Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C1C=CC=CC=1.C[O:11][C:12](=[O:43])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]([C:22]2[S:26][C:25]([NH:27][C:28]([N:30]([CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)[CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:29])=[N:24][CH:23]=2)=[O:21])[CH:14]=1.C1(N(C2CCCCC2)C(=O)NC2SC=C(C(O)=O)N=2)CCCCC1>>[CH:37]1([N:30]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[C:28](=[O:29])[NH:27][C:25]2[S:26][C:22]([C:20]([NH:19][C:15]3[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=3)[C:12]([OH:43])=[O:11])=[O:21])=[CH:23][N:24]=2)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: COC(=O)c1cccc(NC(=O)c2cnc(NC(=O)N(C3CCCCC3)C3CCCCC3)s2)c1
Agent: O=C(O)c1ccccc1
Agent: O=C(O)c1csc(NC(=O)N(C2CCCCC2)C2CCCCC2)n1
Product: O=C(O)c1cccc(NC(=O)c2cnc(NC(=O)N(C3CCCCC3)C3CCCCC3)s2)c1
Yield: 40 %

Procedure:
3-{[2-Dicyclohexylureido)-thiazole-5-carbonyl]-amino}-benzoic acid was prepared in 40% yield as described in general procedure F from 3- {[2-(3,3-Dicyclohexylureido)-thiazole-5-carbonyl]-amino}-benzoic acid methyl ester, which in turn was prepared in 21% yield as described in general procedure H using 2-(3,3-dicyclohexylureido)-thiazole-4-carboxylic acid and methyl-3-amino benzoate.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH:5]([O:29][CH2:30][CH3:31])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[S:18][C:19]=2[CH3:20])=[CH:9][C:8]=1[CH3:28])C.[Li+].[OH-]>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:17]2[S:18][C:19]([CH3:20])=[C:15]([CH2:14][O:13][C:10]3[CH:11]=[CH:12][C:7]([CH2:6][CH:5]([O:29][CH2:30][CH3:31])[C:4]([OH:32])=[O:3])=[C:8]([CH3:28])[CH:9]=3)[N:16]=2)=[CH:22][CH:23]=1
Reactant: CCOC(=O)C(Cc1ccc(OCc2nc(-c3ccc(Cl)cc3)sc2C)cc1C)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCOC(Cc1ccc(OCc2nc(-c3ccc(Cl)cc3)sc2C)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d], [rac]-3-{4-[2-(4-chloro-phenyl)-5-methyl-thiazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid ethyl ester was treated with LiOH to obtain [rac]-3-{4-[2-(4-chloro-phenyl)-5-methyl-thiazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=2[CH3:19])[CH:5]=1.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[N:29]1[C:33]([CH2:34]O)=[C:32]([CH:36]([CH3:38])[CH3:37])[N:31]=[N:30]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:34][C:33]3[N:29]([C:23]4[C:22]([Cl:21])=[CH:27][CH:26]=[CH:25][C:24]=4[Cl:28])[N:30]=[N:31][C:32]=3[CH:36]([CH3:38])[CH3:37])=[CH:14][C:13]=2[CH3:19])[CH:5]=1
Reactant: COC(=O)c1cccc(C=Cc2ccc(O)cc2C)c1
Reactant: CC(C)c1nnn(-c2c(Cl)cccc2Cl)c1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(C=Cc2ccc(OCc3c(C(C)C)nnn3-c3c(Cl)cccc3Cl)cc2C)c1
Reaction time: 8 h
Yield: 21.2 %

