Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:3]=1[C:4]([CH2:6][CH2:7][CH2:8][CH2:9]O)=[O:5].CS([O-])(=O)=O.[NH:24]1[CH2:29][CH2:28][C:27]2([C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:31][O:30]2)[CH2:26][CH2:25]1>>[Cl:1][C:2]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:3]=1[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][N:24]1[CH2:29][CH2:28][C:27]2([C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:31][O:30]2)[CH2:26][CH2:25]1)=[O:5]
Reactant: O=C(CCCCO)c1cc(C(F)(F)F)ccc1Cl
Reactant: c1ccc2c(c1)COC21CCNCC1
Agent: CS(=O)(=O)[O-]
Product: O=C(CCCCN1CCC2(CC1)OCc1ccccc12)c1cc(C(F)(F)F)ccc1Cl

Procedure:
4-(2-Chloro-5-trifluoromethylbenzoyl)-1-butanol, prepared as described in EXAMPLE 17, was converted to the corresponding methanesulfonate by the method described in EXAMPLE 2. Treatment with spiro[isobenzofuran-1(3H),4'-piperidine] according to the method described in EXAMPLE 2 gave 1'-[4-(2-chloro-5-trifluoromethylbenzoyl)-1-butyl]-spiro[isobenzofuran-1(3H),4'-piperidine]. Conversion to the corresponding hydrazone and ring closure according to the method described in EXAMPLE 17 gave the title compound, 18, mp: 146-47° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:7]=1.[C:14]([Si:16]([CH3:19])([CH3:18])[CH3:17])#[CH:15].C(N(C(C)C)CC)(C)C>CN(C=O)C.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.[Cu]I>[N:9]1([CH2:8][C:6]2[CH:5]=[N:4][CH:3]=[C:2]([C:15]#[C:14][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:7]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: C#C[Si](C)(C)C
Reactant: Brc1cncc(CN2CCCC2)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1cncc(CN2CCCC2)c1
Temperature: 50 °C

Procedure:
A mixture of 3-bromo-5-(pyrrolidin-1-ylmethyl)pyridine (0.76 mmol), ethynyltrimethylsilane (0.91 mmol), Pd(PPh3)4 (0.038 mmol), CuI (0.076 mmol), and 0.26 mL (1.52 mmol) of diisopropylethylamine in 3.8 mL of DMF can be heated at 50° C. overnight under an atmosphere of N2. Upon cooling to ambient temperature, the reaction mixture is concentrated and the crude product is purified by silica gel flash chromatography (eluted with 50% EtOAc/hexanes).
Reaction SMILES: N1C2C(=CC=CC=2)C(C(O)=O)=CC=1.[NH:14]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:17](=O)[C:15]1=[O:16].NC1C=CC=CC=1.ClC(Cl)(Cl)C(O)O.Cl.[NH2:40][OH:41]>>[CH:21]1[CH:20]=[CH:19][C:24]([NH:14][C:15](/[CH:17]=[N:40]/[OH:41])=[O:16])=[CH:23][CH:22]=1
Reactant: NO
Reactant: O=C1Nc2ccccc2C1=O
Agent: Cl
Agent: O=C(O)c1ccnc2ccccc12
Agent: OC(O)C(Cl)(Cl)Cl
Solvent: Nc1ccccc1
Product: O=C(/C=N/O)Nc1ccccc1

