Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].C(N(CC)CC)C.[C:27](OC(=O)C)(=[O:29])[CH3:28]>C(#N)C.CN(C)C1C=CN=CC=1>[C:27]([O:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[S:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccccc1-c1sc(-c2ccccc2)cc1O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)Oc1cc(-c2ccccc2)sc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Hydroxy-2-(2-methylphenyl)-5-phenylthiophene (537 mg, 2.02 mmol) was dissolved in acetonitrile (4.0 mL), and 4-dimethylaminopyridine (15 mg, 0.12 mmol) and triethylamine (0.65 mL, 470 mg, 6.9 mmol) were added followed by acetic anhydride (0.65 mL, 700 mg, 6.9 mmol). The reaction was stirred overnight at 25° C. The reaction mixture was evaporated and the residue was chromatographed on 30 g of silica gel eluting with 700 mL of 15% ethyl acetate in hexane. 3-Acetoxy-2-(2'-methylphenyl)-5-phenylthiophene was isolated as 370 mg of viscous oil. The product could be distilled bulb-to-bulb, bp (0.4 mm) 140°-150° C.
Reaction SMILES: [F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14](Cl)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.[NH2:18][C:19]1[CH:27]=[CH:26][C:25]2[NH:24][C:23]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:22][C:21]=2[C:20]=1[C:32]#[N:33].C(N(CC)CC)C>CN(C=O)C>[C:28]([C:23]1[NH:24][C:25]2[C:21]([CH:22]=1)=[C:20]([C:32]#[N:33])[C:19]([NH:18][C:14]([C:11]1([C:9]3[CH:8]=[CH:7][C:5]4[O:6][C:2]([F:17])([F:1])[O:3][C:4]=4[CH:10]=3)[CH2:13][CH2:12]1)=[O:15])=[CH:27][CH:26]=2)([CH3:31])([CH3:29])[CH3:30]
Reactant: O=C(Cl)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Reactant: CC(C)(C)c1cc2c(C#N)c(N)ccc2[nH]1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc2c(C#N)c(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (26 mg, 0.1 mmol) was added to a solution of 5-amino-2-tert-butyl-1H-indole-4-carbonitrile (21 mg, 0.1 mmol) and triethylamine (41.7 μL, 0.3 mmol) in DMF (1 mL). The reaction was stirred at room temperature overnight, then filtered and purified by reverse-phase HPLC to yield the product, N-(2-tert-butyl-4-cyano-1H-indol-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 437.2, found 438.7 (M+1)+, Retention time 2.10 minutes. 1H NMR (400 MHz, DMSO-d6) δ 11.48 (s, 1H), 8.88 (s, 1H), 7.52 (d, J=8.5 Hz, 2H), 7.41 (d, J=8.3 Hz, 1H), 7.32 (dd, J=1.5, 8.3 Hz, 1H), 7.03 (d, J=8.6 Hz, 1H), 6.21 (d, J=1.8 Hz, 1H), 1.51-1.49 (m, 2H), 1.36 (s, 9H), 1.18-1.16 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1.[C:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[OH:27])([CH3:20])([CH3:19])[CH3:18].C([O-])([O-])=O.[K+].[K+]>CC#N>[C:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)c1ccccc1O
Reactant: NC(=O)c1cc(-c2ccc(CBr)cc2)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)c1ccccc1OCc1ccc(-c2cc(C(N)=O)on2)cc1
Temperature: 90 °C
Yield: 74.7 %

Procedure:
To a mixture of 3-(4-bromomethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 14; 30 mg, 0.107 mmol) in CH3CN (2 mL) were added 2-tert-butylphenol (28 μL, 0.182 mmol) and K2CO3 (30 mg, 0.22 mmol). The mixture was heated at 90° C. for 16 h and then evaporated to dryness. The residue was purified by chromatography (66-75% EtOAc/hexanes) to give 3-[4-(2-tert-butyl-phenoxymethyl)-phenyl]-isoxazole-5-carboxylic acid amide (28 mg, 75%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.39 (s, 1H), 8.02 (s, 1H), 7.95 (d, J=8.5 Hz, 2H), 7.57-7.67 (m, 2H), 7.12-7.28 (m, 2H), 7.00-7.09 (m, 1H), 6.82-6.94 (m, 1H), 5.20 (s, 2H), 1.34 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[C:3]=1[OH:15].CC(C)([O-:19])C.[K+].[OH-].[K+].Cl>O.CN1C(=O)CCC1>[Cl:1][C:2]1[C:7]([OH:19])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[C:3]=1[OH:15]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(Cl)c1O
