Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[NH:10][C:9]2=[O:16])=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].N([O-])=O.[Na+].[I-:25].[Na+].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>O.C(Cl)Cl>[CH3:14][C:11]1([CH3:15])[NH:10][C:9](=[O:16])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([I:25])=[C:3]([C:17]([F:20])([F:19])[F:18])[CH:4]=2)[C:12]1=[O:13]
Reactant: CC1(C)NC(=O)N(c2ccc(N)c(C(F)(F)F)c2)C1=O
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC1(C)NC(=O)N(c2ccc(I)c(C(F)(F)F)c2)C1=O
Reaction time: 0.25 h
Yield: 95.1 %

Procedure:
140 g of the product of Example 1 and 210 ml of demineralized water are introduced at 20°±2° C., agitation is carried out and 210 ml of pure 22°Be hydrochloric acid is added over about 5 minutes. The reaction medium is maintained at 35°-40° C. for 30 minutes under agitation then cooled down to 0°±5° C. under agitation. Then 28 ml of methylene chloride is added, a solution of 43.7 g of sodium nitrite in 70 ml of demineralized water is then added over about 30 minutes, at 0°±5° C. The reaction medium is maintained for another hour under agitation at 0°±5° C., a solution of 87.7 g of sodium iodide in 140 ml of demineralized water is added over 45 minutes. The reaction medium is maintained under agitation for another hour and 700 ml of methylene chloride is added. Agitation is carried out for 15 minutes at 0°±5° C., 28 g of sodium metabisulphite is added in one go and agitation is carried out for another 30 minutes while leaving the temperature to return to 20° C. After pouring, the organic phase is decanted, the aqueous phase is reextracted with 280 ml of methylene chloride, then the organic phases are washed with 3×140 ml of a saturated aqueous solution of NaCl. The joint chloromethylenic phases are dried, followed by filtering and washing with 3×70 ml of methylene chloride and 184.5 g of expected product (white crystals) is obtained, M.p.=164-165° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:34]=[CH:35]/[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42](=[O:50])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C@@:22]([OH:33])([CH2:30][CH2:31][OH:32])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[C:51](OC(=O)C)(=[O:53])[CH3:52].C(N(CC)CC)C.CN(C1C=CC=CN=1)C>ClCCl>[C:51]([O:32][CH2:31][CH2:30][C@:22]([OH:33])([C@@H:21]([C:19](=[O:20])[NH:18][C@H:13]([C:14]([O:16][CH3:17])=[O:15])[CH2:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:1][C:2]#[C:3][CH3:4])=[CH:11][CH:10]=1)/[CH:34]=[CH:35]/[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42](=[O:50])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])(=[O:53])[CH3:52]
Reactant: CC(=O)OC(C)=O
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCO)C(=O)OC(C)(C)C)C(=O)OC)cc1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCOC(C)=O)C(=O)OC(C)(C)C)C(=O)OC)cc1
Reaction time: 1.5 h
Yield: 76 %

Procedure:
No. 5217614, tert-butyl (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-hydroxy-2-(2-hydroxy-ethyl)-12-oxo-nonadec-4-enoate, Compound D (13.7 g, 19.6 mmol) was dissolved in dichloromethane (274 mL), and then acetic anhydride (4.64 mL, 49.1=mop, triethylamine (2.74 mL, 19.7 mmol), and dimethylaminopyridine (240 mg, 1.96 mmol) were added at 0° C. After stirring for 1.5 hours, the mixture was quenched with water (195 mL) and then separated. The aqueous layer was extracted with dichloromethane (195 mL). The dichloromethane layers were combined, then washed with a saturated aqueous solution (140 mL) of sodium chloride, then dried over anhydrous sodium sulfate, and filtered. The organic layer was concentrated under reduced pressure. The residue was purified on Biotage (silica gel, n-hexane/ethyl acetate) to obtain 11.0 g (14.8 mmol, yield 76%) of No. 5318799 (Compound R).
Reaction SMILES: C[O:2][C:3](=[O:17])[CH2:4][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH:7]([CH3:9])[CH3:8].O.[OH-].[Li+]>C1COCC1.O.C(OCC)(=O)C>[C:13]([O:12][C:10]([N:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[CH2:4][C:3]([OH:17])=[O:2])=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: COC(=O)CN(CC(C)C)C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CN(CC(=O)O)C(=O)OC(C)(C)C
Yield: 39.9 %

