Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.Br.Br.[CH2:4]([C:6]1[C:7]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([C:23]4[NH:24][C:25]5[CH2:30][CH2:29][NH:28][CH2:27][C:26]=5[N:31]=4)=[N:19][NH:20]3)=[CH:16][CH:15]=2)=[CH:8][C:9]([F:13])=[C:10]([OH:12])[CH:11]=1)[CH3:5].[O:32]([C:39]1[CH:47]=[CH:46][C:42]([C:43](O)=[O:44])=[CH:41][N:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:4]([C:6]1[CH:11]=[C:10]([OH:12])[C:9]([F:13])=[CH:8][C:7]=1[C:14]1[CH:22]=[C:21]2[C:17]([C:18]([C:23]3[NH:24][C:25]4[CH2:30][CH2:29][N:28]([C:43]([C:42]5[CH:41]=[N:40][C:39]([O:32][C:33]6[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=6)=[CH:47][CH:46]=5)=[O:44])[CH2:27][C:26]=4[N:31]=3)=[N:19][NH:20]2)=[CH:16][CH:15]=1)[CH3:5]
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNC4)n[nH]c2c1
Reactant: O=C(O)c1ccc(Oc2ccccc2)nc1
Agent: Br
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3ccc(Oc5ccccc5)nc3)C4)n[nH]c2c1
Yield: 6.7 %

Procedure:
The title compound was prepared from 5-ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-phenol trihydrobromide salt (Preparation 25, 50 mg, 80 μmol) and 6-phenoxy-nicotinic acid (17 mg, 80 μmol) using the method of Example 1. The crude material was purified by HPLC Method A to afford 3.1 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[F:8][C:9]([F:27])([F:26])[C:10]1[C:15]([CH:16]([C:18]2[C:19]([O:24][CH3:25])=[N:20][CH:21]=[N:22][CH:23]=2)[OH:17])=[CH:14][N:13]=[CH:12][N:11]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C>C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>[F:27][C:9]([F:8])([F:26])[C:10]1[C:15]([CH:16]([C:18]2[C:19]([O:24][CH3:25])=[N:20][CH:21]=[N:22][CH:23]=2)[O:17][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])=[CH:14][N:13]=[CH:12][N:11]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1ncncc1C(O)c1cncnc1C(F)(F)F
Agent: CN(C)c1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ncncc1C(OC(=O)C(C)(C)C)c1cncnc1C(F)(F)F
Yield: 80.1 %

Procedure:
Trimethylacetyl chloride (36 μl, 35.1 mg, 0.28 mmol, 3.2 equivalent) was added via syringe to a solution of 1-(4-trifluoromethylpyrimidin-5-yl)-1-(4-methoxypyrimidin-5-yl)methanol (25.1 mg, 0.0877 mmol), triethylamine (70 μl, 50.5 mg, 0.50 mmol, 5.7 equivalents) and dimethylaminopyridine (DMAP) (cat.) in toluene (5 ml) and the solution heated to reflux for 2 hours. The solution was cooled, diluted with NaHCO3 (sat.), and extracted with EtOAc (3 times). The combined extracts were washed with brine (sat.), dried (MgSO4), filtered and concentrated in vacuo. Preparative thin layer chromatography (SiO2 ; hexane/EtOAc, 1:1) gave 26 mg of 1-(4-trifluoromethylpyrimidin-5-yl)-1-(4-methoxypyrimidin-5-yl)-1-trimethylacetoxymethane as a solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:6][CH:5]=1.[C:15]([C:19]1[CH:29]=[CH:28][C:22]([O:23][CH2:24][C:25](Cl)=[O:26])=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16]>N1C=CC=CC=1>[C:15]([C:19]1[CH:29]=[CH:28][C:22]([O:23][CH2:24][C:25]([NH:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:8][CH:9]=2)=[O:26])=[CH:21][CH:20]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1
Reactant: CC(C)(C)c1ccc(OCC(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(OCC(=O)NCc2ccc(NS(C)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.3 %

