Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6](=O)[C:7](=[CH:18]N(C)C)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.C(O)(=[O:27])C.[CH:29]([NH2:31])=[NH:30]>C(N)=N>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:31]=[CH:29][N:30]=[CH:18][C:7]=3[CH2:8][N+:9]([O-:27])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: N=CN
Reactant: CC(=O)O
Reactant: CN(C)C=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2C1=O
Product: [O-][N+]1=C(c2ccccc2Cl)c2cc(Cl)ccc2-c2ncncc2C1

Procedure:
A mixture of 0.4 g (1.1 mmol) of 8-chloro-1-(2-chlorophenyl)-3,4-dihydro-4-[(dimethylamino)methylene]-5H-2-benzazepin-5-one and 1.0 g (9.6 mmol) of formamidine acetate in 20 ml of formamidine was heated on a steam bath for 7 hr. The mixture was poured over ice and extracted with methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate and concentrated at reduced pressure. The residue was triturated with ether to give an off-white solid, mp 215°-217° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:14][C:13]=2[O:23][CH3:24])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30].[Cl:33][C:34]1[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:35]=1[S:41](Cl)(=[O:43])=[O:42].N1C=CC=CC=1>ClCCl>[Cl:33][C:34]1[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:35]=1[S:41]([NH:1][C:2]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:14][C:13]=2[O:23][CH3:24])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])(=[O:43])=[O:42]
Reactant: COC(=O)Cc1ccc(Oc2ccc3c(cnn3COCC[Si](C)(C)C)c2N)c(OC)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)Cc1ccc(Oc2ccc3c(cnn3COCC[Si](C)(C)C)c2NS(=O)(=O)c2ccc(Cl)cc2Cl)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-(4-(4-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-yloxy)-3-methoxyphenyl)acetate (42 mg, 0.092 mmol) in dichloromethane (1 mL) was added 2,4-dichlorobenzene sulfonyl chloride (25 mg, 0.1 mmol) and pyridine (10 μl, 0.12 mmol). The resulting mixture was stirred overnight at room temperature. The mixture was then diluted with dichloromethane (20 mL) and washed with dilute aqueous hydrochloric acid (20 mL) and water (20 mL), then dried over magnesium sulfate and concentrated under reduced pressure. The desired sulfonamide was isolated by column chromatography (10% ethyl acetate/hexane). 1H NMR (400 MHz) (CDCl3) δ 8.40 (s, 1H); 7.81 (s, 1H); 7.72 (d, J=8.5 Hz, 1H); 7.32 (d, J=9 Hz, 1H); 7.19 (d, J=1.9 Hz, 1H); 7.15 (dd, J=1.9, 8.5 Hz, 1H); 6.90 (d, J=1.8 Hz, 1H); 6.88 (d, J=9 Hz, 1H); 6.60 (dd, J=1.8, 8.2 Hz, 1H); 6.35 (d, J=8.2 Hz, 1H); 5.68 (s, 2H); 3.84 (s, 3H); 3.75 (s, 3H), 3.62 (s, 2H); 3.57 (t, J=8.2 Hz, 2H); 0.89 (t, J=8.2 Hz, 2H), 0.0 (s, 9H).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:35][C:36]3[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[C:39]([NH2:46])=[C:38]([Cl:47])[CH:37]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][C@H:28]4[C:32]([OH:34])=[O:33])[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:48]=[CH:49][CH:50]=[CH:51][C:4]=2[NH:3]1.[N:52]1([CH2:58][CH2:59]O)[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:35][C:36]3[CH:41]=[C:40]([C:42]([F:43])([F:45])[F:44])[C:39]([NH2:46])=[C:38]([Cl:47])[CH:37]=3)[C:19]([N:21]3[CH2:22][CH2:23][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][C@H:28]4[C:32]([O:34][CH2:59][CH2:58][N:52]4[CH2:57][CH2:56][O:55][CH2:54][CH2:53]4)=[O:33])[CH2:25][CH2:26]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:48]=[CH:49][CH:50]=[CH:51][C:4]=2[NH:3]1
Reactant: OCCN1CCOCC1
Reactant: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCC[C@H]3C(=O)O)CC2)cc1C(F)(F)F
Product: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCC[C@H]3C(=O)OCCN3CCOCC3)CC2)cc1C(F)(F)F

