Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:13]([CH3:28])=[C:12]2[CH2:29][C:30]([NH2:32])=[O:31])C.[OH-].[Na+].O.Cl>CO>[NH2:32][C:30](=[O:31])[CH2:29][C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:33])=[O:3])[CH:10]=2)[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:13]=1[CH3:28]
Reactant: CCCCCCCCCCn1c(C)c(CC(N)=O)c2cc(OCCCC(=O)OCC)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCCCCCn1c(C)c(CC(N)=O)c2cc(OCCCC(=O)O)ccc21
Yield: 77 %

Procedure:
A mixture of 590 mg (1.3 mmol) of [4-[[3-(2-amino-2-oxoethyl)-1-decyl-2-methyl-1-H-indol-5-yl]oxy]butanoic acid ethyl ester and 1.5 mL of 5N NaOH in 20 mL of MeOH was heated to maintain reflux for 2.5 hours, cooled, poured into water and made strongly acidic with 5N HCl. The precipitate was filtered and recrystallized from MeOH. There was obtained 430 mg (77% yield) of [4-[[3-(2-amino-2-oxoethyl)-1-decyl-2-methyl-1-H-indol-5-yl]oxy]butanoic acid, mp, 163-165° C.
Reaction SMILES: [C:1]1([NH:7][CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]=O>CO>[C:1]1([N:7]2[CH2:8][CH2:9][O:10][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCNc1ccccc1
Reactant: C=O
Solvent: CO
Product: c1ccc(N2CCOC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3POX A 500 mL 3-neck flask was equipped with a magnetic stirrer, a reflux condenser, an addition funnel, and a heating mantle with power supply. The flask was charged with 137.17 g (1.0 mole) of N-phenylethanolamine (NPEA) and 25 g of methanol. The addition funnel was charged with 55.20 g of Formcel® (1.01 moles of formaldehyde). The NPEA solution was stirred at room temperature under a blanket of nitrogen, and the Formcel® was added over a period of 1.25 hours. After completing the addition, the reaction mixture was stirred at room temperature overnight. The bulk of the solvent was removed from the reaction mixture by rotary evaporation. Toluene was added to remove water as an azeotrope. The yield of 3POX was 144.54 g (97%) as a clear, amber oil. Product structure was confirmed by NMR and GC/MS analyses.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[C:8]([Cl:10])[CH:9]=1.[N+:12](C1C=C([N+]([O-])=O)C=CC=1ON)([O-])=O>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[C:6]([O:11][NH2:12])[CH:7]=[C:8]([Cl:10])[CH:9]=1
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: Oc1cc(Cl)cc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NOc1cc(Cl)cc(Cl)c1
Temperature: 2 °C

Procedure:
Sodium hydride (50% in mineral oil), 4.0 grams (0.084 mole), is placed in a reaction vessel and washed with three portions of hexane. The sodium hydride is then stirred with 30 mL of N,N-dimethylformamide, and a solution of 13.7 grams (0.084 mole) of 3,5-dichlorophenol in 45 mL of N,N-dimethylformamide is added dropwise. Upon completion of addition, the reaction mixture is warmed to 70°-90° C. where it is stirred for about 45 minutes. After this time the reaction mixture is cooled to about 2° C., and 13.4 grams (0.068 mole) of O-(2,4-dinitrophenyl)hydroxylamine [prepared by the method of T. Sheradsky et al., Tetrahedron, 28, 3833 (1972)] is added in one portion. Upon completion of addition, the reaction mixture is stirred at about 2° C. for 10 minutes. The cooling medium is then removed, and the reaction mixture is allowed to warm to ambient temperature where it is stirred for about 3.5 hours. After this time the reaction mixture is poured into about 1000 mL of ice-water. The resultant precipitate is collected by filtration and washed with water. The solid is dried and then is dissolved in ethyl acetate. The solution is then washed, in turn, with one 60 mL portion of aqueous 5% sodium hydroxide, one 150 mL portion of water, one 60 mL portion of aqueous 5% sodium hydroxide, two 300 mL portions of water, and one 100 mL portion of an aqueous solution saturated with sodium chloride. The organic layer is dried with sodium sulfate and filtered. The filtrate is concentrated under reduced pressure, yielding O-(3,5-dichlorophenyl)hydroxylamine.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].C([Sn](CCCC)(CCCC)[C:16]([O:18]CC)=[CH2:17])CCC.Cl>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:16]([C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8])(=[O:18])[CH3:17]
Reactant: NC(=O)c1cncc(Br)c1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(=O)c1cncc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.6 %

