Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[O:3][C:4]1[CH:42]=[CH:41][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:18]3[S:19][C:20]4[CH:25]=[N:24][NH:23][C:22](=[O:26])[C:21]=4[N:27]=3)[CH2:15][CH2:14][N:13]2[S:28]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)(=[O:30])=[O:29])=[O:11])=[CH:6][CH:5]=1.CO.[C:47]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[F:44][C:2]([F:1])([F:43])[O:3][C:4]1[CH:42]=[CH:41][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:18]3[S:19][C:20]4[CH:25]=[N:24][N:23]([CH3:47])[C:22](=[O:26])[C:21]=4[N:27]=3)[CH2:15][CH2:14][N:13]2[S:28]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:38])([F:39])[F:40])=[CH:33][CH:32]=2)(=[O:30])=[O:29])=[O:11])=[CH:6][CH:5]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CN(c2nc3c(=O)[nH]ncc3s2)CCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: CO
Solvent: C1CCOC1
Product: Cn1ncc2sc(N3CCN(S(=O)(=O)c4ccc(C(F)(F)F)cc4)[C@@H](C(=O)NCc4ccc(OC(F)(F)F)cc4)C3)nc2c1=O
Yield: 71 %

Procedure:
To a solution of the compound (40 mg) obtained in Step 6 in THF (0.8 ml) were added methanol (3.7 μl), triphenylphosphine (24 mg) and diisopropyl azodicarboxylate (18 μl) with stirring under ice-cooling, and the mixture was stirred overnight at room temperature. Methanol (1.2 μl), triphenylphosphine (8 mg) and diisopropyl azodicarboxylate (6 μl) was added at room temperature, and the mixture was stirred for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol:chloroform=5:95) to give the title compound (29 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([CH2:12][CH2:13][C:14]([OH:16])=O)[O:9][N:8]=1.Cl.[NH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1.C(N(CC)CC)C.O>ClCCl.[Cl-].[Na+].O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([CH2:12][CH2:13][C:14]([NH:18][CH:19]2[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24]2)=[O:16])[O:9][N:8]=1
Reactant: O=C(O)CCc1nc(-c2ccccn2)no1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)CCc2nc(-c3ccccn3)no2)CC1
Yield: 47.2 %

Procedure:
3-[3-(2-Pyridinyl)-1,2,4-oxadiazol-5-yl]propanoic acid (0.60 g) was dissolved in dichloromethane (10 ml). 1,1-Carbonyldiimidazole (0.33 g) was added followed by tert-butyl 4-amino-1-piperidinecarboxylate hydrochloride (0.5 g) and triethylamine (0.31 ml). After 2 hours water, brine and dichloromethane were added and the phases separated. The organic phase was dried, filtered and evaporated and the residue was purified by chromatography eluting with ethyl acetate:methanol (33:1) to give the subtitle compound (0.40 g).
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][S:12][CH2:13][C@H:14]1[O:18][C@@H:17]([N:19]2[CH:27]=[C:25]([CH3:26])[C:23](=[O:24])[NH:22][C:20]2=[O:21])[CH2:16][C@@H:15]1[OH:28].[N:29]1C=C[CH:32]=[CH:31][CH:30]=1.C(NC(C)C)(C)C.[CH:42]([N:45]([CH:53]([CH3:55])[CH3:54])[P:46](Cl)[O:47]CCC#N)([CH3:44])[CH3:43]>O1CCCC1>[C:30]([CH2:31][CH2:32][PH:46]([O:28][C@@H:15]1[C@@H:14]([CH2:13][S:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[O:18][C@@H:17]([N:19]2[CH:27]=[C:25]([CH3:26])[C:23](=[O:24])[NH:22][C:20]2=[O:21])[CH2:16]1)([N:45]([CH:42]([CH3:43])[CH3:44])[CH:53]([CH3:54])[CH3:55])[OH:47])#[N:29]
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CSCc3ccc4ccccc4c3)O2)c(=O)[nH]c1=O
Reactant: c1ccncc1
Reactant: CC(C)N(C(C)C)P(Cl)OCCC#N
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1cn([C@H]2C[C@H](O[PH](O)(CCC#N)N(C(C)C)C(C)C)[C@@H](CSCc3ccc4ccccc4c3)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 56 %

