Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:5]1[C:18](=[O:19])[CH2:17][C:8]2([C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9]2)[CH2:7][C:6]1=[O:20])(=O)[CH2:2][CH3:3].Cl.[CH2:22]([O:24][NH2:25])[CH3:23].C([O-])(=O)C.[Na+].Cl>C(O)C>[CH2:22]([O:24][N:25]=[C:1]([CH:5]1[C:18](=[O:19])[CH2:17][C:8]2([C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9]2)[CH2:7][C:6]1=[O:20])[CH2:2][CH3:3])[CH3:23]
Reactant: CCC(=O)C1C(=O)CC2(CCc3ccccc32)CC1=O
Reactant: CCON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCON=C(CC)C1C(=O)CC2(CCc3ccccc32)CC1=O

Procedure:
4-Propionylspiro[cyclohexane-1,1'-indan]-3,5-dione (0.54 g), ethoxyamine hydrochloride (1.3 equiv), anhydrous sodium acetate (1.3 equiv) and absolute ethanol (20 ml) were stirred at room temperature for 3 hr. The mixture was poured into a very dilute aqueous hydrochloric acid solution which was then immediately extracted with diethyl ether. The dried (MgSO4) organic fraction was evaporated to give 4-[1-(ethoxyimino)propyl]spiro[cyclohexane-1,1'indan]-3,5-dione (5) as a pale yellow oil. Pmr spectrum (CDCl3 ; δ in ppm): 1.09-1.41 (6H, 2×t); 2.06 (2H, t); 2.6-3.1 (8H, m); 4.12 (2H, q); 7.2 (4H, m); 14.93 (1H, brs).
Reaction SMILES: C([C@@H:8]1COC(=O)[N:9]1[C:14](=[O:36])[C@H:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:22][C:21]=1[Cl:35])[CH2:16]C=O)C1C=CC=CC=1.[NH:37]1[C:45]2[CH:44](N)[CH2:43][CH2:42][CH2:41][C:40]=2[CH:39]=[N:38]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(#N)C>[CH2:28]([O:27][C:23]1[CH:22]=[C:21]([Cl:35])[C:20]([CH2:19][C@@H:15]2[CH2:16][CH2:8][N:9]([CH:44]3[C:45]4[NH:37][N:38]=[CH:39][C:40]=4[CH2:41][CH2:42][CH2:43]3)[C:14]2=[O:36])=[C:25]([Cl:26])[CH:24]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=CC[C@@H](Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: NC1CCCc2cn[nH]c21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: O=C1[C@H](Cc2c(Cl)cc(OCc3ccccc3)cc2Cl)CCN1C1CCCc2cn[nH]c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
Add a solution of (R)-4-((R)-4-benzyl-2-oxo-oxazolidin-3-yl)-3-(4-benzyloxy-2,6-dichloro-benzyl)-4-oxo-butyraldehyde, Preparation 38, (9.95 g, 18.9 mmol) in CH2Cl2 (300 mL) to a solution of 4,5,6,7-tetrahydro-1H-indazol-7-ylamine (2.60 g, 19.00 mmol) in acetonitrile (300 mL) and stir for 30 minutes at room temperature under N2. Add sodium triacetoxyborohydride (12.02 g, 56.9 mmol) to the reaction and stir for 72 hours. Remove the solvent in vacuo and extract solid with ethyl acetate, water and saturated NaHCO3. Dry the organic layer (Na2SO4), filter and concentrate under vacuum. Purify the residue by silica gel chromatography with a gradient of 0 to 10% methanol in CH2Cl2 to afford 2.53 g (28%) of the title compound. MS (m/z): 470 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:26])[C:9](=[O:25])[CH2:10][CH:11]([CH2:18][CH2:19]OS(C)(=O)=O)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[C:27]1([C:33]2([OH:39])[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CCOC(C)=O.O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:26])[C:9](=[O:25])[CH2:10][CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:18][CH2:19][N:36]2[CH2:37][CH2:38][C:33]([OH:39])([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:34][CH2:35]2)=[CH:4][CH:3]=1
Reactant: CN(C(=O)CC(CCOS(C)(=O)=O)c1ccccc1)c1ccc(Cl)cc1
Reactant: OC1(c2ccccc2)CCNCC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C(=O)CC(CCN1CCC(O)(c2ccccc2)CC1)c1ccccc1)c1ccc(Cl)cc1
Temperature: 80 °C
Yield: 40.3 %

