Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Si:7]([O:14][CH2:15][CH2:16][CH2:17]Br)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].[Cl:19][C:20]1[CH:21]=[C:22]([CH:28]=[C:29]([F:32])[C:30]=1[OH:31])[C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C=O)C>[Si:7]([O:14][CH2:15][CH2:16][CH2:17][O:31][C:30]1[C:29]([F:32])=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][C:20]=1[Cl:19])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: CCOC(=O)c1cc(F)c(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(F)c(OCCCO[Si](C)(C)C(C)(C)C)c(Cl)c1
Temperature: 50 °C

Procedure:
Potassium carbonate and 3-(tert-butyldimethylsilyloxy)propyl bromide were added to a DMF solution of ethyl 3-chloro-5-fluoro-4-hydroxybenzoate, and the mixture was stirred at 50° C. to obtain ethyl 4-[3-(tert-butyldimethylsilyloxy)propoxy]-3-chloro-5-fluorobenzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([O:20][CH2:21][CH:22]=[C:23]([Cl:25])[Cl:24])[CH:17]=[C:16]([Cl:26])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][C:12](=[N:14][OH:15])[CH3:13].C(N(CC)CC)C.[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1.Cl>O1CCCC1>[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40]([O:15][N:14]=[C:12]([CH2:11][O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][O:4][C:3]2[C:2]([Cl:1])=[CH:19][C:18]([O:20][CH2:21][CH:22]=[C:23]([Cl:25])[Cl:24])=[CH:17][C:16]=2[Cl:26])[CH3:13])(=[O:42])=[O:41])=[CH:36][CH:35]=1
Reactant: CC(COCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)=NO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(COCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)=NOS(=O)(=O)c1ccc(C)cc1

Procedure:
First, 0.45 g of 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentyloxyacetone oxime, 0.12 g of triethylamine, and 10 ml of tetrahydrofuran are placed in a reaction vessel, to which a solution of 0.23 g of p-toluenesulfonyl chloride dissolved in 5 ml of tetrahydrofuran is slowly added dropwise with stirring under ice cooling. After completion of the addition, the reaction mixture is further stirred at room temperature for 30 minutes, poured into diluted hydrochloric acid, and extracted twice with diethyl ether. The diethyl ether layers are combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product is subjected to silica gel chromatography, which affords 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentyloxyacetone O-(p-toluenesulfonyl)oxime.
Reaction SMILES: C(OC([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20]COCC[Si](C)(C)C)[N:14]=1)=O)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[NH:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[N:14]=[C:15]([CH2:19][OH:20])[CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)n1cccc1-c1cccc(COCOCC[Si](C)(C)C)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: OCc1cccc(-c2ccc[nH]2)n1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
3 g of 2-[6-(2-trimethylsilanyl-ethoxymethoxy-methyl)pyridin-2-yl]pyrrole-1-carboxylic acid tert-butyl ester (7.41 mmol) are added to a solution of 3 ml of 1.1 M tetrabutylammonium fluoride in tetrahydrofuran, 45 ml of tetrahydrofuran and 5 ml of hexamethylphosphoramide, containing 10 g of molecular sieve (4 angstrom). The mixture is stirred at 45° C. under argon for 8 hours. After filtration of the insoluble matter on celite, the tetrahydrofuran is evaporated off. The title product is purified by chromatography on a silica column (eluent: dichloromethane/ethyl acetate; 99:1). 0.50 g of a white solid is recovered.
Reaction SMILES: [Cl:1]C1C=C(N)C=C(Cl)C=1OC1C=[N:11]C2C(C=1)=CC=CC=2.Cl[C:22]1[CH:27]=[C:26](Cl)[CH:25]=[CH:24][C:23]=1[S:29](Cl)(=[O:31])=[O:30].Cl>>[ClH:1].[C:23]1([S:29]([NH2:11])(=[O:31])=[O:30])[CH:24]=[CH:25][CH:26]=[CH:27][CH:22]=1
Reactant: Nc1cc(Cl)c(Oc2cnc3ccccc3c2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Agent: Cl
Product: NS(=O)(=O)c1ccccc1
Yield: 99 %

