Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[Cl:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[CH2:49][S:50](Cl)(=[O:52])=[O:51]>C(#N)C>[Cl:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[CH2:49][S:50]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:52])=[O:51]
Reactant: O=S(=O)(Cl)Cc1ccccc1Cl
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)Cc3ccccc3Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 37.7 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0313 g, 0.0678 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0570 mL, 0.407 mmol) and (2-chlorophenyl)methanesulfonyl chloride (0.0460 g, 0.203 mmol) to obtain 4-[(2-chlorophenyl)methanesulfonyloxy]-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0166 g, yield 29%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:11]([C:21]1[O:25][N:24]=[C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[N:22]=1)([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[CH2:12][CH3:13].CN1CCOCC1.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]([C:21]2[O:25][N:24]=[C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[N:22]=2)([N:6]2[C:7]3[C:3](=[C:2]([NH:1][S:39]([CH3:38])(=[O:41])=[O:40])[CH:10]=[CH:9][CH:8]=3)[CH:4]=[N:5]2)[CH2:12][CH3:13])=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1noc(C(CC)(c2ccc(Cl)cc2)n2ncc3c(N)cccc32)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCOC(=O)c1noc(C(CC)(c2ccc(Cl)cc2)n2ncc3c(NS(C)(=O)=O)cccc32)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the product from Step D above (0.080 g, 0.17 mmol) and N-methylmorpholine (0.035 g, 0.35 mmol) in DCM (1.0 mL) was added methanesulfonyl chloride (0.019 g, 0.17 mmol) at 0° C. After stirring at RT for 30 min, the reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with dioxane/water, acidified with TFA, and purified directly on RP-HPLC to give the title compound. LC/MS m/z=504.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([O:24]C)=[O:23])=[CH:12][CH:11]=2)[C:7]2[C:26]([C:30]([O:32]C)=[O:31])=[CH:27][CH:28]=[CH:29][C:6]=2[N:5]=1)[CH3:2].[OH-].[Na+]>CO>[CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([OH:24])=[O:23])=[CH:14][CH:15]=2)[C:7]2[C:26]([C:30]([OH:32])=[O:31])=[CH:27][CH:28]=[CH:29][C:6]=2[N:5]=1)[CH3:2]
Reactant: CCOc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Temperature: 80 °C
Yield: 82.3 %

Procedure:
To a solution of methyl 2-ethoxy-1-[(2′-methoxycarbonyl-biphenyl-4-yl)methyl]benzimidazole-7-carboxylate (0.7 g) in methanol (10 ml) was added 1N NaOH (5 ml) and the mixture was stirred at 80° C. for 3 Hours. After evaporation of the methanol, the aqueous residue was neutralized with 1N hydrochloric acid to give crystals. The crystals were recrystallized from methanol-chloroform to afford colorless crystals (0.54 g, 83%), m.p. 213-215° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[OH:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].CO[C:16](OC)([CH3:18])[CH3:17].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:17][C:16]1([CH3:18])[O:13][C:12]2[CH:11]=[CH:10][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][C:2]=2[O:1]1
Reactant: CCOC(=O)c1ccc(O)c(O)c1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc2c(c1)OC(C)(C)O2