Procedure:
N-(4-Chlorophenyl)-beta-(2-methanesulfonyloxyethyl)-N-methyl-benzenepropanamide (1.44 g) in DMF (10 mL) was treated with 4-phenyl-4-hydroxypiperidine (1.61 g) and the mixture heated at 80° C. for 2 hours. The cooled reaction mixture was diluted the EtOAc (50 mL) and water (50 mL) and the aqueous phase removed. The aqueous layer was extracted with EtOAc (2×50 mL) and the combined organic extracts, washed with water (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give an oil. Silica gel chromatography eluting with 10% MeOH:CH2Cl2 gave the title compound (0.7 g). Mass spectrum (FAB): 477.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N+:12]([O-:14])=[O:13])=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[C:21]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])#[N:22].CC(=O)OCC>C1COCC1>[C:21]([CH:23]([C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N+:12]([O-:14])=[O:13])=[CH:4][N:3]=1)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])#[N:22]
Reactant: O=[N+]([O-])c1cnc(Cl)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C(C#N)c1ncc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 70 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
To a solution of 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (5 g, 22.07 mmol) and K2CO3 (6.10 g, 44.1 mmol) in THF (150 mL) was added tert-butyl 2-cyanoacetate (3.74 g, 26.5 mmol). The resulting mixture was stirred at 70° C. overnight under N2. After TLC analysis (PE/EA=10/1) showed the starting material was consumed, the solvent was removed in vacuo. The residue was dissolved in EA (100 mL) and washed with H2O (50 mL) and brine (50 mL). The organic layer was dried over Na2SO4, filtered and concentrated to yield a solid of tert-butyl 2-cyano-2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)acetate (7 g, 21.13 mmol, 96% yield): 1H NMR (400 MHz, CD3OD) δ 9.08 (s, 1H), 8.59 (br. s., 1H), 4.63 (br. s., 1H), 1.55 (s, 9H); ES-LCMS m/z: 332.1 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:48]=[CH:47][C:7]([O:8][C:9]2[C:14]([F:15])=[C:13]([F:16])[C:12]([C:17]3[C:22]([F:23])=[C:21]([F:24])[C:20]([O:25][C:26]4[CH:31]=[CH:30][C:29]([N+:32]([O-])=O)=[C:28]([O:35]CC5C=CC=CC=5)[CH:27]=4)=[C:19]([F:43])[C:18]=3[F:44])=[C:11]([F:45])[C:10]=2[F:46])=[CH:6][C:5]=1[O:49]CC1C=CC=CC=1)([O-])=O.[H][H]>O1CCCC1.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:48]=[CH:47][C:7]([O:8][C:9]2[C:10]([F:46])=[C:11]([F:45])[C:12]([C:17]3[C:22]([F:23])=[C:21]([F:24])[C:20]([O:25][C:26]4[CH:31]=[CH:30][C:29]([NH2:32])=[C:28]([OH:35])[CH:27]=4)=[C:19]([F:43])[C:18]=3[F:44])=[C:13]([F:16])[C:14]=2[F:15])=[CH:6][C:5]=1[OH:49]
Reactant: O=[N+]([O-])c1ccc(Oc2c(F)c(F)c(-c3c(F)c(F)c(Oc4ccc([N+](=O)[O-])c(OCc5ccccc5)c4)c(F)c3F)c(F)c2F)cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2c(F)c(F)c(-c3c(F)c(F)c(Oc4ccc(N)c(O)c4)c(F)c3F)c(F)c2F)cc1O
Reaction time: 168 h

