Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:26])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[N:14][O:15][C:16]=2[CH2:17][OH:18])[CH:9]=1)=O.[CH:27]([NH2:30])([CH3:29])[CH3:28]>>[CH:27]([NH:30][C:3]([C:5]1[N:6]([CH3:26])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[N:14][O:15][C:16]=2[CH2:17][OH:18])[CH:9]=1)=[O:2])([CH3:29])[CH3:28]
Reactant: CC(C)N
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2CO)nn1C
Product: CC(C)NC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2CO)nn1C
Yield: 56 %

Procedure:
As described for example 91h, 5-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (150 mg, 0.42 mmol) was converted, using isopropylamine instead of 4-aminotetrahydropyran, to the title compound (90 mg, 56%) which was obtained as a white solid. MS: m/e=387.0 [M−H]−.
Reaction SMILES: [CH:1]1([NH:7][C:8]([NH:10][C:11]2[N:12]=[C:13]3[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:14]3=[N:15][CH:16]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C(=O)N([I:35])C(=O)C1>CC(C)=O>[CH:1]1([NH:7][C:8]([NH:10][C:11]2[N:12]=[C:13]3[C:19]([I:35])=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:14]3=[N:15][CH:16]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCC(=O)N1I
Reactant: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCCCC3)cnc21
Solvent: CC(C)=O
Product: C[Si](C)(C)CCOCn1cc(I)c2nc(NC(=O)NC3CCCCC3)cnc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.2 %

Procedure:
The mixture of 1-Cyclohexyl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea (2.67 g) and NIS (742 mg, 3.30 mmol) in 12 mL of acetone was stirred at RT for 4 hr, filtered, and washed with small amount of acetone. The solid was dried under high vacuum to give 701 mg of 1-cyclohexyl-3-[7-iodo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea as an off-white solid (45% yield for 2 steps).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:17]2[C:8]3[CH:9]=[N:10][C:11]4[C:16]([C:7]=3[C:6](=[N:20][OH:21])[C:5]=2[CH:4]=1)=[CH:15][CH:14]=[CH:13][CH:12]=4.Cl[CH2:23][CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.Cl.COC1C=CC2C3C(N4CCNCC4)=NC4C(C=3C(=O)C=2C=1)=CC=CC=4.C(C1OC1)Cl>>[N:25]1([CH2:24][CH2:23][O:21][N:20]=[C:6]2[C:7]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=[CH:9][C:8]=3[C:17]3[CH:18]=[CH:19][C:3]([O:2][CH3:1])=[CH:4][C:5]2=3)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COc1ccc2c(c1)C(=NO)c1c-2cnc2ccccc12
Reactant: ClCCN1CCCC1
Agent: COc1ccc2c(c1)C(=O)c1c-2c(N2CCNCC2)nc2ccccc12
Agent: Cl
Solvent: ClCC1CO1
Product: COc1ccc2c(c1)C(=NOCCN1CCCC1)c1c-2cnc2ccccc12

Procedure:
9-methoxy-11H-indeno[1,2-c]quinolin-11-one O-2-(pyrrolidin-1-yl)ethyl oxime (6aa) was prepared substantially according to the procedures as set forth in the above Synthesis Example 18, except that compound 6a and 1-(2-chloroethyl)pyrrolidine·HCl were used in place of compound 5x and epichlorohydrin, respectively, giving the title compound at a yield of 56%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:21](=[O:22])[N:20]([CH2:23][CH3:24])[C:9]2[N:10]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:13][C:8]=2[C:7]=1Cl)=[O:5])[CH3:2].[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:21](=[O:22])[N:20]([CH2:23][CH3:24])[C:9]2[N:10]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:13][C:8]=2[C:7]=1[N:28]([CH2:29][CH3:30])[CH2:26][CH3:27])=[O:5])[CH3:2]
Reactant: CCNCC
Reactant: CCOC(=O)c1c(Cl)c2cnc(-c3ccccc3)nc2n(CC)c1=O
Solvent: CCO
Product: CCOC(=O)c1c(N(CC)CC)c2cnc(-c3ccccc3)nc2n(CC)c1=O

