Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[C:25]([O:28][C:29]1[CH:39]=[CH:38][C:32]([CH:33]=[CH:34][C:35](O)=[O:36])=[CH:31][CH:30]=1)(=[O:27])[CH3:26].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:25]([O:28][C:29]1[CH:39]=[CH:38][C:32]([CH:33]=[CH:34][C:35]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)=[O:36])=[CH:31][CH:30]=1)(=[O:27])[CH3:26]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: CC(=O)Oc1ccc(C=CC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1ccc(OC(C)=O)cc1
Yield: 94 %

Procedure:
The same procedures as in Example 2 were carried out from methyl L-tryptophanate hydrochloride (3.0 g), triethylamine (2.0 mL), 4-acetoxycinnamic acid (2.9 g), WSC.HCl (2.7 g), and methylene chloride (80 mL), to give the captioned compound (4.5 g, 93%) as an oily product.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9](Cl)[C:8]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:16][N:17]1CCCC1=O.C([Cu])#N>O>[CH3:1][C:2]1[CH:10]=[C:9]([C:16]#[N:17])[C:8]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CN1CCCC1=O
Reactant: Cc1cc(Cl)c(S(C)(=O)=O)cc1C(=O)O
Agent: N#C[Cu]
Solvent: O
Product: Cc1cc(C#N)c(S(C)(=O)=O)cc1C(=O)O
Reaction time: 72 h

Procedure:
8.3 g of 2-methyl-4-chloro-5-methylsulphonylbenzoic acid are mixed together with 70 ml of N-methylpyrrolidone and 7.4 g of CuCN, and the whole is stirred at 150° for 3 days. The reaction mixture is then poured into 250 ml of water and working-up takes place in the customary manner. After recrystallization from methanol, 2-methyl-4-cyano-5-methylsulphonylbenzoic acid is obtained, m.p. 248°-249°.
Reaction SMILES: Cl[C:2]1(OCC)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]1[C:13]#[N:14].[Cl:18][C:19]1[CH:20]=[C:21]([NH2:32])[CH:22]=[CH:23][C:24]=1[S:25][C:26]1[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=1.Cl.N1C=CC=CC=1.[CH2:40]([O:42]CCO)[CH3:41]>>[Cl:18][C:19]1[CH:20]=[C:21]([NH:32][C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:12])=[C:9]([O:42][CH2:40][CH3:41])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:13]#[N:14])[CH:22]=[CH:23][C:24]=1[S:25][C:26]1[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=1
Reactant: CCOC1(Cl)c2ccc(F)cc2N=CC1C#N
Reactant: CCOCCO
Reactant: Cn1ccnc1Sc1ccc(N)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCOc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1F

Procedure:
Following the procedure of Example 1, a mixture of 2.4 g (9.72 mmol) 4-chloro-4-ethoxy-7-fluoro-3-quinolinecarbonitrile, 2.56 g (10.7 mmol) of 3-chloro-4-(1-methyl-1H-imidazole-2-ylsulfanyl)phenylamine and 1.2 g (10.38 mmol) of pyridine hydrochloride are refluxed in 2-ethoxyethanol (30 mL) at 110° C. for 1 hour to yield 4-({3-chloro-4-[(1-methyl-1H-imidazole-2-yl)sulfanyl]phenyl}amino)-6-ethoxy-7-fluoro-3-quinolinecarbonitrile as a pink solid, mp 251-254° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7]([C:10]([O:12]C)=[O:11])[CH:8]=2)[CH:3]=[N:2]1.[OH-].[Na+]>CO.O>[NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=2)[CH:3]=[N:2]1
Reactant: COC(=O)c1cnc2cn[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cnc2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 20.8 %

