:28])[CH:14]([CH:15]3[CH:24]([CH2:25][CH2:26]2)[C:23]2([CH3:29])[C:18](=[CH:19][C:20](=[O:30])[CH2:21][CH2:22]2)[CH2:17][CH2:16]3)[CH2:13][CH2:12]1)=[O:10])=[N+:32]=[N-:33]
Reactant: CC12CCC(=O)C=C1CCC1C2CCC2(C)C(C(=O)COCCCCCBr)CCC12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC12CCC(=O)C=C1CCC1C2CCC2(C)C(C(=O)COCCCCCN=[N+]=[N-])CCC12
Temperature: 65 °C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
To a solution of 7 (125 mg, 0.261 mmol) in anhydrous N,N-dimethylformamide (7 mL) was added sodium azide (169 mg, 2.61 mmol). The reaction mixture was heated to 65° C. and stirred overnight. Excess sodium azide was filtered off and the solvent was removed by rotary evaporation. The crude residue was dissolved in ethyl acetate and washed with water three times. The organic layer was dried over sodium sulfate and concentrated followed by flash chromatography in hexanes/ethyl acetate (2:1) to give 9 (78 mg, 68%). 1H NMR (500 MHz, CD3OD) δ 5.61 (d, J=4.9 Hz, 1H), 3.39 (t, J=6.4 Hz, 2H), 3.25-3.17 (m, 4H), 2.60 (t, J=9.1 Hz, 1H), 2.45-2.33 (m, 2H), 2.25-2.15 (m, 2H), 2.12-2.03 (m, 1H), 1.99 (m, 1H), 1.89-1.76 (m, 2H), 1.70-1.29 (m, 15H), 1.29-1.15 (m, 2H), 1.13 (d, J=11.0 Hz, 4H), 1.04-0.87 (m, 2H), 0.60 (s, 3H). 13C NMR (125 MHz, CD3OD) δ 210.81, 202.29, 174.92, 124.24, 78.00, 72.34, 62.71, 59.71, 57.39, 55.16, 52.43, 45.67, 39.99, 39.72, 36.81, 34.72, 33.90, 33.20, 30.15, 29.75, 25.52, 24.46, 24.17, 23.76, 22.15, 17.67, 13.96. ESI-MS m/z [M+Na]+ observed: 464.2, calculated: 464.3.
Reaction SMILES: [N+](=[CH2:3])=[N-].[Cl:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9]>CCOCC>[Cl:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([O:10][CH3:3])=[O:9]
Reactant: C=[N+]=[N-]
Reactant: O=C(O)c1cccc(Cl)c1
Solvent: CCOCC
Product: COC(=O)c1cccc(Cl)c1
Temperature: 0 °C
Yield: 67.8 %

Procedure:
An excess solution of diazomethane in ether was added to an ice-cooled and stirred solution of m-chlorobenzoic acid (8.26 g, 52.8 mmol) in 50 ml of ether. The mixture was concentrated and distilled under reduced pressure to give a colorless transparent oil of methyl m-chlorobenzoate (6.1 g, 35.8 mmol, yield 67.8%, b.p. 116°-121° C./21 mmHg), which was assigned the structure by the following data:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[CH:4](Br)[CH3:5].[F:8][C:9]1[C:10]2[NH:17][CH:16]=[C:15]([I:18])[C:11]=2[CH:12]=[N:13][CH:14]=1>>[F:8][C:9]1[C:10]2[N:17]([CH:4]([CH3:5])[C:3]([O:2][CH3:1])=[O:7])[CH:16]=[C:15]([I:18])[C:11]=2[CH:12]=[N:13][CH:14]=1
Reactant: COC(=O)C(C)Br
Reactant: Fc1cncc2c(I)c[nH]c12
Product: COC(=O)C(C)n1cc(I)c2cncc(F)c21

