Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:29])[C@@H:13]([OH:28])[CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][C@@H:17](O)[C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5](O)=[O:6].C1CCC(N=C=NC2CCCCC2)CC1.[SH:45][C:46]1[S:47][CH2:48][CH2:49][N:50]=1>C(Cl)Cl>[OH:25][CH:23]1[CH2:24][CH:19]2[C:20]([CH3:26])([CH:15]3[CH:16]([CH2:17][CH2:18]2)[CH:11]2[C:12]([CH3:29])([CH:8]([CH:2]([CH3:1])[CH2:3][CH2:4][C:5]([N:50]4[CH2:49][CH2:48][S:47][C:46]4=[S:45])=[O:6])[CH2:9][CH2:10]2)[CH:13]([OH:28])[CH2:14]3)[CH2:21][CH2:22]1
Reactant: SC1=NCCS1
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(CCC(=O)N1CCSC1=S)C1CCC2C3CCC4CC(O)CCC4(C)C3CC(O)C12C
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.3 %

Procedure:
To a vigorously stirred solution of cholic acid (1 g, 2.6 mmol) in CH2Cl2 (60 mL) was added DCC (684 mg, 3.6 mmol), 2-mercaptothiazoline (354 mg, 3 mmol), and catalytic amount (40 mg) of N,N-dimethyl amino pyridine (DMAP). The reaction mixture was stirred for 24 h at room temperature at which time the reaction mixture was transferred to a separate-funnel and sequentially washed with 0.5N NaOH solution (100 mL×2), and 0.1N HCl (100 mL×2). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to provide pure yellow solid 2 (1.07 g, 82%). 1H NMR (CDCl3) δ 0.68 (s, 3H), 0.90 (s, 3H), 0.98 (d, 3H), 1.10-1.95 (m, 23H), 3.25-3.35 (m, 4H), 3.53-3.67 (m, 1H), 3.98 (s, 1H), 4.57 (t, 2H); 13C NMR (CDCl3) δ12.73, 17.49, 23.16, 23.76, 26.17, 27.21, 27.63, 28.33, 28.60, 30.40, 30.74, 33.52, 34.11, 35.32, 35.48, 35.87, 36.00, 36.40, 42.08, 46.52, 47.44, 48.09, 53.59, 56.16, 71.53, 72.99, 175.35, 201.52. HRMS (Positive ion FAB) Calcd for C27H44N3O2 [M+H]+ m/z 494.2763. Found: [M+H]+ m/z 494.2744.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:12][CH:11]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.Br[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.O>[CH3:1][N:2]([CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:3][C:4]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:12][CH:11]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: BrCCc1ccccc1
Reactant: CNCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CN(CCc1ccccc1)CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Yield: 21.1 %

Procedure:
Methyl-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-ylmethyl}amine (150 mg, 0.45 mmol) was treated with (2-bromoethyl)benzene (100 mg, 0.54 mmol) and potassium carbonate (187 mg, 1.35 mmol) in a sealed tube under microwave (Smith Personal Synthesiser) (55° C.) for 80 min. The reaction mixture was taken in DCM (10 mL) and water (5 mL). The organic layer was separated and washed twice with water and brine. The combined organic extracts were dried over Na2SO4, filtered, concentrated in vacuo and purified by column chromatography on silica gel eluting with DCM:MeOH (90:10) with 10% NH3 to give the title compound as a colorless oil (41.4 mg, 20%). 1H NMR (400 MHz, CDCl3) δ7.23 (m, 7H), 6.87 (d, 2H), 4.00 (t, 2H), 3.66 (m, 2H), 3.51 (m, 2H), 3.29 (t, 2H), 3.20 (t, 2H), 2.62 (t, 2H), 2.51 (m, 6H), 2.10 (m, 2H), 1.99 (m, 2H), 1.90 (m, 2H), 1.86 (s, 3H), 1.78 (m, 4H).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([CH2:10][OH:11])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[Cl:12]N1C(=O)CCC1=O>O1CCCC1.COCC>[CH2:1]([C:5]1[NH:6][C:7]([CH2:10][OH:11])=[C:8]([Cl:12])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(CO)[nH]1
Reactant: O=C1CCC(=O)N1Cl
Agent: CCOC
Solvent: C1CCOC1
Product: CCCCc1nc(Cl)c(CO)[nH]1
Reaction time: 48 h
Yield: 52.4 %

