Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[CH:3]2[CH2:7][CH2:8][CH:9]=[CH:10][CH:2]12.[Cl:12][C:13]1[C:19]([CH2:20][O:21][CH2:22][CH3:23])=[CH:18][C:16]([NH2:17])=[C:15]([F:24])[CH:14]=1>>[Cl:12][C:13]1[C:19]([CH2:20][O:21][CH2:22][CH3:23])=[CH:18][C:16]([N:17]2[C:1](=[O:11])[C:2]3[CH2:10][CH2:9][CH2:8][CH2:7][C:3]=3[C:4]2=[O:6])=[C:15]([F:24])[CH:14]=1
Reactant: CCOCc1cc(N)c(F)cc1Cl
Reactant: O=C1OC(=O)C2CCC=CC12
Product: CCOCc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl

Procedure:
Tetrahydrophthalic anhydride (0.58 g, 0.0039 mole), and 4-chloro-5-ethoxymethyl-2-fluoroaniline in glacial acetic acid from Step C was heated at 100° C. overnight. Acetic acid was removed under reduced pressure. The residue was dissolved in ethyl acetate (100 ml) and washed successively with a saturated aqueous solution of sodium bicarbonate (5×50 ml) and a 10% aqueous solution of hydrochloric acid. The dried (magnesium sulfate) organic layer was concentrated under reduced pressure. The residue was passed through a column of silica gel eluting with ethyl acetate:heptane (3:17). Appropriate fractions were combined and concentrated under reduced pressure yielding N-[4-chloro-2-fluoro-5-ethoxymethylphenyl]-3,4,5,6-tetrahydrophthalimide as an amber solid, m.p. 89°-91° C. The nmr spectrum was consistent for the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([NH2:11])[CH:10]=1)[C:5]([OH:7])=[O:6].C(N([CH2:17][CH3:18])CC)C.[C:19](Cl)(=[O:29])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>C(Cl)Cl.C1COCC1>[O:29]=[C:19]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([NH:11][C:19](=[O:29])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:17][CH3:18])[CH:10]=1)[C:5]([OH:7])=[O:6])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCN(CC)CC
Reactant: CCCCCCCCCC(=O)Cl
Reactant: Nc1cc(N)cc(C(=O)O)c1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCCCCCCC(=O)Nc1cc(NC(=O)CCCCCCCCC)cc(C(=O)O)c1
Temperature: 25 °C
Yield: 56.6 %

Procedure:
To a mixture of 5 g (0.033 mol) of 3,5-diaminobenzoic acid in 100 ml of methylene chloride, 50 ml of THF and 18 ml (0.13 mol) of triethylamine stirred at room temperature was added 17 ml (0.08 mol) of decanoyl chloride dropwise over 10 minutes. The reaction mixture was stirred for 18 hours, filtered and the filtrate was concentrated at reduced pressure. Water was added to the residue and the product was extracted with ethyl acetate. The dried extract was concentrated at reduced pressure and the solid residue was recrystallized twice from methanol-water to give 8.6 g (57% yield, mp 208°-209°) of 3,5-bis[(1-oxodecyl)amino]benzoic acid.
Reaction SMILES: C([N:8]1[CH:13]=[CH:12][C:11]2=[C:14]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[N:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[N:16]=[C:10]2[C:9]1=O)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:35]>>[Cl:35][C:9]1[C:10]2=[N:16][N:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[C:14]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=[C:11]2[CH:12]=[CH:13][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1c2nn(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)c2ccn1Cc1ccccc1
Product: Clc1ccc(-c2c3ccnc(Cl)c3nn2-c2ccc(Cl)cc2Cl)cc1
Yield: 58 %

