Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]2[O:16][C:13]([CH3:15])([CH3:14])[C:10]([CH3:12])([CH3:11])[O:9]2)=[CH:4][C:3]=1[O:17][CH3:18].[C:19]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:20]=1.C(O)C.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.CCOC(C)=O>[CH2:19]([O:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]2[O:9][C:10]([CH3:12])([CH3:11])[C:13]([CH3:14])([CH3:15])[O:16]2)=[CH:4][C:3]=1[O:17][CH3:18])[CH3:20]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1OC
Reaction time: 17.5 h

Procedure:
To a mixture of 4-hydroxy-3-methoxyphenylboronic acid pinacol ester (Aldrich, Buchs, Switzerland, 200 mg, 0.800 mmol), triphenylphosphine (315 mg, 1.200 mmol) and ethanol (0.056 ml, 0.960 mmol) in THF (4 ml) under Argon was added dropwise diisopropyl azodicarboxylate (0.253 ml, 1.20 mmol). The RM was stirred at it for 17.5 h. Then the RM was diluted with EtOAc and the organic layer was washed with brine (2×), before being dried over Na2SO4, filtered and evaporated. The residue was absorbed on silica gel and purified by MPLC (hexane/EtOAc 0 to 30%). The fractions containing product were together evaporated to give the title compound as a white solid. (HPLC: tR 3.58 min (Method A); M+H=279 MS-ES)
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12][C:7]=3[CH:8]=2)[NH:3]1.CC(C)([O-])C.[K+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>CN(C=O)C.C(OCC)(=O)C>[CH2:30]([N:3]1[C:4]2[C:9](=[CH:8][C:7]3[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16][C:6]=3[CH:5]=2)[CH2:10][CH2:11][C:2]1=[O:1])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2cc3c(cc2CC1)NC(=O)CC3
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2cc3c(cc2CC1)N(Cc1ccccc1)C(=O)CC3
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 600 mg of t-butyl 2-oxo-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate in 9 ml DMF were added 426 mg of potassium t-butoxide and 451 μl of benzyl bromide in an ice-bath, followed by stirring at room temperature for 3 hours. Water and ethyl acetate were added thereto, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 644 mg of t-butyl 1-benzyl-2-oxo-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]([OH:19])[CH2:10][CH2:11][NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH:5]=[CH:6][C:7]=1[CH3:8].[C:20]([C:22]([OH:29])([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])#[CH:21]>>[F:15][C:14]([F:17])([F:16])[C:13]([NH:12][CH2:11][CH2:10][CH:9]([OH:19])[C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([C:21]#[C:20][C:22]([OH:29])([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH:3]=1)=[O:18]
Reactant: Cc1ccc(C(O)CCNC(=O)C(F)(F)F)cc1Br
Reactant: C#CC(O)(CCC)CCC
Product: CCCC(O)(C#Cc1cc(C(O)CCNC(=O)C(F)(F)F)ccc1C)CCC

Procedure:
N-(3-(3-Bromo-4-methylphenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide was coupled with 4-ethynylheptan-4-ol to give 2,2,2-trifluoro-N-(3-hydroxy-3-(3-(3-hydroxy-3-propylhex-1-ynyl)-4-methylphenyl)propyl)acetamide as a yellow oil. Yield (0.286 g, 28%): 1H NMR (400 MHz, DMSO-d6) δ 9.31 (t, J=5.2 Hz, 1H), 7.27 (s, 1H), 7.18 (d, J=7.6 Hz, 1H), 7.16 (dd, J=7.6, 1.8 Hz, 1H), 5.30 (d, J=4.8 Hz, 1H), 5.10 (s, 1H), 4.54-4.50 (m, 1H), 3.25-3.14 (m, 2H), 2.30 (s, 3H), 1.78-1.72 (m, 2H), 1.63-1.36 (m, 8H), 0.89 (t, J=7.2 Hz, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]1[CH2:23][CH2:22][CH2:21][CH:20](CC(N)=O)[CH2:19]1)[C:13]([CH3:28])=[CH:12]2)[CH3:2].C1(N2C3C(=CC(O)=CC=3)C([CH2:46][C:47]([NH2:49])=[O:48])=C2C)CCCCC1.[H-].[Na+].BrCCCC(OCC)=O>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[C:13]([CH3:28])=[C:12]2[CH2:46][C:47]([NH2:49])=[O:48])[CH3:2]
Reactant: Cc1c(CC(N)=O)c2cc(O)ccc2n1C1CCCCC1
Reactant: CCOC(=O)CCCOc1ccc2c(c1)cc(C)n2C1CCCC(CC(N)=O)C1
Agent: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CCCOc1ccc2c(c1)c(CC(N)=O)c(C)n2C1CCCCC1
Yield: 46 %