Procedure:
To a solution of 2-n-butyl-5-hydroxymethylimidazole (25 g, 0.162 mol, prepared in Example 1 (i)) in 250 ml of tetrahydrofuran and 250 ml of 2-methoxyethane under argon was added portionwise N-chlorosuccinimide (26 g, 0.195 mol). The reaction mixture was heated at 50°-55° C. for 2 hours. The solvents were removed in vacuo and the residue for 48 hours. The solid was filtered and then stirred with 100 ml of diethyl ether for 1 hour. The solid was collected to give 16 g (52%) of 2-n-butyl-4-chloro-5-hydroxymethylimidazole.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([S:17]([N:20]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)(=[O:19])=[O:18])=[CH:14][CH:15]=2)[CH:10]=[C:9]1B(O)O)=O)(C)(C)C.I[C:37]1[C:38](=[O:47])[NH:39][C:40]2[C:45]([CH:46]=1)=[CH:44][CH:43]=[CH:42][CH:41]=2.[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:20]1([S:17]([C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[NH:8][C:9]([C:37]2[C:38](=[O:47])[NH:39][C:40]4[C:45]([CH:46]=2)=[CH:44][CH:43]=[CH:42][CH:41]=4)=[CH:10]3)(=[O:19])=[O:18])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1
Reactant: O=c1[nH]c2ccccc2cc1I
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc3c(c2)cc(B(O)O)n3C(=O)OC(C)(C)C)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: C1COCCO1
Product: O=c1[nH]c2ccccc2cc1-c1cc2cc(S(=O)(=O)N3CCNCC3)ccc2[nH]1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
1-(tert-Butoxycarbonyl)-5-{[4-(tert-butoxycarbonyl)piperazin-1-yl]sulfonyl}-1H-indol-2-ylboronic acid (2-3, 1.88 g, 3.69 mmol, 2.0 equiv) was added in four equal portions at 30 minute intervals to a solution of 3-iodo-1H-quinolin-2-one (1-3, 0.500 g, 1.84 mmol, 1 equiv), lithium chloride (0.235 g, 5.54 mmol, 3.00 equiv), tetrakis(triphenylphosphine)palladium (0.107 g, 0.093 mmol, 0.050 equiv), and aqueous sodium carbonate solution (2 M, 4.61 mL, 9.22 mmol, 5.00 equiv) in dioxane (50 mL) at 90° C. The reaction mixture was heated for 2 h at 90° C. following the final addition. The mixture was then partitioned between brine (100 mL) and EtOAc (2×100 mL). The combined organic layers were dried over sodium sulfate and concentrated. A solution of the residue in dichloromethane (100 mL) was treated with trifluoroacetic acid (100 mL), and the resulting mixture was stirred for 45 minutes, then concentrated. The residue was purified by reverse-phase liquid chromotography (H2O/CH3CN gradient w/0.1% TFA present) to give 3-[5-(piperazin-1-ylsulfonyl)-1H-indol-2-yl]quinolin-2(1H)-one (2-4) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 12.23 (br s, 1H), 12.11 (s, 1H), 8.62 (s, 1H), 8.00 (br s, 1H), 7.77 (d, 1H, J=7.8 Hz), 7.74 (d, 1H, J=8.6 Hz), 7.56 (t, 1H, J=7.8 Hz), 7.51 (s, 1H), 7.44 (d, 1H, J=8.6 Hz), 7.40 (d, 1H, J=8.1 Hz), 7.27 (t, 1H, J=7.8 Hz), 2.77 (m, 4H), 2.71 (m, 4H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][Si](C)(C)C)=[CH:10][C:9]=2[CH3:20])[C:6](=[S:21])[N:5]([CH3:22])[N:4]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:14]([C:11]1[CH:12]=[CH:13][C:8]([N:7]2[C:6](=[S:21])[N:5]([CH3:22])[N:4]=[C:3]2[C:2]([F:24])([F:23])[F:1])=[C:9]([CH3:20])[CH:10]=1)#[CH:15]
Reactant: Cc1cc(C#C[Si](C)(C)C)ccc1-n1c(C(F)(F)F)nn(C)c1=S
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc(-n2c(C(F)(F)F)nn(C)c2=S)c(C)c1
Reaction time: 0.33 h
Yield: 70.7 %