Procedure:
A stirred suspension of 6-benzyl-3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-2,6-dihydropyrazolo[3,4-c]pyridin-7-one (I-1A-1b; 153 mg, 0.32 mmol) in POCl3 (3.5 ml) was heated to reflux for 48 hr. After the reaction was cooled and concentrated, in vacuo, an ethyl acetate solution of the residue was washed with saturated aqueous NaHCO3 and then brine. The solution was dried (Na2SO4), concentrated, in vacuo, and then purified on a Biotage™ Flash 12M column using 0-15-30% ethyl acetate in hexanes to afford I-1A-1c as an off-white solid (75 mg, 58%): +ESI MS (M+1) 408.0; 1H NMR (400 MHz, CD2Cl2) δ 8.01 (d, J=5.8 Hz, 1H), 7.57-7.53 (m, 3H), 7.47 (dd, J=8.7, 2.1 Hz, 1H), 7.41 (d, J=8.7 Hz, 2H), 7.27 (d, J=8.7 Hz, 2H).
Reaction SMILES: [CH3:1][C:2](C)([CH3:7])[CH2:3][CH2:4]CC>C(Cl)(Cl)(Cl)Cl>[CH3:3][C:2]([CH3:7])=[CH2:1].[CH3:7][C:2]([CH:3]=[CH2:4])=[CH2:1]
Reactant: CCCCC(C)(C)C
Solvent: ClC(Cl)(Cl)Cl
Product: C=C(C)C
Product: C=CC(=C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 3.5% solution of 10 g of poly(isobutylene-co-isoprene) was prepared in 96.5% of a 1:1 mixture of trimethylpentane and CCl4. The solution was purged with N2 and with the temperature adjusted to 75° C., 0.2 g of benzoyl peroxide was added and the solution stirred for 1 hour. After this period 1.0 g of methylmethacrylate was added and the system was stirred for 16 hours under a N2 atmosphere. At the end of 16 hours, 0.3 g of benzoyl peroxide or azobisisobutyronitrile was added and 40 g of methyl methacrylate was added over an hour. The polymerization was continued for 16 hours with constant mechanical stirring under a N2 atmosphere. The reaction mixture was cooled to room temperature and the particles cleaned by successive steps of centrifugation, decanting, and resuspension. The particles were freeze dried to a powder.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:5]=1[OH:16])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:5]=1[OH:16]
Reactant: O=[N+]([O-])c1ccc(-c2ccccc2)cc1O
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(-c2ccccc2)cc1O
Reaction time: 8 h

Procedure:
A solution of 2-nitro 5-phenyl phenol (1.2 g, 5.5 mmol) in methanol was treated with 10% Pd/C (1.2 g). The reaction mixture was flushed with hydrogen and allowed to stir overnight. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to afford desired (1.01 g, 98%). EI-MS m/z 186 (M+H)+
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:23][CH2:24][CH2:25][CH2:26]Br>CC#N>[Br-:23].[Br:23][CH2:24][CH2:25][CH2:26][N+:1]12[CH2:6][CH2:5][C:4]([C:9]([OH:10])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)([CH2:3][CH2:2]1)[CH2:7][CH2:8]2
Reactant: BrCCCBr
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Solvent: CC#N
Product: OC(c1ccccc1)(c1ccccc1)C12CC[N+](CCCBr)(CC1)CC2
Product: [Br-]
Yield: 43 %

