Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[C:13]#[N:14])C.[CH3:16][O:17][CH2:18][C:19]([NH:21][NH2:22])=O>>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]2[NH:5][C:4](=[O:3])[N:22]3[N:21]=[C:19]([CH2:18][O:17][CH3:16])[N:14]=[C:13]3[C:7]=2[CH:8]=1
Reactant: CCOC(=O)Nc1ccc(Cl)cc1C#N
Reactant: COCC(=O)NN
Product: COCc1nc2c3cc(Cl)ccc3[nH]c(=O)n2n1
Yield: 88 %

Procedure:
As described for example 1a) (4-chloro-2-cyano-phenyl)-carbamic acid ethyl ester (71.0 g, 316 mmol) using methoxymethyl-carboxylic acid hydrazide instead of cyclopropane-carboxylic acid hydrazide, was converted to the title compound (73.9 g, 88%) which was obtained as a yellow solid. MS: m/e=264.9 [M+H]+.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:47][CH:48]1[C@H:52]2[C@H:53](OC3CCCCO3)[N:54](C(OC(C)(C)C)=O)[C:55]3[CH:62]=[C:61]([O:63][CH3:64])[CH:60]=[CH:59][C:56]=3[C:57](=[O:58])[N:51]2[CH2:50][CH2:49]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH:16]1[C@H:20]2[C@H:21](OC3CCCCO3)[N:22](C(OC(C)(C)C)=O)[C:23]3[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:24]=3[C:25](=[O:26])[N:19]2[CH2:18][CH2:17]1.C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH2:8]([O:47][CH:48]1[C@@H:52]2[CH:53]=[N:54][C:55]3[CH:62]=[C:61]([O:63][CH3:64])[CH:60]=[CH:59][C:56]=3[C:57](=[O:58])[N:51]2[CH2:50][CH2:49]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH:16]1[C@@H:20]2[CH:21]=[N:22][C:23]3[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:24]=3[C:25](=[O:26])[N:19]2[CH2:18][CH2:17]1
Reactant: COc1ccc2c(c1)N(C(=O)OC(C)(C)C)[C@@H](OC1CCCCO1)[C@@H]1C(OCCCCCCCOC3CCN4C(=O)c5ccc(OC)cc5N(C(=O)OC(C)(C)C)[C@@H](OC5CCCCO5)[C@H]34)CCN1C2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1ccc2c(c1)N=C[C@H]1C(OCCCCCCCOC3CCN4C(=O)c5ccc(OC)cc5N=C[C@@H]34)CCN1C2=O
Reaction time: 1 h
Yield: 63.2 %

Procedure:
95% TFA (3 mL) was added drop-wise to dimer compound 8e (195 mg, 0.19 mmol) at 0° C. This was then stirred for 1 hr and the mixture was poured into saturated NaHCO3 (30 mL) solution to naturalize the reaction mixture. The mixture was extracted with chloroform (3×20 mL). The organic layer was then washed water (20 mL), brine (20 mL) then dried (MgSO4) and filtrated. The excess solvent was removed under reduced pressure to give the crude product, which was subjected to flash column chromatography (SiO2, 2% methanol-chloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 9e (76 mg, 0.12 mmol, 68%) as a solid: [α]20D=+473° (c=0.14, CHCl3); 1H NMR (CDCl3, 400 MHz): δ 1.41-1.55 (m, 6H, 14-H, 14′-H, 15-H), 1.85-1.94 (m, 4H, 13-H, 13′-H), 2.04-2.10 (m, 4H, 2-H, 2′-H), 2.28-2.38 (m, 4H, 1-H, 1′-H), 3.56-3.63 (m, 2H, 3-H, 3′-H), 3.72-3.76 (m, 2H, 11a-H, 11a′-H), 3.79-3.85 (m, 2H, 3-H, 3′-H), 3.92 (s, 6H, 7-OMe, 7′-OMe), 4.01-4.19 (m, 4H, 12-H, 12′-H), 6.79 (s, 2H, 9-H, 9′-H), 7.49 (s, 2H, 6-H, 6′-H), 7.64 (d, 2H, J=4, 11-H, 11′-H); 13C NMR (CDCl3, 400 MHz): δ 24.1, 25.9, 29.0, 29.2, 29.6, 46.6, 53.7, 56.0, 69.1, 109.6, 112.5, 120.2, 140.5, 147.1, 151.6, 162.2, 164.6; IR (neat): 3325, 2935, 1600, 1506, 1448, 1388, 1261, 1217, 1022 cm−1; MS (FAB) m/z (relative intensity) 653 ([M+2×MeOH]+., 14), 621 ([M+MeOH]+., 20), 589 (M+., 100).
Reaction SMILES: Br[CH2:2][C:3]1[C:8](I)=[CH:7][N:6]=[C:5]([Cl:10])[CH:4]=1.[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH:22]=[CH2:23])=[C:16]([NH:18][C:19](=[O:21])[CH3:20])[CH:17]=1.C(N1C2C=CC=CC=2C=CC2N=C(Cl)C(F)=CC=2C1)(=O)C>>[C:19]([N:18]1[C:16]2[CH:17]=[C:12]([Cl:11])[CH:13]=[CH:14][C:15]=2[CH:22]=[CH:23][C:8]2[CH:7]=[N:6][C:5]([Cl:10])=[CH:4][C:3]=2[CH2:2]1)(=[O:21])[CH3:20]
Reactant: Clc1cc(CBr)c(I)cn1
Reactant: C=Cc1ccc(Cl)cc1NC(C)=O
Agent: CC(=O)N1Cc2cc(F)c(Cl)nc2C=Cc2ccccc21
Product: CC(=O)N1Cc2cc(Cl)ncc2C=Cc2ccc(Cl)cc21