Procedure:
To a solution of methyl 1H-pyrazolo[4,3-b]pyridine-6-carboxylate (3.52 g, 20 mmol) in methanol (250 mL) and water (190 mL) at 0° C. was added aqueous sodium hydroxide (2M, 64 mL, 128 mmol), dropwise. The suspension was then allowed to warm to ambient temperature and stirred for 18 hours. The methanol was then removed in vacuo and the aqueous mixture extracted with ethyl acetate (250 mL) before being acidified (to pH 5-6) with aqueous hydrochloric acid (2 M, 70 mL). The cream solid which had precipitated out was then filtered off and dried in a desiccator to yield the title compound (0.675 g, 4.16 mmol, 21 yield). 1HNMR (400 MHz, DMSO-d6): δ ppm 8.97 (s, 1H), 8.45 (s, 1H), 8.39 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5](=[NH:8])[NH:6][OH:7].Br[C:14]1C=C(C=CC=1C)C#N.Cl.NO.[C:26](=[O:29])([O-])[O-].[Na+].[Na+]>C(O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[N:8]([CH3:14])[C:26](=[O:29])[O:7][N:6]=2)[CH:9]=[CH:10][C:11]=1[CH3:12]
Reactant: Cc1ccc(C(=N)NO)cc1Br
Reactant: Cc1ccc(C#N)cc1Br
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(-c2noc(=O)n2C)cc1Br
Temperature: 25 °C

Procedure:
Step-1: 3-Bromo-N-hydroxy-4-methylbenzimidamide: To a stirred solution of 3-bromo-4-methylbenzonitrile (2.0 g, 10.2 mmol, 1.0 eq) in ethanol (20 mL) was added hydroxylamine hydrochloride (1.77 g, 25.5 mmol, 2.5 eq) followed by a solution of sodium carbonate (2.70 g, 25.5 mmol, 2.5 eq) in water (2 mL). The resulting mixture was refluxed for 6 h. The reaction was cooled to room temperature and the solvent was removed under vacuum. The residue was taken in DCM (100 mL) and washed with water (30 mL), brine (30 mL), dried (Na2SO4) and filtered. The filtrate was rotary evaporated to afford 1.5 g of the title compound as a white solid. 1HNMR (400 MHz, CDCl3) δ 9.70 (s, 1H), 7.86 (d, J=1.5 Hz, 1H), 7.59 (dd, J=7.5, 1.5 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 5.86 (s, 2H), 2.34 (s, 3H); ESI-MS (m/z) 229, 231 [(MH)+ Br79,81].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[C@H:10]([OH:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.Cl[CH2:30][O:31][CH3:32]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[C@H:10]([O:19][CH2:30][O:31][CH3:32])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCl
Reactant: CC(=O)OC[C@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1COC(C)=O
Temperature: 0 °C
Reaction time: 12 h
Yield: 93.1 %

Procedure:
To a solution of (±)-cis-4-acetoxymethyl-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (45.0 mmol, 12.3 g) in anhydrous DCM (100 mL) at room temperature was added N,N-diisopropylethyl amine (180 mmol, 31.4 mL). The reaction mixture was cooled to 0° C. using an ice bath. To this was added chloromethylmethyl ether (135 mmol, 11.4 mL) dropwise over 15 minutes. After completion of addition, the reaction was stirred for 12 hours while coming to room temperature. All volatiles were removed under reduced pressure. The residue was dissolved in ethyl acetate (250 mL) and washed with water (3×50 mL) and brine (50 mL). The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on 110 g SiO2 cartridge using ethyl acetate/hexanes gradient to give (±)-cis-4-acetoxymethyl-3-methoxymethoxy-piperidine-1-carboxylic acid tert-butyl ester (13.3 g).
Reaction SMILES: C[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[N:15]([CH3:16])[N:14]=[N:13][N:12]=3)[CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1.[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:17][C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[N:15]([CH3:16])[N:14]=[N:13][N:12]=3)[CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1
Reactant: Cc1csc2ccc(-c3nnnn3C)cc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1nnnc1-c1ccc2scc(Br)c2c1
Yield: 62.4 %

Procedure:
Following the procedure of Example 11, Step 6, 0.666 g (2.89 mmol) 3-methyl-5-(1-methyltetrazol-5-yl)benzo[b]thiophene was reacted with 0.515 g (2.89 mmol) of N-bromosuccinimide and 38.1 mg of benzoyl peroxide in 30 ml of carbon-tetrachloride. The reaction mixture was evaporated in vacuo and chromatographed on flash silica, eluting with 0-3% methanol/dichloromethane to give 0.532 g of crude 3-bromo-5-(1-methyltetrazol-5-yl) benzo[b]thiophene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N+:16]([O-:18])=[O:17])[CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][C:9]([C:13]#[N:14])=[C:8]2O.P(Cl)(Cl)(Cl)(Cl)[Cl:20].P(Cl)(Cl)(Cl)=O>CCCCCC>[Cl:20][C:8]1[C:7]2[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[C:5]([N+:16]([O-:18])=[O:17])[CH:6]=2)[N:11]=[CH:10][C:9]=1[C:13]#[N:14]
Reactant: COc1cc([N+](=O)[O-])cc2c(O)c(C#N)cnc12
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCCCCC
Product: COc1cc([N+](=O)[O-])cc2c(Cl)c(C#N)cnc12
Yield: 48.6 %

