Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].Cl.[CH3:4][N:5]([CH3:16])[CH2:6][CH2:7][CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[OH:9].Cl[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1>CS(C)=O>[CH3:16][N:5]([CH3:4])[CH2:6][CH2:7][CH:8]([O:9][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: CN(C)CCC(O)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C)CCC(Oc1ccc([N+](=O)[O-])cc1)c1ccccc1
Temperature: 22 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
26 ml of dimethylsulfoxide were added to 2.6 g of a 50% dispersion of sodium hydride in oil and the mixture was stirred at 60°-65° C. for 30 minutes and was then cooled to 22° C. 5.8 g of N,N-dimethyl-3-phenyl-3-hydroxy-propanamine hydrochloride were added to the mixture which was then stirred for 10 minutes at 25° C. Then, 8.95 g of p-chloronitrobenzene were added to the mixture which was stirred at room temperature for 15 minutes. The mixture was extracted with methylene chloride and the organic phase was washed with water, dried, filtered and evaporated to dryness under reduced pressure to obtain 17 g of raw product. The latter was extracted 3 times with 200 ml of N hydrochloric acid and the neutral fraction was eliminated 3 times with 200 ml of ether. The combined aqueous phases were made alkaline with excess concentrated ammonium hydroxide and the precipitate was extracted with methylene chloride. The extract was dried, filtered and evaporated to dryness under reduced pressure to obtain 7.7 g of N,N-dimethyl-γ-(4-nitrophenoxy)benzene-propanamine.
Reaction SMILES: O1CCCCC1[O:7][CH:8]1[CH2:14][N:13]([CH2:15][C:16]2[N:21]=[C:20]([NH:22][C:23]3[CH:27]=[CH:26][N:25](COCC[Si](C)(C)C)[N:24]=3)[CH:19]=[N:18][CH:17]=2)[CH2:12][CH2:11][NH:10][CH2:9]1.[F:36][C:37]1[C:45]([C:46]([F:49])([F:48])[F:47])=[CH:44][CH:43]=[CH:42][C:38]=1[C:39](O)=[O:40].FC(F)(F)C(O)=O>>[F:36][C:37]1[C:45]([C:46]([F:47])([F:48])[F:49])=[CH:44][CH:43]=[CH:42][C:38]=1[C:39]([N:10]1[CH2:9][CH:8]([OH:7])[CH2:14][N:13]([CH2:15][C:16]2[N:21]=[C:20]([NH:22][C:23]3[CH:27]=[CH:26][NH:25][N:24]=3)[CH:19]=[N:18][CH:17]=2)[CH2:12][CH2:11]1)=[O:40]
Reactant: C[Si](C)(C)CCOCn1ccc(Nc2cncc(CN3CCNCC(OC4CCCCO4)C3)n2)n1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1F
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cccc(C(F)(F)F)c1F)N1CCN(Cc2cncc(Nc3cc[nH]n3)n2)CC(O)C1

Procedure:
The amidation reaction was performed in the same manner as in Example 3-(2) using 6-((6-(tetrahydro-2H-pyran-2-yloxy)-1,4-diazepan-1-yl)methyl)-N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyrazin-2-amine and 2-fluoro-3-(trifluoromethyl)benzoic acid. Next, the deprotection reaction was performed in the same manner as in Example 16-(4) using trifluoroacetic acid to give the title compound.