Procedure:
3,5-dichloro-4-(quinolin-3-yloxy)-phenylamine (5) was then reacted with 2,4-dichlorobenzenesulfonylchloride, followed by treatment with hydrochloric acid, to give 2,4-dichloro-N-[3,5-dichloro-4-quinolin-3-yloxy)phenyl]-benzenesulfonamide HCl (1; the hydrochloride salt of compound 101) in 99% yield.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:30])[CH2:9][C:8]([CH3:11])([CH3:10])[CH2:7][CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]2[CH2:23][CH2:22][N:21]([CH2:24][C@@H:25]3[CH2:27][C@H:26]3[CH2:28][OH:29])[CH2:20][CH2:19]2)[CH2:5]1.I[CH3:32]>CN(C)C=O.O.C(OCC)(=O)C>[CH3:32][O:29][CH2:28][C@@H:26]1[CH2:27][C@H:25]1[CH2:24][N:21]1[CH2:22][CH2:23][N:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH:6]2[CH2:7][C:8]([CH3:10])([CH3:11])[CH2:9][C:4]([CH3:30])([CH3:3])[CH2:5]2)[CH2:19][CH2:20]1
Reactant: CI
Reactant: CC1(C)CC(c2ccccc2N2CCN(C[C@@H]3C[C@H]3CO)CC2)CC(C)(C)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC[C@@H]1C[C@H]1CN1CCN(c2ccccc2C2CC(C)(C)CC(C)(C)C2)CC1
Temperature: 25 °C
Yield: 45 %

Procedure:
Sodium hydride (60%, oily) (31 mg, 0.78 mmol) was suspended in dimethylformamide (3 mL), and the suspension was stirred at room temperature under a nitrogen atmosphere. To the suspension was added a solution of trans-(2-{4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazin-1-ylmethyl}cyclopropyl)methanol (60 mg, 0.156 mmol) produced in Example (91a) in dimethylformamide (3 mL), and the mixture was stirred for 30 minutes under the same conditions. The reaction mixture was cooled in ice water, and then iodomethane (0.015 mL, 0.241 mmol) was added. The reaction mixture was then stirred for 3 hours and 30 minutes while increasing the temperature to room temperature. The reaction mixture was cooled at an external temperature of 0C, and water was carefully added while blowing nitrogen. Then, ethyl acetate and water were added thereto and extraction was performed with ethyl acetate. The separated organic layer was washed twice with water and then once with brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 28 mg of trans-1-(2-methoxymethylcyclopropylmethyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine as a colorless oil.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C@@:9]2([OH:23])[C:13]3=[C:14]([F:22])[CH:15]=[N:16][C:17]4[CH:18]=[CH:19][C:20](=[O:21])[N:11]([C:12]=43)[CH2:10]2)[CH2:4][CH2:3]1.NC1CCN(C[C@]2(O)C3=C([F:45])C=NC4C=CC(=O)N(C=43)C2)CC1>>[NH2:1][CH:2]1[CH2:3][CH2:4][N:5]([CH2:8][C@@:9]2([OH:23])[C:13]3=[C:14]([F:22])[CH:15]=[N:16][C:17]4[CH:18]=[C:19]([F:45])[C:20](=[O:21])[N:11]([C:12]=43)[CH2:10]2)[CH2:6][CH2:7]1
Reactant: NC1CCN(C[C@@]2(O)Cn3c(=O)ccc4ncc(F)c2c43)CC1
Reactant: NC1CCN(C[C@]2(O)Cn3c(=O)ccc4ncc(F)c2c43)CC1
Product: NC1CCN(C[C@]2(O)Cn3c(=O)c(F)cc4ncc(F)c2c43)CC1

Procedure:
A portion of this material (740 mg, estimated ratio of E1:E2 ca. 3:1) was resolved by preparative chiral HPLC into the two enantiomers E1 and E2, using a Chiralpak AD column, eluting with 50:50:0.1-CH3CN:isopropylalcohol:isopropylamine affording 553 mg of the desired E1 (4S) enantiomer (>99.5% ee) as the first eluting enantiomer.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:18](C)=O.[Na+]>CO>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[CH3:18])=[CH:7][CH:8]=1
Reactant: Brc1ccc(C2CCCN2)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN1CCCC1c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 111.2 %

