Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:11][CH2:10][CH:9]2[CH:4]([CH2:5][CH:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)[CH2:3]1.[NH2:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:23]=1[C:24]#[N:25].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CCCCCC.C(OCC)(=O)C>[F:30][C:26]1[C:23]([C:24]#[N:25])=[C:22]([NH:21][C@H:2]2[CH2:11][CH2:10][C@@H:9]3[C@@H:4]([CH2:5][C@@H:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]3)[CH2:3]2)[CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)C1CC2CC(=O)CCC2CN1C(=O)OC
Reactant: N#Cc1c(N)cccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)[C@@H]1C[C@H]2C[C@@H](Nc3cccc(F)c3C#N)CC[C@H]2CN1C(=O)OC
Yield: 1.2 %

Procedure:
Following the procedures from Example 3A, and using 5.38 g (19.0 mmol) of ethyl 6-oxo-2-(methoxycarbonyl)-decahydroisoquinoline-3-carboxylate, 1.36 g (10.0 mmol) of 2-amino-6-fluorobenzonitrile, 3.6 mL (60 mmol) of glacial acetic acid, 5.7 g (27.0 mmol) of sodium triacetoxyborohydride, flash chromatography (silica gel, hexane-ethyl acetate 3:1) afforded 50 mg (1% yield) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[CH:14]=[C:15]([C:18]([NH:20][NH2:21])=[O:19])[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)=[CH:5][CH:4]=1.[F:22][C:23]([F:36])([F:35])[C:24]1[CH:25]=[C:26]([CH2:30][CH2:31][C:32](O)=O)[CH:27]=[CH:28][CH:29]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:19][C:32]([CH2:31][CH2:30][C:26]5[CH:27]=[CH:28][CH:29]=[C:24]([C:23]([F:22])([F:35])[F:36])[CH:25]=5)=[N:21][N:20]=4)[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-n2cnc3ccc(C(=O)NN)cc32)cc1
Reactant: O=C(O)CCc1cccc(C(F)(F)F)c1
Product: COc1ccc(-n2cnc3ccc(-c4nnc(CCc5cccc(C(F)(F)F)c5)o4)cc32)cc1
Yield: 50 %

Procedure:
In the same manner as in Example 14 and using 1-(4-methoxyphenyl)-1H-benzimidazole-6-carbohydrazide instead of 1H-benzotriazole-5-carbohydrazide and 3-[3-(trifluoromethyl)phenyl]propionic acid instead of 3-(3-cyanophenyl)propionic acid, the title compound (yield 50%) was obtained as colorless crystals.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:7]=1[O:8][CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1)=O.C1COCC1.CO.C(=O)([O-])[O-].[Na+].[Na+].Cl>O>[NH2:5][C:6]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:7]=1[O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc(COc2cc(Cl)ccc2NC(=O)C(F)(F)F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(COc2cc(Cl)ccc2N)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
To a solution of methyl 4-(2-trifluoroacetylamino-5-chlorophenoxy-methyl)benzoate (300 mg; prepared in Reference Example 6.) in mixture of THF-MeOH (4 ml+10 ml), a solution of sodium carbonate (440 mg) in water (2 ml) was added. The solution was stirred for 8 hours at 60° C. and overnight at room temperature. The reaction mixture was poured into diluted HCl and extracted with ethyl acetate. The organic layer was washed, dried over and concentrated under the reduced pressure. The residue was purified on silica gel column chromatography (AcOEt-benzene) to give the title compound (194 mg) having the following physical data.
Reaction SMILES: C(Cl)Cl.S(Cl)(Cl)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:23][CH2:22][C:21]3=[N:24][NH:25][CH:26]=[C:20]3[CH:19]2[CH:27]=O)(=[O:17])=[O:16])=[CH:11][CH:10]=1.[C:29]1([NH2:36])[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH2:35]>CCO>[NH:35]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:36]=[C:27]1[CH:19]1[C:20]2=[CH:26][NH:25][N:24]=[C:21]2[CH2:22][CH2:23][N:18]1[S:15]([C:12]1[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=1)(=[O:17])=[O:16]
Reactant: Nc1ccccc1N
Reactant: O=CC1c2c[nH]nc2CCN1S(=O)(=O)c1ccc(Cl)cc1
Solvent: O=S(Cl)Cl
Solvent: CCO
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Cl)cc1)N1CCc2n[nH]cc2C1c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.6 %