Procedure:
Two grams (0.0056 mole) of 5-chloro-7,8-dihydro-8-ethyl-7-oxo-2-phenylpyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (prepared by the method of Example 3, first paragraph) and 0.82 g. (0.011 mole) of diethylamine were added together in ethanol in an autoclave and heated on a steam bath for 2 hours. The reaction mixture was then filtered and the filtrate chilled in ice. The precipitate which formed was collected on a suction filter. Recrystallization from ethyl acetate gave 0.8 g. of product m.p. 110°-115° C.
Reaction SMILES: [CH:1]1([CH3:33])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([O:10][C:11]([CH:13]2[N:18]3[CH:19]=[CH:20][CH:21]=[C:17]3[C:16](=[O:22])[N:15]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:25]=3[F:31])[C:14]2=[O:32])=[O:12])[CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43]>CN(C)C=O>[C:45]([O:44][C:42](=[O:43])[CH2:41][C:13]1([C:11]([O:10][CH:3]2[CH:4]([CH:7]([CH3:8])[CH3:9])[CH2:5][CH2:6][CH:1]([CH3:33])[CH2:2]2)=[O:12])[N:18]2[CH:19]=[CH:20][CH:21]=[C:17]2[C:16](=[O:22])[N:15]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:25]=2[F:31])[C:14]1=[O:32])([CH3:48])([CH3:47])[CH3:46]
Reactant: CC1CCC(C(C)C)C(OC(=O)C2C(=O)N(Cc3ccc(Br)cc3F)C(=O)c3cccn32)C1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1CCC(C(C)C)C(OC(=O)C2(CC(=O)OC(C)(C)C)C(=O)N(Cc3ccc(Br)cc3F)C(=O)c3cccn32)C1
Temperature: 70 °C
Reaction time: 2.5 h

Procedure:
A mixture of 2-(4-bromo-2-fluorobenzyl)-1,3-dioxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-carboxylic acid (-)-menthyl ester (67.0 g), anhydrous potassium carbonate (36.0 g) and tert-butyl bromoacetate (33.0 g) in anhydrous dimethylformamide (200 ml) was stirred under the stream of nitrogen at 70° C. for 2.5 hours. After removal of the insoluble materials by filtration, the filtrate was poured into water and extracted with ethyl acetate. The extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was recrystallized from n-hexane to give the title compound (Diastereomer A) (23.5 g, 28.8%) as colorless crystals, mp 99°-100° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28].C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C>O>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28])=[CH:11][CH:10]=1
Reactant: Oc1ccc(-c2cccc(F)c2F)cc1
Reactant: OCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: OCCCCCCCCCCCOc1ccc(-c2cccc(F)c2F)cc1
Yield: 87.6 %

Procedure:
First, 5.0 g of 2,3-difluoro-4'-hydroxybiphenyl, 7.3 g of 11-bromo-1-undecanol, 6.7 g of potassium carbonate, and 150 ml of methyl ethyl ketone were placed in a 200 ml flask. The mixture was stirred under reflux for 20 hours. The reaction mixture was poured into water and an organic layer was extracted with toluene. The toluene layer was washed with water and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was recrystallized from acetone to obtain 8 g of 2,3-difluoro-4'-(11-hydroxyundecyl)oxybiphenyl (Y: 88%). The compound thus obtained had a purity of 98.8% by GC.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([OH:18])=[CH:8][CH:9]=[C:10]([C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[O:12])[C:5]=2[O:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[CH:26]=[CH2:27].Cl>CC(C)=O.O>[CH3:1][C:2]1[C:6]2[C:7]([O:18][CH2:27][CH:26]=[CH2:25])=[CH:8][CH:9]=[C:10]([C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[O:12])[C:5]=2[O:4][CH:3]=1
Reactant: Cc1coc2c(C(=O)c3cccs3)ccc(O)c12
Reactant: C=CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: C=CCOc1ccc(C(=O)c2cccs2)c2occ(C)c12

