Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH3:20])[C@H:13]3[C:14]([F:18])([F:17])[CH2:15][CH2:16][C@H:12]3[O:11][C:10]([NH2:19])=[N:9]2)[CH:7]=1.[F:22][C:23]([C:26]1[N:27]=[CH:28][C:29]([C:32](O)=[O:33])=[N:30][CH:31]=1)([F:25])[CH3:24]>>[NH2:19][C:10]1[O:11][C@@H:12]2[CH2:16][CH2:15][C:14]([F:17])([F:18])[C@@H:13]2[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:32]([C:29]3[CH:28]=[N:27][C:26]([C:23]([F:25])([F:22])[CH3:24])=[CH:31][N:30]=3)=[O:33])[CH:3]=[CH:4][C:5]=2[F:21])([CH3:20])[N:9]=1
Reactant: CC(F)(F)c1cnc(C(=O)O)cn1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)O[C@@H]2CCC(F)(F)[C@@H]21
Product: CC(F)(F)c1cnc(C(=O)Nc2ccc(F)c([C@@]3(C)N=C(N)O[C@@H]4CCC(F)(F)[C@@H]43)c2)cn1
Yield: 52 %

Procedure:
The coupling of (4S,4aR,7aR)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-4,4a,5,6,7,7a-hexahydro-cyclopenta[e][1,3]oxazin-2-ylamine (intermediate XIIIa-1) and 5-(1,1-difluoro-ethyl)-pyrazine-2-carboxylic acid (CAS 1262803-63-315) following procedure Q yielded the title compound as a white solid (52% yield). MS: m/z=470.3 [M+H]+.
Reaction SMILES: Cl.[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([NH2:11])[CH2:7][CH2:6]1)(=[O:4])[CH3:3].C(N(C(C)C)CC)(C)C.[F:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>ClCCl>[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([NH:11][S:28]([C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)(=[O:30])=[O:29])[CH2:7][CH2:6]1)(=[O:4])[CH3:3]
Reactant: CC(=O)N1CCC(N)CC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC(NS(=O)(=O)c2ccc(F)cc2)CC1
Reaction time: 6.5 h
Yield: 67058.9 %

Procedure:
To a suspension of 1-acetyl-4-aminopiperidine hydrochloride (715 mg) in dichloromethane (7 ml) were added diisopropylethylamine (1.83 ml) and a solution of 4-fluorobenzenesulfonyl chloride (0.83 mg) in dichloromethane (2 ml) at ambient temperature. After stirring for 6.5 hours, the reaction mixture was diluted with dichloromethane and washed with water, saturated aqueous sodium hydrogen carbonate, and brine. After drying with magnesium sulfate, the solvents were removed under reduced pressure. A residue was purified by column chromatography (silica gel 50 ml, dichloromethane:methanol=50:1 to 20:1). After rinse with diisopropyl ether, N-(1-acetylpiperidin-4-yl)-4-fluorobenzenesulfonamide (859 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]([CH2:20][C:21](O)=[O:22])[S:10]([C:13]2[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.[CH2:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=1)[CH3:25]>>[CH2:24]([N:26]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=1)[C:21](=[O:22])[CH2:20][N:9]([C:6]1[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11])[CH3:25]
Reactant: COc1ccc(N(CC(=O)O)S(=O)(=O)c2ccccc2C)cn1
Reactant: CCNCc1cccc(C)n1
Product: CCN(Cc1cccc(C)n1)C(=O)CN(c1ccc(OC)nc1)S(=O)(=O)c1ccccc1C

Procedure:
prepared by reaction of [(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-acetic acid with ethyl-(6-methyl-pyridin-2-ylmethyl)-amine
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:11][CH3:12])=[C:4]([NH:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=2)=[O:15])[CH:3]=1.CC1(C)C(C)(C)OB([C:31]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:32]=2[CH:33]=[CH:34][NH:35]3)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[CH2:11]([N:8]1[C:9]2[C:5](=[C:4]([NH:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=3)=[O:15])[CH:3]=[C:2]([C:31]3[CH:39]=[CH:38][CH:37]=[C:36]4[C:32]=3[CH:33]=[CH:34][NH:35]4)[CH:10]=2)[CH:6]=[N:7]1)[CH3:12]
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: CCn1ncc2c(NC(=O)c3cccc(C)n3)cc(Br)cc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCn1ncc2c(NC(=O)c3cccc(C)n3)cc(-c3cccc4[nH]ccc34)cc21
Temperature: 150 °C
Yield: 45.2 %