Procedure:
Following the general procedure outlined in Example 3, 1-azabicyclo[2.2.2]oct -4-yl(diphenyl)methanol (0.0979 g, 0.334 mmol) and 1,3-dibromopropane (0.35 mL, 3.448 mmol) in 2 CH3CN/3CHCl3 (15.0 mL) were reacted to give the desired product (0.0712 g, 43.1%). EI-MS m/z 415(M+) Rt (1.79 min).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[NH:12][CH:13]([C:21]4[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=4)[CH:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:5]([C:6]=23)=[N:4][NH:3]1.C(Cl)Cl.[CH2:32]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH:35]1[CH3:40])[CH3:33].[BH4-].[Na+]>CC(O)=O>[CH2:32]([N:34]1[CH2:39][CH2:38][N:37]([CH2:25][C:24]2[CH:23]=[CH:22][C:21]([CH:13]3[NH:12][C:7]4[C:6]5[C:5](=[N:4][NH:3][C:2](=[O:1])[C:11]=5[CH:10]=[CH:9][CH:8]=4)[CH:14]3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:28][CH:27]=2)[CH2:36][CH:35]1[CH3:40])[CH3:33]
Reactant: CCN1CCNCC1C
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCN1CCN(Cc2ccc(C3Nc4cccc5c(=O)[nH]nc(c45)C3c3ccccc3)cc2)CC1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
To a stirred solution of 4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (86 mg, 0.23 mmol) in dryness DCM (15 mL) was added HOAc followed by 1-ethyl-2-methylpiperazine (90 mg, 0.7 mmol), after the addition the mixture was stirred at room temperature overnight. Then the mixture was cooled to 0° C. Sodium borohydride (85 mg, 1.4 mmol) was added. After the addition, the mixture was stirred at this temperature for 12 hr. DCM was removed under reduced pressure. The residue was washed with ethyl acetate/methanol (10/1) and filtered. The filtrate was concentrated to give the crude product, which was purified by prep-HPLC to give the title compound as white solid (90 mg, yield 71%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.30 (t, 3H), 1.42 (m, 3H), 3.23 (s, 1H), 3.47-3.56 (m, 6H), 3.80 (t, 2H), 4.46 (m, 3H) 4.91 (m, 10H), 7.20-7.29 (m, 3H), 7.30-7.32 (m, 3H), 7.46-7.48 (m, 3H), 7.59 (m, 1H), 7.69 (t, 1H). LC-MS (ESI) m/z: 552 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7](B(O)O)[N:8]2[CH3:11])=[CH:4][CH:3]=1.[C:15]([C:18]1[CH:19]=[C:20](Br)[CH:21]=[N:22][CH:23]=1)(=[O:17])[CH3:16]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:20]3[CH:19]=[C:18]([C:15](=[O:17])[CH3:16])[CH:23]=[N:22][CH:21]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(=O)c1cncc(Br)c1
Reactant: Cn1c(B(O)O)cc2ccc(Cl)cc21
Product: CC(=O)c1cncc(-c2cc3ccc(Cl)cc3n2C)c1

Procedure:
6-Chloro-1-methyl-indole-2-boronic acid and 5-acetyl-3-bromo-pyridine are processed according to the method described in Example 100 to give 1-[5-(6-chloro-1-methyl-1H-indol-2-yl)-pyridin-3-yl]-ethanone. MS (ESI) m/z 284.98 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[CH:9][NH:8][C:7]2=O)[CH3:2].O=P(Cl)(Cl)[Cl:19]>C1(C)C=CC=CC=1>[Cl:19][C:7]1[C:6]2[C:11](=[CH:12][C:13]([O:14][CH3:15])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)[N:10]=[CH:9][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOc1cc2c(=O)[nH]cnc2cc1OC
Solvent: Cc1ccccc1
Product: CCOc1cc2c(Cl)ncnc2cc1OC
Temperature: 125 °C
Yield: 34 %