Procedure:
Prepared analogously to Example 9.2 from 70 mg (0.10 mmol) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-((S)-2-carboxy-pyrrolidin-1-yl) -piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 13.2 mg (0.11 mmol) 2-morpholin-4-yl-ethanol.
Reaction SMILES: [S:1](Cl)(Cl)=[O:2].[OH:5][CH:6]([CH3:17])[CH:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:8].N1C=CC=CC=1.C(OCC)(=O)C>C(#N)C.CN(C)C1C=CN=CC=1>[CH3:8][CH:7]1[CH:6]([CH3:17])[O:5][S:1](=[O:2])[N:9]1[C:10]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:16]
Reactant: O=S(Cl)Cl
Reactant: CC(O)C(C)NC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CC#N
Product: CC1OS(=O)N(C(=O)OC(C)(C)C)C1C
Temperature: -40 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
To a stirred solution of thionyl chloride (4.1 mL, 56.8 mmol) in acetonitrile (30 mL) cooled to −45° C. is added a solution of tert-butyl (3-hydroxybutan-2-yl)carbamate (4.30 g, 22.7 mmol) in acetonitrile (40 mL) by syringe over 10 min, keeping the internal temperature below −40° C. When the addition is complete, 4-dimethylamino pyridine (277.5 mg, 2.3 mmol) is added followed by the dropwise addition of pyridine (9.2 mL, 113.6 mmol), keeping the temperature below −40° C. The reaction mixture is stirred at −40° C. for 1 h. Ethyl acetate (70 mL) is added to the suspension and the mixture is filtered at −35° C. The solid is washed with EtOAc and the filtrates are combined. Saturated Na2HPO4 solution (40 mL) is added and the mixture is stirred vigorously for 30 min. The organic layer is separated, washed with 1M NaHSO4, dried (MgSO4) and concentrated to afford the title crude compound (4.83 g, 90%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[C:4]([CH3:27])[CH:3]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][C:30]=1[C:38]([O:40][CH3:41])=[O:39].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:41][O:40][C:38](=[O:39])[C:30]1[CH:31]=[C:32]([O:26][C:23]2[CH:22]=[CH:21][C:20]([CH:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[CH3:27])[CH2:9][C:10]([C:12]3[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=3)=[O:11])=[CH:25][CH:24]=2)[CH:33]=[CH:34][C:29]=1[F:28]
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(O)cc1
Reactant: COC(=O)c1cc(B(O)O)ccc1F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc(Oc2ccc(C(CC(=O)c3ccc(=O)n(C)c3)c3ccc(Cl)cc3C)cc2)ccc1F

Procedure:
In analogy to example 222, step 1, 5-[3-(4-chloro-2-methyl-phenyl)-3-(4-hydroxy-phenyl)-propionyl]-1-methyl-1H-pyridin-2-one (example 346, step 1) was reacted with 4-fluoro-3-methoxycarbonylphenylboronic acid in dichloromethane in the presence of copper(II) acetate, pyridine and air to give the title compound as a colourless solid, MS (ESI+): m/z=534.2 [M+H]+.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][C:8]=1[C:17]([F:20])([F:19])[F:18].Cl[CH2:22]Cl>>[OH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16][CH3:22])=[O:15])=[CH:9][C:8]=1[C:17]([F:20])([F:19])[F:18]
Reactant: COc1ccc(CC(=O)O)cc1C(F)(F)F
Reactant: ClCCl
Agent: BrB(Br)Br
Product: COC(=O)Cc1ccc(O)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 33.2 %

Procedure:
Boron tribromide (8.02 mL, 84.87 mmol) was added dropwise to 2-(4-methoxy-3-(trifluoromethyl)phenyl)acetic acid (3.31 g, 14.13 mmol) in dichloromethane (250 mL) while maintaining the temperature below 10° C. After complete addition the reaction mixture was removed from the ice bath and allowed to stir at ambient temperature under nitrogen for 90 minutes. The reaction mixture was added dropwise to ice cold methanol (150 mL) and the mixture was stirred at ambient temperature for a further 40 minutes. The reaction mixture was evaporated to afford to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 2-(4-hydroxy-3-(trifluoromethyl)phenyl)acetate (1.100 g, 33.2%) as a pale yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:5]([CH:14]=[N:15][OH:16])[C:4]([CH3:17])=[N:3]1.[OH-].[K+].Cl[CH2:21][C:22]1[CH:32]=[CH:31][C:25]([C:26](=[O:30])[S:27][CH2:28][CH3:29])=[CH:24][CH:23]=1.O>CS(C)=O>[CH3:1][N:2]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:5]([CH:14]=[N:15][O:16][CH2:21][C:22]2[CH:32]=[CH:31][C:25]([C:26](=[O:30])[S:27][CH2:28][CH3:29])=[CH:24][CH:23]=2)[C:4]([CH3:17])=[N:3]1
Reactant: CCSC(=O)c1ccc(CCl)cc1
Reactant: Cc1nn(C)c(Oc2ccccc2)c1C=NO
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCSC(=O)c1ccc(CON=Cc2c(C)nn(C)c2Oc2ccccc2)cc1
Reaction time: 3 h
Yield: 79.5 %