Procedure:
To a solution of compound 3 (0.50 g, 1.92 mmol) in acetone (10 mL) was added sequentially potassium carbonate (0.53 g, 3.84 mmol) and allyl bromide (0.47 g, 3.84 mmol). The mixture was heated to reflux for two hours, cooled, diluted with water (50 mL), and acidified with 2N HCl. The aqueous mixture was extracted with methylene chloride (3×25 mL) and the combined extracts dried (Na2SO4) and concentrated to an oil. The crude 3-methyl-4-allyloxy-7-(2-thienoyl)benzofuran thus obtained was sufficiently pure for further synthesis. 1H NMR d 2.44 (3H, d, J=2 Hz), 4.74 (2H, d, J=4 Hz), 5.44 (2H, m), 6.12 (1H, m), 6.71 (1H, d, J=8 Hz), 7.15 (1H, m), 7.36 (1H, d, J=2 Hz), 7.68 (3H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH2:5]2.ClC(Cl)(Cl)[C:14]([N:16]=C=O)=[O:15].[OH-].[K+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([C:14]([NH2:16])=[O:15])[CH2:7][CH2:6][CH2:5]2
Reactant: Brc1cnc2c(c1)CCCN2
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: NC(=O)N1CCCc2cc(Br)cnc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
To a cooled (0° C.) solution of 6-bromo-1,2,3,4-tetrahydro-[1,8]naphthyridine (6.4 g, 30.0 mmol) in DCM (75 mL) is added a trichloroacetyl isocyanate (3.8 mL, 31.5 mmol). After stirring for 1 h at 0° C., a solution of methanolic KOH (1M, 10 mL) is added. The resulting mixture is allowed to warm and stir at room temperature for 16 h. The reaction is concentrated and purified by silica gel column (0-100% EtOAc in heptane) to afford the title compound (7.4 g).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[C:10]1([C@H:16]([NH2:18])[CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)C(C)C)(C)C>C(O)C>[Br:1][C:2]1[C:3]([NH:18][C@@H:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:17])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Nc1nc(Cl)ncc1Br)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.7 %

Procedure:
To a solution of 5-bromo-2,4-dichloropyrimidine (5 g, 22 mmol) and (R)-1-phenylethanamine (2.7 g, 22 mmol) in ethanol (50 mL) was added N,N-diisopropylethylamine (4.3 g, 33 mmol). The reaction solution was stirred at room temperature for 12 hours. The resultant mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=6:1) to give (R)-5-bromo-2-chloro-N-(1-phenylethyl)pyrimidin-4-amine as a white solid (5 g, 74%). LRMS (M+H) m/z: calcd 310.98. found 310. 1H NMR (300 MHz, CDCl3): δ 8.10 (s, 1H), 7.41-7.25 (m, 5H), 5.73 (d, J=6.9 Hz, 1H), 5.39-5.34 (m, 1H), 1.61 (d, J=6.6 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([C:12]2[S:13][CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[N:16]=2)=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].O1CCOCC1.C([O-])([O-])=O.[K+].[K+].[C:37]1(B(O)O)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)Cl.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>[Cl:24][C:19]1[CH:18]=[C:17]([C:15]2[N:16]=[C:12]([C:9]3[CH:8]=[C:3]([C:4]([OH:6])=[O:5])[C:2]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[CH:11][CH:10]=3)[S:13][CH:14]=2)[CH:22]=[CH:21][C:20]=1[Cl:23]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccccc1
Temperature: 100 °C
Yield: 19.4 %

Procedure:
Methyl 2-bromo-5-(4-(3,4-dichlorophenyl)thiazol-2-yl)benzoate (177 mg, 0.4 mmol) was taken up in CH2Cl2 and washed with aqueous Na2CO3. The organic layer was dried (MgSO4), filtered, and evaporated. Dioxane (2 mL) was added, along with tetrakis(triphenylphosphine)palladium(0) (37 mg, 0.032 mmol), 3 M aqueous K2CO3 (267 μL, 0.8 mmol) and phenylboronic acid (available from ASDI Incorporated; 97.5 mg, 0.8 mmol). The vial was evacuated and filled with nitrogen, and then the mixture was heated at 100° C. for 20 h. The mixture was purified on an ISCO Combiflash system, using 0-15% ethyl acetate/hexanes as eluent. Fractions homogeneous for the product were evaporated, and the resulting material was dissolved in THF (2 mL). 1 M aqueous NaOH (2 mL) was added and the mixture was heated at 60° C. overnight. 1 M aqueous HCl was added to bring the pH to approximately 2, and the mixture was extracted 4 times with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, evaporated, and purified by preparative HPLC, using the conditions outlined in General Procedure A for Suzuki Coupling and Hydrolysis in Parallel Mode, to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2-carboxylic acid (33 mg, 20%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.45 (s, 1H), 8.32 (d, J=1.6 Hz, 2H), 8.20 (dd, J=8.2, 2.0 Hz, 1H), 8.07 (dd, J=8.2, 2.0 Hz, 1H), 7.74 (d, J=8.6 Hz, 1H), 7.55 (d, J=8.2 Hz, 1H), 7.35-7.48 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12].[CH:14]([C:17]1[N:18]=[C:19]([C:22](Cl)=[O:23])[S:20][CH:21]=1)([CH3:16])[CH3:15].C(C1C=CC(OC)=CC=1NC(C1SC=C(C(C)C)N=1)=O)(=O)C>>[C:11]([C:3]1[C:2]([NH:1][C:22]([C:19]2[S:20][CH:21]=[C:17]([CH:14]([CH3:16])[CH3:15])[N:18]=2)=[O:23])=[C:7]([Cl:8])[C:6]([O:9][CH3:10])=[CH:5][CH:4]=1)(=[O:13])[CH3:12]
Reactant: CC(C)c1csc(C(=O)Cl)n1
Reactant: COc1ccc(C(C)=O)c(N)c1Cl
Agent: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(C)C)cs2)c1
Product: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(C)C)cs2)c1Cl
Yield: 80 %