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(O)c(Cl)c1O
Temperature: 85 °C
Yield: 20.9 %

Procedure:
A solution of 2,3-dichloro-4,6-dinitrophenol (2.2 g, 0,008 mol, from previous example), 4.5 g of potassium t-butoxide, 0.4 g of potassium hydroxide, 30 mL of N-methyl pyrrolidinone, and 15 mL of water in a 100 mL round-bottomed flask with stir bar is heated to 85° C. for 6 hours. Upon completion, the reaction mixture is poured into 50 mL of aqueous hydrochloric acid. The resulting product is isolated by filtration, washed with cold water, and air dried. The product is recrystallized from a minimal amount of methanol to yield 1.97 g of 2-chloro-4,6-dinitroresorcinol (95% yield) (85% overall from 1,2-dichloro-3,5-dinitrobenzene).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[OH:32][C:33]1[CH:34]=[C:35]([CH:40]=[CH:41][C:42]=1[N+:43]([O-:45])=[O:44])[C:36]([O:38][CH3:39])=[O:37].[CH3:46][C:47](=[CH2:50])[CH2:48]O.Cl>O1CCCC1.O>[CH3:48][C:47](=[CH2:46])[CH2:50][O:32][C:33]1[CH:34]=[C:35]([CH:40]=[CH:41][C:42]=1[N+:43]([O-:45])=[O:44])[C:36]([O:38][CH3:39])=[O:37]
Reactant: C=C(C)CO
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: C=C(C)COc1cc(C(=O)OC)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
Triphenyl phosphine (7.87 g, 30 mmol) was dissolved in 80 mL of tetrahydrofuran followed by the addition of diethyl azodicarboxylate (5.23 g, 30 mmol) in a dry ice bath. The reaction mixture was stirred 30 minutes, added dropwise with a solution of methyl 3-hydroxy-4-nitro-benzoate 1b (2.96 g, 15 mmol) in tetrahydrofuran, and stirred 10 minutes followed by the addition of 2-methyl-allyl alcohol (1.41 g, 19.50 mmol), then stirred for another 1 hour. The resulting mixture was heated to room temperature and stirred for 12 hours. The resulting mixture was added with 10 mL of water, added dropwise with 1 M hydrochloric acid to adjust pH to 2 to 3 and extracted with ethyl acetate (50 mL×3). The combined organic phase was added dropwise with 1 M sodium hydroxide solution to adjust pH to 9 to 10, extracted with ethyl acetate (50 mL×2). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound methyl 3-(2-methylallyloxy)-4-nitro-benzoate 4a (3 g, yield: 79.6%) as a light yellow solid.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]([F:17])([F:16])/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12].C1(C)C=CC(S([CH2:27][N+:28]#[C-:29])(=O)=O)=CC=1>O1CCCC1>[F:7][C:8]([F:16])([F:17])[C:9]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:27][NH:28][CH:29]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)/C=C/C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c[nH]cc1C(F)(F)F
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
A solution of potassium t-butoxide (8.11 g, 0.075 mol) in tetrahydrofuran at -60° C. is treated dropwise with a mixture of ethyl 4,4,4-trifluorocrotonate (10.5 g, 0.063 mol) and p-tolylsulfonylmethylisocyanide (12.2 g, 0.063 mol) in tetrahydrofuran over a 1 hour period, stirred at -60° C. for 30 minutes, allowed to warm to room temperature and quenched with water. The reaction mixture is extracted with ether and ethyl acetate. The combined extracts are washed with brine, dried (MgSO4) and concentrated in vacuo to give a solid residue. Recrystallization from 1,2-dichloroethane affords the title compound as a tan solid, 7.3 g (56%), mp 163°-164° C.