Reaction SMILES: [Cl:1][C:2]([Cl:33])([Cl:32])[CH2:3][O:4][C:5]([NH:7][C:8]1[C:9]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)=[N:10][O:11][N:12]=1)=[O:6].O[CH:35]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:36]([O:38][CH3:39])=[O:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>CN(C=O)C.O>[C:28]([O:27][C:25]([N:22]1[CH2:21][CH2:20][N:19]([C:16]2[CH:17]=[CH:18][C:13]([C:9]3[C:8]([N:7]([C:5]([O:4][CH2:3][C:2]([Cl:32])([Cl:1])[Cl:33])=[O:6])[C@H:35]([C:36]([O:38][CH3:39])=[O:37])[CH2:40][CH:41]([CH3:43])[CH3:42])=[N:12][O:11][N:10]=3)=[CH:14][CH:15]=2)[CH2:24][CH2:23]1)=[O:26])([CH3:30])([CH3:29])[CH3:31]
Reactant: COC(=O)C(O)CC(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3nonc3NC(=O)OCC(Cl)(Cl)Cl)cc2)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC(C)C)N(C(=O)OCC(Cl)(Cl)Cl)c1nonc1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To tert-butyl 4-[4-(4-{[(2,2,2-trichloroethoxy)carbonyl]amino}-1,2,5-oxadiazol-3-yl)phenyl]piperazine-1-carboxylate (485 mg, 0.932 mmol), methyl 2-hydroxy-4-methylpentanoate (275 mg, 1.87 mmol) and triphenyl phosphine (490 mg, 1.87 mmol) in dry DMF (15 mL) at 0° C. under dry nitrogen was added diisopropyl azodicarboxylate (0.375 mL, 1.87 mmol) dropwise over ½ hour and the reaction mixture stirred overnight at rt. The reaction was poured into water and the product extracted with Et2O (2×), dried over Na2SO4, concentrated in vacuo and purified by flash chromatography over silica gel (EtOAc/Hex, 2/8) to afford methyl N-(4-{4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl}-1,2,5-oxadiazol-3-yl)-N-[(2,2,2-trichloroethoxy)carbonyl]leucinate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:23]=[C:24]([CH3:26])[CH:25]=1)[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[S:14]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].[CH:27]([N:30]=[C:31]=[O:32])([CH3:29])[CH3:28].C(N(CC)CC)C>C(Cl)Cl>[C:10]([C:9]1[CH:12]=[CH:13][C:6]([O:5][C:4]2[CH:3]=[C:2]([CH3:1])[CH:25]=[C:24]([CH3:26])[CH:23]=2)=[C:7]([S:14]([N:17]2[CH2:22][CH2:21][N:20]([C:31]([NH:30][CH:27]([CH3:29])[CH3:28])=[O:32])[CH2:19][CH2:18]2)(=[O:16])=[O:15])[CH:8]=1)#[N:11]
Reactant: Cc1cc(C)cc(Oc2ccc(C#N)cc2S(=O)(=O)N2CCNCC2)c1
Reactant: CC(C)N=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)cc(Oc2ccc(C#N)cc2S(=O)(=O)N2CCN(C(=O)NC(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 11.4 %

Procedure:
To a solution of compound 24 (0.100 g, 0.27 mmol) in CH2Cl2 (3 mL) was added isopropyl isocyanate (0.032 g, 0.38 mmol) and triethylamine (0.039 g, 0.38 mmol). Reaction was stirred for 20 hrs at room temperature, whereupon the starting material was consumed (TLC, 1% MeOH in CH2Cl2). The reaction mixture was then concentrated in vacuo, redissolved in a minimal amount of CH2Cl2, and chromatographed over normal phase silica (MeOH/CH2Cl2). The fractions containing the desired product were combined and concentrated in vacuo to yield a white powder, which was then triturated with CH2Cl2/hexanes and vacuum filtered to yield a powder. The powder was redissolved in CH2Cl2 and chromatographed for a second time over normal phase silica (MeOH/CH2Cl2). The fractions containing the desired product were combined and concentrated in vacuo to yield a white powder, which was then triturated with hexanes and vacuum filtered to afford compound 58 as a white powder (0.014 g, 11.3% yield, 99.1% HPLC purity). 