Procedure:
[4-[[3-(2-Amino-2-oxoethyl)-cyclohexyl-2-methyl-1-H-indol-5-yl]oxy]butanoic acid ethyl ester. 1-Cyclohexyl-5-hydroxy-2-methyl-1H-indole-3-acetamide (300 mg, 1.0 mmol) was reacted with 40 mg (1.0 mmol) of 60% NaH/mineral oil and then 0.143 mL (1.0 mmol) of ethyl 4-bromobutyrate as described in Example 50, Part D to give a product that was chromatographed on silica gel (eluted with 2% MeOH/methylene chloride) to give 190 mg (46% yield) of [4-[[3-(2-amino-2-oxoethyl)-1-cyclohexyl-2-methyl-1-H-indol-5-yl]oxy]butanoic acid ethyl ester, mp, 92°-94° C.
Reaction SMILES: [C:1]1([S:7]([CH2:10][CH2:11][CH2:12]Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][N:15]1[C:23](=[O:24])[C:22]2[N:21]([CH2:25][CH:26]([OH:34])[CH2:27][N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[CH:20]=[N:19][C:18]=2[N:17]([CH3:35])[C:16]1=[O:36]>>[CH3:14][N:15]1[C:23](=[O:24])[C:22]2[N:21]([CH2:25][CH:26]([OH:34])[CH2:27][N:28]3[CH2:29][CH2:30][N:31]([CH2:12][CH2:11][CH2:10][S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[CH2:32][CH2:33]3)[CH:20]=[N:19][C:18]=2[N:17]([CH3:35])[C:16]1=[O:36]
Reactant: Cn1c(=O)c2c(ncn2CC(O)CN2CCNCC2)n(C)c1=O
Reactant: O=S(=O)(CCCCl)c1ccccc1
Product: Cn1c(=O)c2c(ncn2CC(O)CN2CCN(CCCS(=O)(=O)c3ccccc3)CC2)n(C)c1=O

Procedure:
In a similar manner, but replacing the 3-phenylsulfonyl-1-chloropropane as needed with other appropriate compounds of Formula 4, the preparation of which is described in Preparation 1, and optionally substituting for the 1-[3-(1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dion-7-yl)-2-hydroxypropyl]piperazine other appropriate compounds of Formula 5, the following compounds of Formula I are obtained:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]1[C:10]2[C:11]([CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:12][CH:13]=[CH:14][C:9]=2[N:8](C(OC(C)(C)C)=O)[C:7]1=[O:27])[CH3:2].Cl>C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[CH2:16]([CH:15]([C:11]1[C:10]2[N:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:28])[C:7](=[O:27])[NH:8][C:9]=2[CH:14]=[CH:13][CH:12]=1)[CH2:18][CH3:19])[CH3:17]
Reactant: CCOC(=O)Cn1c(=O)n(C(=O)OC(C)(C)C)c2cccc(C(CC)CC)c21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1c(=O)[nH]c2cccc(C(CC)CC)c21
Reaction time: 2 h
Yield: 93 %

