Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([F:28])=[C:4]([N:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11](=[O:16])[C:10]([C:17]3[N:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:20]=[CH:19][CH:18]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.Cl.[F:30][C:31]([F:38])([F:37])[CH:32]1[CH2:36][CH2:35][NH:34][CH2:33]1.CC([O-])(C)C.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:28][C:3]1[C:2]([N:34]2[CH2:35][CH2:36][CH:32]([C:31]([F:38])([F:37])[F:30])[CH2:33]2)=[CH:7][CH:6]=[CH:5][C:4]=1[N:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11](=[O:16])[C:10]([C:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:20]=[CH:19][CH:18]=2)=[N:9]1
Reactant: FC(F)(F)C1CCNC1
Reactant: COc1cn(-c2cccc(Br)c2F)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COc1cn(-c2cccc(N3CCC(C(F)(F)F)C3)c2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 90 °C
Yield: 38.6 %

Procedure:
A mixture of 1-(3-bromo-2-fluorophenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (300 mg, 0.68 mmol), 3-(trifluoromethyl)pyrrolidine hydrochloride (143 mg, 0.82 mmol), NaOt-Bu (170 mg, 1.8 mmol), Xantphos (31 mg, 0.054 mmol) and Pd2(dba)3 (12 mg, 0.014 mmol) in 1,4-dioxane (4 mL) was heated at 90° C. for 14 h under Ar. The mixture was extracted with AcOEt, dried over Na2SO4, filtered, concentrated in vacuo and purified by column chromatography on basic silica gel (hexane/AcOEt=10/90 to 0/100) to yield the title compound (131 mg, 39% yield) as a white amorphous solid: 1H NMR (300 MHz, CDCl3): δ ppm 2.09-2.40 (2H, m), 3.05 (1H, s), 3.38-3.75 (4H, m), 3.83-3.99 (3H, m), 5.88-6.07 (1H, m), 6.65 (1H, td, J=8.3, 1.5 Hz), 6.80-6.95 (1H, m), 7.22 (1H, d, J=2.3 Hz), 7.30-7.49 (5H, m), 7.72 (1H, d, J=2.6 Hz), 7.74-7.80 (1H, m); MS Calcd.: 499; MS Found: 500 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[C:8]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)([CH3:11])([CH3:10])[CH3:9].[CH:18]1([C@H:21]([NH:29][C:30]([C:32]2[C:41]3[C:36](=[C:37]([Cl:42])[CH:38]=[CH:39][CH:40]=3)[C:35](=[O:43])[N:34]([CH2:44][CH2:45][CH3:46])[C:33]=2[CH2:47]Br)=[O:31])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)[CH2:20][CH2:19]1.[OH-].[Na+]>C1COCC1>[CH:18]1([C@H:21]([NH:29][C:30]([C:32]2[C:41]3[C:36](=[C:37]([Cl:42])[CH:38]=[CH:39][CH:40]=3)[C:35](=[O:43])[N:34]([CH2:44][CH2:45][CH3:46])[C:33]=2[CH2:47][N:15]2[CH2:16][CH2:17][N:12]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:13][CH2:14]2)=[O:31])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)[CH2:20][CH2:19]1
Reactant: CC(C)(C)N1CCNCC1
Reactant: CCCn1c(CBr)c(C(=O)N[C@H](c2cccc(F)c2)C2CC2)c2cccc(Cl)c2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCn1c(CN2CCN(C(C)(C)C)CC2)c(C(=O)N[C@H](c2cccc(F)c2)C2CC2)c2cccc(Cl)c2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