Procedure:
A flask was charged with silica (0.06 g) and CH2Cl2 (5 mL). Thionyl chloride (0.015 mL) was added dropwise. After the addition was complete, the reaction stirred at room temperature for 1 hour. Compound 79 (0.05 g, 0.15 mmol) was added, followed by phenylenediamine (0.017 g, 0.15 mmol). The reaction stirred at room temperature for 18 hours. The mixture was diluted with EtOH and the resulting suspension was filtered. The filtrate was concentrated in vacuo and the resulting residue was purified by preparative HPLC using Method [1] to yield 7.8 mg (13%) 80 as a white powder. 1H NMR (CD3OD) δ 9.13 (s, 1H), 8.33 (s, 1H), 8.05-8.01 (m, 2H), 7.85-7.73 (m, 2H), 7.66 (d, J=8.7 Hz, 2H), 7.39 (d, J=9.0 Hz), 3.42-3.34 (m, 3H); MS (m/z) 414.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].[H-].[Na+].Cl[C:17]1[C:18]2[CH:25]=[CH:24][N:23]([CH3:26])[C:19]=2[N:20]=[CH:21][N:22]=1.C(OCC)(=O)C>CN(C)C=O.O>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:17]2[C:18]3[CH:25]=[CH:24][N:23]([CH3:26])[C:19]=3[N:20]=[CH:21][N:22]=2)[CH:6]=1)=[O:4]
Reactant: COC(=O)c1c[nH]c2ccccc12
Reactant: Cn1ccc2c(Cl)ncnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cn(-c2ncnc3c2ccn3C)c2ccccc12
Temperature: 20 °C
Reaction time: 1 h

Procedure:
1.40 g (8 mmol) of 3-methoxycarbonyl-1H-indole are added to 30 cm3 of dimethylformamide at a temperature in the region of 20° C. under an argon atmosphere, and 0.32 g (10 mmol) of sodium hydride are then added. The reaction mixture is stirred at a temperature in the region of 20° C. for 1 hour, 1.35 g (8.05 mmol) of 4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine in 10 cm3 of dimethylformamide are then added, and the mixture is heated at a temperature in the region of 100° C. for 16 hours. The reaction mixture is then cooled to a temperature in the region of 20° C. and then poured into a mixture of 200 cm3 of ethyl acetate and 200 cm3 of water. The organic phase is separated out after the phases have settled, washed with twice 200 cm3 of water and then with 200 cm3 of saturated aqueous sodium chloride solution, and then dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by flash chromatography on silica gel [eluent: cyclohexane/ethyl acetate (80/20 by volume)]. After the fractions containing the expected product have been concentrated to dryness under reduced pressure (2.7 kPa), 1.35 g of 3-methoxycarbonyl-1-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-indole are obtained in the form of an off-white solid. Mass spectrum (EI): m/e 306 (M+) (base peak).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][NH:6][C:7]([C:9]1[S:13][C:12]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]2=[O:20])=[N:11][C:10]=1[CH3:21])=[O:8].Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][NH:6][C:7]([C:9]1[S:13][C:12]([N:14]2[CH2:19][CH2:18][CH2:17][CH:16]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:31][CH:32]=3)[C:15]2=[O:20])=[N:11][C:10]=1[CH3:21])=[O:8]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: Cc1nc(N2CCCCC2=O)sc1C(=O)NCc1cccc(F)c1
Product: Cc1nc(N2CCCC(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)NCc1cccc(F)c1
Yield: 41 %