Procedure:
According to the procedure described in Example 6A Step 5, a mixture of 6-ethoxy-7-methoxyquinazolin-4(3H)-one (0.52 g, 2.36 mmol) and POCl3 (1 mL) in toluene (10 mL) was heated at 125° C. for 3.5 hours. The residue was purified by silica gel chromatography with 0-25% EtOAc/hexane as eluants to afford 4-chloro-6-ethoxy-7-methoxyquinazoline as a solid (0.19 g, 34%). 1H NMR (300 MHz, CDCl3) δ 8.9 (s, 1H), 7.4 (s, 1H), 7.3 (s, 1H), 4.3 (t, 2H), 4.1 (s, 3H), 1.6 (t, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[C:11]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[N:10]=1)#[N:2].[Br:28][C:29]1[N:34]=[C:33](NC)[CH:32]=[CH:31][CH:30]=1.C1N=C[N:39](C(N2C=NC=C2)=O)[CH:38]=1>CN(C=O)C>[Br:28][C:29]1[N:34]=[C:33]([CH2:38][NH:39][C:13](=[O:14])[C:12]2[CH:16]=[CH:17][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]#[N:2])=[N:10][C:11]=2[NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: N#Cc1ccccc1-c1ccc(C(=O)O)c(NCCc2cccc(F)c2)n1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CNc1cccc(Br)n1
Solvent: CN(C)C=O
Product: N#Cc1ccccc1-c1ccc(C(=O)NCc2cccc(Br)n2)c(NCCc2cccc(F)c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of 6-(2-cyanophenyl)-2-(3-fluorophenethylamino)nicotinic acid (582 mg, 1.61 mmol) and 6-bromo-pyridin-2-yl-methylamine (300 mg, 1.61 mmol) in DMF was added CDI (261 mg, 1.61 mmol). The reaction mixture was stirred at r.t. for 2 h. The reaction mixture was purified on RP-HPLC to give N-((6-bromopyridin-2-yl)methyl)-6-(2-cyanophenyl)-2-(3-fluorophenethylamino)nicotinamide (700 mg, 82%) LRMS (M+H+) m/z 530.1.
Reaction SMILES: O.O.O.O.O.O.[Cl-:7].[Cl-:8].[Ni+2:9].[CH:10]1[CH:15]=[C:14]([S:16]([O-:19])(=[O:18])=[O:17])[CH:13]=[C:12]([P:20]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([S:37]([O-:40])(=[O:39])=[O:38])[CH:32]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([S:27]([O-:30])(=[O:29])=[O:28])[CH:22]=2)[CH:11]=1.[Na+:41].[Na+].[Na+]>O>[Cl:7][Ni:9][Cl:8].[CH:35]1[CH:34]=[C:33]([S:37]([O-:40])(=[O:39])=[O:38])[CH:32]=[C:31]([P:20]([C:12]2[CH:11]=[CH:10][CH:15]=[C:14]([S:16]([O-:19])(=[O:17])=[O:18])[CH:13]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([S:27]([O-:30])(=[O:29])=[O:28])[CH:22]=2)[CH:36]=1.[Na+:41].[Na+:41].[Na+:41]
Reactant: [Ni+2]
Reactant: [Cl-]
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Agent: [Na+]
Solvent: O
Product: Cl[Ni]Cl

Procedure:
Nickel chloridehexahydrate (0.05 mols) was reacted with tppts (0.12 mols) in water sufficient to dissolve and formed complex was precipitated by ethanol
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([N:11]3[C:19]4[CH:18]=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=4[C:13]4[CH2:21][N:22]([CH3:25])[CH2:23][CH2:24][C:12]3=4)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[CH:26]([O-])=[O:27].[NH4+]>CO.[Pd]>[CH3:25][N:22]1[CH2:23][CH2:24][C:12]2[N:11]([C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[CH2:1][N:2]([CH:26]=[O:27])[CH2:3][CH2:4]4)[C:19]3[CH:18]=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[C:13]=2[CH2:21]1
Reactant: Cc1ccc2c(c1)c1c(n2-c2ccc3cnccc3c2)CCN(C)C1
Reactant: O=C[O-]
Agent: [Pd]
Agent: [NH4+]
Solvent: CO
Product: Cc1ccc2c(c1)c1c(n2-c2ccc3c(c2)CCN(C=O)C3)CCN(C)C1
Yield: 27.8 %

Procedure:
To a de-aerated solution of 5-isoquinolin-6-yl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (35 mg, 0.10 mmol) in MeOH (5 mL) were added 10% Pd—C (18 mg) and ammonium formate (68 mg, 1.07 mmol). The reaction mixture was refluxed for 15 h and filtered through Celite. The filtrate was concentrated under reduced pressure to afford crude material, which was purified by column chromatography using silica (100:200) and 3% MeOH-DCM to yield 6-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-3,4-dihydro-1H-isoquinoline-2-carbaldehyde (10 mg). 1H NMR (HCl salt, CD3OD) δ (ppm): 8.2 (s, 1H), 7.41 (s, 1H), 7.3 (s, 1H), 7.25 (m, 2H), 7.1 (d, 1H), 7.03 (d, 1H), 4.7 (d, 1H), 4.4 (d, 1H), 3.8 (m, 3H), 3.57 (m, 3H), 3.17 (s, 3H), 3.0 (m, 4H), 2.4 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][C@@H:7]([C:9]([OH:11])=[O:10])[NH2:8])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:18]O>C(OCC)(=O)C>[CH3:18][O:10][C:9](=[O:11])[C@H:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:13][CH:12]=1)[NH2:8]
Reactant: Nc1ccc(C[C@H](N)C(=O)O)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](N)Cc1ccc(N)cc1
Yield: 88.5 %