Yield: 48.5 %

Procedure:
Ethyl 3,4-dihydroxybenzoate (910.9 mg, 5 mmol) was combined with 2,2-dimethoxypropane (1.23 mL, 10 mmol) and a catalytic amount of p-toluene sulfonic acid in toluene. The mixture was heated to reflux using a Dean-Stark trap for 20 hours. After solvent removal under reduced pressure, the crude was dissolved in ethyl acetate and washed successively with a saturated aqueous solution of sodium bicarbonate, water, and brine. The organic layer was dried over anhydrous sodium sulfate. Purification by chromatography on silica gel using a gradient hexane:ethyl acetate, 90:10 to 75:25, afforded a white powder (539.1 mg, 49%). 1H NMR (CDCl3): 1.36 (t, 3H, J=7.2 Hz), 1.69 (s, 6H), 4.32 (q, 2H, J=7.1 Hz, J=14.2 Hz), 6.74 (d, 1H, d, J=8.2 Hz), 7.38 (d, 1 h, J=1.7 Hz), 7.61 (dd, 1H, J=1.8 Hz, J=8.3 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([O:7][N:8]=[C:9]([NH2:13])[CH:10]([OH:12])[CH3:11])=O.C([O-])(=O)C.[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:7][N:8]=[C:9]([CH:10]([OH:12])[CH3:11])[N:13]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: CC(O)C(N)=NOC(=O)c1cccc(Cl)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(O)c1noc(-c2cccc(Cl)c2)n1
Temperature: 25 °C
Yield: 25.6 %

Procedure:
27.2 g crude N′-[(3-chlorobenzoyl)oxy]-2-hydroxypropanimidamide was dissolved in ethanol (250 mL) and refluxed for 1 h, followed by addition of 14.0 g (170 mmol) sodium acetate in water (40 mL). After refluxing o.n., cooling to r.t. and addition of water (250 mL) the mixture was concentrated in vacuo to about ½ of its volume, resulting in a precipitate which was filtered off and recrystallized from EA/Hep to yield 6.45 g (25%) of the title compound. 1H NMR: 8.14 (s, 1 H), 8.02 (d, 1 H), 7.57 (d, 1 H), 7.47 (t, 1 H), 5.04-5.14 (m, 1 H), 2.51 (d, 1 H), 1.67 (d, 3 H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[N:10]2[C:14]3[C:15]4[C:20]([CH2:21][C:13]=3[C:12]([C:24]3[CH:28]=[CH:27][S:26][CH:25]=3)=[N:11]2)=[CH:19][C:18]([CH2:22][NH2:23])=[CH:17][CH:16]=4)=[CH:5][CH:4]=1.[C:37]([N:44]1[CH:48]=[CH:47][N:46]=[CH:45]1)(N1C=CN=C1)=[O:38].NCCN1C[CH2:56][O:55][CH2:54][CH2:53]1>C1COCC1>[CH3:36][O:35][C:32]1[CH:31]=[CH:30][C:29]([CH:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[N:10]2[C:14]3[C:15]4[C:20]([CH2:21][C:13]=3[C:12]([C:24]3[CH:28]=[CH:27][S:26][CH:25]=3)=[N:11]2)=[CH:19][C:18]([CH2:22][NH:23][C:37]([NH:44][CH2:48][CH2:47][N:46]2[CH2:45][CH2:56][O:55][CH2:54][CH2:53]2)=[O:38])=[CH:17][CH:16]=4)=[CH:34][CH:33]=1
Reactant: NCCN1CCOCC1
Reactant: COc1ccc(C(c2ccc(OC)cc2)n2nc(-c3ccsc3)c3c2-c2ccc(CN)cc2C3)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1ccc(C(c2ccc(OC)cc2)n2nc(-c3ccsc3)c3c2-c2ccc(CNC(=O)NCCN4CCOCC4)cc2C3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Example 891D (800 mg, 1.62 mmol) in THF (15 mL) was added 1,1′-carbonyldiimidazole (320 mg, 1.94 mmol). The mixture was stirred at rt for 2 h, then a solution of 4-(2-aminoethyl)morpholine (253 mg, 1.94 mmol) in THF (3 mL) was added. The resulting mixture was stirred at rt for 6 h, then concentrated in vacuo. The residue was purified by flash chromatography eluting with EtOAc to give a crude oil. (326 mg).
