Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]=[C:12]=[S:13])=[O:10])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:40]=[CH:39][C:18]([O:19][C:20]2[CH:25]=[C:24]([NH:26][C:27]([N:29]3[CH2:34][CH2:33][CH:32]([CH2:35][N:36]([CH3:38])[CH3:37])[CH2:31][CH2:30]3)=[O:28])[N:23]=[CH:22][N:21]=2)=[C:17]([F:41])[CH:16]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1.C(O)C>[CH3:38][N:36]([CH2:35][CH:32]1[CH2:33][CH2:34][N:29]([C:27]([NH:26][C:24]2[CH:25]=[C:20]([O:19][C:18]3[CH:39]=[CH:40][C:15]([NH:14][C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[S:13])=[CH:16][C:17]=3[F:41])[N:21]=[CH:22][N:23]=2)=[O:28])[CH2:30][CH2:31]1)[CH3:37]
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Reactant: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3F)ncn2)CC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Solvent: Cc1ccccc1
Product: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)CC1
Reaction time: 2 h
Yield: 40 %

Procedure:
After adding a solution of 2-(4-fluorophenyl)acetyl isothiocyanate in toluene (0.2 M, 3.0 ml) to a solution of 4-(4-amino-2-fluorophenoxy)-6-{[4-(dimethylaminomethyl)piperidin-1-yl]carbonylamino}pyrimidine (118 mg) and (+)-10-camphorsulfonic acid (70.6 mg) in ethanol (3.0 ml) at room temperature, the mixture was stirred for 2 hours. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate and brine and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate:heptane=4:1) to provide the title compound (70.0 mg, 40%) as white powder.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7](=O)[CH2:8]Br)=[CH:5][CH:4]=1)#[N:2].[CH3:13][C@@H:14]([NH:19][C:20]([NH2:22])=[S:21])[C:15]([F:18])([F:17])[F:16].C(=O)(O)[O-].[Na+]>C(O)C>[CH3:13][C@@H:14]([NH:19][C:20]1[S:21][CH:8]=[C:7]([C:6]2[CH:11]=[CH:12][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[N:22]=1)[C:15]([F:18])([F:17])[F:16]
Reactant: C[C@@H](NC(N)=S)C(F)(F)F
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: C[C@@H](Nc1nc(-c2ccc(C#N)cc2)cs1)C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 50.8 %

Procedure:
Dissolve 4-cyanophenacyl bromide (1.82 g, 8.14 mmol), (R)-(1-methyl-2,2,2-trifluoroethyl)-thiourea (1.4 g, 8.14 mmol) and sodium bicarbonate (0.68 g, 8.14 mmol) in absolute ethanol. Heat at reflux 2 h, cool to room temperature and let stand over 2 days. Filter and collect the resulting crude product as a tan solid. Purify by chromatography on silica gel (34 g) eluting with hexane/EtOAc (19:1 to 4:1 over 30 min, 4:1 over 10 min; 40 mL/min) to obtain the desired intermediate as a white solid (1.23 g, 52%). MS (ES+) m/z: 298 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]([N:11]([CH:20]([CH3:22])[CH3:21])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[O:10])[C:6]2[CH:23]=[CH:24][CH2:25][CH2:26][C:5]=2[C:4](=O)[O:3]1.[NH2:28][C@@H:29](C(O)=O)[CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1.C(N(CC)CC)C>O>[NH:33]1[C:34]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:31]([CH2:30][C@@H:29]2[C:2](=[O:1])[N:7]([CH2:8][C:9]([N:11]([CH:20]([CH3:22])[CH3:21])[C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[O:10])[C:6]3[CH:23]=[CH:24][CH:25]=[CH:26][C:5]=3[C:4](=[O:3])[NH:28]2)=[CH:32]1
Reactant: COc1ccc(N(C(=O)Cn2c3c(c(=O)oc2=O)CCC=C3)C(C)C)cc1
Reactant: N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(N(C(=O)CN2C(=O)[C@@H](Cc3c[nH]c4ccccc34)NC(=O)c3ccccc32)C(C)C)cc1
Reaction time: 5 h
Yield: 33.9 %