Procedure:
To a suspension of 2-(4-bromophenyl)pyrrolidine hydrogen chloride (200 mg, 0.76 mmol) in anhydrous MeOH (5 mL) was added formaldehyde (114 mg, 3.80 mmol) under N2. The mixture was stirred at room temperature for 2 h under N2. After 2 h, NaBH(OAc)3 (242 mg, 1.14 mmol) was added and the mixture was stirred at room temperature under N2 overnight. Additional formaldehyde (2 mL) and NaBH(OAc)3 (242 mg, 1.14 mmol) were then added and the mixture was stirred at room temperature for 5 hrs. The reaction was concentrated and water was added (20 mL) with dichloromethane (8 mL). The layers were separated and the water was extracted with dichloromethane (8 mL×3). The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated to afford the title compound (0.203 g, quantitative yield) which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.51 (d, 2H), 7.28 (d, 2H), 3.15-3.10 (t, 1 H), 3.04-3.00 (t, 1 H), 2.22-2.18 (q, 1H), 2.13-2.09 (m, 1H), 2.05 (s, 3H), 1.80-1.65 (m, 2H), 1.53-1.50 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)[CH:5]=[O:6].[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O>[C:10]1([C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=2)[CH:5]=[O:6])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OB(O)c1ccccc1
Reactant: O=Cc1ccnc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1ccnc(-c2ccccc2)c1
Temperature: 25 °C

Procedure:
A mixture of commercially available 2-bromoisonicotinaldehyde (3.000 g; 16.12 mmol), phenylboronic acid (3.009 g; 24.19 mmol), and Pd(PPh3)4 (931 mg; 0.80 mmol) in toluene (40 ml) and aq. 2 M Na2CO3 (34 ml) was heated to reflux, under nitrogen, for 4 h. After cooling to rt, water and AcOEt were added. The separated aq. layer was further extracted with AcOEt. The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (heptane/AcOEt=7/3) afforded 2-phenylisonicotinaldehyde as a yellow oil. LC-MS (conditions A): tR=0.39 min.; [M+H]+: 184.47 g/mol.
Reaction SMILES: [CH3:1][C:2]([C@@H:4]1[CH2:9][CH:8]=[C:7]([CH2:10][OH:11])[CH2:6][CH2:5]1)=[CH2:3].[CH3:12][C:13]1([CH3:22])[CH:18]2[CH2:19][CH:14]1[CH2:15][CH2:16][C:17]12[O:21][CH2:20]1>>[CH3:3][C:2]([CH:4]1[CH2:5][CH:6]=[C:7]([CH2:10][O:11][C:20]([CH3:17])=[O:21])[CH2:8][CH2:9]1)=[CH2:1].[CH3:12][C:13]1([CH3:22])[CH:18]2[CH2:19][CH:14]1[CH2:15][CH2:16][C:17]12[O:21][CH2:20]1
Reactant: C=C(C)[C@@H]1CC=C(CO)CC1
Agent: CC1(C)C2CCC3(CO3)C1C2
Product: C=C(C)C1CC=C(COC(C)=O)CC1

