Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[N:4]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([NH:33][CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])=[O:32])=[CH:27][CH:26]=1>>[CH:18]1([CH:2]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]([NH:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:32])=[CH:29][CH:30]=2)[C:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[N:4]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: ClC(c1nn(C2CCCCC2)c2ccccc12)C1CCCCC1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Product: O=C(O)CCNC(=O)c1ccc(NC(c2nn(C3CCCCC3)c3ccccc23)C2CCCCC2)cc1
Yield: 72.6 %

Procedure:
Using 3-[chloro(cyclohexyl)methyl]-1-cyclohexyl-1H-indazole (400 mg) synthesized in Example A18(4) and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (286 mg) synthesized in Example 1(2) and in the same manner as in Example A7(3), the title object compound (441 mg, 72%) was obtained as a white solid.
Reaction SMILES: [OH:1][C:2]([CH3:27])([CH:9]=[CH:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)[CH2:3][C:4]([O:6]CC)=[O:5].[OH-].[Na+].[Br:30]Br.C(=O)([O-])O.[Na+]>CO>[OH:1][C:2]1([CH3:27])[CH:9]([Br:30])[CH:10]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)[O:6][C:4](=[O:5])[CH2:3]1
Reactant: BrBr
Reactant: CCOC(=O)CC(C)(O)C=CCCc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(O)CC(=O)OC(CCc2ccc(OCc3ccccc3)cc2)C1Br
Yield: 52.9 %

Procedure:
The carboxylic acid (22.4 g) prepared by hydrolyzing 29.6 g of ethyl 3-hydroxy-3-methyl-7-(p-benzyloxyphenyl)-4-heptenoate with 80 ml of 4 N sodium hydroxide solution in 500 ml of methanol, was treated with 9.73 g of bromine in an aqueous sodium hydrogen carbonate solution and the reaction mixture was worked up according to the method described in Example 1 (b). The product was recrystallized from a mixture of n-hexane and acetone (10:1) to yield 13.5 g of the desired compound melting at 155°-160° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=O)[CH3:10])=[CH:4][C:3]=1[S:12]([CH3:15])(=[O:14])=[O:13].BrBr.BrC(C1C=CC(S(C)(=O)=O)=C(F)C=1)C(=O)C.[CH3:34][O:35][C:36]1[N:41]=[CH:40][C:39]([NH:42][C:43]([NH2:45])=[S:44])=[CH:38][CH:37]=1>O1CCOCC1.C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:44][C:43]([NH:42][C:39]3[CH:40]=[N:41][C:36]([O:35][CH3:34])=[CH:37][CH:38]=3)=[N:45][C:9]=2[CH3:10])=[CH:4][C:3]=1[S:12]([CH3:15])(=[O:14])=[O:13]
Reactant: CC(=O)Cc1ccc(Cl)c(S(C)(=O)=O)c1
Reactant: COc1ccc(NC(N)=S)cn1
Agent: BrBr
Agent: CC(=O)C(Br)c1ccc(S(C)(=O)=O)c(F)c1
Solvent: CCO
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc(C)c(-c3ccc(Cl)c(S(C)(=O)=O)c3)s2)cn1
Temperature: 10 °C
Reaction time: 0.25 h

Procedure:
1-(4-chloro-3-methanesulfonyl-phenyl)-propan-2-one (32b) (0.23 g, 1 mmol) is dissolved in dioxan (10 ml) and the solution is cooled to 10° C. at which point the mixture is semi-frozen. Bromine (0.045 ml, 0.8 mmol, 0.8 eq.) is added slowly and the mixture is stirred for an additional 15 minutes in a semi frozen state. The mixture is then allowed to warm to room temperature and the solvent is removed to give a brown oil containing starting material and 1-bromo-1-(3-fluoro-4-methanesulfonyl-phenyl)-propan-2-one. This material is dissolved in ethanol (10 ml). (6-Methoxy-pyridine-3-yl)-thiourea (0.183 g, 1 mmol) is added in one portion. The mixture is stirred at 60° C. for 30 minutes then allowed to cool whereupon the product crystallised. Filtration affords the titled compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])=[O:15])[C:10]([OH:12])=O)[CH:6]=[CH:7][CH:8]=1.[Cl:24][C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][C:34]=1[O:35][CH2:36][C@@H:37]([NH:39][CH3:40])[CH3:38])[C:28]([O:30][CH3:31])=[O:29].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O>[Cl:24][C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][C:34]=1[O:35][CH2:36][C@@H:37]([N:39]([CH3:40])[C:10](=[O:12])[CH:9]([NH:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])=[O:15])[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:38])[C:28]([O:30][CH3:31])=[O:29]
Reactant: CN[C@@H](C)COc1ccc(C(=O)OC)cc1Cl
Reactant: COc1cccc(C(NC(=O)Nc2ccccc2F)C(=O)O)c1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC[C@H](C)N(C)C(=O)C(NC(=O)Nc2ccccc2F)c2cccc(OC)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.2 %

