Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=2[OH:18])=[O:10])=[CH:4][CH:3]=1.[C:19]([Cu])#[N:20].O.CCOC(C)=O>CN(C=O)C>[OH:18][C:12]1[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:11]=1[C:9](=[O:10])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:19]#[N:20])=[CH:3][CH:4]=1
Reactant: O=C(Cc1ccc(Br)cc1)c1ccc(O)cc1O
Reactant: N#C[Cu]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(CC(=O)c2ccc(O)cc2O)cc1
Temperature: 150 °C
Reaction time: 6 h
Yield: 36.3 %

Procedure:
A mixture of 2-(4-bromophenyl)-1-(2,4-dihydroxyphenyl)ethanone (5 g, 16.3 mmol) and CuCN (5.8 g, 65.4 mmol) in DMF (50 ml) was stirred at 150° C. for 6 h under nitrogen. Water (100 ml) and EtOAc (100 ml) was added to the mixture. The precipitate was filtered off and the filtrate was washed with brine (100 ml), dried over Na2SO4 and concentrated to give black oil, which was purified by Combiflash (PE/EtOAc=3/1) to afford product as a yellow powder (1.5 g, 36.6%). MS (ESI): m/z 254.1 [M+1]+.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH3:19])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])(C)C)=[O:13])[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].O=C1CCC(=O)N1OC(=O)OC[C:33]1[CH:38]=[CH:37]C=[CH:35][CH:34]=1>Cl>[CH2:15]([O:14][C:12]([N:9]1[CH2:8][CH2:7][C:6]([CH3:19])([C:4]([OH:3])=[O:5])[CH2:11][CH2:10]1)=[O:13])[C:18]1[CH:37]=[CH:38][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CCOC(=O)C1(C)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC1(C(=O)O)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
4-Methyl-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (2.71 g, 10 mmol) is heated with 6M aq. HCl (20 mL) at 95° C. for 2 days. The mixture is cooled, basified with 33% aq. NaOH (ice bath cooling) and extracted with ether (2×50 mL). A spatula of NaH2PO4 is added, then the pH adjusted to 7 with conc. aq. HCl, CH2Cl2 (50 Vol %) is added and the mixture cooled at 0° C. Carbonic acid benzyl ester 2,5-dioxo-pyrrolidin-1-yl ester (1.508 g, 5 mmol) is added to the strongly stirred biphasic system and the mixture is stirred for 2 h. The pH is adjusted to 14 with aq. NaOH (1M) and the phases are separated. The aq. phase is extracted with CH2Cl2 (2×50 mL), the organic extracts are discarded. The pH is adjusted to 2 and the mixture is extracted with CHCl3 (4×50 mL). The organic extracts are dried (Na2SO4), filtered and evaporated to provide the title compound.
Reaction SMILES: [OH:1][CH:2]([CH2:8][CH:9]([OH:15])[CH:10]=[CH:11][CH:12]=[CH:13][CH3:14])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[C:16]1(=O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH:10]([C@H:9]1[O:15][C:16]2([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[O:1][C@@H:2]([CH2:3][C:4]([O:6][CH3:7])=[O:5])[CH2:8]1)=[CH:11][CH:12]=[CH:13][CH3:14]
Reactant: CC=CC=CC(O)CC(O)CC(=O)OC
Reactant: O=C1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC=CC=C[C@@H]1C[C@H](CC(=O)OC)OC2(CCCCC2)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.7 %

Procedure:
Methyl 3,5-dihydroxy-6,8-decadienoate (7.6 g, 35.5 mmol) and p-toluenesulfonic acid (0.1 g) was added to cyclohexanone (10 g, 100 mmol) and stirred for 16 hours at ambient temperature. The yellow solution was loaded directly onto a silica gel column and the product eluted with diethyl ether:hexane (1:4). The appropriate fractions were combined to give 3.52 g (33.6%) of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([Br:18])=[CH:4][C:3]=1C(O)=O.[OH-].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([Br:18])=[CH:4][CH:3]=1
Reactant: Nc1c(C(=O)O)cc(Br)c2c1C(=O)c1ccccc1C2=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(Br)c2c1C(=O)c1ccccc1C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.9 %