Procedure:
To a stirred pyridine (15 ml) suspension of N-[4-(aminomethyl)-phenyl]methane sulfonamide hydrochloride (376 mg, 1.59 mmol) was added (4-tert-butylphenoxy)acetic acid chloride (300 mg, 1.3 mmol) at 0° C. and the mixture was stirred for 1 hour at ambient temperature. The reaction was then partitioned with ethylacetate and 2M aqueous solution of hydrogen chloride and the organic layer was separated, washed with brine, dried over magnesium sulfate. Then, filtration to remove magnesium sulfate, evaporation under reduced pressure gave the residue, which was applied to a silica gel chromatography column and eluted with a volume mixture of hexane/ethylacetate (1/1 to 1/2) to furnish 240 mg (62% yield) of title compound as a white solid.
Reaction SMILES: C([O-])(=[O:3])C.[NH4+].[N+]([C@@H:9]1[CH2:14][CH2:13][C:12](=[O:15])[NH:11][C@H:10]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([O-])=O.C[O-].[Na+].Cl>O.CO.[Cl-].[Cl-].[Cl-].[Ti+3]>[O:15]=[C:12]1[CH2:13][CH2:14][C:9](=[O:3])[CH:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:11]1
Reactant: CC(=O)[O-]
Reactant: O=C1CC[C@@H]([N+](=O)[O-])[C@H](c2ccccc2)N1
Agent: [Ti+3]
Agent: C[O-]
Agent: Cl
Solvent: CO
Solvent: O
Product: O=C1CCC(=O)C(c2ccccc2)N1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a 5L flask containing ammonium acetate (450g) which had been thoroughly purged with nitrogen was added a freshly prepared solution of titanium trichloride (300 g, 1.95 mol) in deoxygenated water (2.1L) with ice-bath cooling. To the resulting green solution was added a solution of trans-3-nitro-6-oxo-2-phenylpiperidine (Example 1a, 90 g, 0.409 mol) and sodium methoxide (27 g, 0.5 mol) in methanol (750 ml). The solution was stirred for 1 hr at 0° C. and for a further 1 hr at room temperature. Concentrated hydrochloric acid (240 ml) was added dropwise, and the resulting mixture extracted with ethyl acetate (1000 ml, 3×500 ml). The combined organic extracts were washed with saturated brine (1000 ml), dried (MgSO4), and evaporated under reduced pressure. The residue was suspended in ether and filtered and the pale yellow crystalline solid was washed with ether (3×100 ml) and dried in vacuo to afford 2,5-dioxo-6-phenylpiperidine (58 g, 75%): m.p. 160°-164° C.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[O:3].Cl.[CH2:8]([O:15][C:16](=[O:19])[CH2:17][NH2:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([O:15][C:16](=[O:19])[CH2:17][NH:18][C:1](=[O:5])[C:2]([CH3:4])=[O:3])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)C(=O)Cl
Reactant: NCC(=O)OCc1ccccc1
Agent: Cl
Product: CC(=O)C(=O)NCC(=O)OCc1ccccc1
Yield: 85 %

Procedure:
The improved method of synthesis involves the reaction of sodium pyruvate with thionyl chloride or preferably with oxalyl chloride to form pyruvyl chloride. The pyruvyl chloride is then reacted with glycine benzyl ester hydrochloride to form the pyruvyl-glycine benzyl ester, with a yield of about 85%. The pyruvyl-glycine benzyl ester then undergoes hydrogenolysis to obtain pyruvyl-glycine with a yield of about 90%. It can be readily appreciated that the ultimate yield of pyruvyl-glycine using this improved method is substantially higher than the yield associated with the traditional method of synthesis. This improved method is set forth below.
Reaction SMILES: [Cl:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:11][NH:12][CH3:13].[O:14]=[C:15]1[CH2:20][O:19][C:18]2[CH:21]=[C:22](/[CH:25]=[CH:26]/[C:27]([OH:29])=O)[CH:23]=[N:24][C:17]=2[NH:16]1.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.CN(C)CCCN=C=NCC>CN(C=O)C.O>[Cl:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:11][N:12]([CH3:13])[C:27](=[O:29])/[CH:26]=[CH:25]/[C:22]1[CH:23]=[N:24][C:17]2[NH:16][C:15](=[O:14])[CH2:20][O:19][C:18]=2[CH:21]=1
Reactant: O=C(O)/C=C/c1cnc2c(c1)OCC(=O)N2
Reactant: CNCc1oc2ccccc2c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1oc2ccccc2c1Cl)C(=O)/C=C/c1cnc2c(c1)OCC(=O)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.1 %