Procedure:
1.0 Gram (0.0043 mole) of 1,3-dimethyl-5-phenoxypyrazole-4-carbaldehyde oxime was dissolved in 20 ml of dimethyl sulfoxide, and after adding 0.3 g (0.0053 mole) of powdery potassium hydroxide, the resulting solution was stirred. To this solution was added 0.92 g (0.0043 mole) of S-ethyl 4-cloromethylbenzothiate, and reaction was carried out at room temperature for 3 hours. After completion of the reaction, 200 ml of water was added to the reaction solution which was then extracted with ethyl acetate. The ethyl acetate extract was washed with water and dried, and ethyl acetate was removed by evaporation to obtain an oily product. This oily product was column-chromatographed on silica gel to obtain 1.4 g of the desired compound.
Reaction SMILES: C(OC(=O)C[C@@H](N1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)=[CH:26]1)C(N[C@@H](CC1C=CC=CC=1)CO)=O)C1C=CC=CC=1.FC(F)(F)C(O)=[O:48].[CH2:52]([O:59][C:60](=[O:74])[CH2:61][C@@H:62]([NH2:73])[C:63]([NH:65][CH:66]([CH2:71][OH:72])[C:67]([CH3:70])([CH3:69])[CH3:68])=[O:64])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>ClCCCl>[CH2:52]([O:59][C:60](=[O:74])[CH2:61][C@@H:62]([N:73]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][C:39]([C:42](=[O:48])[NH2:43])=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)=[CH:26]1)[C:63]([NH:65][C@H:66]([CH2:71][OH:72])[C:67]([CH3:70])([CH3:69])[CH3:68])=[O:64])[C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1
Reactant: N#Cc1ccc(-c2ccc(-c3ccn([C@H](CC(=O)OCc4ccccc4)C(=O)N[C@H](CO)Cc4ccccc4)c3)cc2)cc1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)C(CO)NC(=O)[C@H](N)CC(=O)OCc1ccccc1
Solvent: ClCCCl
Product: CC(C)(C)[C@@H](CO)NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccc(C(N)=O)cc3)cc2)c1
Yield: 41 %

Procedure:
As described for Example 4(a) for the preparation of N-(1(S)-benzyl-2-hydroxyethyl)-3(R)-[3-(4'-cyano-biphenyl-4-yl)-1H-pyrrol-1-yl]succinamic acid benzyl ester, crude 3-(4'-carboxamidobiphenyl)-2,5-dimethoxy-tetrahydrofuran and 3(R)-amino-N-(1-hydroxymethyl-2,2-dimethyl-propyl)succinamic acid benzyl ester trifluoroacetate salt were condensed in 1,2-dichloroethane to furnish 110 mg (41%) of 3(R)-[3-(4'-carbamoylbiphenyl-4-yl)-1H-pyrrol-1-yl]-N-(1(S)-hydroxymethyl-2,2-dimethyl-propyl)succinamic acid benzyl ester as a solid, mp 201-3° C. 1H NMR (CDCl3): δ 7.88 (d, 2H, J=8.1 Hz), 7.69 (d, 2H, J=8.4 Hz), 7.61 (d, 2H, J=8.4 Hz), 7.56 (d, 2H, J=8.7 Hz), 7.36-7.26 (m, 5H), 7.10 (d, 1H, J=1.9 Hz), 6.81 (d, 1H, J=2.5 Hz), 6.61 (t, 1H, J=1.6 Hz), 5.60-5.56 (m, 1H), 5.10-5.02 (m, 3H), 3.80-3.70 (m, 2H), 3.50-3.38 (m, 3H), 3.24 (dd, 1H, J=4.0, 17.0 Hz), 0.80 (s, 9H). IR KBr): 3356, 2961, 1735, 1655, 1606, 1560, 1542, 1406, 1200 cm-1. Anal. Calculated for C34H37N3O5.0.25 CH2Cl2 : C, 69.85; H, 6.42; N, 7.14. Found: C, 69.82, H, 6.67; N, 7.12.
Reaction SMILES: [C:1]1([P:7]2[C:12]([CH3:14])([CH3:13])[CH2:11][C:10](=O)[CH2:9][C:8]2([CH3:17])[CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]([NH2:21])[CH2:19][CH3:20].[B-]C#N.[Na+].Cl>CO>[CH2:18]([NH:21][CH:10]1[CH2:11][C:12]([CH3:14])([CH3:13])[P:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]([CH3:17])([CH3:16])[CH2:9]1)[CH2:19][CH3:20]
Reactant: CCCN
Reactant: CC1(C)CC(=O)CC(C)(C)P1c1ccccc1
Agent: Cl
Agent: [B-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCNC1CC(C)(C)P(c2ccccc2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 76.9 %

