Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[O:8][C:7]([C:14]([F:17])([F:16])[F:15])=[C:6]([C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1)[C:5]2=[O:28].[C:29]([Cu])#[N:30]>CN1C(=O)CCC1>[C:29]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[O:8][C:7]([C:14]([F:17])([F:16])[F:15])=[C:6]([C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1)[C:5]2=[O:28])#[N:30]
Reactant: N#C[Cu]
Reactant: COC(=O)c1ccc(-c2c(C(F)(F)F)oc3cc(OC)c(Br)cc3c2=O)cc1
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(-c2c(C(F)(F)F)oc3cc(OC)c(C#N)cc3c2=O)cc1
Temperature: 150 °C
Reaction time: 8 h
Yield: 40.8 %

Procedure:
To a solution of methyl 4-(6-bromo-7-methoxy-4-oxo-2-(trifluoromethyl)-4H-chromen-3-yl)benzoate (350 mg, 0.76 mmol) in NMP (3 mL) was added CuCN (340 mg, 3.8 mmol). The mixture was stirred at 150° C. for 8 h under the protection of nitrogen. The mixture was cooled to room temperature and quenched with water (10 mL) and filtered. The cake was washed with acetone (15 mL×2). The filtrate was concentrated in vacuo to give brown oil, which was purified by prep-TLC (PE/EA=5/1) to give product (125 mg, 40%) as a yellow solid. MS (ESI): 404.0 [M+1]+.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:14]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:15]=2[C:16]([OH:18])=[O:17])=O)=[C:4]1[CH3:26])[CH3:2].[CH3:27][N:28]([CH3:38])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]([CH3:37])[CH3:36])[CH:30]=1>C(OC(=O)C)(=O)C>[CH3:36][N:35]([CH3:37])[C:31]1[CH:30]=[C:29]([N:28]([CH3:38])[CH3:27])[CH:34]=[CH:33][C:32]=1[C:12]1([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:3]([CH2:1][CH3:2])[C:4]=2[CH3:26])[C:14]2[C:15](=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=2)[C:16](=[O:18])[O:17]1
Reactant: CN(C)c1cccc(N(C)C)c1
Reactant: CCn1c(C)c(C(=O)c2ccc([N+](=O)[O-])cc2C(=O)O)c2ccccc21
Solvent: CC(=O)OC(C)=O
Product: CCn1c(C)c(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3cc([N+](=O)[O-])ccc32)c2ccccc21
Temperature: 90 °C
Yield: 76.2 %

Procedure:
A mixture of 3.68 g (0.01 mole) of 2-[(1-ethyl-2-methyl-3-indolyl)carbonyl]-5-nitrobenzoic acid, prepared as described in part A above, and 2.0 g (0.012 mole) of N,N,N',N'-tetramethyl-m-phenylenediamine in 10.0 ml of acetic anhydride was heated at 90° C. for one hour and then allowed to cool to 25° C. The solid which separated was collected by filtration, washed with diethylether and dried to obtain 3.8 g of 3-[2,4-bis(dimethylamino)phenyl]-3-(1-ethyl-2-methyl-3-indolyl)-6-nitrophthalide (Formula III: R°=R1 =R3 =Y1 =H; R2 =NO2 ; R=R5 =CH3 ; R4 =N(CH3)2; R6 =CH2CH3) as an orange solid which melted over the range 185°-187° C. The nuclear magnetic resonance spectrum was in accord with the assigned structure. A benzene solution of this product developed a black-purple color when spotted on silica gel.
Reaction SMILES: C(O)(=O)C.[CH:5]1([CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12](/[CH:16]=[CH:17]/[N+:18]([O-:20])=[O:19])[CH:11]=2)[CH2:7][CH2:6]1.[BH4-].[Na+]>CS(C)=O>[CH:5]1([CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH2:17][N+:18]([O-:20])=[O:19])[CH:11]=2)[CH2:7][CH2:6]1
Reactant: O=[N+]([O-])/C=C/c1cccc(OCC2CC2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: O=[N+]([O-])CCc1cccc(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.8 %