Procedure:
To a solution of 3-(2-(4-hydroxy-2-methyl-phenyl)-vinyl)-benzoic acid methyl ester (0.09 4 g, 0.351 mmol) and (3-(2,6-dichloro-phenyl)-5-isopropyl-3H-(1,2,3)triazol-4-yl)-methanol (0.100 g, 0.351 mmol) in THF (3 mL) are added triphenylphosphine (0.184 g, 0.702 mmol) and diethyl azodicarboxylate (0.120 g, 0.720 mmol). The reaction is stirred overnight. The reaction is partitioned between ether and water. The organic layer is washed with brine and dried over sodium sulfate. The organic layers are filtered and concentrated. The crude solid is purified via flash chromatography using hexane:ethyl acetate (2:1) as eluent to give 3-(2-(4-(3-(2,6-Dichloro-phenyl)-5-isopropyl-3-H-(1,2,3)triazol-4ylmethyoxy)-2-methyl-phenyl)-vinyl)-benzoic acid methyl ester (0.04 g). ES/MS m/e (35Cl/37Cl) 535.8/538.2 (M+1).
Reaction SMILES: C([O:8][C:9]1[C:14]([CH2:15][N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[C:19]([CH3:31])[C:20]([C:26]([N:28]([CH3:30])[CH3:29])=[O:27])=[CH:21][CH:22]=3)[C:17]2=[O:32])=[C:13]([CH3:33])[CH:12]=[C:11]([CH3:34])[N:10]=1)C1C=CC=CC=1>CO.[Pd]>[CH3:33][C:13]1[CH:12]=[C:11]([CH3:34])[NH:10][C:9](=[O:8])[C:14]=1[CH2:15][N:16]1[CH2:25][CH2:24][C:23]2[C:18](=[C:19]([CH3:31])[C:20]([C:26]([N:28]([CH3:29])[CH3:30])=[O:27])=[CH:21][CH:22]=2)[C:17]1=[O:32]
Reactant: Cc1cc(C)c(CN2CCc3ccc(C(=O)N(C)C)c(C)c3C2=O)c(OCc2ccccc2)n1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C)c(CN2CCc3ccc(C(=O)N(C)C)c(C)c3C2=O)c(=O)[nH]1
Yield: 49.8 %

Procedure:
A mixture of 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-N,N,8-trimethyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-7-carboxamide (76f, 80 mg, 0.175 mmol) and 10% Pd/C (10 mg) in MeOH (10 mL) was hydrogenated under H2 balloon at room temperature for 20 hours. The mixture was filtered and the solids were washed with MeOH (2×10 mL). The filtrate was concentrated under vacuum and the residue was purified by column chromatography (EtOAc/MeOH=5:1) to give the title compound (Example 76, 32 mg, 49.7%) as a white solid. 1H NMR (400 MHz, methanol-d4) δ 7.22-7.2 (d, 1H), 7.17-7.15 (d, 1H), 6.11 (s, 1H), 4.77 (s, 2H), 3.45-3.43 (m, 2H), 3.13 (s, 3H), 2.9-2.85 (m, 5H), 2.28 (s, 3H), 2.25 (s, 3H); MS 367.9 [M+H].
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:7][N:6]=1)=[O:4].O.[OH-].[Li+].Cl>C1COCC1.O>[F:16][C:13]([F:14])([F:15])[CH2:12][NH:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(NCC(F)(F)F)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(NCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.4 %

Procedure:
5-(2,2,2-Trifluoroethylamino)-pyridine-2-carboxylic acid methyl ester (Intermediate 280, 75 mg, 0.320 mmol) was dissolved in a mixture of THF (0.75 mL) and water (0.25 mL) and lithium hydroxide monohydrate (27 mg, 0.640 mmol) was added. The mixture was stirred at room temperature for 18 h. The mixture was diluted with water (5 mL), brought to approximately pH 4 by the addition of 1M HCl, then extracted with DCM (4×9 mL). The combined organic extracts were washed with brine (5 mL), dried over sodium sulfate and evaporated under vacuum to afford the title compound as a white solid (51 mg, 72%). Method B HPLC-MS: MH+ requires m/z=221. Found: m/z=221, Rt=1.30 min (100%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O.ClCCl.O>[CH:20]1([C:11]2([CH2:14][N:15]3[CH:19]=[N:18][CH:17]=[N:16]3)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCC(Cn2cncn2)(C2CCCCC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: c1ncn(CC2(C3CCCCC3)CCNCC2)n1
Reaction time: 0.75 h

