Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][N:20]2[CH2:29][CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([S:30]([N:33](CC4C=CC(OC)=CC=4OC)[C:34]4[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]5[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=5)=[CH:36][C:35]=4[F:51])(=[O:32])=[O:31])[CH:26]=3)[CH2:21]2)=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9].C(Cl)(Cl)Cl.C(=O)([O-])O.[Na+]>C1(OC)C=CC=CC=1>[C:8]([C:12]1[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][N:20]2[CH2:29][CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([S:30]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]5[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=5)=[CH:36][C:35]=4[F:51])(=[O:31])=[O:32])[CH:26]=3)[CH2:21]2)=[CH:16][CH:17]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: COc1ccc(CN(c2ccc(OCCCCc3ccccc3)cc2F)S(=O)(=O)c2ccc3c(c2)CCN(CCc2ccc(C(C)(C)C)cc2)C3)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1ccc(CCN2CCc3cc(S(=O)(=O)Nc4ccc(OCCCCc5ccccc5)cc4F)ccc3C2)cc1
Reaction time: 21 h

Procedure:
Trifluoroacetic acid (1 mL) was added to a turbid solution of 2-[2-(4-tert-butylphenyl)ethyl]-N-(2,4-dimethoxybenzyl)-N-[2-fluoro-4-(4-phenylbutoxy)phenyl]-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide obtained (440 mg) in anisole (5 mL) and chloroform (5 mL) while cooling in ice, and the mixture was stirred for 21 hr while cooling in ice. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture while cooling in ice and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate and then the desiccant was filtered off, followed by concentration under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=3:1→ethyl acetate only) to afford the title compound as a colorless amorphous substance (240 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][OH:15])[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[C:18](OC)([CH3:20])[CH3:19]>C1(C)C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>[CH3:19][C:18]1([CH3:20])[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@@H:9]([C:10]([O:12][CH3:13])=[O:11])[CH2:14][O:15]1
Reactant: COC(=O)[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 110 °C
Reaction time: 8 h
Yield: 63.6 %

Procedure:
A solution of methyl (2R)-2-{[(tert-butoxy)carbonyl]amino}-3-hydroxypropanoate (22 g, 0.1 mol), 2,2-dimethoxypropane (20.8 g, 0.2 mol) and 4-methylbenzene-1-sulfonic acid (0.5 g) in toluene was heated with stirring at 110° C. overnight. The solvent was removed under reduced pressure. The residue was treated with ethyl acetate, washed with water and brine. The organic layer was dried over sodium sulfate, concentrated under reduced pressure. The residue distilled at 0.6 mbar to give 16.5 g of 3-tert-butyl 4-methyl (4R)-2,2-dimethyl-1,3-oxazolidine-3,4-dicarboxylate (yield was 63.6%) as an amber oil.
Reaction SMILES: C(O)(C(F)(F)F)=O.O=C1NC[C@H]([C@H](O[C:17]2[C:18]3[N:19]([N:35]=[CH:36][C:37]=3[C:38]#[N:39])[CH:20]=[C:21](C3C=CC(N4CCNCC4)=CC=3)[N:22]=2)C)C1.CCN(C(C)C)C(C)C.O1CC(=O)C1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[N:35]1[N:19]2[CH:20]=[CH:21][N:22]=[CH:17][C:18]2=[C:37]([C:38]#[N:39])[CH:36]=1
Reactant: C[C@@H](Oc1nc(-c2ccc(N3CCNCC3)cc2)cn2ncc(C#N)c12)[C@H]1CNC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C1COC1
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cnn2ccncc12
Temperature: 50 °C
Reaction time: 3 h