Procedure:
To an acetic acid (3.7 mL) and dimethyl sulfoxide (63 mL) solution of 1-cyclopropylmethoxy-3-((E)-2-nitro-vinyl)-benzene (3.73 g, 17 mmol) described in Manufacturing Example 66-1-2 was added sodium borohydride (1.03 g, 27.2 mmol) at room temperature while cooling appropriately. This mixture was stirred for 4 hours at room temperature. That mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=10:1) to obtain the title compound (2.21 g, 59%).
Reaction SMILES: [CH:1]([C:3]1[C:4]([OH:15])=[C:5]([CH:11]=[C:12]([CH3:14])[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])=O.C([O-])([O-])=O.[K+].[K+].C(N(CC)CC)C.[F:29][C:30]([F:39])([F:38])/[CH:31]=[CH:32]/[C:33]([O:35][CH2:36][CH3:37])=[O:34].Cl>CS(C)=O>[CH3:14][C:12]1[CH:13]=[C:3]2[C:4](=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:11]=1)[O:15][CH:31]([C:30]([F:29])([F:39])[F:38])[C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:1]2
Reactant: CCOC(=O)c1cc(C)cc(C=O)c1O
Reactant: CCOC(=O)/C=C/C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCOC(=O)C1=Cc2cc(C)cc(C(=O)OCC)c2OC1C(F)(F)F
Temperature: 90 °C
Reaction time: 15 h
Yield: 42.3 %

Procedure:
A mixture of ethyl 3-formyl-2-hydroxy-5-methylbenzoate (6.18 g, 29.69 mmole), K2CO3 (8.19 g, 59.38 mmole), triethylamine (1.99 g, 118.75 mmole), and ethyl 4,4,4-trifluorocrotonate (19.95 g, 118.75 mmole) in anhydrous DMSO (40.0 mL) was heated to 90° C. under a dry N2 atmosphere for 5 hrs. The mixture was then cooled and allowed to stir at room temperature for 15 hours. The reaction was poured into 1.2 N HCl (100 mL) and extracted with EtOAc (2×100 mL). The combined extracts were washed with brine (100 mL), dried over MgSO4, filtered and concentrated in vacuo to give a dark red oil which was subject to flash chromatography (silica gel) and eluted with 100% CH2Cl2 to give a light orange solid (4.5 g, 42%): 1H NMR (acetone-d6/400 MHz) 7.84 (s, 1H), 7.61 (s, 1H), 7.46 (s, 1H), 5.86 (q, 1H, J=7.0 Hz), 4.30 (m, 4H), 2.31 (s, 3H), 1.33 (m, 6H).
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[C:9]([C:10]([OH:12])=[O:11])=[C:8]([O:13][CH3:14])[CH:7]=[CH:6][CH:5]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[Br:1][C:5]1[CH:6]=[CH:7][C:8]([O:13][CH3:14])=[C:9]([C:4]=1[CH3:3])[C:10]([OH:12])=[O:11]
Reactant: BrBr
Reactant: COc1cccc(C)c1C(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(Br)c(C)c1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.8 %

Procedure:
A mixture of bromine (102 ml, 2.0 mol) and acetic acid (225 ml) is added to a mixture of 50A (304.0 g, 1.8 mol),), sodium acetate (164.0 g, 2.0 mol) and acetic acid (3.0 l) at a temperature of 10 to 15° C. The reaction mixture is stirred at room temperature for 16 hours. The solid material is collected by vacuum filtration, washed with water and dried yielding off-white crystals 321.0 g (72.6.%), mp 81-83° C.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:14]O.O=S(Cl)[Cl:18]>C(Cl)Cl>[Cl:18][CH2:14][C:2]1[CH:3]=[CH:4][C:5]2[O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[C:9]=2[CH:1]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc2oc3ccccc3c2c1
Solvent: ClCCl
Product: ClCc1ccc2oc3ccccc3c2c1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 99 %