Procedure:
Nα-(tert-Butyloxycarbonyl)-Nα-(2-methylpropyl) glycine methyl ester (960 mg, 3.91 mmol) was dissolved in THF/H2O (9:1, 25 ml). Lithium hydroxide monohydrate (492 mg, 11.7 mmol) was added. After 18 h at room temperature the reaction mixture was diluted with ethyl acetate (100 ml). This solution was washed with 1M HCl, water and brine, dried (Na2SO4) and evaporated in vacuo to give a colourless oil identified as the title compound (360 mg, 1.56 mmol, 40%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:11]([OH:13])=[O:12])=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:20](I)[CH3:21]>O>[NH2:1][C:2]1[C:3]([C:11]([O:13][CH2:20][CH3:21])=[O:12])=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH3:10]
Reactant: CCCc1ccnc(C(=O)O)c1N
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: CCCc1ccnc(C(=O)OCC)c1N
Reaction time: 0.25 h
Yield: 80 %

Procedure:
3-Amino-4-n-propylpyridine-2-carboxylic acid (Preparation 4; 0.36 g, 0,002 mol) was added to a stirred mixture of cesium carbonate (0,325 g, 0.001 mol) in water (20 ml), then this mixture was evaporated under vacuum and the residue azeotroped with dimethylformamide (2×20 ml). The resulting cesium salt was suspended in dimethylformamide (3 ml) and the stirred suspension then treated dropwise with ethyl iodide (0.17 ml, 0.0021 mol). After a further 0.25 hour, the solvent was evaporated under vacuum and the residue partitioned between water (20 ml) and ethyl acetate (20 ml). The organic phase was washed with water (10 ml), dried (MgSO4) and evaporated under vacuum, then the residue crystallised from acetone:hexane to give the title compound as an off-white solid (0.35 g, 84%), m.p. 93°-96° C. Found: C,63.39; H,7.73; N,13.39. C11H16N2O2 requires C,63.44; H,7.74; N,13.45%.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH:7]2[CH2:8][CH:3]1[C:4](=C)[CH2:5][C:6]2=[O:9].[O:12]=[O+][O-].CSC>CO>[CH3:11][C:2]1([CH3:1])[CH:3]2[CH2:8][CH:7]1[C:6](=[O:9])[CH2:5][C:4]2=[O:12]
Reactant: O=[O+][O-]
Reactant: C=C1CC(=O)C2CC1C2(C)C
Solvent: CO
Solvent: CSC
Product: CC1(C)C2CC1C(=O)CC2=O
Reaction time: 8 h

Procedure:
A solution of 6,6-dimethyl-4-methylene-bicyclo[3.1.1]heptan-2-one (2(10)pinen-4-one, 6.8 g, 45.3 mmol) in dry methanol (300 mL) under a nitrogen atmosphere was cooled to −78° C. in a dry ice/acetone bath. The stirred reaction was treated with ozone for 20 minutes, during which time the solution turned a light blue color, indicating accumulation of ozone and completion of the reaction. The reaction was purged with oxygen (5 minutes), followed by nitrogen (10 minutes) at −78° C., and then dimethyl sulfide (5.0 ml, 68.2 mmole) was added dropwise via a syringe. The resulting reaction mixture was stirred overnight, during which time it came up to room temperature. Methanol was removed on a rotary evaporator, and the residue was partitioned between ethyl acetate (300 mL) and water (300 mL). The aqueous layer was extracted with two additional portions of ethyl acetate (300 mL), and the combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The desired product was isolated by column chromatography on silica gel (20% ethyl acetate/hexane) to gave the desired product as a white solid (5.7 g; 83% yield), mp=80–81° C.; MS (−) ESI m/z=151 (M−H)−.
Reaction SMILES: [C:1]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH:9]=[CH:8][CH2:7][CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.[H][H]>[Pd]>[C:1]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: O=C1CCC=CCCC=CCCC1
Agent: [Pd]
Product: O=C1CCCCCCCCCCC1