Procedure:
To a stirred solution of p-aminophenylalanine (2.05 g, 9.9 mmol) in methanol (100 ml) at 0° C. was added thionyl chloride (20 ml) dropwise. Upon complete addition the reaction mixture was heated under reflux. After 24 hours the reaction mixture was cooled and reduced under pressure to give a brown oil. The brown oil was taken up in ethyl acetate (200 ml) and washed with saturated sodium bicarbonate solution (200 ml). The aqueous layer was further extracted with ethyl acetate (5×200 ml). The combined organic layer was dried over MgSO4 and reduced under pressure to yield the title compound as a brown solid (1.7 g, 88.5%).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[C:18]([CH:19]=[CH2:20])=[CH:17][C:16]([C:21]#[N:22])=[CH:15][C:14]=1[NH:23][C:24]1[N:29]=[C:28]([NH:30][CH:31]2[CH2:33][CH2:32]2)[C:27]2=[N:34][CH:35]=[C:36]([C:37]#[N:38])[N:26]2[N:25]=1>C(Cl)(Cl)Cl>[Cl:12][C:13]1[C:18]([CH:19]2[CH2:20][O:9]2)=[CH:17][C:16]([C:21]#[N:22])=[CH:15][C:14]=1[NH:23][C:24]1[N:29]=[C:28]([NH:30][CH:31]2[CH2:32][CH2:33]2)[C:27]2=[N:34][CH:35]=[C:36]([C:37]#[N:38])[N:26]2[N:25]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1cc(C#N)cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c1Cl
Solvent: ClC(Cl)Cl
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(C2CO2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.9 %

Procedure:
Added MCPBA (70% wet, 3330 mg, 13.5 mmol) in portions to an ice-cooled suspension of 2-((2-chloro-5-cyano-3-vinylphenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 399)(339 mg, 0.900 mmol) in CHCl3 (90 mL). The bath was removed and the reaction was left stirring at room temperature for 2 days. This was diluted with CHCl3 and washed with 5% aq. NaHSO3 solution and then 3 times 1 N Na2CO3 solution. After drying with sodium sulfate, the solvent was removed and radial silica gel chromatography eluting with DCM containing 0 to 10% EtOAc afforded 2-((2-chloro-5-cyano-3-(oxiran-2-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (293 mg) as a white solid.
Reaction SMILES: [F:1][C:2]([F:11])([C:7]([F:10])([F:9])[F:8])[C:3](I)([F:5])[F:4].C1([Mg]Br)C=CC=CC=1.[Cl:20][CH2:21][C:22]([CH2:24][Cl:25])=[O:23].C(O)(=O)C>C(OCC)C.O>[Cl:20][CH2:21][C:22]([C:3]([F:5])([F:4])[C:2]([F:11])([F:1])[C:7]([F:10])([F:9])[F:8])([OH:23])[CH2:24][Cl:25]
Reactant: FC(F)(F)C(F)(F)C(F)(F)I
Reactant: O=C(CCl)CCl
Agent: Br[Mg]c1ccccc1
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: O
Product: OC(CCl)(CCl)C(F)(F)C(F)(F)C(F)(F)F
Temperature: -20 °C
Reaction time: 1 h