Procedure:
N-(6-Bromo-1-ethyl-1H-indazol-4-yl)-6-methyl-2-pyridinecarboxamide (50 mg, 0.14 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (available from Frontier Scientific, 38 mg, 0.17 mmol), Pd(dppf)Cl2 (23 mg), aqueous sodium carbonate (2M, 0.272 ml) and 1,4-dioxane (2 ml) were combined and heated at 150° C. for 10 mins under microwave conditions. The reaction was extracted into DCM (2×20 ml) and the combined organic layers were evaporated to dryness, before purification by Mass Directed Automated Preparative HPLC (Method B). Pure fractions were evaporated to give the title compound (25 mg).
Reaction SMILES: [NH2:1][CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].Br[CH:23]1[CH2:29][CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=2[N:25]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:24]1=[O:40]>C(Cl)Cl>[CH2:38]([O:37][C:35]([CH2:34][N:25]1[C:26]2[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=2[CH2:28][CH2:29][CH:23]([NH:1][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:24]1=[O:40])=[O:36])[CH3:39]
Reactant: CCOC(=O)CN1C(=O)C(Br)CCc2ccccc21
Reactant: CCOC(=O)C(N)CCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)CN1C(=O)C(NC(CCc2ccccc2)C(=O)OCC)CCc2ccccc21

Procedure:
Ethyl 2-amino-4-phenylbutyrate is treated in the presence of potassium carbonate in methylene chloride with 3-bromo-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one to give 1-ethoxycarbonylmethyl-3-(1-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H[1]benzazepin-2-one of example 10.
Reaction SMILES: [C:1]([Si:3]([CH3:6])([CH3:5])[CH3:4])#[CH:2].Br[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][O:16][CH3:17])=[CH:10][CH:9]=1>N1CCCCC1.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.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:17][O:16][CH2:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:2]#[C:1][Si:3]([CH3:6])([CH3:5])[CH3:4])=[CH:9][CH:10]=1
Reactant: COCCc1ccc(Br)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: COCCc1ccc(C#C[Si](C)(C)C)cc1
Temperature: 100 °C
Yield: 80.7 %

Procedure:
Ethynyltrimethylsilane (3.42 g, 34.9 mmol) was added via syringe to a mixture of 1-bromo-4-(2-methoxyethyl)benzene (5 g, 23.25 mmol), bis(triphenylphosphine)palladium dichloride (0.326 g, 0.465 mmol), triphenylphosphine (0.305 g, 1.162 mmol) and copper(I) iodide (0.089 g, 0.465 mmol) in piperidine (25 mL). The mixture was heated to 100° C. for 1 h under a nitrogen atmosphere, then cooled and concentrated under vacuum. The residue was taken up in ethyl acetate (70 mL), filtered and concentrated to give the crude product that was then purified by flash chromatography on silica gel (ISCO 120 g column, 0-20% ethyl acetate in n-heptane as the eluent). Product (4.36 g) was obtained as a brown oil (MS: (M+H)+=233.3).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]([CH3:44])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:40]([CH3:43])[CH2:41][CH3:42])[C@H:33]([O:38][CH3:39])[CH2:34][C:35](O)=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:20])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[CH3:46][O:47][C@@H:48]([C@@H:64]1[CH2:68][CH2:67][CH2:66][NH:65]1)[C@@H:49]([CH3:63])[C:50]([NH:52][CH2:53][C:54]1([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH2:56][CH2:55]1)=[O:51].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C)C=O.ClCCl>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]([CH3:44])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:40]([CH3:43])[CH2:41][CH3:42])[C@H:33]([O:38][CH3:39])[CH2:34][C:35]([N:65]3[CH2:66][CH2:67][CH2:68][C@H:64]3[C@H:48]([O:47][CH3:46])[C@@H:49]([CH3:63])[C:50](=[O:51])[NH:52][CH2:53][C:54]3([C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)[CH2:55][CH2:56]3)=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:20])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CO[C@@H]([C@@H]1CCCN1)[C@@H](C)C(=O)NCC1(c2ccccc2)CC1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCC1(c2ccccc2)CC1)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Yield: 75.4 %