Procedure:
Prepared according to the method described for Preparation 45 using 2-bromo-propionic acid methyl ester and 7-fluoro-3-iodo-pyrrolo[3,2-c]pyridine (Preparation 61). Purified using silica gel column chromatography eluting with 0-5% MeOH in DCM.
Reaction SMILES: [NH2:1][C@@H:2]([CH:52]1[CH2:57][CH2:56][S:55][CH2:54][CH2:53]1)[C:3]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[C:23]4[C:28](=[CH:29][CH:30]=3)[CH:27]=[C:26]([C:31]3[NH:35][C:34]([C@@H:36]5[CH2:40][CH2:39][CH2:38][N:37]5[C:41](=[O:51])[C@@H:42]([NH:46][C:47](=[O:50])[O:48][CH3:49])[CH:43]([CH3:45])[CH3:44])=[N:33][CH:32]=3)[CH:25]=[CH:24]4)=[CH:17][CH:16]=2)=[CH:13][N:14]=1)=[O:4].C([O-])([O-])=O.[Na+].[Na+].Cl[C:65]([O:67][CH3:68])=[O:66]>O>[CH3:68][O:67][C:65](=[O:66])[NH:1][C@@H:2]([CH:52]1[CH2:53][CH2:54][S:55][CH2:56][CH2:57]1)[C:3]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[C:26]([C:31]5[NH:35][C:34]([C@@H:36]6[CH2:40][CH2:39][CH2:38][N:37]6[C:41](=[O:51])[C@@H:42]([NH:46][C:47]([O:48][CH3:49])=[O:50])[CH:43]([CH3:44])[CH3:45])=[N:33][CH:32]=5)[CH:27]=4)[CH:22]=3)=[CH:17][CH:16]=2)=[CH:13][N:14]=1)=[O:4]
Reactant: COC(=O)Cl
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc([C@@H]6CCCN6C(=O)[C@@H](N)C6CCSCC6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc([C@@H]6CCCN6C(=O)[C@@H](NC(=O)OC)C6CCSCC6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 39.4 %

Procedure:
To methyl (S)-1-((S)-2-(5-(6-(4-(2-((S)-1-((S)-2-amino-2-(tetrahydro-2H-thiopyran-4-yl)acetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (30 mg, 0.06 mmol) in water (0.3 mL) was add Na2CO3 (13 L, 0.09 mmol). The reaction mixture was cooled to 0° C. and methyl chloroformate (0.12 mmol) was added and then stirred for 2 hours. The resulting mixture was then directly purified on reverse phase prep. HPLC to afford title compound as white solid (20 mg, 65%). MS (ESI) m/z 848 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[N:9]=[N:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=2)[CH2:3][CH2:2]1.[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>ClC(Cl)C>[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:1]2[CH2:6][CH2:5][CH:4]([NH:7][C:8]3[N:9]=[N:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=3)[CH2:3][CH2:2]2)=[CH:21][CH:20]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: FC(F)(F)c1ccc(NC2CCNCC2)nn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: CC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(CN2CCC(Nc3ccc(C(F)(F)F)nn3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.9 %

Procedure:
A suspension of D2 (1.7 g, 5.32 mmol), 4-fluorobenzaldehyde (0.66 g, 5.32 mmol), di-isopropylethylamine (1.37 g, 10.6 mmol) and triacetoxyborohydride on resin (Argonaut Technologies; 2.2 mmol/g; 3 eq.) in dichloroethane (10 ml) was stirred at room temperature for 18 h. After this period, the reaction mixture was filtered and the solvents evaporated in vacuo. The crude product was purified by chromatography (silica; 2%-6% ammonia in methanol (7 M)/dichloromethane) to give E2 (0.79 g, 42%). C17H18F4N4 requires 354; Found 355 (MH+); mp: 163.3-165.3° C. 1H NMR (DMSO-D6) δ 1.48 (q, J=10.8 Hz, 2H), 1.95 (br.d, J=12.5 Hz, 2H), 2.09 (t, J=11.1 Hz, 2H), 2.78 (br.d, J=11.3 Hz, 2H), 3.47 (s, 2H), 3.89 (br.s, 1H), 6.94 (d, J=9.4 Hz, 1H), 7.15 (t, J=8.8 Hz, 2H), 7.34 (dd, J=8.3, 5.7 Hz, 2H), 7.53 (br.d, J=7.3 Hz, 1H), 7.63 (d, J=9.4 Hz, 1H)
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:4]=[C:5]([CH:13]=[C:14]([N:18]([CH3:20])[CH3:19])[C:15]=1[O:16][CH3:17])[CH:6](O)CS(C)(=O)=O.C[O-].[Na+].[NH:25]([CH2:32][CH2:33][C:34]#[N:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CS(C)=O>[NH:25]([CH:32]=[C:33]([CH2:6][C:5]1[CH:13]=[C:14]([N:18]([CH3:19])[CH3:20])[C:15]([O:16][CH3:17])=[C:3]([N:2]([CH3:21])[CH3:1])[CH:4]=1)[C:34]#[N:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1c(N(C)C)cc(C(O)CS(C)(=O)=O)cc1N(C)C
Reactant: N#CCCNc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1c(N(C)C)cc(CC(C#N)=CNc2ccccc2)cc1N(C)C