Procedure:
Heptafluoropropyliodide (5 g, 6.9 mmole) was stirred at -78° C. in dry diethylether (20 ml). A solution of phenylmagnesium bromide in ethyl ether (10 ml of a 1.88 M solution) was added over a half-hour period. When this addition was complete, the reaction mixture was stirred at -20° C. for one hour. To this solution was added, at -78° C., 1,3-dichloroacetone (3.25 g, 25.6 mmole) in dry diethylether (20 ml) dropwise, keeping the temperature below -65° C. The mixture was then stirred four hours between -20° and -50° C. Glacial acetic acid (3 ml) in diethylether (5 ml) was added slowly followed by water (15 ml). The mixture was allowed to warm to 5° C. and then the phases were separated. The aqueous phase was washed with ether (2×25 ml). The ethereal extracts were combined, dried (MgSO4) and evaporated to give crude 1,3-dichloro-2-(heptafluoropropyl)propan-2-ol, which was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[NH2:19][C:20]1[CH:38]=[C:37]([Cl:39])[C:23]([CH2:24][CH:25]2[CH2:29][CH2:28][N:27]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:26]2=[O:36])=[C:22]([Cl:40])[CH:21]=1>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8]([NH:19][C:20]2[CH:38]=[C:37]([Cl:39])[C:23]([CH2:24][CH:25]3[CH2:29][CH2:28][N:27]([CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)[C:26]3=[O:36])=[C:22]([Cl:40])[CH:21]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(Cl)c(CC2CCN(C3CCCCC3)C2=O)c(Cl)c1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1cc(Cl)c(CC2CCN(C3CCCCC3)C2=O)c(Cl)c1
Yield: 58 %

Procedure:
Place 3-Chloro-2-methyl-benzenesulfonyl chloride (160 mg, 0.70 mmol) in CH2Cl2 (10 mL) and cool to 0° C. Slowly add pyridine (0.06 mL, 0.70 mmol) and stir for 15 minutes. Add 3-(4-Amino-2,6-dichloro-benzyl)-1-cyclohexyl-pyrrolidin-2-one (Example 183), 200 mg, 0.59 mmol) and stir for 12 hours. Quench with 1N HCl and extract with dichloromethane. Wash the extract with NaHCO3, brine. Dry over sodium sulfate, filter, and concentrate. Purify by silica gel (10-80% ethyl acetate in hexanes) to afford 181 mg (58%) of the title compound: Mass spectrum (apci) m/z=529.05 (M+H).
Reaction SMILES: [C:1]1(=O)[C:13]2[C:5]([C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:4][CH:3]=[CH:2]1.[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22].[OH-:23].[Na+]>C(S)CCCCCCCCCCC>[OH:22][C:17]1[CH:18]=[CH:19][C:20]([C:13]2([C:1]3[CH:2]=[CH:3][C:6]([OH:23])=[C:5]([CH3:13])[CH:4]=3)[C:5]3[CH:4]=[CH:9][CH:8]=[CH:7][C:6]=3[C:11]3[C:12]2=[CH:1][CH:2]=[CH:3][CH:10]=3)=[CH:21][C:16]=1[CH3:15]
Reactant: O=C1C=CC=C2C1=Cc1ccccc12
Reactant: [OH-]
Reactant: Cc1ccccc1O
Agent: CCCCCCCCCCCCS
Agent: [Na+]
Product: Cc1cc(C2(c3ccc(O)c(C)c3)c3ccccc3-c3ccccc32)ccc1O
Temperature: 80 °C
Yield: 813.8 %

Procedure:
A reaction was carried out by (a) feeding 23.0 g of fluorenone, 0.4 g of dodecyl mercaptan, 276.0 g of 2-methyl phenol, and 17.5 g of Nafion (registered trademark) NR50 (perfluorosulfonic acid cation-exchange resin manufactured by DuPont) into a 500 ml glass reactor vessel equipped with a stirrer, a condenser and a thermometer, and (b) stirring a mixture at 95° C. for 8 hours. The amount of remaining fluorenone was determined by HPLC, and found to be 0.1% or less. The ion exchange resin was removed by filtration to obtain a reaction mixture liquid. To the reaction mixture liquid thus obtained, 0.5 g of 29% sodium hydroxide aqueous solution was added, and thereafter 95.0 g of 2-methyl phenol was distilled away from an organic phase by concentration under reduced pressure. To an obtained concentrated liquid, 161 g of toluene and 23 g of water were added, and the mixture liquid was stirred at 80° C. Thereafter, an aqueous phase was separated and removed, and a target substance partitioned in the organic phase was recovered. The organic phase was further washed twice with 23 g of water, and cooled to 10° C. Then, precipitated crystals were subjected to filtration and drying to obtain 38.5 g of 9,9-bis(4-hydroxy-3-methylphenyl)fluorene (yield: 85.7%, LC purity: 99.5%). Obtained 9,9-bis(4-hydroxy-3-methylphenyl)fluorene was dissolved by heat at 230° C. for 2 hours. The 9,9-bis(4-hydroxy-3-methylphenyl)fluorene thus dissolved show a hue of 2 in Gardner. The total amount of toluene used in the production was 4.2 parts by weight relative to 1 part by weight of the 9,9-bis(4-hydroxy-3-methylphenyl)fluorene.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])([CH3:7])[C:4]([OH:6])=[O:5].Br[CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])([CH3:7])[C:4]([O:6][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1)=[O:5]
Reactant: CC(C)(C(=O)O)C(F)(F)F
Reactant: BrCc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C(=O)OCc1ccc2ccccc2c1)C(F)(F)F
Temperature: 30 °C
Reaction time: 8 h