Procedure:
79.7 mg (0.2 mmol) of 5'-[(2-naphthyl)methylthio]-5'-deoxythymidine [prepared as described in step (a) above] were dried by azeotropic distillation with pyridine and then dissolved in 2.5 ml of tetrahydrofuran. 0.084 ml (0.48 mmol) of diisopropylamine was then added to the solution. 54 μl (0.24 mmol) of 2-cyanoethyl N,N-diisopropylchlorophosphoramidite were then added dropwise to the mixture, under an atmosphere of argon. The resulting mixture was stirred at room temperature for 1.75 hours under the same atmosphere. The tetrahydrofuran was then removed by distillation under reduced pressure. The resulting residue was dissolved in 10 ml of ethyl acetate, and the solution was washed with a 10% w/v aqueous solution of sodium carbonate and with a saturated aqueous solution of sodium chloride, in that order. The solution was then dried over anhydrous magnesium sulfate, after which the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography through 10 g of silica gel (70-230 mesh), using ethyl acetate as the eluent, to give 67 mg (yield 56%) of the title compound as a foam-like substance.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]3[C:13]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][C:18]=4[O:23]COC)=[CH:14][CH:15]=[CH:16][C:10]=3[CH:9]=2)[C:5]([F:27])=[CH:4][N:3]=1.Cl>C1COCC1.C(=O)(O)[O-].[Na+].ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]3[C:13]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][C:18]=4[OH:23])=[CH:14][CH:15]=[CH:16][C:10]=3[CH:9]=2)[C:5]([F:27])=[CH:4][N:3]=1
Reactant: COCOc1cnccc1-c1cccc2cc(-c3nc(Cl)ncc3F)sc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Oc1cnccc1-c1cccc2cc(-c3nc(Cl)ncc3F)sc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 8.4 %

Procedure:
Treat a solution of 2-chloro-5-fluoro-4-[7-(3-methoxymethoxy-pyridin-4-yl)-benzo[b]thiophen-2-yl]-pyrimidine (4 g, 10 mmol) in THF (10 mL) with 5 N HCl (3 mL). Stir the mixture at room temperature for 6 hours. Concentrate the reaction in vacuo and dilute with saturated aqueous sodium bicarbonate and dichloromethane. Separate the layers and filter each layer. Wash the solid from the organic phase with dichloromethane to give the title compound (300 mg) as a tan solid. Wash the solid from the aqueous layer with water and dry to give the title compound (300 mg) as a tan solid. Combine the solids to give the title compound (600 mg, 17%) as a tan solid. MS (ES) m/z 358 [M+1]+.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH:10]=1)(=O)=O.[I-:28].[Na+]>>[Si:21]([O:20][CH2:19][CH2:18][N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]([CH2:8][CH2:7][CH2:6][I:28])=[CH:10]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: [I-]
Reactant: CC(C)(C)[Si](C)(C)OCCn1cc(CCCOS(C)(=O)=O)c2ccccc21
Agent: [Na+]
Product: CC(C)(C)[Si](C)(C)OCCn1cc(CCCI)c2ccccc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 71.6 %

Procedure:
To a solution of 3-[1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-1H-indol-3-yl]propyl methanesulfonate (Intermediate 42; 3.5 g, 8.5 mmol) in ketone (20 mL) was added sodium iodide (2.55 g, 17 mmol). The reaction mixture was stirred overnight at 50° C. The crude reaction was filtered and the solvent was removed under reduced pressure. The crude obtained was purified over silica gel eluting with hexane:ether (100/0 to 0/100) to obtain the title compound (2.7 g, 71%).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(N(CC)CC)C.[F:12][C:13]([F:26])([F:25])[C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=1)[CH2:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[CH:1]1([NH:4][S:18]([CH2:17][C:16]2[CH:22]=[CH:23][CH:24]=[C:14]([C:13]([F:12])([F:25])[F:26])[CH:15]=2)(=[O:20])=[O:19])[CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)Cc1cccc(C(F)(F)F)c1
Reactant: NC1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(Cc1cccc(C(F)(F)F)c1)NC1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.6 %