Procedure:
A mixture of 4 g (16 mmol) of 8-Methoxy-4-hydroxy-6-nitro-quinoline-3-carbonitrile, 6.66 g (32 mmol) of phosphorous pentachloride, and 15 ml of phosphorous oxychloride was refluxed for 2.5 hours. The mixture was diluted with hexane and the solid was collected. The solid was dissolved in 500 ml of ethyl acetate and washed with cold diluted sodium hydroxide solution. The solution was dried over magnesium sulfate and filtered through a pad of silica gel. The solvent was removed giving 2.05 g of tan solid: mass spectrum (electrospray, m/e) M+H 263.7.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]1[CH3:15].[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][OH:22])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([O:22][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([F:16])=[CH:18][CH:19]=2)[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]1[CH3:15]
Reactant: Cc1ccc(C)n1-c1ccc(I)cc1F
Reactant: OCc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1ccc(OCc2ccc(F)cc2)cc1F
Temperature: 25 °C
Yield: 75.1 %

Procedure:
A solution of 1-(2-fluoro-4-iodo-phenyl)-2,5-dimethyl-1H-pyrrole (33.18 g, 105 mmol), 4-fluorobenzylalcohol (26.6 g, 211 mmol), cesium carbonate (68.6 g, 211 mmol), cuprous iodide (2.0 g, 11 mmol) and 1,10-phenanthroline (3.8 g, 21 mmol) in toluene (52 mL) was heated at 100° C. in an autoclave for 48 h. After cooling to room temperature, the mixture was filtered and poured into sodium hydroxide (1N). The resulting mixture was extracted with toluene and the organic extracts washed with brine, dried and evaporated. The residue was triturated with boiling hexane to leave the title compound (24.7 g, 75%) as a light brown solid. MS: m/e=314.1 (M++H).
Reaction SMILES: [CH2:1]([NH2:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[C:8](=[S:10])=[S:9].[NH3:11]>CO>[CH2:1]([NH:7][C:8](=[S:9])[S-:10])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[NH4+:11]
Reactant: N
Reactant: NCc1ccco1
Reactant: S=C=S
Solvent: CO
Product: S=C([S-])NCc1ccco1
Product: [NH4+]
Reaction time: 16 h
Yield: 32.7 %

Procedure:
Furfurylamine (4.85 g) is added dropwise over 50 minutes to a vigorously stirred mixture of 3.75 ml of CS2 and 8.3 ml of 29.7% aqueous ammonia cooled in ice and methyl alcohol. The cooling bath is removed and the thick orange suspension stirred 16 hours more, filtered and air dried to yield 3.11 g (32.7% yield) of desired product characterized by m.p. equal to 88° C. dec.
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:10]([Li])CCC.CI.Cl>CCCCCC.C(COC)OC>[CH3:10][O:9][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:2]#[CH:1]
Reactant: C#CC(O)CCCCC
Reactant: [Li]CCCC
Agent: Cl
Solvent: CI
Solvent: CCCCCC
Solvent: COCCOC
Product: C#CC(CCCCC)OC
Temperature: 60 °C

Procedure:
To an ice-cooled solution of 63 g. of 1-octyne-3-ol in 300 ml. of dimethoxyethane is added under an inert atmosphere 312 ml. of 1.6 M n-butyllithium in hexane dropwise over 1 hour. To the mixture is then added 145 g. of methyl iodide and the resulting mixture is stirred at ambient temperatures for 24 hours and then heated to 60° C. for 1 hour. The mixture is cooled and poured into cold dilute hydrochloric acid. The organic phase is separated, washed with water and saturated brine, dried (Na2SO4), and evaporated to an oil, dried (Na2SO4), and evaporated to an oil. Fractional distillation of the oil in vacuo yields the product as a colorless oil.
Reaction SMILES: [O:1]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[O:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>C1COCC1.CCOC(C)=O>[O:1]1[C:6]2([CH2:11][CH2:10][N:9]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH2:8][CH2:7]2)[O:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C1COC2(CCNCC2)OC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC2(CC1)OCCCO2
Temperature: 25 °C
Reaction time: 18 h
Yield: 68 %

