Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12](/[NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=3)\[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[O-:30][C:31]#[N:32].[K+].C(O)(=O)C>C(O)C>[CH3:29][O:28][C:26]([C:23]1[CH:22]=[CH:21][C:20]([NH:19]/[C:12](=[C:6]2\[C:7](=[O:11])[NH:8][C:9]3[C:5]\2=[CH:4][CH:3]=[C:2]([NH:1][C:31]([NH2:32])=[O:30])[CH:10]=3)/[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:25][CH:24]=1)=[O:27]
Reactant: COC(=O)c1ccc(N/C(=C2\C(=O)Nc3cc(N)ccc32)c2ccccc2)cc1
Reactant: N#C[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)c1ccc(N/C(=C2\C(=O)Nc3cc(NC(N)=O)ccc32)c2ccccc2)cc1

Procedure:
560 mg of 6-amino-3-(Z)-[1-(4-methoxycarbonyl-anilino)-1-phenyl-methylidene]-2-indolinone, 236 mg of potassium cyanate and 3.8 ml of glacial acetic acid are dissolved in 20 ml of ethanol and refluxed for 1 hour. After this time the solvent is evaporated, the residue is taken up in methylene chloride, washed with water and dried over sodium sulphate. After evaporation, the product is dried in the desiccator.
Reaction SMILES: CS([C:5]1[N:14]2[C:8]([CH2:9][C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[CH:12]=[CH:13]2)=[N:7][N:6]=1)(=O)=O.[O-:19][CH2:20][CH3:21].[Na+].C(O)C.C[O-].[Na+].CO>>[CH2:20]([O:19][C:5]1[N:14]2[C:8]([CH2:9][C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[CH:12]=[CH:13]2)=[N:7][N:6]=1)[CH3:21]
Reactant: CS(=O)(=O)c1nnc2n1C=Cc1ccccc1C2
Reactant: CC[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CCOc1nnc2n1C=Cc1ccccc1C2

Procedure:
By a procedure similar to that described in Example 34, 3-methylsulfonyl-11H-s-triazolo[3,4-b][3] benzazepine was reacted with sodium ethoxide/ethanol, in lieu of sodium methoxide/methanol, to obtain 3-ethoxy-11H-s-triazolo[3,4-b][3]benzazepine as crystals. Recrystallization from acetone yielded colorless needles, melting point: 143°-144° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([C:8]2[N:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1.[B:15]1(B2OCC(C)(C)CO2)[O:20]CC(C)(C)C[O:16]1>>[F:14][C:5]1[CH:4]=[CH:3][C:2]([B:15]([OH:20])[OH:16])=[CH:7][C:6]=1[C:8]1[N:9]=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: Fc1ccc(Br)cc1-c1cccnn1
Reactant: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Product: OB(O)c1ccc(F)c(-c2cccnn2)c1

Procedure:
3-(5-Bromo-2-fluorophenyl)pyridazine (304 mg, 1.20 mmol) was reacted with bis(neopentyl glycolato)diboron (298 mg, 1.32 mmol) using the method in Example 51 to give 4-fluoro-3-(pyridazin-3-yl)phenylboronic acid as a white solid: m/z (ES+) 219 (M++H).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:12])[N:4]([CH3:11])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[CH3:8].Br[CH2:14][CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:17]1(=[O:26])[N:16]([CH2:15][CH2:14][NH:1][C:2]2[C:3](=[O:12])[N:4]([CH3:11])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=2[CH3:8])[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]12
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: Cc1c(N)c(=O)n(C)c(=O)n1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1c(NCCN2C(=O)c3ccccc3C2=O)c(=O)n(C)c(=O)n1C