Procedure:
According to general procedure D, from #32 (550 mg, 0.902 mmol, 1 eq.), #58 (350 mg, 0.992 mmol, 1.1 eq.) dichloromethane (10 mL, 0.08 M) and N,N-dimethylformamide (2 mL), HATU (446 mg, 1.17 mmol, 1.3 eq.) and triethylamine (0.503 mL, 3.61 mmol, 4 eq.) was synthesized the crude desired material, which was purified by silica gel chromatography (Gradient: 0% to 30% acetone in heptane), producing #59 (618 mg, 69%) as an off-white solid. LC-MS: m/z 908.7 [M+H+], 930.7 [M+Na+], retention time=1.07 minutes; HPLC (Protocol B at 45° C.): m/z 908.5 [M+H+], retention time=8.721 minutes (purity >97%); 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ 7.89 (d, J=7.5 Hz, 2H), 7.38-7.44 (m, 2H), 7.30-7.36 (m, 2H), [4.49 (dd, J=8.5, 7.8 Hz) and 4.59 (dd, J=8.7, 6.9 Hz), total 1H], 4.18-4.26 (m, 3H), 3.93-4.01 (br m, 1H), 3.23 and 3.26 (2 s, total 3H), 3.16 and 3.16 (2 s, total 3H), 2.91 and 3.05 (2 br s, total 3H), 1.36 and 1.37 (2 br s, total 3H), 1.30 and 1.32 (2 br s, total 3H), [1.00 (d, J=6.7 Hz) and 1.02 (d, J=6.6 Hz), total 3H], 0.67-0.78 (m, 7H).
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]2[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=2)=[N:6]1)[CH:2]([CH3:4])[CH3:3].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH2:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12][N:30]2[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]2)=[CH:8][C:7]([C:18]2[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=2)=[N:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CSc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)cc1
Reactant: CN1CCNCC1
Product: CSc1ccc(-c2cc(CN3CCN(C)CC3)c(=O)n(CC(C)C)n2)cc1
Yield: 68.3 %

Procedure:
Following the procedure of Example 1(10), 2-isobutyl-4-methanesulfonyloxymethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 68.3%).
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[S:12][C:13](Br)=[C:14]([CH3:21])[C:15]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:23]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[C:1]1([S:7]([NH:10][C:11]2[S:12][C:13]([C:25]3[CH:26]=[CH:27][O:23][CH:24]=3)=[C:14]([CH3:21])[C:15]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc(Br)c1C
Reactant: OB(O)c1ccoc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc(-c2ccoc2)c1C
Temperature: 150 °C
Yield: 36.2 %

Procedure:
A mixture of ethyl 2-benzenesulphonylamino-5-bromo-4-methylthiophene-3-carboxylate (Intermediate 34, 0.134 g), 3-furan boronic acid (0.056 g) and potassium carbonate (0.114 g) in dioxane (1.3 ml) and water (0.33 ml) was degassed and placed under nitrogen. Tetrakis(triphenylphosphine)palladium(0) (0.019 g) was added and the mixture was heated in the microwave at 150° C. for 15 minutes. The solvent was removed and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane (0-20%) to give ethyl 2-benzenesulphonylamino-5-(furan-3-yl)-4-methyl-thiophene-3-carboxylate (0.047 g) as a white solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:27])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:26])[N:16]([CH3:25])[C:17]([C:21]([F:24])([F:23])[F:22])=[CH:18][C:19]=2[CH3:20])=[CH:10][CH:9]=1)[NH2:6].[Cl:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:30]=1[C:31](Cl)=[O:32].CCN(C(C)C)C(C)C>C1COCC1.C(OCC)(=O)C>[CH3:2][O:3][C:4](=[O:27])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:26])[N:16]([CH3:25])[C:17]([C:21]([F:22])([F:23])[F:24])=[CH:18][C:19]=2[CH3:20])=[CH:12][CH:13]=1)[NH:6][C:31]([C:30]1[C:29]([Cl:28])=[CH:37][CH:36]=[CH:35][C:34]=1[Cl:38])=[O:32]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2c(C)cc(C(F)(F)F)n(C)c2=O)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccc(-c2c(C)cc(C(F)(F)F)n(C)c2=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Reaction time: 0.08 h
Yield: 94.1 %

