Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: II.Cl[CH2:4][C:5]([CH3:7])=[CH2:6].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([NH:17][CH2:18][CH2:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[CH3:16])=[CH:11][CH:10]=1>O1CCCC1>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:15]([NH:17][CH2:18][CH2:19][C:20]([OH:24])([CH2:6][C:5]([CH3:7])=[CH2:4])[CH:21]([CH3:23])[CH3:22])[CH3:16])=[CH:13][CH:14]=1
Reactant: C=C(C)CCl
Reactant: CC(C)C(=O)CCN[C@@H](C)c1ccc(Br)cc1
Agent: II
Solvent: C1CCOC1
Product: C=C(C)CC(O)(CCN[C@@H](C)c1ccc(Br)cc1)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a suspension of Mg (11 g, 458 mmol) and I2 (0.5 g) in anhydrous tetrahydrofuran (50 mL) was added 3-chloro-2-methylprop-1-ene (1 mL) to initiate the reaction. Tetrahydrofuran (300 mL) was added, more solution of 3-chloro-2-methylprop-1-ene (15 mL) in tetrahydrofuran (20 mL) was dropped into the reaction at 0° C. under N2 over 30 min A solution of 1-[(S)-1-(4-bromophenyl)-ethylamino]-4-methyl-pentan-3-one (5 g) in tetrahydrofuran (50 mL) was added dropwise at −78° C. over 45 min. The reaction mixture was stirred at room temperature for 2 h. The reaction was cautiously quenched with saturated aqueous NH4Cl, and the reaction mixture was filtered. The filtrate was extracted with EtOAc (3×100 mL) and the combined extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo to give 3-{(S)-2-[1-(4-bromophenyl)-ethylamino]-ethyl}-2,5-dimethyl-hex-5-en-3-ol (6.4 g, 90% yield), which was used for the next step without further purification.
Reaction SMILES: C[O:2][C:3](=[O:19])[C@@H:4]([NH2:18])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[Br:20][C:21]1[C:22]([O:33][CH3:34])=[C:23]([C:27]([O:31][CH3:32])=[C:28]([Cl:30])[CH:29]=1)[C:24](O)=[O:25]>>[C:9]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=[CH:11][C:6]([CH2:5][C@H:4]([NH:18][C:24](=[O:25])[C:23]2[C:27]([O:31][CH3:32])=[C:28]([Cl:30])[CH:29]=[C:21]([Br:20])[C:22]=2[O:33][CH3:34])[C:3]([OH:2])=[O:19])=[CH:7][CH:8]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: COc1c(Cl)cc(Br)c(OC)c1C(=O)O
Product: COc1c(Cl)cc(Br)c(OC)c1C(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O
Yield: 80.6 %

Procedure:
2-(S)-amino-3-biphenyl-4-yl-propionic acid methyl ester (128 mg, 0.5 mmol) was reacted with 3-bromo-5-chloro-2,6-dimethoxybenzoic acid (148 mg, 0.5 mmol) as described in general procedure A. The resulting compound was hydrolyzed according to general procedure C to afford the title product (209 mg) as a pure white solid.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:32]([CH3:33])=[CH:31][C:13]2[N:14]=[C:15]([N:17]3[CH2:22][CH2:21][O:20][C:19]([C:24]4[CH:29]=[CH:28][C:27](Cl)=[CH:26][CH:25]=4)(C)[CH2:18]3)[S:16][C:12]=2[C:11]=1[C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:41][N:42]1C2C(=CC(C3OCCNC3)=CC=2)[CH:44]=[N:43]1>>[C:1]([O:5][C@@H:6]([C:10]1[C:32]([CH3:33])=[CH:31][C:13]2[N:14]=[C:15]([N:17]3[CH2:22][CH2:21][O:20][CH:19]([C:24]4[CH:25]=[C:26]5[C:27](=[CH:28][CH:29]=4)[N:43]([CH3:44])[N:42]=[CH:41]5)[CH2:18]3)[S:16][C:12]=2[C:11]=1[C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc2nc(N3CCOC(C)(c4ccc(Cl)cc4)C3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Reactant: Cn1ncc2cc(C3CNCCO3)ccc21
Product: Cc1cc2nc(N3CCOC(c4ccc5c(cnn5C)c4)C3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(2S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-(1-methyl-1H-indazol-5-yl)morpholino)benzo[d]thiazol-6-yl)acetic acid was prepared using the similar procedure as (2S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-(4-chlorophenyl)-2-methylmorpholino)-5-methylbenzo[d]thiazol-6-yl)acetic acid except 2-(1-methyl-1H-indazol-5-yl)morpholine was used instead of 2-(4-chlorophenyl)-2-methylmorpholine. LCMS-ESI+: calc'd for C32H33ClN4O4S: 605.2, 607.2 (M+H+); found: 605.3, 607.3 (M+H+). 1H-NMR: 400 MHz, (CD3OD) δ: 7.99 (s, 1H), 7.82 (s, 1H), 7.62 (d, J=7.6 Hz, 1H), 7.49-7.56 (m, 5H), 7.32 (s, 1H), 5.13 (s, 1H), 4.72 (d, J=7.2 Hz, 1H), 4.11 (m, 2H), 4.05 (s, 3H), 3.85 (m, 2H), 3.35 (m, 1H), 3.30 (t, J=12 Hz, 1H), 2.50 (s, 3H), 0.94 (s, 9H).
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[C:8]([C:10](OC)=[O:11])[CH:9]=[C:4]2[CH:3]=[N:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH:1]1[C:5]2=[CH:6][N:7]=[C:8]([CH2:10][OH:11])[CH:9]=[C:4]2[CH:3]=[N:2]1
Reactant: COC(=O)c1cc2cn[nH]c2cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc2cn[nH]c2cn1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 97 %