1H NMR (500 MHz, CDCl3): 8.27 (d, J=2 Hz, 1H), 7.67 (dd, J1=9 Hz, J2=2 Hz, 1H) 6.93 (s, 1H), 6.89 (s, J=9 Hz, 1H), 6.69 (s, 2H), 4.17 (m, 1H), 3.95 (m, 1H), 3.44 (m, 4H), 3.35 (m, 4H), 2.34 (s, 6H), 1.14 (d, J=7 Hz, 6H); MS (ESI, EI+): m/z=457 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:14][C@@H:15]([C@@H:17]2[CH2:21][C:20](=[O:22])[N:19]([C@@H:23]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[CH3:24])[CH2:18]2)[CH3:16])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2/[CH:11]=[N:12]/O)[CH:7]=1>C(OC(=O)C)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:14][C@@H:15]([C@@H:17]2[CH2:21][C:20](=[O:22])[N:19]([C@@H:23]([C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[CH3:24])[CH2:18]2)[CH3:16])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:11]#[N:12])[CH:7]=1
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(Br)cn4ncc(/C=N/O)c34)CC2=O)cc1
Solvent: CC(=O)OC(C)=O
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(Br)cn4ncc(C#N)c34)CC2=O)cc1

Procedure:
To an appropriate sized microwave vial, crude (E)-6-bromo-4-((R)-1-((R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbaldehyde oxime (511 mg, 1.02 mmol) was heated in acetic anhydride (5.0 mL) at 100° C. for 24 h. The reaction was concentrated under reduced pressure, neutralized with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were washed with brine, dried, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford 6-bromo-4-((R)-1-((R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH3:47])[CH2:30][CH2:31][N:32]([C:37]1[C:42]([N+:43]([O-:45])=[O:44])=[CH:41][C:40]([NH2:46])=[CH:39][CH:38]=1)[S:33]([CH3:36])(=[O:35])=[O:34]>>[CH3:28][N:29]([CH3:47])[CH2:30][CH2:31][N:32]([C:37]1[CH:38]=[CH:39][C:40]([NH:46]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:41][C:42]=1[N+:43]([O-:45])=[O:44])[S:33]([CH3:36])(=[O:34])=[O:35]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CN(C)CCN(c1ccc(N)cc1[N+](=O)[O-])S(C)(=O)=O
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(CCN(C)C)S(C)(=O)=O)c([N+](=O)[O-])c1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 6-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-3-amino-nitrobenzene Rf value: 0.6 (silica gel, methylene chloride/methanol=5:1) C28H29N5O7S.
Reaction SMILES: C(O[NH:9][CH:10]1[CH2:19][CH2:18][CH2:17][C:16]2[N:15]=[C:14]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:13]=[CH:12][C:11]1=2)C1C=CC=CC=1.B.O>C1COCC1>[CH2:21]([O:20][C:14]1[CH:13]=[CH:12][C:11]2[CH:10]([NH2:9])[CH2:19][CH2:18][CH2:17][C:16]=2[N:15]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: c1ccc(CONC2CCCc3nc(OCc4ccccc4)ccc32)cc1
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: NC1CCCc2nc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
A solution of O-benzyl-N-(2-benzyloxy-5,6,7,8-tetrahydro-quinolin-5-yl)-hydroxylamine (51.0 g, 142 mmoL) dissolved in dry THF (65 mL) was cooled in ice-water bath under nitrogen. Borane (1.0 M in THF, 427 mL) was added dropwise in 30 min via an addition funnel. The reaction was allowed to warm up to room temperature and stirred for overnight. The mixture was then heated to reflux. After 2 h, the heating was stopped and the reaction was allowed to cool to room temperature. Water (120 mL) was added dropwise via an addition funnel. The mixture was then concentrated, and 20% aqueous sodium hydroxide (200 mL) was added. The resulting mixture was heated to reflux for 2 h. The reaction was allowed to cool to room temperature, and extracted with methylene chloride (×3). The combined methylene chloride extract was dried, filtered and concentrated. Purification by column chromatography on silica gel with 20% methanol/1% ammonium hydroxide/methylene chloride provided the desired product (32.0 g, 89%) as colorless oil.