Procedure:
To a suspension of 4-[1,4-dimethyl-6-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine methyl ester hydrochloride salt (216 mg, 0.53 mmol) and 2,6-dichlorobenzoyl chloride (120 mg, 0.57 mmol) in THF (6 mL) was added DIEA (210 μL, 1.19 mmol) at room temperature. After 5 min, a clear solution was obtained which was stirred for 18 h. Then, the mixture was diluted with ethyl acetate (50 mL). The ethyl acetate solution was washed successively with 0.5 N HCl (50 mL), saturated NaHCO3 solution (50 mL) and brine solution (50 mL) and was dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration gave crude product, which was dissolved in ethyl acetate (˜3 mL) and hexanes (˜3-4 mL) was added and stored in the refrigerator. The solid was collected and washed with hexanes. After drying under high vacuum, 270 mg (93.5% yield) of N-[(2,6-dichlorophenyl)carbonyl]-4-[1,4-dimethyl-6-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine methyl ester was obtained a white solid: mp 170-173° C. ES-HRMS m/e calcd for C25H21Cl2F3N2O4 (M+Na) 563.0724. found 563.0730. Preparation of N-[(2,6-dichlorophenyl)carbonyl]-4-(1,4-dimethyl-6-(trifluoromethyl)-2-oxo-3-pyridinyl)-L-phenylalanine
Reaction SMILES: [CH3:1][N:2]1[N:11]=[N:10][C:9]2[N:5]([CH:6]=[N:7][C:8]=2[C:12]([NH2:14])=[O:13])[C:3]1=[O:4].Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=O>>[CH3:1][N:2]1[C:3](=[O:4])[N:5]2[CH:6]=[N:7][C:8]([C:12]3[O:13][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:14]=3)=[C:9]2[N:10]=[N:11]1
Reactant: O=C(CBr)c1ccccc1
Reactant: Cn1nnc2c(C(N)=O)ncn2c1=O
Product: Cn1nnc2c(-c3nc(-c4ccccc4)co3)ncn2c1=O
Temperature: 130 °C
Yield: 1 %

Procedure:
Temozolomide (0.200 g; 1.03 mmol) and 2-bromoacetophenone (0.246 g; 1.24 mmol) were stirred in a sealed tube under nitrogen, and heated to 130° C. for 1 hour. The mixture was cooled, and then concentrated in vacuo before being applied directly to the head of a chromatography column (SiO2) and purified by column chromatography (DCM:MeOH, 5:1), to give the title compound as a yellow powder (0.003 g; 1%). δH (DMSO-d6) 8.97 (1H, s), 8.88 (1H, s), 7.91 (2H, t, J=7.4), 7.50 (2H, t, J=7.4), 7.39 (1H, t, J=7.4), 3.90 (3H, s).
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([N:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32]3[C:33]([CH3:38])=[N:34][N:35]([CH3:37])[CH:36]=3)[N:26]=2)=[CH:21][C:20]1=[O:39])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([F:18])[CH:12]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C@H:10]([N:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32]4[C:33]([CH3:38])=[N:34][N:35]([CH3:37])[CH:36]=4)[N:26]=3)=[CH:21][C:20]2=[O:39])[CH2:9][OH:8])=[CH:12][C:13]=1[F:18]
Reactant: Cc1nn(C)cc1Nc1nccc(-c2ccn([C@H](CO[Si](C)(C)C(C)(C)C)c3ccc(Cl)c(F)c3)c(=O)c2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nn(C)cc1Nc1nccc(-c2ccn([C@H](CO)c3ccc(Cl)c(F)c3)c(=O)c2)n1
Reaction time: 1 h
Yield: 73.3 %