Reaction SMILES: [N+:1]([O:4][CH:5]([CH2:35][O:36][N+:37]([O-:39])=[O:38])[CH2:6][CH2:7][CH2:8][O:9][C:10]([O:12][CH2:13]/[C:14](/[C:25]1[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1)=[C:15](/[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)\[C:16]([OH:18])=[O:17])=[O:11])([O-:3])=[O:2].[CH2:40](I)[CH3:41].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:1]([O:4][CH:5]([CH2:35][O:36][N+:37]([O-:39])=[O:38])[CH2:6][CH2:7][CH2:8][O:9][C:10]([O:12][CH2:13]/[C:14](/[C:25]1[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:27][CH:26]=1)=[C:15](/[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)\[C:16]([O:18][CH2:40][CH3:41])=[O:17])=[O:11])([O-:3])=[O:2]
Reactant: CCI
Reactant: CS(=O)(=O)c1ccc(/C(COC(=O)OCCCC(CO[N+](=O)[O-])O[N+](=O)[O-])=C(/C(=O)O)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C(=C(\COC(=O)OCCCC(CO[N+](=O)[O-])O[N+](=O)[O-])c1ccc(S(C)(=O)=O)cc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of 2.6 g (2Z)-4-[({[4,5-bis(nitrooxy)pentyl]oxy}carbonyl)oxy]-3-[4-(methylsulfonyl)phenyl]-2-phenylbut-2-enoic acid in 20 mL of DMF at RT was added 3 mL of ethyl iodide and 485 mg of potassium carbonate under nitrogen. The reaction was stirred for 30 min, and then quenched by addition of NH4Cl sat., extracted with EtOAc, washed with water (3×), brine and dried over sodium sulfate. Purification by flash chromatography afforded 1.42 g of the titled compound as a colorless oil. 1H NMR (acetone-d6, 500 MHz): δ 7.78 (d, 2H), 7.45 (d, 2H), 7.17 (t, 3H), 7.09 (d, 2H), 5.52 (d, 1H), 5.26 (s, 2H), 5.00 (dd, 1H), 4.73 (dd, 1H), 4.28 (q, 2H), 4.16-4.12 (m, 2H), 3.06 (s, 3H), 1.88-1.79 (m, 4H), 1.27 (t, 3H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]([CH3:25])([CH3:24])[CH2:12][C@H:13]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.CS(C)=O.C(NC(=O)[C@H](C)C[C@H](O)[C@@H](NC(OC(C)(C)C)=O)CC(C)(C)CC(N1C2C(=CC=CC=2)CC(C(OCC)=O)C1)=O)CCC>C(N(CC)CC)C>[CH2:1]([O:8][CH2:9][CH2:10][C:11]([CH3:25])([CH3:24])[CH2:12][C@H:13]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:14]=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(CCOCc1ccccc1)C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC(C)(C)CC(=O)N1CC(C(=O)OCC)Cc2ccccc21)NC(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(CCOCc1ccccc1)C[C@@H](C=O)NC(=O)OC(C)(C)C

Procedure:
The title compound is prepared starting from 28.1 g of 6-benzyloxy-2(S)-tert-butoxycarbonylamino-4,4-dimethyl-hexan-1-ol, 10.5 ml of oxalyl chloride, 11.4 ml of dimethyl sulfoxide and 45 ml of triethylamine analogously to Example 1g): Rf (A)=0.62; Rt (I)=28.1 min; FAB-MS: (M+H)+ =350.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[S:12]([Cl:16])(=O)(=[O:14])[OH:13]>>[Cl:16][S:12]([C:9]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]([CH:8]=1)[C:5]([OH:7])=[O:6])(=[O:14])=[O:13]
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccccc1C(=O)O
Product: COc1ccc(S(=O)(=O)Cl)cc1C(=O)O
Yield: 58.2 %

Procedure:
2-Methoxybenzoic acid (available from Aldrich, 5.0 g, 32.9 mmol) was warmed with chlorosulfuric acid (164 mmol, 5.0 eq., 19.1 g, 11.0 mmol) at 50° C. for 2 h. The resulting thick brown liquid was poured on crushed ice with vigorous stirring. The resulting white precipitates were filtered, washed with H2O, and dried overnight under high vacuum to give Intermediate 6 (4.8 g, 58%) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:3]=1.[Cl:12]N1C(=O)CCC1=O.O>CN(C=O)C>[Cl:12][C:3]1[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:5][NH:6][C:2]=1[CH3:1]