Procedure:
Dibenzo[b,d]furan-2-ylmethanol CCH 34116 (174 mg, 878 μmol) was immediately dissolved in dry CH2Cl2 (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer before slow addition of SOCl2 (1.0 mL, 13.78 mmol) and the reaction mixture was stirred for 20 min at 80° C. under microwave irradiation. After cooling to RT, the volatiles were removed at 40° C. under vacuum. The residue was taken up in CH2Cl2 (20 mL) before concentration back to dryness at 40° C. under vacuum (done 3 times) to give 2-(chloromethyl)dibenzo[b,d]furan CCH 34116-2 as a grey solid (189 mg, 99% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20])[CH:5]=[C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15].C(=O)([O-])[O-].[Na+].[Na+].[CH:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][C:30]=1B(O)O>C1(C)C=CC=CC=1.C(O)C.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>[CH3:20][O:19][C:18]1[C:17]([O:21][CH3:22])=[CH:16][C:4]([CH:5]=[C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]2=[O:15])=[C:3]([C:31]2[CH:30]=[CH:29][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=2)[CH:2]=1
Reactant: COc1cc(C=C2C(=O)Nc3ccccc32)cc(Br)c1OC
Reactant: OB(O)c1ccc2ccccc2c1
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: CCO
Solvent: Cc1ccccc1
Product: COc1cc(C=C2C(=O)Nc3ccccc32)c(-c2ccc3ccccc3c2)cc1OC
Reaction time: 12 h
Yield: 30.9 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0) (0.02 g) was added to a solution of 3-(3-bromo-4,5-dimethoxybenzylidene)-1,3-dihydroindol-2-one (0.20 g) in toluene (1 ml) and ethanol (1 ml) followed by addition of 2M aqueous sodium carbonate (1.1 ml). To this mixture was added naphthalene-2-boronic acid (0.11 g), and the mixture was held at 100° C. in a sealed tube for 12 hours. The precipitate which formed was filtered, washed with ethanol and then dissolved in 20% methanol/toluene, filtered and concentrated. The resulting solid was triturated with hexanes and dried to afford 0.07 g (29%) of 3-(4,5-dimethoxy-2-naphthalen-2-ylbenzylidene)-1,3-dihydroindol-2-one as an orange solid.
Reaction SMILES: [CH3:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[C:5](/[CH:20]=C/C3C=CC=CC=3)[CH:6]=[CH:7][C:8]=2[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:3]1.S(OOS([O-])(=O)=O)([O-])(=O)=[O:29].[K+].[K+].[O-]S([O-])=O.[Na+].[Na+]>CN(C=O)C>[CH:20]([C:5]1[CH:6]=[CH:7][C:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[C:9]2[C:4]=1[CH2:3][N:2]([CH3:1])[C:10]2=[O:11])=[O:29]
Reactant: CN1Cc2c(/C=C/c3ccccc3)ccc(NC(=O)OC(C)(C)C)c2C1=O
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: O=S([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1Cc2c(C=O)ccc(NC(=O)OC(C)(C)C)c2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl {2-methyl-3-oxo-7-[(E)-2-phenylethenyl]-2,3-dihydro-1H-isoindol-4-yl}carbamate (Compound 109D, 1.0E2 mg, 0.27 mmol) was added in one portion to a pre-stirred mixture (room temperature, 45 min) of potassium osmate dihydrate (1.0 mg, 0.0027 mmol) and potassium monopersulfate (170 mg, 1.1 mmol) in DMF (1.35 mL). After stirring overnight at room temperature, the reaction mixture was treated with 1.35 mL of saturated aqueous Na2SO3. The resulting slurry was extracted with EtOAc (3×) and the combined organic layers were washed with 1N HCl (3×) and brine and concentrated in vacuo. The desired product was obtained after chromatography using an ISCO Combiflash unit (0-15% EtOAc in Heptane) as 23 mg of a tan solid (29% yield). 1H NMR (400 MHz, DMSO-d6) δ=1.51 (s, 9H), 3.08 (s, 3H), 4.74 (s, 2H), 8.12 (d, J=8.6 Hz, 1H), 8.21 (d, J=8.6 Hz, 1H), 9.95 (s, 1H), 10.01 (s, 1H). MS (ES+): m/z 291.28 (100) [MH+]; HPLC: tR=1.27 min (UPLC, Analytical).
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:11][CH3:12])=[O:9])[C:4](=[O:21])O1.[CH3:23][N:24]1[CH:28]=[C:27]([S:29]([NH2:32])(=[O:31])=[O:30])[N:26]=[CH:25]1>>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:10]([O:11][CH3:12])[C:8](=[O:9])[CH:7]=[C:5]([OH:6])[C:4]([NH:32][S:29]([C:27]2[N:26]=[CH:25][N:24]([CH3:23])[CH:28]=2)(=[O:31])=[O:30])=[O:21])=[CH:19][CH:18]=1
Reactant: CON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Reactant: Cn1cnc(S(N)(=O)=O)c1
Product: CON(Cc1ccc(F)cc1)C(=O)C=C(O)C(=O)NS(=O)(=O)c1cn(C)cn1