Procedure:
The quinoline-4-carboxylic acid [E] can be prepared using the classical Sandmeyer isatin synthesis followed by the Pfitzinger reacton. The aniline was reacted with chloral hydrate and hydroxylamine hydrochloride to afford the substituted isonitrosoacetanilide which was cyclized using a suitable acid catalyst to afford the isatin as described in. Alternatively the isatin can be bought from commercial sources. The isatin can then be converted into the corresponding substituted quinoline-4-carboxylic acid using the Pfitzinger reaction as in reference 17. In some instances the Pfitzinger reaction yielded a quinoline-2,4-dicarboxylic acid which was decarboxylated to the quinoline-4-carboxylic acid by reacting it in water for 2 h using a pressured tube at 200° C.
Reaction SMILES: [C:1]([Si:5]([CH:10]([CH3:12])[CH3:11])([CH:7]([CH3:9])[CH3:8])Cl)([CH3:4])([CH3:3])[CH3:2].C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.C(N(CC)CC)C.[C:36]([OH:40])(=[O:39])[CH:37]=[CH2:38]>C1(C)C=CC=CC=1>[C:36]([O:40][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH:10]([CH3:12])[CH3:11])[CH:7]([CH3:9])[CH3:8])(=[O:39])[CH:37]=[CH2:38]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)(C)C
Reactant: C=CC(=O)O
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CC(=O)O[Si](C(C)C)(C(C)C)C(C)(C)C
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A flask equipped with a stirrer, reflux condenser, dropping funnel and thermometer was charged with 41.4 g (0.20 mol) of tert-butyldiisopropylchlorosilane, 60 ml of By toluene, and 0.06 g of 2,6-di-tert-butyl-4-methylphenol. At room temperature, 22.3 g (0.22 mol) of triethylamine was added dropwise over one hour. At the end of dropwise addition, the flask was heated at 80° C. After the internal temperature became constant, 15.9 g (0.22 mol) of acrylic acid was added dropwise over one hour. After the completion of dropwise addition, the reaction solution was stirred for 2 hours at 80° C. The reaction solution was then cooled to room temperature, and the resulting hydrochloric acid salt removed by filtration. The filtrate was distilled, collecting 42.9 g of a fraction having a boiling point of 80-83° C./0.27 kPa.
Reaction SMILES: [CH:1]([NH:3][C@@H:4]1[C:9](=[O:10])[O:8][C:6](=[O:7])[CH2:5]1)=[O:2].[NH2:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CO>O>[CH:1]([NH:3][C@H:4]([C:9]([NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[CH2:5][C:6](=[O:7])[OH:8])=[O:2]
Reactant: O=CN[C@H]1CC(=O)OC1=O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Solvent: O
Solvent: CO
Product: O=CN[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
In the process of the present invention, N-formyl-L-aspartic acid anhydride is condensated with L-phenylalanine in water or water containing methanol at a pH in the range of 7-12 to form N-formyl-α-L-aspartyl-L-phenylalanine.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]([CH3:14])=[CH2:13])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:15][C:16]1[CH:17]=[CH:18][C:19](B2OC(C)(C)C(C)(C)O2)=[N:20][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].[Cu]Cl>[C:12]([C:10]1[N:11]=[C:2]([C:19]2[CH:18]=[CH:17][C:16]([CH3:15])=[CH:21][N:20]=2)[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=1)([CH3:14])=[CH2:13]
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)nc1
Reactant: C=C(C)c1cc(C(=O)OC)cc(Cl)n1
Agent: Cl[Cu]
Agent: Cl[Pd]Cl
Agent: [Fe]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=C(C)c1cc(C(=O)OC)cc(-c2ccc(C)cn2)n1
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 86.9 %

Procedure:
To a solution of methyl 2-chloro-6-isopropenylisonicotinate (0.5 g, 2.36 mmol) in DMF (12 mL) were added 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.3 g, 5.9 mmol), palladium(II)acetate (26.5 mg, 0.12 mmol), cesium carbonate (1.54 g, 4.72 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.13 g, 0.24 mmol) and copper(I) chloride (0.23 g, 2.36 mmol). The mixture was purged with argon and heated to 100° C. After 45 min, saturated aqueous NaHCO3 was added. The mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with water (3×), brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→75% hexanes/ethyl acetate) gave the title compound (0.55 g). MS 269.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([I:11])=[N:9][NH:10][C:4]=2[CH:3]=1.[H-].[Na+].[C:14](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([I:11])=[N:9][N:10]([C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:4]=2[CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Clc1cc2[nH]nc(I)c2cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1cc2c(cn1)c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.83 h