Procedure:
A mixture of 2-(2,4-Dioxo-6H-benzo[d][1,3]oxazin-1-yl)-N-isopropyl-N-(4-methyoxy-phenyl)-acetamide (1.00 g, 2.71 mmol), D-tryptophan (554 mg, 2.71 mmol) and triethylamine (0.378 mL, 2.71 mmol) are combined in water (20 mL) and stirred for 5 hrs. at 50° C. After concentration in vacuo, the reaction mixture is combined with glacial acetic acid (20 mL) and refluxed for 5 hrs. The reaction mixture is filtered and then concentrated in vacuo to an oil. The oil is dissolved in ethyl acetate and washed consecutively with water (2×), saturated aqueous sodium bicarbonate, and brine. The solution is dried over anyhydrous magnesium sulfate, filtered, treated with activated charcoal, filtered and concentrated in vacuo to a yellow foam. The product is crystallized from methanol (15 mL). The resulting slurry is cooled with an ice/water bath, filtered and washed with cold methanol (3×4 mL), and dried under high vacuum to provide the title compound as white solid (469 mg, 0.918 mmol). 1H NMR (300 MHz, CDCl3): 1.11 (m, 6H); 3.22 (m, 1H); 3.46 (m, 1H); 3.69 (d, 1H, J=16.6 Hz); 3.83 (s, 3H); 4.20 (m, 1H); 4.45 (d, 1H, J=16.6 Hz); 5.06 (m, 1H); 6.06 (d, 1H, J=5.4 Hz); 6.88-7.37 (m, 10H); 7.50 (m, 2H); 7.73 (m, 1H); 8.14 (s, 1H). MS(FAB): [M+H]+ =511.
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12]([NH:18][S:19]([C:22]([F:25])([F:24])[F:23])(=[O:21])=[O:20])=[CH:13]3)=[CH:4][CH:3]=1.[Cl:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[C:33]([Cl:35])[CH:34]=1.CS(C)=O>O>[Cl:28][C:29]1[CH:30]=[C:31]([C:2]2[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]3[CH:17]=[CH:16][CH:15]=[C:14]4[C:9]=3[CH:10]=[CH:11][C:12]([NH:18][S:19]([C:22]([F:24])([F:23])[F:25])(=[O:21])=[O:20])=[CH:13]4)=[CH:4][CH:3]=2)[CH:32]=[C:33]([Cl:35])[CH:34]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: O=S(=O)(Nc1ccc2c(OCc3ccc(Br)cc3)cccc2c1)C(F)(F)F
Solvent: CS(C)=O
Solvent: O
Product: O=S(=O)(Nc1ccc2c(OCc3ccc(-c4cc(Cl)cc(Cl)c4)cc3)cccc2c1)C(F)(F)F