Triethyl amine (280 μL, 2 mmol) and 1-tert-butyl-piperazine (96 mg, 0.67 mmol) were added to 3-bromomethyl-8-chloro-1-oxo-2-propyl-1,2-dihydro-isoquinoline-4-carboxylic acid [(S)-cyclopropyl-(3-fluoro-phenyl)-methyl]-amide (0.56 mmol) in 10 mL THF. The reaction mixture was stirred at room temperature for 30 minutes and poured into 50 mL 0.5 N NaOH (aq). The mixture was extracted with ethyl acetate (100 mL). The organic phase was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude product was flash chromatographed on silica gel (gradient heptane-ethyl acetate/methanol) to give 190 mg of the title compound, yield 60%. LC-MS (m/z) 567.8 (MH+); tR=1.07.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N:12]([S:16]([CH3:19])(=[O:18])=[O:17])[CH2:13][CH2:14][CH3:15])[N:11]=1)[C:5](OC)=[O:6].[Li+].[BH4-]>C1COCC1>[Cl:1][C:2]1[N:11]=[C:10]([N:12]([CH2:13][CH2:14][CH3:15])[S:16]([CH3:19])(=[O:17])=[O:18])[CH:9]=[C:4]([CH2:5][OH:6])[CH:3]=1
Reactant: CCCN(c1cc(C(=O)OC)cc(Cl)n1)S(C)(=O)=O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCN(c1cc(CO)cc(Cl)n1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of methyl 2-chloro-6-[(methylsulfonyl)(propyl)amino]isonicotinate (3.5 g, 11.5 mmol) in THF (50 mL) cooled to 0° C. was added LiBH4 (17.2 mL, 34.4 mmol, 2 M in THF). After 10 min, the reaction mixture was allowed to warm to rt and stirred for 3.5 h. The reaction mixture was carefully quenched with EtOAc, MeOH and water. Following dilution with EtOAc, the organic layer was extracted, washed with brine, dried over sodium sulfate and concentrated in vacuo to provide N-[6-chloro-4-(hydroxymethyl)pyridin-2-yl]-N-propylmethanesulfonamide which was used as is in the bromination step.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH2:15][C:16]([N:18]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:19][CH2:20][C:21]([CH3:26])([CH3:25])[CH2:22][C:23]#[CH:24])=[O:17])[CH:9]2C(O)=O)=[CH:4][C:3]=1[O:31][CH3:32].O.[NH4+].[OH-]>C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+]>[C:27]([N:18]1[CH2:19][CH2:20][C:21]([CH3:25])([CH3:26])[CH2:22][C:23]2[CH:24]=[C:9]3[C:10]4[CH:11]=[C:2]([Br:1])[C:3]([O:31][CH3:32])=[CH:4][C:5]=4[CH2:6][CH2:7][N:8]3[C:15]=2[C:16]1=[O:17])([CH3:30])([CH3:29])[CH3:28]
Reactant: C#CCC(C)(C)CCN(C(=O)CN1CCc2cc(OC)c(Br)cc2C1C(=O)O)C(C)(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COc1cc2c(cc1Br)-c1cc3c(n1CC2)C(=O)N(C(C)(C)C)CCC(C)(C)C3
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.1 %

Procedure:
A solution of 350 mg of 24g in 5 ml of acetic anhydride and 300 mg of sodium acetate, was heated at 90-100° C. for 3 h. The reaction was cooled to rt and 10 ml of water was added and stirring at ambient temperature was prolonged for 1 hr. The mixture was neutralized by addition of cold conc. NH4OH and the product was extracted with ethyl acetate. The organic extract was washed with water, dried and concentrated, and the remainders chromatographed over silicagel (using a gradient of heptane/ethyl acetate as eluent), to give 70 mg 24h (white crystalline material, triturated with heptane); Mp 175-177° C. Rf (heptane/ethyl acetate 1/1) 0.75.