Procedure:
A mixture of 5-bromonicotinamide (2.5 g, 12.4 mmol), tributyl(1-ethoxyvinyl)tin (5.0 g, 13.8 mmol) and dichlorobis(triphenylphosphine)palladium(II) (800 mg, 1.1 mmol) in 25 mL toluene was heated to reflux for 3 hours. The mixture was cooled to room temperature, treated with 25 mL 2N HCl (aq.), and stirred for 1 hour. The aqueous layer was washed with ethyl acetate, adjusted to pH >7 with solid K2CO3, and extracted six times into 20% isopropanol/chloroform. The combined extracts were dried (Na2SO4), filtered, and concentrated to provide the desired product (1.6 g, 78%).
Reaction SMILES: [C:1]([C:4]([C@@H:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].C(N(CC)CC)C.Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][OH:37]>C(#N)C>[C:1]([C:4]([C@@H:17]1[CH2:21][CH2:20][N:19]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][OH:37])[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: OCCCCCCCBr
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)[C@@H]1CCNC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: NC(=O)C(c1ccccc1)(c1ccccc1)[C@@H]1CCN(CCCCCCCO)C1
Temperature: 50 °C
Yield: 55.7 %

Procedure:
To a stirred solution of (S)-3-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (40 g, 142.7 mmol) and triethylamine (59.6 mL, 428 mmol) in acetonitrile (1.1 L) at 40° C. under a nitrogen atmosphere was added 7-bromo-1-heptanol (24 mL, 146 mmol) in acetonitrile (100 mL) dropwise. The reaction mixture was heated to 50° C. for 9 hours. The reaction mixture was allowed to cool before removing the solvent under reduced pressure. The crude residue was dissolved in dichloromethane (500 mL) and the organic layer washed with saturated aqueous sodium bicarbonate (2×300 mL), followed by water (300 mL) and saturated aqueous sodium chloride (300 mL), and then dried over magnesium sulfate (10 g). The magnesium sulfate was filtered off and washed with dichloromethane (100 mL). The solvent was then removed in vacuo to give the crude product which was purified on a short column (SiO2) by varying the eluant from 19:1:0.1 to 3:1:0.1 CH2Cl2/MeOH/NH4OH to give 31.35 g of the title intermediate as a white solid (56% yield; >95% purity by HPLC Method A).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(Nc2nccc(-c3cccnc3)n2)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cccc(Nc2nccc(-c3cccnc3)n2)c1
Reaction time: 8 h

