Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]([O:10][CH3:11])[C:4](=[O:9])/[CH:5]=[CH:6]\[CH2:7][CH3:8].[I-].[Na+]>C(O)(=O)C>[CH3:11][O:10][CH:3]([O:2][CH3:1])[C:4](=[O:9])/[CH:5]=[CH:6]/[CH2:7][CH3:8]
Reactant: CC/C=C\C(=O)C(OC)OC
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC/C=C/C(=O)C(OC)OC

Procedure:
The crude product produced in Example V is dissolved in 6 ml of acetic acid with 0.1 g of sodium iodide. By GLC on Carbowax(polyethylene glycol) it is clear that the 1,1-dimethoxy-cis-3-hexene-2-one is converted to a new material of later retention time. After one-half hour less than 5 percent of "cis" material remains.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=3)[CH:3]=[CH:2]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1ccc2ccn(S(=O)(=O)c3ccc(C)cc3)c2c1
Yield: 99.3 %

Procedure:
A solution of methyl indole-6-carboxylate (15.0 g) in 2-butanone (214 ml) was treated with 4-methylbenzenesulfonylchloride (33 g) and potassium carbonate (47.0 g) and heated to reflux under a nitrogen atmosphere for 18 hours. The hot reaction mixture was filtered, and the filtrate was evaporated to give a solid which was triturated with ether to give methyl 1-(4-methylphenylsulfonyl)indole-6-carboxylate (28.0 g, 99%) as an ivory solid NMR (80 MHz, CDC3): 2.33(s, 3H, ArCH3), 3.95(s, 3H, OCH3), 6.67(dd, 1H, H3-indole), 7.16-7.98(7H, m, Ar), 8.7(m, 1H, H7 -indole)
Reaction SMILES: [F:1][C:2]([F:30])([C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([CH3:27])([CH3:26])[CH2:21][CH2:20][C:19]2([CH3:29])[CH3:28])[C:3]([NH:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11]C)=[O:10])=[O:4].O.[OH-].[K+]>CO>[F:1][C:2]([F:30])([C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([CH3:26])([CH3:27])[CH2:21][CH2:20][C:19]2([CH3:29])[CH3:28])[C:3]([NH:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([OH:11])=[O:10])=[O:4]
Reactant: COC(=O)c1cccc(NC(=O)C(F)(F)c2ccc3c(c2)C(C)(C)CCC3(C)C)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(C(F)(F)C(=O)Nc3cccc(C(=O)O)c3)ccc21
Temperature: 70 °C
Yield: 84 %

Procedure:
Methyl 3-(2,2-difluoro-2-(1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalen-6-yl)acetamido)benzoate 19 (0.50 g, 1.20 mmol) was dissolved in methanol (33.5 mL). Water (3.35 mL) was added via syringe at RT and KOH (0.27 g, 4.81 mmol) was added. The reaction mixture was heated at 70° C. for 2 h. After cooling to RT the mixture was evaporated in vacuo. The crude product was dissolved in water (30 mL) and extracted with ether (2×50 mL). The aqueous layer was acidified by a solution of HCl 1M to about pH=1. The aqueous layer was extracted with ether (2×100 mL), dried over MgSO4, filtered and evaporated. The crude product was purified by column chromatography using as eluent cyclohexane: EtOAc=98:02. 3-(2,2-Difluoro-2-(1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalen-6-yl)acetamido)benzoic acid 20 was obtained (0.41 g, 84% yield) as an orange solid.
Reaction SMILES: [CH3:1][C:2](=[CH2:5])[CH2:3][OH:4].[H-].[Na+].[CH2:8]([O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C=O)C>[CH2:8]([O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][O:4][CH2:3][C:2]([CH3:5])=[CH2:1])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: C=C(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(C)COCc1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.3 %