Procedure:
In a reactor battery consisting of a tubular reactor with liquid circuit and a postreactor, cyclododeca-4,8-dien-1-one was hydrogenated continuously (30 bar, temperatures 130°, each reactor in trickle mode, catalyst 0.2% Pd on alumina), which also comprised approx. 0.5% polyunsaturated C12-aldehydes. The entire amount of hydrogen (2.1 molar equivalents based on reactant, i.e. 5 mol % hydrogen excess) was introduced into the main reactor and transferred together with the product stream into the postreactor. Downstream of the postreactor, the residual gas was discharged as offgas. At a total catalyst hourly space velocity of 0.5 kg of dienone/liter of catalyst×h, the conversion was 99.8%, i.e. the reaction effluent still contained 0.2% of unconverted olefin. In a subsequent distillation, it was possible to obtain cyclododecanone in a purity of 99.4%; 0.2% of unsaturated cyclododecanone was undesired secondary constituent.
Reaction SMILES: C([Li])C1C=CC=CC=1.[CH2:9]([C:16]1[C:25](Cl)=[N:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C-:27]#[N:28]>>[CH2:9]([C:16]1[C:25]([C:27]#[N:28])=[N:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: [C-]#N
Reactant: Clc1nc2ccccc2nc1Cc1ccccc1
Agent: [Li]Cc1ccccc1
Product: N#Cc1nc2ccccc2nc1Cc1ccccc1

Procedure:
Intermediate 3 can be prepared from the starting material 2,3-dichloroquinoxaline 1 following the reaction in Scheme 1. In this manner, quinoxaline 1 can be reacted with benzylmagnesium chloride in THF to afford 2-benzyl-3-chloroquinoxaline 2. 2-Benzylquinoxalines can also be prepared by reaction with alternative alkylating reagents, such as, but not limited to, benzyllithium. 2-Benzyl-3-chloroquinoxaline 2 can be reacted with cyanide to obtain intermediate 2-benzyl-3-cyanoquinoxaline 3.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[C:25]4[C:21]([C:22]([CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])=[CH:23][NH:24]4)=[CH:20][C:19]=3[F:34])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[OH-].[Na+].Cl>C(O)(C)C.O>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[C:25]4[C:21]([C:22]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:23][NH:24]4)=[CH:20][C:19]=3[F:34])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: CCOC(=O)CCc1c[nH]c2cc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)c(F)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC(C)Oc1ccc(-c2nc(-c3cc4[nH]cc(CCC(=O)O)c4cc3F)no2)cc1C#N
Temperature: 20 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To a solution of ethyl 3-[6-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-fluoro-1H-indol-3-yl]propanoate (D157) (180 mg) in isopropanol (25 mL) and water (5 mL) was added 0.8 mL 20% aqueous NaOH solution. The reaction mixture was stirred at 20° C. overnight. Afterwards, the mixture was adjusted to pH 3 by addion of 6 M HCl and evaporated. The residue was treated with 6 mL DMF and filtered. The filtrate was purified by MDAP to give the designed product 3-[6-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-fluoro-1H-indol-3-yl]propanoic acid (E110) (115 mg). δH (DMSO-d6, 400 MHz): 1.32 (6H, d), 2.55 (2H, t), 2.88 (2H, t), 4.92 (1H, m), 7.37 (1H, s), 7.47 (1H, d), 7.50 (1H, d), 8.05 (1H, d), 8.35 (1H, dd), 8.44 (1H, d), 11.23 (1H, s), 12.05 (1H, s); δF (DMSO-d6, 376 MHz): −121.7; MS (ES): C23H19FN4O4 requires 434; found 435.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][C:20]=2[N:21]2[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]2)=[O:13])=[C:5]2[N:6]=[CH:7][C:8]([Cl:10])=[CH:9][N:4]2[N:3]=1.NC1C(C(ON2C3C=CC=CC=3N=N2)=O)=C2N=C[C:35]([CH2:37][C:38]#[N:39])=CN2N=1.C([O-])=O.[NH4+]>C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][C:20]=2[N:21]2[CH2:26][CH2:25][CH:24]([N:39]3[CH2:35][CH2:37][CH2:38]3)[CH2:23][CH2:22]2)=[O:13])=[C:5]2[N:6]=[CH:7][C:8]([Cl:10])=[CH:9][N:4]2[N:3]=1
Reactant: N#CCc1cnc2c(C(=O)On3nnc4ccccc43)c(N)nn2c1
Reactant: Nc1nn2cc(Cl)cnc2c1C(=O)Nc1cnccc1N1CCC(=O)CC1
Agent: O=C[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: Nc1nn2cc(Cl)cnc2c1C(=O)Nc1cnccc1N1CCC(N2CCC2)CC1
Temperature: 25 °C

