Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:44][C:45]1[C:46]([C:55]([NH:57][NH2:58])=[O:56])=[N:47][CH:48]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:50]=1>CN1C(=O)CCC1.O>[NH2:44][C:45]1[C:46]([C:55]([NH:57][NH:58][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[O:56])=[N:47][CH:48]=[C:49]([C:51]([F:53])([F:52])[F:54])[CH:50]=1
Reactant: NNC(=O)c1ncc(C(F)(F)F)cc1N
Reactant: CC(O)(C(=O)O)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(O)(C(=O)NNC(=O)c1ncc(C(F)(F)F)cc1N)C(F)(F)F
Reaction time: 1 h

Procedure:
To 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (324 mg, 2.049 mmol) in NMP (5 ml) was added HATU (935 mg, 2.458 mmol) and DIPEA (1.073 ml, 6.15 mmol). After stirring for 5 minutes 3-amino-5-(trifluoromethyl)picolinohydrazide (Intermediate I) (451 mg, 2.049 mmol) was added and stirring continued at RT for 1 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with 1M HCl (100 ml), water (2×100 ml), brine and dried (phase separator) and concentrated in vacuo. Purification by chromatography on silica eluting with 0-30% EtOAc in iso-hexane afforded the title compound; 1H NMR 400 MHz, DMSO-d6: δ 10.3 (1H, s), 10.0 (1H, s), 8.0 (1H, s), 7.5 (1H, s), 7.1 (3H, s, overlap), 1.5 (3H, s). LC-MS Rt=0.98 min [M+H]+ 361.2 Method 2minLC_v003.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([S:14][C:15]2[CH:20]=[C:19]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH:18]=[C:17](Br)[CH:16]=2)=[CH:9][C:8]=1[CH3:27])[CH3:2].[CH2:29]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)[C:30]#[CH:31]>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([S:14][C:15]2[CH:16]=[C:17]([C:31]#[C:30][CH2:29][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:18]=[C:19]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH:20]=2)=[CH:9][C:8]=1[CH3:27])[CH3:2]
Reactant: CCOC(=O)COc1cc(C)c(Sc2cc(Br)cc(OCC(C)C)c2)cc1C
Reactant: C#CCN1CCOCC1
Product: CCOC(=O)COc1cc(C)c(Sc2cc(C#CCN3CCOCC3)cc(OCC(C)C)c2)cc1C

Procedure:
The title product was prepared from [4-(3-Bromo-5-isobutoxy-phenylsulfanyl)-2,5-dimethyl-phenoxy]-acetic acid ethyl ester (400 mg; 0.86 mmol) and 4-prop-2-ynyl-morpholine
Reaction SMILES: C(OC(=O)[NH:7]C1CCC(NCC2C=C(C3C=NC=CC=3)C=CC=2OC)CC1)(C)(C)C.C(OC(=O)N[CH2:38][CH:39]1[CH2:44][CH2:43][CH:42]([N:45]([C:61]([C:63]2[S:64][C:65]3[C:72]([F:73])=[CH:71][CH:70]=[C:69]([F:74])[C:66]=3[C:67]=2[Cl:68])=[O:62])[CH2:46][C:47]2[CH:52]=[C:51]([C:53]3[CH:58]=[CH:57][N:56]=[CH:55][CH:54]=3)[CH:50]=[CH:49][C:48]=2[O:59][CH3:60])[CH2:41][CH2:40]1)(C)(C)C.Cl>CCO>[CH3:60][O:59][C:48]1[CH:49]=[CH:50][C:51]([C:53]2[CH:58]=[CH:57][N:56]=[CH:55][CH:54]=2)=[CH:52][C:47]=1[CH2:46][N:45]([C:42]1([NH2:7])[CH2:41][CH2:40][CH:39]([CH3:38])[CH2:44][CH2:43]1)[C:61]([C:63]1[S:64][C:65]2[C:72]([F:73])=[CH:71][CH:70]=[C:69]([F:74])[C:66]=2[C:67]=1[Cl:68])=[O:62]
Reactant: COc1ccc(-c2cccnc2)cc1CNC1CCC(NC(=O)OC(C)(C)C)CC1
Reactant: COc1ccc(-c2ccncc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(CNC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCO
Product: COc1ccc(-c2ccncc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1(N)CCC(C)CC1
Temperature: 5 °C
Reaction time: 4.5 h