Procedure:
The crude TFA salt of 5.67 (0.089 mmol) was taken up in THF (2 mL) and was treated with iPr2NEt (16 μL, 0.089 mmol), 3-oxetanone (29 μL, 0.45 mmol) and sodium triacetoxyborohydride (132 mg, 0.62 mmol). The resulting mixture was heated to 50° C. and was stirred for 3 h. The reaction mixture was then partitioned between DCM, water, and 5% (w/v) saturated aqueous Na2CO3 and the phases were separated. The aqueous phase was extracted with DCM (3×20 mL) and the combined organics were dried over Na2SO4, filtered, and concentrated. The concentrate was purified by silica gel chromatography (0-20% MeOH in DCM) to provide 6-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-4-4R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyrazine-3-carbonitrile 5.70. LCMS-ESI+ (m/z): [M+H]+ calcd for C26H30N7O3: 488.2; found: 488.0. 1H NMR (400 MHz, Chloroform-d) δ 8.40 (s, 1H), 8.18 (s, 1H), 7.84-7.77 (m, 2H), 7.03-6.96 (m, 2H), 5.99 (s, 1H), 5.64-5.53 (m, 1H), 4.76-4.63 (m, 4H), 3.64-3.51 (m, 2H), 3.50-3.41 (m, 1H), 3.38-3.30 (m, 4H), 3.12-2.97 (m, 1H), 2.60 (dd, J=17.1, 9.2 Hz, 1H), 2.56-2.49 (m, 4H), 2.43 (dd, J=17.1, 8.0 Hz, 1H), 1.54 (d, J=6.2 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][C:12]([O:14]C)=[O:13])[CH:8]=[C:7]2[S:16]([CH2:19][CH2:20][CH2:21][C:22]([O:24]C)=[O:23])(=[O:18])=[O:17].[CH:26]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][O:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:30][CH:29]=1)=[CH2:27]>>[C:12]([CH2:11][N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2/[CH:27]=[CH:26]/[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][O:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:30][CH:29]=2)[C:7]([S:16]([CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])(=[O:18])=[O:17])=[CH:8]1)([OH:14])=[O:13]
Reactant: C=Cc1ccc(OCCCCOc2ccccc2)cc1
Reactant: COC(=O)CCCS(=O)(=O)c1cn(CC(=O)OC)c2c(Br)cccc12
Product: O=C(O)CCCS(=O)(=O)c1cn(CC(=O)O)c2c(/C=C/c3ccc(OCCCCOc4ccccc4)cc3)cccc12

Procedure:
Except for using the compound prepared in Example 103 in place of the compound prepared in Example 2 and 1-ethenyl-4-{[4-(phenyloxy)butyl]oxy}benzene in place of 4-vinylphenyl acetate, the same operation as in Example 3→Example 6 was conducted to obtain the titled compound having the following physical properties.
Reaction SMILES: C(OC([N:11]1[CH:16]2[CH2:17][NH:18][CH2:19][CH:12]1[CH2:13][O:14][CH2:15]2)=O)C1C=CC=CC=1.[CH2:20]=O.[BH4-].[Na+]>CO>[CH3:20][N:18]1[CH2:17][CH:16]2[NH:11][CH:12]([CH2:13][O:14][CH2:15]2)[CH2:19]1
Reactant: O=C(OCc1ccccc1)N1C2CNCC1COC2
Reactant: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1CC2COCC(C1)N2
Temperature: 25 °C
Yield: 80.4 %

Procedure:
To a solution of 3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-9-carboxylic acid benzyl ester (Compound X) (84 mg, 0.28 mmol) in MeOH (5 mL) was added paraformaldehyde (41 mg, 1.38 mmol) and NaBH4 (21 mg, 0.56 mmol). The reaction mixture was refluxed for 16 hours under argon atmosphere, and then quenched with sat. NaHCO3, then extracted with EtOAc (20 mL) three times. The combined organic layer was washed successively with sat. NH4Cl, NaHCO3 and brine, and then dried over Na2SO4. The solvent was concentrated under reduced pressure. The residue was dissolved in MeOH (20 mL). To the solution was added 10% Pd on carbon (20 mg). The mixture was stirred under one atmosphere pressure of hydrogen at room temperature. After the reaction was completed, the mixture was filtered and concentrated to give the crude 7-methyl-3-oxa-7,9-diaza-bicyclo[3.3.1]nonane (Compound Z) (32 mg, 81%) which was directly used for next step. MS: calc'd (MH+) 143, measured (MH+) 143.
Reaction SMILES: [C:1](C1NC=CN=1)(C1NC=CN=1)=[O:2].[NH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=1[NH:24][CH3:25].C(OCC)(=O)C>O1CCCC1>[CH3:25][N:24]1[C:15]2[CH:16]=[C:17]([C:18]([O:20][CH3:21])=[O:19])[CH:22]=[CH:23][C:14]=2[NH:13][C:1]1=[O:2]
Reactant: CNc1cc(C(=O)OC)ccc1N
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2[nH]c(=O)n(C)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.2 %