Procedure:
The title compound was prepared from the product of Example 1 and 3,5-dichloro phenyl boronic acid according to the procedure of Example 2, m.p. 138-140 DMSO: δ 12.1(s, 1H), 7.0-8.3(m, 13H, arom), 5.38 (s, 2H). CHN 53.84, 3.20, 2.62 (0.5 M H2O) Found 53.97, 3.02, 2.40.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[N:17]=[CH:16][CH:15]=[N:14]2)=[CH:9][CH:8]=1.CCN(CC)CC.[CH:26]1([CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=2)[CH2:28][CH2:27]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:18])[CH2:4][N:5]([S:37]([C:34]1[CH:33]=[CH:32][C:31]([O:30][CH2:29][CH:26]2[CH2:27][CH2:28]2)=[CH:36][CH:35]=1)(=[O:39])=[O:38])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[N:14]=[CH:15][CH:16]=[N:17]2)=[CH:11][CH:12]=1
Reactant: COC(=O)CNCc1ccc(-n2nccn2)cc1
Reactant: O=S(=O)(Cl)c1ccc(OCC2CC2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CN(Cc1ccc(-n2nccn2)cc1)S(=O)(=O)c1ccc(OCC2CC2)cc1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
To a solution of 79.5 g (323.2 mmol) of the compound of stage 3.2, 80.9 ml (581.6 mmol) of Et3N and 1.97 g (16.1 mmol) of DMAP in 1000 ml of CH2Cl2, a solution of 99.6 g (404 mmol ) of 4-cyclopropylmethoxy-benzenesulfonyl chloride in 150 ml of CH2Cl2 is added and stirred for 60 min. at 0-5° C. After stirring for additional 18 h at r.t., the reaction mixture is quenched with ice water and extracted with CH2Cl2. The combined extracts are washed with H2O, brine, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by CC on silica gel (n-Hexane:AcOEt=4:1-2:1) to give the title compound as colorless solid; 1H-NMR (400 MHz, CDCl3): 0.35-0.45 (m, 2H), 0.65-0.75 (m, 2H), 1.25-1.35 (m, 1H), 3.58 (s, 3H), 3.87 (d, 2H, J=7.04 Hz), 3.94 (s, 2H), 4.52 (s, 2H), 6.99 (d, 2H, J=7.04 Hz), 7.37 (d, 2H, J=8.56 Hz), 7.81(s, 2H), 7.82 (d, 2H, J=7.04 Hz), 8.02 (d, 2H, J=8.56 Hz).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2].Cl.[CH:24]1([NH:27][CH3:28])[CH2:26][CH2:25]1.CCN(CC)CC>CS(C)=O>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:27]([CH:24]2[CH2:26][CH2:25]2)[CH3:28])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CNC1CC1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN(c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C(F)(F)F)C1CC1

Procedure:
The title compound was prepared from (5-chloro-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example B5) (3.40 g, 10 mmol) and cyclopropyl-methyl-amine hydrochloride (3.22 g, 30 mmol) and Et3N (6.97 mL, 50 mmol) in DMSO (50 mL) at 23° C. according to the general procedure C. Obtained as a yellow solid (3.74 g).
Reaction SMILES: [CH3:1][C:2]1[C:3]([B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)=[CH:4][C:5]2[NH:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.C([O-])([O-])=O.[K+].[K+].N#N.[CH2:29](Br)[CH:30]=[CH2:31]>CN(C=O)C.O>[CH2:31]([N:10]1[CH2:9][CH2:8][O:7][C:6]2[CH:11]=[C:2]([CH3:1])[C:3]([B:12]3[O:13][C:14]([CH3:20])([CH3:19])[C:15]([CH3:18])([CH3:17])[O:16]3)=[CH:4][C:5]1=2)[CH:30]=[CH2:29]
Reactant: C=CCBr
Reactant: Cc1cc2c(cc1B1OC(C)(C)C(C)(C)O1)NCCO2
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCN1CCOc2cc(C)c(B3OC(C)(C)C(C)(C)O3)cc21
Temperature: 70 °C
Yield: 52.9 %