Procedure:
A flask, under nitrogen, was charged with a mixture of 12.4 grams (0.05 mole) of 1-phenyl-2,2,6,6-tetra methyl-4-phosphorinanone, 17.7 grams (0.30 mole) of n-propylamine, 1.89 grams (0.03 mole) of sodium cyanotrihydroborate, 20 mls of 5N methanolic hydrochloric acid and 150 mls of methanol. The mixture was stirred at ambient temperature for three days and then treated with 20 mls of conc. hydrochloric acid. The reaction mixture was concentrated in vacuo and 30 mls of water and 25 mls of diethylether were added. The layers were separated and to the aqueous layer was added 8 grams of solid sodium hydroxyde. The resultant basic mixture was extracted sequentially with five 25 ml portions of diethylether. The combined extracts were dried over anhydrous sodium sulfate, the solvent removed in vacuo and the residue distilled under reduced pressure to give 11.2 grams (77% yield) of colorless liquid, b.p. 140°-144° C. (0.1 mm Hg)
Reaction SMILES: [H-].[Na+].[BH4-].[Na+].O.[NH2:6][C:7]1[N:12]=[C:11]([SH:13])[N:10]=[C:9]([OH:14])[CH:8]=1.Cl[C@@H:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:17]>CN(C=O)C>[NH2:6][C:7]1[N:12]=[C:11]([S:13][C@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])[N:10]=[C:9]([OH:14])[CH:8]=1
Reactant: Nc1cc(O)nc(S)n1
Reactant: C[C@@H](Cl)c1ccccc1
Agent: [BH4-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](Sc1nc(N)cc(O)n1)c1ccccc1
Reaction time: 0.5 h
Yield: 46.5 %

Procedure:
NaH (60% in oil) (0.5 g, 12.5 mmol) followed by NaBH4 (40 mg, 1 mmol) was added to 6-amino-2-mercaptopyrimidin-4-ol monohydrate (1.6 g, 10 mmol) in DMF (20 mL). After 30 min, [(1R)-1-chloroethyl]benzene (1.4 g, 10 mmol) was added and the reaction mixture was stirred for 16 h. The reaction was concentrated in vacuo to ca. 10 mL volume and then poured into water (ca. 50 mL). The precipitated solid material was filtered off and washed with water and ether to give the title compound (1.15 g, 46% yield).
Reaction SMILES: [O:1]([C:8]1[CH:12]=[CH:11][S:10][C:9]=1[CH:13]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[S:20]([CH2:23][C:24]#[N:25])(=[O:22])=[O:21]>>[O:1]([C:8]1[CH:12]=[CH:11][S:10][C:9]=1/[CH:13]=[C:23](/[S:20]([C:16]1[S:15][CH:19]=[CH:18][CH:17]=1)(=[O:22])=[O:21])\[C:24]#[N:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1sccc1Oc1ccccc1
Reactant: N#CCS(=O)(=O)c1cccs1
Product: N#C/C(=C\c1sccc1Oc1ccccc1)S(=O)(=O)c1cccs1