Procedure:
A suspension of 17.0 g (0.058 mol) of N-(3-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine-amine in 1700 ml of tetrahydrofuran is stirred with 1.7 g of palladium on active carbon (5%) under a hydrogen atmosphere at normal pressure for 21 hours. The suspension is filtered and the filtrate is concentrated in a rotary evaporator. The yellow solid product that remains behind is stirred overnight in 200 ml of methylene chloride. Filtration and drying yield N-(3-aminophenyl)-4-(3-pyridyl)-2-pyrimidine-amine; m.p. 89°-90°, Rf =0.38 (chloroform:methanol=9:1).
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]([C:14](=[O:32])[NH:15][CH2:16][CH2:17][C:18]2[N:22]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:21]=[N:20][CH:19]=2)[CH2:11][C@H:10]([C:33]([O:35][CH3:36])=[O:34])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:36][O:35][C:33]([C@H:10]1[CH2:11][C@@H:12]([C:14](=[O:32])[NH:15][CH2:16][CH2:17][C:18]2[N:22]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:21]=[N:20][CH:19]=2)[CH2:13][NH:8][CH2:9]1)=[O:34]
Reactant: COC(=O)[C@H]1C[C@@H](C(=O)NCCc2cncn2Cc2ccc(C#N)cc2)CN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1CNC[C@H](C(=O)NCCc2cncn2Cc2ccc(C#N)cc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-(t-Butoxycarbonyl)-cis-3-methoxycarbonyl-5-[N-(1-(4- cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl]piperidine (1.14 g, 2.30 mmol) was dissolved in CH2Cl2 (12 mL). Trifluoroacetic acid (6 mL) was added and the solution was stirred at ambient temperature for 3 h. The solution was concentrated to dryness to give the title compound.
Reaction SMILES: B(Br)(Br)[Br:2].[C:5]([NH:8][CH:9](OCC)[C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])(=[O:7])[CH3:6].C(Cl)Cl>>[C:5]([NH:8][CH:9]([Br:2])[C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])(=[O:7])[CH3:6]
Reactant: CCOC(NC(C)=O)C(=O)NCc1ccccc1
Reactant: BrB(Br)Br
Solvent: ClCCl
Product: CC(=O)NC(Br)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A BBr3 solution (1M in CH2Cl2, 1.1 equiv) was added to a solution of 2-acetamido-N-benzyl-2-ethoxyacetamide (1 equiv) in CH2Cl2 (10 mmol/125 mL). The mixture was stirred at room temperature (5 h) and then concentrated to dryness in vacuo to give 2-acetamido-N-benzyl-2-bromoacetamide as a pale yellow crystalline material. The bromo adduct was then dissolved in THF (10 mmol/250 mL), cooled (-78° C.), and then added over a 15 min interval to a cooled (-78° C.) solution of the heteroatom nucleophile in THF (1 mmol/1 mL). The reaction mixture was stirred at this temperature (30 min) and then at room temperature (90 min). The insoluble salts were filtered and the filtrate concentrated in vacuo. The residue was then purified by flash column chromatography on SiO2 gel using the indicated solvent as the eluent.
Reaction SMILES: [F:1][C:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]2[CH2:11][CH2:12][N:13]([C:16]3[N:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:29]=[C:28]([NH:30][C:31]5[CH:36]=[CH:35][C:34]([N:37]6[CH2:42][CH2:41][N:40]([CH:43]7[CH2:46][O:45][CH2:44]7)[CH2:39][CH2:38]6)=[CH:33][N:32]=5)[C:27](=[O:47])[N:26]([CH3:48])[CH:25]=4)[C:17]=3[CH:18]=[O:19])[C:14](=[O:15])[C:3]=12.[BH4-].[Na+]>CO>[F:1][C:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]2[CH2:11][CH2:12][N:13]([C:16]3[C:17]([CH2:18][OH:19])=[C:20]([C:24]4[CH:29]=[C:28]([NH:30][C:31]5[CH:36]=[CH:35][C:34]([N:37]6[CH2:38][CH2:39][N:40]([CH:43]7[CH2:46][O:45][CH2:44]7)[CH2:41][CH2:42]6)=[CH:33][N:32]=5)[C:27](=[O:47])[N:26]([CH3:48])[CH:25]=4)[CH:21]=[CH:22][N:23]=3)[C:14](=[O:15])[C:3]=12
Reactant: Cn1cc(-c2ccnc(N3CCn4c5c(c(F)c4C3=O)CCCC5)c2C=O)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1cc(-c2ccnc(N3CCn4c5c(c(F)c4C3=O)CCCC5)c2CO)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 20 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
To a solution of 134d (200 mg, 0.30 mmol) in MeOH (20 mL) was added NaBH4 (40 mg, 0.9 mmol). The mixture was stirred at 20° C. for 2 h. After reaction it was evaporated and the residue was purified by reverse-phase prep-HPLC to afford 134 (108 mg, yield 54%) as a yellow solid. MS: (M+H)+ 655. 1H NMR (500 MHz, DMSO-d6) δ 8.61 (d, J=2.0, 1H), 8.49 (d, J=5.0, 1H), 8.43 (s, 1H), 7.85 (d, J=2.5, 1H), 7.45 (d, J=1.5, 1H), 7.37-7.39 (m, 1H), 7.35 (d, J=5.0, 1H), 7.24 (d, J=9.0, 1H), 4.99 (s, 1H), 4.56 (t, J=6.5, 2H), 4.40-4.47 (m, 4H), 4.18-4.22 (m, 2H), 4.05-4.09 (m, 1H), 3.84-3.96 (m, 1H), 3.60 (s, 3H), 3.41-3.46 (m, 1H), 3.07 (s, 4H), 2.54-2.61 (m, 2H), 2.39-2.42 (m, 6H), 1.78 (s, 2H), 1.69 (s, 2H)
Reaction SMILES: [F:1][CH:2]1[CH2:8][N:7]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-])=O)[CH2:6][CH2:5][CH:4]([NH:18]C(=O)OC(C)(C)C)[CH2:3]1.C(OC([NH:33][C:34]1[S:38][C:37]([C:39]2[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=2[F:46])=[N:36][C:35]=1[C:47](O)=[O:48])=O)(C)(C)C.CO.C(Cl)Cl.N>CO>[NH2:33][C:34]1[S:38][C:37]([C:39]2[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=2[F:46])=[N:36][C:35]=1[C:47]([NH:15][C:10]1[CH:11]=[N:12][N:13]([CH3:14])[C:9]=1[N:7]1[CH2:6][CH2:5][C@@H:4]([NH2:18])[CH2:3][C@H:2]([F:1])[CH2:8]1)=[O:48]
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCC(NC(=O)OC(C)(C)C)CC(F)C1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: N
Solvent: CO
Solvent: ClCCl
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CC[C@@H](N)C[C@H](F)C1