Reaction SMILES: C([N:9]1[C:21]2[CH2:20][CH:19]([C:22]([OH:24])=[O:23])[CH2:18][CH2:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[C:13]([Cl:25])[CH:14]=2)(=O)C1C=CC=CC=1.[OH-].[Na+]>>[Cl:25][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:21]1[CH2:20][CH:19]([C:22]([OH:24])=[O:23])[CH2:18][CH2:17][C:16]2=1
Reactant: O=C(O)C1CCc2c(n(C(=O)c3ccccc3)c3ccc(Cl)cc23)C1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1CCc2c([nH]c3ccc(Cl)cc23)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred mixture of 100 mg. of 9-benzoyl-6-chloro-1,2,3,4-tetrahydrocarbazole-2-carboxylic acid and 5 ml. of 3N sodium hydroxide was heated on a steam bath for 5 minutes and cooled to room temperature. After 1 hour at room temperature, the reaction mixture was further cooled in an ice bath, filtered and the filter cake was washed with 10 drops of cold water. The filter cake was dissolved in 20 ml. of warm water, and the resulting warm solution was made strongly acid with 1N hydrochloric acid. Following filtration, washing with warm water and drying, 56 mg. of (±) 6-chloro-1,2,3,4-tetrahydrocarbazole-2-carboxylic acid was obtained, m.p. 247°-249°.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([NH2:15])[CH:9]=2)[CH2:7][CH2:6]1)=[O:4].[CH:16](OC)(OC)OC>CN(C=O)C.O>[CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]3[O:14][CH:16]=[N:15][C:10]=3[CH:9]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(OC)OC
Reactant: COC(=O)C1(c2ccc(O)c(N)c2)CC1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1(c2ccc3ocnc3c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.4 %

Procedure:
To a solution of 1-(3-amino-4-hydroxyphenyl)cyclopropanecarboxylic acid methyl ester (3.00 g, 14.5 mmol) in DMF were added trimethyl orthoformate (5.30 g, 14.5 mmol) and a catalytic amount of p-tolueneslufonic acid monohydrate (0.3 g) at room temperature. The mixture was stirred for 3 hours at room temperature. The mixture was diluted with water and extracted with EtOAc (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give 1-benzooxazol-5-yl-cyclopropanecarboxylic acid methyl ester (3.1 g), which was directly used in the next step. 1H NMR (CDCl3, 400 MHz) δ 8.09 (s, 1), 7.75 (d, J=1.2 Hz, 1H), 7.53-7.51 (m, 1H), 7.42-7.40 (m, 1H), 3.66 (s, 3H), 1.69-1.67 (m, 2H), 1.27-1.24 (m, 2H).
Reaction SMILES: [Br:1]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:22]([O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[O:34][CH2:33][C:32]([CH2:38]O)=[CH:31]2)[CH2:23][CH2:24][CH2:25][CH3:26]>C(#N)C.CCOCC.CCCCCC>[CH2:22]([O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[O:34][CH2:33][C:32]([CH2:38][Br:1])=[CH:31]2)[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCOc1ccc2c(c1)C=C(CO)CO2
Solvent: CC#N
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCCCOc1ccc2c(c1)C=C(CBr)CO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2 g (4.7 mmol) of dibromotriphenylphosphorane are added to a solution of 1.15 g (4.6 mmol) of the alcohol obtained in Step C in 25 ml of anhydrous acetonitrile. The medium is stirred for 1 hour at ambient temperature; the solvent is then evaporated in vacuo. The residue obtained is taken up in a mixture of ether/hexane (1/1); the solid formed is then filtered off over Celite. Evaporation of the filtrate yields the brominated compound of the title in the form of a chestnut-brown syrup.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:12].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](Cl)=[O:23])=[CH:17][CH:16]=1.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[CH:5]=[CH:4][C:3]=1[NH:12][C:22](=[O:23])[CH2:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1
Reactant: Cc1nc2c(Cl)c(N)ccc2s1
Reactant: COc1ccc(CC(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(CC(=O)Nc2ccc3sc(C)nc3c2Cl)cc1
Yield: 56 %

Procedure:
Reaction of 4-chloro-2-methyl-benzothiazol-5-ylamine (50 mg, 0.25 mmol) in THF (1.5 mL) with 4-methoxyphenylacetyl chloride (46 μL, 0.30 mmol) in presence of triethylamine (42 μL, 0.30 mmol) according to method A gave N-(4-chloro-2methyl-benzothiazol-5-yl)-2-(4-methoxy-phenyl)-acetamide (50 mg, 0.14 mmol, 56% yield) as a white powder after crystallisation in hexane/DCM.
Reaction SMILES: [SH:1][CH2:2][CH:3]([CH3:18])[C:4]([N:6]1[CH2:13][C:12]([O:16][CH3:17])([O:14][CH3:15])[CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5].II>>[CH3:18][C@H:3]([CH2:2][S:1][S:1][CH2:2][C@@H:3]([CH3:18])[C:4]([N:6]1[CH2:13][C:12]([O:16][CH3:17])([O:14][CH3:15])[CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[C:4]([N:6]1[CH2:13][C:12]([O:16][CH3:17])([O:14][CH3:15])[CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5]
Reactant: COC1(OC)C[C@@H](C(=O)O)N(C(=O)C(C)CS)C1
Agent: II
Product: COC1(OC)C[C@@H](C(=O)O)N(C(=O)[C@H](C)CSSC[C@@H](C)C(=O)N2CC(OC)(OC)C[C@H]2C(=O)O)C1

Procedure:
(S)-1-(3-Mercapto-2-methyl-1-oxopropyl)-4,4-dimethoxy-L-proline from Example 4 is reacted with iodine according to the procedure of Example 125 to yield (S,S,S,S)-1,1'-[dithiobis(2-methyl-1-oxo-3,1-propanediyl)]bis[4,4-dimethoxy-L-proline].