Procedure:
A solution of 6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine (1.874 g, 6.71 mmol) in THF (20 mL) was treated with NaH (60% in mineral oil; 0.402 g, 10.06 mmol) at 0° C. and the mixture was stirred for 50 min. Trityl chloride (2.244 g, 8.05 mmol) was added at 0° C. and the mixture was stirred for 16 h at room temperature, quenched with saturated NH4Cl, and extracted with EtOAc. The organic phase was washed with water, brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified via flash chromatography (0-10% EtOAc-hexanes) to yield 6-chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridine. MS ESI calc'd. for C25H18ClIN3[M+1]+ 522. found 522.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:14]([NH:16][C@H:17]([C:25]([OH:27])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH3:13])=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:11][C@H:12]([C:14]([NH:16][C@H:17]([C:25]([OH:27])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH3:13]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: [Pd]
Solvent: CCO
Product: C[C@H](N)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 20 °C
Reaction time: 16 h
Yield: 91.9 %

Procedure:
A mixture of N-benzyloxycarbonyl-L-alanyl-L-phenylalanine (0.208 g, 0.562 mmol) and 10% Pd on carbon (0.1 g) in 95% ethyl alcohol (50 mL) was shaken on a Parr hydrogenation apparatus for 16 h at 20° C. The reaction mixture was filtered and the filtrate rinsed with water (100 mL). The combined solutions were concentrated to give 0.122 g (92%) of L-alanyl-L-phenylalanine as a white solid. HPLC analysis showed >99.5% purity and no evidence of racemization.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[CH2:7][CH:6]3[CH2:23][O:24][CH2:25][CH2:26][N:5]3[C:4]=2[N:3]=1.[F:27][C:28]1[CH:29]=[CH:30][C:31](B2OC(C)(C)C(C)(C)O2)=[C:32]2[C:36]=1[NH:35][CH:34]=[C:33]2[CH3:37]>O1CCOCC1.C([O-])(O)=O.[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:27][C:28]1[CH:29]=[CH:30][C:31]([C:2]2[N:11]=[CH:10][C:9]3[N:8]([CH2:12][C:13]4[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=4)[CH2:7][CH:6]4[CH2:23][O:24][CH2:25][CH2:26][N:5]4[C:4]=3[N:3]=2)=[C:32]2[C:36]=1[NH:35][CH:34]=[C:33]2[CH3:37]
Reactant: Cc1c[nH]c2c(F)ccc(B3OC(C)(C)C(C)(C)O3)c12
Reactant: CS(=O)(=O)c1ccc(CN2CC3COCCN3c3nc(Cl)ncc32)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: Cc1c[nH]c2c(F)ccc(-c3ncc4c(n3)N3CCOCC3CN4Cc3ccc(S(C)(=O)=O)cc3)c12

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 2 using 2-chloro-5-(4-(methylsulfonyl)benzyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x9, 66.0 mg, 0.167 mmol), 7-fluoro-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (92 mg, 0.334 mmol) and PdCl2(dppf) (9.79 mg, 0.013 mmol) in dioxane (1 mL) and aqueous saturated NaHCO3 (0.2 mL). 1H NMR (400 MHz, DMSO-d6) δ 1.93-2.07 (m, 3 H), 2.89-2.99 (m, 1 H), 3.21-3.34 (m, 6 H), 3.47-3.49 (m, 1 H), 3.67-3.72 (m, 1 H), 3.86-3.99 (m, 2 H), 4.35-4.44 (m, 1 H), 4.57-4.64 (m, 2 H), 6.83-6.91 (m, 1 H), 7.02-7.08 (m, 1 H), 7.11-7.17 (m, 1 H), 7.58-7.66 (m, 3 H), 7.87-7.96 (m, 2 H), 11.23-11.30 (m, 1 H). ESI-MS m/z [M+H]+ calc'd for C26H26FN5O3S, 508.17; found 508.5.
Reaction SMILES: ClC1C(OCC2(C#N)CCCCC2)=C[C:5](F)=[C:6]([CH:14]=1)C(OC(C)(C)C)=O.Cl[C:27]1[C:28]([O:38][CH:39]2[CH2:46][CH2:45][C:42]3([CH2:44][CH2:43]3)[CH2:41][CH2:40]2)=[CH:29][C:30]([F:37])=[C:31]([CH:36]=1)[C:32]([O:34][CH3:35])=[O:33]>>[CH:14]1([C:27]2[C:28]([O:38][CH:39]3[CH2:46][CH2:45][C:42]4([CH2:44][CH2:43]4)[CH2:41][CH2:40]3)=[CH:29][C:30]([F:37])=[C:31]([CH:36]=2)[C:32]([O:34][CH3:35])=[O:33])[CH2:6][CH2:5]1
Reactant: COC(=O)c1cc(Cl)c(OC2CCC3(CC2)CC3)cc1F
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC2(C#N)CCCCC2)cc1F
Product: COC(=O)c1cc(C2CC2)c(OC2CCC3(CC2)CC3)cc1F