Procedure:
To a stirred mixture of 4.40 g (0.0119 mole) of 3-trifluoromethyl-4,5-dihydro-1-methyl-4-(2-methyl-4-trimethylsilylethynylphenyl)-1,2,4-triazol-5-(1H)-thione in 75 ml of tetrahydrofuran was added 10.8 g (0.0414 mole) of tetrabutylammonium fluoride. This mixture was stirred for about 20 minutes, and the reaction was partitioned between 75 ml of diethyl ether and 150 ml of an aqueous sodium chloride solution. The organic phase was dried over anhydrous magnesium sulfate and was filtered. The filtrate was evaporated under reduced pressure, leaving a residue. This residue was purified by column chromatography on silica gel, eluting with diethyl ether, to yield 2.5 g of 4-(4-ethynyl-2-methylphenyl)-3-trifluoromethyl-4,5-dihydro-1-methyl-1,2,4-triazol-5(1H)-thione as an oil, Compound 111 of Table 1. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[CH2:7][C:6]=2[CH:12]=1.[CH2:13](O)[CH2:14][OH:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8]3([O:15][CH2:14][CH2:13][O:11]3)[CH2:7][C:6]=2[CH:12]=1
Reactant: O=C1COc2ccc(Br)cc2C1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Brc1ccc2c(c1)CC1(CO2)OCCO1
Temperature: 100 °C
Yield: 94.7 %

Procedure:
To a solution of 6-bromo-2H-1-benzopyran-3(4H)-one (300 mg, 1.13 mmol) in toluene (2 mL) was added ethyleneglycol (163 mg 2.64 mmol) and para-toluenesulfonic acid (27 mg, 0.13 mmol). The reaction mixture was heated at 100° C. for 6 hrs. The reaction mixture was cooled and the solvent concentrated. The resultant residue was partitioned between ethyl acetate and water. The organic phase was washed with water, brine, dried over Na2SO4 and concentrated under vacuum to give the title compound (290 mg, 79% yield) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([Br:13])=[CH:7][C:3]=1[C:4](O)=[O:5].[NH:14]1CCCC[CH2:15]1.N1C=NC=NC=1>CO>[Br:13][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][C:9]=1[O:11][CH3:12])[N:1]=[CH:15][NH:14][C:4]2=[O:5]
Reactant: COc1cc(N)c(C(=O)O)cc1Br
Reactant: C1CCNCC1
Agent: c1ncncn1
Solvent: CO
Product: COc1cc2nc[nH]c(=O)c2cc1Br
Temperature: 25 °C
Yield: 63 %

Procedure:
2-Amino-5-bromo-4-methoxybenzoic acid (1.56 g, 6.34 mmol) is dissolved in methanol (15 ml), treated with piperidine (0.063 ml, 0.63 mmol) and 1,3,5-triazine (772 mg, 9.5 mmol) and refluxed for one hour. After cooling to room temperature, the resulting crystals are filtered off with suction and washed with methanol. The desired product is obtained in 63% yield (1.01 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]2/[C:13](=[N:16]/[S@](C(C)(C)C)=O)/[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C[C@H]2/C(=N/[S@](C(C)(C)C)=O)/CC[C@H]2C1)C1C=CC=CC=1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]2[C@@H:13]([NH2:16])[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[S@](=O)/N=C1\CC[C@@H]2CN(Cc3ccccc3)C[C@H]12
Agent: CC(C)(C)[S@](=O)/N=C1\CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Product: N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21

Procedure:
(3aR,4S,6aS)-2-Benzyloctahydrocyclopenta[c]pyrrol-4-amine was prepared according to the procedure described in Example 16 Steps A-E substituting (S,E)-N-((3aR,6aS)-2-benzylhexahydrocyclopenta[c]pyrrol-4(5H)-ylidene)-2-methylpropane-2-sulfinamide from Step A in Example 14 for (S,E)-N-((3aS,6aR)-2-benzylhexahydrocyclopenta[c]pyrrol-4(5H)-ylidene)-2-methylpropane-2-sulfinamide in Step A of Example 16 to give (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine: 1H NMR (300 MHz, CDCl3) δ ppm 7.34-7.28 (m, 4H), 7.25-7.18 (m, 1H), 3.54 (s, 2H), 3.09 (dd, J=4.8, 10.9, 1H), 2.75-2.58 (m, 1H), 2.48 (dd, J=8.6, 16.5, 2H), 2.40 (dd, J=3.9, 9.3, 1H), 2.30 (dd, J=3.9, 9.0, 1H), 2.21-2.09 (m, 1H), 2.01-1.84 (m, J=6.9, 12.0, 2H), 1.47-1.25 (m, 4H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=O.[C@@H:16]1([NH2:26])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1>>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][NH:26][C@@H:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: O=Cc1cccc(Oc2ncccn2)c1
Product: c1cnc(Oc2cccc(CN[C@H]3CCCc4ccccc43)c2)nc1
Yield: 17.2 %