Procedure:
To a 3 L 3-neck RB flask with a mechanical stirrer, addition funnel, temperature probe and N2 inlet is added {4-[(3-chloro-4,7-difluorobenzothiophene-2-carbonyl)-(2-methoxy-5-pyridin-4-ylbenzyl)amino]cyclohexyl}methylcarbamic acid tert-butyl ester P6 (54.92 g, 83.70 mmol) and EtOH (1.5 L). The resulting beige slurry is cooled to 5° C. and concentrated HCl (800 mL) is added over 1 h. The cold bath is removed and the solution is stirred for 4.5 h at room temperature. The reaction mixture is concentrated by removing 1.5 L solvent in vacuo and H2O (500 mL) is added. The mixture is extracted with CH2Cl2 (2×350 mL). The aqueous layer is cooled to 2° C. and 50% NaOH (300 mL) is added to pH=13. The mixture is extracted with CH2Cl2 (3×600 mL) and the combined organic layers are washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo to give 3-chloro-4,7-difluoro-benzo[b]thiophene-2-carboxylic acid (2-methoxy-5-pyridin-4-ylbenzyl)-(4-methyl-aminocyclohexyl)amide n (46.5 g, 99%) as a tan foam.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18](B4OC(C)(C)C(C)(C)O4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].Br[C:34]1[CH:35]=[C:36]([CH:39]=[C:40]([CH:42]=[O:43])[CH:41]=1)[C:37]#[N:38].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:37]([C:36]1[CH:35]=[C:34]([C:18]2[CH:19]=[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:9]2[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:7][CH2:8]2)[CH:41]=[C:40]([CH:42]=[O:43])[CH:39]=1)#[N:38]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(B4OC(C)(C)C(C)(C)O4)cc23)CC1
Reactant: N#Cc1cc(Br)cc(C=O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(C#N)cc(C=O)c4)cc23)CC1

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (46 mg, 0.1 mmol) in dioxane (2.0 mL) and H2O (0.7 mL) was added 3-bromo-5-formylbenzonitrile (68 mg, 0.3 mmol), and potassium carbonate (83 mg, 0.6 mmol). The mixture was degassed for 5 min before addition of tetrakis(triphenylphosphine) palladium (0) (12 mg, 0.01 mmol). The mixture was reacted in the microwave at 160° C. for 20 min. The compound was purified by Gilson Preparatory HPLC to give 5-(3-cyano-5-formylphenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide.
Reaction SMILES: CO[C:3]1[C:4](=[O:14])[C:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:10]=2[C:11](=[O:13])[CH:12]=1.[Cl-].[Ce+3].[Cl-].[Cl-].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[NH:19]([C:3]1[C:4](=[O:14])[C:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:10]=2[C:11](=[O:13])[CH:12]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccccc1
Reactant: COC1=CC(=O)c2ncccc2C1=O
Agent: [Ce+3]
Agent: [Cl-]
Solvent: CCO
Product: O=C1C(Nc2ccccc2)=CC(=O)c2ncccc21
Yield: 16 %

Procedure:
Six grams of 6-methoxyquinoline-5,8-quinone were dissolved in 500 ml of absolute ethanol and 9 g of cerium chloride were added. After the reaction was stirred, 3.3 g of aniline were added. The reaction mixture was refluxed for several hours, then it was stirred overnight at room temperature. The ethanol was evaporated to dryness and partitioned between chloroform and an aqueous sodium chloride solution. The chloroform layer was washed with an aqueous sodium chloride solution, dried with sodium sulfate, and then evaporated. The product was crystallized from absolute ethanol and weighed 3 g (16% yield). It had a melting point of about 182°-184° and the mass spectrum indicated the expected molecular ion at m/e=250.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)=[O:4].C([Mg]Br)C.[CH3:18][C:19]1([CH3:27])[C:21]([CH3:23])([CH3:22])[CH:20]1[C:24](Cl)=[O:25]>ClCCl.[Cl-].[Zn+2].[Cl-]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[C:24]([CH:20]1[C:21]([CH3:23])([CH3:22])[C:19]1([CH3:27])[CH3:18])=[O:25])=[O:4]
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: COC(=O)c1ccc2[nH]cc(C(=O)C3C(C)(C)C3(C)C)c2c1
Yield: 64.7 %