Procedure:
To a solution of trifluoroacetic acid/dichloromethane/water (1:1:0.1, 10 mL) is added 4-cyclohexyl-4-[1,2,4]triazole-1-ylmethyl-piperidine-1-carboxylic acid tert-butyl ester, 3, (3.5 g, 10 mmol) which was obtained in the procedure herein above and the reaction mixture is allowed to stir for 30 to 60 minutes. The reaction solution is then concentrated in vacuo and partitioned between aqueous NaHCO3 and EtOAc. The organic phase is concentrated in vacuo and the crude product purified by HPLC over silica gel to afford the desired product.
Reaction SMILES: [N-:1]([S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])[S:2]([C:5]([F:8])([F:7])[F:6])(=[O:4])=[O:3].[Li+].[CH3:17][N:18]([C:20]([N:23]([CH3:25])[CH3:24])(Cl)[Cl:21])[CH3:19]>O>[N-:1]([S:2]([C:5]([F:8])([F:6])[F:7])(=[O:4])=[O:3])[S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10].[CH3:17][N:18]([C+:20]([N:23]([CH3:25])[CH3:24])[Cl:21])[CH3:19]
Reactant: CN(C)C(Cl)(Cl)N(C)C
Agent: O=S(=O)([N-]S(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Li+]
Solvent: O
Product: CN(C)[C+](Cl)N(C)C

Procedure:
134.1 g (0.467 mol) of lithium bis(trifluoromethanesulfonyl)imide in 200 ml of water are added with stirring at room temperature to a solution of 80.0 g (0.468 mol) of bis(dimethylamino)dichloromethane in 300 ml of water. The mixture is stirred for half an hour, and the solid is subsequently filtered off. After repeated washing with 100 ml of water, the crystals formed are dried at 50° C. under a reduced pressure of 10.0 Pa, giving 165.5 g of bis(dimethylamino)chlorocarbenium bis(trifluoromethanesulfonyl)imide, corresponding to a yield of 85.1%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](C2C=CC(F)=CC=2)=C1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=[O:27]>>[C:1]([O:5][C:6]([NH:8][C:16]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:10][OH:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)n1cc(-c2ccc(F)cc2)c2ccccc21
Product: CC(C)(C)OC(=O)Nc1ccccc1CO
Yield: 79 %

Procedure:
1-(t-Butoxy)carbonyl-3-(4-fluorophenyl)indole (0.340 g) was freed from the protecting group with the use of trifluoroacetic acid and then treated as in the above Production Example 54 to give the title compound (0.184 g) as a pale yellow oil (yield: 79.0%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:14]=[CH:13][C:7]2[O:8][CH2:9][C:10](=[O:12])[NH:11][C:6]=2[CH:5]=1.[CH3:15]I>CN(C=O)C>[Br:3][C:4]1[CH:14]=[CH:13][C:7]2[O:8][CH2:9][C:10](=[O:12])[N:11]([CH3:15])[C:6]=2[CH:5]=1
Reactant: O=C1COc2ccc(Br)cc2N1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)COc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To sodium hydride (63 mg) in DMF (3 mL) under an atmosphere of nitrogen was added 6-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (0.3 g) and the mixture was stirred at room temperature for 1 h. Methyl iodide (0.123 mL) was added and the mixture was stirred overnight at room temperature. The mixture was poured onto ice/water and extracted into ethyl acetate (×2). The ethyl acetate was washed with water (×3), dried and the solvent was evaporated. The resulting material was purified by chromatography on silica eluting with 10% ethyl acetate/isohexane to afford the sub-titled compound (299 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[N+:32]([C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1)([O-:34])=[O:33]>O1CCCC1>[CH:18]1([CH2:17][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][S:41]([C:38]3[CH:37]=[CH:36][C:35]([N+:32]([O-:34])=[O:33])=[CH:40][CH:39]=3)(=[O:42])=[O:43])=[CH:7][CH:6]=2)[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 47.4 %

Procedure:
A solution of 2-(4-amino-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (63.0 mg, 0.20 mmol) in tetrahydrofuran (10 mL) was treated with N,N-diisopropylethylamine (0.04 mL, 0.24 mmol) and 4-nitro-benzene sulfonyl chloride (49.0 mg, 0.20 mmol). The reaction mixture was stirred at 25° C. for 21 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-[4-(4-nitro-benzenesulfonylamino)-phenyl]-N-thiazol-2-yl-propionamide (47.5 mg, 47.5%) as a yellow solid: mp 120-125° C.; FAB-HRMS m/e calcd for C23H24N4O5S2 (M+H)+ 501.1266, found 501.1264.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12]([OH:23])=[C:13]([C:19]([O:21]C)=O)[N:14]([CH3:18])[S:15](=[O:17])(=[O:16])[C:5]=3[C:4]=2[CH:3]=1.[NH2:24][C:25]1[S:26][CH:27]=[CH:28][N:29]=1.B(OCCCC)(OCCCC)OCCCC.CO>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12]([OH:23])=[C:13]([C:19]([NH:24][C:25]4[S:26][CH:27]=[CH:28][N:29]=4)=[O:21])[N:14]([CH3:18])[S:15](=[O:17])(=[O:16])[C:5]=3[C:4]=2[CH:3]=1
Reactant: Nc1nccs1
Reactant: COC(=O)C1=C(O)c2c(c3cc(Cl)ccc3n2C)S(=O)(=O)N1C
Agent: CCCCOB(OCCCC)OCCCC
Solvent: CO
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2nccs2)=C(O)c2c(c3cc(Cl)ccc3n2C)S1(=O)=O
Yield: 70 %