Procedure:
To a solution of 1,5-dioxa-9-aza spiro[5.5]undecane (15.0 g, 95.4 mmol) and triethylamine (17.6 mL, 126 mmol) in THF (140 mL) cooled to 0° C. was added dropwise a solution of benzyl chloroformate (14 mL, 97.5 mmol) dissolved in THF (30 mL). The resulting mixture was stirred at room temp for 18 h. After diluting with EtOAc, the mixture was washed with water and brine and dried (Na2SO4). Concentration gave yellow oil that was purified by flash chromatography eluting with 20%-50% EtOAc/hexane to give the title compound as colorless oil (18.9 g, 68% yield). 1H NMR (300 MHz, CDCl3) δ: 7.36-7.27 (5H, m), 5.09 (2H, s), 3.89-3.85 (4H, m), 3.51-3.47 (4H, m), 1.87-1.66 (6H, m). LCMS (M+H) calcd for C16H22NO4: 292.15; found: 292.00.
Reaction SMILES: ClCOC(N[C@@H](CCC(OCC1C=CC=CC=1)=O)C(OCC1C=CC=CC=1)=O)=O.[NH2:30][C@@H:31]([CH2:42][CH2:43][C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33].Cl[C:55]([O:57][CH2:58]Cl)=[O:56].[Cl:60][C:61]1[C:62]([F:101])=[C:63]([C@@H:67]2[C@:71]([C:74]3[CH:79]=[CH:78][C:77]([Cl:80])=[CH:76][C:75]=3[F:81])([C:72]#[N:73])[C@H:70]([CH2:82][C:83]([CH3:86])([CH3:85])[CH3:84])[NH:69][C@H:68]2[C:87]([NH:89][C:90]2[CH:98]=[CH:97][C:93]([C:94]([OH:96])=[O:95])=[CH:92][C:91]=2[O:99][CH3:100])=[O:88])[CH:64]=[CH:65][CH:66]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(Cl)Cl.CN(C)C=O.N1C=CC=CC=1>[Cl:60][C:61]1[C:62]([F:101])=[C:63]([C@@H:67]2[C@:71]([C:74]3[CH:79]=[CH:78][C:77]([Cl:80])=[CH:76][C:75]=3[F:81])([C:72]#[N:73])[C@H:70]([CH2:82][C:83]([CH3:85])([CH3:86])[CH3:84])[NH:69][C@H:68]2[C:87]([NH:89][C:90]2[CH:98]=[CH:97][C:93]([C:94]([O:96][CH2:58][O:57][C:55]([NH:30][C@@H:31]([CH2:42][CH2:43][C:44]([O:46][CH2:47][C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)=[O:45])[C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])=[O:56])=[O:95])=[CH:92][C:91]=2[O:99][CH3:100])=[O:88])[CH:64]=[CH:65][CH:66]=1
Reactant: O=C(Cl)OCCl
Reactant: N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: O=C(CC[C@H](NC(=O)OCCl)C(=O)OCc1ccccc1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COc1cc(C(=O)OCOC(=O)N[C@@H](CCC(=O)OCc2ccccc2)C(=O)OCc2ccccc2)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 23, (S)-dibenzyl 2-((chloromethoxy)-carbonylamino)pentanedioate was prepared from (S)-dibenzyl 2-aminopentanedioate and chloromethyl chloroformate in the presence of pyridine in methylene chloride. It was then reacted with chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid and cesium carbonate in dimethylformamide to give chiral (S)-dibenzyl 2-(((4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoyloxy)methoxy)carbonylamino)-pentanedioate as a white solid. MS (ES+) m/z calcd. for C52H51Cl2F2N4O10 [(M+H)+]: 999, found: 999.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:16])[CH:14]=[O:15])[CH:7]=[CH:6]2.C(O)(=[O:19])C.CC1C=CC=C(C)N=1.C(OO)(=O)C>C(OCC)(=O)C>[CH3:16][C@H:13]([C:14]([OH:19])=[O:15])[C:8]1[CH:7]=[CH:6][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:10]=2[CH:9]=1
Reactant: CC(=O)O
Reactant: COc1ccc2cc([C@H](C)C=O)ccc2c1
Agent: CC(=O)OO
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Product: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Yield: 88.5 %