Procedure:
The title compound was prepared from 25D and 6C in two steps by a route analogous to that used for the preparation of 1D. HPLC Rt=2.809 min; LCMS Found: (M+H)+=319.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([F:22])[CH:15]=3)=[CH:12][C:11]([C:23]([OH:25])=O)=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=C(N2C(C3C=C(OC)C=C(F)C=3)=CC(C([N:49]3[CH2:53][C:52](=[O:54])[NH:51][CH2:50]3)=O)=N2)C=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([F:22])[CH:15]=3)=[CH:12][C:11]([C:23]([N:49]3[CH2:53][C:52](=[O:54])[NH:51][CH2:50]3)=[O:25])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc(F)cc(-c2cc(C(=O)O)nn2-c2ccc(F)c(Cl)c2)c1
Reactant: COc1cc(F)cc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1
Product: COc1cc(F)cc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2ccc(F)c(Cl)c2)c1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 92A in analogy to the synthesis of the compound of Example 21. 29 mg (24% of theory) of the title compound are obtained.
Reaction SMILES: [F:1][C:2]1[C:3](/[C:12](/I)=[CH:13]/[C:14](=O)[C:15]2[NH:16][CH:17]=[CH:18][CH:19]=2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[C:22]([O:26][C:27](=[O:32])[NH:28][CH2:29][CH2:30][SH:31])([CH3:25])([CH3:24])[CH3:23].[H-].[Na+].[H][H]>>[C:22]([O:26][C:27](=[O:32])[NH:28][CH2:29][CH2:30][S:31][C:12]1[CH:13]=[C:14]([C:15]2[NH:16][CH:17]=[CH:18][CH:19]=2)[C:5]2[C:6](=[O:11])[NH:7][C:8]3[C:4]=2[C:3]=1[C:2]([F:1])=[CH:10][CH:9]=3)([CH3:25])([CH3:23])[CH3:24]
Reactant: O=C1Cc2c(ccc(F)c2/C(I)=C/C(=O)c2ccc[nH]2)N1
Reactant: CC(C)(C)OC(=O)NCCS
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)NCCSc1cc(-c2ccc[nH]2)c2c3c(ccc(F)c13)NC2=O
Temperature: 120 °C
Reaction time: 2 h