Procedure:
Following the procedure as described in Example 2, making variation as required to use N-(3-fluorobenzyl)-4-methyl-2-(2-oxopiperidin-1-yl)thiazole-5-carboxamide in place of N-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide to react with 1-(bromomethyl)-4-(trifluoromethyl)benzene, the title compound was obtained as a white solid in 41% yield: mp 177-178° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.52 (d, J=8.1 Hz, 2H), 7.30-7.27 (m, 3H), 7.10-6.92 (m, 3H), 6.11 (t, J=5.6 Hz, 1H), 4.56 (d, J=5.6 Hz, 2H), 4.33-4.21 (m, 1H), 4.00-3.88 (m, 1H), 3.53-3.56 (m, 1H), 2.94-2.73 (m, 2H), 2.62 (s, 3H), 2.11-1.95 (m, 1H), 1.94-1.75 (m, 2H), 1.62-1.43 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 171.7, 162.9, 162.7, 156.9, 152.4, 143.2, 140.6, 130.3, 129.6, 128.9, 125.9, 125.5, 125.4, 123.3, 122.4, 119.3, 114.7, 114.5, 48.0, 43.9, 43.3, 37.3, 24.9, 21.3, 17.4; MS (ES+) m/z 506.3 (M+1).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[OH:23].C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1>[C:11]([C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([O:23][C:17]2[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=2[Cl:15])[CH:10]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: Oc1ccc(F)cc1Cl
Reactant: CC(C)(C)c1ccc(C(=O)O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(C(=O)O)c(Oc2ccc(F)cc2Cl)c1
Temperature: 120 °C
Yield: 72.2 %

Procedure:
In a pressure-vessel, a stirring mixture of 2-bromo-4-tert-butylbenzoic acid (1.00 g, 3.89 mmol) and 2-chloro-4-fluorophenol (860 mg, 620 μL, 5.87 mmol) in toluene (20 mL) was added Cs2CO3 (2.53 g, 7.78 mmol) followed by copper(I) triflate benzene complex (98 mg, 0.19 mmol). The sealed vessel was heated to 120° C. for 16 h. After cooling to room temperature, the reaction mixture was partitioned between 50 mL EtOAc and 50 mL H2O. The aqueous layer was acidified using 2.0 N HCl(aq) and re-extracted with EtOAc. The combined organic solution was dried over Na2SO4, filtered, and concentrated. The residue was purified via silica gel chromatography using 0-3% MeOH/CH2Cl2 to give the product, 4-tert-butyl-2-(2-chloro-4-fluorophenoxy)benzoic acid as a white solid (907 mg, 2.81 mmol) in 72% yield. LC/MS: m/z 323.2 (M+H)+ at 1.99 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].CN(C)CC[N:11]1[C:19]2[CH:18]=[CH:17][C:16](Cl)=[C:15]3[C:21](=[O:28])[C:22]4[CH:23]=[N:24][CH:25]=[CH:26][C:27]=4[C:13]([C:14]=23)=[N:12]1>N1C=CC=CC=1>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][C:16]1[CH:17]=[CH:18][C:19]2[NH:11][N:12]=[C:13]3[C:27]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[C:21](=[O:28])[C:15]=1[C:14]=23
Reactant: CN(C)CCN
Reactant: CN(C)CCn1nc2c3c(c(Cl)ccc31)C(=O)c1cnccc1-2
Solvent: c1ccncc1
Product: CN(C)CCNc1ccc2[nH]nc3c2c1C(=O)c1cnccc1-3
Temperature: 80 °C