Reaction SMILES: C[C:2]1[C:3]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)C(Br)=[C:5]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1)[C:4]=2[C:23]1C=CC=CC=1.CB(O)O.C([O-])([O-])=O.[Na+].[Na+].[C:39]1([CH3:45])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>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>[CH3:23][C:4]1[C:3]2[C:2]([CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[C:45]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:5]=1[C:13]1[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=1
Reactant: Cc1ccccc2c(Br)c(-c3ccc(S(C)(=O)=O)cc3)c(-c3ccccc3)c1-2
Reactant: Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB(O)O
Agent: O=C([O-])[O-]
Product: Cc1c2cccccc-2c(-c2ccccc2)c1-c1ccc(S(C)(=O)=O)cc1
Temperature: 0 °C

Procedure:
To a solution of methyl 1-bromo-2-(4-methylsulfonylphenyl)-3-phenylazulene (0.20 g) in toluene (10.0 ml) was added methylboronic acid (0.13 g), tetrakis(triphenylphosphine)palladium (0) (0.05 g) and 2M aqueous Na2CO3 (0.9 ml), and the reaction mixture was heated under reflux for 2 hr. The reaction mixture was poured into ice-water, followed by extracted with EtOAc. The combined EtOAc extracts were washed with water and brine, dried over Na2SO4, and concentrated. The crude product was purified by SiO2 column chromatography (benzenee/EtOAc, 20: 1) to give the title compound (0.15 g) as violet crystals; mp 165°-167° C.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.[CH3:26][C:27]1[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][C:28]=1[NH2:29].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(C)([O-])C.[Na+]>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([NH:29][C:28]3[CH:30]=[CH:31][C:32]([CH3:34])=[CH:33][C:27]=3[CH3:26])[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: Cc1ccc(N)c(C)c1
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1ccc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c(C)c1
Temperature: 140 °C
Yield: 37.4 %

Procedure:
A mixture of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (200 mg, 468 mol), 2,4-dimethylaniline (85.1 mg, 526 mol), BINAP (14.6 mg, 23.4 mol), palladium (II) acetate (26.3 mg, 117 mol) and sodium tert-butoxide (112 mg, 1.17 mmol) in DMF (1 mL) and toluene (500 μL) was heated in a microwave at 140° C. for 20 min. The reaction mixture was diluted with water then extracted into ethyl acetate (3×). The combined organic extracts were washed with brine then dried over magnesium sulfate. Purification by chromatography (silica, 20-60% ethyl acetate in hexanes) gave N-tert-butyl-2-(2,4-dimethylphenylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (82 mg, 175 mol, 37.5%) as a brown gum. (EI/CI) m/z: 468.4 [M+H].
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:29])[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:18]=1.C(N(CC)C(C)C)(C)C.[CH2:39]([O:41][C:42](Cl)=[O:43])[CH3:40]>ClCCl>[C:42](=[O:43])([O:41][CH2:39][CH3:40])[O:29][C:5]1[N:6]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)[CH:18]=2)[C:7]2[C:3]([N:4]=1)=[C:2]([NH2:1])[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=2
Reactant: CCOC(=O)Cl
Reactant: COCCOc1nc(N)c2nc(O)n(Cc3cccc(CN4CCCC4)c3)c2n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Oc1nc2c(N)nc(OCCOC)nc2n1Cc1cccc(CN2CCCC2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