Procedure:
Methyl-indole-5-carboxylate (Lancaster, 3.0 g, 17 mmol), ethylmagnesium bromide (1.0 M solution in THF, 21 mL, 21 mmol), zinc chloride (1.0 M solution in Et2O, 21 mL, 21 mmol) and the product of Example 1A (26 mmol) in 50 mL of dichloromethane were processed as described in Example 1B to provide the title compound (3.4 g, 11 mmol, 66% yield). MS (DCI/NH3) m/z 300 (M+H)+.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11])[CH2:2]1.C12BC(CCC1)CCC2.[CH2:21]([C:31]1[CH:32]=[N:33][C:34]([C:37]2[CH:42]=[CH:41][C:40](Br)=[CH:39][CH:38]=2)=[N:35][CH:36]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(=O)([O-])[O-].[K+].[K+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.CN(C=O)C.C1COCC1>[O:1]1[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]([C:40]2[CH:39]=[CH:38][C:37]([C:34]3[N:33]=[CH:32][C:31]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:36][N:35]=3)=[CH:42][CH:41]=2)[CH2:10][CH3:11])[CH2:2]1
Reactant: CCCCCCCCCCc1cnc(-c2ccc(Br)cc2)nc1
Reactant: C=CCCCCCCC1CO1
Agent: [Pd]
Agent: B1C2CCCC1CCC2
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCc1cnc(-c2ccc(C(CC)CCCCCC3CO3)cc2)nc1
Temperature: -17 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
1.36 g (8.8 mmol) of optically active 1,2-epoxy-9-decene and 6 ml of THF were injected, and they were cooled to -17° C. Then, 9-borabicyclo [3.3.1]nonane (0.5M THF solution) was dripped, and stirring at 0° C. was performed for one hour. Then, stirring at room temperature was performed for one hour, and then 0.26 g (0.073 mmol) of tetrakis (triphenylphosphine) palladium, 3.00 g (8.00 mmol) of 5-decyl-2-(4-bromophenyl) pyrimidine, 10 ml of DMF, and 2.21 g (16.0 mmol) of potassium carbonate were added, and stirring at 60° C. was performed for 5 hours. After reactions had been completed, water was added, and extraction with ethyl acetate was performed. The extracted solution was dried, and then the solvent was removed by filtration. Then, refining was performed with a silica gel column chromatography (developing solvent: toluene/ethyl acetate=50/1) and by recrystallization (toluene/methanol) so that 2.10 g of 1,2-epoxy-8-{4-(5-decylpyrimidine-2-yl) phenyl}decane was obtained (yield 58%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:20]=[C:21]([N+:23]([O-:25])=[O:24])[CH:22]=1)[C:16]([NH:18][NH2:19])=[O:17].C(N(CC)CC)C.[C:33](Br)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CC(N(C)C)=O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:20]=[C:21]([N+:23]([O-:25])=[O:24])[CH:22]=1)[C:16]([NH:18][NH:19][C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:17]
Reactant: NNC(=O)c1cc(OCc2ccc3ccccc3c2)cc([N+](=O)[O-])c1
Reactant: O=C(Br)c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: O=C(NNC(=O)c1cc(OCc2ccc3ccccc3c2)cc([N+](=O)[O-])c1)c1ccccc1
Reaction time: 8 h

