Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:6]([CH3:12])[C:7]([Br:11])=[C:8]([Br:10])[CH:9]=1)=[O:4].[C:15](=O)([O-])[O-:16].[K+].[K+]>CO>[CH3:15][O:16][C:3]([C:5]1[N:6]([CH3:12])[C:7]([Br:11])=[C:8]([Br:10])[CH:9]=1)=[O:4]
Reactant: Cn1c(C(=O)C(Cl)(Cl)Cl)cc(Br)c1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1cc(Br)c(Br)n1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
2,2,2-Trichloro-1-(4,5-dibromo-1-methyl-1H-pyrrol-2-yl)-ethanone 14 (1.00 g, 2.60 mmol), anhydrous potassium carbonate (0.719 g, 5.20 mmol), and anhydrous methanol (20 mL) were charged into a reaction flask. The resulting suspension was stirred for 16 h at room temperature upon which the reaction was quenched with water (10 mL). The methanol was removed under reduced pressure and the residue partitioned between ethyl acetate (100 mL) and water (20 mL). The organic layer was subsequently washed with sat. NaHCO3 (2×30 mL), brine (2×20 mL), dried over anhydrous sodium sulfate, and filtered. Evaporation of the filtrate yielded the title compound (0.710 g, 92%) as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 7.05 (s, 1H), 3.90 (s, 3H), 3.76 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 159.38, 123.62, 118.51, 113.93, 98.06, 51.58, 35.78; HRMS (FAB) calcd for C7H7Br2NO2 (M+) 294.8844, found 294.8861.
Reaction SMILES: C(OC(=O)C)(=O)C.[C:8]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=1)(=[O:10])[CH3:9].[CH2:19]([O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[N+:35]([O-:37])=[O:36])[CH:30]=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)(Cl)Cl>[C:8]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=[CH:30][C:29]2[CH:32]=[CH:33][C:34]([N+:35]([O-:37])=[O:36])=[C:27]([O:26][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:28]=2)[N:13]=1)(=[O:10])[CH3:9]
Reactant: O=Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Reactant: CC(=O)Nc1cccc(C)n1
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cccc(C=Cc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)n1
Temperature: 180 °C
Yield: 23.1 %

Procedure:
A mixture of acetic anhydride (6 ml), 2-acetamido-6-methylpyridine (8.00 g) and 3-benzyloxy-4-nitrobenzaldehyde (13.7 g), was heated at 180° C. for 22 hours with stirring. After cooling, the reaction mixture was dissolved in chloroform (150 ml). The solution was washed with aqueous potassium carbonate, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (640 g) by eluting with chloroform and washed with a mixture of ethyl acetate and diisopropyl ether to give 2-acetamido-6-[2-(3-benzyloxy-4-nitrophenyl)vinyl]pyridine (4.80 g).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]3[C@@:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]4=[O:22])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[C:33]([S:37]([NH2:40])(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:22]=[C:14]1[C@@:13]2([CH2:12][C@H:11]2[C:7]2[CH:6]=[C:5]3[C:10]([C:2]([C:31]4[CH:32]=[C:33]([S:37]([NH2:40])(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=4)=[N:3][NH:4]3)=[CH:9][CH:8]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15]1
Reactant: CC1(C)OB(c2cccc(S(N)(=O)=O)c2)OC1(C)C
Reactant: O=C1Nc2ccccc2[C@]12C[C@H]2c1ccc2c(I)n[nH]c2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: NS(=O)(=O)c1cccc(-c2n[nH]c3cc([C@@H]4C[C@@]45C(=O)Nc4ccccc45)ccc23)c1
Yield: 8.1 %