Procedure:
A mixture of 3-methoxy-[N′-(2-fluorophenyl)ureido]phenylacetic acid (296 mg, 0.93 mmol), methyl (S)-3-chloro-4-(2-methylamino-1-propoxy)benzoate (240 mg, 0.93 mmol), EDC (hydrochloride) (268 mg, 1.40 mmol), HOBt (189 mg, 1.40 mmol), and DMAP (23 mg, 0.19 mmol) in DMF (8 mL) was stirred at room temp for 1.5 hr. The mixture was diluted with EtOAc, washed with 0.5 N HCl, brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica-gel with 5% MeOH in CHCl3 as eluent to give 520 mg (100%) methyl (S)-3-chloro-4-[2-[N-methyl-N-[3-methoxy-[N′-(2-fluorophenyl)ureido]phenylacetyl]amino]-1-propoxy]benzoate as a red-brown amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:16][CH2:17][C:18]2([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[C:12]([O:14]C)=[O:13])[C:8]2[C:4](=[CH:5][N:6]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[N:7]=2)[CH:3]=1.O.[OH-].[Li+]>O1CCCC1.CO.O>[C:27]([O:26][C:24]([N:21]1[CH2:22][CH2:23][C:18]([CH2:17][O:16][CH:11]([C:9]2[C:8]3[C:4](=[CH:5][N:6]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:43])([CH3:44])[CH3:45])[N:7]=3)[CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:12]([OH:14])=[O:13])([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:19][CH2:20]1)=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: COC(=O)C(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COC(C(=O)O)c2cc(Cl)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccc(F)cc2)CC1
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-2-methoxy-2-oxoethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (150 mg, 0.226 mmol) in tetrahydrofuran (1 mL) and methanol (1 mL) at 0° C. was added a solution of lithium hydroxide monohydrate (28.5 mg, 0.679 mmol) in water (0.5 mL). After 1 h, the reaction was concentrated to remove most of the solvent. The resulting residue was dissolved in a minimum of water, and acidified with 1N hydrochloric acid to give a white solid which was collected by filtration. 1H-NMR (CDCl3, 500 MHz) δ 8.83 (bs, 1H), 8.05 (s, 1H), 7.59 (d, J=1.8 Hz, 1H), 7.28 (dd, J=8.9, 5.5 Hz, 2H), 7.10 (s, 1H), 6.98 (dd, J=8.9, 8.6 Hz, 2H), 5.65 (s, 2H), 5.23 (s, 1H), 3.62-3.82 (m, 3H), 3.58 (t, J=8.2 Hz, 2H), 3.37 (d, J=8.9 Hz, 1H), 3.02 (m, 2H), 2.17 (m, 1H), 2.08 (m, 1H), 1.92 (m, 1H), 1.84 (m, 1H), 1.41 (s, 9H), 0.91 (m, 2H), −0.05 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 170.7, 161.5 (d, J=246 Hz), 155.1, 145.3, 138.1, 128.9 (d, J=7.7 Hz), 128.2, 126.5, 126.4, 123.3, 122.7, 119.9, 115.3 (d, J=20.2 Hz), 82.0, 79.7, 78.7, 77.7, 68.0, 41.3, 39.8, 32.1, 31.9, 28.5, 17.9, −1.4.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH:3]1[C:8]([O:10][C:11](=[O:12])[CH:2]21)=[O:9].[CH3:13][OH:14]>>[CH3:13][O:14][C:8]([CH:3]1[CH:2]([C:11]([OH:10])=[O:12])[CH:1]2[CH2:7][CH:4]1[CH:5]=[CH:6]2)=[O:9]
Reactant: CO
Reactant: O=C1OC(=O)C2C3C=CC(C3)C12
Product: COC(=O)C1C2C=CC(C2)C1C(=O)O
Reaction time: 3 h