Procedure:
A mixture of (Z)-5-fluoro-4-[1-iodo-3-oxo-3-(1H-pyrrol-2-yl)-propenyl]-1,3-dihydro-indol-2-one (from Example 8 above) (600 mg, 1.28 mmol) and neat tert-butyl-N-(2-mercaptoethyl)-carbamate (Aldrich, 19 mL) was treated with NaH (Aldrich, 460 mg, 19.15 mmol) in small portions e within a period of 30 minutes at room temperature. After the evolution of hydrogen had stopped, 55 the mixture was heated gradually to 120° C. The viscous slurry was stirred at this temperature for 2 hours and then allowed to cool. The mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted twice more with ethyl acetate. The combined organic layer was dried and concentrated to give a solid residue. This residue was washed with pentane and purified by HPLC (silica gel, 25% ethyl acetate in hexanes), followed by precipitation out of THF with excess pentane to give [2-[6-fluoro-2-oxo-3-(1H-pyrrol-2-yl)-1,2-dihydro-benzo[cd]indol-5-ylsulfanyl]-ethyl]-carbamic acid tert-butyl ester as a yellow solid. (Yield 470 mg, 84%).
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:8]=3[C:7]=2[CH:6]=1)(=[O:4])=[O:3].[CH:22]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:22]1([NH:28][S:2]([C:5]2[CH:14]=[CH:13][C:12]3[NH:11][C:10](=[O:15])[C:9]4[NH:16][CH:17]=[CH:18][C:8]=4[C:7]=3[CH:6]=2)(=[O:3])=[O:4])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.[CH2:18]([C:19]([O-:21])=[O:20])[CH3:17]
Reactant: NC1CCCCC1
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)Cl)cc3c12
Product: CCC(=O)[O-]
Product: O=c1[nH]c2ccc(S(=O)(=O)NC3CCCCC3)cc2c2cc[nH]c12
Yield: 27.3 %

Procedure:
This compound is prepared according to synthesis 25, from 115 mg (0.35 mmol) of 8-chlorosulfonyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (synthesis 2) and 48 μL (0.42 mmol) of cyclohexylamine. After purification by chromatography on silica (eluent dichloromethane/methanol 95/5), 20 mg (14%) of 8-cyclohexylsulfamoyl-4-oxo-4,5-dihydro-3H -pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:43])([CH2:13][C:14]2[N:15]([C:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:16]=[C:17]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[N:18]=2)[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[NH:44]1[CH:48]=[CH:47][N:46]=[N:45]1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.O.[Cu]I>[CH3:21][C:20]([CH3:23])([CH3:22])[CH2:19][C:17]1[N:18]=[C:14]([CH2:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:45]3[N:46]=[CH:47][CH:48]=[N:44]3)=[CH:3][CH:4]=2)([OH:43])[C:9]([F:12])([F:11])[F:10])[N:15]([C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:16]=1
Reactant: c1c[nH]nn1
Reactant: CC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(O)(c2ccc(Br)cc2)C(F)(F)F)n1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(O)(c2ccc(-n3nccn3)cc2)C(F)(F)F)n1

Procedure:
A mixture of copper (I) iodide (1 mg, 0.01 mmol), 2-(4-bromophenyl)-3-[4-(2,2-dimethylpropyl)-1-trityl-1H-imidazol-2-yl]-1,1,1-trifluoropropan-2-ol (50 mg, 0.08 mmol), 1,2,3-triazole (11 mg, 0.15 mmol) and potassium carbonate (21 mg, 0.15 mmol) in N-methylpyrrolidinone (1 mL) were irradiated in a microwave reactor at 195° C. for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were dried (magnesium sulfate), filtered and concentrated in vacuo. High pressure liquid chromatography (KR100-5C18 100×21.2 mm column) eluting with 10-100% acetonitrile/water containing 0.1% trifluoroacetic acid afforded 3-[4-(2,2-dimethylpropyl)-1-trityl-1H-imidazol-2-yl]-1,1,1-trifluoro-2-[4-(2H-1,2,3-triazol-2-yl)phenyl]propan-2-ol.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C([C:13]1[C:21]2[C:16](=[C:17]([CH2:23][S:24][CH3:25])[CH:18]=[C:19](F)[CH:20]=2)[NH:15][CH:14]=1)CCO.[CH:26]1([C:29]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[F:39])(O)[CH3:30])[CH2:28][CH2:27]1.C1(C(C2C3C(=C(CSC)C=CC=3)NC=2)(C2C=CC(F)=CC=2)C)CC1>>[CH:26]1([C:29]([C:13]2[C:21]3[C:16](=[C:17]([CH2:23][S:24][CH3:25])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[F:39])[CH3:30])[CH2:28][CH2:27]1
Reactant: CC(O)(c1ccc(F)cc1F)C1CC1
Reactant: CSCc1cc(F)cc2c(C(CCO)c3ccc(Cl)cc3Cl)c[nH]c12
Agent: CSCc1cccc2c(C(C)(c3ccc(F)cc3)C3CC3)c[nH]c12
Product: CSCc1cccc2c(C(C)(c3ccc(F)cc3F)C3CC3)c[nH]c12