Procedure:
To a mixture of (1R*,2S*)-2-(3-iodo-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-one (80.2 mg, 0.2 mmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (68.2 mg, 0.24 mmol) in DME (4 mL) was added 1 M Na2CO3 (0.24 mL, 0.24 mmol), followed by Pd(PPh3)2Cl2 (14 mg, 0.02 mmol). The resulting mixture was purged with argon and microwaved 2 h at 120° C. It was diluted with H2O, extracted with EtOAc and dried (Na2SO4). Removal of solvents provided an oil which was triturated with EtOAc/hex then MeOH/CH2Cl2/hex to give the title compound as a white solid (7 mg, 8%). 1H NMR (400 MHz, DMSO-d6) δ 13.41 (s, 1H), 10.63 (s, 1H), 8.41 (s, 1H), 8.19 (d, J=6.8 Hz, 1H), 8.00 (d, J=8.4 Hz, 1H), 7.20 (d, J=8.0 Hz, 1H), 7.69 (t, J=7.6 Hz, 1H), 7.54 (s, 1H), 7.47 (s, 2H, NH2), 7.08 (d, J=8.4 Hz, 1H), 7.00 (t, J=7.2 Hz, 1H), 6.85 (d, J=6.8 Hz, 1H), 6.54 (t, J=7.4 Hz, 1H), 6.05 (d, J=6.4 Hz, 1H), 3.22 (t, J=7.6 Hz, 1H), 2.38-2.30 (m, 1H), 2.05-1.98 (m, 1H); MS ESI 431.1 [M+H]+, calcd for [C23H18N4O3S+H]+ 431.1.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:5]=[CH:6][CH:7]=[C:8]2[C:12]([CH3:13])=[C:11]([CH3:14])[NH:10][C:9]=12.I[CH2:16][CH:17]([CH3:19])[CH3:18].O>O1CCCC1>[Cl:3][C:4]1[N:5]=[CH:6][CH:7]=[C:8]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:9]=12
Reactant: Cc1[nH]c2c(Cl)nccc2c1C
Reactant: CC(C)CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C)n(CC(C)C)c2c(Cl)nccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
Sodium hydride (60%, 33 mg, 0.83 mmol) was added to a solution of 7-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine (100 mg, 0.53 mmol) prepared in Step 1 in anhydrous tetrahydrofuran (2.8 ml). The reaction mixture was stirred for 30 minutes at room temperature. 1-Iodo-2-methylpropane (64 t, 0.67 mmol) was added to the reaction mixture, which was then stirred overnight at room temperature. Water was added to the reaction mixture, which was then extracted with dichloromethane. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/9, v/v) to give 108 mg of the titled compound as a white solid. (Yield: 86%)
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([NH2:22])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:23]#[C:24]Br>CCO.CCOC(C)=O.C([O-])(O)=O.[Na+]>[CH2:1]([O:8][C:9]1[N:14]=[C:13]2[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:24]([NH2:23])=[N:22][C:12]2=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CBr
Reactant: Nc1ccc(OCc2ccccc2)nc1Nc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1nc2ccc(OCc3ccccc3)nc2n1-c1ccccc1
Yield: 13.2 %

Procedure:
A solution of 6-(benzyloxy)-N2-phenylpyridine-2,3-diamine (3.106 g, 10.66 mmol), and cyanogen bromide (1.694 g, 15.99 mmol) in EtOH (50 mL) was stirred overnight at room temperature. The mixture was diluted with EtOAc and saturated NaHCO3. The layers were separated and the aqueous phase was back-extracted with EtOAc. The organics were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (446 mg). LCMS m/z=317.1 [M+H]+.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[CH2:18][C:19]#[N:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl>O1CCCC1.C(O)C.[Ni]>[Si:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[CH2:18][CH2:19][NH2:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2c1ccn2CC#N
Agent: [Ni]
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)Oc1cccc2c1ccn2CCN
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
To a solution of (4-{[tert-butyl(dimethyl)silyl]oxy}-1H-indol-1-yl)acetonitrile (259 mg, 0.904 mmol) in tetrahydrofuran (20 mL) are added a 2.0M hydrochloric acid in ethanol (1 mL) and active Raney-nickel (manufactured by Kawaken Fine Chemicals Co., Ltd., about 1 mL), and the mixture is vigorously stirred under hydrogen atmosphere under pressure (0.5 Pa) at room temperature for 1 hour. To the mixture is further added active Raney-nickel (about 1.5 mL), and the mixture is vigorously stirred under the same conditions for 4 hours. The catalyst is removed by filtration through celite, and the filtrate is concentrated under reduced pressure. The obtained residue is purified by silica gel column (ammonia-chloroform:methanol=100:1→50:1→30:1) to give the title compound as pale brown oil (207 mg, yield: 79%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][C:14](=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[CH:21]=[CH:20][C:19]4[CH:28]=[CH:29][CH:30]=[CH:31][C:18]3=4)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>>[C:32]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][C:14](=[C:17]3[C:18]4[CH:31]=[CH:30][CH:29]=[CH:28][C:19]=4[CH:20]=[CH:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]3=4)[CH2:13][CH2:12]2)=[CH:6][CH:7]=1)(=[O:34])[CH3:33]
Reactant: Nc1ccc(CCCN2CCC(=C3c4ccccc4C=Cc4ccccc43)CC2)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(CCCN2CCC(=C3c4ccccc4C=Cc4ccccc43)CC2)cc1
Yield: 92.9 %