Procedure:
Under a nitrogen atmosphere N,N-dimethylethylenediamine (1.79 mL) is added to a stirred solution of 2-[2-(dimethylamino)ethyl]-5-chloroisoquino[5,6,7-cd]indazole-6(2H)-one of Example 8 (0.539 g) in pyridine (6.80 mL) and the resulting solution is heated at 80° C. for 12 hours. The pyridine and excess N,N-dimethylethylenediamine are removed by roto-evaporation and the obtained residue is purified by silica gel column chromatography eluting first with methylene chloride, then with methylene chloride/methanol 95/5 and finally with methylene chloride/methanol/concd. ammonia from 95/5/0.5 to 95/5/1 v/v/v. The fractions containing the yellow desired product are pooled and the solvents roto-evaporated. The obtained residue (0.529 g) is crystallized from diisopropylether to give 2-[2-(dimethylamino)ethyl)]-5-[[2-(dimethylamino)ethyl]amino]isoquino[5,6,7-cd]indazole-6(2H)-one as a yellow powder (0.291 g).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:16](=[N:17][CH:18]=2)[NH:15][CH2:14][CH2:13][CH2:12]3)[CH:6]=[N:7][CH:8]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:30])[CH3:29]>C(Cl)Cl>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:16](=[N:17][CH:18]=2)[N:15]([C:28](=[O:30])[CH3:29])[CH2:14][CH2:13][CH2:12]3)[CH:6]=[N:7][CH:8]=1
Reactant: FC(F)(F)c1cncc(-c2cnc3c(c2)CCCN3)c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCCc2cc(-c3cncc(C(F)(F)F)c3)cnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 18.6 %

Procedure:
6-(5-Trifluoromethyl-pyridin-3-yl)-1,2,3,4-tetrahydro-[1,8]naphthyridine (200 mg, 0.72 mmol), whose synthesis is described in Step 1 of Example 4, is dissolved in DCM (25 mL). Triethylamine (220 mg, 2.1 mmol) is added followed by the addition of acetyl chloride (67 mg, 0.86 mmol) under N2 atmosphere at 0° C. The mixture is stirred at room temperature for 3 hrs. The solvent is removed and the residue is purified by preparative TLC to give 43 mg of the titled product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[O:11][C:12](=[O:19])[C:13]([CH:16]([CH3:18])[CH3:17])([CH3:15])[N:14]=2)[CH3:9])=[CH:4][CH:3]=1.C[Li].[CH3:22]COCC.C(OCC)(=O)C.O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:9])[C:10]([NH:14][C:13]([CH3:15])([CH:16]([CH3:18])[CH3:17])[C:12](=[O:19])[CH3:22])=[O:11])=[CH:4][CH:3]=1
Reactant: CC(C1=NC(C)(C(C)C)C(=O)O1)c1ccc(Cl)cc1
Reactant: CCOCC
Agent: [Li]C
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)C(C)(NC(=O)C(C)c1ccc(Cl)cc1)C(C)C
Yield: 55.6 %

Procedure:
4.8 g (18 mmol) of 2-[1-(4-chlorophenyl)ethyl]-4-isopropyl-4-methyl-1,3-oxazol-5-one was dissolved in 40 ml of tetrahydrofuran. Thereto was dropwise added, at 5° C., a solution obtained by diluting 20.4 ml of a 1.14 M/liter methyllithium ether solution (23.3 mmol) with 50 ml of tetrahydrofuran. The mixture was kept at 10° C. or below and subjected to a reaction for 1 hour. After the completion of the reaction, ethyl acetate and water were added for phase separation. The separated organic layer was concentrated. The resulting concentrate was subjected to column chromatography to obtain 2.9 g (0.01 mol) (yield=55%) of 2-(4-chlorophenyl)-N-[1-methyl-1-isopropyl-2-oxopropyl]propanamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10](I)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:13][C:14]1[CH:15]=[CH:16][C:17]([Sn](CCCC)(CCCC)CCCC)=[N:18][CH:19]=1>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.O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:17]2[CH:16]=[CH:15][C:14]([CH3:13])=[CH:19][N:18]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)cc(I)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(Br)cc(-c2ccc(C)cn2)c1