Procedure:
3.0 gm (8.4 millimols) of methyl 8-chloro-2,5-dihydro-2,5-dimethyl-4-hydroxy-1,2-thiazino[5,6-b]indole-3-carboxylate 1,1-dioxide, 0.9 gm (9 millimols) of 2-amino-thiazole and 50 mgm of tri-n-butyl borate were refluxed in 300 ml of dry xylene for 6 hours. The methanol released by the reaction was separated by means of a 4-A-molecular sieve in a Soxhlet-attachment. 3.1 gm of crystals were separated from the cooled reaction mixture by filtration and subsequently boiled in a mixture of 100 ml of acetonitrile and 1 ml of glacial acetic acid. After filtration and drying, 2.5 gm (68% of theory) of 8-chloro-2,5-dihydro-2,5-dimethyl-4-hydroxy-N-(2-thiazolyl)-1,2-thiazino[5,6-b]indole-3-carboxamide-1,1-dioxide were obtained; M.p.: 282° C. (decomposition).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[N:3]=1.[NH2:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[N:26]=[CH:25]2>C(O)(C)C>[N+:18]([C:14]1[CH:13]=[C:12]([C:4]2[N:3]=[C:2]([NH:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[N:26]=[CH:25]4)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH:17]=[CH:16][CH:15]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1cccc(-c2nc(Cl)c3ccccc3n2)c1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(N)ccc21
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc([N+](=O)[O-])c4)nc4ccccc34)ccc21
Temperature: 95 °C

Procedure:
A suspension of 4-chloro-2-(3-nitrophenyl)quinazoline (6.3 g, 21.9 mmole), tert-butyl 5-amino-1H-indazole-1-carboxylate (5.10 g, 21.9 mmole) in isopropanol (300 mL) was heated at 95° C. for 1.5 h. The suspension was filtered and the filtered solid was washed with isopropanol. The product was dried under high vacuum for several hours to give the desired product tert-butyl 5-(2-(3-nitrophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate. (8.3 g, mmol, 79%).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:14]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9][C:8]=2[N:7]=[CH:6][N:5]=1.Cl[CH2:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([CH:25]2[CH2:28][CH2:27][CH2:26]2)[CH2:21][CH2:20]1)=[O:18].C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>C(#N)C>[CH:25]1([N:22]2[CH2:23][CH2:24][N:19]([C:17](=[O:18])[CH2:16][N:11]3[CH2:12][CH2:13][C:14]4[C:4]([Cl:3])=[N:5][CH:6]=[N:7][C:8]=4[CH2:9][CH2:10]3)[CH2:20][CH2:21]2)[CH2:28][CH2:27][CH2:26]1
Reactant: O=C(CCl)N1CCN(C2CCC2)CC1
Reactant: Clc1ncnc2c1CCNCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: O=C(CN1CCc2ncnc(Cl)c2CC1)N1CCN(C2CCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-chloro-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine dihydrochloride (0.57 g, 2.2 mmol), 2-chloro-1-(4-cyclobutyl-piperazin-1-yl)-ethanone (0.48 g, 2.2 mmol), K2CO3 (1 g, 7.2 mmol), and NaI (0.33 g, 2.2 mmol) in acetonitrile is stirred overnight at rt. The solvent is evaporated and water is added. The mixture is extracted with DCM. The combined organic layers are dried (MgSO4) and solvent removed in vacuo to give the crude product, which is purified by PTLC (5% MeOH in DCM) to give the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)=[CH:10][C:9]=1[NH2:19])(C)(C)C.C(O[C:26](=[O:38])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][N:33]=[C:32]([C:36]#[N:37])[CH:31]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1.C(Cl)Cl>[O:38]=[C:26]1[CH2:27][C:28]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([C:36]#[N:37])[CH:31]=2)=[N:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:18]=[CH:17][CH:16]=[CH:15]3)=[CH:10][C:9]=2[NH:19]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-n2cccc2)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: N#Cc1cc(C2=Nc3ccc(-n4cccc4)cc3NC(=O)C2)ccn1
Temperature: 100 °C
Yield: 35.8 %