Procedure:
Add carbonyl diimidazole (587 mg, 3.50 mmol) to a solution of methyl 4-amino-3-(methylamino)benzoate (586 mg, 3.19 mmol) in tetrahydrofuran (20 mL) at room temperature. Stir the yellow solution at room temperature for 16 hours. Add carbonyl diimidazole (500 mg, 0.96). Stir at room temperature for 4 hours. Add ethyl acetate (75 mL). Wash with 10% citric acid (5 mL), 1N sodium hydroxide (5 mL), and brine (5 mL). Dry the organics over magnesium sulfate, filter, concentrate, and dry under high vacuum to yield a crude yellow solid (690 mg, 100%). Triturate this crude solid with ethyl acetate (10 mL). Filter the precipitate and dry under high vacuum to yield methyl 3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate (422 mg, 64%). 1H NMR (400 MHz, CDCl3) δ ppm 3.46 (s, 3H), 3.92 (s, 3H), 7.12 (d, J=8.21 Hz, 1H), 7.68 (s, 1H), 7.84 (dd, J=8.31, 1.47 Hz, 1H), 9.87-10.03 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:13])[CH2:11]Cl.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(CC)C(C)C)(C)C>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:13])[CH2:11][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: Cc1cccc(C)c1NC(=O)CCl
Reactant: C1CNCCN1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(C)c1NC(=O)CN1CCNCC1

Procedure:
To a solution of compound 3 (5 g, 25.2 mmol) in ethanol (100 mL) was added piperazine 4 (2.1 g, 25.0 mmol) and N,N-diisopropylethylamine (3.2 g, 25.2 mmol). The reaction mixture was refluxed for 24 h. The mixture was concentrated in vacuo and the residue was purified by column chromatography (10:1 DCM: MeOH) to afford compound 5.
Reaction SMILES: C(#N)C.[CH2:4]([O:6][C:7]([C:9]1[NH:13][N:12]=[C:11]([CH3:14])[CH:10]=1)=[O:8])[CH3:5].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>O>[CH2:4]([O:6][C:7]([C:9]1[N:13]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]=[C:11]([CH3:14])[CH:10]=1)=[O:8])[CH3:5]
Reactant: CCOC(=O)c1cc(C)n[nH]1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1cc(C)nn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.4 %

Procedure:
An acetonitrile (8.0 mL) mixture of ethyl-3-methyl-1H-pyrazole-5-carboxylate (15) (0.50 g. 3.2 mmol), benzyl bromide (0.48 mL, 4.0 mmol), and K2CO3 (0.90 g, 6.5 mmol) was stirred at room temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane. The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. After removal of solvent under reduced pressure, the residue was purified by flash column chromatography [silica gel, eluting with mixtures of ethyl acetate and hexanes (0% ramped to 15% EtOAc/hexanes)] to yield 0.30 g of ethyl-1-benzyl-3-methylpyrazole-5-carboxylate (16). 1H NMR (CDCl3): δ 7.30-7.22 (m, 5H), 6.65 (s, 1H), 5.71 (s, 2H), 4.28 (q, J=7.2 Hz, 2H), 2.32 (s, 3H), 1.32 (t, J=7.2 Hz, 3H); LCMS: purity: 99%; MS (m/z): 345 (MH+).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[CH2:2][C:3]([NH:5][C@H:6]([C:14]([OH:16])=[O:15])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:13])[NH2:12])=[O:4].Cl.Cl.CC(O)=O>CO>[NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:14]([OH:16])=[O:15])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:12])[NH2:13])=[O:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: N=C(N)NCCC[C@H](NC(=O)CN)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 189.9 %

Procedure:
125.7 Grams (0.25 mol) of BOC-Gly-Arg-CHA.HCl was dissolved in a small quantity of MeOH and to the solution was added with 500 ml of 2N-HCl/AcOH and the mixture was reacted under stirring at room temperature for 1 hour. After the reaction was completed, the reaction mixture was reprecipitated in 4.5 liters of diethyl ether and the crystals precipitated were collected by filtration and dried to obtain 109.8 g (100%) of H-Gly-Arg-CHA.2HCl. Rf3 =0.09. Melting point: 219.5° C. (decomposed). [α]D20 -21.0 (C=1, AcOH:H2O=1:1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.CON(C)[C:16](=[O:23])[CH2:17][C:18]1[CH:22]=[CH:21][S:20][CH:19]=1.[NH4+].[Cl-]>C1COCC1>[C:2]1([C:16](=[O:23])[CH2:17][C:18]2[CH:22]=[CH:21][S:20][CH:19]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)Cc1ccsc1
Reactant: Brc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(Cc1ccsc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 54.9 %