Procedure:
A microwave vial was charged with methyl 3-bromo-5-iodobenzoate (2.00 g, 5.87 mmol), 5-methyl-2-(tributylstannyl)pyridine (2.24 g, 5.87 mmol), tetrakis(triphenylphosphine)palladium(0) (340 mg, 0.30 mmol) and 1,4-dioxane (30 mL). The reaction mixture was subjected to microwave irradiation at 120° C. for 1 hour. After cooling, the mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography to afford the product as a white solid. 1H NMR (400 MHz, DMSO-d6): 8.64 (t, J=1.51 Hz, 1H), 8.55 (m, 1H), 8.52 (t, J=1.89 Hz, 1H), 8.07 (t, J=1.89 Hz, 1H), 8.03 (d, J=8.31 Hz, 1H), 7.75 (dd, J=8.31 & 2.27 Hz, 1H), 3.91 (s, 1H), 2.36 (s, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)[CH:8]=[C:9]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C:12]2=[O:20])[CH:10]=1)=[O:4].O.[OH-].[Na+].Cl>CO.C1COCC1>[CH3:27][C:24]1[CH:25]=[CH:26][C:21]([C:7]2[CH:8]=[C:9]([N:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:13][C:12]3=[O:20])[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=2)=[CH:22][CH:23]=1
Reactant: COC(=O)c1cc(-c2ccc(C)cc2)cc(N2C(=O)Cc3ccccc32)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)O)cc(N3C(=O)Cc4ccccc43)c2)cc1
Reaction time: 2.5 h

Procedure:
The crude 4′-methyl-5-(2-oxo-2,3-dihydro-indol-1-yl)-biphenyl-3-carboxylic acid methyl ester from step 2 was in a mixture of methanol (3 mL), water (1 mL) and THF (1 mL), and 2M aqueous NaOH (0.4 mL) was added. The mixture was stirred for 2.5 hours, then neutralized by addition of 1N aqueous HCl. The mixture was concentrated under reduced pressure and co-evaporated with toluene three times to afford crude 4′-methyl-5-(2-oxo-2,3-dihydro-indol-1-yl)-biphenyl-3-carboxylic acid, which was used directly in the next step.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Li]CCCC.[F:18][C:19]1[CH:20]=[C:21]([CH:28]=[CH:29][CH:30]=1)[C:22](N(OC)C)=[O:23].Cl>C1COCC1.O>[F:18][C:19]1[CH:20]=[C:21]([CH:28]=[CH:29][CH:30]=1)[C:22]([C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])=[O:23]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: CON(C)C(=O)c1cccc(F)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2cccc(F)c2)c(C(=O)O)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
A −78° C. solution of 2-bromo-5-methoxybenzoic acid (26.0 g, 112.5 mmol) in THF (100 mL) was treated with n-BuLi (1.6 M in hexane) (140 mL, 225 mmol) and stirred at −78° C. for 1 h. 3-fluoro-N-methoxy-N-methylbenzamide (15.3 g, 83.8 mmol) in THF (40 mL) was added dropwise then warmed to rt for 16 h. The reaction mixture was diluted with water (100 mL), acidified with 5N HCl (25 mL) and extracted with EtOAc (3×200 mL). The organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain 2-(3-fluorobenzoyl)-5-methoxybenzoic acid (21.0 g, 68%) (274.83 [M+H]); 1H NMR: (400 MHz, DMSO) δ: 3.89 (s, 3H), 7.26-7.29 (m, 1H), 7.37-7.45 (m, 4H), 7.50-7.55 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[S:27][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]4[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=4)[C:21]([OH:23])=O)[CH2:13][CH2:12]3)[C:4]=2[CH:3]=1.Cl.CN.C[CH2:32][N:33](C(C)C)C(C)C>S(Cl)(Cl)=O.C(Cl)Cl>[Cl:1][C:2]1[S:27][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][CH:11]3[CH2:12][CH2:13][N:14]([CH2:17][C:18]4[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=4)[C:21]([NH:33][CH3:32])=[O:23])[CH2:15][CH2:16]3)[C:4]=2[CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1cccc(CN2CCC(Nc3ncnc4sc(Cl)cc34)CC2)c1
Agent: CN
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CNC(=O)c1cccc(CN2CCC(Nc3ncnc4sc(Cl)cc34)CC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.1 %