Procedure:
A solution of 7-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (0.488 g, 1.774 mmol, prepared according to the procedures outlined for related compounds in Ref. WO20100130034) and K2CO3 (0.490 g, 3.55 mmol) in dry DMF (5 mL) was sparged with N2 for 5 min, treated with allyl bromide (0.773 mL, 8.87 mmol), then heated (70° C.) for 22 h. The reaction was diluted with water (50 mL) and extracted into EtOAc (50 mL) and washed with water, brine and then dried (Na2SO4), filtered, and concentrated. The crude was purified by biotage column chromatography (12 g SiO2, 0% (3 CV), 0-40% (10 CV), 40% (2 CV), EtOAc in hexanes). Product rich fractions were re-purified by biotage (0% (3 CV), 0-40% (15 CV), 40% (2 CV), EtOAc in hexanes) to afford the desired product (0.345 g, 0.938 mmol, 52.9% yield), as a colorless viscous oil. 1H NMR (500 MHz, CDCl3) δ 7.20 (s, 1H), 6.62 (d, J=0.5 Hz, 1H), 5.92 (ddt, J=16.9, 10.4, 5.9 Hz, 1H), 5.29 (dq, J=17.2, 1.6 Hz, 1H), 5.23 (dq, J=10.2, 1.4 Hz, 1H), 4.30-4.24 (m, 2H), 3.89 (dt, J=5.9, 1.3 Hz, 2H), 3.27-3.18 (m, 2H), 2.43 (s, 3H), 1.33 (s, 12H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:25])[C:5]([C:8]2([CH2:11][NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]([F:23])([F:22])[F:21])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH:26]1([B-](F)(F)F)[CH2:28][CH2:27]1.[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.O>[Cl:25][C:4]1[C:5]([C:8]2([CH2:11][NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]([F:23])([F:22])[F:21])[CH2:10][CH2:9]2)=[N:6][CH:7]=[C:2]([CH:26]2[CH2:28][CH2:27]2)[CH:3]=1
Reactant: F[B-](F)(F)C1CC1
Reactant: O=C(NCC1(c2ncc(Br)cc2Cl)CC1)c1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(NCC1(c2ncc(C3CC3)cc2Cl)CC1)c1ccccc1C(F)(F)F
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 44.7 %

Procedure:
150 mg of N-[[1-(5-bromo-3-chloro-2-pyridyl)cyclopropyl]methyl]-2-(trifluoromethyl)benzamide (step 4), 61 mg potassium cyclopropyltrifluoroborate and 340 mg cesium carbonate were dissolved in 3 ml of a mixture of toluene and water (3:1) in a microwave vial. The reaction mixture was degassed with argon for 1 min and 14 mg of [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) was added. The vial was sealed and the reaction mixture was then stirred at 100° C. in a microwave reactor for 30 min, then at 130° C. for 30 min. Then the mixture was cooled to ambient temperature, water was added and the reaction mixture was extracted with dichloromethane. The organic phase was dried with anhydrous sodium sulfate, filtered and concentrated. Crude material was obtained as a brown sticky solid, which was purified by flash chromatography on silica gel with heptane/ethyl acetate as a solvent. Thus, 61 mg of N-[[1-(3-chloro-5-cyclopropyl-2-pyridyl)cyclopropyl]methyl]-2-(trifluoromethyl)benzamide was obtained as a pale yellow sticky solid. 1H-NMR (CDCl3): 8.19 ppm (d, 1H), 7.65 ppm (d, 1H), 7.52 ppm (m, 2H), 7.40 ppm (d, 1H), 7.30 ppm (d, 1H), 6.20 ppm (s, 1H, broad), 3.68 ppm (d, 2H), 1.85 ppm (m, 1H), 1.05 ppm (m, 5H), 0.88 ppm (m, 1H), 0.70 ppm (m, 2H).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[CH2:11][CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=1)[CH3:2].Br[CH2:13][CH:14]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(=O)([O-])[O-].[Na+].[Na+]>COCCO>[CH2:23]([CH:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:13][N:7]1[C:6]2[CH2:8][CH2:9][CH2:10][CH2:11][C:5]=2[N:4]=[C:3]1[CH2:1][CH3:2])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCc1nc2c([nH]1)CCCC2
Reactant: CCCCCCCCC(CBr)CCCCCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCO
Product: CCCCCCCCC(CCCCCC)Cn1c(CC)nc2c1CCCC2