Procedure:
To a solution of 1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid, methyl ester (1.5 g, 8.5 mmol) in THF (350 mL) at 0° C. was added LAH (958 mg) in two portions. The reaction was stirred at 0° C. for 1.5 hr, and at rt for 1 hr. The reaction was quenched with con. NaOH at 0° C., and the solid was filtered off and washed with MeOH. The filtrate was concentrated. Purification by column afforded 1H-pyrazolo[3,4-c]pyridine-5-methanol (1.23 g, 96%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12](=[O:13])[C:11]2[N:10]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[C:9]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:33])([F:32])[F:31])[CH:24]=3)=[N:8][C:7]=2[N:6]([CH3:34])[C:5]1=[O:35].[CH3:36][CH:37]([S:39](Cl)(=[O:41])=[O:40])[CH3:38]>C(Cl)Cl.O>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:10]2[C:11]3[C:12](=[O:13])[N:4]([CH2:3][CH2:2][NH:1][S:39]([CH:37]([CH3:38])[CH3:36])(=[O:41])=[O:40])[C:5](=[O:35])[N:6]([CH3:34])[C:7]=3[N:8]=[C:9]2[O:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:33])([F:31])[F:32])[CH:24]=2)=[CH:20][CH:19]=1
Reactant: Cn1c(=O)n(CCN)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)S(=O)(=O)NCCn1c(=O)c2c(nc(Oc3cccc(OC(F)(F)F)c3)n2Cc2ccc(Cl)cc2)n(C)c1=O
Temperature: 40 °C
Reaction time: 16 h
Yield: 16.5 %

Procedure:
To a solution of 1-(2-aminoethyl)-7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (100 mg, 0.197 mmol) and TEA (40 mg, 0.393 mmol) in DCM (10 mL) was added propane-2-sulfonyl chloride (42 mg, 0.295 mmol) dropwise at 0° C. The resulting mixture was stirred at 40° C. for 16 h. The mixture was diluted with DCM and water, and the phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give crude product. This crude material was recrystallized from ethanol to give N-(2-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)ethyl)propane-2-sulfonamide (20 mg, 16.5% yield) as white solid. 1H-NMR (DMSO-d6) δ 7.63-7.59(t, 1H), 7.48(s, 1H), 7.45-7.41(m, 5H), 7.35-7.33(d, 1H), 7.26-7.18(m, 1H), 5.45(s, 2H), 4.01-3.97(t, 1H), 3.29(s, 6H). LCMS retention time 3.195 min; LCMS MH+ 616.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([Cl:13])[N:6]=[CH:5]2.[CH3:14][O:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.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:13][C:7]1[N:6]=[CH:5][C:4]2[C:9](=[CH:10][C:11]([Cl:12])=[C:2]([C:18]3[CH:17]=[C:16]([O:15][CH3:14])[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=3)[CH:3]=2)[N:8]=1
Reactant: Clc1ncc2cc(Br)c(Cl)cc2n1
Reactant: COc1cc(OC)cc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(OC)cc(-c2cc3cnc(Cl)nc3cc2Cl)c1
Temperature: 85 °C
Reaction time: 3 h
Yield: 55.2 %