Procedure:
A mixture of 9.76 g. of 3,5-bis(dimethylamino)-4-methoxy-α-[(methylsulfonyl)methyl]benzyl alcohol, 1.8 g. of sodium methylate and 4.8 g. of β-anilinopropionitrile in 20 ml. of dimethylsulfoxide was stirred with the exclusion of moisture for 5 hours at 50° C. The mixture was poured into 250 ml. of water, the precipitated oil extracted with ethyl acetate, the ethyl acetate solution dried over sodium sulfate and evaporated. By recrystallization of the residue from high-boiling petroleum ether, there was obtained α-(anilinomethylene)-3,5-bis(dimethylamino)-4-methoxyhydrocinnamonitrile, having a melting point of 103°-105° C.
Reaction SMILES: [CH3:1][NH2:2].[C:3]1(=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C:5](=[O:13])[O:4]1>C1COCC1>[CH3:1][NH:2][C:5](=[O:13])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=1[C:3]([OH:4])=[O:14]
Reactant: O=C1Cc2ccccc2C(=O)O1
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)Cc1ccccc1C(=O)O
Temperature: 25 °C

Procedure:
To 20 ml of 2.0 M methylamine in THF is added 1.62 g (10 mmol) of isochroman-1,3-dione at 0° C. The mixture is stirred at 25° C. for 45 m and concentrated to dryness. The residue is stirred in 40 ml of 0.3 N HCl. The white solid is filtered off, washed with water, and dried to give 1.74 g (90%); 1H NMR (DMSO-d6) δ 7.80 (s, 1H), 7.81 (s, 1H), 7.40 (m, 3H), 3.83 (s, 2H), 2.57 (s, 3H); MS (ES−) m/z 192.1 (M−H)−1: Analysis for C10H11NO3: Calcd: C, 62.17; H, 5.74; N, 7.25. Found: C, 62.16; H, 5.81; N, 7.24
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][N:3]=1.C1C(=O)N([Br:21])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:21][CH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][N:3]=1
Reactant: Cc1cnc(-c2ccccc2)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cnc(-c2ccccc2)cn1

Procedure:
Synthesized using compound 71b (724 mg, 4.25 mmol), NBS (832 mg, 4.68 mmol) and DBPO (52 mg, 0.21 mmol) in carbon tetrachloride according to Method A. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (3:1) as eluent. Product was used directly in the next step without further characterization. Yellow solid. Yield: 571 mg, 54%. (ESI): m/z=250.80 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[O:6].Br[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][C:5]([O:4][CH3:3])=[O:6])=[C:9]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:10]=1
Reactant: BrCCc1ccccc1
Reactant: COC(=O)Cc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(Cl)cc1CCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.4 %

Procedure:
To a solution of 4.35 g of 60% sodium hydride in 50 ml of DMF was added dropwise 20.0 g of methyl 4-chlorophenyl acetate in 25 ml of DMF. Once the evolution had ceased a mixture of 20.0 g of 2-bromoethyl benzene in 25 m of DMF was added and the reaction was stirred at room temPerature overnight. The reaction was then partitioned between 400 ml of ether and 200 ml of H2O. The ether extracts were washed with H2O, dried over magnesium sulfate, filtered and concentrated to 32.9 g of a yellow oil. Chromatography on silica gel with 5% ethyl acetate in hexane afforded 12.6 g of the title compound as a clear, colorless oil.
Reaction SMILES: C1C2C(COC(=O)[NH:17][CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:52])[C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30]4[N:31]=[CH:32][C:33]5[N:39]([CH3:40])[C:38](=[O:41])[C:37]([F:43])([F:42])[CH2:36][N:35]([CH:44]6[CH2:48][CH2:47][CH2:46][CH2:45]6)[C:34]=5[N:49]=4)=[C:25]([O:50][CH3:51])[CH:24]=3)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>ClCCl>[NH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:52])[C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]2[N:31]=[CH:32][C:33]3[N:39]([CH3:40])[C:38](=[O:41])[C:37]([F:42])([F:43])[CH2:36][N:35]([CH:44]4[CH2:48][CH2:47][CH2:46][CH2:45]4)[C:34]=3[N:49]=2)=[C:25]([O:50][CH3:51])[CH:24]=1
Reactant: COc1cc(C(=O)NCCCNC(=O)OCC2c3ccccc3-c3ccccc32)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Solvent: C1CCNCC1
Solvent: ClCCl
Product: COc1cc(C(=O)NCCCN)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.5 %

Procedure:
To the suspension 0.12 g (0.16 mmole) of {3-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoylamino]-propyl}-carbamic acid 9H-fluoren-9-ylmethyl ester (I-73) in 2 mL of dichloromethane was added 0.4 mL of piperidine. The mixture was stirred at room temperature for 1 hour, then volatiles were removed under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-0:100) gave 0.027 g of N-(3-amino-propyl)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzamide (I-74) as a white solid.