Procedure:
3-(2-Pyrimidinyloxy)benzaldehyde (0.67 g, 3.35 mmol) and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine (0.49 g, 3.33 mmol) were processed as described in Example 106A. The residue was purified by flash chromatography (silica gel, 6:4 ethyl acetate:hexanes to 1:1 ethyl acetate:hexanes) to provide the title compound (190 mg, 19% yield).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]([C:16]#[C:17][CH3:18])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1[C:28]1[CH:33]=[CH:32][C:31](O)=[CH:30][C:29]=1[CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1COCC1>[F:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1[C:28]1[CH:33]=[CH:32][C:31]([O:1][CH2:2][C:3]2[CH:4]=[C:5]([CH:9]([C:16]#[C:17][CH3:18])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=2)=[CH:30][C:29]=1[CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37]
Reactant: CC#CC(CC(=O)OCC)c1cccc(CO)c1
Reactant: COc1ccc(F)c(-c2ccc(O)cc2CC(C)(C)C)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CC#CC(CC(=O)OCC)c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1
Reaction time: 16 h
Yield: 82.1 %

Procedure:
Under a nitrogen atmosphere, to a solution of ethyl 3-(3-(hydroxymethyl)phenyl)hex-4-ynoate (100 mg) and 2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-ol (117 mg) in THF (5.8 mL) were added 1,1′-(azodicarbonyl)dipiperidine (164 mg) and tributylphosphine (160 μL) at room temperature, and the mixture was stirred for 16 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (172 mg) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].[C:14](Cl)(Cl)=[O:15]>ClCCl.C(=O)(O)[O-].[Na+].C1(C)C=CC=CC=1>[Br:13][C:10]1[CH:11]=[CH:12][C:2]([N:1]=[C:14]=[O:15])=[C:3]([CH:9]=1)[C:4]([N:6]([CH3:7])[CH3:8])=[O:5]
Reactant: O=C(Cl)Cl
Reactant: CN(C)C(=O)c1cc(Br)ccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CN(C)C(=O)c1cc(Br)ccc1N=C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-amino-5-bromo-N,N-dimethyl-benzamide (1.48 g, 6.09 mmol) was dissolved in a mixture of dichloromethane (60 mL) and saturated aqueous sodium bicarbonate (60 mL). 16 mL of 20% w/w phosgene in toluene was added and the mixture stirred at room temperature for 30 min. The layers were separated and the aqueous layer extracted three times with dichloromethane (20 mL). The combined organic layers were dried over sodium sulfate and evaporated. The residue was concentrated down several times from ether and dichloromethane to afford 5-bromo-2-isocyanato-N,N-dimethyl-benzamide as a yellow power. 1H-NMR (250 MHz, d6-DMSO) δ 7.95 (d, J=2.4 Hz, 1H), 7.80 (dd, J=6.3, 2.7 Hz, 1H), 7.16 (d, J=8.88 Hz, 1H), 3.10 (s, 6H).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](Cl)=[O:29])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:19])=[O:29])=[CH:23][CH:22]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: CN1CCN(c2nn(N)c(=O)c3ccccc23)CC1
Product: CN1CCN(c2nn(NC(=O)Cc3ccc(Cl)cc3)c(=O)c3ccccc23)CC1

Procedure:
The product from Example 107B and (4-chlorophenyl)acetyl chloride were processed using a method similar to that described in Example 4C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 11.55 (s, 1H), 9.77 (s, 1H), 8.32 (d, J=7.9, 1H), 8.03-7.97 (m, 2H), 7.96-7.89 (m, 1H), 7.45-7.36 (m, 4H), 3.68 (s, 2H), 3.65-3.50 (m, 4H), 3.08-2.98 (m, 2H), 2.91 (s, 3H), 2.49-2.44 (buried m, 2H); MS (APCI+) M/Z 412 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:15]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:15])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]cnc2cc(Br)ccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2cc(Br)ccc12