Procedure:
Following the procedure for Example 101, Intermediate 20, tert-butyl 6-fluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ylcarbamate and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid from Example 25 gave, after silica gel column chromatography (0-10% MeOH/DCM, 1% 7 N ammonia in MeOH), a white solid (273 mg, 19% over three steps). Compound 153 was obtained as a single enantiomer from SFC chiral separation of the racemic mixture. 1H NMR (400 MHz, DMSO) δ 8.77 (s, 1H), 7.61-7.41 (m, 4H), 7.27 (dd, J=14.5, 5.8 Hz, 2H), 4.84-4.56 (m, 1H), 3.67 (d, J=7.4 Hz, 3H), 3.44-3.34 (m, 2H), 3.21-2.86 (m, 3H), 2.22-2.07 (m, 1H), 1.87 (ddt, J=34.3, 21.1, 7.4 Hz, 3H), 1.70-1.53 (m, 1H). MS (ESI) m/z: 466.1 [M+H+].
Reaction SMILES: [CH2:1]([N:5]([CH2:36][CH2:37][CH2:38][CH3:39])[C:6]([C:8]1[C:12]([Cl:13])=[C:11]([CH3:14])[N:10]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=2[C:22]([N:24]2[C@H:33]([CH2:34][OH:35])[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25]2)=[O:23])[N:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4].I[CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:45]([O:44][C:42](=[O:43])[CH2:41][O:21][C:18]1[CH:19]=[CH:20][C:15]([N:10]2[C:11]([CH3:14])=[C:12]([Cl:13])[C:8]([C:6](=[O:7])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:36][CH2:37][CH2:38][CH3:39])=[N:9]2)=[C:16]([C:22]([N:24]2[C@H:33]([CH2:34][OH:35])[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25]2)=[O:23])[CH:17]=1)[CH3:46]
Reactant: CCOC(=O)CI
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(O)cc2C(=O)N2Cc3ccccc3C[C@H]2CO)c(C)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(OCC(=O)OCC)cc2C(=O)N2Cc3ccccc3C[C@H]2CO)c(C)c1Cl
Yield: 7.6 %

Procedure:
A mixture of 4-chloro-1-[4-hydroxy-2-((S)-3-hydroxymethyl-3,4-dihydro-1H-isoquinoline-2-carbonyl)-phenyl]-5-methyl-1H-pyrazole-3-carboxylic acid dibutylamide (intermediate D, 170 mg, 0.31 mmol), ethyl 2-iodoacetate (99 mg, 0.46 mmol), potassium carbonate (13 mg, 0.092 mmol), and triethylamime (0.085 mL, 0.62 mmol) was stirred in acetonitrile (3 mL) at ambient temperature for 12 hours. The solvent was removed in vacuo. The crude material was purified by eluting through a silica gel column with a 10 to 100% ethyl acetate/heptane gradient to afford the title compound (15 mg, 7.6% yield). MS (ESI) [m/e, (M+H)+]=639.3. 1H NMR (400 MHz, chloroform-d) δ ppm 6.73-7.39 (m, 7H), 2.51-5.41 (m, 17H), 2.16-2.41 (m, 3H), 0.68-1.70 (m, 16H).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:15])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]([CH3:8])[C:6]=1[CH3:7].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[OH:24].N>O.CC(O)C.[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+]>[CH3:16][O:17][C:18]1[C:19](=[O:24])[CH:20]=[CH:21]/[C:22](=[N:1]\[C:2]2[C:3](=[O:15])[N:4]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:5]([CH3:8])[C:6]=2[CH3:7])/[CH:23]=1
Reactant: Cc1c(N)c(=O)n(-c2ccccc2)n1C
Reactant: COc1ccccc1O
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: N
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: COC1=C/C(=N/c2c(C)n(C)n(-c3ccccc3)c2=O)C=CC1=O