Procedure:
A solution of 2-methyl-2-propen-1-ol (120) (1.17 mL, 13.9 mmol) in anhydrous DMF (5 mL, then 2×1 mL to rinse) was added to a suspension of 60% NaH (674 mg, 16.9 mmol) in anhydrous DMF (5 mL) under N2 at 0° C. and the mixture was stirred at 0° C. for 30 min. A solution of 4-(benzyloxy)benzyl chloride (3.87 g, 16.6 mmol) in anhydrous DMF (6 mL, then 2×2 mL to rinse) was added and the mixture was stirred at room temperature for 16 h. The resulting mixture was added to ice/aqueous NaHCO3 (100 mL) and extracted with EtOAc (4×100 mL). The extracts were washed with water (100 mL), the EtOAc was removed, and the residual oil was chromatographed on silica gel. Elution with petroleum ether firstly gave foreruns, then further elution with 0-25% CH2Cl2/petroleum ether gave 1-(benzyloxy)-4-{[(2-methyl-2-propenyl)oxy]methyl}benzene (122) (reported by Wennerberg et al., 1999 via alkylation of 4-(benzyloxy)benzyl alcohol) (3.48 g, 93%) as an oil that was used directly in the next step; 1H NMR (CDCl3) δ 7.45-7.28 (m, 5H), 7.27 (dt, J=8.5, 2.4 Hz, 2H), 6.95 (dt, J=8.7, 2.4 Hz, 2H), 5.07 (s, 2H), 4.99 (m, 1H), 4.91 (m, 1H), 4.42 (s, 2H), 3.91 (s, 2H), 1.76 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH3:28])[C:25](O)=O)=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:16]([O:20][C:21](=[O:22])[NH:23][C@H:24]([C:25]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=2[N:8]=1)[CH3:28])([CH3:19])([CH3:18])[CH3:17]
Reactant: Nc1ccc(F)cc1Nc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 57.4 %

Procedure:
A mixture of 4-fluoro-N2-phenylbenzene-1,2-diamine (1.19 g, 5.88 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (1.22 g, 6.47 mmol), HOAt (881 mg, 6.47 mmol), 4-methylmorpholine (1.42 mL, 12.95 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.24 g, 6.47 mmol) in DCM (30 mL) was stirred at RT for 21 h. The reaction mixture was then partitioned between additional DCM and an aqueous solution of NaHCO3. The organic layer was dried and concentrated in vacuo and the resulting residue (2.40 g) was dissolved in AcOH (50 mL) and stirred for 48 h at 60° C. After cooling to RT, volatiles were evaporated under reduced pressure and the residue was partitioned between EtOAc and a saturated solution of NaHCO3. The organic layer was washed with brine, dried (Na2SO4) and then concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-50% EtOAc in DCM) affording [(S)-1-(6-Fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tertbutyl ester as a yellow foam (1.20 g, 57%). LCMS: RT 3.50 min [M+H]+ 356.2
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:26]=[CH:25][C:11]([CH2:12][N:13]3[C:17]4[N:18]=[C:19]([S:23][CH3:24])[NH:20][C:21](=[O:22])[C:16]=4[CH:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:31]I>COCCOC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:26]=[CH:25][C:11]([CH2:12][N:13]3[C:17]4[N:18]=[C:19]([S:23][CH3:24])[N:20]([CH3:31])[C:21](=[O:22])[C:16]=4[CH:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CI
Reactant: CSc1nc2c(ccn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c(=O)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CSc1nc2c(ccn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c(=O)n1C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 35.4 %

Procedure:
Under argon gas, 7-[4-(4-chlorobenzoyl)benzyl]-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (82 mg) was dissolved in anhydrous DME (10 ml)-anhydrous DMF (4 ml). Then, 60% sodium hydride-oil (9.6 mg) was added with ice-cooling and, after 30 minutes of agitation, methyl iodide (34 mg) was added. Then, at room temperature, the mixture was stirred for 2.5 hours. This reaction mixture was diluted with ethyl acetate, washed with saturated aqueous NaCl solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by flash column chromatography (hexane: ethyl acetate=4:1) to provide the title compound (30 mg). 1H-NMR (CDCl3) δ: 2.58(3H,s), 3.60(3H,s), 5.37(2H,s), 6.67(1H,d,J=3.4Hz), 6.75(1H,d,J=3.4Hz), 7.30(2H,d,J=8.OHz), 7.45(2H,d,J=8.6Hz), 7.73(2H,d,J=8.6Hz), 7.74(2H,d,J=8.OHz).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[CH2:26]([NH2:30])[C@H:27]([NH2:29])[CH3:28]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:30][CH2:26][C@H:27]([NH2:29])[CH3:28])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: C[C@@H](N)CN
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC[C@@H](C)N)c2c1