Procedure:
This was prepared from 1-(4-Aminophenyl)-3-[4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl]propane (compound 8) and acetic anhydride. Yield 92.9%
Reaction SMILES: [OH:1][CH:2]([CH2:19][NH:20][CH:21]([CH3:23])[CH3:22])[CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([CH2:11][CH2:12][C:13]([NH:15]C)=[O:14])=O)=[CH:7][CH:6]=1.O.[NH2:25]N>C(O)(=O)C>[OH:1][CH:2]([CH2:19][NH:20][CH:21]([CH3:23])[CH3:22])[CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]2[CH2:11][CH2:12][C:13](=[O:14])[NH:15][N:25]=2)=[CH:7][CH:6]=1
Reactant: CNC(=O)CCC(=O)c1ccc(OCC(O)CNC(C)C)cc1
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: CC(C)NCC(O)COc1ccc(C2=NNC(=O)CC2)cc1
Yield: 52.4 %

Procedure:
3-[4-(2-Hydroxy-3-isopropylaminopropoxy)benzoyl]-N-methylpropionamide (5g, 0.015 mole) in 50% aqueous acetic acid (50 ml) was treated with hydrazine hydrate (2.4 ml, 0.047 mole) and heated under reflux for one hour. After evaporation under reduced pressure, the residue was dissolved in water, neutralised with aqueous sodium bicarbonate and extracted with dichloromethane. Evaporation of the dried organic solution gave 6-[4-(2-hydroxy-3-isopropylaminopropoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone (2.4 g, 50%, m.p. 108°-115° C). Crystallisation from water gave the pure pyridazinone, m.p. 116.5°-118° C.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](Cl)[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)[C:5]1=[O:26])(=O)C.[CH3:27][N:28]([CH2:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1)[CH3:29].[OH-].[Na+]>CN(C=O)C.CO>[CH3:29][N:28]([CH2:30][C:31]1[CH:32]=[CH:33][C:34]([NH:35]/[C:16](=[C:6]2\[C:5](=[O:26])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)=[CH:36][CH:37]=1)[CH3:27]
Reactant: COc1cccc(C(Cl)=C2C(=O)N(C(C)=O)c3ccc([N+](=O)[O-])cc32)c1
Reactant: CN(C)Cc1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cccc(/C(Nc2ccc(CN(C)C)cc2)=C2/C(=O)Nc3ccc([N+](=O)[O-])cc32)c1

Procedure:
Prepared analogously to Example 2 from 1-acetyl-3-[1-chloro-1-(3-methoxyphenyl)-methylidene)-5-nitro-2-indolinone and 4-dimethylaminomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P:11]([OH:13])[OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.[O:26]=[C:27]([CH:29]=[C:30]([CH3:32])[CH3:31])[CH3:28]>C(Cl)(Cl)Cl>[OH:12][P:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([C:30]([CH3:32])([CH3:31])[CH2:29][C:27](=[O:26])[CH3:28])=[O:13]
Reactant: CC(=O)C=C(C)C
Reactant: OP(O)CCCCc1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)CC(C)(C)P(=O)(O)CCCCc1ccccc1
Yield: 37.8 %

Procedure:
To a solution of 4-phenylbutyl phosphonous acid (0.5 g, 0.0025 mole) in chloroform (15 ml) was added triethylamine (0.77 ml, 0.005 mole), trimethyl silylchloride (0.70 ml, 0.005 mole) and mesityl oxide (0.32 ml, 0.0025 mole). The reaction mixture was stirred at reflux temperature for 18 hours. CHCl3 was removed in vacuo. The residue was diluted with ether and washed with 5% aqueous NaHCO3 solution. The aqueous layer was acidified with concentrated HCl and extracted twice with ether and once with EtOAc. Organic layers were combined and extracted with brine, dried over Na2SO4 and solvent was removed to give 0.28 g of the product an an oil.
Reaction SMILES: [CH:1]1([N:7]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C(=O)N([Cl:29])C(=O)C1.O>C(Cl)Cl>[Cl:29][C:13]1[S:12][C:11]([NH:10][C:8](=[O:9])[N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[N:15][CH:14]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(Nc1nccs1)N(C1CCCCC1)N1CCCCC1
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1ncc(Cl)s1)N(C1CCCCC1)N1CCCCC1