Procedure:
To a solution of tert-butyl 3-(2-ethoxy-2-oxoethyl)-4-(1-ethylpropyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxylate (6.16 g, 15.8 mmol) in ethyl acetate (15 mL) was added a 4N solution of hydrogen chloride in ethyl acetate (15 mL) at 0° C., and the mixture was stirred at the same temperature for 2 hr. An additional 4N solution of hydrogen chloride in ethyl acetate (15 mL) was added to the mixture at 0° C., followed by stirring at the same temperature for 1 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate and ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated in vacuo. The resulting solid was washed with n-hexane to give the title compound (4.28 g, 14.7 mmol, 93%) as a colorless crystal.
Reaction SMILES: C[O:2][C:3](=[O:35])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:9][C:10]1[C:11]2[C:16]([C:17]3[CH:18]=[C:19]4[O:26][CH2:25][O:24][C:20]4=[CH:21][C:22]=3[CH:23]=1)=[CH:15][C:14]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:13][CH:12]=2.N>>[CH2:25]1[O:26][C:19]2[C:20](=[CH:21][C:22]3[CH:23]=[C:10]([CH2:9][N:5]4[CH2:6][CH2:7][CH2:8][C@H:4]4[C:3]([OH:35])=[O:2])[C:11]4[C:16]([C:17]=3[CH:18]=2)=[CH:15][C:14]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:13][CH:12]=4)[O:24]1
Reactant: COC(=O)[C@@H]1CCCN1Cc1cc2cc3c(cc2c2cc(OCc4ccccc4)ccc12)OCO3
Agent: N
Product: O=C(O)[C@@H]1CCCN1Cc1cc2cc3c(cc2c2cc(OCc4ccccc4)ccc12)OCO3

Procedure:
General procedure e from 17 (100%); white powder; mp 147-149° C.; 1H NMR (400.13 MHz) δ 8.11 (d, J=4 Hz, 1H), 7.84 (d, J=2 Hz, 1H), 7.75 (s, 1H), 7.42 (s, 1H), 7.40 (d, J=4 Hz, 2H), 7.30 (t, J=4 Hz, 2H), 7.27 (m, 1H), 7.23 (dd, J=4 Hz, 2 Hz, 1H), 7.14 (s, 1H), 6.01 (s, 2H), 5.16 (s, 2H), 4.30 (s, 2H), 3.24 (m, 1H), 2.48 (m, 2H), 2.0 (m, 2H), 1.68 (m, 2H); MS (DCI/NH3) m/e: 456 (M+H)+. Anal. (C28H25O5N.1.0H2O) C, H, N.
Reaction SMILES: [N:1]1([C:7]2[CH:27]=[CH:26][C:10]([C:11]([NH:13][C:14]3[C:15]4[S:21][C:20]([C:22]([O:24]C)=[O:23])=[CH:19][C:16]=4[NH:17][N:18]=3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO>[N:1]1([C:7]2[CH:27]=[CH:26][C:10]([C:11]([NH:13][C:14]3[C:15]4[S:21][C:20]([C:22]([OH:24])=[O:23])=[CH:19][C:16]=4[NH:17][N:18]=3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cc2[nH]nc(NC(=O)c3ccc(N4CCOCC4)cc3)c2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(Nc1n[nH]c2cc(C(=O)O)sc12)c1ccc(N2CCOCC2)cc1
Temperature: 50 °C
Yield: 98.5 %