Procedure:
The title compound was prepared in analogy to Example 5-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and (2R)-propane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 411, 1H NMR (400 MHz, CD3OD) δ ppm 7.97 (d, J=7.83 Hz, 1 H), 7.82 (d, J=7.58 Hz, 1 H), 7.70-7.55 (m, 2 H), 7.46-7.37 (m, 2 H), 7.33-7.22 (m, 2 H), 6.10-5.99 (m, 1 H), 5.13 (brs, 2 H), 3.65-3.52 (m, 3 H), 3.37 (m, 2 H), 3.31-3.20 (m, 2 H), 2.41 (s, 3 H), 1.32-1.22 (m, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:14]([OH:16])=O)=[C:8]([CH3:13])[N:9]2[CH3:12])=[CH:5][CH:4]=1.O=S(Cl)Cl.[CH:21]1([CH2:24][NH2:25])[CH2:23][CH2:22]1>>[CH:21]1([CH2:24][NH:25][C:14]([C:7]2[C:6]3[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:9]([CH3:12])[C:8]=2[CH3:13])=[O:16])[CH2:23][CH2:22]1
Reactant: COc1ccc2c(C(=O)O)c(C)n(C)c2c1
Reactant: NCC1CC1
Solvent: O=S(Cl)Cl
Product: COc1ccc2c(C(=O)NCC3CC3)c(C)n(C)c2c1
Yield: 38.4 %

Procedure:
This material was prepared from 6-methoxy-1,2-dimethyl-1H-indole-3-carboxylic acid 16c (0.80, 3.65 mmole) with SOCl2 (0.799 ml, 10.95 mmole) and cyclopropylmethylamine (0.38 ml, 4.38 mmole) in a manner as previously described for example 9d to give a pale yellow solid (0.382 g, 38%). 1H NMR (300 MHz, CD3OD) δ7.50 (1H, d, J=8.7 Hz), 6.81 (1H, d, J=2.2 Hz), 6.69 (1H, dd, J=2.2, 8.7 Hz), 3.74 (3H, s), 3.56 (3H, s), 3.20 (2H, m), 2.50 (3H, m), 1.07 (1H, m), 0.44 (2H, m), 0.21 (2H, m); ESIMS (MH+): 273.10.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[N:5]([CH2:9][C@@H:10]2[C@H:13]([NH:14][C:15](=[O:31])/[C:16](=[N:23]\[O:24][C:25]([CH3:30])([CH3:29])[C:26]([OH:28])=[O:27])/[C:17]3[N:18]=[C:19]([NH2:22])[S:20][CH:21]=3)[C:12](=[O:32])[N:11]2[S:33]([OH:36])(=[O:35])=[O:34])[CH2:4]1.Cl.[N:38]1([C:43](N)=[NH:44])C=CC=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:22][C:19]1[S:20][CH:21]=[C:17](/[C:16](=[N:23]/[O:24][C:25]([CH3:29])([CH3:30])[C:26]([OH:28])=[O:27])/[C:15]([NH:14][C@@H:13]2[C:12](=[O:32])[N:11]([S:33]([OH:36])(=[O:34])=[O:35])[C@@H:10]2[CH2:9][N:5]2[CH2:4][C@@H:3]([CH2:2][NH:1][C:43]([NH2:44])=[NH:38])[O:7][C:6]2=[O:8])=[O:31])[N:18]=1
Reactant: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1CN1C[C@@H](CN)OC1=O)c1csc(N)n1)C(=O)O
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1CN1C[C@@H](CNC(=N)N)OC1=O)c1csc(N)n1)C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 53.8 %