Procedure:
72 g of 4,4'-Bis(4-nitro-3-benzyloxyphenoxy)octafluorobiphenyl prepared as described in Example 1 (0.09 mol) are dissolved in 600 ml of a mixture of tetrahydrofuran and ethyl acetate (volume ratio 1:1), and 7 g of Pd/C (palladium/carbon) are added to the solution. The mixture is then hydrogenated at room temperature in an autoclave with vigorous stirring using hydrogen at a pressure of 1 bar; after 7 days, the reaction is terminated. The yellow-beige solution is evaporated to half in a rotary evaporator and left to stand overnight at room temperature, during which the reaction product precipitates in crystalline form. The reaction product is then collected and dried for 48 hours under nitrogen at 40° C./10 mbar in a vacuum drying cabinet (yield: 96%0).
Reaction SMILES: [C:1]([C:4]1[N:5]([CH2:9][C:10]2[CH:11]=[C:12]([C:16]3[CH:20]=[C:19]([CH2:21][CH:22]([CH3:24])[CH3:23])[S:18][C:17]=3[S:25]([NH:28]C(C)(C)C)(=[O:27])=[O:26])[CH:13]=[CH:14][CH:15]=2)[CH:6]=[CH:7][N:8]=1)(=[O:3])[CH3:2].C1(OC)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+].Cl[C:48]([O:50][CH2:51][CH2:52][CH2:53][CH3:54])=[O:49]>C(O)(C(F)(F)F)=O.C(Cl)Cl.O>[CH2:51]([O:50][C:48]([NH:28][S:25]([C:17]1[S:18][C:19]([CH2:21][CH:22]([CH3:23])[CH3:24])=[CH:20][C:16]=1[C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][N:5]2[CH:6]=[CH:7][N:8]=[C:4]2[C:1](=[O:3])[CH3:2])[CH:11]=1)(=[O:27])=[O:26])=[O:49])[CH2:52][CH2:53][CH3:54]
Reactant: CCCCOC(=O)Cl
Reactant: CC(=O)c1nccn1Cc1cccc(-c2cc(CC(C)C)sc2S(=O)(=O)NC(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCOC(=O)NS(=O)(=O)c1sc(CC(C)C)cc1-c1cccc(Cn2ccnc2C(C)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
To a solution of 3-[3-(2-acetylimidazol-1-ylmethyl)phenyl]-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (62.4 mg, 0.132 mmol; see step (b)) in TFA (2 mL) was added anisole (150 μL) and the reaction mixture was stirred overnight at ambient temperature. The reaction mixture was concentrated in vacuo and dried in vacuo overnight. To the crude product dissolved in CH2Cl2 (2 mL) was added Na2CO3 (302 mg, 2.85 mmol), water (0.8 mL) and butyl chloroformate (83.8 μL, 0.659 mmol) and the reaction mixture was stirred overnight at ambient temperature. The reaction mixture was diluted with CH2Cl2 (30 mL) and washed with citric acid (10% aq), brine and water, dried (over anhydrous MgSO4), concentrated in vacuo, and the residue purified by flash chromatography using MeOH:CH2Cl2 (5:95) as eluent to give the title compound as a white solid in 34% yield, over two steps, (23 mg, 0.0045 nmol).
Reaction SMILES: Cl[Si:2]([CH3:5])([CH3:4])[CH3:3].[CH2:6]([OH:11])[C:7]([CH3:10])([CH3:9])[CH3:8].CN1C=CN=C1>>[CH3:8][C:7]([CH3:10])([CH3:9])[CH2:6][O:11][Si:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)(C)CO
Agent: Cn1ccnc1
Product: CC(C)(C)CO[Si](C)(C)C
Temperature: 0 °C
Yield: 85.8 %

Procedure:
6.50 g (56.7 mmol) of chlorotrimethylsilane were added dropwise to a solution of 5.00 g (56.7 mmol) of neopentyl alcohol (2,2-dimethyl-1-propanol) and 11.6 g (142 mmol) of 1-methylimidazole while stirring at 0° C. The reaction mixture was stirred for a further 2 hours at 0° C. and for 2.5 hours at 20° C. The upper phase was separated off to give 7.80 g (theory: 9.09 g) of 2,2-dimethyl-1-trimethylsilyloxypropane as a colorless oil having a purity of 96% (GC).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:3]=1.[Cl:20][C:21]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:22]=1[NH2:23]>>[Cl:20][C:21]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:22]=1[NH:23][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:3]=1
Reactant: Clc1cc(-c2ccccn2)nc(-c2ccccn2)n1
Reactant: COc1ccc(Cl)c(N)c1
Product: COc1ccc(Cl)c(Nc2cc(-c3ccccn3)nc(-c3ccccn3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2,6-di(2-pyridinyl)pyrimidine (25 mg, 0.093 mmol) and 2-chloro-5-methoxyaniline (27 mg, 0.140 mmol) similar to Example 111 and isolated as a white solid (20 mg, 55%). 1H NMR (CDCl3): 8.87–8.82 (m, 1H), 8.72–8.64 (m, 3H), 8.08 (d, J=2.7 Hz, 1H), 7.92 (s, 1H), 7.90–7.86 (m, 2H), 7.45–7.38 (m, 3H), 7.33 (d, J=8.7 Hz, 1H), 6.67 (dd, J=3.0, 9.0 Hz, 1H), 3.91 (s, 3H).
Reaction SMILES: CC1S[C:4]([C:10]2[CH:15]=CC=C[CH:11]=2)=[C:5]([C:7]([OH:9])=O)[N:6]=1.C(N(C(C)C)CC)(C)C.[C:25](Cl)([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>ClCCl>[OH:9][CH2:7][C@H:5]1[N:6]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:11][C@@H:10]2[C@H:4]1[CH2:15]2
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2)s1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)N1C[C@H]2C[C@H]2[C@H]1CO
Temperature: 25 °C