Procedure:
Among other routes that have been developed to prepare perillyl alcohol from beta pinene oxide is that reported by T. K. Keenan in 1966 who produced perillyl acetate from beta-pinene oxide by refluxing beta-pinene oxide with acetic anhydride and acetic acid for seven hours followed by removal of the acetate to afford a nine percent (9%) yield of perillyl alcohol based on the starting beta-pinene oxide (B.S. Thesis Mass. Institute of Tech.). The applicants found the process to be reproducible albeit in low yield. F. C. Delay in Swiss Patent 5671/84 reported the production of perillyl alcohol in which he treated beta-pinene oxide with nitromethane and ammonium nitrite at a temperature between 20° C. and 90° C. in an overall yield of thirty percent (30%). Two years later Wang and co-workers published in Tetrahedron 1986, 620-638 complete details of this procedure and reported an overall yield of sixty-eight percent (68%) perillyl alcohol.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Si:7]([O:14][C@H:15]1[C@H:19]2[O:20][CH2:21][CH:22]([CH2:23][C:24](OCC)=[O:25])[C@H:18]2[O:17][CH2:16]1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]>C1COCC1>[Si:7]([O:14][C@H:15]1[C@H:19]2[O:20][CH2:21][CH:22]([CH2:23][CH2:24][OH:25])[C@H:18]2[O:17][CH2:16]1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CCOC(=O)CC1CO[C@H]2[C@@H]1OC[C@H]2O[Si](C)(C)C(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@@H]2C(CCO)CO[C@@H]21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
LiAlH4 (1.077 ml, 1.077 mmol) was added to a stirred, cooled (0° C.) mixture of ethyl 2-((3aR,6R,6aS)-6-((tert-butyldimethylsilyl)oxy)hexahydrofuro[3,2-b]furan-3-yl)acetate (178 mg, 0.539 mmol) in THF (5 ml) and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with 1N NaOH (1 mL), stirred for 10 minutes, filtered through Celite™ and washed with EtOAc (50 mL). The solution was washed with brine (20 mL), dried (Na2SO4) and concentrated to dryness to give title compound. LC-MS: calculated for C14H28O4Si 288.18 observed m/e: 289.21 (M+H)+ (Rt 1.16/2 min)
Reaction SMILES: Cl.[O:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]1)=[O:8].[NH2:19][C@@H:20]([CH2:38][O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[CH:26][CH:25]=1)=[O:22]>>[CH2:40]([O:39][CH2:38][C@H:20]([NH:19][C:16](=[O:18])[CH2:15][N:12]1[CH2:11][CH2:10][N:9]([C:7]([CH:3]2[CH2:4][CH2:5][CH2:6][O:2]2)=[O:8])[CH2:14][CH2:13]1)[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[CH:26][CH:25]=1)=[O:22])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C(O)CN1CCN(C(=O)C2CCCO2)CC1
Agent: Cl
Product: O=C(CN1CCN(C(=O)C2CCCO2)CC1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 39.9 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-(tetrahydrofuran-2-carbonyl)piperazin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 237, (2S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-(tetrahydrofuran-2-carbonyl)piperazin-1-yl)acetamido)propanamide (19.3 mg, 39.9%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.24 (s, 1H), 8.03 (d, 1H), 7.61 (d, 2H), 7.30 (m, 5H), 7.21 (t, 2H), 7.04-6.99 (m, 4H), 4.70 (m, 1H), 4.65 (t, 1H), 4.53 (s, 2H), 3.78-3.72 (m, 4H), 3.35 (m, 6H), 3.04 (s, 2H), 2.44 (m, 2H), 1.97 (dd, 2H), 1.80 (m, 2H). MS (EI) for C33H37FN4O6. found 605.7 (MH+).
Reaction SMILES: BrC1C(NCC(OCC)=O)=NC=C(Br)N=1.Cl.C(N)C.C(N(CC)C(C)C)(C)C.[Br:29][C:30]1[N:31]=[C:32]([NH:43][CH2:44][CH3:45])[C:33]([NH:36][CH2:37][C:38](OCC)=[O:39])=[N:34][CH:35]=1>CN1C(=O)CCC1.CO.C(O)(=O)C.C(OCC)(=O)C.O>[Br:29][C:30]1[N:31]=[C:32]2[N:43]([CH2:44][CH3:45])[C:38](=[O:39])[CH2:37][NH:36][C:33]2=[N:34][CH:35]=1
Reactant: CCNc1nc(Br)cnc1NCC(=O)OCC
Agent: CCN
Agent: CCOC(=O)CNc1ncc(Br)nc1Br
Agent: Cl
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCN1C(=O)CNc2ncc(Br)nc21
Temperature: 105 °C
Reaction time: 0.17 h
Yield: 77 %