Procedure:
Reflux a solution of 7-bromo-3H-quinazolin-4-one (1.24 g, 0.0055 mol) in POCl3 for 3.5 h. Remove the excess POCl3 under reduced pressure and partition the residue between EtOAc and saturated aqueous NaHCO3. Dry the EtOAc layer and remove the solvent under reduced pressure to give 7-bromo-4-chloro-quinazoline as a yellow solid.
Reaction SMILES: [O:1]=[O+:2][O-].[C:4]([O:8][CH2:9]C)([CH3:7])([CH3:6])[CH3:5].[O:11]=[O+][O-].OO>C(OC)(C)(C)C>[CH:9]([O:8][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:11].[OH:1][OH:2]
Reactant: O=[O+][O-]
Reactant: CCOC(C)(C)C
Agent: OO
Solvent: COC(C)(C)C
Product: CC(C)(C)OC=O

Procedure:
Referring to FIG. 12, primary and secondary reactions of MTBE with Ozone are shown. Karpel vel Leitner, R. N., A. L Papailhous, J. P. Crove, J. Payrot, and M. Dore (1994) “Oxidation of Methyl tert-Butyl Ether (MTBE) and Ethyl tert-Butyl Ether (ETBE) by Ozone and Combined Ozone/Hydrogen Peroxide” Ozone Science and Engineering 16, 41-54, described reaction pathways of ozone and MTBE in dilute aqueous solution using controlled experimental conditions. The primary reaction (90% of the consumed mass of MTBE) results in the formation of tert-butyl formate and hydrogen peroxide. A second parallel reaction (less than 10% of the consumed mass of MTBE) generates formaldehyde, TBA, and oxygen.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N:25]5[CH2:33][C:32]6[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=6)[C:26]5=[O:34])[C:20]=4[CH3:35])=[CH:9][CH:10]=[C:11]([C:16]([NH2:18])=[O:17])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1.[C:36](O)(=[O:39])[CH2:37][OH:38].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>C(#N)C.C1COCC1>[OH:39][CH2:36][C:37]([NH:1][CH2:2][C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N:25]5[CH2:33][C:32]6[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=6)[C:26]5=[O:34])[C:20]=4[CH3:35])=[CH:9][CH:10]=[C:11]([C:16]([NH2:18])=[O:17])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)=[O:38]
Reactant: O=C(O)CO
Reactant: Cc1c(-c2ccc(C(N)=O)c3[nH]c4cc(CN)ccc4c23)cccc1N1Cc2ccccc2C1=O
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC#N
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(C(N)=O)c3[nH]c4cc(CNC(=O)CO)ccc4c23)cccc1N1Cc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.7 %

Procedure:
A solution of crude 7-(aminomethyl)-4-(2-methyl-3-(1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide (Example 33-1, 25 mg, 0.054 mmol), glycolic acid (8.26 mg, 0.109 mmol), HOAT (13.30 mg, 0.098 mmol), and EDC (20.81 mg, 0.109 mmol) in acetonitrile-THF (2:1) (5 mL) was treated with DIEA (0.028 mL, 0.163 mmol) and stirred at rt overnight. The mixture was concentrated and purified by preparative HPLC. The appropriate effluent fractions were concentrated to afford an aqueous suspension, which was treated with NaHCO3 (aq). The precipitate was collected by filtration, washed with water and dried to provide 7-((2-hydroxyacetamido)methyl)-4-(2-methyl-3-(1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide (17 mg, 59%). 1H NMR (400 MHz, DMSO-d6) δ 11.49 (1H, s), 8.22-8.28 (1 H, m), 8.17 (1 H, br. s.), 7.97-8.05 (1 H, m), 7.81 (1 H, d, J=7.5 Hz), 7.69 (2 H, d, J=3.7 Hz), 7.54-7.66 (3 H, m), 7.42-7.54 (2 H, m), 7.28-7.38 (1H, m), 7.03 (1 H, d, J=7.9 Hz), 6.94-7.00 (1 H, m), 6.86-6.94 (1 H, m), 5.45 (1 H, br.), 4.88-5.05 (2 H, m), 4.33-4.48 (2 H, m), 3.88 (2 H, s), 1.83 (3 H, s). Mass spectrum m/z 519.2 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH2:9][OH:10].[Cl:11][C:12]1[CH:17]=[N:16][CH:15]=[C:14](Cl)[N:13]=1>>[Cl:11][C:12]1[CH:17]=[N:16][CH:15]=[C:14]([O:10][CH2:9][CH2:8][CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[N:13]=1
Reactant: Clc1cncc(Cl)n1
Reactant: OCCCc1ccccn1
Product: Clc1cncc(OCCCc2ccccn2)n1