Procedure:
To a stirred solution of 3-[(2-naphthyl)methoxy]-5-nitrobenzhydrazide (0.30 g, 0.89 mmol) and triethylamine (0.14 mL, 0.98 mmol) in DMA (25 mL) at room temperature was added benzoyl bromide (0.11 mL, 0.89 mmol), and stirring was continued overnight. Yellowish solution was poured onto ice-water (50 g) and set aside for 24 h. Precipitate formed was filtered, washed with water, and air-dried. Off-white solid, yield 0.34 g (87%). 1H NMR (DMSO-d6, 400 MHz), δ: 10.92 (s, 1H); 10.66 (s, 1H); 8.12-7.89 (m, 8H); 7.67-7.50 (m, 6H); 5.53 (s, 2H).
Reaction SMILES: [CH3:1][Si:2]([CH3:15])([CH3:14])[C:3]#[C:4][B:5]1[O:9][C:8]([CH3:11])([CH3:10])[C:7]([CH3:13])([CH3:12])[O:6]1.[OH:16]/[N:17]=[C:18](\Cl)/[CH3:19].C(=O)([O-])O.[K+]>COCCOC>[CH3:19][C:18]1[C:4]([B:5]2[O:9][C:8]([CH3:10])([CH3:11])[C:7]([CH3:13])([CH3:12])[O:6]2)=[C:3]([Si:2]([CH3:14])([CH3:15])[CH3:1])[O:16][N:17]=1
Reactant: C/C(Cl)=N/O
Reactant: CC1(C)OB(C#C[Si](C)(C)C)OC1(C)C
Agent: O=C([O-])O
Agent: [K+]
Solvent: COCCOC
Product: Cc1noc([Si](C)(C)C)c1B1OC(C)(C)C(C)(C)O1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution of trimethyl[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethynyl]silane (240 g, 1.07 mol) in 1,2-dimethoxyethane (8000 mL) was added (1Z)—N-hydroxyethanimidoyl chloride (120 g, 1.28 mol) and potassium hydrogen carbonate (214.4 g, 2.141 mol). The reaction mixture was heated to 50° C. After 16 hours, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified via chromatography on silica gel (10% ethyl acetate/hexanes, linear gradient) to afford 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trimethylsilyl)isoxazole. MS ESI calc'd. for C13H24BNO3Si [M]+ 281. found 281. 1H NMR (400 MHz, CDCl3) δ 2.39 (s, 3H), 1.31 (s, 12H), 0.37 (s, 9H).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[O:15])[O:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[Pd]>[CH2:8]([C:9]1[CH:10]=[C:11]([CH:14]=[O:15])[O:12][CH:13]=1)[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1cc(C#Cc2ccccc2)co1
Agent: [Pd]
Solvent: CO
Product: O=Cc1cc(CCc2ccccc2)co1
Temperature: 25 °C
Reaction time: 14 h
Yield: 97.5 %

Procedure:
To a solution of 4-phenylethynyl-furan-2-carbaldehyde (1.54 g, 7.84 mmol) in MeOH was added Pd/C (154 mg, 10% Pd by weight). A vacuum was applied to the reaction mixture and back filled (×4) with H2. The reaction was then allowed to stir at rt for 14 h under an atmosphere of H2 before being filtered through a plug of Celite® with EtOAc. The reaction was then concentrated in vacuo to give 4-phenethyl-furan-2-carbaldehyde as a colorless oil (1.53 g, 97%). 1H NMR (400 MHz, CDCl3) δ ppm 9.59 (d, J=0.6 Hz, 1H) 7.40 (d, J=0.8 Hz, 1H) 7.28-7.34 (m, 2H) 7.20-7.26 (m, 1H) 7.14-7.20 (m, 2H) 7.05 (d, J=0.6 Hz, 1H) 2.87-2.94 (m, 2H) 2.78-2.85 (m, 2H).
Reaction SMILES: CN(C)[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[CH2:12][C:11](=O)[CH2:10]2)=C[CH:4]=1.C([O-])(=O)C.[NH4+:22]>>[NH2:22][C:11]1[CH2:10][C:9]2([CH2:4][CH2:3][CH2:8][CH2:7][CH2:6]2)[CH2:14][C:13](=[O:15])[CH:12]=1
Reactant: [NH4+]
Reactant: CN(C)c1ccc(C2CC(=O)CC(=O)C2)cc1
Agent: CC(=O)[O-]
Product: NC1=CC(=O)CC2(CCCCC2)C1