Procedure:
A mixture of methyl 3-[(4-morpholin-4-ylbenzoyl)amino]-1H-thieno[3,2-c]pyrazole-5-carboxylate (2.3 g, 6 mmol) and aqueous sodium hydroxide (12.5 ml of a 2N solution)in MeOH (50 ml) was heated for 8 h at 50° C. After cooling the methanol was removed by evaporation under reduced pressure, water (5 ml) was added, and the pH was adjusted at 7 by adding aqueous hydrochloric acid. The precipitate was separated by filtration, washed with water and ethyl ether, and dryed at 50° C. under vacuum. 2.2 g of title compound were obtained. LC-MS, chromatographic method A, Rt 2.06, [M+H]+ 373.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:37])[NH:27][C:28]4[CH:36]=[CH:35][C:31]([C:32]([OH:34])=O)=[CH:30][CH:29]=4)=[CH:21][CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:71]1[CH2:76][CH2:75][CH:74]([N:77]2[CH2:82][CH2:81][O:80][CH2:79][CH2:78]2)[CH2:73][CH2:72]1>CN1C(=O)CCC1>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[N:10]=[C:9]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:27][C:28]4[CH:29]=[CH:30][C:31]([C:32]([N:71]5[CH2:76][CH2:75][CH:74]([N:77]6[CH2:82][CH2:81][O:80][CH2:79][CH2:78]6)[CH2:73][CH2:72]5)=[O:34])=[CH:35][CH:36]=4)=[O:37])=[CH:23][CH:24]=3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(Nc1ccc(C(=O)O)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Reactant: C1CC(N2CCOCC2)CCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(=O)N2CCC(N3CCOCC3)CC2)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Yield: 61.6 %

Procedure:
To the stirred solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid (50 mg; 0.099 mmol), Hunig's base (103 μL, 0.594 mmol), HBTU (188 mg, 0.495 mmol) in 1 mL of NMP was reacted according to example 68 with 4-(piperidin-4-yl)morpholine (67 mg, 0.396 mmol). Evaporated the solvent and purified by HPLC to give the product (40.1 mg, 62% yield); MS (ESI) m/z=658.7
Reaction SMILES: [CH3:1][CH2:2][N:3](C(C)C)C(C)C.[NH:10]1[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11]1.Cl.C(N)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH2:2]([NH:3][C:15]([C:12]1[CH:13]=[CH:14][NH:10][CH:11]=1)=[O:17])[CH3:1]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1cc[nH]c1
Agent: CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCNC(=O)c1cc[nH]c1
Reaction time: 0.33 h

Procedure:
DIPEA (10.4 mL, 7.8 g, 60 mmol) was added to a solution of 1H-pyrrole-3-carboxylic acid (2.2 g, 20 mmol) and ethylamine hydrochloride (2.5 g, 30 mmol) in DMF (50 mL) at 0° C. Stirring for 20 min, HATU (9.9 g, 26 mmol) was added at 0° C. The reaction mixture was stirred overnight at room temperature, diluted with EtOAc (300 mL), washed with H2O (3×30 mL) and dried over Na2SO4. The crude product was purified by MPLC using EtOAc on silica gel to give 4.0 mL of a solution of the desired product in DMF. Small amount of the desired product was purified again by MPLC using EtOAc on silica gel for NMR. 1H NMR (400 MHz, CHLOROFORM-D) δ 1.22 (t, J=7.23 Hz, 3 H), 3.39-3.51 (m, 2 H), 5.84 (s, 1 H), 6.37-6.42 (m, 1 H), 6.77 (dd, J=4.98, 2.44 Hz, 1 H), 7.30-7.39 (m, 1 H), 8.85 (t, 1 H).
Reaction SMILES: [Cl-].[F:2][CH2:3][C@@H:4]([NH3+:24])[C@H:5]([OH:23])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:16][N:15]=[C:14]([CH2:17][NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:13]=2)=[CH:8][CH:7]=1.C(N(C(C)C)CC)(C)C.[Cl:34][CH:35]([Cl:39])[C:36](Cl)=[O:37]>CN(C)C=O>[Cl:34][CH:35]([Cl:39])[C:36]([NH:24][C@H:4]([CH2:3][F:2])[C@H:5]([OH:23])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:16][N:15]=[C:14]([CH2:17][NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:13]=2)=[CH:8][CH:7]=1)=[O:37]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CS(=O)(=O)NCc1cc(-c2ccc([C@@H](O)[C@H]([NH3+])CF)cc2)on1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)NCc1cc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)on1
Temperature: 0 °C
Yield: 52.3 %