Procedure:
The same procedure as that of process (I) of Example 1 was conducted to obtain a 50% by weight methanol solution of (A1). In the same manner, to a 1 liter flask were added 24.00 g of 5-norbornene-2,3-dicarboxylic anhydride and 33.37 g of methanol, and the resulting mixture was stirred under reflux in a water bath kept at 90° C. Ninety minutes after initiation of the stirring, solid components disappeared, 3 hours after, the temperature was lowered to room temperature to obtain a 50% by weight methanol solution of 5-norbornene-2,3-dicarboxylic monomethyl ester.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][CH2:7][CH2:6][C@@H:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]([CH3:15])[C:3]1=[O:16].[F:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26]([NH:28][C@H:29]([C:31](O)=[O:32])[CH3:30])=[O:27])[CH:21]=[C:22]([F:24])[CH:23]=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>C(Cl)Cl>[F:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26]([NH:28][C@H:29]([C:31]([NH:1][C@H:2]2[CH2:8][CH2:7][CH2:6][C@@H:5]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:4]([CH3:15])[C:3]2=[O:16])=[O:32])[CH3:30])=[O:27])[CH:21]=[C:22]([F:24])[CH:23]=1
Reactant: CN1C(=O)[C@@H](N)CCC[C@H]1c1ccccc1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@H]1CCC[C@@H](c2ccccc2)N(C)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
To a solution of (3S,7S)-3-amino-1-methyl-7-phenylazepan-2-one (2e) (57 mg) in DCM (3 mL) at 0° C. under N2 was added N-[(3,5-difluorophenyl)acetyl]-L-alanine (95 mg), HOBt-hydrate (88 mg), EDAC.HCl (75 mg) and N-methyl morpholine (42 mg). The reaction mixture was stirred 1 h at 0° C. and 3H at room temperature, then diluted with 30% Hexanes/EtOAc (100 mL). The organic phase was consecutively washed with H2O, 0.2 N HCl, saturated NaHCO3, and brine, dried (Na2SO4), filtered and evaporated. The crude product was purified by flash chromatography (2% MeOH/DCM) to afford the title compound as an off-white solid (80 mg, 70%). 1H NMR (300 MHz, CDCl3) δ 1.40 (d, 3H), 1.51 (m, 1H), 1.90-2.01 (m, 3H), 2.12-2.15 (m, 2H), 2.52 (s, 3H), 3.55 (s, 2H), 4.47-4.56 (m, 1H), 4.92-5.00 (m, 2H), 6.29 (bd, 1H), 6.69-6.76 (m, 1H), 6.84 (bd, 2H), 7.27-7.41 (m, 6H). MS APCI, m/z=444 (M+1)/466 (M+Na). LC/MS 2.54 min., Method A.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5](=[O:11])[CH2:6][CH2:7]/[CH:8]=[CH:9]/[CH3:10].C1(C)C=CC(S([N:22]=[N+:23]=[N-])(=O)=O)=CC=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:12])[C:4](=[N+:22]=[N-:23])[C:5](=[O:11])[CH2:6][CH2:7]/[CH:8]=[CH:9]/[CH3:10]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: C/C=C/CCC(=O)CC(=O)OC
Solvent: CCN(CC)CC
Product: C/C=C/CCC(=O)C(=[N+]=[N-])C(=O)OC
Yield: 85.5 %