Procedure:
3-((4-(6-Chlorothieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)benzoic acid (118 mg, 0.29 mmol) was heated in 3 mL of thionylchloride at 80° C. for 3 h. The reaction was cooled to room temperature and the thionylchloride was removed under reduced pressure. The residue obtained was dissolved in 25 mL of DCM followed by addition of methylamine hydrochloride (60 mg, 0.88 mmol) and DIEA (227 mg, 1.76 mmol). The reaction was allowed to stir at room temperature for 16 h and washed with 25 mL of water. The DCM layer was dried over Na2SO4 and evaporated under reduced pressure; the crude product was purified by silica chromatography in 5% MeOH-DCM to obtain 58 mg of product in 48% yield. 1H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 7.76 (s, 1H), 7.65 (d, 1H), 7.45 (d, 1H), 7.39 (t, 1H), 7.02 (s, 1H), 6.22 (bs, 1H), 4.96 (bs, 1H), 4.18 (m, 1H), 3.57 (s, 2H), 3.03 (d, 3H), 2.87 (d, 2H), 2.23 (t, 2H), 2.08 (d, 2H), 1.59 (m, 2H); MS (ESI) m/z: Calculated for C20H23ClN5OS, 416.13; Observed: 416.2 (M++1).
Reaction SMILES: C([Li])CCC.CCCCCC.C(C(C1C=CC(Cl)=CC=1)=[C:20]1[C:32]2[C:24]([CH:25]=[C:26]3[C:31]=2[CH:30]=[C:29]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:28]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:27]3)=[C:23](C2C=CC=C2)[C:22]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[C:21]1[C:54]([CH3:57])([CH3:56])[CH3:55])C1C=CC=CC=1.[CH3:65][C:66]([C:72]1[CH:77]=[CH:76][C:75]([CH3:78])=[CH:74][CH:73]=1)=[C:67]1[CH:71]=[CH:70][CH:69]=[CH:68]1>O1CCCC1>[CH3:65][C:66]([C:72]1[CH:73]=[CH:74][C:75]([CH3:78])=[CH:76][CH:77]=1)([CH:67]1[CH:68]=[CH:69][CH:70]=[CH:71]1)[C:23]1[C:24]2[CH2:25][C:26]3[C:31](=[CH:30][C:29]([C:33]([CH3:34])([CH3:36])[CH3:35])=[C:28]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH:27]=3)[C:32]=2[CH:20]=[C:21]([C:54]([CH3:56])([CH3:55])[CH3:57])[C:22]=1[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: CC(C)(C)c1cc2c(cc1-c1ccccc1)=Cc1c(C3C=CC=C3)c(-c3ccccc3)c(C(C)(C)C)c(=C(Cc3ccccc3)c3ccc(Cl)cc3)c1=2
Reactant: CC(=C1C=CC=C1)c1ccc(C)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(C(C)(c2c3c(cc(C(C)(C)C)c2-c2ccccc2)-c2cc(C(C)(C)C)c(-c4ccccc4)cc2C3)C2C=CC=C2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Under a nitrogen atmosphere, a solution of n-butyllithium in hexane (6.3 ml, 10.2 mmol) was dropped into a solution of 2,7-diphenyl-3,6-di-tert-butylfluorene (4.0 g, 9.3 mmol) in dry tetrahydrofuran (50 ml) at −10° C., and then the product was stirred at room temperature for 20 hours. Then, 6-methyl-6-(p-tolyl)fulvene (1.9 g, 10.2 mmol) was dropped into this solution at −10° C., and the product was stirred at room temperature for 2 hours to induce a reaction. After the reaction was terminated, dilute aqueous hydrochloric acid was added thereto, the product was subjected to extraction with hexane, the organic layer was subsequently washed with water and then dehydrated with anhydrous magnesium sulfate, and then the solvent was distilled off to produce a light brown solid. The produced solid was recrystallized with methanol to obtain 5.1 g of an objective. The analytical values were as follows.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:9][CH:8]=1.C1COCC1.[CH3:24][Si:25]([C:28]#[C:29][C:30]1[CH:49]=[CH:48][C:33]([C:34]([C:36]2[CH:41]=[CH:40][C:39]([C:42]#[C:43][Si:44]([CH3:47])([CH3:46])[CH3:45])=[CH:38][CH:37]=2)=[O:35])=[CH:32][CH:31]=1)([CH3:27])[CH3:26]>CCOCC.O>[CH3:16][Si:15]([C:14]#[C:13][C:10]1[CH:11]=[CH:12][C:7]([C:34]([C:33]2[CH:32]=[CH:31][C:30]([C:29]#[C:28][Si:25]([CH3:24])([CH3:26])[CH3:27])=[CH:49][CH:48]=2)([C:36]2[CH:37]=[CH:38][C:39]([C:42]#[C:43][Si:44]([CH3:47])([CH3:46])[CH3:45])=[CH:40][CH:41]=2)[OH:35])=[CH:8][CH:9]=1)([CH3:18])[CH3:17]
Reactant: C[Si](C)(C)C#Cc1ccc(C(=O)c2ccc(C#C[Si](C)(C)C)cc2)cc1
Reactant: C[Si](C)(C)C#Cc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)C#Cc1ccc(C(O)(c2ccc(C#C[Si](C)(C)C)cc2)c2ccc(C#C[Si](C)(C)C)cc2)cc1
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 77 %