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-methoxy-acetamide was treated with 1-methyl-1H-imidazole-4-sulfonic acid amide as described in the preparation of compound 1 to yield the title compound. 1H NMR (500 MHz, CDCl3) δ: 3.63 (s, 3), 3.83 (s, 3), 4.75 (s, 2), 6.40 (s, 1), 7.02 (m, 2), 7.27 (m, 2), 7.74 (s, 1), 7.80 (s, 1). 13C NMR (125 MHz, CDCl3) δ: 34.75, 48.21, 63.10, 92.33, 115.65, 115.82, 127.65, 130.24, 130.34, 131.11, 136.85, 139.42, 159.30, 159.55, 161.67, 163.63, 170.81.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([S:13]([CH3:16])(=[O:15])=[O:14])=[C:5]2[N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[CH:23]1(B(O)O)[CH2:25][CH2:24]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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>[CH:23]1([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([CH3:12])[C:6]([S:13]([CH3:16])(=[O:14])=[O:15])=[C:5]3[N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH2:25][CH2:24]1
Reactant: Cc1nc2ccc(Br)cc2c(N2CCOCC2)c1S(C)(=O)=O
Reactant: OB(O)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1nc2ccc(C3CC3)cc2c(N2CCOCC2)c1S(C)(=O)=O
Yield: 22.2 %

Procedure:
6-Bromo-3-methanesulfonyl-2-methyl-4-morpholin-4-yl-quinoline (compound of example 6) (0.5 g, 1.3 mmol), cyclopropyboronic acid (0.167 g, 1.95 mmol), potassium phosphate tribasic (0.826 g, 3.89 mmol) and tetrakis(triphenylphosphine)palladium(0) (45 mg, 0.039) were mixed together in dioxane (7 mL) and heated at reflux under argon for 8 h. After extraction with dichloromethane and half-saturated NaCl solution, the crude product was purified chromatography on silica gel in dichloromethane/ethyl acetate with a gradient from 100:0 to 90:10. One obtained 0.1 g (21%) of white crystals. MS: m/z=347 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.C(O)(=O)C.[N+:16]([O-])([OH:18])=[O:17]>O>[N+:16]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[OH:1])([O-:18])=[O:17]
Reactant: Oc1ccc2ccccc2c1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1c(O)ccc2ccccc12
Reaction time: 8 h

Procedure:
2-hydroxynaphthalene (1 g.) is dissolved in boiling acetic acid (30 ml.), and when the solution temperature reaches 45'C, a molecular equivalent amount of concentrated nitric acid is slowly added. After standing overnight at room temperature, the reaction mixture is mixed with water. The precipitated solids are filtered, washed with water, and purified by chromatography on alumina, to yield 1-nitro-2-hydroxynaphthalene.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([NH2:18])[C:4]=1[C:19]([O:21]CC)=[O:20].[OH-].[Na+].Cl>C(O)C>[F:12][C:9]([F:10])([F:11])[C:7]1[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([NH2:18])[C:4]([C:19]([OH:21])=[O:20])=[C:3]([CH:2]([F:1])[F:24])[N:8]=1
Reactant: CCOC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)O)c1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 122.5 g (0.344 mol) of product of Example 100 in 125 ml of ethanol was added 137 ml of 10% NaOH (0.344 mol) slowly. After stirring at room temperature of 1 hour, reaction was complete (19F-NMR). The solution was poured into 1 L of 10% HCl and extracted with 500 ml of ether. The ether layer was washed with one 500 ml portion of 10% HCl, dried (CaSO4), filtered and concentrated to 100 g (87%) of off-white solid; mp 142.5°-151° C. Recrystallization from chloroform gave an analytical sample; mp 169.5°-171° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10])#[CH:2].[CH2:11]([O:13][C:14](=[O:18])/[CH:15]=[CH:16]\I)[CH3:12]>>[CH2:11]([O:13][C:14](=[O:18])[CH:15]=[CH:16][C:2]#[C:1][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10])[CH3:12]
Reactant: C#Cc1ccccc1OC
Reactant: CCOC(=O)/C=C\I
Product: CCOC(=O)C=CC#Cc1ccccc1OC