Procedure:
Compound 42d was synthesized from 1-(2-amino-3-chloro-4-methoxyphenyl)ethanone and compound 38 as a beige solid in 80% yield, according to the procedure as described for compound 42a.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[NH:13][N:12]=[C:11]([CH:14]3[CH2:16][CH2:15]3)[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[S:17]([N:27]1[C:35]2[C:30](=[C:31]([CH2:36][NH2:37])[CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28]1)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18].CCN(C(C)C)C(C)C>CC(O)C>[CH:14]1([C:11]2[NH:12][N:13]=[C:9]([NH:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:37][CH2:36][C:31]4[CH:32]=[CH:33][CH:34]=[C:35]5[C:30]=4[CH:29]=[CH:28][N:27]5[S:17]([C:20]4[CH:21]=[CH:22][C:23]([CH3:24])=[CH:25][CH:26]=4)(=[O:19])=[O:18])[N:7]=3)[CH:10]=2)[CH2:16][CH2:15]1
Reactant: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(CN)cccc32)cc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2ccc3c(CNc4nccc(Nc5cc(C6CC6)[nH]n5)n4)cccc32)cc1
Temperature: 120 °C
Yield: 47.9 %

Procedure:
A tube was charged with 53 (415 mg, 1.38 mmol), 46 (486 mg, 2.07 mmol), DIPEA (1.0 ml) and IPA (3 mL), degassed, sealed and heated at 120° C. overnight. The mixture was concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with a DCM/MeOH gradient (3.3 to 5% MeOH) to afford 330 mg (48%) of N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-((1-tosyl-1H-indol-4-yl)methyl)pyrimidine-2,4-diamine (50) as yellow solid: MS (ESI) m/z=500.3 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[C:15]1[NH:19][N:18]=[N:17][N:16]=1.C(N(CC)CC)C.Cl[CH2:28][C:29]1[N:30]([CH3:34])[CH:31]=[CH:32][N:33]=1>CN(C)C(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[C:15]1[N:19]([CH2:28][C:29]2[N:30]([CH3:34])[CH:31]=[CH:32][N:33]=2)[N:18]=[N:17][N:16]=1
Reactant: Cn1ccnc1CCl
Reactant: COc1cc2ncnc(-c3nnn[nH]3)c2cc1OC
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(-c3nnnn3Cc3nccn3C)c2cc1OC
Temperature: 27.5 °C
Reaction time: 0.29 h
Yield: 35.2 %