Procedure:
A solution of 2-amino-6-chloro-N-[4-(4-oxo-1-piperidyl)-3-pyridyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (50 mg, 0.1296 mmol), azetidine (Hydrochloric Acid (1)) (12.12 mg, 0.1296 mmol) and ammonium formate (8.172 mg, 0.1296 mmol) in toluene was heated at reflux for 1 h with a Dean-Stark apparatus. The reaction was cooled to room temperature and evaporated. The resulting yellow solid was dissolved in DMSO and purified by fractionlynx to yield 2-amino-N-(4-(4-(azetidin-1-yl)piperidin-1-yl)pyridin-3-yl)-6-chloropyrazolo[1,5-a]pyrimidine-3-carboxamide as a white solid. (27 mg, 31%). MS (ES+) 427.2.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[C:19]2[C:18](=[O:20])[N:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:16](=[O:27])[N:15]([CH2:28][C:29]3[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=3[F:36])[C:14]=2[S:13][C:12]=1[C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:44]([NH:46][O:47][CH3:48])=[O:45])=[CH:39][CH:38]=1)C)C1C=CC=CC=1.Cl>C(O)C.[C].[Pd]>[F:36][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]([F:35])[C:29]=1[CH2:28][N:15]1[C:14]2[S:13][C:12]([C:37]3[CH:42]=[CH:41][C:40]([NH:43][C:44]([NH:46][O:47][CH3:48])=[O:45])=[CH:39][CH:38]=3)=[C:11]([CH2:10][NH:8][CH3:1])[C:19]=2[C:18](=[O:20])[N:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[C:16]1=[O:27]
Reactant: CONC(=O)Nc1ccc(-c2sc3c(c2CN(C)Cc2ccccc2)c(=O)n(-c2ccccn2)c(=O)n3Cc2c(F)cccc2F)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CNCc1c(-c2ccc(NC(=O)NOC)cc2)sc2c1c(=O)n(-c1ccccn1)c(=O)n2Cc1c(F)cccc1F
Reaction time: 20 h
Yield: 71.2 %

Procedure:
To a solution of the compound obtained in Example 1 (1.59 g, 2.38 mmol) in ethanol (40 ml) were added 1N hydrochloric acid (7 ml) and 10% palladium-carbon (50% wet, 0.63 g), and the mixture was stirred vigorously under hydrogen atmosphere for 20 hours. The catalyst was removed, and the filtrate was neutralized with 1N sodium hydroxide solution. The solvent was distilled off. The residue was distributed between ethyl acetate and water, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the obtained powders were washed with diethyl ether to give the title compound (980 mg, 71%) as pale yellow powders.
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5](=[O:15])[CH:4]=1)[NH2:2].[S:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([CH:25]=O)=[CH:17]1.[CH:27]([C:29]1[N:33]([CH3:34])[CH:32]=[C:31]([C:35]([OH:37])=[O:36])[CH:30]=1)=O>>[S:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([CH2:25][N:2]2[C:27]([C:29]3[N:33]([CH3:34])[CH:32]=[C:31]([C:35]([OH:37])=[O:36])[CH:30]=3)=[C:4]3[C:3]([N:8]([CH2:9][CH:10]([CH3:11])[CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[C:5]3=[O:15])=[N:1]2)=[CH:17]1
Reactant: O=Cc1csc2ccccc12
Reactant: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Reactant: Cn1cc(C(=O)O)cc1C=O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)O)cn3C)n(Cc3csc4ccccc34)nc21