Procedure:
Following the procedure as described in Example 374 Step 3 and making non-critical variations to replace tert-butyl 5-chloro-4-((1-cyanocyclohexyl)methoxy)-2-fluorobenzoate with methyl 5-chloro-2-fluoro-4-(spiro[2.5]octan-6-yloxy)benzoate, the title compound was obtained as a colorless syrup (0.389 g, 72% yield): 1H NMR (300 MHz, CDCl3) δ 7.42 (d, J=8.5 Hz, 1H), 6.56 (d, J=13.0 Hz, 1H), 4.46-4.39 (m, 1H), 3.86 (s, 3H), 2.10-2.01 (m, 1H), 1.99-1.90 (m, 2H), 1.86-1.76 (m, 2H), 1.54-1.24 (m, 4H), 0.96-0.84 (m, 3H), 0.66-0.60 (m, 2H), 0.32-0.26 (m, 4H); MS (ES+) m/z 287.05 (M−31).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH3:13])[CH2:10][C@@H:9]1[C:14](OC)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH3:13])[CH2:10][C@@H:9]1[CH2:14][OH:15])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)[C@H]1C[C@H](C)CN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Product: C[C@H]1C[C@H](CO)N(C(=O)OC(C)(C)C)C1

Procedure:
(2R,4S)-4-Methylpyrrolidine-2-carboxylic acid described in J. Chem. Soc. C, pp. 514–522 (1971) is reacted with di-tert-butyl dicarbonate to give (2R,4S)-1-tert-butoxycarbonyl-4-methylpyrrolidine-2-carboxylic acid. (2R,4S)-1-tert-Butoxycarbonyl-4-methylpyrrolidine-2-carboxylic acid is reacted with methyl iodide in the presence of potassium carbonate in acetonitrile solvent to give methyl (2R,4S)-1-tert-butoxycarbonyl-4-methylpyrrolidine-2-carboxylate. Methyl (2R,4S)-1-tert-butoxycarbonyl-4-methylpyrrolidine-2-carboxylate is reduced with lithium borohydride to give (2R,4S)-1-tert-butoxycarbonyl-2-hydroxymethyl-4-methylpyrrolidine. (2R,4S)-1-tert-Butoxycarbonyl-2-hydroxymethyl-4-methylpyrrolidine is reacted with 4N hydrogen chloride-dioxane to give (2R,4S)-2-hydroxymethyl-4-methylpyrrolidine hydrochloride. (2R,4S)-2-Hydroxymethyl-4-methylpyrrolidine hydrochloride is reacted with acrylonitrile to give 3-[(2R,4S)-2-hydroxymethyl-4-methylpyrrolidin-1-yl]propionitrile. In the same manner as in Example 1b (e) and using 3-[(2R,4S)-2-hydroxymethyl-4-methylpyrrolidin-1-yl]propionitrile and N,N-diethyl-2,3-dimethylbenzamide, 3-(2-[(2R,4S)-2-hydroxymethyl-4-methylpyrrolidin-1-yl]ethyl)-5-methyl-2H-isoquinolin-1-one is obtained.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([S:16][CH2:17][C@H:18]2[O:23]C(C)(C)[O:21][C@@H:20]([CH2:26][C:27]([O:29]C(C)(C)C)=O)[CH2:19]2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C(#N)C.C(Cl)Cl>C(Cl)Cl>[C:12]([C:9]1[CH:8]=[C:7]([S:16][CH2:17][C@H:18]2[O:23][C:27](=[O:29])[CH2:26][C@H:20]([OH:21])[CH2:19]2)[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:14])([CH3:13])[CH3:15]
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CSc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)OC(C)(C)O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)c1cc(SC[C@@H]2C[C@@H](O)CC(=O)O2)cc(C(C)(C)C)c1O
Yield: 80.3 %