Procedure:
In accordance with the process of Example 2, (E)-3-oxo-6-octenoic acid methyl ester (3.42 g; 20.1 m mol), triethylamine (2.03 g; 20.1 m mol), p-toluenesulfonyl azide(3.99 g; 20 m mol) were used as starting materials to obtain 3.37 g of (E)-2-diazo-3-oxo-6-octenoic acid methyl ester as yellow oily product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1I.[CH3:15][Si:16]([CH3:33])([CH3:32])/[CH:17]=[CH:18]/[Sn](CCCC)(CCCC)CCCC>ClC(Cl)C.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>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1/[CH:18]=[CH:17]/[Si:16]([CH3:33])([CH3:32])[CH3:15]
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1I
Reactant: CCCC[Sn](/C=C/[Si](C)(C)C)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(Cl)Cl
Product: COC(=O)c1nc(Cl)c(F)c(N)c1/C=C/[Si](C)(C)C
Temperature: 70 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
Methyl 4-amino-6-chloro-5-fluoro-3-iodopicolinate (0.5 g, 1.513 mmol), (E)-trimethyl(2-(tributylstannyl)vinyl)silane (0.589 g, 1.513 mmol), and bis(triphenylphosphine)palladium(II) chloride (0.106 g, 0.151 mmol) were combined in dichloroethane (3 mL) and stirred at 70° C. overnight. The reaction mixture was concentrated onto celite then purified by flash chromatography (SiO2, hexanes/EtOAc gradient) to afford the title compound (285 mg, 0.941 mmol, 62.2% yield) as an orange solid: mp 103-105° C.; 1H NMR (400 MHz, CDCl3) δ 6.99 (d, J=19.8 Hz, 1H), 6.21 (d, J=19.9 Hz, 1H), 4.72 (s, 2H), 3.89 (s, 3H), 0.19 (s, 9H); 19F NMR (376 MHz, CDCl3) δ −139.10; ESIMS m/z 301 [(M−H)−].
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2C3C(=CC=CC=3)N=C(C)N=2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:27][C:28]1[NH:37][C:36](=O)[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=1.[CH3:39]N([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.C(OC(=O)NC1C=CC(N)=CC=1)(C)(C)C>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:26])[N:7]([CH3:39])[C:8]1[CH:9]=[CH:10][C:11]([N:14]([CH3:15])[C:36]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]=[C:28]([CH3:27])[N:37]=2)=[CH:12][CH:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1nc2ccccc2c(=O)[nH]1
Reactant: Cc1nc(Nc2ccc(NC(=O)OC(C)(C)C)cc2)c2ccccc2n1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1nc(N(C)c2ccc(N(C)C(=O)OC(C)(C)C)cc2)c2ccccc2n1
Reaction time: 24 h

Procedure:
[4-(2-Methyl-quinazolin-4-ylamino)-phenyl]-carbamic acid tert-butyl ester: A mixture of 2-methyl-3H-quinazolin-4-one (5 g, 31.2mmol), BOP reagent (16.5 g, 37.4 mmol) and ethyl-diisopropyl-amine (8 mL, 46.8 mmol) in DMF (100 mL) was reacted at ambient temperature for 15 min, followed by treatment with (4-amino-phenyl)-carbamic acid tert-butyl ester (10.7 g, 51.4 mmol). The reaction was run for 24 hours. The reaction mixture was diluted with EtOAc and washed with satd NaHCO3, brine, dried (MgSO4), filtered and concentrated. Isolation was done by MPLC (0-100% EtOAc/hexanes as eluent) to give 1 g of the title compound. 1H NMR (DMSO-d6) δ 8.4-7.6 (8H), 2.6 (s, 3H), 1.5 (s, 9H); LC-MS (ESI+; 351 ([M+H]+)).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[H-].[Na+].[CH2:12](Cl)[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.CCOC(C)=O>[CH2:14]([O:13][CH2:12][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc2[nH]cnc2c1
Reactant: ClCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: c1ccc(COCn2cnc3ccccc32)cc1
Reaction time: 0.33 h
Yield: 44.9 %

Procedure:
To a solution of benzimidazole (500 mg, 4.23 mmol) in 10 mL DMF at 0° C., was added NaH (60%, 169 mg, 4.23 mmol). The mixture was stirred for 20 min, then BOM-Cl (802 μL, 4.65 mmol) was added. The mixture was stirred at rt for 4 h, then was diluted with EtOAc. The organic phase was washed with H2O (3×) and brine, dried (Na2SO4), filtered through 1″ SiO2 (eluting with EtOAc). The crude product was purified by flash chromatography (30 to 100% EtOAc/hexanes gradient) to afford 453 mg of Intermediate 10.1 as a white crystalline solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:31]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:16]2=[N:17][CH:18]=[C:19]([CH2:21][NH:22][C:23](=O)C3C=CC=CC=3)[N:20]=[C:15]2[CH:14]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1>O1CCOCC1.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:31]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:38])([CH3:37])[CH3:39])[C:16]2[N:17]=[CH:18][C:19]3[N:20]([CH:23]=[N:22][CH:21]=3)[C:15]=2[CH:14]=1
Reactant: COc1ccc2c(c1)c(-c1cc3nc(CNC(=O)c4ccccc4)cnc3n1COCC[Si](C)(C)C)cn2C
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)c(-c1cc3c(ncc4cncn43)n1COCC[Si](C)(C)C)cn2C
Temperature: 80 °C
Reaction time: 1 h
Yield: 56.4 %