Procedure:
2-Ethyl-4,5,6,7-tetrahydrobenzimidazole (14.3 parts), 2-methoxyethanol (30 parts), 1-bromo-2-hexyldecane (35 parts) and sodium carbonate (5.7 parts) are stirred together and heated at 125°-135° C. below a reflux condenser for 15 hours. The reaction mixture is cooled and extracted with a mixture of toluene (150 parts) and ethyl acetate (50 parts) and the extract is washed successively with water, dilute sulphuric acid, dilute sodium hydroxide, and water, and then distilled yielding 1-(2'-hexyldecyl)-2-ethyl-4,5,6,7-tetrahydrobenzimidazole (V) (16.6 parts), b.p. 185°-200° at 0.2 mm pressure.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](O)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([C:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([C:38]2[CH:43]=[CH:42][C:41]([NH:44][C:21]3[N:20]=[CH:19][C:18]4=[CH:17][CH:16]=[C:15]([C:11]5[CH:12]=[CH:13][CH:14]=[C:9]([S:6](=[O:7])(=[O:8])[NH:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH:10]=5)[N:23]4[N:22]=3)=[CH:40][CH:39]=2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)cc4)nn23)c1

Procedure:
4-{4-[7-(3-tert-Butylsulfamoyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester was prepared from N-tert-butyl-3-(2-hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide and 4-(4-amino-phenyl)-piperidine-1-carboxylic acid tert-butyl ester in an analogous manner to Example 1052a. Product isolated as an orange foam (82 mg, 47%). LCMS (m/e) 627 (M+Na); 1H-NMR (CDCl3, 400 MHz) δ 8.79 (s, 1H), 8.74 (s, 1H), 8.29 (d, 1H, J=8.1 Hz), 7.87 (d, 1H, J=7.9 Hz), 7.62-7.53 (m, 3H), 7.31-7.24 (m, 2H), 7.08 (d, 1H, J=4.8 Hz), 6.88-6.80 (m, 2H), 4.46 (s, 1H), 4.37-4.18 (m, 2H), 2.89-2.75 (m, 2H), 2.75-2.60 (m, 1H), 1.90-1.81 (m, 2H), 1.71-1.60 (m, 2H), 1.49 (s, 9H), 1.17 (s, 9H).
Reaction SMILES: [CH3:1][Si:2]([O:23]C)([O:21]C)[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([Si:15]([CH3:20])([O:18]C)[O:16]C)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(O)(=O)C>CCOCC>[CH3:20][Si:15]([OH:18])([OH:16])[C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:7]=[CH:8][C:3]([Si:2]([CH3:1])([OH:21])[OH:23])=[CH:4][CH:5]=2)=[CH:10][CH:11]=1
Reactant: CO[Si](C)(OC)c1ccc(-c2ccc([Si](C)(OC)OC)cc2)cc1
Solvent: CCOCC
Solvent: CC(=O)O
Product: C[Si](O)(O)c1ccc(-c2ccc([Si](C)(O)O)cc2)cc1
Yield: 32 %

Procedure:
A suspension of 4,4′-bis-(methyldimethoxysilyl)biphenyl (2.4 g, 6.62 mmol) in 5 ml of ether was stirred vigorously with 3 ml of 0.5% acetic acid solution for 32 days. The white suspension was filtered and the solid was washed three times with acetone and ether. The resulting fine white solid was dried for one day under vacuum at room temperature and gave 4,4′bis-(methyldihydroxysilyl)biphenyl in 32% yield (0.65 g, 2.10 mmol). 1H NMR (DMSO-d6, δ, ppm) 7.66 (8H, s); 6.40 (4H, s); 0.19 (6H, s). 13C NMR (DMSO-d6, δ, ppm) 144.7, 139.3, 134.9, 126.6, 0.38. 29Si NMR (DMSO-d6, δ, ppm) −21.22. Anal. Calcd.; For C14H18O4Si2: C, 54.87; H, 5.92; Si, 18.33%. Found: C, 54.82; H, 5.79; Si, 18.80%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]2[N:14]=[C:15]([O:17]S(C3C=CC(C)=CC=3)(=O)=O)[CH:16]=[C:12]2[CH:11]=[N:10][N:9]=1.[OH-].[Na+]>O1CCOCC1.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]2[N:14]=[C:15]([OH:17])[CH:16]=[C:12]2[CH:11]=[N:10][N:9]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2cc3cnnc(-c4ccccc4F)n3n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Oc1cc2cnnc(-c3ccccc3F)n2n1
Temperature: 60 °C
Yield: 83 %