Procedure:
This compound was made following the procedure described above, starting with 6-hydrazino-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first with 1-benzothiophene-3-carbaldehyde, followed by 5-formyl-1-methyl-1H-pyrrole-3-carboxylic acid. Mass: 492.09 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Li]CCCC.[CH2:15](Br)[CH:16]=[C:17]([CH3:19])[CH3:18]>C1COCC1>[CH2:15]([C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:16]=[C:17]([CH3:19])[CH3:18]
Reactant: CC(C)=CCBr
Reactant: c1ccc2[nH]ccc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)=CCc1cc2ccccc2[nH]1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To silyl protected indole B (724 mmol, 1.52 mmol) in THF was added a few 4 Å molecular sieves and the mixture was cooled to −78° C. After n-BuLi (0.75 ml, 2.3M in hexanes) was added, the mixture was stirred for 20 min and prenyl bromide (420 mmol, 2.82 mmol) was added. The next day the reaction mixture was quenched by addition of NH4Cl (sat), and extracted with Et2O. The combined organic layers were washed with brine, dried (MgSO4), and filtered, and the filtrated was concentrated in vacuo. Final purification by flash column chromatography (5% EtOAc in hexanes) afforded prenyl indole C (560 mg, 68%) as well as recovered starting material (76 mg, 10%): 1H NMR δ 7.91 (d, J=0.8 Hz, 1H), 7.73 (d, J=8.4 Hz, 2H), 7.25, (d, J=8.5 Hz, 2H), 6.99 (s, 1H), 6.52 (d, J=0.8 Hz, 1H), 5.47 (m, 1H), 5.31 (s, 2H), 4.90 (s, 2H), 3.74 (d, J=7.2 Hz, 2H), 3.55 (s, 3H), 2.40 (s, 3H), 1.86 (s, 3H), 1.71 (s, 3H) 1.05 (s, 9H), 0.20 (s, 6H); 13C NMR δ 149.5, 144.5, 139.9, 138.7, 138.6, 136.5, 134.5, 129.7 (2C), 126.3 (2C), 119.8, 119.6, 106.5, 106.3, 105.3, 94.8, 65.5, 56.0, 27.9, 25.9 (3C), 25.7, 21.4, 18.3, 17.7, −5.2 (2C); HRMS (EI+) calcd for C29H41NO5SSi [M+] 543.2475. found 543.2476.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][C:12]1[N:13]=[CH:14][O:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1.[Cl:27]C(Cl)(Cl)C(Cl)(Cl)Cl>O1CCCC1>[Cl:27][C:14]1[O:15][C:16]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:22]=2)=[C:12]([CH3:11])[N:13]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: Cc1ncoc1-c1ccc(C(F)(F)F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(Cl)oc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.9 %

Procedure:
Lithium bis(trimethylsilyl)amide (1 M in tetrahydrofuran, 19.4 mL, 19.4 mmol) was added dropwise to a solution of Example 12A (4.0 g, 17.6 mmol) in tetrahydrofuran (80 mL) at −78° C. After stirring 30 min, solid hexachloroethane (8.34 g, 35.2 mmol) was added in one portion, and the reaction was allowed to gradually warm to ambient temperature. After 16 hours the reaction was quenched with half-saturated NH4Cl solution. The product was extracted with diethyl ether, and the combined organic layer was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (Analogix Intelliflash 280; 0% to 25% ethyl acetate/hexanes; SF65-600 g column; loading with hexane/CH2Cl2) to yield 4.69 g of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 7.87 (m, 2H), 7.82 (m, 2H), 2.40 (s, 3H). MS (DCI+) m/z 262 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)([CH2:16][CH2:17]O)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.[F:27][CH2:28][CH2:29][NH2:30]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:16][CH2:17][NH:30][CH2:29][CH2:28][F:27])([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1
Reactant: NCCF
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCNCCF)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one and 2-fluoroethylamine following procedures analogous to those described in Example 178. LC-MS Method 2 tR=1.1 min, m/z=489; 1H NMR (CDCl3) 1.50 (d, 3H), 1.97-2.38 (m, 7H), 2.41-2.56 (m, 1H), 2.79-2.98 (m, 3H), 4.45 (m, 1H), 4.54 (m, 1H), 5.61 (m, 1H), 6.80 (d, 2H), 7.03-7.14 (t, 2H), 7.21-7.31 (m, 6H).
Reaction SMILES: [Li+].[OH-].C([O:5][C:6](=[O:20])[CH2:7][NH:8][C:9](=[O:19])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)C>C1COCC1.CO.O>[OH:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH2:10][C:9]([NH:8][CH2:7][C:6]([OH:20])=[O:5])=[O:19])=[CH:13][CH:14]=1
Reactant: CCOC(=O)CNC(=O)CCc1ccc(O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)CNC(=O)CCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.6 %