Procedure:
A mixture of 6-bromo-2,7-dichloroquinazoline (3 g, 10.8 mmol), 3,5-dimethoxyphenylboronic acid (2.2 g, 11.9 mmol), cesium carbonate (1.06 g, 32.4 mmol) and Pd(PPh3)2Cl2 (702 mg, 1.08 mmol) in THF (50 mL) and water (10 mL) was degassed with nitrogen three times, and the reaction mixture was stirred at 85° C. for 3 hours. The reaction mixture was cooled to room temperature and directly concentrated. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=10:1˜4:1) to give the title compound (2.0 g, yield: 55%) as a yellowish solid. MS (ES+) requires: 334, 336, C16H12Cl2N2O2, found: 335, 337 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:14]([OH:16])=[O:15])[C:8](=[CH:12][CH:13]=1)[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2]>S(Cl)(Cl)=O>[C:1]([C:5]1[CH:6]=[C:7]2[C:14](=[O:15])[O:16][C:9](=[O:11])[C:8]2=[CH:12][CH:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(C(=O)O)c(C(=O)O)c1
Solvent: O=S(Cl)Cl
Product: CC(C)(C)c1ccc2c(c1)C(=O)OC2=O
Yield: 94.2 %

Procedure:
Subsequently, a 1 liter round bottom flask was fitted with a reflux condenser, to which was added 173.66 grams (0.7814 mole) of 4-t-butylphthalic acid and 500 milliliters of thionyl chloride. The yellow solution was magnetically stirred and refluxed for 3 hours, after which the thionyl chloride was removed from the anhydride under reduced pressure. The resultant white crystalline solid was washed three times with anhydrous hexane and the hexane was removed under reduced pressure to yield 150.33 grams (0.7361 mole) of the 4-t-butyl-phthalic anhydride product, which exhibited a melting point of 77° to 78° C. The identity of the 4-t-butyl-phthalic anhydride product was confirmed by IR spectrum.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]2[CH2:14][CH2:13][N:12](C(OCC)=O)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O>Br>[C:1]1([CH2:7][CH2:8][CH:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)N1CCC(CCc2ccccc2)CC1
Agent: Br
Solvent: O
Product: c1ccc(CCC2CCNCC2)cc1
Temperature: 100 °C
Yield: 82.8 %

Procedure:
A mixture of 0.70 g of ethyl 4-(2-phenylethyl)piperidine-1-carboxylate in 6 ml of 47% hydrobromic acid was heated under reflux at 100° C. for 6 hours. A small amount of water was added for dissolution of the resultant crystals, the solution was washed with ether, and the aqueous layer was made alkaline with 20% sodium hydroxide. After salting out with sodium chloride, the aqueous layer was extracted with ether. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 0.42 g of 4-(2-phenylethyl)piperidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9]C(OC)=O)=[CH:4][C:3]=1[N:14]1[C:18](=[O:19])[C:17](=[C:20]([CH3:22])[CH3:21])[O:16][C:15]1=[O:23].ClC1C=C(Cl)C(OC(OC)=O)=CC=1[N+]([O-])=O.C(=O)([O-])[O-].[K+].[K+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:14]1[C:18](=[O:19])[C:17](=[C:20]([CH3:21])[CH3:22])[O:16][C:15]1=[O:23]
Reactant: COC(=O)Oc1cc(N2C(=O)OC(=C(C)C)C2=O)c(Cl)cc1Cl
Agent: COC(=O)Oc1cc([N+](=O)[O-])c(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)=C1OC(=O)N(c2cc(O)c(Cl)cc2Cl)C1=O
Yield: 56.9 %

Procedure:
To a dried methanol solution (100 ml) of 3-(2',4'-dichloro-5'-methoxycarbonyloxyphenyl)-5-isopropylidene-1,3-oxazolidine-2,4-dione (3.60 g, 10 mmol), which was synthesized from 2,4-dichloro-5-methoxycarbonyloxy nitrobenzene as a starting material in a method similar to that shown in Reference Example 6, 9, 10 and 4, was added potassium carbonate (0.69 g, 5 mmol) and the mixture was heated under reflux for 2 hours. 3-(2',4'-dichloro-5'-hydroxyphenyl)-5-isopropylidene-1,3-oxazolidine-2,4-dione (1.72 g) was obtained by a treatment similar to that in Reference Example 1.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:25][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9].[CH3:26][N:27]([CH3:33])[CH2:28][CH2:29][CH2:30][CH2:31][NH2:32]>>[CH3:26][N:27]([CH3:33])[CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:25][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9]
Reactant: CN(C)CCCCN
Reactant: O=C(O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1OCC1CC21
Product: CN(C)CCCCNc1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OCC1CC21