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH:5]=[O:6].[CH2:7](O)[CH2:8][OH:9].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>O.O1CCOCC1.C1C=CC=CC=1>[CH3:1][S:2][CH2:3][CH2:4][CH:5]1[O:9][CH2:8][CH2:7][O:6]1
Reactant: CSCCC=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: c1ccccc1
Product: CSCCC1OCCO1
Reaction time: 2 h

Procedure:
1040 g (10 moles) of freshly distilled methional, 650 g (10.5 moles) of ethylene glycol, 400 cc of benzene, 800 cc of dioxan and 10 g of p-toluene sulphonic acid are heated under reflux until the azeotropic entrainment of the water formed during the reaction, which takes 2 hours, is over. The acid medium is then neutralized by the addition of 10 g of dry sodium carbonate, after which the solution is concentrated to dryness in a water pump vacuum.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[C:6]([CH2:16][C:17]#[N:18])=[CH:5][CH:4]=1.[C:19]([O:23][CH3:24])(=[O:22])[CH:20]=[CH2:21]>C(#N)C.C(OCC)(=O)C>[CH3:24][O:23][C:19](=[O:22])[CH2:20][CH2:21][C:16]([C:17]#[N:18])([C:6]1[C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][C:8]=2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:21][CH2:20][C:19]([O:23][CH3:24])=[O:22]
Reactant: COc1ccc(CC#N)c2c1oc1ccccc12
Reactant: C=CC(=O)OC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)CCC(C#N)(CCC(=O)OC)c1ccc(OC)c2oc3ccccc3c12
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a solution of (4-methoxy-dibenzofuran-1-yl)-acetonitrile (7 g, 0.029 mol) in acetonitrile (200 ml), Triton B (2.7 ml, 0.0147 mol) was added under N2 at RT. The reaction mass was heated to reflux and at reflux temperature methyl acrylate (28.25 ml, 0.295 mol) was added drop wise. The reaction mass was stirred for 4 hrs at 90° C. Once the product is formed, the reaction mass was diluted with ethyl acetate and concentrated under vacuum. 4-cyano-4-(4-methoxy-dibenzofuran-1-yl)-heptane dioic acid dimethyl ester was isolated by column chromatography. Yield 8 g (65%)
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][S:11]([C:14]1[N:18]=[C:17]([NH2:19])[NH:16][N:15]=1)(=[O:13])=[O:12].[C:20]([Cl:26])(=O)[CH2:21][C:22]([Cl:24])=O.O=P(Cl)(Cl)Cl>C(#N)C>[Cl:24][C:22]1[CH:21]=[C:20]([Cl:26])[N:16]2[N:15]=[C:14]([S:11]([NH:10][C:3]3[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=3[Cl:1])(=[O:13])=[O:12])[N:18]=[C:17]2[N:19]=1
Reactant: Cc1ccc(Cl)c(NS(=O)(=O)c2n[nH]c(N)n2)c1Cl
Reactant: O=C(Cl)CC(=O)Cl
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(Cl)c(NS(=O)(=O)c2nc3nc(Cl)cc(Cl)n3n2)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
To a stirred solution of 6.44 g (0.02 moles) of N-(3-(((2,6-dichloro-3-methylphenyl)amino)sulfonyl)-1H-1,2,4-triazol-5-yl)amine in 100 mL of dry acetonitrile was added 2.82 g (0.02 moles) of freshly distilled malonyl chloride. The mixture was stirred at room temperature overnight after which time some starting material remained. Additional malonyl chloride (0.56 g) was added and stirring was continued for 4 hrs. The reaction mixture was concentrated to dryness and the residue was slurried with POCl3 (122 g; 0.8 moles) and heated at 90° C. for 9 hrs. The reaction mixture was cooled and concentrated under reduced pressure and the residue was poured into ice-water. The resulting precipitate was filtered and dried to give 8.35 g of product having a purity of 75 percent (73 percent yield).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)=[N:7][C:6]=2[CH:23]=1.[F:24][C:25]1[CH:30]=[C:29]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:28]=[CH:27][C:26]=1B1OC(C)(C)C(C)(C)O1>>[F:24][C:25]1[CH:30]=[C:29]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:28]=[CH:27][C:26]=1[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:12][CH2:11]3)=[N:7][C:6]=2[CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc3cc(Br)ccc3o2)CC1
Reactant: CC1(C)OB(c2ccc(S(C)(=O)=O)cc2F)OC1(C)C
Product: CC(C)(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(S(C)(=O)=O)cc4F)ccc3o2)CC1
Yield: 21.1 %

Procedure:
Following the General Procedure-1, the titled compound (40 mg) was prepared from Intermediate 7 (150 mg, 0.4 mmol) and Intermediate 3 (154 mg, 0.51 mmol) as an off-white solid. M.P.: 144-147° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 7.87 (s, 1H), 7.82 (d, J 8, 1H), 7.77 (dd, J 1.4, 9.4, 1H), 7.67 (t, J 7.5, 1H), 7.59 (d, J 8.4, 1H), 7.50 (d, J 8.5, 1H), 4.15 (d, J 7.7, 2H), 3.22-3.10 (m, 4H), 3.00 (t, J 11.3, 2H), 2.21-2.12 (m, 2H), 2.00-1.88 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH2:19][O:20][CH3:21])[CH:14]=[CH:15][CH:16]=3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:37]2[CH:45]=[CH:44][CH:43]=[C:42]3[C:38]=2[CH:39]=[N:40][NH:41]3)O1>>[NH:41]1[C:42]2[C:38](=[C:37]([C:2]3[N:3]=[C:4]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:5]4[S:10][C:9]([C:11]5[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH2:19][O:20][CH3:21])[CH:14]=[CH:15][CH:16]=5)=[CH:8][C:6]=4[N:7]=3)[CH:45]=[CH:44][CH:43]=2)[CH:39]=[N:40]1
Reactant: COCC(=O)Nc1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: COCC(=O)Nc1cccc(-c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)c1

Procedure:
3-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzenamine (60 mg), methoxyacetyl chloride (23 mg), and 36 μL of triethylamine in dichloromethane was stirred for 1 h. The reaction mixture was evaporated to give N-(3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)-2-methoxyacetamide. 70 mg of the crude N-(3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)-2-methoxyacetamide was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A. The product was purified by reverse phase HPLC to yield 17.3 mg of 120. MS (Q1) 501 (M)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]4[CH:30]=[C:29]5[C:24]([CH:25]=[CH:26][C:27](=[O:31])[NH:28]5)=[CH:23][CH:22]=4)[CH2:12][CH2:11]3)=[CH:7][CH:8]=[CH:9][C:2]1=2.C(N(CC)CC)C.[CH:39]1([C:45](Cl)=[O:46])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1.O>ClCCl>[CH:39]1([C:45]([O:31][C:27]2[CH:26]=[CH:25][C:24]3[C:29](=[CH:30][C:21]([O:20][CH2:19][CH2:18][CH2:17][CH2:16][N:13]4[CH2:12][CH2:11][N:10]([C:6]5[C:3]6[CH:4]=[CH:5][S:1][C:2]=6[CH:9]=[CH:8][CH:7]=5)[CH2:15][CH2:14]4)=[CH:22][CH:23]=3)[N:28]=2)=[O:46])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: O=c1ccc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc2[nH]1
Reactant: O=C(Cl)C1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Oc1ccc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc2n1)C1CCCCC1

Procedure:
To a solution of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one (800 mg) synthesized in the same manner as in WO2006/112464 (Example 1) in dichloromethane (20 ml) was added triethylamine (0.64 ml), with stirring under ice-cooling, cyclohexanecarbonyl chloride (0.49 ml) was added and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=4:1) to give 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-quinolin-2-yl cyclohexanecarboxylate (1.08 g).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1([CH:12]=[CH:11][CH:10]=[C:8]([OH:9])[CH:7]=1)[OH:6].Cl[CH:14]([CH3:18])[C:15](Cl)=[O:16]>[N+](C1C=CC=CC=1)([O-])=O>[OH:6][C:5]1[CH:12]=[CH:11][C:10]2[C:15](=[O:16])[CH2:14][CH2:18][O:9][C:8]=2[CH:7]=1
Reactant: Oc1cccc(O)c1
Reactant: CC(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C1CCOc2cc(O)ccc21
Yield: 25 %

Procedure:
Under ice cooling, AlCl3 (3 molar equivalent) was added little by little to a solution composed of 11 g of resorcinol, 12.7 g of 2-chloropropionyl chloride and 120 ml of nitrobenzene. After the addition, the mixture was heated at 40° to 50° C. for 4 hours with stirring. The reaction mixture was worked up and purified in a customary manner to give 4.1 g of 2,3-dihydro-7-hydroxy-4-oxobenzopyran. The resulting compound was benzylated, reduced with sodium borohydride in methanol, and then methylated with methyl iodide in tetrahydrofuran in the presence of sodium hydride. In a customary manner, the methylated product was hydrogenated to give 1.7 g (yield 9.4%) of the desired product as a colorless liquid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:19]([C:25]1[CH:31]=[CH:30][C:28]([OH:29])=[CH:27][C:26]=1[OH:32])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].Cl>S1(CCCC1)(=O)=O.CO.O>[OH:29][C:28]1[CH:27]=[C:26]([OH:32])[C:25]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:31][C:30]=1[C:2]1[N:7]=[C:6]([C:30]2[CH:31]=[C:25]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:26]([OH:32])=[CH:27][C:28]=2[OH:29])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: Clc1nc(Cl)nc(-c2ccccc2)n1