Procedure:
To a stirred solution of 16.67 g (77.8 mmol) of (S)-2-(6-methoxy-2-naphthyl)propionaldehyde (naproxen aldehyde) in ethyl acetate (78 mL) cooled in a wet-ice bath (ca. 2° C.) was added concurrently 4.67 g (77.8 mmol) of glacial acetic acid and 8.33 g (77.8 mmol) of 2,6-dimethylpyridine (2,6-lutidine). To this solution was then added slowly dropwise 8.87 g (116.7 mmol) of a 23.7 weight percent solution of peracetic acid in ethyl acetate, at a rate slow enough such that the reaction temperature did not exceed 10° C. (ca. 1 hour). After the initial exotherm, the temperature returned to 2° C., and the reaction was maintained at this temperature for an additional 3.5 hours. Conversion of aldehyde at this time was ca. 99%, as monitored by GC (DB-1 column). The cold reaction solution was then transferred into a separatory funnel, was diluted with ethyl acetate (300 mL), and was washed with a 5% aqueous solution of sodium thiosulfate (Na2S2 O3, 100 mL). The ethyl acetate layer was further washed with two portions of water (110 mL each), and the combined water washes were back-extracted with ethyl acetate (100 mL). The combined ethyl acetate layers were extracted with two portions of a 5% aqueous solution of sodium hydroxide (NaOH, 110 mL each). The combined NaOH solutions of sodium naproxenate were acidified to pH=1 with a 10% aqueous solution of hydrochloric acid, precipitating the naproxen acid. The mixture was cooled in a wet-ice bath, and then was vacuum filtered through a #4 Whatman filter. The white solid thus obtained was dried in a vacuum oven overnight at 45° C. (25 mm Hg), giving 15.85 g (88.5%) of naproxen. HPLC analysis of this material (Chiracel OD-H column) indicated an `S` acid content of 99.2%, the same as the starting aldehyde as measured following KMnO4 oxidation.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][OH:15])[NH:11][CH2:10][C@H:9]1[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:18][C:19]([F:37])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:20]1[N:25]=[CH:24][C:23]2[C:26]([CH3:30])([CH3:29])[CH2:27][NH:28][C:22]=2[CH:21]=1.Cl[CH2:39][C:40](Cl)=[O:41].CCN(C(C)C)C(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][OH:15])[N:11]([CH2:39][C:40]([N:28]2[C:22]3[CH:21]=[C:20]([C:19]([F:18])([F:37])[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:25]=[CH:24][C:23]=3[C:26]([CH3:30])([CH3:29])[CH2:27]2)=[O:41])[CH2:10][C@H:9]1[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)CCl
Reactant: C[C@@H]1CN[C@@H](CO)CN1C(=O)OC(C)(C)C
Reactant: CC1(C)CNc2cc(C(F)(F)c3ccccc3)ncc21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(CC(=O)N2CC(C)(C)c3cnc(C(F)(F)c4ccccc4)cc32)[C@@H](CO)CN1C(=O)OC(C)(C)C
Yield: 78.6 %

Procedure:
The title compound was prepared following methods similar to those described in Preparation 203 starting from (2R,5R)-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (1.1 g, 3.2 mmol), 6-(difluoro-phenyl-methyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine hydrochloride (1.0 g, 3.55 mmol), chloroacetyl chloride (282 μL, 3.55 mmol) and DIPEA (2 mL, 11.3 mmol) to give the title compound (1.37 g) as an orange gum. MS: [M+H]+=545.
Reaction SMILES: C=O.[F:3][C:4]([F:31])([F:30])[C:5]1[CH:29]=[CH:28][C:8]2[NH:9][C:10]3[CH:27]=[CH:26][CH:25]=[CH:24][C:11]=3[N:12]=[C:13]([N:14]3[CH2:19][CH2:18][NH:17][C@@H:16]([CH2:20][CH2:21][O:22][CH3:23])[CH2:15]3)[C:7]=2[CH:6]=1.[C:32](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[F:31][C:4]([F:30])([F:3])[C:5]1[CH:29]=[CH:28][C:8]2[NH:9][C:10]3[CH:27]=[CH:26][CH:25]=[CH:24][C:11]=3[N:12]=[C:13]([N:14]3[CH2:19][CH2:18][N:17]([CH3:32])[C@@H:16]([CH2:20][CH2:21][O:22][CH3:23])[CH2:15]3)[C:7]=2[CH:6]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COCC[C@H]1CN(C2=Nc3ccccc3Nc3ccc(C(F)(F)F)cc32)CCN1
Agent: C=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COCC[C@H]1CN(C2=Nc3ccccc3Nc3ccc(C(F)(F)F)cc32)CCN1C
Reaction time: 0.03 h
Yield: 81 %