Procedure:
N-((6-(5-Methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)benzamide (0.118 g, 0.218 mmol) in 1,4-dioxane (3 mL) was treated with Lawesson's Reagent (0.070 g, 0.17 mmol) and was heated to about 80° C. in an oil bath for about 20 min. The mixture was cooled to ambient temperature and then mercuric acetate (0.073 g, 0.23 mmol) was added. The mixture was stirred for about 60 min at ambient temperature then another portion of mercuric acetate (0.069 g, 0.22 mmol) was added and stirring was continued for about 20 min at ambient temperature. The mixture was diluted with EtOAc (20 mL) and then filtered. The filtrate was concentrated under reduced pressure and the material was purified by silica gel chromatography eluting with EtOAc to give 7-(5-methoxy-1-methyl-1H-indol-3-yl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (0.055 g, 48%): LC/MS (Table 2, Method d) Rt=1.91 min; MS m/z: 524 (M+H)+.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-]#N.[Na+].[C:12]1(/[CH:18]=[CH:19]/[C:20](=[O:22])[CH3:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C=O)C>[C:2]1([C:1](=[O:8])[CH:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:19][C:20](=[O:22])[CH3:21])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)/C=C/c1ccccc1
Reactant: O=Cc1ccccc1
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)CC(C(=O)c1ccccc1)c1ccccc1
Reaction time: 1.5 h
Yield: 38.7 %

Procedure:
A solution of benzaldehyde (10.10 ml, 100 mmol) in DMF (50 ml) was added dropwise in the course of ½ hour to a mixture of sodium cyanide (2.450 g, 50 mmol) in DMF (50 ml) at 35° C. Stirring was continued for 1.5 hours at 35° C. A solution of (E)-4-phenylbut-3-en-2-one (10.9 g, 74.6 mmol) in DMF (50 ml) was slowly added dropwise over the course of 1.5 hours at 35° C. Stirring was continued for 3.5 hours at the same temperature. The reaction was quenched with twice its quantity of water and extracted with DCM, combined extracts were washed with water and brine, dried over Na2SO4, filtered and concentrated to give a liquid residue. This was purified by chromatography on silica gel using an automated Biotage system and EtOAc/Hexanes, 0-50%, to give 1,2-diphenylpentane-1,4-dione (7.3 g, 28.9 mmol, 38.8% yield). 1H NMR (400 MHz, CDCl3) δ (ppm) 7.97-7.94 (m, 2H), 7.49-7.49 (m, 1H), 7.39-7.35 (m, 2H), 7.29-7.20 (m, 5H), 5.10 (dd, 1H), 3.61 (dd, 1H), 2.75 (dd, 1H), 2.19 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[C:10]1[C:11](=[O:21])[N:12]([CH3:20])[C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][N:15]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:29]([CH3:34])[C:30]([O:32][CH3:33])=[O:31].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:29]([C:30]([O:32][CH3:33])=[O:31])[CH3:34])=[CH:4][C:3]=1[C:10]1[C:11](=[O:21])[N:12]([CH3:20])[C:13]([C:16]([F:18])([F:17])[F:19])=[CH:14][N:15]=1
Reactant: COC(=O)C(C)Br
Reactant: Cn1c(C(F)(F)F)cnc(-c2cc(O)c(Cl)cc2Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)Oc1cc(-c2ncc(C(F)(F)F)n(C)c2=O)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
Then, 0.15 g of 3-(2,4-dichloro-5-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-357) was dissolved in 0.90 ml of N,N-dimethylformamide, to which 0.092 g of potassium carbonate and 54 μl of methyl 2-bromopropionate were added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 0.184 g (yield, 98%) of 3-(2,4-dichloro-5-(1-methoxycarbonylethoxy)phenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-387).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[CH3:9][P:10]([O-:16])[O:11][CH2:12][CH:13]([CH3:15])[CH3:14].C(N(CC)CC)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:9][PH:10](=[O:16])[O:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:3][CH:4]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CC(C)COP(C)[O-]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC(C)CO[PH](=O)Cc1ccc(F)cc1
Temperature: 100 °C
Yield: 82.1 %