Procedure:
To a dimethylformamide (3 ml) solution of (1R,2S)-3-fluoro-1-hydroxy-1-(4-(3-(methylsulfonamidomethyl)isoxazol-5-yl)phenyl)propan-2-aminium chloride (150 mg, 0.40 mmol) is added diisopropylethylamine (0.255 g, 2 mmol). After cooling the reaction mixture to 0° C. dichloroacetyl chloride (62 mg, 0.42 mmol) is added. The reaction is stirred at 0° C. for twenty minutes then quenched by the addition of water (1 ml). The reaction mixture is concentrated to a volume of approximately two milliliters and subjected to reverse phase HPLC purification to give the title compound (95 mg): 1H NMR (400 MHz, CDCl3) 3.06 (s, 3H) 4.30-4.43 (m, 1H) 4.49 (d, J=6.32 Hz, 2H) 4.56-4.67 (m, 2H) 4.93 (m, br, 1H) 5.19-5.24 (m, 1H) 5.87 (s, 1H) 6.61 (s, 1H) 7.03 (d, J=9.09 Hz, 1H) 7.52 (d, J=8.08 Hz, 2H) 7.79 (d, J=8.59 Hz, 2H); m/z (CI) 454, 456, 458 ([M+H]+.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([N:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2N)[C:13]1=[O:23])[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2].N([O-])=O.[Na+].CS(C)=O.[IH:32].C([O-])(O)=O.[Na+]>>[C:1]([O:4][CH2:5][CH:6]([N:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[I:32])[C:13]1=[O:23])[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2]
Reactant: I
Reactant: CC(=O)OCC(COC(C)=O)n1ccc2c(N)cccc2c1=O
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)OCC(COC(C)=O)n1ccc2c(I)cccc2c1=O
Temperature: 35 °C
Reaction time: 0.75 h

Procedure:
2-(5-Amino-1-oxoisoquinolin-2(1H)-yl)propane-1,3-diyl diacetate (4.2 g, 0.013 mol) was added to a solution of sodium nitrite (4 g, 0.05 mol) in dimethyl sulfoxide (70 mL, 1 mol) at 35° C. Aqueous hydrogen iodide (7 mL, 0.05 mol) in dimethyl sulfoxide (70 mL, 1 mol) was added, the mixture was stirred at 35° C. for 45 minutes. The cooled mixture was neutralized with sat. aq. NaHCO3, extracted with CH2Cl2 (50 mL×3), washed with brine, and dried over MgSO4. Filtered, evaporated and purified via flash column chromatography (12 g of silica gel, 50-100% EtOAc/Hexane) to give the desired product as a yellow oil. MS m/z (M+H) 430.1.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[N:15]=[C:14]([NH2:16])[N:13]=[C:12]2[NH:17][N:18]=[CH:19][C:11]=12>ClC(Cl)C>[Br:1][C:19]1[C:11]2[C:12](=[N:13][C:14]([NH2:16])=[N:15][C:10]=2[Cl:9])[NH:17][N:18]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1nc(Cl)c2cn[nH]c2n1
Solvent: CC(Cl)Cl
Product: Nc1nc(Cl)c2c(Br)n[nH]c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-bromosuccinimide (673 mg, 3.8 mmol) is added to a suspension of 4-Chloro-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (500 mg, 2.96 mmol) in dichloroethane (30 ml) and heated to reflux overnight. The reaction mixture is cooled to room temperature and the solvent is removed in vacuo. The resulting solid is diluted with water, stirred for 30 minutes at room temperature, then collected by filtration to afford the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH:23]([N:26]1[CH2:30][CH2:29][C@@H:28]([CH2:31][NH:32][CH3:33])[CH2:27]1)([CH3:25])[CH3:24]>>[CH:23]([N:26]1[CH2:30][CH2:29][C@H:28]([CH2:31][N:32]([CH3:33])[C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:3]=[N:2][NH:1][CH:5]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:27]1)([CH3:25])[CH3:24]
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: CNC[C@@H]1CCN(C(C)C)C1
Product: CC(C)N1CC[C@H](CN(C)C(=O)c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)C1