Procedure:
To a stirred solution of toluene-4-sulfonic acid 7-(2-fluorophenyl)pyrazolo[1,5-d][1,2,4]triazin-2-yl ester (82.0 mg, 0.213 mmol) in 1,4-dioxane (4 ml) and water (0.8 ml) was added aqueous 4 N NaOH solution (0.270 ml, 1.08 mmol). The solution was heated at 60° C. for 3 h, then the solvents were removed in vacuo. The residue was dissolved in water (10 ml) and washed with ethyl acetate (10 ml). The aqueous layer was acidified to pH<3 and extracted with dichloromethane (6×25 ml). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo to leave 40.7 mg (83%) of the title compound; 1H NMR (360 MHz, d6-DMSO) δ 6.34 (1H, s), 7.42-7.48 (2H, m), 7.71 (1H, m), 7.79 (1H, td, J 7.2 and 1.7 Hz), 9.40 (1H, s), 11.74 (1H, s).
Reaction SMILES: Cl[C:2]1[C:3]2[C:11]([CH3:12])=[C:10]([CH3:13])[N:9]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])[C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.[C-:23]#[N:24].[K+]>CS(C)=O.O>[CH3:8][C:6]1[N:7]=[C:2]([C:23]#[N:24])[C:3]2[C:11]([CH3:12])=[C:10]([CH3:13])[N:9]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])[C:4]=2[N:5]=1
Reactant: Cc1cc(C)c(-n2c(C)c(C)c3c(Cl)nc(C)nc32)c(C)c1
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(C)c(-n2c(C)c(C)c3c(C#N)nc(C)nc32)c(C)c1
Temperature: 130 °C
Yield: 65.3 %