Procedure:
A mixture of (2-amino-4-pyrrol-1-yl-phenyl)-carbamic acid tert-butyl ester (Example J2) (0.14 g) and 3-(2-cyano-pyridin-4-yl)-3-oxo-propionic acid tert-butyl ester (Example K3) (0.14 g) in toluene (1.5 mL) was heated to 100° C. for 4 h, a fine precipitate being formed. The mixture was cooled and the precipitae was isolated by filtration. A solution of this solid in CH2Cl2 (2.5 mL) and TFA (2.5 mL) was stirred for 0.5 h at 20° C. and then evaporated in vacuum. The residual oil was dissolved in AcOEt and the solution was washed with saturated Na2CO3 solution and with brine, dried over Na2SO4 and evaporated in vacuum. The solid residue was triturated with CH2Cl2 to give the title compound (0.06 g) as light-yellow crystals.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11].[Br:17][CH:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19](Cl)=[O:20].C(=O)([O-])O.[Na+]>C(#N)C>[Br:17][CH:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19]([NH:8][C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:20]
Reactant: O=C(Cl)C(Br)c1ccccc1
Reactant: CCOC(=O)C(C)(C)N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)C(C)(C)NC(=O)C(Br)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 41.4 %

Procedure:
Triethylamine (11 g) was added suspension of ethyl aminoisobutyrate (7.5 g) in acetonitrile (80 mL) cooled to 0° C., and to the mixture was slowly added dropwise a solution of α-bromophenylacetyl chloride (11 g) in acetonitrile (20 mL). After the addition was completed, the solution was warmed to room temperature, and stirred overnight. The reaction solution was poured into a sodium hydrogencarbonate aqueous solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then the resulting crude product was washed with diisopropyl ether to give 6.4 g of ethyl 2-(α-bromophenylacetylamino)isobutyrate.
Reaction SMILES: [Li]CCCC.[C:6](#[N:8])[CH3:7].CO[C:11](=[O:21])[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[N:14][C:13]=1[O:19][CH3:20]>C1COCC1>[CH3:20][O:19][C:13]1[C:12]([C:11](=[O:21])[CH2:7][C:6]#[N:8])=[CH:17][CH:16]=[C:15]([CH3:18])[N:14]=1
Reactant: COC(=O)c1ccc(C)nc1OC
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc(C)ccc1C(=O)CC#N
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-BuLi (1.2 M, 96.0 mL, 115.6 mmol) is added to a solution of acetonitrile (6.08 mL, 115.4 mmol) in THF (300 mL) at −78° C. and allowed to stir for 30 min at −78° C. 2-Methoxy-6-methyl-nicotinic acid methyl ester (20 g, 105.1 mmol) THE (200 mL) is added and stirred at −78° C. for another 30 min. The reaction mixture is quenched at −78° C. with water (500 mL) and washed with EtOAc (2×250 mL). The aqueous layer is separated and evaporated. This is co-distilled twice with toluene to obtain 3-(2-methoxy-6-methyl-pyridin-3-yl)-3-oxo-propionitrile. Yield=21.4 g (crude). ES/MS m/z 191.1 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[C:5]=1[S:14]([O-:17])(=O)=[O:15])(O)=[O:2].[Na+].P(Cl)(Cl)(Cl)(Cl)Cl.[Cl-:25].[Cl-:26].[Cl-].[P+3]=O>>[Cl:25][C:1]([C:4]1[S:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[C:5]=1[S:14]([Cl:26])(=[O:17])=[O:15])=[O:2]
Reactant: [Cl-]
Reactant: Cc1ccc2c(S(=O)(=O)[O-])c(C(=O)O)sc2c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=[P+3]
Agent: [Na+]
Product: Cc1ccc2c(S(=O)(=O)Cl)c(C(=O)Cl)sc2c1
Yield: 82 %