Procedure:
A mixture of 50.0 g (289 mmol) of 4-bromofluorobenzene, 43.3 g (318 mmol) of isobutyl methanephosphonite, 43.8 ml (318 mmol) of triethylamine, 1.64 g (0.29 mmol,1 mol %) of bis(dibenzylideneacetone)-palladium and 1.50 g (0.58 mmol, 2 mol %) of triphenylphosphine was heated for 20 hours at 100° C. under an inert gas atmosphere. At 23° C., the solution was filtered off from the ammonium salt formed and the filtrate was evaporated under reduced pressure. Fractional distillation under reduced pressure gave 54.60 g (83% of theory) of isobutyl 4-fluorophenylmethylphosphinate having a boiling point of 83° C./0.08 mbar.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:24])([CH:16]([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.ClC1C=C(C=CC=1)C(OO)=[O:30]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:24])([CH:16]([C:18]1[CH:19]=[CH:20][N+:21]([O-:30])=[CH:22][CH:23]=1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(c1ccncc1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Solvent: ClCCl
Product: CC(c1cc[n+]([O-])cc1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 24 h
Yield: 95.4 %

Procedure:
A solution of 2-(2,4-difluorophenyl)-3-(pyridin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (diastereoisomeric pair B from Example 2) (20.0 g) and 85% w/w 3-chloroperoxybenzoic acid (12.3 g) in dichloromethane (250 ml) was stirred at room temperature for 18 hours. Further 3-chloroperoxybenzoic acid (2.50 g) was then added and stirring was continued for 24 hours. The solution was evaporated and the residue was dissolved in ether. A solid formed on standing which was filtered off and chromatographed on silica gel. Elution with dichloromethane/methanol/0.88 ammonia solution (100:4:0.5) gave the title compound as a solid, (20.0 g), m.p. 195°-198°.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]#[N:29])=[CH:18][CH:17]=2)=[C:5]([C:11]([O:13]CC)=[O:12])[N:6]([CH3:10])[C:7]=1[CH2:8][CH3:9])#[N:2].C1COCC1.[Li+].[OH-].C>CO>[C:1]([C:3]1[C:4]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]#[N:29])=[CH:18][CH:17]=2)=[C:5]([C:11]([OH:13])=[O:12])[N:6]([CH3:10])[C:7]=1[CH2:8][CH3:9])#[N:2]
Reactant: CCOC(=O)c1c(-c2ccc(-c3ccccc3C#N)cc2)c(C#N)c(CC)n1C
Agent: C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1c(C#N)c(-c2ccc(-c3ccccc3C#N)cc2)c(C(=O)O)n1C
Reaction time: 24 h
Yield: 92.2 %

Procedure:
Add ethyl 4-cyano-3-[4-(2-cyanophenyl)phenyl]-5-ethyl-1-methylpyrrole-2-carboxylate to a round bottom flask with a nitrogen inlet, thermocouple and magnetic stirring. Add THF (4.0 volumes). MeOH (1.0 volume) and 1.20 equiv. of 2N LiOH and stir the reaction mixture at RT. After stirring for 24 h no starting material remains. Add Darco (40 w %) and stir the slurry for 30 min. Then filter the reaction mixture through a plug of Hyflo Super Cel® (about ½″ thick) and rinse 2 times with 1 volume of water. Filter this initial filtrate again through a Whatman® GF/F filter to collect small black particulates that escape through the first filtration. Acidify the filtrate slowly with 1 N HCl (1.5 equiv as compared to the LiOH added) {slow addition is very important for polymorph control—about 90 min. addition on 100 g scale}. Stir the milky suspension for 15 min. Filter the thick suspension through a glass frit to obtain a wet solid. Wash this wet solid 4 times with 5 volumes of water (breaking vacuum and stirring the solids with the water each time). Place the wet solid in a vacuum oven at 40° C. overnight (˜15 h) to provide the title compound (92.2% yield).