Procedure:
Add aqueous 37% formaldehyde (1.1 equiv.) to a solution of (S)-2-trifluoromethyl-11-[3-(2-methoxy-ethyl)-piperazin-1-yl]-5H-dibenzo[b,e][1,4]diazepine (470 mg) in dichloroethane (0.2M). Stir the mixture 2 minutes and add sodium triacetoxyborohydride (1.5 equiv). Stir the suspension for 30 minutes and quench with a saturated aqueous solution of sodium bicarbonate. Extract the aqueous phase 3 times with dichloromethane and combine the organic phases, dry over magnesium sulfate, filter and concentrate. Purify the residue via chromatography on silica gel (methylene chloride/methanol (90:10) to afford the title compound as a yellow solid (394 mg, 81%): mp 48-56° C.; 1H NMR (CDCl3): δ 1.70-1.56 (m, 1H), 2.04-1.92 (m, 1H), 2.31 (m, 1H), 2.37 (s, 3H), 2.43 (dt, 1H), 2.81 (t, 1H), 2.89 (d, 1H), 3.13 (t, 1H), 3.25 (s, 3H), 3.38 (t, 2H), 3.73 (bs, 2H), 5.10 (s, 1H), 6.69 (dd, 1H), 6.93-6.88 (m, 2H), 7.00 (dt, 1H), 7.10 (dd, 1H), 7.56-7.50 (m, 2H); MS (ESI/neg) m/z (rel intensity) 417.4 (100).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH2:18][C@@H:17]2[C:21]3[CH:22]=[CH:23][C:24]([NH2:28])=[CH:25][C:26]=3[CH2:27][C@H:16]12)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>ClCCl>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH2:18][C@@H:17]2[C:21]3[CH:22]=[CH:23][C:24]([NH:28][C:1](=[O:3])[CH3:2])=[CH:25][C:26]=3[CH2:27][C@H:16]12)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]2c3ccc(N)cc3C[C@@H]21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc2c(c1)C[C@H]1[C@@H]2CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Acetic anhydride (50 μL) is added to a solution of cis-7-amino-2,3,4,4a,9,9a-hexahydro-indeno[2,1-b]pyridine-1-carboxylic acid tert-butyl ester (140 mg) and triethylamine (70 μL) in dichloromethane (3 mL) at room temperature. The solution is stirred for 1 h at room temperature and then aqueous NaHCO3 solution is added. The mixture is stirred vigorously for 20 min and then extracted with dichloromethane. The combined extract is concentrated and the residue is chromatographed (cyclohexane/ethyl acetate 7:3→1:9) to give the title compound. Yield: 100 mg (62% of theory); LC (method 1): tR=3.60 min.
Reaction SMILES: [CH2:1]([N:3]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[CH:9]2)=[N:4]1)[CH3:2].[Br:12]Br.O>C(O)C>[CH2:1]([N:3]1[C:11]([Br:12])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[CH:9]2)=[N:4]1)[CH3:2]
Reactant: CCn1cc2ccccc2n1
Reactant: BrBr
Solvent: O
Solvent: CCO
Product: CCn1nc2ccccc2c1Br
Yield: 65.5 %

Procedure:
To a solution of 2-ethyl indazole (2.32 g, 15.87 mmol) in ethanol (20 mL) was added bromine (2.54 g, 15.87 mmol) in ethanol (1 mL)/water (1 mL) at 0° C. After stirring at 0° C. for 10 min. and at rt for 1h, the reaction was quenched with aq. sodium bicarbonate. The mixture was partitioned between ethyl acetate and aq. sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (3×). The combined organic phase was washed with brine, and dried over anhydrous magnesium sulfate. Purification by flash chromatography (hexanes:ethyl acetate=1:1, then 100% ethyl acetate) gave 2.34 g of the title compound as a viscous oil.