Procedure:
A mixture of 3,3,3-trifluoro-2,2-dimethylpropanoic acid (2.96 g, 19.0 mmol), 2-(bromomethyl)naphthalene (4.19 g, 19.0 mmol), and potassium carbonate (7.86 g, 56.9 mmol) in 50 ml of anhydrous DMF was stirred at 30° C. overnight. Diluted with 150 ml of EtOAc, washed with 150 ml of H2O, 2×100 ml of 1N NaOH, 2×100 ml of 1N HCl, dried (Na2SO4) and concentrated to give an oil that was purified by ISCO using EtOAc in hexanes (5%) as eluents to provide the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:14][CH2:15][CH2:16][CH:17]([OH:27])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1.[Na].[I-].[K+]>CC(O)C.C(O)CCC>[ClH:14].[ClH:14].[F:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][CH2:18][CH:17]([OH:27])[CH2:16][CH2:15][N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)=[CH:21][CH:22]=1.[ClH:14]
Reactant: Cc1ccc(N2CCNCC2)cc1
Reactant: OC(CCCl)COc1ccc(F)cc1
Agent: [I-]
Agent: [K+]
Agent: [Na]
Solvent: CCCCO
Solvent: CC(C)O
Product: Cc1ccc(N2CCN(CCC(O)COc3ccc(F)cc3)CC2)cc1
Product: Cl

Procedure:
This compound was prepared according to the procedure of Example 97. A mixture of 1.8 g (0.01 mole) of 1-(4-methylphenyl)piperazine, 2.2 g (0.01 mole) of 4-chloro-1-(4-fluorophenoxy)-2-butanol, 5.2 g (0.05 mole) of anhydrous sodium carboate, and 0.1 g of potassium iodide in a total volume of 200 ml of 1-butanol gave a golden oil as residue. The hydrochloride was formed in 2-propanol saturated with hydrogen chloride and the collected solid was recrystallized from methanol-water-ethyl ether to give 1.8 g (41%) of white solid, m.p. 200°-205° C.
Reaction SMILES: [CH2:1]([CH:4]1[C:8]2[NH:9][C:10]([C:12]([O:14]C)=[O:13])=[CH:11][C:7]=2[CH2:6][CH2:5]1)[CH2:2][CH3:3].O.[OH-].[Li+].CO>C1COCC1>[CH2:1]([CH:4]1[C:8]2[NH:9][C:10]([C:12]([OH:14])=[O:13])=[CH:11][C:7]=2[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCCC1CCc2cc(C(=O)OC)[nH]c21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCCC1CCc2cc(C(=O)O)[nH]c21
Yield: 53.9 %

Procedure:
The title compound was synthesized from methyl 6-propyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.15 g, 0.72 mmol) and lithium hydroxide monohydrate (0.3 g, 7.24 mmol), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (10 mL) was used. The resulting product was purified by chromatography over silica gel (gradient 0 to 100% EtOAc in heptane over 20 min) to give the title compound (75 mg). 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.94 (t, J=7.0 Hz, 3H) 1.32-1.49 (m, 3H), 1.62-1.80 (m, 1H), 1.93-2.08 (m, 1H), 2.43-2.65 (m, 3H), 3.01 (br. s, 1H) 6.57 (s, 1H). LCMS m/e 249 (M−H) and 96% pure by HPLC.