Procedure:
Prepared by proceeding in a similar manner to Example 26, starting from (1aRS,7bSR)-5-(2-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (Intermediate 67) and 4-dimethylaminobutylamine.
Reaction SMILES: [C:1]1(Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:18])[CH2:16][CH3:17])=[CH:11][CH:10]=1.C(O[Na])(C)(C)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.COC1C=CC=C(N(C)C2C=CC=CC=2)C=1P(C1CCCCC1)C1CCCCC1>[C:1]1([CH:16]([CH3:17])[C:15]([C:12]2[CH:13]=[CH:14][C:9]([CH3:8])=[CH:10][CH:11]=2)=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Clc1ccccc1
Reactant: CCC(=O)c1ccc(C)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)O[Na]
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)C(C)c2ccccc2)cc1
Yield: 97.5 %

Procedure:
This reaction is carried out in the same manner as the reaction in example 3. The difference is that, the reactants are phenyl chloride (111.0 mg, 0.99 mmol), 1-(4-methylphenyl)-1-propanone (177.8 mg, 1.2 mmol), palladium acetate (6.7 mg, 0.030 mmol), 2-Methoxy-6-(N-methyl-N-phenyl-amino)phenyl(dicyclohexyl)phosphine (18.4 mg, 0.045 mmol), t-BuONa (115.8 mg, 1.2 mmol) in 3 mL dry toluene at 110° C. for 16.5 h. 2-Phenyl-1-(p-tolyl)-1-propanone (216.5 mg, contaminated with 11.9% of 1-(4-methylphenyl)propanone determined by 1H NMR) was obtained with a yield of 90% as liquid. 1H NMR (300 MHz, CDCl3) δ 7.87-7.80 (m, 2H, ArH), 7.30-7.20 (m, 4H, ArH), 7.20-7.08 (m, 3H, ArH), 4.64 (q, J=7.0 Hz, 1H, CH), 2.27 (s, 3H, ArCH3), 1.50 (d, J=7.0 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3) δ 199.7, 143.3, 141.6, 133.7, 129.0, 128.74, 128.72, 127.5, 126.6, 47.5, 21.3, 19.3; IR (neat) v (cm−1) 3061, 3028, 2975, 2930, 2870, 1682, 1606, 1570, 1492, 1452, 1408, 1372, 1332, 1304, 1253, 1225, 1210, 1177, 1008; MS (70 eV, EI) m/z (%): 224 (M+, 0.64), 119 (100).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]=2[CH:5]=[C:4]([Br:18])[CH:3]=1.[F:19][C:20]([F:25])([F:24])[CH2:21][CH:22]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.C(Cl)Cl.O>[Br:18][C:4]1[CH:3]=[C:2]([NH:1][CH2:22][CH2:21][C:20]([F:25])([F:24])[F:19])[C:10]2[N:9]=[CH:8][N:7]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[C:6]=2[CH:5]=1
Reactant: CC(C)(C)OC(=O)n1cnc2c(N)cc(Br)cc21
Reactant: O=CCC(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1cnc2c(NCCC(F)(F)F)cc(Br)cc21
Reaction time: 2 h
Yield: 99.7 %

Procedure:
To a stirred solution of tert-butyl 4-amino-6-bromo-1H-benzimidazole-1-carboxylate (5.85 g, 18.74 mmol) in DCE (1000 mL) at rt was added 3,3,3-trifluoropropanal (6.30 g, 56.22 mmol, 3 eq), sodium triacetoxy borohydride (19.86 g, 93.70 mmol, 5 eq) and acetic acid (21.5 mL, 374.79 mmol, 20 eq) and the mixture was stirred for 2 h. Water and DCM was added, and the organic phase was separated and washed with water After addition of DCM (100 mL), the organic phase was washed with water and evaporated to yield 7.63 g tert-butyl 6-bromo-4-[(3,3,3-trifluoropropyl)amino]-1H-benzimidazole-1-carboxylate (81.79%).
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[S:10][CH:11]=[CH:12][C:6]=2[N:5]2[CH:13]=[N:14][C:15]([C:16]([O:18][CH2:19]C)=[O:17])=[C:4]2[CH2:3]1.[C-]#N.[K+]>CO>[CH3:1][N:2]1[C:8](=[O:9])[C:7]2[S:10][CH:11]=[CH:12][C:6]=2[N:5]2[CH:13]=[N:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:4]2[CH2:3]1
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1sccc1-2
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Product: COC(=O)c1ncn2c1CN(C)C(=O)c1sccc1-2