Procedure:
Following Example 216, to a well stirred solution of 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid and (S)-1-(1-isopropylpyrrolidin-3-yl)-N-methylmethanamine to give 222. MS: (ESI+)=452.2
Reaction SMILES: C(OC([NH:8][C:9]1[CH:17]=[N:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])=O)(C)(C)C.Cl>CO>[NH2:8][C:9]1[CH:17]=[N:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12]
Reactant: CC(C)(C)OC(=O)Nc1cnccc1C(=O)O
Agent: Cl
Solvent: CO
Product: Nc1cnccc1C(=O)O
Temperature: 25 °C
Yield: 100.4 %

Procedure:
3-tert-Butoxycarbonylamino-isonicotinic acid (450 mg) was dissolved in methanol (8 mL) and 6N hydrochloric acid (5 mL) was added to the solution. The resulting suspension was stirred under reflux for 2.5 hours, cooled to room temperature and washed 3× with chloroform. The aqueous layer was adjusted to pH-14 by addition of 2N sodium hydroxide solution, washed 3× with chloroform and adjusted again to pH-3 by addition of 2N hydrochloric acid. The aqueous layer was concentrated on a rotary evaporator to complete dryness and the residue was extracted with hot ethanol. The ethanol extract was filtered to remove insoluble material and concentrated in vacuum to afford 262 mg of the title compound of formula
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[O:12][C:13]2[CH:20]=[C:19](B3OC(C)(C)C(C)(C)O3)[CH:18]=[CH:17][C:14]=2[C:15]=1[CH3:16])=[O:10].Br[C:31]1[N:36]=[C:35]([CH2:37][NH:38][C:39](=[O:41])[CH3:40])[CH:34]=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[O:12][C:13]2[CH:20]=[C:19]([C:31]3[N:36]=[C:35]([CH2:37][NH:38][C:39](=[O:41])[CH3:40])[CH:34]=[CH:33][CH:32]=3)[CH:18]=[CH:17][C:14]=2[C:15]=1[CH3:16])=[O:10]
Reactant: CC(=O)NCc1cccc(Br)n1
Reactant: Cc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc(B3OC(C)(C)C(C)(C)O3)ccc12
Product: CC(=O)NCc1cccc(-c2ccc3c(C)c(C(=O)c4ccc(Cl)cc4Cl)oc3c2)n1

Procedure:
N-{6-[2-(2,4-dichloro-benzoyl)-3-methyl-benzofuran-6-yl]-pyridin-2-ylmethyl}-acetamide was prepared via a Suzuki coupling of ((2,4-dichlorophenyl)-[3-methyl-6-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-benzofuran-2-yl]-methanone and N-(6-Bromo-pyridin-2-ylmethyl)-acetamide as described in method 6 step 2. 1H-NMR (CD3OD) δ 8.19 (s, 1H), 8.05 (dd, J=9 Hz, J=2 Hz, 1H), 7.99-7.89 (m, 3H), 7.64 (d, J=2 Hz, 1H), 7.57-7.51 (m, 2H), 7.40 (d, J=7 Hz, 1H), 4.59 (s, 2H), 2.62 (s, 3H), 2.07 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][C@H:6]([CH3:13])[CH2:5]2.[CH2:14](N(CC)CC)[CH3:15].C([B-](F)(F)F)=C.[K+]>CCO.C(Cl)(Cl)Cl>[CH:14]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][C@H:6]([CH3:13])[CH2:5]2)=[CH2:15]
Reactant: CCN(CC)CC
Reactant: C[C@@H]1Cc2cc(Br)ccc2C(=O)O1
Agent: C=C[B-](F)(F)F
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: C=Cc1ccc2c(c1)C[C@@H](C)OC2=O
Temperature: 100 °C