Procedure:
In 6.5 ml of anhydrous methylene chloride was dissolved 0.647 g (1.346 mmol) of tert-butyl [(4R,6S)-6-[[(3,5-di-tert-butyl-4-hydroxyphenyl)thio]methyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate. Thereto was added dropwise 1.3 ml of trifluoroacetic acid with cooling with ice and stirred for a half hour at the same temperature, further stirred for 2 hours at room temperature. The reaction solution was distilled away under reduced pressure. To the residue was added toluene, and again the mixture was distilled away under reduced pressure. After repeating such procedure twice, the obtained residue was purified by subjecting to silica gel column chromatography [eluent: acetonitrile-methylene chloride (1:9 to 1:4)]to give 0.396 g of (4R,6S)-6-[[(3,5-di-tert-butyl-4-hydroxyphenyl)thio]methyl]-4-hydroxytetrahydropyrane-2-one as crystals (yield: 83%). The desired compound was recrystallized from hexane.
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:23][CH2:24][P:25]([O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([O:38]CC2C=CC=CC=2)=[O:37])=[CH:32][CH:31]=1)([O:27][CH3:28])=[O:26])[C:13]([O:15]CC1C=CC=CC=1)=[O:14])=O)C1C=CC=CC=1.[H][H]>C(O)(=O)C.O.[C].[Pd]>[NH2:11][CH:12]([CH2:23][CH2:24][P:25]([O:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]([OH:38])=[O:37])=[CH:34][CH:35]=1)([O:27][CH3:28])=[O:26])[C:13]([OH:15])=[O:14]
Reactant: [H][H]
Reactant: COP(=O)(CCC(NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)Oc1ccc(C(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Product: COP(=O)(CCC(N)C(=O)O)Oc1ccc(C(=O)O)cc1
Yield: 88 %

Procedure:
Next, 1.40 g (2.22 mmol) of benzyl 2-(N-benzyloxycarbonylamino)-4-[4-(benzyloxycarbonyl)phenyl(methyl)phosphono]butanoate was dissolved in 28 mL of a solvent mixture of acetic acid and water at 2:1 and mixed with 200 mg of 5% palladium-carbon and hydrogen gas was introduced at room temperature for 2.2 hours. Thereafter, the palladium-carbon was removed by Celite filtration and the filtrate was vacuum-concentrated, and the residue was freeze-dried from water to obtain 2-amino-4-[4-carboxyphenyl(methyl)phosphono]butanoic acid (0.62 g, yield 89%) as a colorless solid.
Reaction SMILES: C([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[CH:18]=[C:17]([S:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)(=[O:25])=[O:24])[CH:16]=[CH:15][C:14]=3[N:13]([CH3:32])[C:12]=2[CH2:11][CH2:10]1)(=O)C1C=CC=CC=1.[OH-].[K+].[ClH:35]>C(O)CO.O.C(Cl)Cl.CO>[ClH:35].[CH3:32][N:13]1[C:14]2[CH:15]=[CH:16][C:17]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:24])=[O:25])=[CH:18][C:19]=2[C:20]2[CH2:21][CH2:22][NH:9][CH2:10][CH2:11][C:12]1=2
Reactant: Cn1c2c(c3cc(S(=O)(=O)c4ccccc4)ccc31)CCN(C(=O)c1ccccc1)CC2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: OCCO
Product: Cn1c2c(c3cc(S(=O)(=O)c4ccccc4)ccc31)CCNCC2