Procedure:
A suspension of 430 mg (1.5 mmol) of ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepine-3-carboxylate and 99 mg (1.5 mmol) of potassium cyanide in 15 ml of absolute methanol is heated under reflux for 3 hours while stirring. After evaporation in vacuo, the residue is treated with ca 20 ml of ice/water and extracted three times with ca 30 ml of chloroform each time. The combined chloroform phases are washed twice with ca 20 ml of water each time, dried over magnesium sulphate and evaporated. After washing with boiling ethyl acetate, there is obtained methyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepine-3-carboxylate of melting point 244°-245° C.
Reaction SMILES: Br[CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:15]([NH:18][CH:19]([C:30]([OH:32])=[O:31])[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1)(=[O:17])[CH3:16]>>[C:15]([NH:18][CH:19]([CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1)[C:30]([O:32][CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:31])(=[O:17])[CH3:16]
Reactant: CC(=O)NC(Cc1c[nH]c2ccccc12)C(=O)O
Reactant: BrC(c1ccccc1)c1ccccc1
Product: CC(=O)NC(Cc1c[nH]c2ccccc12)C(=O)OC(c1ccccc1)c1ccccc1

Procedure:
Following the method of Example 1, bromodiphenyl methane (5.0 g) and N-acetyl-D,L-tryptophan (5.0 g) gave the title compound which was recrystallised from diethyl ether (2.2 g), m.p. 147°-148° C., 1H NMR (360 MHz, CDCl3) δ7.88 (1H, s), 7.47 (1H, d, J=7 Hz), 7.34-7.28 (15H, m), 6.67 (1H, s), 6.40 (1H, d, J=2 Hz), 5.95 (1H, d, J=7 Hz), 5.14-5.09 (1H, m), 3.40-5.09 (2H, m), 1.91 (3H, s). Found: C, 75.53; H, 6.04; N, 6.88 C26H24N2O3 requires C, 75.71; H, 5.86; N, 6.79%.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:25]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[CH:32]=2)=[O:29])=[CH:24][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:15][CH:14]=[C:13]([C:16]([NH:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:17])[CH:12]=2)[CH:6]=1.[CH3:38]N(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.COC(=O)CCN.Cl>CN(C=O)C.O>[F:1][C:2]1[CH:27]=[CH:26][C:25]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[CH:32]=2)=[O:29])=[CH:24][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:15][CH:14]=[C:13]([C:16]([NH:18][CH2:19][CH2:20][C:21]([O:23][CH3:38])=[O:22])=[O:17])[CH:12]=2)[CH:6]=1
Reactant: Cc1cccc(NC(=O)c2ccc(F)c(Oc3ccnc(-c4cc(C(=O)NCCC(=O)O)c[nH]4)c3)c2)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: COC(=O)CCN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCNC(=O)c1c[nH]c(-c2cc(Oc3cc(C(=O)Nc4cccc(C)c4)ccc3F)ccn2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-[4-(2-fluoro-5-{[(3-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylic acid (Example 275) (100 mg, 0.23 mmol) in 10 ml of anhydrous DMF were added HATU (100 mg, 0.26 mmol) and N,N-diisopropylethylamine (85 mg, 0.66 mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of β-alanine methyl ester hydrochloride (46 mg, 0.33 mmol). The mixture was stirred for another minutes and poured into 100 ml of water. 2M HCl was added dropwise with vigorous stirring until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give methyl 3-[({5-[4-(2-fluoro-5-{[(3-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]propanoate as white solid. Yield: 110 mg, 92%.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[Cl:4][C:5]1[N:6]=[C:7](Cl)[C:8]2[CH2:14][O:13][CH2:12][CH:11]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=3)[C:9]=2[N:10]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:4][C:5]1[N:6]=[C:7]([NH:3][CH2:1][CH3:2])[C:8]2[CH2:14][O:13][CH2:12][CH:11]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=3)[C:9]=2[N:10]=1
Reactant: Fc1cc(F)cc(C2COCc3c(Cl)nc(Cl)nc32)c1
Reactant: CCN
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCNc1nc(Cl)nc2c1COCC2c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
The mixture of ethanamine (406 μL, 0.812 mmol), 2,4-dichloro-8-(3,5-difluorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine (Preparation X)(117 mg, 0.369 mmol) and DIEA (161 μL, 0.922 mmol) in THF (1845 μL) was stirred at RT for 2 h. The mixture was concentrated and purified by column chromatography on silica gel to give 2-chloro-8-(3,5-difluorophenyl)-N-ethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine (104 mg, 0.319 mmol, 87% yield). LC-MS (M+H)+=326.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[CH:20]=[C:19]([F:21])[C:16]([C:17]#[N:18])=[C:15]([F:22])[CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].OO>C(O)C.C1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[C:17]([C:16]1[C:19]([F:21])=[CH:20][C:13]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:14][C:15]=1[F:22])#[N:18]
Reactant: COc1ccc(B(O)O)cc1
Reactant: N#Cc1c(F)cc(Br)cc1F
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: OO
Solvent: c1ccccc1
Solvent: CCO
Product: COc1ccc(-c2cc(F)c(C#N)c(F)c2)cc1
Temperature: 2 °C