Procedure:
To a solution of (3-chlorobenzofuran-2-yl)-N-methylmethanamine (100 mg, 0.51 mmol) in DMF (5 mL) were added in sequential order (E)-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)acrylic acid (107 mg, 0.46 mmol), 1-hydroxybenzotriazole (71 mg, 0.51 mmol), diisopropylethylamine (243 uL, 1.39 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (102 mg, 0.51 mmol). The mixture was stirred at room temperature overnight, cooled in an ice bath and water was added with rapid stirring. The product precipitated and was filtered, triturated with ether and dried to yield title compound as a white solid (55 mg, 30%): 1H NMR (400 MHz, CDCl3) δ 9.21 (s, 1H), 8.12-8.19 (m, 1H), 7.28-7.6 (m, 7H), 4.81-4.95 (rotamers, 2s, 2H), 4.714 (s, 2H); 3.21 (s, 3H); MS (ESI) m/e 398 (C20H16ClN3O4+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18](O)=[O:19])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1.[C:27]([O:31][C:32](=[O:43])[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[C:37]([F:42])[CH:36]=1)([CH3:30])([CH3:29])[CH3:28].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:27]([O:31][C:32](=[O:43])[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([NH:41][C:18](=[O:19])[CH:17]([C:16]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:9]=[C:10]3[C:15]=2[CH2:14][CH2:13][CH2:12][CH2:11]3)[CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)=[C:37]([F:42])[CH:36]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: O=C(O)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1
Reactant: CC(C)(C)OC(=O)CCc1ccc(N)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCc1ccc(NC(=O)C(c2c3c(nn2-c2ccc(Cl)cc2)CCCC3)C2CCCCC2)c(F)c1

Procedure:
In analogy to the procedure described in example 59, [2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-cyclohexyl-acetic acid (example 5.1) was reacted with 3-(4-amino-3-fluoro-phenyl)-propionic acid tert-butyl ester in the presence of DIPEA and HATU in DMF to give the title compound yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[O:17])=[CH:12][CH:11]=2)[CH:9]=1)=[O:4].CO.O1CCCC1.[BH4-].[Na+]>C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cnn(-c2ccc(C=O)cc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cnn(-c2ccc(CO)cc2)c1
Reaction time: 0.25 h
Yield: 103.1 %

Procedure:
A mixture of 1-(4-formylphenyl)-1H-pyrazol-4-carboxylic acid methyl ester (1.00 g), methanol (10 ml) and tetrahydrofuran (25 ml) was treated with sodium borohydride at 0° C. After 15 minutes, the mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate, filtered, and concentrated by evaporation to give 1-(4-hydroxymethylphenyl)-1H-pyrazol-4-carboxylic acid methyl ester (1.04 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:16])([CH3:15])[C:7](=[O:14])[N:8]2[CH:11]2[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[F:17][C:18]1[C:23]([C:24](O)=[O:25])=[CH:22][C:21]([CH3:27])=[N:20][CH:19]=1>>[CH:11]1([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:24](=[O:25])[C:23]4[C:18]([F:17])=[CH:19][N:20]=[C:21]([CH3:27])[CH:22]=4)[CH:10]=3)[C:6]([CH3:16])([CH3:15])[C:7]2=[O:14])[CH2:12][CH2:13]1
Reactant: CC1(C)C(=O)N(C2CC2)c2cc(N)ccc21
Reactant: Cc1cc(C(=O)O)c(F)cn1
Product: Cc1cc(C(=O)Nc2ccc3c(c2)N(C2CC2)C(=O)C3(C)C)c(F)cn1

Procedure:
Prepared in analogy to example 26 from 6-amino-1-cyclopropyl-3,3-dimethyl-1,3-dihydro-indol-2-one (example 14c) and 5-fluoro-2-methyl-isonicotinic acid (prepared according to U. Abel et al., WO200645514). The title compound was obtained as light yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[C:20]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=2)[N:19]([CH2:32][C:33](=[O:39])[NH:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:18]3=[O:40])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.FC(F)(F)C(O)=O>>[C:35]([NH:34][C:33](=[O:39])[CH2:32][N:19]1[C:18](=[O:40])[C:17]2[C:22](=[CH:23][CH:24]=[C:15]([N:11]3[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]3)[CH:16]=2)[N:21]=[C:20]1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=1)([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)NC(=O)Cn1c(-c2cccc(Cl)c2)nc2ccc(N3CCCN(C(=O)OC(C)(C)C)CC3)cc2c1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)Cn1c(-c2cccc(Cl)c2)nc2ccc(N3CCCNCC3)cc2c1=O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 67.6 %