Procedure:
In this example, 5.3 g of cyclopropylamine is mixed with 9.4 g of triethylamine and then added dropwise to a solution containing 20 g of 3-trifluoromethylbenzylsulfonyl chloride in methylene chloride at 0° C. The resulting reaction mixture is stirred at room temperature (i.e., about 20°-25° C.) for 3 hours. The reaction mixture is washed with saturated aqueous ammonium chloride and then with aqueous 1 wt.% hydrochloric acid until it was neutral. The organic layer is separated, washed twice with 50 ml of aqueous saturated sodium chloride solution, dried over magnesium sulfate and then evaporated to dryness affording 20 g of N-cyclopropyl-3-trifluoromethylbenzylsulfonamide.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:12][CH2:11][CH2:10][O:9][C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[CH3:13][O-:14].[Na+]>CO>[CH3:13][O:14][C:2]1[C:3]2[CH2:12][CH2:11][CH2:10][O:9][C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1
Reactant: Nc1nc(Cl)c2c(n1)OCCC2
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(N)nc2c1CCCO2

Procedure:
6,7-Dihydro-4-hydroxy-5H-pyrano[2,3-d]pyrimidin-2-amine can be prepared from diethyl 3-chloropropylmalonate, guanidine carbonate and sodium ethoxide in ethanol. Treatment of the product ##STR56## with phosphorus oxychloride gives 4-chloro-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-amine and subsequent reaction with sodium methoxide in refluxing methanol affords 6,7-dihydro-4-methoxy-5H-pyrano[2,3-d]pyrimidin-2-amine.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:14])[CH2:12][CH3:13])=[C:4](Cl)[N:3]=1.C(O)CCC.[CH2:21]([NH2:24])[CH2:22][CH3:23]>C(OCC)(=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:14])[CH2:12][CH3:13])=[C:4]([NH:24][CH2:21][CH2:22][CH3:23])[N:3]=1
Reactant: CCC(C)n1cnc2c(Cl)nc(Cl)nc21
Reactant: CCCN
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: CCCNc1nc(Cl)nc2c1ncn2C(C)CC
Reaction time: 22 h