Procedure:
1-Amino-4-bromoanthraquinone-2-carboxylic acid (38 grams, 0.11 mole) was dissolved in 200 ml. of water and 50 ml. of 10 M sodium hydroxide solution. The mixture was heated on a steam bath to 90°-100° C., and 40 g (b 0.23 mole) sodium hydrosulfite was added. Heating was continued with stirring for 2 hours, after which the mixture was cooled to room temperature. The resuting solid was collected by filtration and washed with water until the filtrate was neutral. The solid was dried at 80° C. to give 24.9 g (75% yield) of 1-amino-4-bromoanthraquinone. The Thin Layer Chromatogram of the crude product showed the presence of a small amount of impurity.
Reaction SMILES: [C:1]([O:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[C:14]([F:17])([F:16])[F:15])[NH:7][C:6]=1[CH3:18])(=[O:3])[CH3:2].[Na].C(O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:1]([O:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[C:14]([F:17])([F:15])[F:16])[NH:7][C:6]=1[CH2:18][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C)[nH]c2cccc(C(F)(F)F)c12
Reactant: OCc1ccccc1
Agent: [Na]
Product: CC(=O)Oc1c(Cc2ccccc2)[nH]c2cccc(C(F)(F)F)c12

Procedure:
A solution of 0.05 mole of methyl-(4-trifluoromethyl-3-indolyl) acetate and 0.01 mole of sodium in 60 ml. anhydrous benzyl alcohol is slowly fractioned over a period of 41/2 hours through a Vigreux column to remove methanol. The excess benzyl alcohol is removed by distillation at 60° and 2.5 mm. to give a residue of crude benzyl-(4-trifluoromethyl-3-indolyl) acetate.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[C:6](N)[CH:5]=1)(=[O:3])[CH3:2].[H+].[B-](F)(F)(F)[F:21]>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[C:6]([F:21])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(-c2ccc(F)cc2F)c(N)c1
Reactant: F[B-](F)(F)F
Agent: [H+]
Product: CC(=O)c1ccc(-c2ccc(F)cc2F)c(F)c1

Procedure:
4-Acetyl-2-amino-2',4'-difluorobiphenyl prepared as described in Example 1 was subjected to the Schiemann reaction using fluoboric acid to give 4-acetyl-2,2',4'-trifluorobiphenyl, m.p. 92°-94° C. By a similar method, starting from the appropriate products of Example 1, there were obtained 4-acetyl-4'-chloro-2,2'-difluorobiphenyl, m.p. 69°-70° C. and 4-acetyl-4'-bromo-2,2'-difluorobiphenyl, m.p. 75°-76° C.
Reaction SMILES: C(O)/C=C\CCCCCCC.[CH2:12]([OH:24])[C:13]#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].N1C2C(=CC=CC=2)C=CC=1>>[CH2:12]([OH:24])/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCC#CCO
Agent: CCCCCCC/C=C\CO
Solvent: c1ccc2ncccc2c1
Product: CCCCCCCCC/C=C\CO

Procedure:
cis-2-Dodecen-1-ol was prepared as described above for cis-2-decen-1-ol except that 35 g of 2-dodecyn-1-ol, 1.0 g of catalyst, and 3.0 ml of quinoline was used. A clear oil, 33.86 g, was obtained after kugelrohr distillation. 1H NMR δ5.57 (m, 2), 4.19 (d, 2, J=5 Hz), 2.07 (dd, 2, J=6, 12 Hz), 1.5-1.2 (m, 14), 0.88 (t, 3, J=7 HZ).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Br[C:14]1[S:18][C:17]([CH:19]=[O:20])=[CH:16][CH:15]=1.C(N(CC)CC)C>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[C:1]([C:15]1[CH:16]=[C:17]([CH:19]=[O:20])[S:18][CH:14]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: C#CCCCCCCCCCC
Reactant: O=Cc1ccc(Br)s1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCC#Cc1csc(C=O)c1
Temperature: 25 °C
Yield: 98.1 %