Procedure:
A mixture of 3-benzoyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (Step III, 1.25 g, 2.81 mmol) and potassium hydroxide (1.58 g, 28.1 mmol) in ethylene glycol (30 mL) is heated at 130° under nitrogen for 92 hr. Upon cooling, the mixture is diluted with H2O and extracted into ethyl acetate (3×). The combined extracts are washed with H2O (2×) and saline, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give a solid. The solid is dissolved in hot methylene chloride/methanol and treated with methanolic hydrochloric acid. The resultant mixture is concentrated and crystallized from ethyl acetate/methanol to give the title compound, mp>300°; IR (drift) 2820, 2792, 2747, 2717, 2704, 2665, 2651, 1299, 1147, 1096, 803, 729, 687, 643 and 621 cm−1; NMR (300 MHz, DMSO-d6) 9.41, 8.13, 7.85-7.95, 7.50-7.65, 3.70 and 3.10-3.40 δ; MS (EI) m/z 340 (M+), 298, 157, 156, 128, 78, 74, 73, 58 and 57; HRMS (FAB) calculated for C19H21N2O2S=341.1324, found=341.1319.
Reaction SMILES: C1(C)C=CC(S([CH2:10][N+:11]#[C-:12])(=O)=O)=CC=1.CO.C[O-].[Na+].[CH3:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([CH:29]=[O:30])[CH:27]=2)[NH:22][N:21]=1>O>[CH3:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:29]3[O:30][CH:12]=[N:11][CH:10]=3)[CH:27]=2)[NH:22][N:21]=1
Reactant: Cc1n[nH]c2ccc(C=O)cc12
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1n[nH]c2ccc(-c3cnco3)cc12
Temperature: 0 °C
Yield: 81.3 %

Procedure:
To a 150 mL round-bottom flask was added p-toluenesulfonylmethyl isocyanide (1.46 g, 7.5 mmol) and MeOH, followed by sodium methoxide (4.60 mL, 21.2 mmol) and a MeOH solution of 3-methyl-1H-indazole-5-carbaldehyde (1.00 g, 6.24 mmol) (prepared as described in WO 2007/124288). The solution was stirred at reflux for about 1 hour and followed by LCMS. Water was added (50 mL) and the MeOH was removed in vacuo. The suspension was cooled to 0° C. and the resulting precipitate was filtered and dried in the vacuum oven overnight to give 3-methyl-5-(oxazol-5-yl)-1H-indazole (1.01 g, 81% yield) as a tan powder. LCMS (API-ES) m/z (%): 200 (100%, M++H).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:16])=[O:12])=O)(C)(C)C.[Br:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39]Br)=[CH:37][CH:36]=1.C(#N)C>C(Cl)(Cl)Cl>[NH2:8][C:9]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:39][C:38]2[CH:41]=[CH:42][C:35]([Br:34])=[CH:36][CH:37]=2)[CH2:21][CH2:20]1)=[O:16])=[O:12]
Reactant: BrCc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1C(=O)NCC(=O)NCC1CCNCC1
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: Nc1ccc(OC(F)(F)F)cc1C(=O)NCC(=O)NCC1CCN(Cc2ccc(Br)cc2)CC1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
A mixture of 4-[{N-(2-(tert-butoxycarbonylamino)-5-trifluoromethoxybenzoyl)glycyl}aminomethyl]piperidine (0.050 mmol), 4-bromobenzyl bromide (0.060 mmol), piperidinomethylpolystyrene (60 mg), acetonitrile (0.8 mL) and chloroform (0.5 mL) was stirred at 60° C. for 12 h. The reaction mixture was cooled, loaded onto Varian™ SCX column and washed with 50% CHCl3/CH3OH (10 mL) and CH3OH (10 mL). Product was eluted using 2 N NH3 in CH3OH (5 mL) and concentrated. To the resulting material was added 4 N HCl in 1,4-dioxane (2 mL), and the solution was stirred overnight at room temperature. Concentration and preparative TLC afforded 4-[{N-(2-amino-5-trifluoromethoxybenzoyl)glycyl}aminomethyl]-1-(4-bromobenzyl)piperidine (Compound No. 1910) (6.5 mg, 24%): The purity was determined by RPLC/MS (96%); ESI/MS m/e 545 (M++H, C23H26BrF3N4O3).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][NH:4][C:5]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:23])=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]([F:13])([F:12])[CH2:3][NH:4][C:5]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)=[S:23]
Reactant: O=C(NCC(F)(F)F)c1cccs1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: FC(F)(F)CNC(=S)c1cccs1
Temperature: 100 °C
Reaction time: 3 h
Yield: 92.9 %