Procedure:
24.7 g. 5-Amino-1,3,6-trimethylpyrimidine-2,4(1H,3H)-dione, 44.5 g. N-(2-bromoethyl)-phthalimide and 30.2 g. potassium carbonate are stirred in 450 ml. acetonitrile for 4 days in an autoclave at 110° to 130° C. The inorganic salts are filtered off with suction and the filtrate is evaporated. The residue is purified over silica gel using ethyl acetate as elution agent. There are obtained 13.7 g. (27% of theory) of the desired product in the form of colorless crystals; m.p. 178°-180° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:12]3[CH:13]=[N:14][C:15]([NH2:17])=[CH:16][C:11]=3[N:10]([C:18]([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)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[Xe](F)[F:38]>C1COCC1>[F:38][C:16]1[C:11]2[N:10]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:9]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)[C:12]=2[CH:13]=[N:14][C:15]=1[NH2:17]
Reactant: F[Xe]F
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3cc(N)ncc23)ccn1
Solvent: C1CCOC1
Product: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3c(F)c(N)ncc23)ccn1
Temperature: 0 °C

Procedure:
A 200 mL round bottom flask was charged with 3-(2-methylpyridin-4-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-amine (0.76 g, 1.625 mmol) and the flask was put under an atmosphere of argon. The reaction was charged with 10 mL THF and the slurry was cooled to 0° C. in an ice bath. Xenon Difluoride (0.056 ml, 1.418 mmol) was added with vigorous stirring in several portions. Then stirring was continued with warming to ambient temperature.
Reaction SMILES: N1C=CC=CC=1N[CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]([CH:22]([CH3:24])[CH3:23])[C:19]([OH:21])=[O:20])[CH:15]=[CH:16][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.OCCC[CH2:48][NH:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][N+:51]=1[O-].N(C(OCC)=O)=NC(OCC)=O>CN(C=O)C>[N:51]1[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=1[NH:49][CH2:48][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]([CH:22]([CH3:23])[CH3:24])[C:19]([OH:21])=[O:20])[CH:15]=[CH:16][CH:17]=1
Reactant: [O-][n+]1ccccc1NCCCCO
Reactant: CC(C)C(C(=O)O)c1cccc(OCCCNc2ccccn2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)C(C(=O)O)c1cccc(OCCCCNc2ccccn2)c1
Reaction time: 1 h
Yield: 50.5 %

Procedure:
To a solution of the product from Example 5, Step 3 (720 mg, 3.24 mmol) in DMF (9 mL) was added triphenylphosphine (850 mg, 3.24 mmol). The reaction solution was kept at ambient temperature for 1 hour and a solution of 2-(4-hydroxybutylamino)pyridine N-oxide (590 mg, 3.24 mmol) and diethyl azodicarboxylate (0.51 mL, 3.24 mmol) in DMF (5 mL) was added. The reaction solution was kept at room temperature for 18 hours and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water. The aqueous solution was back extracted with ethyl acetate. The combined organic solution was washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by chromatography (98:1:1 CH2Cl2:MeOH:NH4OH) to give the desired product, (560 mg, 45% yield).
Reaction SMILES: [CH3:1][C:2]1([NH:6][C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:18][C:17]4([CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]4)[CH2:16]3)[CH2:11][CH2:10]2)=[O:8])[CH2:5][CH2:4][CH2:3]1.[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31]>C(Cl)Cl>[F:33][C:32]([F:35])([F:34])[C:30]([OH:36])=[O:31].[CH2:18]1[C:17]2([CH2:22][CH2:21][NH:20][CH2:19]2)[CH2:16][CH:15]1[N:12]1[CH2:11][CH2:10][CH:9]([C:7]([NH:6][C:2]2([CH3:1])[CH2:5][CH2:4][CH2:3]2)=[O:8])[CH2:14][CH2:13]1
Reactant: CC1(NC(=O)C2CCN(C3CC4(CCN(C(=O)OC(C)(C)C)C4)C3)CC2)CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(NC(=O)C2CCN(C3CC4(CCNC4)C3)CC2)CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 2-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate (0.747 g, 1.84 mmol) was dissolved in DCM (8 mL) and TFA (2 mL) was added. The reaction mixture was stirred at rt overnight under nitrogen, then the solvents were removed in vacuo, to give 1-(6-azaspiro[3.4]oct-2-yl)-N-(1-methylcyclobutyl)piperidine-4-carboxamide trifluoroacetate as a dark yellow oil which was used directly without further purification. The residue was dissolved in DCM (10 mL) and NEt3 (0.56 g, 0.77 mL, 5.52 mmol) and 4-nitrophenyl chloroformate (0.555 g, 2.76 mmol) were added and the reaction mixture was stirred at rt overnight under nitrogen. The solvents were removed in vacuo, and the residue was partitioned between DCM (15 mL) and 1 N NaOH sol. (15 mL). The aqueous layer was extracted with DCM (4×20 mL), dried over MgSO4 and the solvent evaporated. The residue was semi-purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 25 g, 40-63 μm, 60 A, 25 mL per min, gradient 0% to 10% MeOH in DCM]) to give 4-nitrophenyl 2-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate (0.60 g, 69%) as a yellow gum as a mixture of diastereomers.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][C:8]2[N:11]([CH2:24][C@@H:25]3[CH2:27][O:26]3)[N:12]=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[C:7]=2[CH2:6]1)(=[O:4])=[O:3].[CH3:28][N:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]([CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[C:30]1=[O:44]>CCO.ClC(Cl)C>[OH:26][C@H:25]([CH2:24][N:11]1[C:8]2[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][C:7]=2[C:13]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:23])[F:22])=[CH:18][CH:19]=2)=[N:12]1)[CH2:27][N:41]1[CH2:40][CH2:39][CH:38]([N:31]2[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[N:29]([CH3:28])[C:30]2=[O:44])[CH2:43][CH2:42]1
Reactant: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2C[C@@H]2CO2)C1
Reactant: Cn1c(=O)n(C2CCNCC2)c2ccccc21
Solvent: CCO
Solvent: CC(Cl)Cl
Product: Cn1c(=O)n(C2CCN(C[C@H](O)Cn3nc(-c4ccc(C(F)(F)F)cc4)c4c3CCN(S(C)(=O)=O)C4)CC2)c2ccccc21
Yield: 63.4 %