Procedure:
A solution of 1-dodecyne (23.9 g), 5-bromo-2-thiophenecarboxaldhyde (25.0 g) and triethylamine (39.7 g) in dry tetrahydrofuran (75 ml) was degasseal and stirred at room temperature under a nitrogen atmosphere. Two mole percent of bis(triphenylphosphine)palladium(II)chloride (1.8 g) followed by one mole percent of copper(I)iodide (0.25 g) was added. The mixture was degassed and stirred at room temperature under nitrogen for three days. The precipitate was filtered, and the filter cake was washed with ethyl acetate. The filtrate was evaporated, and the residue was flash chromatographed (silica, 7:3-Hexane:dichloromethane). The appropriate fractions were collected and evaporated. The residue was dried at 50° C. under vacuum for three hrs to give 35.5 g (98%) of product.
Reaction SMILES: [CH3:1][C:2]([CH2:5][C@H:6]1[NH:10][C@@H:9]([C:11]([NH:13][CH:14]2[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]2)=[O:12])[C@H:8]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=2[F:28])[C@:7]21[C:37](=[O:38])[NH:36][C:30]1[CH:31]=[C:32]([Cl:35])[CH:33]=[CH:34][C:29]2=1)([CH3:4])[CH3:3]>CO.O>[CH3:4][C:2]([CH2:5][C@@H:6]1[NH:10][C@@H:9]([C:11]([NH:13][CH:14]2[CH2:15][CH2:16][CH:17]([OH:20])[CH2:18][CH2:19]2)=[O:12])[C@H:8]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=2[F:28])[C@@:7]21[C:37](=[O:38])[NH:36][C:30]1[CH:31]=[C:32]([Cl:35])[CH:33]=[CH:34][C:29]2=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)C[C@H]1N[C@@H](C(=O)NC2CCC(O)CC2)[C@H](c2cccc(Cl)c2F)[C@@]12C(=O)Nc1cc(Cl)ccc12
Solvent: O
Solvent: CO
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)NC2CCC(O)CC2)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Reaction time: 72 h
Yield: 26 %

Procedure:
In an alternative procedure, MI-773 (77 mg) was dissolved in 15 mL MeOH/H2O (v/v=1:1). After 3 days, the needle crystals that had formed were collected, washed with cold MeOH/H2O (v/v=1:1) and dried in vacuum to give MI-77301 as the free amine (20 mg; >95% purity as determined by HPLC). 1H NMR (300 MHz, MeOH-d4): 7.49-7.55 (m, 1H), 7.25-7.31 (m, 1H), 7.10-7.16 (m, 1H), 6.82 (d, J=1.8 Hz, 1H), 6.50-6.71 (m, 1H), 6.49 (d, J=8.4 Hz, 1H), 4.32 (d, J=9.0 Hz, 1H), 4.09 (d, J=8.7 Hz, 1H), 3.57-3.69 (m, 1H), 3.49 (d, J=9.2 Hz, 1H), 3.46-3.57 (m, 1H), 1.83-2.07 (m, 3H), 1.68-1.80 (m, 1H), 1.54 (dd, J=9.0, 14.3 Hz, 1H), 1.12-1.45 (m, 5H), 0.80 (s, 9H). The absolute stereochemical configuration of MI-77301 was determined by X-ray analysis.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:4][C:3]=1[NH:14][NH2:15].[C:16]([CH2:19][C:20](=O)[CH3:21])(=O)[CH3:17].C(O)C.O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][S:10]([CH3:13])(=[O:11])=[O:12])=[CH:4][C:3]=1[N:14]1[C:20]([CH3:21])=[CH:19][C:16]([CH3:17])=[N:15]1
Reactant: CC(=O)CC(C)=O
Reactant: CS(=O)(=O)Oc1cc(NN)c(F)cc1Cl
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(C)n(-c2cc(OS(C)(=O)=O)c(Cl)cc2F)n1
Yield: 92 %