Procedure:
(S)-1-(2-(tert-Butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (0.070 g, 0.12 mmol) was placed in THF (3 mL). TBAF (0.14 mL, 0.14 mmol) was added, and the mixture was stirred for 1 hour, then poured into water, and extracted with DCM. The combined organic fractions were dried (MgSO4), filtered, and concentrated to give the crude product, which was purified by column chromatography (500:20-500:30 DCM/MeOH) to give the product (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (0.040 g, 71% yield). m/z (APCI-pos) M+1=455.
Reaction SMILES: [CH3:1][N:2]1[C:8](=O)[C:7]2[CH:10]=[CH:11][S:12][C:6]=2[N:5]2[CH:13]=[N:14][C:15](C(O)=O)=[C:4]2[CH2:3]1.C(=O)=[O:20]>ClC(Cl)Cl>[CH3:1][N:2]1[CH2:8][C:7]2[CH:10]=[CH:11][S:12](=[O:20])[C:6]=2[N:5]2[CH:13]=[N:14][CH:15]=[C:4]2[CH2:3]1
Reactant: CN1Cc2c(C(=O)O)ncn2-c2sccc2C1=O
Reactant: O=C=O
Solvent: ClC(Cl)Cl
Product: CN1CC2=C(n3cncc3C1)S(=O)C=C2

Procedure:
27 g of 5,6-dihydro-5-methyl-4-oxo-4H-imidazo[1,5-a]thieno[3,2-f][1,4]diazepine-7-carboxylic acid was immersed in a flask filled with argon in a heating bath pre-heated to 280°. The substance melts with decarboxylation. After completion of the evolution of carbon dioxide (about 7 to 8 min.) the flask was cooled slightly. Even before it had solidified, the reaction mixture was mixed with 250 ml of trichloromethane. The solution was evaporated in a vacuum and the residue was recrystallized from ethyl acetate/diisopropyl ether. There was obtained 5,6-dihydro-5-methyl-4H-imidazo[1,5-a]thieno[3,2-f][1,4]diazepine-one of melting point 160°-163°. After recrystallization from ethyl acetate the melting point was 163°-164°.
Reaction SMILES: [ClH:1].C(OC([NH:9][C@H:10]1[C@@H:14]([CH2:15][F:16])[CH2:13][NH:12][CH2:11]1)=O)(C)(C)C>O>[ClH:1].[ClH:1].[NH2:9][C@H:10]1[C@@H:14]([CH2:15][F:16])[CH2:13][NH:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNC[C@@H]1CF
Agent: Cl
Solvent: O
Product: N[C@@H]1CNC[C@@H]1CF
Reaction time: 0.17 h
Yield: 75 %

Procedure:
Concentrated hydrochloric acid (1 ml) was added to 3-(S)-tert-butoxycarbonylamino-4-(S)-fluoromethylpyrrolidine (441 mg, 2.02 mmol) which was cooled in an ice bath, and the mixture was stirred for 10 minutes. The reaction solution was mixed with water (5 ml) and washed with dichloromethane (5 ml×3) and diethyl ether (5 ml×1). The aqueous layer was concentrated under a reduced pressure, and the resulting residue was purified by its recrystallization from methanol to give 288 mg (75%) of the title compound in the form of white crystals.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][CH2:7][C:8]#[C:9][CH:10]([C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)[OH:11])[CH3:5])[CH3:2]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:1]([O:3][CH:4]([O:6][CH2:7][C:8]#[C:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]([S:18][CH3:19])=[CH:16][CH:17]=1)=[O:11])[CH3:5])[CH3:2]
Reactant: CCOC(C)OCC#CC(O)c1ccc(SC)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCOC(C)OCC#CC(=O)c1ccc(SC)cc1
Reaction time: 0.25 h

Procedure:
A solution of 10.9 g (3B.9 mmol) of 4-(1-ethoxyethoxy)-1-[4-(methylthio)phenyl]-2-butyn-1-ol in 50 ml of methylene chloride was added dropwise at 0° to a suspension of 100 g (1.15 mol) of manganese dioxide in 170 ml of methylene chloride. The reaction mixture was stirred at 0° for 15 minutes, filtered over magnesium sulphate and concentrated. Flash chromatography of the residue on 200 g of silica gel (elution agent ether/hexane 1:1) yielded 4-(1 -ethoxyethoxy)1-[4-(methylthio)phenyl]-2-butyn-1-one as an oil.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.Cl.[CH3:11][N:12]1[CH:16]=[C:15]([NH2:17])[CH:14]=[C:13]1[C:18]([O:20][CH3:21])=[O:19].C(N(C(C)C)CC)(C)C>>[Br:1][C:2]1[C:3]([NH:17][C:15]2[CH:14]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[N:12]([CH3:11])[CH:16]=2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: COC(=O)c1cc(N)cn1C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(Nc2nc(Cl)ncc2Br)cn1C