Procedure:
A solution of compound 1 (11.50 g, 0.076 mol) in ethanol (90 ml) was added dropwise to a stirred mixture of compound 7 (15.0 g, 0.069 mol) and tetrakis(triphenylphosphine)palladium(O) (2.38 g, 2.06 mmol) in benzene (130 ml) and 2M-sodium carbonate (100 ml) at room temperature under dry nitrogen. The stirred mixture was heated under reflux (90°-95° C.) for 4.5 h (i.e., until glc analysis revealed absence of starting material). The mixture was cooled and stirred for 1 h at room temperature with 30% hydrogen peroxide (2 ml). The mixture was further cooled to 2° C., and the product was filtered off and washed with water. The product was dried (CaCl2) in vacuo to give fawn-coloured needles.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[CH:18][C:19]([C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:30][CH3:31])=[C:27]([F:29])[CH:28]=3)[N:10]=2)=CC=1>C(O)(C(F)(F)F)=O>[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[CH:17]=[CH:18][C:19]([C:32]3[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=3)=[N:20][C:21]=2[NH:22][C:23]2[CH:24]=[N:25][C:26]([O:30][CH3:31])=[C:27]([F:29])[CH:28]=2)[N:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3ccc(-c4ccncc4)nc3Nc3cnc(OC)c(F)c3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(Nc2nc(-c3ccncc3)ccc2-c2nc(C)nc(N)n2)cc1F
Temperature: 25 °C
Yield: 64.8 %

Procedure:
A solution of 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-N-(5-fluoro-6-methoxypyridin-3-yl)-2,4′-bipyridin-6-amine (0.139 g, 0.216 mmol) in TFA (8.0 mL) (Aldrich) was heated at 80° C. overnight. The solution was cooled to room temperature and concentrated to about 50% of the original volume under a stream of argon. The remaining mixture was pipetted carefully into a saturated solution of NaHCO3 which had been cooled in an ice bath. The resulting precipitate was removed by filtration and washed with water. The impure solid was suspended in IPA, and the suspension was subjected to filtration. The solid was washed with DMSO, followed by water to give 5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-N-(5-fluoro-6-methoxypyridin-3-yl)-2,4′-bipyridin-6-amine (0.0565 g, 0.140 mmol, 64.8% yield). 1H NMR (400 MHz, d6-DMSO) δ 12.03 (s, 1H); 8.93 (d, J=8.0 Hz, 1H); 8.75 (d, J=5.9 Hz, 2H); 8.54 (d, J=1.8 Hz, 1H); 8.32-8.38 (m, 1H); 8.00 (d, J=5.7 Hz, 2H); 7.95 (br. s., 1H); 7.81 (br. s., 1H); 7.67 (d, J=8.0 Hz, 1H); 3.97 (s, 3H); 2.46 (s, 3H). m/z (ESI, +ve ion) 405.0 (M+H)+.