Procedure:
Prepared analogous to Example 1(b) from monosodium 2-carboxy-6-methyl-benzo[b] thiophene-3-sulfonate and phosphorus-(V)-chloride in the presence of phosphorus oxide trichloride with a yield of 82% of theory. The product, which crystallized upon cooling, was used in the next step without further purification.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:23](O)=[O:24])[CH:20]([CH3:22])[CH3:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.Cl.[CH3:45][O:46][C@@H:47]([C@@H:56]([NH:61][CH3:62])[C@@H:57]([CH3:60])[CH2:58][CH3:59])[CH2:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50]>CC1CCCO1>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:23]([N:61]([CH3:62])[C@@H:56]([C@@H:57]([CH3:60])[CH2:58][CH3:59])[C@H:47]([O:46][CH3:45])[CH2:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=[O:24])[CH:20]([CH3:21])[CH3:22])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC[C@H](C)[C@H](NC)[C@@H](CC(=O)OC(C)(C)C)OC
Reactant: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: CC1CCCO1
Solvent: CN1CCOCC1
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Reaction time: 3 h
Yield: 113.1 %

Procedure:
To a mixture of N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-valine (18.53 g, 54.60 mmol, 1.3 eq.) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) (9.58 g, 54.6 mmol, 1.3 eq.) in 2-methyltetrahydrofuran (118.00 mL, 0.34 M) was added N-methylmorpholine (6.52 mL, 59.1 mmol, 1.5 eq.) followed by #4 (11.80 g, 39.9 mmol, 1 eq.). After 3 hours, the reaction was quenched with water (50 mL) and stirred for 15 minutes. The aqueous layer was separated and back-extracted with 2-methyltetrahydrofuran (50 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution (50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to give a colorless oil, which was purified by silica gel chromatography (Gradient: 5% to 40% ethyl acetate in heptane) to give #5 (26.2 g, 91%) as a colorless foam. LC-MS (Protocol I) m/z 581.3 [M+H+] 1604.3 [M+Na+], retention time=4.993 minutes; 1H NMR (400 MHz, DMSO-d6), possibly a mixture of rotamers, characteristic major signals: δ 7.88 (d, J=7.4 Hz, 2H), 7.71 (d, J=7.4 Hz, 2H), 7.62 (d, J=8.6 Hz, 1H), 7.41 (dd, J=7.4, 7.4 Hz, 2H), 7.27-7.34 (m, 2H), 4.13-4.32 (m, 4H), 3.70-3.82 (br m, 1H), 3.24 (s, 3H), 2.92 (br s, 3H), 2.54 (dd, J=15.7, 2.4 Hz, 1H), 2.17 (dd, J=15.4, 9.4 Hz, 1H), 1.95-2.07 (m, 1H), 1.70-1.83 (br m, 1H), 1.40 (s, 9H), 0.83-0.94 (m, 9H), 0.69 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[Br-].[O:13]=[C:14]1[C:23]2[C:18](=[CH:19][C:20]([CH2:24][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:21][CH:22]=2)[CH:17]=[N:16][NH:15]1.O>CS(C)=O>[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6](/[CH:7]=[CH:24]\[C:20]2[CH:19]=[C:18]3[C:23](=[CH:22][CH:21]=2)[C:14](=[O:13])[NH:15][N:16]=[CH:17]3)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: O=c1[nH]ncc2cc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)ccc12
Agent: [Br-]
Solvent: CS(C)=O
Solvent: O
Product: CN(C)c1ccc(/C=C\c2ccc3c(=O)[nH]ncc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.2 %

Procedure:
4-dimethylaminobenzaldehyde (9 gm) in DMSO (30 ml) was added to a solution of 1-oxo-2H-phthalazin-6-ylmethyl triphenylphosphonium bromide (0.04 mole) in DMSO (100 ml) and stirred overnight at room temperature. The reaction mixture was added to water (1 L), stirred, and the precipitate was filtered to give a solid. The solid was air dried, slurried with acetone (200 ml) and filtered and dried to give a mixture of cis and trans isomers (9.9 gm). The solid was recrystallized from DMF (65 ml) and filtered to give pure cis product (4.8 gm), mp=312°-318° C.