Reactant: CCOC(=O)c1cc(C)[nH]n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1n[nH]c(C)c1Cl
Temperature: 60 °C
Yield: 95.3 %

Procedure:
To a solution of ethyl 5-methyl-1H-pyrazole-3-carboxylate (Maybridge, 4.41 g, 28.6 mmol) in DMF (14 mL) was added N-chlorosuccinimide (3.86 g, 28.9 mmol). The resulting solution was heated at 60° C. for 3 h and then cooled to room temperature. Water was added until a white precipitate formed, and the solid was collected by filtration washing with water. The solid was dissolved in CH2Cl2, washed with water (2×), dried over MgSO4 and concentrated in vacuo to provide the title compound (5.14 g, 90%) as a white solid. 1H NMR (CDCl3) δ 8.03 (s, 1H), 4.42 (q, J=7.0 Hz, 2H), 2.32 (s, 3H), 1.42 (t, J=7.1 Hz, 3H); MS(ESI+) m/z 188.9 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH:15]1[CH:19]=[CH:18][CH:17]=[N:16]1.CCN(C(C)C)C(C)C>CCO>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[N:15]1[CH:19]=[CH:18][CH:17]=[N:16]1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: c1cn[nH]c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1-n1cccn1
Temperature: 120 °C
Yield: 80.1 %

Procedure:
1-Fluoro-2-nitro-4-trifluoromethyl-benzene (209 mg, 1 mmol) was dissolved in EtOH (4.5 mL) in a 5 mL microwave reaction vessel. 1H-pyrazole (83.5 mg, 1.2 mmol), DIPEA (329 μL, 2 mmol) and a stirrbar was added followed by sealing of the reaction vessel. The reaction mixture was then heated in the microwave for 30 min at 120° C. The reaction was concentrated in vacuo and the residue purified by flash chromatography (Silica, Hexane: EtOAc) to afford the title compound (206 mg, 81%). LC/MS>95%, m/z (ESI+)=258 (MH+).
Reaction SMILES: [CH:1]1([C:4]#[CH:5])[CH2:3][CH2:2]1.Br[C:7]1[CH:8]=[CH:9][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:11][CH:12]=1>C(NC(C)C)(C)C.[Cu](I)I>[CH:1]1([C:4]#[C:5][C:7]2[CH:8]=[CH:9][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccc(Br)cn1
Reactant: C#CC1CC1
Agent: I[Cu]I
Solvent: CC(C)NC(C)C
Product: CCOC(=O)c1ccc(C#CC2CC2)cn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Cyclopropylacetylene (73.7 μL), copper iodide (3.16 mg) and tetrakis (triphenylphosphine)palladium (9.59 mg) were added to a solution of ethyl 5-bromopyridine-2-carboxylate (95.5 mg) in diisopropylamine (2 mL) at room temperature, and the mixture was stirred at room temperature for 17 hours and five minutes. The reaction solution was concentrated under reduced pressure. The residue was purified by NH-silica gel column chromatography to obtain the title compound (19.4 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:24])=[C:11]([CH2:13][C:14]([NH:16][CH2:17][C@@H:18]3[O:23][CH2:22][CH2:21][NH:20][CH2:19]3)=[O:15])[N:12]=2)=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH:34]=O)=[CH:28][CH:27]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH2:34][N:20]2[CH2:21][CH2:22][O:23][C@@H:18]([CH2:17][NH:16][C:14](=[O:15])[CH2:13][C:11]3[N:12]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[O:9][C:10]=3[CH3:24])[CH2:19]2)=[CH:28][CH:27]=1
Reactant: O=CCCc1ccc(Cl)cc1
Reactant: Cc1oc(-c2ccc(F)cc2)nc1CC(=O)NC[C@H]1CNCCO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1oc(-c2ccc(F)cc2)nc1CC(=O)NC[C@H]1CN(CCCc2ccc(Cl)cc2)CCO1
Temperature: 20 °C
Reaction time: 72 h
Yield: 94.3 %

Procedure:
A mixture of Intermediate 28 (0.04 g), 3-(4-chlorophenyl)propanal (0.026 g) and acetic acid (0.02 ml) in dichloromethane (4 ml) was treated with sodium triacetoxyborohydride (0.080 g). The mixture was stirred at 20° C. for 72 h. The mixture was partitioned between chloroform (6 ml) and saturated aqueous sodium hydrogen carbonate (6 ml). The phases were separated and the organic phase applied to an ion exchange cartridge (2 g Isolute SCX, prewashed with methanol). The SCX cartridge was eluted with methanol (10 ml) followed by 10% 0.880 ammonia in methanol (10 ml) and the appropriate fractions were concentrated in vacuo to give the title compound as a colourless gum (0.055 g).
Reaction SMILES: C(Cl)(Cl)Cl.[NH2:5][C@H:6]([C:14]([NH:16][C@H:17]([C:21]([NH:23][C@H:24]([C:35]([OH:37])=[O:36])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:44](Cl)(=[O:51])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>O>[C:44]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:21]([NH:23][C@H:24]([C:35]([OH:37])=[O:36])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)(=[O:51])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: CC(C)[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
A mixture of 30 ml chloroform and 30 ml water containing 1.0 g of phenylalanyl-valyl-tryptophan and 0.6 g of sodium carbonate is cooled to 0° and treated with 0.20 ml of benzoyl chloride. The reaction mixture was allowed to warm to room temperature and stirred overnight. The layers were separated and the aqueous layer extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure to give 0.47 g (53 percent) of the title compound. Analysis calculated for C32H34N4O5.H2O: C, 67.11; H, 6.34; N, 9.79. Found: C, 67.00; H, 6.23; N, 9.13.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:25]([O:27][CH3:28])=[O:26]>[OH-].[Na+].C1COCC1.CCOC(C)=O>[CH3:28][O:27][C:25](=[O:26])[N:10]([C@H:11]1[CH2:12][CH2:13][C@H:14]([C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)[CH2:15][CH2:16]1)[CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)Cl
Reactant: Oc1ccc([C@H]2CC[C@H](NCCCc3ccccc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)N(CCCc1ccccc1)[C@H]1CC[C@H](c2ccc(O)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of trans-4-[4-(3-phenylpropylamino) cyclohexyl]-phenol (0.40 g, 1.3 mmol) in a mixture of 2 N NaOH (5 mL) and THF (5 mL) was added methyl chloroformate (0.12 mL, 1.6 mmol). The reaction mixture was stirred at room temperature for 2 hours. Methyl chloroformate (0.05 mL, 0.65 mmol) was added and stirring continued for another 2 hours. The mixture was diluted with EtOAc (50 mL), washed with H2O, dried (Na2SO4), filtered and concentrated under reduced pressure. Purification by flash chromatography (silica, 97:3 MeOH/CH2Cl2) gave trans-N-[4-(4-hydroxyphenyl)cyclohexyl]-N-(3-phenylpropyl)carbamic acid methyl ester, as an off-white solid (0.068 g, 14%): mp 128-133° C.; IR (KBr): 3403, 2923, 1673, 1518 cm−1; 1H NMR(300MHz, CD3OD) δ 7.31-7.15 (m, 5H), 7.01 (d, J=8 Hz, 2H), 6.68 (d, J=8 Hz, 2H), 3.91-3.78 (m, 1H), 3.67 (s, 3H), 3.25-3.13 (m, 2H), 2.61 (t, J=8 Hz, 2H), 2.40-2.29 (m, 1H), 1.95-1.45 (m, 10H); CI-MS (methane) (m/z): 368 [M+I]+; HRMS-API (m/z): [M+1]+ Calcd for C23H29NO3, 368.2225. found: 368.2227; HPLC: method A, 13.78 minutes (85.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[C:7](=[CH:18][NH:19][C:20]=3[CH3:21])[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.[Cl:24][C:25]([Cl:30])([Cl:29])[C:26](Cl)=[O:27]>C(Cl)Cl>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[C:7](=[C:18]([C:26]([C:25]([Cl:30])([Cl:29])[Cl:24])=[O:27])[NH:19][C:20]=3[CH3:21])[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Cc1[nH]cc2c1-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Solvent: ClCCl