Procedure:
To thiophene-2-carboxylic acid(2,2,2-trifluoroethyl)amide (2.8 g, 13.28 mmol, 1.0 equiv.) in toluene (100 mL) was added Lawesson's reagent (2.71 g, 6.69 mmol, 0.5 equiv.) The solution was stirred at 100° C. for 3 h. The solvent was removed in vacuo and the resulting residue was purified by flash chromatography (5% EtOAc/hexanes as eluent) to afford the title compound (1.4 g) as a yellow solid. MS=225.9 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[N+:15]([O-])=O)=[C:5](O)[CH3:6].C(O)(=O)C>O.C(OCC)(=O)C.[Fe]>[CH3:1][O:2][C:3]([C:4]1[C:8]2[C:9](=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=2)[NH:15][C:5]=1[CH3:6])=[O:18]
Reactant: COC(=O)C(=C(C)O)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1c(C)[nH]c2cc(Cl)ccc12
Temperature: 115 °C

Procedure:
A mixture of 2-(4-chloro-2-nitro-phenyl)-3-hydroxy-but-2-enoic acid methyl ester (4.66 g, 17.2 mmol), iron (5.76 g, 103 mmol) and glacial acetic acid (16 mL) is heated at 115° C. for 1 h and allowed to cool. The reaction mixture is diluted with water and ethyl acetate. The ethyl acetate layer is washed with brine and dried over MgSO4. The mixture of the title compound and a small amount of impurity is used in the next reaction without additional purification. ES/MS m/e 224.0 (M+1).
Reaction SMILES: [CH3:1][C:2]12[O:11][C:10]([CH3:12])=[CH:9][CH:8]3[CH2:13][CH:14]([CH3:15])[CH:5]([CH2:6][CH:7]13)[CH2:4][CH2:3]2.[H][H]>[Pd].CC(O)C>[CH3:1][C:2]12[O:11][CH:10]([CH3:12])[CH2:9][CH:8]3[CH2:13][CH:14]([CH3:15])[CH:5]([CH2:6][CH:7]13)[CH2:4][CH2:3]2
Reactant: [H][H]
Reactant: CC1=CC2CC(C)C3CCC(C)(O1)C2C3
Agent: [Pd]
Solvent: CC(C)O
Product: CC1CC2CC(C)C3CCC(C)(O1)C2C3
Yield: 92.6 %

Procedure:
In an autoclave, 4,6,11-trimethyl-5-oxa-tricyclo[6.2.2.0*4,9*]dodec-6-ene (770 g, obtained as above) and palladium (5%, 7.6 g) on carbon was added to 2-propanol (100 g). The reaction mixture was stirred at a temperature between 70-100° C. under a pressure of 300 psi hydrogen for 6 hours. GC analysis indicated that the reaction was completed. The resulting material was then filtered and distilled under a reduced pressure to provide 4,6,11-trimethyl-5-oxa-tricyclo[6.2.2.0*4,9*]dodecane (720 g), which had a boiling point of 132° C. at a pressure of 0.8 mmHg