Procedure:
The operation is carried out as in Stage 2 of Example 9 starting from 200 mg of the product obtained in Stage 1 of Example 9 and 4 ml of butanol and using 0.132 ml 1-propanamine in place of the benzylamine. Agitation is carried out at ambient temperature then the reaction medium is taken to a temperature of 80 to 85° C. for approximately 22 hours, left to return to ambient temperature, followed by taking up in 5 ml of ethyl acetate, evaporating to dryness, impasting in 5 ml of pentane at ambient temperature, separating, washing with 5 ml of pentane and drying at a temperature of approximately 50° C.
Reaction SMILES: C[CH2:2][C:3]([O:5]CC)=S.ClCl.[CH2:10]([O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1)[CH3:11].C(N(CC)CC)C>C(Cl)Cl.O>[CH2:10]([O:12][C:13]1[CH:19]=[C:18]2[C:16](=[CH:15][CH:14]=1)[NH:17][C:3](=[O:5])[CH2:2]2)[CH3:11]
Reactant: CCOC(=S)CC
Reactant: CCOc1ccc(N)cc1
Agent: ClCl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOc1ccc2c(c1)CC(=O)N2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
23.6 g of ethyl methylthioacetate in 60 ml of DCM are added to a solution, cooled to about -70° C., of 12.5 g of chlorine in 400 ml of DCM. After stirring for 5 minutes at the same temperature, a solution of 4-ethoxyaniline (48.3 g) in 120 ml of DCM is added. The mixture is stirred for one hour at about -70° C., 39.3 ml of triethylamine are added and the resulting mixture is allowed to warm up to room temperature. 200 ml of water are added and the organic phase is decanted, dried over magnesium sulfate and evaporated under reduced pressure. The residue is taken up with 500 ml of isopropanol and 20 ml of concentrated hydrochloric acid. The mixture is stirred for about 16 hours at room temperature and filtered and the precipitate is separated off. The filtrate is concentrated under reduced pressure to give the expected product.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[C:6]([C:8]1([NH:17][C:18](=[O:29])[CH2:19][C:20]2[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=2[CH3:28])[CH2:13][CH2:12][N:11]([O:14][CH2:15][CH3:16])[CH2:10][CH2:9]1)#N.[C:30](=O)([O-])[O-:31].[Na+].[Na+]>CO>[CH3:30][O:31][C:6]([C:8]1([NH:17][C:18](=[O:29])[CH2:19][C:20]2[C:21]([CH3:28])=[CH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])[CH2:13][CH2:12][N:11]([O:14][CH2:15][CH3:16])[CH2:10][CH2:9]1)=[O:2]
Reactant: O=C([O-])[O-]
Reactant: O=S(=O)(O)O
Reactant: CCON1CCC(C#N)(NC(=O)Cc2c(C)cc(C)cc2C)CC1
Agent: [Na+]
Solvent: CO
Product: CCON1CCC(NC(=O)Cc2c(C)cc(C)cc2C)(C(=O)OC)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1.4 ml of concentrated sulfuric acid was slowly added to a solution of 4.3 g of N-(4-cyano-1-ethoxy-piperidin-4-yl)-2-(2,4,6-trimethyl-phenyl)-acetamide in 11 ml of methanol. After stirring 20 hours under reflux, the reaction mixture was allowed to cool down to room temperature and diluted with ice water. Sodium carbonate was added and the aqueous phase was extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated. Chromatography (dichloromethane+1% of ethanol) gave 3.2 g of 1-ethoxy-4-[2-(2,4,6-trimethyl-phenyl)-acetylamino]-piperidine-4-carboxylic acid methyl ester as a solid, mp: 131-132° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[O:3]1.N1C=CC=CC=1.[CH3:17][O:18][CH2:19][C:20](Cl)=[O:21]>ClCCl>[CH3:17][O:18][CH2:19][C:20]([CH:6]1[C:7](=[O:8])[O:9][C:2]([CH3:10])([CH3:1])[O:3][C:4]1=[O:5])=[O:21]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCC(=O)C1C(=O)OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.7 %

Procedure:
To a solution of Meldrum's acid (30 g, 0.208 mol) in dichloromethane (420 mL) was added pyridine (33.7 mL, 0.416 mol) over 3 minutes in an ice-methanol bath under nitrogen atmosphere (−9° C.). To this mixture was added dropwise a solution of methoxyacetyl chloride (24.8 g) in dichloromethane (180 mL) over 1 hour period at the temperature. After addition, the reaction mixture was stirred at the temperature for 1 hour and at ambient temperature for 2 hours. The mixture was quenched with 1N hydrochoric acid (600 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo to give 5-(methoxyacetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione as dark orange oil (38.1 g, 84.7%).
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[C:7](#[N:12])[CH:8]=[CH:9][CH2:10][CH3:11].C(OCC)(=[O:16])CC.Cl>CC1C=CC=CC=1C.O.O1CCCC1>[C:9]([CH:8]([CH2:3][CH:2]=[CH2:1])[C:7]#[N:12])(=[O:16])[CH2:10][CH3:11]
Reactant: CCC=CC#N
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)CC
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1C
Solvent: O
Solvent: C1CCOC1
Product: C=CCC(C#N)C(=O)CC
Temperature: 48 °C
Reaction time: 3 h
Yield: 92.3 %