Procedure:
To the solution of bromo-benzene (1.0 g, 6.36 mmol) in anhydrous THF (30 mL) was added n-BuLi (5.9 mmol, 2.4 mL) at −78° C. under nitrogen, and the mixture was stirred at −78° C. for further 20 min., a solution of N-methoxy-N-methyl-2-(thiophen-3-yl)acetamide (1 g, 5.4 mmol) in anhydrous THF (10 mL) was added. The resulting mixture was stirred at −78° C. under nitrogen for about 30 min., poured into NH4Cl aqueous solution, and extracted with EtOAc. The organic layers were washed with brine, dried over sodium sulfate, concentrated, and purified by column chromatography (PE:EtOAc=20:1) to afford Intermediate 6 (600 mg, yield 55.0%).
Reaction SMILES: F[C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7]C)=[O:5].[OH:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][NH:19][C:20]2=[O:25].CC1NC2C(C=1)=CC(O)=CC=2>>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:9]=[CH:10][C:11]([F:13])=[CH:12][C:2]=1[O:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][NH:19][C:20]2=[O:25]
Reactant: O=C1NCCc2c(O)cccc21
Reactant: CCOC(=O)c1ccc(F)cc1F
Agent: Cc1cc2cc(O)ccc2[nH]1
Product: COC(=O)c1ccc(F)cc1Oc1cccc2c1CCNC2=O

Procedure:
The title compound was prepared by substituting methyl 2,4-difluorobenzoate for ethyl 2,4-difluorobenzoate and 5-hydroxy-3,4-dihydro-2H-isoquinolin-1-one for 2-methyl-5-indolol in EXAMPLE 3A, except here the heating was at 130° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.C(N(CC)CC)C.[F:16][C:17]([F:37])([F:36])[C:18]1[CH:19]=[C:20]([CH:33]=[CH:34][CH:35]=1)[O:21][CH:22]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[C:23]([Cl:25])=[O:24]>CCOCC>[ClH:25].[F:36][C:17]([F:16])([F:37])[C:18]1[CH:19]=[C:20]([CH:33]=[CH:34][CH:35]=1)[O:21][CH:22]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[C:23]([O:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:24]
Reactant: O=C(Cl)C(Oc1cccc(C(F)(F)F)c1)c1ccc(Cl)cc1
Reactant: OCc1cccnc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cl
Product: O=C(OCc1cccnc1)C(Oc1cccc(C(F)(F)F)c1)c1ccc(Cl)cc1
Temperature: -5 °C
Reaction time: 4 h

Procedure:
A solution of 3-pyridylcarbinol (5.7 g., 0.0522 mole) in triethylamine (144 ml., 0.13 mole) is cooled to -15° C. To this solution is added (3-trifluoromethylphenoxy)(4-chlorophenyl)acetyl chloride (18 g., 0.0515 mole) in ether (25 ml.). The reaction mixture is stirred for four hours at -5° C. and then at room temperature for 4 hours. The reaction mixture is filtered and the filtrate is washed successively with water, dilute sodium bicarbonate and then water until neutral. The ether solution is dried over magnesium sulfate filtered and to this solution is added ethanolic HCl. An oil separated which slowly crystallized. The solid is collected and recrystallized from a mixture of of isopropanol (30 ml.) and ether (30 ml.) to afford 8.6 g. of product. A small sample recrystallized for analysis has a melting point of 147°-149° C.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:31]=[CH:30][C:14]([C:15]([NH:17][C@@H:18]3[CH2:26][C@:21]4([O:25][CH2:24][CH2:23][CH2:22]4)[CH2:20][C@@H:19]3[C:27]([O-:29])=O)=[O:16])=[CH:13][CH:12]=2)=[CH:3][CH2:2]1.[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33].Cl.[NH2:40][OH:41]>CO.C[O-].[Na+]>[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33].[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:31]=[CH:30][C:14]([C:15]([NH:17][C@@H:18]3[CH2:26][C@:21]4([O:25][CH2:24][CH2:23][CH2:22]4)[CH2:20][C@@H:19]3[C:27]([NH:40][OH:41])=[O:29])=[O:16])=[CH:13][CH:12]=2)=[CH:3][CH2:2]1
Reactant: NO
Reactant: O=C(N[C@@H]1C[C@@]2(CCCO2)C[C@@H]1C(=O)[O-])c1ccc(C2=CCOc3ccccc32)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C(N[C@@H]1C[C@@]2(CCCO2)C[C@@H]1C(=O)NO)c1ccc(C2=CCOc3ccccc32)cc1
Reaction time: 1 h
Yield: 32 %