Procedure:
A solution of (R)-5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (134 mg, 0.334 mmol) and 1-methyl-3-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one (110 mg, 0.476 mmol) in EtOH (0.8 mL) and dichloroethane (0.8 mL) was heated to 80° C. for 18 h. The mixture was then concentrated and the residue purified by column chromatography (silica, 0-50% acetone/CH2Cl2) to give the title compound (134 mg, 86%). TLC (20% acetone/CH2Cl2) Rf=0.3. MS (electrospray): calculated for C30H36F3N6O4S, [M +H]+ 633.24; m/z found, 633.3. 1H NMR (CDCl3, 400 MHz): 7.72 and 7.66 (A and B of M′BB′, Jab=8.3 Hz, 4H), 7.15 (dd, J=7.0, 1.7 Hz, 1H ), 7.08 (m, 2H), 6.98 (dd, J=6.6, 1.8 Hz, 1H), 4.60 and 4.55 (A and B of AB, Jab=14.5 Hz, 2H), 4.34 (m, 1H), 4.23 (dd, J=13.8, 2.8 Hz, 1H), 4.15 (m, 1H), 4.23 (dd, J=13.8, 6.6 Hz, 1H), 3.71 (m, 2H), 3.40 (s, 3H), 3.08 (m, 2H), 2.96 (m, 2H), 2.89 (s, 3H), 2.56-2.36 (m, 4H), 2.23 (d, J=11.6 Hz, 1H), 1.81 (m, 2H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])O)[CH2:10][CH2:9]1.[CH3:21][S:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:32]=1[NH:31][CH:30]=[CH:29]2>ClCCl>[CH:8]1([CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[C:29]2[C:28]3[C:32](=[C:24]([CH2:23][S:22][CH3:21])[CH:25]=[CH:26][CH:27]=3)[NH:31][CH:30]=2)[CH2:10][CH2:9]1
Reactant: CSCc1cccc2cc[nH]c12
Reactant: OC(c1ccc(Cl)cc1Cl)C1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSCc1cccc2c(C(c3ccc(Cl)cc3Cl)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.2 ml (2.76 mmol) of trifluoroacetic acid was added to 500 mg (2.30 mmol) of the compound from Example 147A and 408 mg (2.30 mmol) of the compound from Example 8A in 32 ml of dichloromethane, and the mixture was stirred at RT for 30 min. It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 342 mg (35% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[N+:26]([O-:28])=[O:27])=[CH:20][C:19]=1[Cl:29].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:10]([N:4]1[CH2:5][CH:25]([N+:26]([O-:28])=[O:27])[CH:24]([C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[C:19]([Cl:29])[CH:20]=2)[CH2:3]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=[N+]([O-])/C=C/c1ccc(Cl)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
A solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (1.96 g, 8.2 mmol) in CH2Cl2 (10 ml) was added drop wise, over a 30 minutes period, to a stirred solution of 1,2-dichloro-4-((E)-2-nitro-vinyl)-benzene (1.0 g, 4.58 mmol) and trifluoroacetic acid (52 mg, 4.45 mmol) in CH2Cl2 (5 ml) at 0° C. The ice bath was removed, and the solution was stirred at 25° C. for an additional 48 h. It was then concentrated and purification by flash chromatography (SiO2, EtOAc/H 1:4) afforded 1.00 g (62%) of the title compound as a colorless oil. ES-MS m/e: 351.4 (M+H+).
Reaction SMILES: [F:1][CH:2]([F:21])[N:3]1[C:7]([C:8]2[CH:9]=[C:10]3[N:19]([CH3:20])[CH:18]=[CH:17][C:11]3=[N:12][C:13]=2[C@@H:14]([NH2:16])[CH3:15])=[CH:6][CH:5]=[N:4]1.Cl[C:23]1[N:31]=[C:30]([NH2:32])[N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][NH:27]2.C(N(C(C)C)C(C)C)C>C(#N)C>[F:21][CH:2]([F:1])[N:3]1[C:7]([C:8]2[CH:9]=[C:10]3[N:19]([CH3:20])[CH:18]=[CH:17][C:11]3=[N:12][C:13]=2[C@@H:14]([NH:16][C:23]2[N:31]=[C:30]([NH2:32])[N:29]=[C:28]3[C:24]=2[N:25]=[CH:26][NH:27]3)[CH3:15])=[CH:6][CH:5]=[N:4]1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1-c1ccnn1C(F)F
Reactant: Nc1nc(Cl)c2nc[nH]c2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@H](Nc1nc(N)nc2[nH]cnc12)c1nc2ccn(C)c2cc1-c1ccnn1C(F)F
Temperature: 120 °C