Reactant: CCCCCCc1ccc(O)cc1O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: O=S1(=O)CCCC1
Solvent: CO
Product: CCCCCCc1cc(-c2nc(-c3ccccc3)nc(-c3cc(CCCCCC)c(O)cc3O)n2)c(O)cc1O
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
To a 750 mL sulfonation flask equipped with a mechanical stirrer, condenser, dropping funnel and a nitrogen atmosphere are charged 34.0 g (150 mmol) of 2,4-dichloro-6-phenyl-s-triazine, 44.0 g (330 mmol) of aluminum chloride and 100 mL of ligroin (boiling range 110°-140° C.). To that suspension, 60 mL of sulfolane are added dropwise with stirring over a 15 minute period with the temperature rising to 50° C. A solution of 62.1 g (320 mmol) of 4-hexylresorcinol in 60 mL of sulfolane is then added dropwise over a 15 minute period. The temperature rises to 60° C. and hydrogen chloride is evolved. The reaction mixture is heated to 80° C. for four hours. The lower layer of the two-phase mixture is poured into a solution of 50 mL of concentrated hydrochloric acid in 500 mL of methanol and 300 mL of water. The mixture is stirred at room temperature for 14 hours. The product obtained is suspended in 800 mL of water at 80° C. for 1 hour, is isolated by filtration and resuspended under the same conditions, finally isolated and dried at 85° C. under vacuum. The title compound is obtained as a crude orange product (77.0 g) and melts at 230°-238° C. It can be used without further purification.
Reaction SMILES: BrC[C:3](Cl)=[O:4].[C:6]([NH:10][C:11]([C:13]1[S:34][C:16]2[N:17]=[C:18]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:19]=[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[CH:22]=3)[C:15]=2[C:14]=1[NH2:35])=[O:12])([CH3:9])([CH3:8])[CH3:7].CCN(C(C)C)C(C)C.[CH2:45]([Cl:47])Cl>>[C:6]([NH:10][C:11]([C:13]1[S:34][C:16]2[N:17]=[C:18]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:19]=[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][C:3](=[O:4])[CH2:45][Cl:47])[CH:22]=3)[C:15]=2[C:14]=1[NH2:35])=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: O=C(Cl)CBr
Reactant: ClCCl
Reactant: CC(C)(C)NC(=O)c1sc2nc(-c3ccccc3)nc(-c3cccc(N)c3)c2c1N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)NC(=O)c1sc2nc(-c3ccccc3)nc(-c3cccc(NC(=O)CCl)c3)c2c1N
Reaction time: 3 h

Procedure:
Bromoacetyl chloride (2.80 ml) was added dropwise to a solution of tert-butyl 5-amino-4-(3-aminophenyl)-2-phenyl-thieno[2,3-d]pyrimidine-6-carboxamide (example 9(g), 5.8 g) and DIPEA (12.2 ml) in DCM (50 ml). After 3 h at room temperature, the mixture was diluted with DCM, washed with sat. aq. NaHCO3, dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel using heptane/EtOAc=3/2 (v/v) as eluent. A 1:1 (mol/mol) mixture of tert-butyl 5-amino-4-(3-(2-bromoacetamido)-phenyl)-2-phenyl-thieno[2,3-d]pyrimidine-6-carboxamide and tert-butyl 5-amino-4-(3-(2-chloroacetamido)-phenyl)-2-phenyl-thieno[2,3-d]pyrimidine-6-carboxamide was obtained.
Reaction SMILES: O[C:2]1[C:7](CC=C(C)C)=[C:6]([O:13][CH3:14])[CH:5]=[CH:4][C:3]=1[C:15](=[O:17])C>C(O)C>[CH:15](=[O:17])[C:3]1[CH:2]=[CH:7][C:6]([O:13][CH3:14])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(C)=O)c(O)c1CC=C(C)C
Solvent: CCO
Product: COc1ccc(C=O)cc1

Procedure:
In 5 ml of ethanol were dissolved 0.4 g of the 2'-hydroxy-4'-methoxy-3'-(3-methyl-2-butenyl)acetophenone obtained in Production Example 2 and 0.3 ml of p-anisaldehyde, and the solution was cooled to 0° C. and 7.5 ml of a saturated solution of potassium hydroxide in ethanol was added to the solution. In a nitrogen current, the mixture was stirred at 0° C. for 30 minutes and at room temperature for 4 days. After the reaction, hydrochloric acid was added to the reaction liquid under cooling and the reaction liquid was gradually made acidic, and the formed precipitate was recovered by filtration and recrystallized from methanol to obtain 0.4 g (yield=64.7%) of 2'-hydroxy-4,4'-dimethoxy-3'-(3-methyl-2-butenyl)chalcone in the form of a yellow needle.