Procedure:
(5R,7S,8R)-8-{[4-(2H-chromen-4-yl)benzoyl]amino}-1-oxaspiro[4.4]nonane-7-carboxylate from reaction (34e) (0.10 g, 0.23 mmol) was dissolved in a solution of hydroxylamine hydrochloride, methanol and sodium methoxide, (2 mL) under nitrogen atmosphere at room temperature. The reaction was stirred for 1 h, made neutral with TFA, concentrated and purified by HPLC on a C-18 column eluting with an acetonitrile:water:TFA gradient, to give the title compound (0.032 g, 32%) as a white solid. MS found: (M−H)+=433.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.C[CH2:12][N:13]=[C:14]=NCCCN(C)C.[CH2:22]([O:29][C:30]([NH:32][C:33]([CH3:39])([CH3:38])[CH2:34][C:35](O)=[O:36])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N(C)C>C(Cl)Cl>[CH2:22]([O:29][C:30](=[O:31])[NH:32][C:33]([CH3:39])([CH3:38])[CH2:34][C:35](=[O:36])[N:13]([CH3:14])[CH3:12])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(CC(=O)O)NC(=O)OCc1ccccc1
Agent: CNC
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CN(C)C(=O)CC(C)(C)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
HOBt (1.242 g, 9.193 mmol) and EDCI (2.35 g, 12.26 mmol) were added to a solution of 3-benzyloxycarbonylamino-3-methyl-butyric acid (1.54 g, 6.129 mmol) in DCM (45 mL) at 0° C. The resulting mixture was stirred at 0° C. for 30 min, and a solution of Me2NH (2 M in THF, 12.26 mL, 24.51 mmol) was added. The reaction mixture was warmed up to RT and stirred overnight. The solvent was evaporated under reduced pressure, and the residue partitioned between EtOAc and a mixture of water, brine and NaHCO3 (sat aq). The organic layer was separated, washed with HCl (1 M), dried over anhydrous MgSO4, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (EtOAc/hexane) to afford (2-dimethylcarbamoyl-1,1-dimethyl-ethyl)-carbamic acid benzyl ester (1.14 g, 67% yield).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.O.[NH4+:13].[OH-].[CH3:15]O>Cl.[Fe]>[NH2:8][C:7]1[C:2]([C:15]#[N:13])=[N:3][C:4]([Cl:11])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: [NH4+]
Reactant: CO
Agent: [Fe]
Agent: Cl
Agent: [OH-]
Solvent: O
Product: N#Cc1nc(Cl)ccc1N
Yield: 58 %

Procedure:
To a solution of 2,6-dichloro-3-nitropyridine (4.8 g, 26.15 mmol) in MeOH (60 mL) and concentrated HCl (25 mL) was slowly added iron powder (5.12 g, 91.53 mmol). After the completion of addition, the mixture was refluxed for 45 minutes and poured into 700 mL of H2O. Filtration of the resulting slurry gave a dull yellow solid. The filtrate was made basic with concentrated NH4OH, the resulting slurry was filtered and both the solid and the filtrates were extracted with ether. The combined extracts were dried (MgSO4) and evaporated to give the title compound as a creamy solid (2.8 g, 58%): mp 162-165° C. which was used in next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C@H:12]([CH2:16][CH3:17])[C:13]([OH:15])=[O:14])=[CH:8][CH2:9]2)=[CH:5][CH:4]=1.C(N(CC)CC)C>CCO.C1COCC1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6](=[CH:5][CH:4]=1)[C@H:7]([C@H:12]([CH2:16][CH3:17])[C:13]([OH:15])=[O:14])[CH2:8][CH2:9]2
Reactant: CC[C@H](C(=O)O)C1=CCc2cc(OC)ccc21
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: C1CCOC1
Product: CC[C@H](C(=O)O)[C@@H]1CCc2cc(OC)ccc21
Yield: 95 %