Procedure:
A mixture of ethyl 2-(3,5-dibromopyrazin-2-ylamino)acetate (See Example 6.B) (1 equiv), ethylamine hydrochloride (3.1 equiv), N,N-diisopropylethylamine (4 equiv) in N-methyl pyrrolidinone was heated at 105° C. under nitrogen for 14 h. Standard ethyl acetate/water work up gave the crude product in 77% yield. This material was used without further purificaction. Crude ethyl 2-(5-bromo-3-(ethylamino)pyrazin-2-ylamino)acetate and acetic acid were combined in methanol. The reaction mixture was refluxed at 60-62° C. under nitrogen for 16 h. The reaction was concentrated under reduced pressure and the resultant residue was diluted with methanol and concentrated. The resultant residue was dissolved in ethyl acetate, treated with sodium carbonate and stirred for 10 min until pH ˜7. The mixture was filtered and washed with ethyl acetate. The filtrate was concentrated and purification by a silica gel plug purification using (0-40% ethyl acetate in hexanes) gave the product as a tan solid. Additionally the filter-cake was suspended in water to remove potassium carbonate. The remaining solid product was collected by filtration. The process afforded product in a combined yield of 75%.
Reaction SMILES: [NH2:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][C@H:9]([C@H:12]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:8]2[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:4][CH:3]=1>CO>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@H:7]2[CH2:11][CH2:10][C@H:9]([C@H:12]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:8]2[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1C(Cc2ccc(N)cc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(N)cc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1

Procedure:
The intermediate i-3 (tert-butyl(5R)-2-(4-aminobenzyl)-5-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(phenyl)methyl]pyrrolidine-1-carboxylate (4:1 mixture of cis and trans) was taken up in methanol and purified via the Berger Multigram SFC (supercritical) using an eluent of 30% methanol:60% carbon dioxide to separate the two diastereomers. The first isomer of the column was labeled minor isomer 1 and the second isomer was labeled major isomer 2.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Cl:8].[CH3:9][P:10]([O:14]CC)[O:11]CC.Cl>>[Cl:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[P:10]([CH3:9])(=[O:11])[OH:14]
Reactant: Clc1ccccc1I
Reactant: CCOP(C)OCC
Agent: Cl
Product: CP(=O)(O)c1ccccc1Cl