Procedure:
To a solution of 2-(((Z)-(2-(((2R,3S)-2-(((R)-5-(aminomethyl)-2-oxooxazolidin-3-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-1-(2-aminothiazol-4-yl)-2-oxoethylidene)amino)oxy)-2-methylpropanoic acid (30.1 mg, 0.055 mmol) and Pyrazole-1-carboxamidine hydrochloride (16.1 mg, 0.110 mmol) in DMF (548 μl) was added DIPEA (38.3 μl, 0.219 mmol). After 5 h of stirring at rt, the solution was concentrated in vacuo and purified by reverse phase prep HPLC (XSelect CSH, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min), affording the title compound (17.5 mg, 49%) as a white powder. LCMS: Rt=0.30 min, m/z=592.2 (M+1) Method 2m_acidic; 1H NMR (400 MHz, D2O) δ 6.97 (s, 1H), 5.31 (d, J=5.9 Hz, 1H), 4.74 (dtd, J=9.3, 5.9, 3.2 Hz, 1H), 4.55 (ddd, J=9.2, 5.9, 3.1 Hz, 1H), 3.86 (t, J=9.3 Hz, 1H), 3.66 (dd, J=15.0, 9.5 Hz, 1H), 3.53 (dd, J=15.5, 3.2 Hz, 1H), 3.47-3.34 (m, 3H), 1.39 (s, 3H), 1.37 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[CH:16]=[CH:15][S:14][C:13]=1Br)=[O:11].[C:18](=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:18][C:15]1[S:14][C:13]2[O:1][C:2]3[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=3[NH:9][C:10](=[O:11])[C:12]=2[CH:16]=1
Reactant: Cc1ccc(NC(=O)c2ccsc2Br)c(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc2c(c1)Oc1sc(C)cc1C(=O)N2
Temperature: 145 °C
Reaction time: 1 h
Yield: 44.9 %

Procedure:
To a solution of N-(2-hydroxy-4-methylphenyl)-2-bromo-3-thiophenecarboxamide (3.4 g) in dimethyl sulfoxide (30 ml) was added potassium carbonate (2.9 g) and the mixture was stirred at 140-150° C. for 1 hour. The reaction system was cooled to room temperature and the reaction mixture was poured into water. The precipitated crystals were collected by filtration, washed with water and purified by silica gel column chromatography (chloroform) to give 2, 8-dimethylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one (1.2 g).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[CH2:9](B(O)O)[CH2:10][CH3:11]>>[CH2:9]([C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1)[CH2:10][CH3:11]
Reactant: CCCB(O)O
Reactant: O=Cc1ccc(Br)s1
Product: CCCc1ccc(C=O)s1
Yield: 28.7 %

Procedure:
The compound was synthesized as in Example 3.1 using 5-bromothiophene-2-carbaldehyde (250 mg, 1.31 mmol) in place of 5-bromo-2-formylfuran and propylboronic acid (190 mg, 2.16 mmol) in place of hexylboronic acid to give 5-propylthiophene-2-carbaldehyde (58 mg, 29%). Used without further characterization.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:13](=[O:14])[NH:12][C:10](=[O:11])[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>CC(C)=O>[C:1]1([NH:7][C:8]2[C:13](=[O:14])[N:12]([C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10](=[O:11])[CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C1C=C(Nc2ccccc2)C(=O)N1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=C1C=C(Nc2ccccc2)C(=O)N1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
1.88 g. (0.01 mole) of 3-phenylamino-maleinimide are dissolved in 70 ml. of acetone under stirring. To this mixture 2.1 g. (0.015 mole) of benzoyl chloride and 1.51 g. (0.015 mole) of triethylamine are added dropwise under simultaneous stirring. The temperature is maintained at 25°-30° C. during the addition. The mixture is then stirred for 2.5 hours at room temperature and heated for 1.5 hours. The mixture is allowed to stand overnight. The product is precipitating together with triethylaminechlorohydrate. The crystalline mixture is filtered and washed with 2×10 ml. of water. After drying a yellow crystalline product is obtained, which can be recrystallized from chloroform or acetone, if desired. 3-Phenylamino-N-benzoyl-maleinimide is obtained.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](O)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:25][C:26]1[CH:27]=[CH:28][C:29]2[N:33]=[C:32]([CH2:34][OH:35])[NH:31][C:30]=2[CH:36]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21]([NH:25][C:26]4[CH:27]=[CH:28][C:29]5[N:33]=[C:32]([CH2:34][OH:35])[NH:31][C:30]=5[CH:36]=4)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Nc1ccc2nc(CO)[nH]c2c1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc5nc(CO)[nH]c5c4)nn23)c1