Procedure:
In like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro 4-pyrimidineamine, 5-bromo-2,4-dichloropyrimidine and N-methyl-2-carbomethoxy-4-aminopyrrole hydrochloride with added diisopropylethylamine were reacted to produce the desired product 5-bromo-2-chloro-N—(N-methyl-2-carbomethoxypyrrol-4-yl)-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.21 (s, 1H), 7.43 (d, 1H, J=1.8 Hz), 7.13 (br s, 1H), 6.84 (d, 1H, J=1.8 Hz), 3.95 (s, 3H), 3.82 (s, 3H); LCMS: ret. time: 26.96 min.; purity: 91%; MS (m/e): 346 (MH+).
Reaction SMILES: [OH:1][C@@:2]([CH3:53])([C:5](=[O:52])[C@@H:6]([NH:11][C:12]([C@@H:14]([NH:22][C:23](=[O:51])[C@@H:24]([NH:29][C:30](=[O:50])[C@@H:31]([NH:40][C:41](=[O:49])[CH2:42][N:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1)[CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:3][I:4].[C:54](O)(=[O:59])[CH2:55][CH2:56][C:57]#[CH:58].C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.CN(C1C=CN=CC=1)C.CCOC(C)=O>[C:54]([O:1][C@:2]([CH3:53])([CH2:3][I:4])[C:5](=[O:52])[C@H:6]([CH2:7][CH:8]([CH3:9])[CH3:10])[NH:11][C:12](=[O:13])[C@H:14]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[NH:22][C:23](=[O:51])[C@H:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[NH:29][C:30](=[O:50])[C@H:31]([CH2:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[NH:40][C:41](=[O:49])[CH2:42][N:43]1[CH2:44][CH2:45][O:46][CH2:47][CH2:48]1)(=[O:59])[CH2:55][CH2:56][C:57]#[CH:58]
Reactant: CC(C)C[C@H](NC(=O)[C@H](CCc1ccccc1)NC(=O)CN1CCOCC1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)[C@](C)(O)CI
Reactant: C#CCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C#CCCC(=O)O[C@](C)(CI)C(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCc1ccccc1)NC(=O)CN1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.8 %

Procedure:
(2S)—N—((S)-1-((2S,4S)-2-hydroxy-1-iodo-2,6-dimethyl-3-oxoheptan-4-ylcarbamoyl)-2-phenylethyl)-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)-4-methylpentanamide (1.18 g, 1.39 mmol) was dissolved in DMF. DMAP (19.2 mg, 0.139 mmol), 4-pentynoic acid (205 mg, 2.09 mmol) and DCC (430 mg, 2.09 mmol) were added. The mixture was stirred at room temperature for 16 hours and then diluted with 200 mL EtOAc. The organic phase was washed with 1N HCl (50 ml), brine (50 mL), and saturated NaHCO3 solution. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude product was purified by prep HPLC to afford 539 mg of product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.Br[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:3]1([CH3:8])[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16]
Reactant: Cc1ccccc1Br
Reactant: Cc1ccccc1N
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: Cc1ccccc1Nc1ccccc1C
Temperature: 100 °C
Yield: 89.7 %

Procedure:
A mixture of o-toluidine (6.05 g, 56.5 mmol), 1-bromo-2-methylbenzene (8.5 g, 50 mmol), Pd(dppf)Cl2 and sodium tert-butoxide (9.6 g, 0.1 mmol) in toluene (120 mL) was degassed and heated at about 100° C. overnight. The mixture was purified by flash column using eluents of hexanes/dichloromethane 2:1 to give a white solid (Compound 9) (8.84 g, in 89.7% yield).