Procedure:
(S)-1-(6-(1-(Difluoromethyl)-1H-pyrazol-5-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (172 mg, 0.590 mmol), 6-chloro-9H-purin-2-amine (100 mg, 0.590 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.31 mL, 1.8 mmol) were combined in acetonitrile (6 mL). The reaction mixture was heated in a microwave reactor at 120° C. for 2 hours and then concentrated. The residue was taken up in DMF and was purified by preparative HPLC (acid mode) eluting with 5-20% ACN in water. The fractions containing the desired compound were combined and concentrated in vacuo. The residue was further purified by preparative HPLC (basic mode) eluting with 25-35% ACN in water. The fractions containing the desired product were combined and concentrated in vacuo to give the title compound as a white solid. 1H NMR (500 MHz, CD3OD) δ ppm 1.58 (d, J=6.83 Hz, 3 H), 3.87 (s, 3 H), 5.94-6.01 (m, 1 H), 6.64 (d, J=2.93 Hz, 1 H), 6.87 (d, J=2.44 Hz, 1 H), 7.46-7.76 (m, 2 H), 7.93 (s, 1 H), 8.18 (s, 1 H); ESI-MS m/z [M+H]+ calc'd for C19H18F2N10, 425; found 425.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH3:14])[CH2:8][N:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:38]=[CH:37][C:26]([C:27]([NH:29][CH:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[O:28])=[CH:25][C:24]=1[O:39][CH3:40].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH3:12][N:11]1[C:10](=[O:13])[CH:9]([CH3:14])[CH2:8][N:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6]2[N:21]=[C:2]([NH:22][C:23]3[CH:38]=[CH:37][C:26]([C:27]([NH:29][CH:30]4[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]4)=[O:28])=[CH:25][C:24]=3[O:39][CH3:40])[N:3]=[CH:4][C:5]1=2
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Reactant: CC1CN(c2ccccc2)c2nc(Cl)ncc2N(C)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(c1ccccc1)CC(C)C(=O)N2C
Yield: 60.2 %