Procedure:
The title compound was prepared according to the procedure of example 50, step 1, starting from 2-pyridinepropanol (4.08 g, 29.7 mmol), K-t-BuO (3.17 g, 28.3 mmol) and 2,6-dichloropyrazine (3.69 g, 24.8 mmol). The yield of the title compound was 5.18 g (84%) and was obtained as an oil. Anal. (C12H12ClN3O) C, H, N.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18](Cl)=[CH:17][C:16]=2[CH3:23])[C:8]=1[N+:24]([O-])=O)[CH2:4][CH3:5])[CH3:2]>C(O)C.[Pd]>[CH3:21][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:23])[C:15]=1[O:14][C:9]1[C:8]([NH2:24])=[C:7]([NH:6][CH:3]([CH2:1][CH3:2])[CH2:4][CH3:5])[CH:12]=[C:11]([CH3:13])[N:10]=1
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cccc2C)c1N
Yield: 54.2 %

Procedure:
A mixture of (1-ethyl-propyl)-[6-methyl-3-nitro-2-(4-chloro-2,6-dimethyl-phenoxy)-pyridin-4-yl]-amine (800 mg, 2.12 mmol) and 160 mg of 10% Pd/C in 150 ml of ethanol was hydrogenated at 50 psi overnight. The mixture was filtered through Celite™ and the filtrate was concentrated to dryness to give a purple glass form (810 mg) which was purified through silica gel column chromatography using 1:1 chloroform:hexane as eluent to give the title compound as tan crystals (360 mg), mp 98–100° C. 1H NMR (CDCl3) δ 7.05 (m, 3H), 6.11 (s, 1H), 4.00 (brs, 1H), 3.28 (m, 1H), 3.09 (brs, 2H), 2.14 (s, 9H), 1.45–1.75 (m, 4H), 0.98 (t, 6H) ppm. The corresponding HCl salt was prepared as white solid, mp 158–162° C., 1H NMR(D2O) δ 7.27 (s, 3H), 6.67 (s, 1H), 3.65 (m, 1H), 2.27 (s, 3H), 2.16 (s, 6H), 1.45–1.80 (m, 4H), 0.93 (t, 6H) ppm.
Reaction SMILES: C([C:3]1[C:4]([C:16]([NH2:18])=[O:17])=[N:5][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11](Br)[CH:10]=2)[C:7]=1[CH3:8])C.[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CC.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:8][C:7]1[N:6]([C:9]2[CH:10]=[C:11]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][C:20]([F:19])([F:32])[F:31])[CH:12]=[CH:13][CH:14]=2)[N:5]=[C:4]([C:16]([NH2:18])=[O:17])[CH:3]=1
Reactant: OB(O)c1ccccc1OC(F)(F)F
Reactant: CCc1c(C(N)=O)nn(-c2cccc(Br)c2)c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCO
Solvent: Cc1ccccc1
Product: Cc1cc(C(N)=O)nn1-c1cccc(-c2ccccc2OC(F)(F)F)c1
Temperature: 90 °C
Yield: 93.4 %

Procedure:
To a solution of ethyl 1-(3-bromophenyl)-5-methyl-1H-pyrazole-3-carboxamide (0.237 g, 0.8 mmol) and 2-trifluoromethoxyphenyl boronic acid (0.262 g, 1.2 mmol) in n-propanol/toluene (1.27 ml:0.42 ml) mixture were added tetrakis(triphenylphosphine)palladium (0.019 g, 0.01 mmol) and 2M sodium carbonate (0.84 ml). The reaction mixture was heated at 90° C. for 16 hours, and then cooled and partitioned between ethyl acetate and water. The organic phase was washed with saturated sodium bicarbonate and brine, then dried over sodium sulfate and concentrated. The crude product was purified by silica-gel column chromatography (3.5:1.5 hexanes/acetone) to give the product (0.270 g, 88%) as a solid.