Procedure:
A mixture of 2-fluoro-4-chloro-5-methylsulfonyloxyphenylhydrazine (25.5 g), acetylacetone (10.0 g), ethanol (100 ml) and water (100 ml) was refluxed for 2 hours. After cooling, toluene was added to the reaction mixture to separate layers. The toluene layer as separated was washed with water and then subjected to distillation under a reduced pressure to remove the toluene, yielding the titled compound (29.3 g) as pale yellow crystals. Recrystallization from a mixture of hexane/ethyl acetate gave colorless crystals with melting point 77.5°-79° C.
Reaction SMILES: C[O:2][C:3](=[O:37])[C@H:4]([CH2:6][CH:7]([C:10](=[O:36])[C:11]1[CH:16]=[CH:15][C:14](=[CH2:17])[CH:13]([NH:18][C:19]2[N:20]=[C:21]([CH:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH2:25]3)[NH:22][CH:23]=2)[C:12]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[S:8][CH3:9])[NH2:5].[OH-].[Li+].Cl>C1COCC1>[CH:24]1([C:21]2[NH:22][CH:23]=[C:19]([NH:18][CH:13]3[C:14](=[CH2:17])[CH:15]=[CH:16][C:11]([C:10]([CH:7]([S:8][CH3:9])[CH2:6][C@@H:4]([C:3]([OH:37])=[O:2])[NH2:5])=[O:36])=[C:12]3[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:20]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH2:29]1
Reactant: C=C1C=CC(C(=O)C(C[C@H](N)C(=O)OC)SC)=C(c2ccccc2)C1Nc1c[nH]c(C2C=CC=CC2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=C1C=CC(C(=O)C(C[C@H](N)C(=O)O)SC)=C(c2ccccc2)C1Nc1c[nH]c(C2C=CC=CC2)n1
Yield: 22 %

Procedure:
The compound of Example 382A (0.1 g, 0.19 mmol) was dissolved into 2 mL. of THF and cooled to 0° C. Lithium hydroxide (2 mLs, 0.5M) was slowly added to the reaction mixture and stirred for 3 Hrs. The pH was adjusted using 0.5 M HCl and a white precipitate was collected by vacuum filtration and purified twice by reverse phase preparative HPLC (Waters 25×10 cm, C-18 column, 220 nm UV detector, flow rate 15 mLs/min, linear gradient from 5% acetonitrile and 95% water containing 0.1% TFA to 60% acetonitrile in 40 minutes). Fractions containing pure compound were combined and lyophilized to yield the title compound (0.021 g, 18%) as a TFA salt: 1H NMR (300 MHz, methanol-d4) δ 8.04 (d, J=7.8 Hz, 1H), 7.79 (dd, J=7.3 Hz, 2H), 7.60-7.62 (m, 4H), 7.27-7.30 (m, 6H), 6.69 (dd, J=8.4 Hz, 1H), 6.63 (d, J=2.1, 1H) 4.42 (s, 2H), 4.19-4.26 (m, 1H), 2.14-2.32 (m, 2H), 1.98 (s, 3H), 1.75-1.87 (m, 2H).
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[N:8][C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:10][C:5]=2[N:4]([CH2:16][CH2:17][CH2:18][O:19][CH3:20])[CH:3]=1.[CH3:21]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH3:20][O:19][CH2:18][CH2:17][CH2:16][N:4]1[C:5]2[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]=[CH:7][C:6]=2[C:2]([CH3:21])=[CH:3]1
Reactant: CB1OB(C)OB(C)O1
Reactant: CCOC(=O)c1cc2c(cn1)c(Br)cn2CCCOC
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cc2c(cn1)c(C)cn2CCCOC
Temperature: 110 °C
Reaction time: 15 h

Procedure:
To a solution of ethyl 3-bromo-1-(3-methoxypropyl)-1H-pyrrolo[3,2-c]pyridine-6-carboxylate (1.70 g) in 1,4-dioxane (25 mL) were added trimethylboroxine (2.09 mL), cesium carbonate (4.87 g), 2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl (X-Phos) (297 mg) and tris(dibenzylideneacetone)dipalladium (228 mg) under argon, and the mixture was stirred at 110° C. for 15 hours. The reaction solution was cooled, and then thereto was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane→ethyl acetate) to give ethyl 1-(3-methoxypropyl)-3-methyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate [REx(105-4)] (831 mg) as a yellow oil.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[C:28](Cl)(=[O:30])[CH3:29].C(OCC)(=O)C.CCCCCC>C(Cl)Cl>[CH2:18]([N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:28](=[O:30])[CH3:29])[CH2:11][CH2:10]3)[CH2:13][CH2:14]1)[CH2:19][CH3:20]
Reactant: CC(=O)Cl
Reactant: CCCN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCCCCC
Product: CCCN1CCN(c2cccc3c2C[C@H](NC(C)=O)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.1 %