Procedure:
Experimental Procedure: 50.0 ml of N,N-dimethyl acetamide and 5.0 g (0.019 mol) of 6,7-dimethoxy-4-(1H-tetrazol-5-yl)quinazoline were charged into a 250 ml of 4necked round bottom flask, connected to a mechanical stirrer, thermometer socket, condenser and addition flask under mild nitrogen atmosphere. 3.80 g (0.038 mol) of triethyl amine was added at 25-30° C. Stirred the mass for 15-20 min at 25-30° C. Reaction mass temperature was raised to 50-55° C. Maintained the mass temperature at 50-55° C. for 15-20 min. 2-chloro methyl -1-methyl-imidazole solution [2.50 g (0.019 mol) 2-chloro methyl -1-methyl-imidazole was dissolved in 25.0 ml of N,N-dimethyl acetamide] was added slowly at 50-55° C. for 30-45 min. Maintained the mass temperature at 50-55° C. for 15-20 min. Raised the mass temperature to 80-85° C. Maintained the mass temperature at 80-85° C. for 7-8 hours. N,N-dimethyl acetamide was completely distilled under vacuum. Crude compound was purified by the column chromatography by using hexane and ethyl acetate. Obtained pure compound weight 2.40 g (yield 35.2% by theory).
Reaction SMILES: [F:1][C:2](I)([F:4])[F:3].CN(C)P(=O)(N(C)C)N(C)C.[C:17]([C@@H:21]1[CH2:26][CH2:25][C@H:24]([NH:27][C:28]2[C:33](I)=[C:32]([CH2:35][CH3:36])[N:31]=[CH:30][N:29]=2)[CH2:23][CH2:22]1)([CH3:20])([CH3:19])[CH3:18]>[Cu].C(OCC)C>[C:17]([C@@H:21]1[CH2:22][CH2:23][C@H:24]([NH:27][C:28]2[C:33]([C:2]([F:4])([F:3])[F:1])=[C:32]([CH2:35][CH3:36])[N:31]=[CH:30][N:29]=2)[CH2:25][CH2:26]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CCc1ncnc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)c1I
Reactant: FC(F)(F)I
Agent: [Cu]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Product: CCc1ncnc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)c1C(F)(F)F
Temperature: 100 °C
Reaction time: 2 h

Procedure:
8.4 g of trifluoromethyl iodide and 5 g of copper powder were stirred with 20 ml of hexamethylphosphoric triamide in a stainless steel laboratory autoclave (Hastelloy) at 120° C. for 2.5 hours. The mixture was filtered with suction over Celite, under nitrogen, to remove the excess copper powder. 1.92 g (5 mmol) of 4-(cis-4-tert-butyl-cyclohexylamino)-6-ethyl-5-iodopyrimidine (Example 1) were added in order to dissolve the trifluoromethyl-copper complex, and the mixture was stirred under nitrogen at 100° C. for 2 hours. After cooling, 200 ml of diethyl ether were added, the precipitated copper salts were filtered off and the filtrate was extracted by stirring with water. The organic phase was dried and concentrated. The product was purified by filtration over a silica gel column (petroleum ether/ethyl acetate 7:3) to give 0.52 g (32% of theory) of product as a colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[SH:7].[H-].[Na+].Br[C:11]1[CH:12]=[C:13]([O:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:14]([C:17]#[N:18])=[N:15][CH:16]=1.O>CC(N(C)C)=O>[F:26][C:23]1[CH:22]=[CH:21][C:20]([O:19][C:13]2[C:14]([C:17]#[N:18])=[N:15][CH:16]=[C:11]([S:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH:12]=2)=[CH:25][CH:24]=1
Reactant: N#Cc1ncc(Br)cc1Oc1ccc(F)cc1
Reactant: Sc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: N#Cc1ncc(Sc2ccccn2)cc1Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 69.6 %

Procedure:
To a solution of pyridine-2-thiol (2.5 g, 23 mmol) in DMA (25 mL) cooled to 0° C. was added NaH (0.90 g, 23 mmol) and the reaction stirred at ambient temperature for 20 min, followed by addition of the 5-bromo-3-(4-fluorophenoxy)picolinonitrile (6.6 g, 23 mmol) and stirring over night at ambient temperature. The reaction was poured into water (250 mL) and a solid formed. The solid was collected, washed with water, and dried in vacuo to yield 3-(4-fluorophenoxy)-5-(pyridin-2-ylthio)picolinonitrile (5 g, 16 mmol, 70%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[C@H:9]([CH3:16])[CH2:8][N:7]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=3)[C:6]=2[CH:24]=1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[CH:35][C:36](=[O:39])[NH:37][CH:38]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([N:7]2[CH2:8][C@@H:9]([CH3:16])[C:10]3=[N:14][N:13]=[C:12]([CH3:15])[N:11]3[C:5]3[CH:4]=[CH:3][C:2]([C:33]4[CH:34]=[CH:35][C:36](=[O:39])[NH:37][CH:38]=4)=[CH:24][C:6]2=3)=[N:18][CH:19]=1
Reactant: Cc1nnc2n1-c1ccc(Br)cc1N(c1ccc(Cl)cn1)C[C@H]2C
Reactant: CC1(C)OB(c2ccc(=O)[nH]c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nnc2n1-c1ccc(-c3ccc(=O)[nH]c3)cc1N(c1ccc(Cl)cn1)C[C@H]2C
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 29.8 %