Reaction SMILES: Br[CH2:2][C:3]1[S:11][C:10]2[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7](Cl)=[N:6][C:5]=2[CH:4]=1.[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1.C([O-])([O-])=O.[K+].[K+].C[N:31]([CH:33]=O)C>>[N:19]1([CH2:2][C:3]2[S:11][C:10]3[C:9]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)=[N:8][C:7]([C:5]4[CH:4]=[CH:3][CH:2]=[C:33]5[C:10]=4[CH:9]=[N:8][NH:31]5)=[N:6][C:5]=3[CH:4]=2)[CH:23]=[N:22][CH:21]=[N:20]1
Reactant: CN(C)C=O
Reactant: c1nc[nH]n1
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1cc(-c2nc(N3CCOCC3)c3sc(Cn4cncn4)cc3n2)c2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-(bromomethyl)-2-chloro-4-morpholinothieno[3,2-d]pyrimidine 30 from Example 9 (90 mg, 0.3 mmol) in DMF (3 mL) was added 1,2,4-triazole (18 mg, 0.3 mmol) and K2CO3 (50 mg, 0.4 mmol). The resulting solution stirred at room temperature overnight then was concentrated in vacuo. The residue was diluted with water and filtered. The crude product was utilized in a Suzuki coupling using General Procedure A with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 to provide 313 after reverse phase HPLC purification (16 mg). MS (Q1) 419 (M)+
Reaction SMILES: CN1C2C(C(OC)=O)C(O[CH:11]([C:19]3[CH:24]=[CH:23][C:22](F)=[CH:21][CH:20]=3)[C:12]3[CH:17]=[CH:16][C:15](F)=[CH:14]C=3)CC1CC2.[OH:30]OS([O-])=O.[K+].CN([CH:39]=[O:40])C>>[CH2:20]1[CH:19]2[CH:11]3[C:12]([CH:39]=[O:40])([O:30][CH:24]2[CH2:23][CH:22]=[CH:21]1)[CH2:17][CH:16]=[CH:15][CH2:14]3
Reactant: O=S([O-])OO
Reactant: CN(C)C=O
Reactant: COC(=O)C1C(OC(c2ccc(F)cc2)c2ccc(F)cc2)CC2CCC1N2C
Agent: [K+]
Product: O=CC12CC=CCC1C1CC=CCC1O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of R-9 (500 mg, 2.06 mmol) and R-10 (337.6 mg, 2.06 mmol) in DMF (20 mL) is added oxone (758.5 mg, 1.23 mmol) and the solution is stirred at room temperature for 1 hour. The mixture is concentrated in vacuo and the residue is diluted in CH2Cl2 and is washed with saturated aqueous NaHCO3. The organics are dried with Na2SO4, filtered and concentrated in vacuo to give R-11 (787 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])([CH3:8])[C:4]([O:6][CH3:7])=[O:5].[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[S:28](Cl)(=[O:30])=[O:29].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:13]([O:12][C:10]([NH:9][C:3]([CH3:8])([CH2:2][NH:1][S:28]([C:22]1[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:21]=1[Cl:20])(=[O:30])=[O:29])[C:4]([O:6][CH3:7])=[O:5])=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: COC(=O)C(C)(CN)NC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C)(CNS(=O)(=O)c1ccc(Cl)cc1Cl)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
0.103 g (0.341 mmol) of methyl 3-amino-2-benzyloxycarbonylamino-2-methylpropionate, 0.109 g (0.443 mmol) of 2,4 dichlorobenzenesulfonyl chloride and 0.237 ml (1.36 mmol) of DIEA are dissolved in 2 ml of DCM. The mixture is stirred at room temperature overnight. 2 ml are added to the reaction solution, and then the organic phase is separated off and dried over MgSO4, and the solvent is removed in vacuo. The crude product is purified by chromatography on 4 g of SiO2, EtOAc/DCM as eluent (gradient of 0-40%). 0.081 g of the desired product is obtained as an oil. MW=474 (calculated, monoisotopic), measured value: (M+H)+ 475.