Procedure:
A mixture of 4-chloro-2,5,6-trimethyl-7-(2,4,6-trimethyl-phenyl)-7H-pyrrolo[2,3-d]-pyrimidine (10.000 g, 31.90 mmol) and potassium cyanide (20.75 g, 319 mmol) in 100 ml dimethylsulfoxide was heated at 130° C. oil bath over weekend. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated to give 9.61 g (99%) of brown soild. The solid was recrystallized from i-propanol to give 6.34 g (65%) of the title compound as light golden crystals, mp 188-190° C. 1H NMR (CDCl3) δ 1.8(s, 6H), 2.07(s, 3H), 2.36(s, 3H), 2.50(s, 3H), 2.65(s, 3H), 7.00(s, 2H).
Reaction SMILES: C[Mg]Br.[CH3:4]COCC.[CH2:9]([O:16][C:17]([N:19]1[CH2:22][C:21](=[O:23])[CH2:20]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[CH2:9]([O:16][C:17]([N:19]1[CH2:22][C:21]([OH:23])([CH3:4])[CH2:20]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CN(C(=O)OCc2ccccc2)C1
Reactant: CCOCC
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: CC1(O)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a 3.0 M solution of methylmagnesium bromide in Et2O (0.98 mL, 2.92 mmol), at 0° C., was added a solution of 3-oxoazetidine-1-carboxylic acid benzyl ester (0.5 g, 2.44 mmol) in anhydrous THF (5 mL) dropwise over 5 min under argon. The reaction mixture was stirred for 18 h at room temperature, and then quenched by addition of a saturated aqueous solution of NH4Cl (2.5 mL) and water (5 mL). The aqueous phase was extracted with EtOAc (10 mL) The organic layer was separated, dried over sodium sulphate and concentrated in vacuo to give 3-Hydroxy-3-methylazetidine-1-carboxylic acid benzyl ester as a colourless oil (0.54 g, 99%). LCMS (Method A): RT=3.60 min, [M+H]+ 221.9
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH:13]3[CH2:15][O:14]3)=[CH:7][C:5]=2[N:6]=1.[N:16]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>C(O)C>[C:25]([O:24][C:22]([N:16]1[CH2:21][CH2:20][N:19]([CH2:15][CH:13]([OH:14])[CH2:12][O:11][C:8]2[CH:9]=[CH:10][C:4]3[S:3][C:2]([CH3:1])=[N:6][C:5]=3[CH:7]=2)[CH2:18][CH2:17]1)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1nc2cc(OCC3CO3)ccc2s1
Solvent: CCO
Product: Cc1nc2cc(OCC(O)CN3CCN(C(=O)OC(C)(C)C)CC3)ccc2s1
Temperature: 85 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To 2-methyl-5-(oxiran-2-ylmethoxy)benzothiazole (2.21 g, 10 mmol), a compound of formula (3), was added tert-butyl 1-piperazinecarboxylate (1.86 g, 10 mmol), a compound of formula (4), and ethanol (30 ml). The resulting solution was heated to 85° C. and stirred for 8 hours. The solvent was evaporated under reduced pressure, and the residue was chromatographed on silica gel, eluting with 5% methanol/methylene chloride, to yield 4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-piperazine-1-carboxylic acid tert-butyl ester as a clear oil (2.9 g, 7.1 mmol).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[C:7]([CH3:19])=[C:8]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.[F:20][C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:16]2[CH2:15][CH2:14][N:13]([C:8]3[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]4[O:3][CH:2]([CH3:1])[CH2:6][C:5]=4[C:7]=3[CH3:19])[CH2:18][CH2:17]2)=[CH:23][CH:22]=1
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)C2
Reactant: Fc1ccc(I)cc1
Product: Cc1c(C)c(N2CCN(c3ccc(F)cc3)CC2)c(C)c2c1OC(C)C2
Yield: 21.8 %

Procedure:
By using 1-(2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (400 mg, 1.54 mmol) synthesized in Reference example 56 and 1-fluoro-4-iodobenzene (1.54 g, 6.92 mmol), the reaction was carried out in the same manner as Example 23 to synthesize the title compound 119 mg (yield 16%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)(=[O:16])=[O:15])[CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.[NH2:27][CH:28]1[CH2:37][CH2:36][CH2:35][C:34]2[N:33]=[C:32]([CH2:38][CH2:39][OH:40])[N:31]=[CH:30][C:29]1=2.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)(=[O:16])=[O:15])[CH2:9][C:10]([NH:27][CH:28]2[CH2:37][CH2:36][CH2:35][C:34]3[N:33]=[C:32]([CH2:38][CH2:39][OH:40])[N:31]=[CH:30][C:29]2=3)=[O:12])=[CH:4][CH:3]=1
Reactant: O=C(O)CC(NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccc(F)cc1
Reactant: NC1CCCc2nc(CCO)ncc21
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(CC(NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccc(F)cc1)NC1CCCc2nc(CCO)ncc21

Procedure:
A solution of 3-(4-fluorophenyl)-3-(3-trifluoromethyl-benzenesulfonylamino)-propionic acid (172 mg, 0.44 mmol), crude 2-(5-amino-5,6,7,8-tetrahydro-quinazolin-2-yl)-ethanol (Step G, 85 mg, 0.44 mmol), HOBt (65.5 mg, 0.484 mmol) and EDC (93 mg, 0.484 mmol) in 1.5 mL of DMF was stirred overnight at RT. After quenching with Sat. NaHCO3 solution, the mixture was extracted with EtOAc. The combined organic phase was washed brine, dried over Na2SO4, and evaporated in vacuo. Flash chromatography (SiO2, EtOAc/MeOH=100:5 to 100:10 to 100:12) gave the title compound as a white solid. MS: 567.0 (M+1).