Procedure:
1-Cyclohexyl-1-piperidin-1-yl-3-thiazol-2-yl-urea (50 mg, 0.16 mmol), prepared in an identical manner to Example 94 was dissolved in DCM (1 mL) and NCS (26 mg, 0.19 mmol)) was added. The reaction mixture was stirred for 3 days before DCM (20 mL) and water (20 mL) was added. The organic phase was dried (MgSO4) and the solvent was removed in vacuo. MeCN (1 mL) was added whereupon the product precipitated. The product was filtered off and dried. Yield: 20 mg.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]#[N:11])[CH:5]=[CH:6][CH:7]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:26][C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:28]=1[CH2:29]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:26][C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:28]=1[CH2:29][O:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]#[N:11])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(C)c1CO
Reactant: N#CCCc1cccc(O)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cccc(C)c1COc1cccc(CCC#N)c1
Temperature: 25 °C

Procedure:
A solution of 3-(3-hydroxyphenyl)propanenitrile (Step B, 1.25 g, 8.5 mmol) and diisopropyl azodicarboxylate (DIAD, 1.87 g, 9.26 mmol) in dry THF (10 ml) was added drop wise to a solution of 2,6-Dimethylbenzyl alcohol (1.27 g, 9.3 mmol) and triphenylphosphine (TPP, 2.43 g, 9.26 mmol) in dry THF (30 ml) at 0° C. under argon. The reaction mixture was warmed to room temperature for 4 hours or until all the starting material is consumed diluted with ether and washed with water (2×). The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex:ethyl acetate 2:1) to give the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]([N+:15]([O-])=O)=[CH:7][C:6]=1[C:18]([F:21])([F:20])[F:19])(=[O:3])[CH3:2].[H][H]>[Pd].C(O)C>[C:1]([NH:4][C:5]1[C:6]([C:18]([F:20])([F:21])[F:19])=[CH:7][C:8]([NH2:15])=[CH:9][C:10]=1[C:11]([F:12])([F:13])[F:14])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1c(C(F)(F)F)cc([N+](=O)[O-])cc1C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(=O)Nc1c(C(F)(F)F)cc(N)cc1C(F)(F)F

Procedure:
A solution of 7.9 g. of 4-acetylamino-3,5-bis-trifluoromethylnitrobenzene in 200 ml. of ethanol is hydrogenated under 40 lbs. of hydrogen pressure with 1 g. of 5% palladium on charcoal catalyst. When the calculated amount of hydrogen is consumed, the solution is filtered and concentrated in vacuo to give 4-acetylamino-3,5-bis-trifluoromethylaniline.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=4)=[CH:15][C:13]=3[N:14]=2)[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[CH:27]1[C:32]([C:33]([OH:35])=[O:34])=[CH:31][C:30]2[C:36]([O:38][C:39](=O)[C:29]=2[CH:28]=1)=[O:37]>>[CH3:9][O:8][C:5]1[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:20]=[C:21]([F:26])[CH:22]=[C:23]([F:25])[CH:24]=4)=[CH:15][C:13]=3[N:14]=2)=[CH:3][C:2]([N:1]2[C:36](=[O:37])[C:30]3[C:29](=[CH:28][CH:27]=[C:32]([C:33]([OH:35])=[O:34])[CH:31]=3)[C:39]2=[O:38])=[CH:7][CH:6]=1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: COc1ccc(N)cc1-c1nc2cc(-c3cc(F)cc(F)c3)ccc2o1
Product: COc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(-c3cc(F)cc(F)c3)ccc2o1