Procedure:
The title compound was prepared starting from 500 mg (2.82 mmol) of the compound from Example 8 and 615 mg (3.10 mmol) of the compound from Example 78A in analogy to the synthesis of the compound from Example 95. 227 mg (94% purity, 21% of theory) of the target compound were obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][C:10]([NH2:12])=[O:11])=[CH:3][CH:2]=1.[H][H]>C(O)(=O)C.[Pt]=O>[NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][C:10]([NH2:12])=[O:11])[CH2:3][CH2:2]1
Reactant: NC(=O)CCCc1ccncc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CC(=O)O
Product: NC(=O)CCCC1CCNCC1

Procedure:
The crude amide was dissolved in glacial acetic acid and hydrogenated at 60°/60 p.s.i. over a platinum oxide catalyst until uptake of hydrogen ceased. The catalyst was removed by filtration and the filtrate was evaporated in vacuo to give crude 4-(piperid-4-yl)butyramide as an oil.
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13](=O)[N:14]([CH:16]1[CH2:21][CH2:20][N:19]([C:22]2[N:23]=[N:24][C:25]([C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)=[C:26]([CH3:29])[C:27]=2[CH3:28])[CH2:18][CH2:17]1)C)(C)(C)C>C(Cl)Cl>[CH3:28][C:27]1[C:26]([CH3:29])=[C:25]([C:30]2[CH:31]=[CH:32][N:33]=[CH:34][CH:35]=2)[N:24]=[N:23][C:22]=1[N:19]1[CH2:18][CH2:17][CH:16]([NH:14][CH3:13])[CH2:21][CH2:20]1
Reactant: Cc1c(-c2ccncc2)nnc(N2CCC(N(C)C(=O)OC(C)(C)C)CC2)c1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC1CCN(c2nnc(-c3ccncc3)c(C)c2C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 88.8 %

Procedure:
Add CH2Cl2 (20 mL) and trifluoroacetic acid (20 mL) to tert-butyl-1-(4,5-dimethyl-6-(pyridine-4-yl)pyridazin-3-yl)piperidin-4-yl(methyl)carbamate (1.19 g, 2.99 mmol). Stir at ambient temperature for 3 d. Concentrate under reduced pressure to give a residue. Partition the residue between CH2Cl2 and 1 N NaOH. Separate the layers, and extract the aqueous layer twice with CH2Cl2. Combine the organic extracts, dry over Na2SO4, filter, and concentrate under reduced pressure to obtain the title compound (790 mg, 89%). ES/MS m/z 298.2 (M+1).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C:6](Br)=[CH:5][N:4]=1.[C]=[O:15].[CH:16]([OH:19])(C)C>C(N(CC)CC)C.C(OCC)(=O)C.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.Cl[Pd]Cl>[CH3:1][S:2][C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C:6]([C:16]([OH:19])=[O:15])=[CH:5][N:4]=1
Reactant: CSc1ncc(Br)cc1C(F)(F)F
Reactant: [C]=O
Reactant: CC(C)O
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CSc1ncc(C(=O)O)cc1C(F)(F)F
Temperature: 130 °C