Procedure:
A solution of (3R)-6-bromo-3-methyl-3,4-dihydro-1H-isochromen-1-one (2.4 g, 10.0 mmol) and triethylamine (2.8 ml, 19.9 mmol) in EtOH (40 ml) was added to a microwave vial containing commercially available Cl2Pd(dppf)2-DCM (0.41 g, 0.50 mmol) and potassium vinyltrifluoroborate (2.0 g, 15 mmol). The contents of the vial were heated to 100° C. for 1 hour after which the mixture was cooled, diluted with chloroform (50 mL) and washed with aqueous ammonium chloride (25 mL). The organic layer was then dried over magnesium sulfate, filtered and the solvent was evaporated under reduced pressure. MPLC purification (15-60% EtOAc/Hex) gave (3R)-6-ethenyl-3-methyl-3,4-dihydro-1H-isochromen-1-one.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:26][C:27]([NH:29][CH3:30])=[O:28]>CN(C=O)C>[OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:12][CH2:26][C:27]([NH:29][CH3:30])=[O:28])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3]1
Reactant: CNC(=O)CCl
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(OCC(=O)NC)cc(C)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.1 %

Procedure:
To a solution of ethyl 2-(1,6-dihydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (200 mg, 0.8 mmol) in anhydrous DMF (4 mL) was added K2CO3 (165 mg, 1.2 mmol), KI (199.2 mg, 1.2 mmol) and 2-chloro-N-methylacetamide (128.4 mg, 1.2 mmol) at rt. After stirring at room temperature overnight, the resulting mixture was quenched by adding water. The resulting mixture was extract with EtOAc. The extract was washed with brine, dried and concentrated to dryness. The residue was purified by recrystallization from mixture of ethyl acetate and hexane to give 80 mg of pure product as a white solid; 1H NMR (400 MHz, CDCl3) δ 7.11 (s, 1H), 6.87 (s, 1H), 6.86 (br, 1H), 5.61 (d, J=9.2 Hz, 1H), 5.59 (s, 1H), 4.53 (s, 2H), 4.18 (q, 2H), 3.07 (d, 1H), 2.93 (t, 3H), 2.37 (m, 1H), 2.32 (s, 3H). 2.14 (s, 3H) ppm. MS (ESI) m/z=322 [M+H]+.
Reaction SMILES: [CH2:1]1[N:6]2[C:7]3[C:12]([NH:13][C:14](=[O:15])[CH:5]2[CH2:4][NH:3][CH2:2]1)=[CH:11][CH:10]=[CH:9][CH:8]=3.Cl.[N:17]1[CH:22]=[CH:21][C:20]([CH2:23]Cl)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:3]2[CH2:2][CH2:1][N:6]3[C:7]4[C:12]([NH:13][C:14](=[O:15])[CH:5]3[CH2:4]2)=[CH:11][CH:10]=[CH:9][CH:8]=4)=[CH:19][CH:18]=1
Reactant: O=C1Nc2ccccc2N2CCNCC12
Reactant: ClCc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1Nc2ccccc2N2CCN(Cc3ccncc3)CC12

Procedure:
A solution of 2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one 6.1 g. (0.03 mole) and 4.92 g. (0.03 mole) of 4-picolyl chloride hydrochloride, 10 g. of potassium carbonate, 0.5 ml. of tirethylamine in 200 ml. of acetone was refluxed for 40 hours with stirring. The reaction mixture was allowed to cool and the precipitate was filtered and washed with acetone. The acetone was removed under reduced pressure and the oily residue was dissolved in methylene chloride. This solution was washed with water, dried over magnesium sulfate, filtered and the solvent removed. The residue was dissolved in ethanol and treated with dry hydrogen chloride. The product hydrogen chloride was filtered and recrystallized from methanol to give 2 g. of the title compound as the dihydrochloride salt, m.p. 253°-255° C.