Procedure:
4-[3-(tert-Butylcarbamoylmethyl)-2-(3-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-6-yl]perhydro-1,4-diazepine-1-carboxylic acid tert-butyl ester (INTERMEDIATE VIII.1) (38.9 mg, 0.068 mmol) was treated with TFA:DCM (1:1 (v/v), 1 mL) and the solution stirred at room temperature for 40 min. The volatiles were removed in vacuo and the residue partitioned between DCM and 1 M NaOH (aq.). The organics were dried (Na2SO4) and concentrated in vacuo to yield N-tert-butyl-2-[2-(3-chlorophenyl)-4-oxo-6-perhydro-1,4-diazepin-1-yl-4H-quinazolin-3-yl]acetamide (EXAMPLE 1a) (27 mg, 0.046 mmol, 68%) as the trifluoroacetic acid salt.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:10]=1[O:11][CH2:12][CH2:13]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(Cl)(=O)=O.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:38]=[CH:39][C:40]=1[O:41][CH3:42])[CH2:32][CH2:33][N:34](CC)[CH3:35]>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:10]=1[O:11][CH2:12][CH2:13][N:34]([CH2:33][CH2:32][C:31]1[CH:38]=[CH:39][C:40]([O:41][CH3:42])=[C:29]([O:28][CH3:27])[CH:30]=1)[CH3:35])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(OCCO)c(OCc2ccccc2)c1
Reactant: CCN(C)CCc1ccc(OC)c(OC)c1
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COc1ccc(CCN(C)CCOc2ccc([N+](=O)[O-])cc2OCc2ccccc2)cc1OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
2-(2-Benzyloxy-4-nitrophenoxy)ethanol (400 mg, 1.383 mmol) was dissolved in pyridine (5 ml); after cooling at 0° C., methanesulfonyl chloride (0.22 ml, 2.76 mmol) was slowly added dropwise, followed by stirring at room temperature for 2 h. The solvent was evaporated under vacuum and the residue was diluted with a saturated aqueous solution of sodium bicarbonate (10 ml), followed by extraction with chloroform (100 ml). The extracted organic layer was dried with sodium sulfate and the solvent was evaporated; the resulting residue was dissolved in 15 ml of a 1:2 solvent system of ethanol and acetonitrile and, thereafter, 2-[N-(3,4-dimethoxyphenethyl)-N-methylamino]ethane (0.765 ml, 4.148 mmol) was added, followed by stirring at the reflux temperature for 8 h. The reaction solution was cooled to room temperature and thereafter the solvent was evaporated; the resulting residue was purified by being subjected to column chromatography on silica gel using a 1:1 solvent system of n-hexane and ethyl acetate as an eluent. The fractions containing the product were collected and the solvent was evaporated to yield the end compound 1-(2-benzyloxy-4-nitrophenoxy)-2-[N-(3,4-dimethoxyphenethyl)-N-methylamino]ethane (600 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([N+:18]([O-:20])=[O:19])[C:15]([F:17])=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=O)[CH3:6])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:22])[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([N+:18]([O-:20])=[O:19])[C:15]([F:17])=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[S:32])[CH3:6])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)C(C)N1C(=O)COc2cc(F)c([N+](=O)[O-])cc21
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)N1C(=S)COc2cc(F)c([N+](=O)[O-])cc21
Temperature: 25 °C
Yield: 85.3 %