Procedure:
Reaction of 3-phenoxythiophen-2-carboxaldehyde and thien-2-ylsulfonylacetonitrile as in Example 1 gave (E)-3-(3-phenoxythien-2-yl)-2-(thien-2-ylsulfonyl)acrylonitrile
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7][CH2:8][C:9]12[CH2:16][CH2:15][C:12]([C:17]([O:19]C)=[O:18])([CH2:13][CH2:14]1)[CH2:11][CH2:10]2)(=[O:5])=[O:4])[CH3:2].[OH-].[K+].Cl>CO.O>[CH2:1]([S:3]([CH2:6][CH2:7][CH2:8][C:9]12[CH2:10][CH2:11][C:12]([C:17]([OH:19])=[O:18])([CH2:13][CH2:14]1)[CH2:15][CH2:16]2)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)CCCC12CCC(C(=O)OC)(CC1)CC2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCS(=O)(=O)CCCC12CCC(C(=O)O)(CC1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sulfone 11-7 (3.1 g, 10 mmol) was dissolved in 9:1 MeOH/water (50 mL) and treated with potassium hydroxide (3 g). The solution was stirred at room temperature overnight, then the mixture was acidified with 1 N HCl and extracted four times with 50 mL of methylene chloride. The organic layer was dried over anhydrous sodium sulfate and evaporated to afford 4-[3-(ethylsulfonyl)propyl]bicyclo[2.2.2]octane-1-carboxylic acid (11-8) which was used without purification in the next step. 1H NMR (500 MHz, CDCl3): δ 3.03 (2H, q, J=7 Hz), 2.94 (2H, dd, J=7.5 Hz), 1.84 (8H, m), 1.45 (8H, m), 1.30 (2H, m) ppm.
Reaction SMILES: [Cl:1][CH2:2][C:3](=O)[CH2:4][C:5]([O:7][CH3:8])=[O:6].[NH2:10][C:11]([NH2:13])=[S:12]>C1COCC1>[ClH:1].[NH2:13][C:11]1[S:12][CH:2]=[C:3]([CH2:4][C:5]([O:7][CH3:8])=[O:6])[N:10]=1
Reactant: NC(N)=S
Reactant: COC(=O)CC(=O)CCl
Solvent: C1CCOC1
Product: COC(=O)Cc1csc(N)n1
Product: Cl
Temperature: 25 °C
Yield: 88.7 %

Procedure:
To a solution of methyl 4-chloro-acetoacetate (4.0 g, 27 mmol) in 50 mL of THF was added thiourea (2.0 g, 27 mmol) and the resulting suspension was stirred at reflux for 5 h. The mixture was allowed to cool to room temperature. The white solid was filtered off and washed with ether to afford 5.0 g (90%) of the title compound. 1H NMR (D2O) δ 6.6 (broad s, 1H), 3.7 (broad s, 2H), 3.6 (broad s, 3H). MS (NH3 --CI) 173 (M+H)+ (100%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Mg].[Cl:15][CH2:16][Si:17]([CH3:20])([CH3:19])Cl>II>[Cl:15][CH2:16][Si:17]([CH3:20])([CH3:19])[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: C[Si](C)(Cl)CCl
Agent: II
Agent: [Mg]
Product: C[Si](C)(CCl)c1ccc(-c2ccccc2)cc1
Yield: 57.5 %

Procedure:
In the same apparatus and procedures as Example 2-i) were reacted 18.7 g (80 mmol) of 4-bromobiphenyl, 4.8 g of magnesium and 0.7 g of iodine to prepare 4-phenylphenyl Grignard solution. In the same apparatus and procedures were reacted 10.4 ml (80 mmol) of chloromethyldimethylchlorosilane and the prepared 4-phenylphenyl Grignard solution to treat the reaction product. After separating them by using silica gel column (eluent: hexane), 12 g of chloromethyldimethyl(4-phenylphenyl)silane (92%) was obtained.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=3)=[N:7][C:8]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:27][O:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C(O)C.O.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>[Cl:26][C:21]1[CH:20]=[C:19]([NH:18][C:6]2[C:5]3[C:10](=[CH:11][C:2]([C:32]4[CH:33]=[N:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=4)=[CH:3][CH:4]=3)[N:9]=[C:8]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:7]=2)[CH:24]=[CH:23][C:22]=1[F:25]
Reactant: COc1ccc(B(O)O)cn1
Reactant: Fc1ccc(Nc2nc(-c3cccnc3)nc3cc(Br)ccc23)cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2ccc3c(Nc4ccc(F)c(Cl)c4)nc(-c4cccnc4)nc3c2)cn1
Temperature: 120 °C
Yield: 6.6 %