Procedure:
N-tert-Butyl-3-[2-(2-hydroxymethyl-3H-benzoimidazol-5-ylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-benzenesulfonamide was prepared from N-tert-butyl-3-(2-hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide and (6-amino-1H-benzoimidazol-2-yl)-methanol; dihydrochloride in an analogous manner to Example 1052a. Product isolated as a yellow foam (37 mg, 26%). LCMS (m/e) 492 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 10.71 (bs, 1H), 9.00 (s, 1H), 8.68 (s, 1H), 8.17 (s, 1H), 7.90 (d, 1H, J=7.8 Hz), 7.83 (d, 1H, J=7.5 Hz), 7.65-7.54 (m, 1H), 7.44 (d, 1H, J=8.4 Hz), 7.08 (s, 1H), 6.96 (d, 1H, J=4.6 Hz), 6.82 (d, 1H, J=4.7 Hz), 6.73 (bs, 1H), 5.92 (bs, 1H), 4.89 (s, 2H), 2.62 (s, 1H), 1.24 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:10])[CH:5]=[N:6][C:7]=1[O:8][CH3:9].[CH3:11][O:12][C:13]1[CH:49]=[CH:48][C:16]([CH2:17][N:18]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:19]2[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([C:26]3[CH:27]=[C:28]([CH:33]([OH:38])[C:34]([F:37])([F:36])[F:35])[CH:29]=[N:30][C:31]=3F)[N:20]=2)=[CH:15][CH:14]=1.C1COCC1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][N:18]([CH2:39][C:40]2[CH:41]=[CH:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=2)[C:19]2[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([C:26]3[CH:27]=[C:28]([CH:33]([OH:38])[C:34]([F:35])([F:36])[F:37])[CH:29]=[N:30][C:31]=3[NH:10][C:4]3[CH:5]=[N:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=3)[N:20]=2)=[CH:48][CH:49]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(O)C(F)(F)F)cnc3F)n2)cc1
Reactant: COc1ncc(N)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(O)C(F)(F)F)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
To a stirred mixture of 5-fluoro-6-methoxypyridin-3-amine (2.427 g, 17.07 mmol) and 1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoropyridin-3-yl)-2,2,2-trifluoroethanol (4.64 g, 8.54 mmol) in THF (50.00 mL, 610 mmol) was added LiHMDS (1.0 M in THF, Aldrich; 42.7 mL, 42.7 mmol) dropwise at −10° C. and the mixture was stirred at the same temperature for 30 min. The reaction was quenched with water and saturated NH4Cl(aq)(25 mL each) and diluted with EtOAc (25 mL). The separated aqueous layer was extracted with ethyl acetate (2×50 mL) and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give a crude residue which was purified by flash column chromatography (ISCO Combiflash system, 0% to 50% ethyl acetate in hexanes) to obtain the desired product 1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-2,2,2-trifluoroethanol (5.1428 g, 7.73 mmol, 91% yield) as a brown foam.
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1>[C:1]1([C:7]2([C:13]3[CH:14]=[CH:15][C:16]([O:19][C:20](=[O:22])[CH3:21])=[CH:17][CH:18]=3)[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccc(C2(c3ccccc3)CCCCO2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C2(c3ccccc3)CCCCO2)cc1
Temperature: 25 °C