Procedure:
To a solution of racemic 7-1 (7.2 g, 63.6 mmol, synthesized as in Example 1) in dichloromethane (320 mL) at 0° C. was added diisopropylethylamine (10.7 g, 83.0 mmol) followed by CbzCl (11.9 g, 70.0 mmol) and the reaction mixture was slowly warmed to ambient temperature over 48 h. The mixture was then quenched with water and extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to an oil. The oil was purified by normal phase silica gel chromatography (0 to 100% EtOAc in hexanes) to afford the product as an oil. ESI+ MS: [M+H]+ 248.3.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11](=[O:16])[C:12]([O:14]C)=[O:13].C([O-])([O-])=O.[K+].[K+]>CO.O.O>[Br:1][C:2]1[N:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11](=[O:16])[C:12]([OH:14])=[O:13]
Reactant: COC(=O)C(=O)c1c[nH]c2c(Br)ncc(OC)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1cnc(Br)c2[nH]cc(C(=O)C(=O)O)c12
Temperature: 25 °C
Reaction time: 14 h
Yield: 59.3 %

Procedure:
To a solution of methyl 2-(7-bromo-4-methoxy-6-azaindol-3-yl)-2-oxoacetate (0.083 g, 0.265 mmol) in MeOH—H2O (3:1, 3 mL) was added 1M aqueous K2CO3 (1.1 mL, 1.1 mmol). The mixture was stirred at room temperature for 14 h and then it was diluted with H2O (2 mL). The volatiles were removed under reduced pressure and the remaining solution was acidified to pH 1-2 using 6N HCl. The resulting suspension was cooled at 0° C., the precipitate was filtered and the filtercake was washed with H2O and then ether. After drying in vacuo, this gave the title compound (0.047 g, 59%) as a light yellow solid:
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][C:15]([CH3:20])([NH:17][CH:18]=O)[C:14]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1.C(N(CC)CC)C.C(Cl)(Cl)=O>C(Cl)Cl>[F:29][C:2]([F:1])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][C:15]([CH3:20])([N+:17]#[C-:18])[C:14]([C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1
Reactant: CC1(NC=O)CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(Cl)cc1
Agent: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: [C-]#[N+]C1(C)CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(Cl)cc1
Yield: 17.2 %