6-Amino-2-(2-methoxy-ethoxy)-9-(3-pyrrolidin-1-ylmethyl-benzyl)-9H-purin-8-ol (Example A) (60 mg, 0.15 mmol) was dissolved in dichloromethane (2 mL). N,N-diisopropylethylamine (0.1 mL) was added and the mixture was cooled to 0° C. Ethylchloroformate (0.04 mL, 0.42 mmol) was added. After stirring for 30 minutes, the reaction was quenched with water and concentrated under vacuum. Purification by preparative reverse phase HPLC (5-45% acetonitrile/40 mM aqueous HCl) gave 9-(3-(pyrrolidin-1-ylmethyl)benzyl)-6-amino-2-(2-methoxyethoxy)-9H-purin-8-yl ethyl carbonate (Example Q) (24 mg) as a white glassy solid, HCl salt.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([C:24]2[NH:25][CH2:26][C:27]([O:35]S(C)(=O)=O)=[C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[N:29]=2)[CH2:17][CH2:16][CH:15]([CH2:18]OS(C)(=O)=O)[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-:41].[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]12[CH2:13][CH2:14][CH:15]([CH2:16][CH2:17]1)[CH2:18][N:25]1[C:26](=[O:41])[C:27]([OH:35])=[C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[N:29]=[C:24]21)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1=C(OS(C)(=O)=O)CNC(C2(NC(=O)OCc3ccccc3)CCC(COS(C)(=O)=O)CC2)=N1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc2n(c(=O)c1O)CC1CCC2(NC(=O)OCc2ccccc2)CC1
Temperature: 60 °C
Yield: 25 %

Procedure:
A mixture of ethyl 2-(1-(benzyloxycarbonylamino)-4-((methylsulfonyloxy)methyl)cyclohexyl)-5-(methylsulfonyloxy)-1,6-dihydropyrimidine-4-carboxylate (2.25 g, 3.74 mmol) and cesium carbonate (1.22 g, 3.74 mmol) in DMF (40 mL) was heated at 60° C. for 18 h. The reaction mixture was then cooled and concentrated in vacuo. The residue was taken up in ethyl acetate (200 mL) and extracted with 0.2 M aq. NaOH (3×50 mL). The combined aqueous phase was washed with ethyl acetate (250 mL). The aqueous layer was then acidified with conc. HCl and extracted with CH2Cl2 (3×100 mL). The CH2Cl2 extracts were dried (Na2SO4), filtered and concentrated to afford the title compound as a brown solid (400 mg). 1H NMR (500 MHz, CDCl3) δ: 10.81 (s, 1H), 7.29-7.36 (m, 6H), 5.29 (s, 1H), 5.10 (s, 2H), 4.41 (q, 2H, J=7.27 Hz), 4.13 (d, 2H, J=3.66 Hz), 2.43-2.47 (m, 2H), 1.94-2.02 9 m, 2H), 1.79-1.85 (m, 2H), 1.65-1.72 (m, 2H), 1.40 (t, 3H, J=7.17). LCMS (M+H)=428.26.
Reaction SMILES: [NH:1]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[C@H:2]([C:15]([NH:17][C@H:18]([C:26]([NH:28]N)=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Cl.N(OC(C)(C)C)=O.[CH3:48][O:49][C:50]([C@@H:52](N)[CH2:53][C:54]1[NH:58][CH:57]=[N:56][CH:55]=1)=[O:51].Cl.Cl>CN(C)C=O.O1CCOCC1.O.C(N(CC)CC)C>[NH:1]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[C@H:2]([C:15]([NH:17][C@H:18]([C:26]([NH:28][C@H:52]([C:50]([O:49][CH3:48])=[O:51])[CH2:53][C:54]1[N:58]=[CH:57][NH:56][CH:55]=1)=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: COC(=O)[C@@H](N)Cc1cnc[nH]1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)NN
Agent: CC(C)(C)ON=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
5.4 g of Z-Lys(BOC)-Phe-NH-NH2 in 40 ml of dimethylformamide are mixed at -16°C with 6.8 ml of 3.66 N HCl in dioxane and then with 1.5 ml of t-butyl nitrite. After 10 minutes at -10°C to -15°C, 3.5 ml of triethylamine are added. 3.64 g of H-His-OMe. 2 HCl are added in the solid form and 4.2 ml of triethylamine are thereafter added dropwise. The mixture is allowed to warm to 0°C over the course of 1 hour, with a pH of about 7 being set up by adding a total of 0.8 ml of triethylamine. After stirring overnight at 0°C the mixture is poured into 250 ml of water and the smeary product is obtained in the form of a powder by triturating with water. In a thin layer chromatogram on silica gel in chloroform-methanol (9:1) Rf = 0.4. Melting point 136°-137°C (from ethyl acetate).