Procedure:
10 mmol of 4-amino-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one was dissolved in 30 ml of water. This solution was admixed with 10 mmol of 2-methoxyphenol in solution in 30 ml of 2-propanol, 3 ml of 20% aqueous ammonia and 22 mmol of potassium ferricyanide at a temperature ranging from 5 to 10° C.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH3:9])[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].[CH3:10]O>[B-](F)(F)(F)F.[Ag+]>[CH3:10][O:7][C:6](=[O:8])[CH:5]([NH:4][C:1](=[O:3])[CH3:2])[CH3:9]
Reactant: CC(=O)NC(C)C(=O)O
Reactant: CO
Agent: [Ag+]
Agent: F[B-](F)(F)F
Product: COC(=O)C(C)NC(C)=O
Reaction time: 0.33 h

Procedure:
In a glove box, ((tert-Bu)2P(CH2)2P(Me)(tert-Bu))2Rh2Cl2 (4.1 mg, 0.005 mmol) was dissolved in 2 mL MeOH, followed by addition of AgBF4 (1.9 mg, 0.10 mmol, 2 equiv.). The solution turned from pale yellow to yellow with gray precipitates. After being stirred for 20 minutes the solution was filtered into a high-pressure tube containing a stir bar and one of the enamides (1 mmol, 100 equiv.). Another 3 to 5 mL MeOH was added and the solution generally turned lighter upon the addition of the enamide substrate. The vessel was then put under H2 of 30 to 40 Psig and stirred at room temperature. After the reaction was finished, the vessel was then take out of the glove box, and an aliquot of the reaction solution was taken from the vessel and analyzed directly or after work up to determine enantiomeric excess of the reaction product. Reaction of enamide (a) to form 2-acetylamino-propionic acid and reaction of enamide (b) to form 2-acetylamino-propionic acid methyl ester, yielded greater than 99% enantiomeric excess in both instances. Reaction of enamide (c) to form 2-acetylamino-3-phenyl-propionic acid and reaction of enamide (d) to form 2-acetylamino-3-phenyl-propionic acid methyl ester, yielded greater than 98% and 95% enantiomeric excess, respectively.
Reaction SMILES: N[C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:10])[CH2:8][Br:9])[N:6]=1.N([O-])=O.[Na+].[ClH:15]>O.[Cu]Cl>[Cl:15][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:10])[CH2:8][Br:9])[N:6]=1
Reactant: Cl
Reactant: Nc1nc(C(=O)CBr)cs1
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(CBr)c1csc(Cl)n1
Temperature: 0 °C

Procedure:
7.6 g (6.0344 mol) of 2-Amino-4-bromoacetyl-thiazole are dissolved in 20 ml of water and 50 ml of concentrated hydrochloric acid. Now, at 0° C. and with stirring, a solution of 3.44 g (0.0499 mol) of sodium nitrite in 15 ml of water is added dropwise. The resulting diazonium salt solution is then introduced in portions into a vigorously stirred cold solution of 4.93 g (0.0449 mol) of copper(I) chloride in 15 ml of concentrated hydrochloric acid, and the mixture is stirred at room temperature for 20 hours. It is then diluted with 100 ml of water and extracted with ether. The ether extract is dried over sodium sulphate and evaporated. For purification, the crude product is purified on a silica gel column using methylene chloride as the eluant.
Reaction SMILES: [Na].[CH2:2]([O:4][N:5]=[C:6]([C:9]1[C:10](=O)[CH2:11][CH:12]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[CH2:21][CH2:20][CH2:19]3)[CH2:13][C:14]=1[OH:15])[CH2:7][CH3:8])[CH3:3].[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CC(C)=O>[C:26]([C:10]1[CH2:11][CH:12]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[CH2:21][CH2:20][CH2:19]3)[CH2:13][C:14](=[O:15])[C:9]=1[C:6](=[N:5][O:4][CH2:2][CH3:3])[CH2:7][CH3:8])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCON=C(CC)C1=C(O)CC(c2ccc3c(c2)CCC3)CC1=O
Agent: [Na]
Solvent: CC(C)=O
Product: CCON=C(CC)C1=C(C(=O)c2ccccc2)CC(c2ccc3c(c2)CCC3)CC1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 78.5 %