Procedure:
The general procedure was used to convert 1-Ethynyl-2-methoxy-benzene and (Z)-ethyl-3-iodoacrylate to the title product. Purification by flash chromatography (20% ethyl acetate in hexane as the eluent) gave the analytically pure product as a light yellow oil (480 mg, 98% yield). 1H NMR (400 MHz, CDCl3) δ 7.52-7.50 (dd, J=7.5, 1.7, 1H), 7.33-7.29 (m, 1H), 6.93-6.89 (dt, J=7.6, 0.9, 1H), 6.88-6.86 (d, J=8.3, 1H), 6.42-6.39 (d, J=11.4, 1H), 6.11-6.08 (d, J=11.4, 1H), 4.28-4.22 (q, J=7.1, 2H), 3.88 (s, 3H), 1.33-1.29 (t, J=7.1, 3H). 13C NMR (100 MHz, CDCl3) δ 164.86, 160.32, 134.25, 130.84, 127.67, 123.10, 120.54, 111.96, 110.73, 97.93, 90.45, 60.32, 55.81, 14.28. Anal. Calcd. for C14H14O3: C, 73.03; H, 6.13; Found C, 73.08; H, 6.19.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@@H:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])[CH2:11][N:12]2C(=O)C3C(=CC=CC=3)C2=O)=[O:8])=[CH:4][C:3]=1[C:34]1[N:38]([CH3:39])[N:37]=[N:36][CH:35]=1.NN>CO.O>[NH2:12][CH2:11][C@@H:10]([NH:9][C:7]([C:5]1[S:6][C:2]([Cl:1])=[C:3]([C:34]2[N:38]([CH3:39])[N:37]=[N:36][CH:35]=2)[CH:4]=1)=[O:8])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([F:33])([F:32])[F:31]
Reactant: Cn1nncc1-c1cc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)sc1Cl
Agent: NN
Solvent: CO
Solvent: O
Product: Cn1nncc1-c1cc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)sc1Cl
Yield: 90.5 %

Procedure:
A solution of 5-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxamide (700 mg, 1.22 mmol) and hydrazine (0.19 mL, 6.1 mmol) in 5 mL of MeOH was stirred at rt overnight, diluted with 200 ml of H2O and extracted with DCM (100 ml×2). The combined organic layers were concentrated and the resulting solid was dissolved in 6N HCl (50 ml). The aqueous layer was washed with DCM (50 ml×2). The organic layers were discarded and the remaining aqueous solution was concentrated to give the product as an HCl salt (490 mg, 75%): LCMS (ES) m/z 444.0 (M+H)+, 1H NMR (400 MHz, METHANOL-d4) ppm 8.10 (m, 1H), 7.92 (m, 1H), 7.73 (m, 1H), 7.57 (m, 1H), 7.44 (m, 1H), 4.65 (m, 1H), 4.17 (s, 3H), 3.25-3.11 (m, 4H).
Reaction SMILES: [CH:1]1[C:18]2=[C:19]3[C:8]([C:9]4[C:20]5[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=5)[CH:12]=[CH:11][CH:10]=4)=[CH:7][CH:6]=[C:5]2[C:21]([O:23][C:24](=[O:25])[C:3](=[C:4]23)[CH:2]=1)=[O:22].[OH-:26].[K+]>C(O)(C)(C)C>[CH:1]1[C:18]2=[C:19]3[C:8]([C:9]4[C:20]5[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=5)[CH:12]=[CH:11][CH:10]=4)=[CH:7][CH:6]=[C:5]([C:21]([OH:23])=[O:22])[C:4]3=[C:3]([C:24]([OH:25])=[O:26])[CH:2]=1
Reactant: [OH-]
Reactant: O=C1OC(=O)c2ccc3c4cccc5cccc(c6ccc1c2c63)c54
Agent: [K+]
Solvent: CC(C)(C)O
Product: O=C(O)c1ccc2c3cccc4cccc(c5ccc(C(=O)O)c1c25)c43
Yield: 50 %