Procedure:
A microwave vial was charged with 7-bromo-N-(3-chloro-4-fluorophenyl)-2-(pyridin-3-yl)quinazolin-4-amine (synthesized as described in Scheme 1 and 4, substituting 4-bromo-2-nitrobenzoic acid for 2-nitro-5-propoxy-benzoic acid and 3-chloro-4-fluoroaniline for 2-aminobenzamide) (100 mg, 0.233 mmol), 6-methoxypyridin-3-ylboronic acid (44.5 mg, 0.291 mmol, 1.25 equiv), Pd(PPh3)2Cl2 (8.1 mg, 5 mol %) and potassium carbonate (160.1 mg, 1.16 mmol, 5.0 equiv). The mixture was suspended in DME/water/ethanol (7:3:2, 4 mL), and the reaction was heated under microwave irradiation conditions at 120° C. for 10 minutes. The crude reaction mixture was diluted with water (10 mL) and then filtered. The solid residue was dissolved in methanol/THF (1:1, 5 mL) with heating and then filtered through Celite to remove the catalyst. The resulting filtrate was concentrated to afford the desired product as a tan solid (7.0 mg, 6.5%). LCMS m/z=458.1 (M+1) (Method C) (retention time=2.51 min). 1H NMR (300 MHz, DMSO) δ 10.12 (s, 1H), 9.55 (s, 1H), 8.76 (d, J=2.5 Hz, 1H), 8.72-8.65 (m, 2H), 8.62 (d, J=8.6 Hz, 1H), 8.34-8.26 (m, 2H), 8.15 (d, J=1.6 Hz, 1H), 8.02 (d, J=8.7 Hz, 1H), 7.97-7.88 (m, 1H), 7.61-7.49 (m, 2H), 6.99 (d, J=8.7 Hz, 1H), 3.94 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([O:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)[CH3:25].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:33][C:30]4[CH:31]=[CH:32][C:27]([O:26][CH2:24][CH3:25])=[CH:28][CH:29]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 160 °C
Yield: 51.6 %

Procedure:
A mixture of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 50 mg, 0.15 mmol), 4-ethoxyphenol (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 27 mg, 0.19 mmol), and potassium carbonate (27 mg, 0.2 mmol) in dimethylformamide (2 mL) was heated in the microwave oven at 160° C. for 10 min. Ethyl acetate and water were added, and the aqueous layer was extracted twice with ethyl acetate. The ethyl acetate layers were combined, evaporated, and purified by preparative C18 HPLC, eluting with 10-100% acetonitrile/water. Samples containing the product were extracted twice with dichloromethane and the solvent was evaporated under high vacuum to give 4-[4-(4-ethoxy-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (34 mg, 52%) as a white powder. 1H NMR (300 MHz, CDCl3) δ 1.44 (t, 3H, J=7.0 Hz), 1.49 (s, 9H), 1.96-2.05 (m, 2H), 2.17-2.30 (m, 1H), 2.86-3.04 (m, 2H), 4.06 (q, 2H, J=6.9 Hz), 4.23-4.36 (m, 2H), 4.90-5.00 (m, 1H), 6.97 (d, 2H, J=8.8 Hz), 7.15 (d, 2H, J=9.0 Hz), 8.54 (s, 1H), 8.54 (s, 1H). Mass spectrum (ES) MH+=440. HRMS Calcd. for C23H30N5O4 (MH+): 440.2293. Found: 440.2292.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]=[S:13].[CH2:14]([CH:16]([CH2:19][CH3:20])[CH2:17][NH2:18])[CH3:15].Cl[CH:22]([CH:26]([CH3:28])[CH3:27])[C:23](O)=[O:24]>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[N:18]([CH2:17][CH:16]([CH2:19][CH3:20])[CH2:14][CH3:15])[C:23](=[O:24])[CH:22]([CH:26]([CH3:28])[CH3:27])[S:13]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: CCC(CC)CN
Reactant: CC(C)C(Cl)C(=O)O
Product: CCC(CC)CN1C(=O)C(C(C)C)SC1=Nc1ccc([N+](=O)[O-])cc1C

Procedure:
2Methyl-4-nitrophenyl isothiocyanate was reacted with 2-ethyl-1-butylamine followed by 2chloro-3-methylbutanoic acid according to Method C8a to afford 2-(2-methyl-4-nitrophenylimino)-3-(2-ethyl-1-butyl)-5-isopropyl-1,3-thiazolidin-4-one.