Procedure:
The product of Example 7 (2.0 g, 7.4 mmol) was dissolved in a mixture of isopropanol (8 mL) and triethylamine (4 mL) in a 45 mL Hastelloy bomb. Bis(triphenylphosphine)palladium (II) chloride (0.1 g) was added and the vessel charged with carbon monoxide to a pressure of 300 psi. The reaction mixture was heated to 130° C. for 17 hours, allowed to cool to room temperature, and the pressure released. The reaction mixture was diluted with ethyl acetate (25 mL), filtered, and the solvents evaporated under reduced pressure. The residual oil was dissolved in ethyl acetate (50 mL) and washed with water and brine. Evaporation of the solvent under reduced pressure and purification of the resultant oil by chromatography over silica (5% ethyl acetate:hexane) gave 6-methylthio-5-trifluoromethyl-nicotinic acid: isopropyl ester as a clear oil (1.8 g).
Reaction SMILES: [C:1]([C:3]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][O:7][CH:8]2[CH2:14][N:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1)#[N:2].[ClH:28].O1CCOCC1>C(Cl)Cl>[ClH:28].[F:13][C:12]1[CH:11]=[CH:10][C:9]2[CH:8]([CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[O:7][CH2:6][CH2:5][C:4]=2[C:3]=1[C:1]#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCN(CC2OCCc3c2ccc(F)c3C#N)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: N#Cc1c(F)ccc2c1CCOC2CN1CCNCC1
Reaction time: 2 h

Procedure:
A solution of tert-butyl 4-[(5-cyano-6-fluoro-3,4-dihydro-1H-isochromen-1-yl)methyl]piperazine-1-carboxylate (110 mg, 0.29 mmol) in 10 mL of DCM was added 3 mL of 4N HCl/dioxane, then sirred at room temperature for 2 hours. The solvents was removed off under vacuum to afford 6-fluoro-1-(piperazin-1-ylmethyl)-3,4-dihydro-1H-isochromene-5-carbonitrile hydrochloride. 1H-NMR (400 MHz, MeOD) δ ppm 7.63˜7.66 (m, 1H), 7.25˜7.29 (m, 1H), 5.33˜5.30 (m, 1H), 4.25˜4.30 (in, 1H), 3.87˜3.97 (m, 2H), 3.72˜3.83 (m, 3H), 3.58˜3.68 (m, 6H), 3.07˜3.17 (m, 2H).
Reaction SMILES: [Na].Cl.[C:3]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[O:11])=[CH:8][CH:7]=1)(=[NH:5])[NH2:4].[C:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23](=[CH:26]OC)[CH:24]=O)=[CH:19][CH:18]=1)#[N:16]>CO>[C:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[N:5][C:3]([C:6]3[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[O:11])=[CH:8][CH:7]=3)=[N:4][CH:26]=2)=[CH:19][CH:18]=1)#[N:16]
Reactant: COC=C(C=O)c1ccc(C#N)cc1
Reactant: N=C(N)c1ccc(C(N)=O)cc1
Agent: Cl
Agent: [Na]
Solvent: CO
Product: N#Cc1ccc(-c2cnc(-c3ccc(C(N)=O)cc3)nc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
247 mg of sodium are treated at room temperature with 10 ml of methanol. After 15 minutes the solution obtained is treated at room temperature with 1.58 g of 4-amidinobenzamide hydrochloride. A white suspension forms and this is treated dropwise at room temperature within 10 minutes with a solution of 1.42 g of 2-(4-cyanophenyl)-3-methoxyacrolein in 50 ml of methanol. The reaction mixture is stirred at room temperature for a further 2 hours and then suction filtered. The residue is washed with water, tetrahydrofuran and diethyl ether and dried in a high vacuum. 4-[5-(4-Cyanophenyl)-2-pyrimidinyl]benzamide is obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][N:24]([CH3:29])[S:25]([CH3:28])(=[O:27])=[O:26])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:30])[CH3:9])=[CH:4][CH:3]=1.[CH3:31][C:32]1[CH:37]=[C:36](B(O)O)[CH:35]=[CH:34][N:33]=1>>[CH3:29][N:24]([CH2:23][CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:30])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:36]3[CH:35]=[CH:34][N:33]=[C:32]([CH3:31])[CH:37]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1)[S:25]([CH3:28])(=[O:27])=[O:26]
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCN(C)S(C)(=O)=O)(c2ccccc2)OC1=O
Reactant: Cc1cc(B(O)O)ccn1
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CCN(C)S(C)(=O)=O)(c4ccccc4)OC3=O)cc2)ccn1