Procedure:
At a yield of 50% in the reaction in the autoclave, monoimide 2b is a suitable starting material for preparing perylene-3,4-dicarboxylic anhydride 4. To this end, 2b is reacted, for example, with KOH in tert-butyl alcohol, followed by hydrolysis to give the monoamide of perylene-3,4-dicarboxylic acid. Acidification of the alkaline solution of the monoamide thus obtained results in further hydrolysis of a portion thereof to give the desired perylene-3,4-dicarboxylic anhydride (4) (while the other portion reverts to the starting material 2b). A particularly suitable acid is 50 per cent acetic acid, which gives yields of more than 60% of 4; based on conversion, the isolated yield of 4 is even more than 90%. The remaining portion of the cyclization product 2b can be separated off without any difficulty by dissolution with hot potassium carbonate solution, filtration and precipitation with acetic acid, so that the anhydride 4 is obtained in high purity.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][CH:3]=1.[CH3:10][CH:11]1[CH2:16][NH:15][CH:14]([CH3:17])[CH2:13][NH:12]1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:12]2[CH2:13][CH:14]([CH3:17])[NH:15][CH2:16][CH:11]2[CH3:10])=[CH:4][CH:3]=1
Reactant: CC1CNC(C)CN1
Reactant: ClCc1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: CC1CN(Cc2ccc(Cl)cc2)C(C)CN1

Procedure:
Was synthesized in the same way as A) from 1-chloro-4-chloromethyl-benzene (1.27 g, 7.89 mmol) and 2,5-dimethyl-piperazine (1.0 g, 8.77 mmol) in DMF. Yield 701 mg, 37%
Reaction SMILES: C1(O[C:8](=[O:30])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27](=[O:29])[NH2:28])C=CC=CC=1.[N:31]1([CH2:36][CH2:37][CH2:38][CH2:39][NH2:40])[CH2:35][CH2:34][CH2:33][CH2:32]1>>[N:31]1([CH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:8](=[O:30])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27]([NH2:28])=[O:29])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1F
Reactant: NCCCCN1CCCC1
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCCN3CCCC3)c2C(N)=O)c(F)c1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 4-pyrrolidin-1-yl-butylamine by the procedure analogous to Example 1. MS (APCl, m/z): 486 [M+H]+.
Reaction SMILES: Br[C:2]1[N:3]([CH3:23])[C:4]([C:13]2[S:14][C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH2:22])[C:20]=3[N:21]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[N:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].CCOC(C)=O>CN(C=O)C>[CH3:23][N:3]1[C:4]([C:13]2[S:14][C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH2:22])[C:20]=3[N:21]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=[C:2]1[C:27]1[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=1
Reactant: OB(O)c1ccncc1
Reactant: Cn1c(Br)nc(-c2ccccc2)c1-c1nc2c(N)ncnc2s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1c(-c2ccncc2)nc(-c2ccccc2)c1-c1nc2c(N)ncnc2s1
Temperature: 25 °C
Yield: 30.1 %

Procedure:
2-(2-Bromo-1-methyl-4-phenyl-1H-imidazol-5-yl)[1,3]thiazolo[5,4-d]pyrimidin-7-amine (Example 26) (20 mg), PdCl2dppf (8 mg), pyridine-4-boronic acid (8 mg) and 2M sodium carbonate (2.0 mL) were heated in DMF (2.0 mL) at 100° C. under an inert atmosphere. After 3 hours the reaction mixture was cooled to ambient temperature, EtOAc (25 mL) added then washed with water (15 mL), brine (2×10 mL), dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica eluting with 6% MeOH/DCM gave a dark brown solid which was washed with diethyl ether then dried under high vacuum to give the title compound as light brown solid (6 mg, 31%);
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[C:3]=1[C:4]#[N:5].[ClH:23].[F:24][C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=1)[O:28][CH2:29][CH2:30][NH2:31].C(=O)([O-])O.[Na+].CS(C)=O>O>[ClH:1].[ClH:23].[F:24][C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=1)[O:28][CH2:29][CH2:30][NH:31][C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[C:3]=1[C:4]#[N:5]
Reactant: NCCOc1cccc(F)c1
Reactant: Cc1cc(Nc2cc(-c3cccnc3)c(C#N)c(Cl)n2)n[nH]1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(Nc2cc(-c3cccnc3)c(C#N)c(NCCOc3cccc(F)c3)n2)n[nH]1
Temperature: 130 °C
Reaction time: 24 h
Yield: 6.7 %

Procedure:
Compound D (202 mg, 650 μmol), 2-(3-fluorophenoxy)ethylamine hydrochloride (357 mg) and sodium hydrogencarbonate (540 mg) were added to DMSO (3 ml), and the mixture was stirred at 130° C. for 24 hr. After stirring, the reaction mixture was added to cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and concentrated, and the residue was purified by silica gel chromatography (90 mg). This was converted to hydrochloride to give the object compound of 2-(2-(3-fluorophenoxy)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)-4-(pyridin-3-yl)nicotinonitrile dihydrochloride (22 mg).