Procedure:
Prepared by the method of Example 15f), from 2-(3-amino-6-methoxyphenyl)-5-(3,5-difluorophenyl)benzoxazole (70 mg, 0.20 mmol) and 1,2,4-benzenetricarboxylic anhydride (38 mg, 0.20 mmol) the title compound was obtained (72 mg, 68%). 1H NMR (DMSO) δ 13.79(s, 1H), 8.42(dd, 1H), 8.33(s, 1H), 8.23(d, 1H), 8.21(d, 1H), 8.10(d, 1H), 7.90(d, 1H), 7.83(dd, 1H), 7.72(dd, 1H), 7.56(m, 2H), 7.48(d, 1H), 7.26(m, 1H), 4.03(s, 3H). MS 527.3 m/z (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH2:13][CH:14]([CH3:18])[C:15]([NH2:17])=[O:16])[CH:10]=[CH:11][CH:12]=2)[N:5]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[CH:3]=1.[Cl:26][C:27]1[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=1[N:34]=[C:35]=[O:36]>>[NH2:17][C:15](=[O:16])[CH:14]([CH3:18])[CH2:13][C:9]1[CH:8]=[C:7]([N:6]2[C:2]([NH:1][C:35]([NH:34][C:28]3[CH:29]=[CH:30][CH:31]=[C:32]([Cl:33])[C:27]=3[Cl:26])=[O:36])=[CH:3][C:4]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])=[N:5]2)[CH:12]=[CH:11][CH:10]=1
Reactant: O=C=Nc1cccc(Cl)c1Cl
Reactant: CC(Cc1cccc(-n2nc(-c3ccccc3F)cc2N)c1)C(N)=O
Product: CC(Cc1cccc(-n2nc(-c3ccccc3F)cc2NC(=O)Nc2cccc(Cl)c2Cl)c1)C(N)=O
Yield: 17.9 %

Procedure:
Using general method A, 3-(3-(5-amino-3-(2-fluorophenyl)-1H-pyrazol-1-yl)phenyl)-2-methylpropanamide (0.1225 g, 0.362 mmol, 1.00 eq) was combined with 2,3-dichlorophenyl isocyanate (0.102 g, 0.543 mmol, 1.50 eq) to yield 34.2 mg (18%) of pure 1-(1-(3-(3-amino-2-methyl-3-oxopropyl)phenyl)-3-(2-fluorophenyl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea. 1H NMR (DMSO-d6): δ 9.40 (s, 1H), 8.89 (s, 1H), 8.11-8.08 (s, 1H), 8.02-7.98 (m, 1H), 7.53-7.39 (m, 4H), 7.36-7.26 (m, 6H), 6.92-6.91 (m, 1H), 6.76 (brs, 1H), 3.00-2.93 (m, 1H), 2.65-2.57 (m, 2H), 1.03-1.02 (m, 3H); MS (ESI) m/z: 526.0 (M+H), 528.0 (M+2+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[N:12]2[N+:15]([O-])=O)=[CH:4][CH:3]=1.O.O.[Sn](Cl)(Cl)(Cl)Cl.Cl>CCO>[NH2:15][N:12]1[C:11]2[CH:10]=[N:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:14][C:2]([Cl:1])=[CH:3][CH:4]=2
Reactant: O=[N+]([O-])n1c2cnccc2c2ccc(Cl)cc21
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: CCO
Product: Nn1c2cnccc2c2ccc(Cl)cc21
Reaction time: 3.5 h
Yield: 100.2 %

Procedure:
To a suspension of 7-chloro-9-nitro-β-carboline (548 mg, 2.22 mmol) in EtOH (14 ml) at 65° C. to 70° C. was added tin chloride dihydrate (2.5 g, 11.1 mmol). Thereafter, 6M aqueous HCl (14 ml) was added dropwise. The mixture was stirred at 70° C. to 80° C. for 3.5 h and then partitioned slowly into saturated aqueous NaHCO3 (150 ml) and EtOAc (100 ml). The aqueous phase was extracted (2 times) and the combined organic solutions dried (brine; NaSO4) and concentrated to give 484 mg of 9-amino-7-chloro-β-carboline.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([CH3:24])[O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([Cl:23])[CH:17]=1)=[N:8][CH:9]=[N:10]2.[CH3:25][O:26][CH2:27][C:28](O)=[O:29]>>[Cl:23][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[OH:22])[NH:15][C:7]1[C:6]2[C:11](=[CH:12][CH:13]=[CH:14][C:5]=2[O:4][C@H:3]([CH3:24])[CH2:2][NH:1][C:28](=[O:29])[CH2:27][O:26][CH3:25])[N:10]=[CH:9][N:8]=1
Reactant: C[C@H](CN)Oc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Reactant: COCC(=O)O
Product: COCC(=O)NC[C@@H](C)Oc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Yield: 83 %