Procedure:
A solution of 0.050 g (0.000165 mole) of (rac)-2-chloro-5,7-dimethyl-9-phenyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-51), 0.043 g (0.000165 mole) of 4-amino-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide, 0.049 (0.00025 mole) of p-toluenesulfonic acid monohydrate and 4.0 mL of 2-propanol (4.0 mL) was heated at 180 degrees for 2 hours in a microwave reactor. The cooled reaction mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane and washed twice with saturated sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (100:0-75:25), to give 0.0526 g of (rac)-4-(5,7-dimethyl-6-oxo-9-phenyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-51) as white powder. HRMS (ES+) m/z Calcd for C29H35N7O3+H [(M+H)+]: 530.2874. Found: 530.2870.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[P:6]([OH:8])[OH:7].[CH2:9](N(CC)CC)[CH3:10].ClC(OCC)=O>ClCCl>[CH2:9]([O:7][P:6]([CH:2]1[CH2:3][CH2:4][CH2:5][O:1]1)[OH:8])[CH3:10]
Reactant: OP(O)C1CCCO1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Solvent: ClCCl
Product: CCOP(O)C1CCCO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2.6 g of P-tetrahydrofuran-2-yl-phosphonous acid in 20 ml of anhydrous dichloromethane is cooled to 5° under inert gas and treated with 2.03 g of triethylamine. A dichloromethane solution of 2.17 g of ethyl chloroformate is added dropwise whereupon an exothermic reaction and a gas evolution ensues. The suspension is warmed to room temperature and stirred for 3 hours. The reaction mixture is then diluted with dichloromethane and washed with water. Drying of the organic phase with anhydrous magnesium sulphate and removal of the solvent in vacuo affords P-tetrahydrofuran-2-yl phosphonous acid ethyl ester, b.p. 90°/8×10-2 mbar.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[P:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:21]([N:26]=[N+]=[N-])(=[O:25])[O:22][CH2:23][CH3:24]>CCOCC>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[P:8](=[N:26][C:21](=[O:25])[O:22][CH2:23][CH3:24])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1ccccc1P(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)N=[N+]=[N-]
Solvent: CCOCC
Product: CCOC(=O)N=P(c1ccccc1)(c1ccccc1)c1ccccc1C
Reaction time: 48 h

Procedure:
A solution of 1.0 g of (2-methylphenyl)diphenylphosphine in 30 ml of ether was treated with 4 ml of 1M ethyl carbonazidate in ether. The mixture was allowed to stand 48 hours, then repeatedly concentrated and finally treated with fresh ether and refrigerated, giving 930 mg of the desired compound, mp 113°-114° C.
Reaction SMILES: C(Cl)Cl.[Cl:4][C:5]1[S:9][C:8]([S:10](NN)(=[O:12])=[O:11])=[CH:7][CH:6]=1.[Br:15]Br>CCCCCC>[Cl:4][C:5]1[S:9][C:8]([S:10]([Br:15])(=[O:12])=[O:11])=[CH:7][CH:6]=1
Reactant: NNS(=O)(=O)c1ccc(Cl)s1
Reactant: BrBr
Solvent: ClCCl
Solvent: CCCCCC
Product: O=S(=O)(Br)c1ccc(Cl)s1
Temperature: 2 °C
Yield: 50.2 %