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-propylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (85 mg, 0.31 mmol) and triethylamine (38 μL, 0.37 mmol) in methylene chloride (15 mL) was added acetyl chloride (23 μL, 0.31 mmol) in methylene chloride (5 mL) dropwise. After the addition the reaction was allowed to stir at ambient temperature for 15 min and was then washed with water. The methylene chloride phase was dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified on a silica gel column using chloroform/ethanol saturated with (NH3) (100:3) as the eluent. This gave 91 mg (93% yield) of the title compound as an oil which was crystallized from ethyl acetate/hexane. Yield: 61 mg (62%) as white crystals: mp 139-140° C.; [α]21D +26° (c 0.50, chloroform); EIMS (70 eV) m/z (relative intensity) 315 (78, M+).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:18]2[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]2)=[C:4]([C@H:10]([OH:17])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].[CH3:26][C:27](=[CH2:29])[CH3:28].C([O-])([O-])=O.[Na+].[Na+]>ClCCl>[Br:1][C:2]1[C:3]([N:18]2[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]2)=[C:4]([C@H:10]([O:17][C:27]([CH3:29])([CH3:28])[CH3:26])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(C)c([C@H](O)C(=O)OC(C)C)c(N2CCC(C)(C)CC2)c1Br
Reactant: C=C(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CCC(C)(C)CC2)c1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.7 %

Procedure:
A stirred ice-cold yellow mixture of (S)-isopropyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate (6.7 g, 16.21 mmol) and 70% HClO4 (2.2 mL, 25.6 mmol) in dichloromethane (400 mL) was saturated with isobutylene gas by bubbling through the reaction mixture (10 min). The reaction mixture was cloudy sealed in a seal tube, stirred for 24 h at rt. The reaction mixture was recooled in a −10° C. bath, bubbled additional isobutylene (˜15 min). The reaction mixture became a clear solution at this point. The tube was sealed and stirred at rt for 16 h. LCMs at this point showed incomplete reaction. So, the reaction mixture was cooled down to −30° C. and bubbled isobutene (˜15 min). After 24 h, reaction mixture was neutralized with sat. Na2CO3 (20 mL), organic layer separated and aqueous layer was extracted with CH2Cl2 (25 mL). The combined organic layers were dried (MgSO4), filtered, concentrated and purified on a ISCO 120 g column (EtOAc/hex: 0 to 40%) to afford (S)-isopropyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (5.43 g, 9.83 mmol, 60.7% yield) as a viscous oil. 1H NMR (500 MHz, CDCl3) δ 6.26 (br. s., 1H), 5.09-4.97 (m, 1H), 4.06 (br. s., 1H), 3.51 (br. s., 1H), 2.90 (br. s., 1H), 2.65 (s, 3H), 2.56 (s, 3H), 1.72-1.54 (m, 3H), 1.47 (br. s., 1H), 1.37 (br. s., 1H), 1.23-1.20 (m, 12H), 1.15 (d, J=6.1 Hz, 3H), 1.09 (br. s., 3H), 1.04 (br. s., 3H). LCMS (M+H)=471.3.
Reaction SMILES: Cl.[SH2:2].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11][CH2:12][C:13]#[N:14])=[CH:6][CH:5]=1>CO>[ClH:3].[NH2:14][C:13]1[S:2][C:10]([C:7]2[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=2)=[CH:11][CH:12]=1
Reactant: S
Reactant: N#CCCC(=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: CO
Product: Nc1ccc(-c2ccc(Cl)cc2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
HCl and H2S gas are bubbled through a solution of the above nitrile (7.70 g, 40.0 mmol) in 100 ml of methanol at 10°-20° for 7 hours. The suspension is then stirred at RT overnight. It is dried, filtered, washed with ether and dried with suction under an N2 atmosphere to give 2-amino-5-(4-chlorophenyl)thiophene hydrochloric acid salt, a slightly purplish powder.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([NH:12]C(=O)C)=[CH:8][CH:7]=2)=[CH:2]1.[OH-].[Na+].CO>O>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=2)=[CH:2]1
Reactant: CC(=O)Nc1ccc(-c2ccsc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1ccc(-c2ccsc2)cc1
Yield: 115.5 %