Procedure:
4-({5-[(1R)-2-Amino-1-methylethoxy]quinazolin-4-yl}amino)-2-chlorophenol was reacted with methoxyacetic acid using an analogous process to that described in Example 3 (preparation of starting materials) to give N-[(2R)-2-({4-[3-chloro-4-hydroxyanilino]quinazolin-5-yl}oxy)propyl]-2-methoxyacetamide in 83% yield; NMR spectrum (DMSO-d6) 1.4 (d, 3H), 3.1 (s, 3H), 3.35-3.45 (m, 1H), 3.72-3.85 (m, 3H), 4.95-5.05 (m, 1H), 7.05 (d, 1H), 7.31 (d, 1H), 7.4 (dd, 1H), 7.48 (d, 1H), 7.81 (m, 1H), 7.95 (t, 1H), 8.25 (t, 1H), 8.8 (s, 1H), 10.39 (s, 1H), 10.74 (s, 1H) Mass spectrum MH+ 417.
Reaction SMILES: FC(F)(F)C(O)=O.O[C:9]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:10][CH2:11][N:12]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>C(Cl)Cl>[OH:31][C:27]1[CH:26]=[C:25]([C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][CH2:11][N:12]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:30]=[CH:29][CH:28]=1
Reactant: Oc1cccc(C(O)(CCN2CCCNCC2)c2ccccc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Oc1cccc(C(=CCN2CCCNCC2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Trifluoroacetic acid (4.75 mL) was added to a solution of 1-[3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (Compound No. 295, 60 mg, 0.184 mmol) in CH2Cl2 (0.25 mL). The reaction mixture was stirred at room temperature for 2.5 h. The trifluoroacetic acid was evaporated to afford 1-[3-(3-hydroxyphenyl)-3-phenyl-2-propenyl]homopiperazine as a colorless oil used without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[C:13]4[S:18][C:17]([CH2:19][N:20]([CH3:28])[S:21]([CH2:24][CH2:25][CH2:26]Cl)(=[O:23])=[O:22])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[C:13]4[S:18][C:17]([CH2:19][N:20]([CH3:28])[S:21]([CH2:24][CH2:25][CH2:26][N:35]5[CH2:40][CH2:39][O:38][CH2:37][CH2:36]5)(=[O:23])=[O:22])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: C1COCCN1
Reactant: CN(Cc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1)S(=O)(=O)CCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CN(Cc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1)S(=O)(=O)CCCN1CCOCC1
Temperature: 80 °C

Procedure:
To a solution of 3-chloro-propane-1-sulfonic acid [2-(1H-indazol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl]-methylamide (45 mg) in acetonitrile (2 mL) was added morpholine (38 μL), potassium carbonate (18 mg) and potassium iodide (2 mg). the reaction mixture was heated at 80° C. for 72 h and allowed to cool to room temperature before quenching with water (30 mL) and extracting into dichloromethane (2×30 mL). The combined organics were washed with brine (30 mL), dried (MgSO4), reduced in vacuo and purified by column chromatography to give 186 as an off-white solid (27 mg). NMR: CDCl3: 1.97 (m, 2H), 2.36-2.43 (m, 6H), 2.87 (s, 3H), 3.07 (m, 2H), 3.63 (t, J=4.6, 4H), 3.84 (t, J=4.8, 4H), 4.01 (t, J=4.8, 4H), 4.61 (s, 2H), 7.39 (s, 1H), 7.43 (t, J=8.2, 1H), 7.51 (d, J=8.3, 1H), 8.20 (d, J=6.8, 1H), 8.94 (s, 1H), 10.30 (brs, 1H). MS: ESI+: MH+ 572.09
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]#[C:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10]C)=O.Cl.[CH3:17][NH:18][O:19][CH3:20].[Li]CCCC>>[CH3:17][N:18]([O:19][CH3:20])[C:8](=[O:10])[C:7]1[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=1[C:5]#[C:4][CH2:3][O:2][CH3:1]
Reactant: CNOC
Reactant: COCC#Cc1ccccc1C(=O)OC
Agent: Cl
Agent: [Li]CCCC
Product: COCC#Cc1ccccc1C(=O)N(C)OC
Yield: 48 %

Procedure:
Treatment of methyl 2-[3-(methyloxy)-1-propyn-1-yl]benzoate (142) (0.64 g, 3.13 mmol) with a mixture of N,O-dimethylhydroxylamine hydrochloride and nBuLi gave 0.35 g (48%) of the title compound (143) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 3.32 (br s, 3H), 3.43 (s, 3H), 3.50 (br s, 3H), 4.30 (s, 2H), 7.25-7.40 (m, 3H), 7.45-7.55 (m, 1H). LCMS (ESI): m/z 234 (M+H)+.