Procedure:
To 4.5 g (10 mmole) of N-(4-trifluoromethylphenyl)-3-(4-chlorophenyl)-4-methyl-4-(N-formylamino)-4,5-dihydro-1H-pyrazole-1-carboxamide (Example 64) and 3.4 ml (23 mmole) of triethylamine in 25 ml of methylene chloride at reflux was slowly added 5.5 ml of a 2.0M solution of phosgene in methylene chloride. After refluxing for 30 minutes the mixture was twice washed with water, dried over anhydrous magnesium sulfate, filtered, concentrated in vacuo, and chromatographed on silica gel using diethyl ether and hexanes to yield 0.7 g of the title compound, a yellow solid, mp 171°-173° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[C:14]2[CH2:18][C@H:19]([NH:21][C:22](=O)[C@H:23]([OH:30])[C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCCC1.CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[C:14]2[CH2:18][C@H:19]([NH:21][CH2:22][C@@H:23]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[OH:30])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](Cc1c[nH]c2c(OCc3ccccc3)cccc12)NC(=O)[C@H](O)c1cccnc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](Cc1c[nH]c2c(OCc3ccccc3)cccc12)NC[C@H](O)c1cccnc1
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
To a solution of (2R)-N-((1R)-2-(7-(benzyloxy)-1H-indol-3-yl)-1-methylethyl)-2-hydroxy-2-pyridin-3-ylacetamide (283 mg, 0.681 mmol) in tetrahydrofuran (15 mL) is added a 2M solution of boranedimethyl sulfide complex in tetrahydrofuran (2.04 mL, 4.09 mmol), and the mixture is refluxed for 3 hours. To the reaction solution is added a 10% hydrogen chloride solution in methanol (30 mL), and the mixture is stirred for 30 minutes. The solvent is evaporated, and the residue is separated into a saturated aqueous sodium hydrogen carbonate solution and chloroform. The organic layer is washed with a saturated brine, and dried over sodium sulfate. The solvent is distilled off, and the obtained crude product is purified by silica gel column chromatography (a saturated ammonia solution in chloroform-methanol=100:1) to give the title compound (184.8 mg, yield: 68%).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:26]=[CH:25][C:24]([C:27]([NH:29][C:30]([CH3:35])([CH3:34])[C:31](O)=[O:32])=[O:28])=[CH:23][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)(Cl)=O.[NH2:40][C:41]1[CH:50]=[CH:49][C:44]([C:45]([O:47][CH3:48])=[O:46])=[CH:43][CH:42]=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.N1C=CC=CC=1.CN(C)C=O>[CH:1]1([C:7]2[C:8]3[CH:26]=[CH:25][C:24]([C:27]([NH:29][C:30]([CH3:34])([CH3:35])[C:31]([NH:40][C:41]4[CH:42]=[CH:43][C:44]([C:45]([O:47][CH3:48])=[O:46])=[CH:49][CH:50]=4)=[O:32])=[O:28])=[CH:23][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc2c(c1)OCCn1c-2c(C2CCCCC2)c2ccc(C(=O)NC(C)(C)C(=O)O)cc21
Reactant: COC(=O)c1ccc(N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NC(=O)C(C)(C)NC(=O)c2ccc3c(C4CCCCC4)c4n(c3c2)CCOc2cc(OC)ccc2-4)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 41 %

Procedure:
To a solution of 2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)amino]-2-methylpropionic acid (200 mg, 0.42 mmol) in chloroform (4.0 ml) was added a catalytic amount of N,N-dimethylformamide solution, thionyl chloride (0.07 ml, 1.26 mmol) was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 3 hr. Then, and the solvent was evaporated under reduced pressure to give a yellow solid. The obtained solid was dissolved in chloroform (1.5 ml), and added dropwise to a solution of methyl 4-aminobenzoate (95.2 mg, 0.63 mmol) in a mixture of chloroform (1.0 ml) and pyridine (1.0 ml) under ice-cooling. Then, methyl 4-aminobenzoate (32 mg, 0.21 mmol) and pyridine (2.0 ml) were added, and the mixture was stirred at room temperature for 24 hr. To the reaction mixture was added aqueous sodium hydrogen carbonate solution and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. Methanol and chloroform were added to the residue, and the mixture was stirred. The precipitate was collected by filtration to give methyl 4-{2-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)amino]-2-methylpropionylamino}benzoate (105 mg, yield 41%).
Reaction SMILES: [N:1]1([C:15]([O:17][CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13]C)=[O:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1>Cl>[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([CH2:18][O:17][C:15]([N:1]2[C:10]3[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[O:16])[CH:20]=1
Reactant: COC(=O)c1ccc2c(c1)CCCN2C(=O)OCc1cccnc1
Agent: Cl
Product: O=C(O)c1ccc2c(c1)CCCN2C(=O)OCc1cccnc1
Reaction time: 2 h
Yield: 98.2 %

Procedure:
A solution of ester 213 (0.489 g, 1.50 mmol) in 2N HCl (10 mL) was stirred at 110° C. for 3 h then concentrated, suspended in dry acetonitrile (20 mL), stirred for 2 h, diluted with dry benzene (20 mL), and stirred for 6 h. The suspension was concentrated then re-suspended in 1:1 acetonitrile and benzene (20 mL). The solid material was collected by filtration to provide title compound 214 (0.460 g, 88% yield).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+].O1CCCC1>C(O)(=O)C>[C:13]1([C:12]#[C:11][C:8]2[CH:7]=[CH:6][C:5]([OH:4])=[CH:10][CH:9]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(=O)Oc1ccc(C#Cc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Oc1ccc(C#Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 36.2 %