Reaction SMILES: [C:1]([N:4]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[O:15][CH3:16])[C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([N:4]([C:8]1[C:9]([O:15][CH3:16])=[CH:10][CH:11]=[CH:12][C:13]=1[CH2:14][Br:17])[C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2]
Reactant: COc1cccc(C)c1N(C(C)=O)C(C)=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cccc(CBr)c1N(C(C)=O)C(C)=O
Yield: 63.6 %

Procedure:
A mixture of N-acetyl-N-(2-methoxy-6-methylphenyl)acetamide (25.0 g, 0.11 mol), N-bromosuccinimide (20.1 g, 0.11 mol), and benzoyl peroxide (4.5 g, 0.019 mol) in carbon tetrachloride (300 mL) was stirred under reflux for 3 hours. The solution was cooled, filtered, and evaporated, and the residual solid was crystallized from ethyl acetate:hexane to give 21.0 g of N-acetyl-N-(2-(bromomethyl)-6-methoxyphenyl)acetamide, 95% pure by GC analysis.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[NH:10][C@@H:11]([C:14]1([OH:17])[CH2:16][CH2:15]1)[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[C:20]1(C)[N:25]([O])[C:24](C)(C)CCC1.Cl[O-].[Na+].Cl([O-])=O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+].[OH-].[Na+].C(OC(C)C)(C)C>C(#N)C.P([O-])([O-])([O-])=O>[CH2:1]([O:8][C:9](=[O:18])[NH:10][C@@H:11]([C:14]1([OH:17])[CH2:15][CH2:16]1)[C:12]([N:25]([CH3:20])[CH3:24])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@H](CO)C1(O)CC1)OCc1ccccc1
Reactant: CC1(C)CCCC(C)(C)N1[O]
Agent: O=P([O-])([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: CC#N
Product: CN(C)C(=O)[C@@H](NC(=O)OCc1ccccc1)C1(O)CC1
Temperature: 35 °C
Reaction time: 48 h
Yield: 259.1 %

Procedure:
To a mixed solution consisting of benzyl[(1R)-2-hydroxy-1-(1-hydroxycyclopropyl)ethyl]carbamate (900 mg) and 2,2,6,6-tetramethylpiperidine 1-oxyl (39.2 mg) in acetonitrile (5 mL) and phosphate buffer (pH 6.8, 5 mL) were simultaneously added dropwise 0.033M aqueous sodium hypochlorite solution (2.17 mL) and 2M aqueous sodium chlorite solution (3.58 mL) over 30 min. The reaction mixture was stirred at 35° C. for 2 days, and to the reaction mixture was added saturated aqueous sodium thiosulfate solution at room temperature. The mixture was adjusted with 8N aqueous sodium hydroxide solution to about pH at room temperature, and to the reaction mixture was added a small amount of diisopropyl ether. The reaction mixture was vigorously stirred at room temperature for 30 min, and the aqueous layer was separated and adjusted with 6N hydrochloric acid to about pH 2 at room temperature. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. To a solution of the residue, 50% aqueous dimethylamine solution (323 mg) and N-ethyl-N-(1-methylethyl)propan-2-amine (925 mg) in DMF (5 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1361 mg) at room temperature. The reaction mixture was stirred at room temperature for 4 hr, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (190 mg).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]([CH3:19])[N:10]([C:20]2[CH:30]=[CH:29][C:23]([C:24](OCC)=[O:25])=[CH:22][N:21]=2)[N:9]=1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+].[F-].[K+]>O1CCCC1>[CH3:7][C:8]1[C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:11]([CH3:19])[N:10]([C:20]2[N:21]=[CH:22][C:23]([CH2:24][OH:25])=[CH:29][CH:30]=2)[N:9]=1
Reactant: CCOC(=O)c1ccc(-n2nc(C)c(-c3ccccc3)c2C)nc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nn(-c2ccc(CO)cn2)c(C)c1-c1ccccc1
Reaction time: 2 h
Yield: 71.5 %

Procedure:
To a stirred solution of lithium aluminum hydride (0.72 g, 15.1 mmol) and tetrahydrofuran (20 mL) was added slowly a solution of ethyl 6-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)nicotinate (step 1, 2.43 g, 7.56 mmol) and tetrahydrofuran (40 mL) at 0° C. After 2 h, sodium sulfate decahydrate and potassium fluoride were added slowly to the mixture at 0° C. The mixture was filtered through a bed of celite, and the filtrate was concentrated in vacuo. The residue was purified by silica-gel column chromatography eluting with hexane/ethyl acetate (1:1) to give 1.51 g (72%) of title compound as white solids: MS (ESI) m/z 280 [M+H]+, 1H-NMR (CDCl3) δ 8.42-8.41 (1H, m), 7.83-7.82 (2H, m), 7.47-7.28 (5H, m), 4.75 (2H, s), 2.58 (3H, s), 2.33 (3H, s), 2.30 (3H, s).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][C@@H:29]3[CH3:34])[C:16]3[CH2:21][N:20]([CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[CH2:19][C:17]=3[N:18]=2)=[CH:9][C:8]=1[F:35])=[O:5])[CH3:2].CCN(C(C)C)C(C)C.Cl[C:46]([O:48][CH3:49])=[O:47]>O1CCOCC1>[CH2:1]([NH:3][C:4](=[O:5])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][C@@H:29]3[CH3:34])[C:16]3[CH2:21][N:20]([CH:22]4[CH2:23][CH2:24][N:25]([C:46]([O:48][CH3:49])=[O:47])[CH2:26][CH2:27]4)[CH2:19][C:17]=3[N:18]=2)=[CH:9][C:8]=1[F:35])[CH3:2]
Reactant: COC(=O)Cl
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C2CCNCC2)C3)cc1F
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C2CCN(C(=O)OC)CC2)C3)cc1F
Temperature: 25 °C
Yield: 5.3 %

Procedure:
To a stirred solution of (S)-1-ethyl-3-(2-fluoro-4-(4-(3-methylmorpholino)-6-(piperidin-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (90 mg, 0.17 mmol) and DIPEA (30 μL, 0.17 mmol) in Dioxane (5 mL) was added methyl chloroformate (14 μL, 0.19 mmol). Reaction mixture was stirred at room temperature until analysis by LCMS indicated reaction was complete. Solvent was then removed in vacuo. Purified by prep. HPLC (low pH) to afford an orange gum. This was then further purified using a TsOH cartridge to remove residual formic acid from HPLC (loaded in MeOH eluted with 2M methanolic ammonia). This gave a creamy pink solid (4.9 mg, 0.009 mmol, 5.3%).
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][CH2:5][CH:6](P(OCC)(OCC)=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:20][NH:21][C:22]1[CH:23]=[C:24]([C:28]2[CH:33]=[CH:32][C:31]([CH:34]=O)=[CH:30][CH:29]=2)[CH:25]=[CH:26][CH:27]=1.[Cl-].[NH4+]>O1CCCC1>[CH3:20][NH:21][C:22]1[CH:23]=[C:24]([C:28]2[CH:33]=[CH:32][C:31](/[CH:34]=[C:6](\[CH2:5][CH2:4][CH3:3])/[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:30][CH:29]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: CNc1cccc(-c2ccc(C=O)cc2)c1
Reactant: CCCC(C(=O)OCC)P(=O)(OCC)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC/C(=C\c1ccc(-c2cccc(NC)c2)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
197 mg (4.9 mmol) of sodium hydride are added to a mixture of 1.2 mL (4.9 mmol) of triethyl 2-phosphonopentanoate and 415 mg of 3′-methylaminobiphenyl-4-carbaldehyde prepared as described in Example 9b (2.0 mmol) in 10 mL of tetrahydrofuran. The reaction mixture is stirred at room temperature overnight. The reaction medium is poured into saturated ammonium chloride solution and extracted with ethyl acetate. The organic phases are combined, washed with water and dried over sodium sulfate. The solvent is evaporated off and the residue (1 g) is purified by chromatography on a column of silica eluted with a 90/10 heptane/ethyl acetate mixture. 511 mg (81%) of ethyl 2-[1-(3′-methylaminobiphenyl-4-yl)meth-(E)-ylidene]pentanoate are obtained in the form of a yellow oil.