Procedure:
A solution of the product obtained in Example 3 (105 g, 453 mmol), ClRh(PPh3)3 (21.0 g, 5% eq.) and triethylamine (68.8 g, 679.5 mmol) in EtOH (945 mL) and THF (105 mL) was shaken in a 2-L pressure bottle under 60 psi H2 for 16 hours. The solvents were removed at a reduced pressure. The resulting mixture was stirred in 1.5 L of 1N HCl solution and 1.5 L CH2Cl2. The aqueous layer was extracted with CH2Cl2 (2×250 mL). The combined CH2Cl2 layers were washed with 1 L of 1N HCl solution and stirred with 1 L of 1N NaOH solution. The organic layer was extracted with 1N NaOH solution (2×0.5 L). The combined aqueous layer was washed with CH2Cl2 (2×250 mL), and acidified (pH 2.0-3.0) by a slow addition of conc. HCl solution at below 15° C. The acidic mixture was extracted with CH2Cl2 (2×1.5 L), and washed with water (2×0.5 L) until pH 5.0-6.0. After washing with brine and drying over anhydrous Na2SO4, solvent was evaporated under a reduced pressure. The product (101.0 g, 95% yield, 96.8% ee) was obtained as a light yellow oil. 1H NMR (DMSO-d6) δ12.20(s, 1H), 7.04(d, 1H), 6.78(d, 1H), 6.66(dd, 1H), 3.70(s, 3H), 3.28(m, 1H), 2.72(m, 2H), 2.32(m, 1H), 2.06(m, 1H), 1.80(m, 1H), 1.50(m, 1H), 1.36(m, 1H), 0.82(t, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:6][CH:5]=1)([O-])=O.C(OCC)(=O)C.CO>CN(C)C=O.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:6][CH:5]=1
Reactant: CS(=O)(=O)Nc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1ccc(N)cc1
Temperature: 50 °C
Yield: 71.1 %

Procedure:
N-(4-Nitro-phenyl)-methanesulfonamide (Example 3a, 25 g, 115.62 mmol) was dissolved in N,N-dimethylformamide (15 mL) with gentle heating to ˜50° C. via heat gun. Ethyl acetate (100 mL) and methanol (100 mL) were added followed by 10% palladium on carbon (4 g). The mixture was degassed while stirring and the flask was charged with hydrogen gas via balloon. The mixture was stirred at 25° C. for 4.5 h. The mixture was filtered through Celite (rinsed with ethyl acetate) and concentrated in vacuo to a yellow green solution with a volume of ˜10 mL. Dichloromethane (˜50 mL) was added and a solid began to precipitate. The mixture was stirred at 25° C. for 30 min. The solid was collected by vacuum filtration and dried in vacuo to afford the desired product, N-(4-amino-phenyl)-methanesulfonamide (15.32 g, 82.26 mmol, 71% yield) as a beige powder. 1H NMR (400 MHz, DMSO-d6) δ 2.79 (3H, s), 5.00 (2H, s), 6.49 (2H, d, J=8.5 Hz), 6.87 (2H, d, J=8.6 Hz), 8.87 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.[F:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:11]=1[C:12](Cl)=[O:13]>O1CCOCC1>[NH2:8][C:4]1[N:3]=[C:2]([NH:1][C:12](=[O:13])[C:11]2[C:10]([F:9])=[CH:18][CH:17]=[CH:16][C:15]=2[F:19])[CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Nc1cccc(N)n1
Solvent: C1COCCO1
Product: Nc1cccc(NC(=O)c2c(F)cccc2F)n1
Yield: 75.2 %

Procedure:
Using a method similar to Preparation 48, using 2,6-diaminopyridine (2.6 g, 24 mmol), dioxane (75 mL), and 2,6-difluorobenzoyl chloride (1.4 g, 8 mmol) (stir at 25° C. for 16 hr.), gives the title intermediate (1.5 g, 75% yield): mass spectrum (ion spray): m/z=250.1 (M+1).