Procedure:
In a 1-liter, three-neck flask equipped with a magnetic stirrer, a thermometer, an an addition funnel were placed 300 ml of methylene chloride, 10.63 g (0.05 mol) of 5-chloro-2-thiophenesulfonyl hydrazine, and some crushed ice. The slurry was allowed to cool to 2° C., and 16.0 g (0.10 mol) of bromine was added dropwise with stirring at such a rate that the temperature did not exceed 10° C. After the addition was complete, the methylene chloride layer was separated, dried and the methylene chloride removed in vacuo, leaving a yellow-orange oil. The oil was dissolved in hexane and the resulting solution cooled to give 6.56 g of the title compound as slightly yellow crystals, mp 35°-37°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][NH2:11].[O:12](C(OC(C)(C)C)=O)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][NH:11][C:13](=[O:12])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COc1ccc(Br)c(CN)c1
Solvent: ClCCl
Product: COc1ccc(Br)c(CNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
To a solution of 1-(2-bromo-5-methoxyphenyl)methanamine (3.2 mmol) in DCM (15 mL) was added BOC2O (3.2 mmol). The reaction mixture was allowed to stir at rt overnight and then concentrated. The residue was purified by column chromatography to give tert-butyl (2-bromo-5-methoxybenzyl)carbamate (3.1 mmol, 95%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[C:23]1[NH:27][C:26]2[CH:28]=[C:29]([C:31]([O:33][CH3:34])=[O:32])[S:30][C:25]=2[CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH:38]1[CH2:43][CH2:42][CH2:41][CH:40]=[CH:39]1.C(OCC)(=O)C>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[C:23]1[NH:27][C:26]2[CH:28]=[C:29]([C:31]([O:33][CH3:34])=[O:32])[S:30][C:25]=2[C:24]=1[CH:43]1[CH2:42][CH2:41][CH2:40][CH:39]=[CH:38]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc2[nH]c(-c3ccc(OCc4ccccc4)cc3OCc3ccccc3)cc2s1
Reactant: BrC1C=CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2[nH]c(-c3ccc(OCc4ccccc4)cc3OCc3ccccc3)c(C3C=CCCC3)c2s1
Reaction time: 0.33 h
Yield: 84.7 %

Procedure:
To a solution of methyl 5-(2,4-bisbenzyloxyphenyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate (1.36 g, 2.90 mmol) in N,N-dimethylformamide (15 ml) was added sodium hydride (60% in oil, 127 mg, 3.19 mmol) under ice-cooling and the mixture was stirred for 20 min. 3-Bromocyclohexene (0.34 ml, 2.95 mmol) was added and the mixture was stirred under ice-cooling for 50 min. Ethyl acetate (20 ml) was added to the reaction mixture, and the organic layer was washed successively with water (20 ml×3) and saturated brine (10 ml) and dried over sodium sulfate. After filtration and concentration, a mixed solvent (10 ml) of hexane:ethyl acetate (10:1) was added. The precipitated solid was collected by filtration. The solid was washed with a mixed solvent (5 ml×3) of hexane:ethyl acetate (10:1), and dried under reduced pressure to give methyl 5-(2,4-bisbenzyloxyphenyl)-6-(cyclohex-2-enyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate (1.35 g, yield 85%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[Li]CCCC.[B:19](OC(C)C)([O:24]C(C)C)[O:20]C(C)C>C1COCC1.CCCCCC>[F:13][C:2]([F:1])([F:12])[C:3]1[C:8]2[S:9][C:10]([B:19]([OH:24])[OH:20])=[CH:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1cccc2ccsc12
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1cc2cccc(C(F)(F)F)c2s1
Temperature: -30 °C
Reaction time: 0.17 h

Procedure:
To a solution of 7-trifluoromethyl-benzo[b]thiophene (0.52 g, 0.0026 mol) in THF (30 mL) at −78° C. was added 2.5 M of n-BuLi in hexane (1.4 mL). The reaction was then slowly warmed up to −30° C. over 30 min. and stirred at this temperature for 10 min prior to recooling to −78° C. and treatment with triisopropyl borate (0.7255 g, 0.0038 mol). The reaction was then slowly warmed up to 0° C. then was quenched with saturated ammonium chloride and the solvent removed in vacuo. To the residue was added aqueous sodium hydroxide (10 mL, 2N solution) followed by water (30 mL) then this mixture was extracted with DCM. The aqueous solution was acidified using dilute sulfuric acid (2N solution), filtered and the residue dried in vacuo to yield 7-trifluoromethylbenzo[b]thiophen-2-boronic acid. 1H NMR (400 MHz, MeOD) δ ppm 7.55 (1H, t, J=7.45 Hz), 7.75 (1H, d, J=7.07 Hz), 8.02 (1H, s) and 8.17 (1H, d, J=−7.83 Hz).