Procedure:
4-(2-Phenyl-tetrahydro-pyran-2-yl)-phenol (500 mg, 2 mmol) was dissolved in pyridine (10 mL). Acetic anhydride (1 mL) was added at drop wise at 0° C. The reaction temperature was allowed to raise to room temperature. After 1 h the reaction was quenched the addition of water (5 mL). Dichloromethane (20 mL) was added. The organic phase was washed with aqueous HCl (1M, 2×10 mL), brine (10 mL), dried (Na2SO4) and concentrated in vacuo. Purified on a short column (eluent: dichloromethane). Yield: 560 mg.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C@H:11]([C:14]([OH:16])=[O:15])[CH2:12][OH:13])=[O:9])([CH3:6])([CH3:5])[CH3:4].I[CH2:18][C:19]1[CH:20]=[C:21]([CH:28]=[CH:29][CH:30]=1)[C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23].Cl>CN(C=O)C>[CH2:25]([O:24][C:22]([C:21]1[CH:20]=[C:19]([CH:30]=[CH:29][CH:28]=1)[CH2:18][O:13][CH2:12][C@@H:11]([C:14]([OH:16])=[O:15])[NH:10][C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])=[O:23])[CH:26]=[CH2:27]
Reactant: C=CCOC(=O)c1cccc(CI)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1cccc(COC[C@H](NC(=O)OC(C)(C)C)C(=O)O)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Sodium hydride (19.4 g, 60% in mineral oil, 484.4 mmol) is washed with dry hexanes (2×30 mL) to remove the mineral oil and then suspended in anhydrous DMF (330 mL). To this suspension a solution of N-(t-butoxycarbonyl)-L-serine (45.2 g, 220.2 mmol) in DMF (110 mL) at 0° C. is added dropwise with vigorous stirring. The mixture is stirred for an additional 5 minutes at 0° C., and then at room temperature for 30 minutes. The solution is cooled back to 0° C., and a solution of allyl 3-iodomethylbenzoate (66.6 g, 220.2 mmol) in DMF (110 mL) is added dropwise over 15 minutes. The mixture is then warmed to room temperature for 30 minutes. The reaction mixture is poured into ice water (2.2 L) and acidified to pH 2 with 1 N HCl (270 mL). The mixture is extracted with ether (1×600 mL, then 3×300 mL) and the combined ether extracts are then washed with water (5×200 ml) and then dried (MgSO4) and evaporated in vacuo to yield O-[3-(allyloxycarbonyl)-benzyl]-N-(t-butoxycarbonyl)-L-serine as a yellowish oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][CH:10]=1)=[O:4].O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:25]1[C:26]([CH3:48])=[C:27]([C:34]([C:36]2[CH:37]=[C:38]3[C:43](=[CH:44][CH:45]=2)[N:42]=[C:41]([CH3:46])[NH:40][C:39]3=[O:47])=[O:35])[N:28]2[C:33]=1[CH:32]=[CH:31][CH:30]=[CH:29]2>O.CN(C=O)C.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>[CH3:48][C:26]1[C:25]([C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=2)[C:3]([O:2][CH3:1])=[O:4])=[C:33]2[N:28]([C:27]=1[C:34]([C:36]1[CH:37]=[C:38]3[C:43](=[CH:44][CH:45]=1)[N:42]=[C:41]([CH3:46])[NH:40][C:39]3=[O:47])=[O:35])[CH:29]=[CH:30][CH:31]=[CH:32]2
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: Cc1nc2ccc(C(=O)c3c(C)c(Br)c4ccccn34)cc2c(=O)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2c(C)c(C(=O)c3ccc4nc(C)[nH]c(=O)c4c3)n3ccccc23)c1
Temperature: 150 °C
Yield: 58.6 %

Procedure:
0.139 g (0.78 mmol) of [3-(methoxycarbonyl)phenyl]boronic acid, 0.321 g (1.29 mmol) of potassium phosphate dihydrate dissolved in 0.81 ml of water, and 0.0149 g (0.01 mmol) of tetrakis(triphenylphosphine)palladium are added, under an argon atmosphere at ambient temperature, to 0.256 g (0.65 mmol) of 6-[(1-bromo-2-methylindolizin-3-yl)carbonyl]-2-methylquinazolin-4(3H)-one in 9 ml of DMF. The reaction medium is microwave-heated at 150° C. for 15 minutes. After dilution with ethyl acetate, the organic phase is washed with a 1N aqueous solution of hydrochloric acid and then a saturated aqueous solution of sodium chloride, dried over sodium sulphate, filtered, and then concentrated under reduced pressure. The solid obtained is purified by silica gel column chromatography, elution being carried out with a dichloromethane/methanol (95/2) mixture. 172 mg of a yellow solid are obtained.