Procedure:
A suspension of 2-(7-fluoro-6-nitro-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (1.170 g, 3.75 mmol) and Lawesson's reagent (1.516 g, 3.75 mmol) in toluene (40 mL) was heated at reflux for 3 h then cooled to ambient temperature. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column on silica gel (eluting with 0%˜10% EtOAc in petroleum ether) to give 2-(7-fluoro-6-nitro-3-thioxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester as a light yellow solid (1.05 g, 85%). 1H NMR (DMSO-d6, 400 MHz): δ 7.86 (d, J=6.8 Hz, 1H), 7.43 (d, J=11.6 Hz, 1H), 6.16 (brs, 1H), 5.07 (s, 2H), 4.02-4.10 (q, J=7.2 Hz, 2H), 1.58 (d, J=6.8 Hz, 3H), 1.04 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Li]CCCC.[Br:6][C:7]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=[C:9](Br)[CH:8]=1.B(OC)(OC)[O:19]C>C1COCC1>[Br:6][C:7]1[CH:8]=[C:9]([OH:19])[CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1
Reactant: COB(OC)OC
Reactant: CC(C)(C)c1cc(Br)cc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(O)cc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring solution of 34 mL of 1.6 M n-BuLi in hexanes in 20 mL of THF at −78° C. was added 8.15 g of 1,3-dibromo-5-tert-butylbenzene in 80 mL of THF dropwise over a period of 1 h. After 1 h at −78° C., 4.6 mL of B(OMe)3 was added, and after 20 min. the cold bath was removed and stirring continued with warming to r.t. After 1 h, EtOAc and 70 mL of 1 N HCl were added, and the layers were separated. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. To a stirring mixture of the crude product in 105 mL of 1 N NaOH at 0° C. was added 22 mL of H2O2 (30 wt % in H2O) dropwise. After 25 min. 5 N HCl was added to a pH=1. Ethyl acetate was added, and the organic layer was washed with 80 mL of brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (hexanes to 10% EtOAc/hexanes) provided 6.54 g of 3-bromo-5-tert-butylphenol as an orange oil with some impurity.
Reaction SMILES: Cl.[CH3:2][Si:3]([CH3:20])([CH3:19])[CH2:4][CH2:5][O:6][CH2:7][N:8]1[C:12]2=[N:13][CH:14]=[C:15]([NH:17][NH2:18])[N:16]=[C:11]2[CH:10]=[CH:9]1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][C@@H:31]([CH3:34])[C@H:30]([C:35](O)=[O:36])[CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][C@@H:31]([CH3:34])[C@H:30]([C:35]([NH:18][NH:17][C:15]2[N:16]=[C:11]3[CH:10]=[CH:9][N:8]([CH2:7][O:6][CH2:5][CH2:4][Si:3]([CH3:20])([CH3:19])[CH3:2])[C:12]3=[N:13][CH:14]=2)=[O:36])[CH2:29]1)=[O:27])([CH3:23])([CH3:24])[CH3:22]
Reactant: C[Si](C)(C)CCOCn1ccc2nc(NN)cnc21
Reactant: C[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1C(=O)O
Agent: Cl
Product: C[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1C(=O)NNc1cnc2c(ccn2COCC[Si](C)(C)C)n1
Yield: 24.8 %

Procedure:
A mixture of [5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-hydrazine hydrochloride (510 mg, 1.6 mmol, from example 15) and trans-(+/−)-4-methyl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester (480 mg, 1.9 mmol) were reacted under similar conditions to those described in example 16,to provide a crude product. Purification by preparative TLC, eluting with 55% ethyl acetate in hexanes afforded 200 mg of (+/−)-3-{N′-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-hydrazinocarbonyl}-trans-4-methyl-piperidine-1-carboxylic acid tert-butylester as a brown viscous oil. MS (M+H)+=505.
Reaction SMILES: [Li]CCCC.[CH3:6][O:7][C:8](=[O:16])[CH2:9][C@H:10]([CH3:15])[CH2:11][C:12]([OH:14])=[O:13].Cl[C:18]([O:20][CH3:21])=[O:19].Cl>C1COCC1>[CH3:6][O:7][C:8](=[O:16])[CH:9]([C:18]([O:20][CH3:21])=[O:19])[C@H:10]([CH3:15])[CH2:11][C:12]([OH:14])=[O:13]
Reactant: COC(=O)C[C@H](C)CC(=O)O
Reactant: COC(=O)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)OC)[C@H](C)CC(=O)O
Temperature: -78 °C
Yield: 99.7 %