Product: Cc1[nH]c(C(=O)C(Cl)(Cl)Cl)c2c1-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 3.4 g (11 mmole) of 8-chloro-6-(2-fluorophenyl)-1-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine, 2.6 g (14 mmole) of trichloroacetyl chloride, and 100 ml of methylene chloride was stirred at room temperature for 12 hr. The resulting precipitate was collected by filtration, resuspended in methylene chloride, and basified with ammonium hydroxide. The methylene chloride solution was separated, dried over anhydrous sodium sulfate, and concentrated at reduced pressure to give a (mp 222°-225°) colorless solid. A small portion was recrystallized from a mixture of methylene chloride and ether to give colorless prisms, mp 222°-223°.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:31][Si:32]([C:35]#[CH:36])([CH3:34])[CH3:33]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[CH3:31][Si:32]([C:35]#[C:36][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1)([CH3:34])[CH3:33]
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: C#C[Si](C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#C[Si](C)(C)C)cc1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
21.5 g (0.1 mol) of methyl 4-bromobenzoate, 300 ml of triethylamine and a mixture of 200 mg of palladium acetate and 400 mg of triphenylphosphine are introduced into a three-necked flask. 20 g (0.204 mol) of trimethylsilylacetylene are then added, after which the mixture is heated gradually to 90° C. over 1 hour and left at this temperature for 5 hours. The reaction medium is then cooled, the salt is filtered off and the filtrate is evaporated. The residue is taken up in 200 ml of hydrochloric acid (5%) and 400 ml of ethyl ether. The ether phase is separated out after settling has taken place, washed with water, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with dichloromethane. After evaporation of the solvents, 23 g (100%) of the expected derivative are collected in the form of a colourless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10].C(N(CC)CC)C.[C:18]([CH2:22][CH2:23][C:24](Cl)=[O:25])([O:20][CH3:21])=[O:19]>C(Cl)Cl>[CH3:21][O:20][C:18](=[O:19])[CH2:22][CH2:23][C:24](=[O:25])[NH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10]
Reactant: COC(=O)CCC(=O)Cl
Reactant: NCCCN1CCCC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCC(=O)NCCCN1CCCC1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
To a solution of 1-(3-aminopropyl)-2-oxopyrrolidine (570 mg) in methylene chloride (10 ml) were added triethylamine (0.67 ml) and 3-carbomethoxy propionylchloride (600 mg) in sequence under ice-cooling and the mixture was stirred for 0.5 hour. After 3.5 hours' stirring at room temperature, the reaction mixture was poured into ice water and extracted with chloroform. The organic layer was washed with 1N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and saturated brine in sequence, and dried over magnesium sulfate, followed by concentration. The residue was purified by silica gel column chromatography (chloroform-methanol) to give 902 mg of 4-oxo-4-[3-(2-oxo-1-pyrrolidinyl)propylamino]butyric acid methyl ester.