Procedure:
To a solution of (R)-8-bromo-6-(5-chloropyridin-2-yl)-1,4-dimethyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (100 mg, 0.24 mmol) in 1,4-dioxane/H2O (10:1, 2 mL) was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (65 mg, 0.29 mmol), Cesium carbonate (156 mg, 0.48 mmol) and Tetrakis(triphenylphosphine)palladium(0) (18.4 mg, 0.025 mmol). The mixture was purged with N2 and stirred in the microwave at 130° C. for 0.5 hr. After filtration, concentrated in vacuo and purification by prep-TLC (elute: DCM:MeOH=15:1) gave (R)-5-(6-(5-chloropyridin-2-yl)-1,4-dimethyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-8-yl)pyridin-2(1H)-one (30 mg, 30%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)[CH:6]=[CH:7][C:8]=2[OH:12])[CH2:3]1.C(N(CC)CC)C.[CH2:27]([O:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1)[CH2:28][CH2:29][CH3:30]>CN(C)C=O>[OH:12][C:8]1[CH:7]=[CH:6][C:5]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[C:4]2[C:9]=1[CH2:10][CH2:11][C@@H:2]([NH:1][C:36](=[O:37])[C:35]1[CH:34]=[CH:33][C:32]([O:31][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:40][CH:39]=1)[CH2:3]2
Reactant: CCCCOc1ccc(C(=O)Cl)cc1
Reactant: CN1CCN(c2ccc(O)c3c2C[C@H](N)CC3)CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCOc1ccc(C(=O)N[C@@H]2CCc3c(O)ccc(N4CCN(C)CC4)c3C2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of (R)-2-amino-5-hydroxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (100 mg, 0.38 mmol) and triethylamine (79 μL, 0.57 mmol) in N,N-dimethylformamide (30 mL) was 4-butoxybenzoyl chloride in N,N-dimethylformamide (5 mL) added dropwise. After the addition the reaction was stirred at ambient temperature for 15 min. The solvent was evaporated in vacuo and the residue was purified on a silica gel column using chloroform/methanol/concentrated ammonium hydroxide (95:5:0.5) as the eluent. Yield: 73 mg (44%) as an amorphous solid: mp 125° C. (decomp.); [α]21D−20° (c=0.25, chloroform); EIMS (70 eV) m/z (relative intensity) 437 (16, M+).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:25])[N:7]2[C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([C:21]([O:23][CH3:24])=[O:22])[CH:15]=1.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.ClC1C=CC=C(Cl)C=1N1C2C(=C(C3C=CC(F)=CC=3F)C=C(OC)C=2)CCC1=O>>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:25])[N:7]2[C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([C:21]([O:23][CH3:24])=[O:22])[CH:15]=1
Reactant: COC(=O)c1ccc(C)c(N2C(=O)CCc3c(Br)cc(OC)cc32)c1
Reactant: OB(O)c1ccccc1Cl
Agent: COc1cc(-c2ccc(F)cc2F)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)CC2
Product: COC(=O)c1ccc(C)c(N2C(=O)CCc3c(-c4ccccc4Cl)cc(OC)cc32)c1

Procedure:
5-(2-Chlorophenyl)-3,4-dihydro-7-methoxy-1-(3-methoxycarbonyl-6-methylphenyl)-2(1H)-quinolinone was prepared from 5-bromo-3,4-dihydro-7-methoxy-1-(3-methoxycarbonyl-6-methylphenyl)-2(1H)-quinolinone (INTERMEDIATE 16) and 2-chlorophenylboronic acid by a procedure analogous to that described in INTERMEDIATE 2. Mass spectrum (ESI) 436.3 (M+1). 1H NMR (500 MHz, CDCl3): 7.95 (m, 1H); 7.81 (d, J=19.0 Hz, 1H); 7.41 (m, 1H); 7.37 (d, J=8.0 Hz, 1H); 7.27 (m, 2H); 7.21 (m, 1H); 6.35 (s, 1H); 5.76 (s, 1H); 3.81 (s, 3H); 3.55 (s, 3H); 2.65 (m, 4H); 2.11 (d, J=11.5 Hz, 3H).