Procedure:
After dissolving 4.8 grams of o-iodochlorobenzene in 10 ml. of diethyl methylphosphonite, the resulting solution is irradiated for 3 hours. After concentration under reduced pressure and vacuum distillation, a colorless oil is produced having a boiling point from 96°-100° C. (0.05- 0.1 mm. Hg.). The product is combined with 25 ml. of 12M HCl, and the mixture is refluxed for 2 hours. The solution is concentrated to leave a thick oil which crystallizes upon trituration with ether. Upon recrystallization from acetone-ether, 0.5 grams of the solid is collected having a melting point of 97°-98° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([OH:8])=O)=[O:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH:38]1[CH2:43][CH2:42][CH:41]([C:44]2[CH:51]=[CH:50][C:47]([C:48]#[N:49])=[CH:46][CH:45]=2)[CH2:40][CH2:39]1.CCN(C(C)C)C(C)C>CN(C)C=O.CCOC(C)=O>[CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([N:38]1[CH2:43][CH2:42][CH:41]([C:44]2[CH:51]=[CH:50][C:47]([C:48]#[N:49])=[CH:46][CH:45]=2)[CH2:40][CH2:39]1)=[O:8])=[O:2]
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Reactant: Cc1ccc(C(=O)O)cc1C=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
A mixture of 3-formyl-4-methylbenzoic acid (compound 39.1, 660 mg, 4.02 mmol, 1.00 equiv), HBTU (2 g, 5.28 mmol, 1.30 equiv) in N,N-dimethylformamide (20 mL) was stiffed at room temperature. After 1 h, 4-(piperidin-4-yl)benzonitrile hydrochloride (1.5, 890 mg, 4.01 mmol, 1.00 equiv) and DIEA (1.03 g, 7.98 mmol, 2.00 equiv) were added. The resulting mixture was stirred for 5 h at room temperature and then overnight at 60° C. in. After cooling to ambient temperature, the reaction mixture was diluted with 100 mL of EtOAc and washed with 2×50 mL of NH4Cl (aq., sat.) followed by 2×50 mL of sodium bicarbonate (aq., sat.). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 1 g (75%) of the title compound as a brown oil.
Reaction SMILES: [Br:1][C:2]1[S:23][C:5]2[C:6](=[O:22])[NH:7][CH:8]([C:18]([O:20][CH3:21])=[O:19])[CH:9]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=3)[C:4]=2[CH:3]=1.O1C[CH2:27][CH2:26][CH2:25]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C(Br)C=C>>[CH2:27]([N:7]1[CH:8]([C:18]([O:20][CH3:21])=[O:19])[CH:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[C:4]2[CH:3]=[C:2]([Br:1])[S:23][C:5]=2[C:6]1=[O:22])[CH:26]=[CH2:25]
Reactant: COC(=O)C1NC(=O)c2sc(Br)cc2C1c1ccc(Cl)c(Cl)c1
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C=CCBr
Product: C=CCN1C(=O)c2sc(Br)cc2C(c2ccc(Cl)c(Cl)c2)C1C(=O)OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 2-bromo-4-(3,4-dichlorophenyl)-7-oxo-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-5-carboxylate (0.320 g, 0.735 mmol) in tetrahydrofuran (19 mL, 230 mmol) was added lithium bis(trimethylsilyl)amide (1.103 mmol, 1.103 mmol) in tetrahydrofuran (0.956 mL, 11.8 mmol) at −78° C. under argon. The mixture was stirred for 30 min before allyl bromide (1.27 mL, 14.7 mmol) was added. The reaction mixture was warmed to rt and stirred for 3 hr. The mixture was quenched by addition of sat. NH4Cl and then extracted with EtOAc. The organic layer was separated, dried, and concentrated in vacuo. The residue was purified by silica gel chromatography to afford methyl 6-allyl-2-bromo-4-(3,4-dichlorophenyl)-7-oxo-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-5-carboxylate, the first fraction, as a white solid (58 mg, 16%). LCMS: (AA) ES−: 474, 476, 1H NMR (400 MHz, CDCl3) δ 7.36 (dd, J=8.3, 4.1 Hz, 1H), 7.17 (d, J=2.1 Hz, 1H), 6.87 (dt, J=9.8, 4.9 Hz, 1H), 6.79 (s, 1H), 5.36-5.23 (m, 1H), 5.03-4.93 (m, 2H), 4.71 (ddt, J=15.2, 5.2, 1.4 Hz, 1H), 4.63 (s, 1H), 4.18 (d, J=1.5 Hz, 1H), 3.74 (s, 3H), 3.46-3.35 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:9][OH:10])[C:5]([CH:11]([O:19]C(=O)C)[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][N:3]=1.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:9][O:10][S:29]([C:26]2[CH:27]=[CH:28][C:23]([CH3:33])=[CH:24][CH:25]=2)(=[O:31])=[O:30])[C:5]([CH:11]([OH:19])[C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[CH:4][N:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)OC(c1ccc(Cl)cc1)c1cnc(C)c(O)c1CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCc2c(C(O)c3ccc(Cl)cc3)cnc(C)c2O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.4 %

Procedure:
0.24 g (0.66 mmole) of (+)-2-methyl-3-hydroxy-4- hydroxymethyl-5-[4-chloro-α-acetoxybenzyl]pyridine are poured into a 25 ml round bottomed flask and dissolved in 10 ml of methylene chloride. 190 mg (1 mmole) of p-toluene sulphonyl chloride and 75 mg (1 mmole) of pyridine are then added. The reaction mixture is stirred at room temperature for 18 hours the solvent is then removed under reduced pressure. 5 ml of methanolic ammonia are added and the mixture is stirred at room temperature for 2 hours. The solvent is removed under vacuum, dissolved again in 1 ml of methanol and purified by silica TLC. 170 mg of the title compound were obtained as an off-white solid.