Procedure:
LiOH (56 mg, 2.33 mmol) was added at room temperature to a stirred solution of [3-(4-hydroxy-phenyl) propionylamino]-acetic acid ethyl ester (151 mg, 0.6 mmol) in THF:MeOH:H2O (3:1:1, 5 mL). The resulting mixture was stirred at room temperature for five hours. The MeOH and THF were then evaporated and the residue was diluted with water (2 mL), acidified with 20% aqueous HCl and extracted with EtOAc. The organic layer was washed with saturated brine solution, dried over Na2SO4 and concentrated under reduced pressure to afford 120 mg (89.55% yield) of [3-(4-hydroxy-phenyl) propionylamino]-acetic acid as a pale white solid (120 mg). LCMS purity: 90.42%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([S:8]([CH2:11][CH2:12][CH3:13])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.[Cl:15]C1C=CC(S(CCC)(=O)=O)=CC=1>>[Br:1][C:2]1[CH:7]=[C:6]([S:8]([CH2:11][CH2:12][CH3:13])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[Cl:15]
Reactant: CCCS(=O)(=O)c1ccc(F)c(Br)c1
Reactant: CCCS(=O)(=O)c1ccc(Cl)cc1
Product: CCCS(=O)(=O)c1ccc(Cl)c(Br)c1
Yield: 86 %

Procedure:
Following the general method as outlined in Intermediate 106, starting from 1-chloro-4-(propylsulfonyl)benzene (Intermediate 125), the title compound was obtained as an oil which solidified upon standing in 86% yield.
Reaction SMILES: [C:1]1([CH2:7][CH:8]([NH:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC(N)=[S:22].[OH-].[Na+].Cl>C(O)C.O>[C:1]1([CH2:7][CH:8]([NH:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][SH:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NC(CCl)Cc1ccccc1)c1ccccc1
Reactant: NC(N)=S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(NC(CS)Cc1ccccc1)c1ccccc1

Procedure:
80.4 millimole (mm) of 3-phenyl-2-benzamido-1-chloropropane and 80.4 mm of thiourea are dissolved in 300 ml of ethanol. The resulting solution is refluxed for three hours. 6.7 g of sodium hydroxide is dissolved in 40 ml of water and is added under an inert atmosphere to the solution which is thereafter refluxed for an additional 21/2 hours. The solution is then cooled and acidified to pH 1 with 1 N HCl. The resulting mixture is then poured over ice to yield a precipitate which is collected by filtration and then dissolved in chloroform. The chloroform is dried with magnesium sulfate and then evaporated to yield the solid 3-phenyl-2-benzamido-1-propanethiol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([CH2:11][CH3:12])=[CH:7]2.C[Mg]I.[Cl:16][C:17]1[C:18]([Cl:26])=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20](Cl)=[O:21].[NH4+].[Cl-]>CCOCC.C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([CH2:11][CH3:12])=[C:7]2[C:20]([C:19]1[CH:23]=[CH:24][CH:25]=[C:17]([Cl:16])[C:18]=1[Cl:26])=[O:21]
Reactant: CCc1cc2cccc(Br)c2[nH]1
Reactant: O=C(Cl)c1cccc(Cl)c1Cl
Agent: C[Mg]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCc1[nH]c2c(Br)cccc2c1C(=O)c1cccc(Cl)c1Cl
Reaction time: 3 h
Yield: 35.7 %

Procedure:
3.45 g of 7-bromo-2-ethyl-1H-indole are placed under nitrogen in 30 ml of ether and the mixture is cooled to +3° C.; 5.1 ml of methylmagnesium iodide in 20 ml of ether and then 5.9 g of dichlorobenzoyl chloride in 30 ml of ether are added. 10 ml of THF are added and the mixture is allowed to return to AT and is stirred for 3 hours. The medium is poured onto a saturated NH4Cl solution and is then extracted with ether. The organic phase is washed with a 10% HCl solution, a 10% NaOH solution, water and an NaCl solution. It is dried and evaporated and then the residue is chromatographed on silica while eluting with an AcOEt/cyclohexane (3/7, v/v) mixture. 2.18 g of the expected compound are obtained.