Reaction SMILES: ClC(N(C)C)=C(C)C.[CH3:9][N:10]([CH3:37])[C:11]([C:13]1[N:14]=[CH:15][C:16]([O:19][C:20]2[CH:21]=[C:22]([CH:26]=[C:27]([O:29][C@H:30]3[CH2:34][CH2:33][N:32]([CH3:35])[C:31]3=[O:36])[CH:28]=2)[C:23]([OH:25])=O)=[N:17][CH:18]=1)=[O:12].[CH3:38][C:39]1[N:40]=[C:41]([NH2:44])[S:42][CH:43]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:37][N:10]([CH3:9])[C:11]([C:13]1[CH:18]=[N:17][C:16]([O:19][C:20]2[CH:21]=[C:22]([C:23](=[O:25])[NH:44][C:41]3[S:42][CH:43]=[C:39]([CH3:38])[N:40]=3)[CH:26]=[C:27]([O:29][C@H:30]3[CH2:34][CH2:33][N:32]([CH3:35])[C:31]3=[O:36])[CH:28]=2)=[CH:15][N:14]=1)=[O:12]
Reactant: CN(C)C(=O)c1cnc(Oc2cc(O[C@H]3CCN(C)C3=O)cc(C(=O)O)c2)cn1
Reactant: Cc1csc(N)n1
Agent: CC(C)=C(Cl)N(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1csc(NC(=O)c2cc(Oc3cnc(C(=O)N(C)C)cn3)cc(O[C@H]3CCN(C)C3=O)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
1-Chloro-N,N,2-trimethyl-prop-1-en-1-amine (0.14 mL, 1.1 mmol) was added to a solution of 3-[5-(dimethylcarbamoyl)pyrazin-2-yl]oxy-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-benzoic acid (Intermediate 45) (358 mg, 0.9 mmol) in DCM (7 mL) and stirred at ambient temperature for 30 minutes. 4-Methyl-1,3-thiazol-2-amine (CAS no. 1603-91-4) (206 mg, 1.8 mmol) and pyridine (0.15 mL, 1.8 mmol) were added and the reaction stirred for 20 hours. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (30 mL), washed with water (2×10 mL) and brine (10 mL), dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica eluting with a gradient of 0 to 5% methanol in DCM to afford the product (200 mg, 45%). 1H NMR δ (300 MHz, CDCl3) 2.09-2.22 (m, 1H), 2.25 (s, 3H), 2.50-2.65 (m, 1H), 2.93 (s, 3H), 3.18 (d, 6H), 3.34-3.55 (m, 2H), 4.86 (t, 1H), 6.56 (s, 1H), 7.16 (s, 1H), 7.37 (s, 1H), 7.54 (s, 1H), 8.37 (s, 1H), 8.51 (s, 1H), 10.0-11.0 (br s, 1H); m/z 497 (M+H+).
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=2[N:3]=1.[NH2:25][C:26]1[C:27]([CH3:33])=[N:28][N:29]([CH3:32])[C:30]=1[CH3:31].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[Cl:19][C:18]1[C:4]2[N:3]=[C:2]([NH:25][C:26]3[C:27]([CH3:33])=[N:28][N:29]([CH3:32])[C:30]=3[CH3:31])[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]=2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=1
Reactant: CCOC(=O)CCCn1c(Cl)nc2c(Cl)ccc(C(CC)CC)c21
Reactant: Cc1nn(C)c(C)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)CCCn1c(Nc2c(C)nn(C)c2C)nc2c(Cl)ccc(C(CC)CC)c21
Temperature: 150 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
A mixture of ethyl 4-[2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (Reference Example 33; 371 mg, 1.00 mmol), 4-amino-1,3,5-trimethylpyrazole (375 mg, 3.00 mmol) and p-toluenesulfonic acid monohydrate (190 mg, 1.00 mmol) in 1-methyl-2-pyrrolidinone (3 mL) was stirred at 150° C. for 16 hr. After cooling, aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. Organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 0-5% methanol/ethyl acetate gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound (340 mg, 0.74 mmol, 74%) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:4]=1[CH2:5][N:6]([CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[CH2:26])[C:7]([C@H:9]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:10]C=C)=[O:8]>Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1.ClCCl>[CH3:1][O:2][C:3]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:4]=1[CH2:5][N:6]1[CH2:24][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:26][CH2:10][C@@H:9]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:7]1=[O:8]