Procedure:
4-(Phenylethynyl)phenyl acetate (60.6 g, 0.256 moles), 20 percent aqueous sodium hydroxide (400 mL), and tetrahydrofuran (400 mL) are added to a 2-L Erlenmeyer flask and stirred at room temperature for 5 hours. The mixture is acidified with glacial acetic acid (120 mL) until a pH of 7 is reached. The aqueous layer is removed and extracted with tetrahydrofuran. The organic layers are combined and concentrated on a rotovap to give a tan solid. The solid is heated with hexanes (700 mL) on a steam bath and the hot solution decanted from the solid. This is repeated with a second volume of hexanes (700 mL). A white solid crystallizes from the hexane solution upon cooling and is isolated by filtration and dried in vacuo to give 18 g of a white solid, mp 126° C. to 127° C. NMR analysis is consistent with the structure of the desired material.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[C:4]([NH:35][NH2:36])([CH3:34])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]2C3C(=CC=CC=3)C(=O)O2)=[C:8]([O:23][CH:24]2C3C(=CC=CC=3)C(=O)O2)[CH:7]=1.IC>>[CH3:1][O:2][C:3](=[O:37])[C:4]([NH:35][NH2:36])([CH3:34])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:23][CH3:24])[CH:7]=1
Reactant: COC(=O)C(C)(Cc1ccc(OC2OC(=O)c3ccccc32)c(OC2OC(=O)c3ccccc32)c1)NN
Solvent: CI
Product: COC(=O)C(C)(Cc1ccc(OC)c(OC)c1)NN

Procedure:
Following the procedure for preparation of compound 119, and substituting bromophthalide with iodomethane, provided the title compound 120. 1H NMR (CD3OD, 400 MHz): 1.44 (s, 3H), 3.00 (dd, 2H), 3.80 (2 s, 6H), 4.77 (s, 3H), 6.71–6.86 (m, 3H). MS (ESI) m/z 269.33 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:37][C:38]2[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=2)[C@H:13]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]4[O:34][CH2:35][O:36][C:29]=34)=[O:24])[CH2:19][CH2:18]2)[C:14]([OH:16])=O)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[C:44]([O:63][NH2:64])([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.CN1CCOCC1.ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.C(OCC)(=O)C>[C:44]([O:63][NH:64][C:14](=[O:16])[C@H:13]([N:12]([S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])[CH2:37][C:38]1[CH:39]=[CH:40][N:41]=[CH:42][CH:43]=1)[CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]3[O:34][CH2:35][O:36][C:29]=23)=[O:24])[CH2:19][CH2:18]1)([C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: NOC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccncc2)[C@@H](C(=O)O)C2CCN(C(=O)OCCc3cccc4c3OCO4)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)N(Cc2ccncc2)[C@@H](C(=O)NOC(c2ccccc2)(c2ccccc2)c2ccccc2)C2CCN(C(=O)OCCc3cccc4c3OCO4)CC2)cc1
Reaction time: 18 h

Procedure:
To a solution of the crude 2-(R)-[(4-methoxybenzenesulfonyl)(4-picolyl)amino]-2-[(N-(2-(2,3-methylenedioxyphenyl)-ethoxycarbonyl))-4-piperidinyl]acetic acid (0.66 mmol) in methylene chloride (35 ml) is added O-tritylhydroxylamine (547 mg, 1.98 mmol), N-methylmorpholine (0.44 ml, 3.97 mmol), 1-hydroxy-7-azabenzotriazole (90 mg, 0.66 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (165 mg, 0.86 mmol). The reaction mixture is stired at room temperature for 18 hours, diluted with ethyl acetate and washed with water. The aqueous layer is extracted with ethyl acetate, the combined organic layers are washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude product is purified by silica gel chromatography (2% to 4% methanol in methylene chloride) to provide N-(trityl-oxy)-2-(R)-[(4-methoxybenzenesulfonyl) (4-picolyl)amino]-2-[(N-(2-(2,3-methylenedioxy-phenyl)-ethoxycarbonyl))-4-piperidinyl]acetamide.