Procedure:
A solution of n-BuLi (2.1 mL, 3.36 mmol, 1.6 M in hexane) was added to a solution of (4-bromophenylethynyl)trimethylsilane (0.69 mg, 2.74 mmol) in 50 mL of Et2O prechilled to -78° C. The solution was then stirred at -30° C. for 15 minutes. The solution was warmed to room temperature, stirred for 1 hour, and cooled to -30° C. A THF solution (20 mL) of 4,4'-bis(trimethylsilylethynyl)benzophenone (0.83 g, 2.19 nmol) prechilled to -30° C. was added slowly and the resulting mixture was stirred for 15 minutes. The solution was warmed to 0° C. and stirred for 2 hours. After addition of 1 mL of H2O the solution was pumped dry. The residue was chromatographed using CH2Cl2 /hexane (1:5 to 2:1) as eluent to afford tri(4-(trimethylsilylethynyl)phenyl)methanol as a colorless powder in 77% yield (0.92 q). 1H NMR (300 MHz, CDCL3, 25° C., TMS): 0.22 (s, 27 H, CH3), 2.72 (s, 1 h, OH), 7.13 (d, J=8.4 Hz, 6 H, C6H4), 7.38 (d, 6 H, C6H4). To a mixture of tri (4-(trimethylsilylethynyl)phenyl)methanol (0.92 g, 1.68 mmol) and KOH (0.28 g, 5.0 mmol) was added 50 mL of MeOH and the solution was stirred at room temperature for 3 hours. The solution was then extracted with Et2O solution was pumped dry and the residue was chromatographed using EtOAc/hexane (1:50 to 1:5) as eluent to afford tri(4-ethynylphenyl)methanol as a colorless powder in 84% yield (0.47 g). Anal. Calcd for C34H40Si3O: C 74.39, H 7.34. Found: C 74.03, H 7.28. 1H NMR (300 MHz, CDCl3, 25° C., TMS) : 2.73 (s, 1 H, OH), 3.06 (s, 3 H, ≡CH), 7.19 (d, J=8.2 Hz, 6 H, C6H4), 7.43 (d, 6 H, C6H4) ; IR (KBr, cm-1): 1018 (m, C--O), 2107 (w, C≡C); 3554 (m, O--H).