Reactant: C=CC[C@@H](NC(=O)OCc1ccccc1)C(=O)N(CC(=C)c1ccccc1)Cc1ccc(OC)cc1OC
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: ClCCl
Product: COc1ccc(CN2CC(c3ccccc3)=CC[C@@H](NC(=O)OCc3ccccc3)C2=O)c(OC)c1
Temperature: 40 °C
Reaction time: 40 h
Yield: 52.3 %

Procedure:
[1,3-bis-(2,4,6-trimethylphenyl-2-imidazolidinylidene)dichloro(phenylmethylene)-(tricyclohexylphosphine)ruthenium] (Grubbs second generation catalyst) (0.68 g, 0.79 mmol) was added to a solution of benzyl (1R)-1-{[(2,4-dimethoxybenzyl)(2-phenylprop-2-enyl)amino]carbonyl}but-3-enylcarbamate (2.02 g, 3.93 mmol) in dichloromethane (395 mL) and heated to 40° C. After 40 h, the mixture was allowed to cool to ambient temperature and concentrated. Purification by silica gel chromatography (5% ethyl acetate/hexanes→30% ethyl acetate/hexanes) gave the title compound (1.00 g). MS 487 (M+1). 1H NMR (500 MHz, CDCl3) δ 7.39-7.31 (m, 5H), 7.26-7.19 (m, 3H), 7.17 (d, J=8.3 Hz, 1H), 6.99 (d, J=7.1 Hz, 2H), 6.41 (dd, J=8.3, 2.0 Hz, 1H), 6.33 (s, 1H), 6.22 (d, J=6.4 Hz, 1H), 5.77-5.76 (m, 1H), 5.16-5.09 (m, 3H), 4.82 (d, J=14.7 Hz, 1H), 4.65 (dd, J=17.6, 2.7 Hz, 1H), 4.54 (d, J=14.4 Hz, 1H), 3.93 (d, J=17.6 Hz, 1H), 3.77 (s, 3H), 3.64 (s, 3H), 2.91-2.86 (m, 1H), 2.42-2.36 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].C[O:23][CH:24]1[CH:28]([CH:29]=O)[CH2:27][CH:26](OC)O1>C(O)(=O)C.C(OCC)(=O)C>[CH:24]([C:28]1[CH:27]=[CH:26][N:1]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:18])=[O:19])[C:5]3=[O:21])[CH:29]=1)=[O:23]
Reactant: COC1CC(C=O)C(OC)O1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(N)cc2c1=O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(-n3ccc(C=O)c3)cc2c1=O

Procedure:
A solution of N-(6-amino-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (470 mg, 1.49 mmol) and 2,5-dimethoxytetrahydrofuran-3-aldehyde (796 mg, 4.47 mmol) in acetic acid (0.5 ml) is refluxed for five hours. The solvent is removed by rotavapor evaporation to give a brown oil which is dissolved in ethyl acetate and washed three times with water. The organic layer is dried over magnesium sulfate, filtered and the solvent removed by rotavapor evaporation to give the title compound nearly pure as a brown solid, m.p. 230-245° C. (decomp).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=O)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[S:26])=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C(Nc1ccc(F)cc1)c1ccccn1
Solvent: Cc1ccccc1
Product: Fc1ccc(NC(=S)c2ccccn2)cc1
Yield: 53.6 %

Procedure:
N-(4-fluorophenyl)-2-pyridinecarboxamide (11.47 g, 53.0 mmol) and Lawesson's reagent (25.75 g, 63.7 mmol) were refluxed in toluene for 6.5 hours, preadsorbed onto silica gel, and flash chromatographed (500 g of silica gel eluted with 15% ethyl acetate in petroleum ether) affording N-(4-fluorophenyl)-2-pyridinecarbothioamide as a yellow solid (6.60 g, 54%) m.p. 82°-85° C.