Procedure:
The title compound was prepared from N-(2-((S)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)ethyl)-N-methylmethanesulfonamide and 2-methylpyridine-4-boronic acid following a procedure analogous to that described in Example 459 Step 1. LC-MS Method 2 tR=0.989, m/z=508.1; 1H NMR (CDCl3) 1.53 (d, 3H), 2.17-2.32 (m, 5H), 2.63 (s, 3H), 2.71 (s, 3H), 2.81 (s, 3H), 2.93 (m, 2H), 3.22 (m, 1H), 5.67 (m, 1H), 7.08 (m, 2H), 7.21 (s, 2H), 7.25 (m, 3H), 7.33 (m, 2H), 7.61 (s, 1H), 7.71 (d, 1H), 8.72 (d, 1H).
Reaction SMILES: [NH2:1][C@H:2]([C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[NH:23]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C@H:24]([C:40]([NH:42][CH2:43][C:44](O)=[O:45])=[O:41])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:28][CH:27]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.CN(C=O)C>[NH:23]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C@H:24]([C:40]([NH:42][CH2:43][C:44]([NH:1][C@H:2]([C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)=[O:45])=[O:41])[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:30][CH:31]=1
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)NCC(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)NCC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NCc1ccccc1

Procedure:
compound PSV11R. Same procedure as above with Trp-NHCH2Ph (82.43 mg, 0.281 mmol), N-Boc-Tyr(Bn)-Gly-OH (109.26 mg, 0.255 mmol), EDC (53.87 mg, 0.281 mmol) and HOBt (37.97 mg, 0.281 mmol) in CH2Cl2/DMF (2 mL/0.8 mL). The crude residue was triturated with CH2Cl2/pentane to afford a white solid (113.76, 63%). mp 183° C. 1H NMR (300 MHz, CDCl3) δ 1.38 (s, 9H, (CH3)3), 2.81 (m, 2H, CH2 Tyr), 3.26 (m, 2H), 3.72 (m, 2H, CH2 Gly), 4.30 (m, 3H, CHα and CH2Bn), 4.80 (m, 1H, CHα), 5.0 (broad s, 3H, NHBoc and CH2O), 6.72 (m, 1H, NH Gly), 6.90-7.40 (m, 20H, aromatic H and NH), 7.63 (d, 1H, J=7 Hz), 8.35 (s, 1H, NH indole). 13C NMR (75 MHz, CDCl3) δ 28.3 (CH2 Trp and (CH3)3), 37.5 (CH2 Tyr), 43.1, 43.5 (CH2 (Bn), CH2 Gly), 54.0, 55.8 (CHα Tyr, Trp), 70.0 (CH2 (Bn)), 80.4 (C(CH3)3), 110.2, 111.3, 114.9, 118.7, 119.5, 122.0, 123.4, 127.2, 127.4, 127.5, 127.7, 128.0, 128.5, 128.6, 128.7, 130.3, 136.1, 137.0, 137.9 (20 aromatic C), 155.7, 157.7 (Car-O, CO carbamate), 168.9, 171.4, 172.5 (3 CO amide). Anal. Calcd. for C41H45N5O6, 1H2O: C, 68.22; H, 6.56; N, 9.71. Found: C, 68.50; H, 6.48; N, 9.98.
Reaction SMILES: C(O)(=O)C.FC1C(OCCF)=CC(OC)=CC=1C(NC1C=CC(C(N)=N)=CC=1)C1NC(=O)N(C2N=CC=CN=2)N=1.[CH2:41]([C:44]1[CH:49]=[C:48]([Br:50])[CH:47]=[C:46]([O:51][CH3:52])[C:45]=1[OH:53])[CH:42]=[CH2:43].N1C=CN=C1.Cl[Si:60]([CH:67]([CH3:69])[CH3:68])([CH:64]([CH3:66])[CH3:65])[CH:61]([CH3:63])[CH3:62].Cl>CN(C=O)C.C(OCC)(=O)C>[CH2:41]([C:44]1[CH:49]=[C:48]([Br:50])[CH:47]=[C:46]([O:51][CH3:52])[C:45]=1[O:53][Si:60]([CH:67]([CH3:69])[CH3:68])([CH:64]([CH3:66])[CH3:65])[CH:61]([CH3:63])[CH3:62])[CH:42]=[CH2:43]
Reactant: C=CCc1cc(Br)cc(OC)c1O
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: COc1cc(OCCF)c(F)c(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: C=CCc1cc(Br)cc(OC)c1O[Si](C(C)C)(C(C)C)C(C)C
Temperature: 50 °C
Reaction time: 4 h