Procedure:
A mixture of N-(4-thiophen-3-yl-phenyl)-acetamide (90 mg, 0.41 mmol), NaOH (133 mg, 3.3 mmol), MeOH (2 mL) and water (7 mL) was heated to reflux for 12 hr. After completion of the reaction, the reaction mixture was diluted with water, extracted with ethyl acetate, washed with brine solution and dried over sodium sulphate. The organic layer collected was concentrated under reduced pressure to afford 83 mg (crude) of 4-thiophen-3-yl-phenylamine.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[C:17]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[C:16]([O:27][CH2:28][CH2:29][NH2:30])[N:15]=[C:14]([C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)[N:13]=2)(=[O:10])=[O:9])=[N:6][CH:7]=1.[S:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[S:42](Cl)(=[O:44])=[O:43]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[C:17]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[C:16]([O:27][CH2:28][CH2:29][NH:30][S:42]([C:38]3[S:37][CH:41]=[CH:40][CH:39]=3)(=[O:44])=[O:43])[N:15]=[C:14]([C:31]3[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=3)[N:13]=2)(=[O:10])=[O:9])=[N:6][CH:7]=1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccncc2)nc1OCCN
Reactant: O=S(=O)(Cl)c1cccs1
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccncc2)nc1OCCNS(=O)(=O)c1cccs1

Procedure:
According to the procedure described in Example 4a) 107 mg 5-methyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide was reacted with thiophene-2-sulfonylchloride to give 135 mg 5-methyl-N-[6-(2-(2-thiophenesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide. LC-MS: tR=4.33 min, [M+1]+=655.46, [M−1]−=653.50.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([OH:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:28](Br)[CH:29]=[CH2:30]>CC(C)=O>[CH2:30]([O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:20][CH3:21])[N:12]=[CH:11][N:10]=[C:9]2[NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[CH:29]=[CH2:28]
Reactant: COc1cc2ncnc(Nc3cccc(Br)c3)c2cc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc2c(Nc3cccc(Br)c3)ncnc2cc1OC
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(3-bromo-phenylamino)-7-methoxy-quinazolin-6-ol (1.24 g, 3.58 mmol) (from Example 17, Step B, supra) in acetone (250 mL) was added K2CO3 (0.99 g, 7.16 mmol), and allyl bromide (1.55 mL, 17.9 mmol) (Aldrich). The reaction mixture was heated with stirring at 90° C. for 4 hours. The mixture was cooled to room temperature, filtered and the filtrate was concentrated. The residue was purified by chromatography using EtOAc/CH2Cl2/Et3N (2:3:0.02) as eluent to give the desired (6-allyloxy-7-methoxy-quinazolin-4-yl)-(3-bromo-phenyl)-amine as a yellow oil. (Yield 0.55 g, 40%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29][NH:30][CH2:31][CH2:32][CH3:33])[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[C:34](Cl)(=[O:36])[CH3:35]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29][N:30]([CH2:31][CH2:32][CH3:33])[C:34](=[O:36])[CH3:35])[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CC(=O)Cl
Reactant: CCCNCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: CCCN(CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)C(C)=O
Yield: 70 %

Procedure:
The procedure described in Example 5 was repeated using N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-(propylamino)ethoxy]quinazolin-4-amine and acetyl chloride to give the title compound in 70% yield; NMR spectrum (DMSO-d6) 0.82 (t, 3H), 1.53-1.59 (m, 2H), 1.97 (s, 3H), 3.27 (s, 2H), 3.86 (t, 2H), 4.39 (t, 2H), 5.31 (s, 2H), 7.17 (d, 1H), 7.25 (d, 1H), 7.33-7.39 (m, 2H), 7.58-7.60 (m, 2H), 7.71-7.75 (m, 1H), 7.87-7.91 (m, 1H), 7.95 (d, 1H), 8.45 (s, 1H), 8.60 (d, 1H), 9.80 (s, 1H); Mass spectrum MH+ 506.