Procedure:
In analogy to (Baraldi, P. G.; Simoni, D.; Manfredini, S.; Synthesis 1983, (11) 902-903) spiro[5.5]undecane-2,4-dione was reacted with ammonium acetate to give the title compound as a colorless solid.
Reaction SMILES: C[Si](Cl)(C)C.[CH3:6][O:7][C:8](=[O:44])[C@H:9]([CH2:17][C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([O:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]3[CH:40]=[CH:39][C:38]([O:41]C)=[CH:37][CH:36]=3)[CH:29]=2)=[C:20]([Cl:43])[CH:19]=1)[NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13].[I-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C.O>[CH3:6][O:7][C:8](=[O:44])[C@H:9]([CH2:17][C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([O:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]3[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=3)[CH:29]=2)=[C:20]([Cl:43])[CH:19]=1)[NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13]
Reactant: COC(=O)[C@H](Cc1cc(Cl)c(OCCc2cccc(Oc3ccc(OC)cc3)c2)c(Cl)c1)NC(=O)C(F)(F)F
Agent: C[Si](C)(C)Cl
Agent: O=S([O-])([O-])=S
Agent: [I-]
Solvent: O
Solvent: CC#N
Product: COC(=O)[C@H](Cc1cc(Cl)c(OCCc2cccc(Oc3ccc(O)cc3)c2)c(Cl)c1)NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 22 h
Yield: 64.7 %

Procedure:
Trimethylsilyl chloride (0.25 ml, 1.97 mmol) was added dropwise to a solution of 3,5-dichloro-N-trifluoroacetyl-O-[2-[3-(4-methoxyphenoxy)phenyl]ethyl]-L-tyrosine methyl ester (190 mg, 0.324 mmol) and sodium iodide (292 mg, 1.95 mmol) in acetonitrile (3 ml) at room temperature. The mixture was stirred under argon atmosphere at room temperature for 22 hrs. and then heated under reflux for 9 hrs. The reaction mixture was poured into water (30 ml) and 10% aqueous sodium thiosulfate (20 ml) was added thereto. The mixture was extracted with ethyl acetate and the extract was washed with brine and then dried. The solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=3) to give 3,5-dichloro-N-trifluoroacetyl-O-[2-[3-(4-hydroxyphenoxy)-phenyl]ethyl]-L-tyrosine methyl ester (120 mg, 65%) as a colorless oil.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10](=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:15][O:16][CH2:17][CH2:18][NH:19][CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([N:19]([CH2:18][CH2:17][O:16][CH3:15])[CH3:20])[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Reactant: CNCCOC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClCCCl
Product: COCCN(C)C1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 81.3 %

Procedure:
Amine preparation: A mixture of 1-BOC-3-piperidone (0.50 g), N-(2-methoxyethyl)methylamine (0.29 g), sodium triacetoxyborohydride (0.74 g) and acetic acid (0.14 mL) in 1,2-dichloroethane (30 mL) was stirred at room temperature for 6 h. The reaction mixture was then diluted with DCM, washed with sodium bicarbonate solution, dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography to yield 3-[(2-methoxy-ethyl)-methyl-amino]-piperidine-1-carboxylic acid tert-butyl ester (0.556 g). Treatment of this compound with HCl in DCM/MeOH yielded the desired amine, which was isolated as the hydrochloride salt.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH:16]2[C:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[F:30])([C:21]#[N:22])[CH:19]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[NH:18][CH:17]2[C:36]([OH:38])=O)[CH:12]=[CH:13][C:14]=1[F:15].[NH2:39][C:40]1[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][CH:41]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:47][O:46][C:44](=[O:45])[C:43]1[CH:48]=[CH:49][C:40]([NH:39][C:36]([C@H:17]2[C@H:16]([C:11]3[CH:12]=[CH:13][C:14]([F:15])=[C:9]([Cl:8])[CH:10]=3)[C@:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[F:30])([C:21]#[N:22])[C@H:19]([CH2:31][C:32]([CH3:35])([CH3:33])[CH3:34])[NH:18]2)=[O:38])=[CH:41][CH:42]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2ccc(F)c(Cl)c2)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2ccc(F)c(Cl)c2)cc1
Yield: 48.4 %

Procedure:
In a manner similar to the method described in Examples 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 69c (0.25 g, 0.43 mmol) was reacted with methyl 4-aminobenzoate (0.12 g, 0.8 mmol), HATU (0.29 g, 0.43 mmol) and iPr2NEt (0.19 mL, 1.1 mmol) in CH2Cl2 at room temperature to give rac-4-{[(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid methyl ester as a white solid (0.125 g, 48%).
Reaction SMILES: [N:1]([CH2:4][C:5](N)=O)=[N+:2]=[N-:3].ClCC[CH2:11][S:12]([NH2:15])(=[O:14])=[O:13]>>[N:1]([CH2:4][CH2:5][CH2:11][S:12]([NH2:15])(=[O:14])=[O:13])=[N+:2]=[N-:3]
Reactant: NS(=O)(=O)CCCCl
Reactant: [N-]=[N+]=NCC(N)=O
Product: [N-]=[N+]=NCCCS(N)(=O)=O