Procedure:
After dissolving 3g of 2-allyl-4-bromo-6-methoxy-phenol [CAS No. 352019-92-2] in 10 ml of DMF, 1.3 g of imidazole and 2g of chlorotriisopropylsilane were added and the mixture was stirred at 50° C. for 4 hours. Next, 1N hydrochloric acid was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give (2-allyl-4-bromo-6-methoxyphenoxy)triisopropylsilane.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[I-].[Na+].C(N(CC)CC)C.Br[CH:29]([CH3:31])[CH3:30]>CN(C=O)C.O>[CH:29]([N:13]1[CH2:18][CH2:17][N:16]([C:2]2[S:3][C:4]3[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:15][CH2:14]1)([CH3:31])[CH3:30]
Reactant: C1CNCCN1
Reactant: CC(C)Br
Reactant: N#Cc1ccc2nc(Cl)sc2c1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)N1CCN(c2nc3ccc(C#N)cc3s2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.6 %

Procedure:
A solution of 2-chlorobenzothiazole-6-carbonitrile (14.9 g, 0.077 mol) in DMF (250 mL) was added drop-wise at 10° C. to a mixture of anhydrous piperazine (60 g, 0.698 mol) and DMF (300 mL). Then the mixture was stirred for 2 h. Water (1,550 mL) was added and the mixture was extracted with dichloromethane (5×500 mL). The combined organic extracts was washed with water (6×500 mL), dried (Na2SO4), filtered and evaporated to give a residue which was re-crystallised from ethyl acetate. This afforded 10.5 g (56%) of 2-(piperazin-1-yl)benzothiazole-6-carbonitrile. A mixture of this piperazine derivative (19.4 g, 0.08 mol), sodium iodide (1.94 g), triethylamine (9.6 g, 0.095 mol) and DMF (80 mL) was heated with stirring to give a red liquid. A solution of 2-bromopropane (14.7 g, 0.12 mol) in DMF (80 mL) was added drop-wise at 117° C. within in 1 h. The reaction mixture was stirred at 110-117° C. for another 3 h and then allowed to cool to room temperature. Water (110 mL) was added and the mixture was filtered. The filter cake was washed until the filtrate was colourless and then dried. The solid was dissolved in DMF (250 mL) and filtered to remove a solid residue. Water (1000 mL) was added to the filtrate with stirring to give a precipitate. The solid was isolated, washed with water and dried to give 9.4 g (41%) of 2-(4-Isopropylpiperazin-1-yl)-benzothiazole-6-carbonitrile.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[N:17]=[C:16]([S:21][CH3:22])[N:15]=1.[C:23](Cl)(=[O:27])[O:24][CH2:25][CH3:26]>C1COCC1.O>[Cl:13][C:14]1[C:19]([C:23]([O:24][CH2:25][CH3:26])=[O:27])=[C:18]([Cl:20])[N:17]=[C:16]([S:21][CH3:22])[N:15]=1
Reactant: CCOC(=O)Cl
Reactant: CSc1nc(Cl)cc(Cl)n1
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1c(Cl)nc(SC)nc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
Under an argon atmosphere, to a solution of diisopropylamine (15.7 mL, 112 mmol) in THF (70 mL) was added dropwise butyllithium (1.6M hexane solution, 70 mL, 112 mmol) at −78° C. The mixture was stirred at 0° C. for 30 min and cooled to −78° C. A solution of 4,6-dichloro-2-(methylsulfanyl)pyrimidine (14.12 g, 72.4 mmol) in THF (20 mL) was added dropwise thereto, and the mixture was stirred at −78° C. for 1 hr. A solution of ethyl chlorocarbonate (13.9 mL, 145 mmol) in THF (20 ml) was added dropwise thereto, and the mixture was stirred at −78° C. for 30 min, and then at 0° C. for 30 min. Water was added thereto, and the mixture was extracted twice with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluate, hexane:ethyl acetate=100:0→90:10) to give the title compound (13.28 g, 69%) as a colorless solid.