Procedure:
To a 250 mL round-bottomed flask equipped with a stirbar and purged with nitrogen, was added 30 mL anhydrous THF followed by DIPA (2.21 g, 3.5 eq, 21.85 mmol). The mixture was cooled to −78° C. with stirring, n-BuLi (2.5 M, 3.3 eq, Aldrich) was then added dropwise, and the reaction was stirred for 10 min. To the flask was slowly added (R)-5-methoxy-3-methyl-5-oxopentanoic acid (1 g, 6.25 mmol, in 10.0 mL THF, Sumitomo) over about 2 min. After 30 min stirring at −78° C., a solution of methyl chloroformate (2.1 eq, 13.13 mmol) in THF (10 mL) was slowly added to the mixture. After the addition was complete, the reaction mixture was allowed warm to room temperature overnight. The reaction mixture was adjusted to about pH 5 to 6 (using pH paper), with cooling to maintain about ambient temperature using 2N aq. HCl. The reaction mixture was concentrated under reduced pressure, diluted with 75 mL EtOAc and 25 mL aq. 1N HCl. The layers were separated and the aqueous phase was extracted (2×15 mL EtOAc). The combined organics were washed with saturated aqueous NaCl (1×15 mL), dried over MgSO4, and concentrated under reduced pressure to give the product (1.36 g), which was used in the subsequent step without purification.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[CH2:14][CH2:13][CH2:12][C:11]=2[C:5]2[O:6][CH:7]([CH2:9][NH2:10])[CH2:8][C:4]=2[CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27].CC1C=CC(S(OC)(=O)=O)=CC=1>>[Cl:1][C:2]1[C:15]2[CH2:14][CH2:13][CH2:12][C:11]=2[C:5]2[O:6][CH:7]([CH2:9][NH:10][C:26](=[O:27])[O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:8][C:4]=2[CH:3]=1
Reactant: NCC1Cc2cc(Cl)c3c(c2O1)CCC3
Reactant: O=C(Cl)OCc1ccccc1
Agent: COS(=O)(=O)c1ccc(C)cc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2cc(Cl)c3c(c2O1)CCC3)OCc1ccccc1
Yield: 82.7 %

Procedure:
Treatment of (±)-1-(5-chloro-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methanamine (0.51 g, 1.96 mmol) with diisopropylethylamine (0.76 g, 5.88 mmol) followed by benzyl chloroformate (0.50 g, 2.94 mmol) generally according to the procedure described for Intermediate 7 provided 0.58 g (84%) of (±)-benzyl (5-chloro-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methylcarbamate as a white solid. mp 118-121° C.; Anal. calcd. for C20H20ClNO3: C, 67.13; H, 5.63; N, 3.91. Found: C, 66.95; H, 5.93; N, 3.82. Chiral HPLC separation of (±)-benzyl (5-chloro-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methylcarbamate (Chiralpak AD, hexane:isopropanol 9:1) provided two fractions. Fraction 1 (Rt=11.191 min, Chiralpak AD, hexane:isopropanol 9:1); Fraction 2 (Rt=12.735 min, Chiralpak AD, hexane:isopropanol 9:1).
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][C:9](=[S:29])[NH:10][C:11]2[S:21][C:14]3[CH2:15][O:16][C:17]([CH3:20])([CH3:19])[CH2:18][C:13]=3[C:12]=2[C:22]([O:24]C(C)(C)C)=[O:23])=[O:7])=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9](=[S:29])[NH:10][C:11]2[S:21][C:14]3[CH2:15][O:16][C:17]([CH3:20])([CH3:19])[CH2:18][C:13]=3[C:12]=2[C:22]([OH:24])=[O:23])=[O:7])=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)c1c(NC(=S)NC(=O)c2ccc(F)cc2)sc2c1CC(C)(C)OC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)Cc2c(sc(NC(=S)NC(=O)c3ccc(F)cc3)c2C(=O)O)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.8 %

Procedure:
A solution of 40% v/v TFA/DCM (20 mL) was added to tert-butyl 2-(3-(4-fluorobenzoyl)thioureido)-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (0.33 g, 0.71 mmol) and the mixture was stirred at RT for 1 hour. The volatiles were removed at 30° C. and the material was purified by reverse-phase chromatography (10-100% MeCN/water). 2-(3-(4-Fluorobenzoyl)thioureido)-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylic acid (0.21 g, 0.51 mmol, 72% yield) was isolated as a pale, yellow solid. 1H NMR (400 MHz, DMSO) δ 14.81 (s, 1H), 13.36 (s, 1H), 11.83 (s, 1H), 8.11-8.00 (m, 2H), 7.38 (apparent t, J=8.9 Hz, 2H), 4.66 (s, 2H), 2.74 (s, 2H), 1.23 (s, 6H). 13C NMR (101 MHz, DMSO) δ 174.33, 166.13, 165.72, 165.35, 163.63, 146.76, 131.80, 131.70, 129.08, 128.60, 128.57, 124.06, 116.48, 115.54, 115.32, 70.12, 58.80, 37.25, 26.16. LCMS retention time: 3.206 min; LCMS purity at 214 nm=98%. HRMS m/z calculated for C18H18FN2O4S2 [M++1]: 409.0687. found 409.0687. Melting point 205.3° C., decomposition.