Procedure:
The sodium salt of 2-[1-(ethoxyimino)propyl]-3-hydroxy-5-(5-indanyl)cyclohex-2-en-1-one (0.95 mmole) was dissolved in acetone (50 ml) and benzoyl chloride (0.13 g; 0.95 mmole) was added dropwise over a period of 2 minutes. The mixture was stirred at room temperature for 5 minutes, then filtered and evaporated under reduced pressure to give 3-benzoyl-2-[1-(ethoxyimino)propyl]-5-(5-indanyl)cyclohex-2-en-1-one (0.31 g; 75.7%) as a yellow oil.
Reaction SMILES: ClC([S:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)Cl.O.OO>CO>[CH:10]1[C:5]([S:4][S:4][C:5]2[CH:6]=[CH:7][C:8]([Cl:11])=[CH:9][CH:10]=2)=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=1
Reactant: Clc1ccc(SC(Cl)Cl)cc1
Agent: OO
Solvent: CO
Solvent: O
Product: Clc1ccc(SSc2ccc(Cl)cc2)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
A 1-liter, 4-necked flask equipped with a stirrer, thermometer, condenser and gas inlet tube was charged with 227.5 g (1.00 mole) of 4-chlorophenyl dichloromethyl sulfide, 50 g of water and 500 g of methanol. The mixture was heated to 70° C. for 5 hours to complete hydrolysis. After completion of the reaction, 357 g (1.05 moles) of 10% aqueous solution of hydrogen peroxide was added dropwise at 40° C. over a period of 1 hour. The mixture was stirred for 1 hour at the same temperature. The precipitated crystals were filtered, giving 134.7 g of 4,4'-dichlorodiphenyl disulfide in a yield of 93.9% based on 4-chlorophenyl dichloromethyl sulfide.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=1[I:23]>>[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:4]([O:3][C:2]([F:11])([F:12])[F:1])[CH:5]=2)=[O:19])=[CH:16][C:15]=1[I:23]
Reactant: O=C(Cl)c1ccc(Cl)c(I)c1
Reactant: Nc1cccc(OC(F)(F)F)c1
Product: O=C(Nc1cccc(OC(F)(F)F)c1)c1ccc(Cl)c(I)c1

Procedure:
4-Chloro-3-iodo-N-(3-(trifluoromethoxy)phenyl)benzamide was synthesized from 3-(trifluoromethoxy)aniline and 4-chloro-3-iodobenzoylchloride according to the procedure described in Example 183, affording the title compound as a white solid. MS (M−H+) 439.8; Calculated for C14H8ClF3INO2: 441.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:45]([C:49]1[CH:66]=[CH:65][C:52]([CH2:53][NH:54][CH2:55][C@@H:56]([C:58]2[CH:63]=[CH:62][C:61]([Cl:64])=[CH:60][CH:59]=2)[OH:57])=[CH:51][CH:50]=1)([CH3:48])([CH3:47])[CH3:46]>CN(C=O)C.O>[C:45]([C:49]1[CH:66]=[CH:65][C:52]([CH2:53][N:54]([CH2:55][C@@H:56]([C:58]2[CH:59]=[CH:60][C:61]([Cl:64])=[CH:62][CH:63]=2)[OH:57])[C:11]([C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:13])=[CH:51][CH:50]=1)([CH3:48])([CH3:46])[CH3:47]
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNC[C@H](O)c2ccc(Cl)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccc(CN(C[C@H](O)c2ccc(Cl)cc2)C(=O)c2cc(Cl)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 53.8 %

Procedure:
To a solution of 59 mg (0.3 mmol) of 5-chloro-1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 5 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 95 mg (0.3 mmol) of (4-tert-butyl-benzyl)-[(R)-2-(4-chloro-phenyl)-2-hydroxy-ethyl]-amine were added. After stirring for 24 h at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; EtOAc/heptane 1:6) to give 80 mg light yellow solid (43%). MS (ISP) 495.4 (M+H)+.