Procedure:
The reaction was carried out similarly as described in the preparation of compound 411, using compound 3-chloro-propane-1-sulfonic acid amide (19.0 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 35:65 to 65:35 as the eluent to afford the title compound as colourless oil.
Reaction SMILES: C(OC([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[N:10]=[CH:9]1)=O)(C)(C)C.C(N(CC)CC)C>CO>[C:19]([O:18][C:16](=[O:17])[NH:15][CH2:14][CH2:13][C:11]1[N:10]=[CH:9][NH:8][CH:12]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCCc1cn(C(=O)OC(C)(C)C)cn1
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)NCCc1c[nH]cn1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To 4-(2-tert-Butoxycarbonylamino-ethyl)-imidazole-1-carboxylic acid tert-butyl ester, were added 100 mL of methanol and 800 mL (5.73 mol) of triethylamine. The reaction mixture was allowed to stir at room temperature for four days and concentrated to oil. To the residue were added 40 mL of ether and 80 mL of hexane. This mixture was allowed to stand at room temperature resulting in precipitation of product, as a white solid, which were collected. The yield was 1.7 g (8.0 mmol, 40%) (LC/MS M+H 212.1).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([OH:34])(=O)[CH2:14][S:15][CH2:16][C:17]#[C:18][CH2:19][C:20]#[C:21][CH2:22][C:23]#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].[CH2:35]([NH2:41])[CH2:36][O:37][CH2:38][CH2:39][OH:40].[Cl-].[NH4+]>ClCCCl>[OH:40][CH2:39][CH2:38][O:37][CH2:36][CH2:35][NH:41][C:13](=[O:34])[CH2:14][S:15][CH2:16][C:17]#[C:18][CH2:19][C:20]#[C:21][CH2:22][C:23]#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: NCCOCCO
Reactant: CCCCCCCCC#CCC#CCC#CCSCC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCCl
Product: CCCCCCCCC#CCC#CCC#CCSCC(=O)NCCOCCO
Temperature: 25 °C
Yield: 74.1 %

Procedure:
3 g of carbonyldiimidazole are added to a solution of 3.18 g of 3-thia-5,8,11-eicosatriynoic acid in 50 cm3 of 1,2-dichloroethane, stirred at ambient temperature under an inert atmosphere. The mixture thus obtained is heated to a temperature of between 40° and 50° C. for 3 hours. The solution is then cooled to about 10° C. and 2.10 g of diglycolamine are added. 2 hours after the end of the introduction, the reaction mixture is poured into a saturated solution of ammonium chloride. The organic phase is separated off, washed with water, then dried over magnesium sulphate and finally treated with animal charcoal. The solvent is removed by evaporation under vacuum. The product obtained crystallizes on cooling. It is recrystallized from isopropyl ether. 3 g of N[(2-hydroxyethyl) oxyethyl]-3-thia-5,8,11-eicosatriynamide are thus isolated in the form of cream-white crystals having a melting point of 56° C. Elemental analysis: C23H35NO3S
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]([CH:10]1[O:12][CH2:11]1)Br.[OH-].[Na+]>O1CCOCC1>[C:1]1([S:7][CH2:8][CH:10]2[CH2:11][O:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: BrCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: c1ccc(SCC2CO2)cc1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A solution of 5.0 g of thiophenol in 30 ml of 1,4-dioxane was added dropwise at room temperature to a mixture of 6 ml of epibromohydrin, 5.45 g of sodium hydroxide and 30 ml of 1,4-dioxane, and then the mixture was stirred at room temperature for 36 hours. At the end of this time, insoluble solids were removed by filtration, the 1,4-dioxane was evaporated from the filtrate, water was added to the resulting residue, and the mixture was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extract by evaporation under reduced pressure, and the resulting residue was purified by silica gel column chromatography, using a 1:10 by volume mixture of ethyl acetate and hexane as the eluent, to give 6.78 g of the title compound as a colorless oil having an Rf value of 0.60 (on silica gel thin layer chromatography, using a 1:10 by volume mixture of ethyl acetate and hexane as the developing solvent).