Procedure:
In a 20 l jacketed reactor fitted with heating/cooling circuit and reflux condenser, 3500 g of potassium tert-butoxide were initially charged, and 6316 g of tetrahydrofuran was added. At a temperature of at most 10° C., a mixture of 1200 g of pentenenitrile and 1651 g of ethyl propionate was then pumped in over a period of 75 min. Stirring was continued at 8 to 10° C. for 3 h and then at 15° C. overnight. The mixture was then adjusted to pH of 3.8 by pumping in 6316 g of 20% strength hydrochloric acid, with the temperature increasing to 48° C. 2400 ml of water and 4000 ml of o-xylene were then added. The aqueous (lower) phase was then removed, and the organic phase was washed two more times with in each case 2400 ml of water. What remained were 14650 g of organic phase. Concentration on a rotary evaporator at 60° C. and 10 mbar gave 1873 g of an amber product having a content of 87.4% a/a (GC), which was reacted further as such.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:24]([OH:26])=O)[NH:16]C(OC(C)(C)C)=O)=O)C1C=CC=CC=1.[CH:27]1([CH2:33][S:34]([Cl:37])(=[O:36])=[O:35])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>>[ClH:37].[NH2:16][C@H:15]([C:24](=[O:26])[N:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1)[CH2:14][CH2:13][CH2:12][NH:11][S:34]([CH2:33][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)(=[O:36])=[O:35]
Reactant: O=S(=O)(Cl)CC1CCCCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: C1CCNC1
Product: Cl
Product: N[C@@H](CCCNS(=O)(=O)CC1CCCCC1)C(=O)N1CCCC1

Procedure:
Starting from (S)-N5-(benzyloxycarbonyl)-N2-(tert-butyloxycarbonyl)-ornithine, (cyclohexyl)-methanesulphonyl chloride and pyrrolidine, the expected product is obtained according to the procedure described in Example 3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13](N(OC)C)=[O:14])=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([S:25](=[O:32])(=[O:31])[N:26]=CN(C)C)=[C:21]([CH3:33])[CH:20]=3)[C:9]=2[CH3:34])=[CH:4][CH:3]=1.[CH2:35]1COC[CH2:36]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13](=[O:14])[CH2:35][CH3:36])=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([NH2:26])(=[O:31])=[O:32])=[C:21]([CH3:33])[CH:20]=3)[C:9]=2[CH3:34])=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: CON(C)C(=O)c1sc(-c2ccc(Cl)cc2)c(C)c1-c1ccc(S(=O)(=O)N=CN(C)C)c(C)c1
Product: CCC(=O)c1sc(-c2ccc(Cl)cc2)c(C)c1-c1ccc(S(N)(=O)=O)c(C)c1
Temperature: 0 °C
Yield: 18.1 %

Procedure:
Grignard reagent (Ethyl magnesium bromide, 0.42 g, 3.17 ml 1M solution in THF, 3.17 mmol) was added drop wise to a stirred solution of (5-(4-chlorophenyl)-3-(4-(N-((dimethylamino)methylene)sulfamoyl)-3-methylphenyl)-N-methoxy-N,4-dimethylthiophene-2-carboxamide (41e, 0.33 g, 0.63 mmol) in anhydrous THF (20 ml) at 25° C. The reaction mixture was then heated to about 70° C. to 75° C. for 1 hr. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 0° C. The cooled reaction mixture was quenched by adding saturated solution of ammonium chloride (10 ml) and the mixture was then extracted with ethyl acetate (2×30 ml). The combined organic layer was dried over anhydrous Na2SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain a crude product, which was then purified by preparative HPLC to obtain the title compound (0.05 g, 18.1%)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C@@H:7]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14](OC(C)(C)C)=[O:15])[CH2:9]1.O1CCOCC1.N1C=CC=CC=1.[Cl:39]C(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>Cl.C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C@@H:7]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([Cl:39])=[O:15])[CH2:9]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COCCCO[C@@H](c1ccccc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: COCCCO[C@@H](c1ccccc1)[C@@H]1CCCN(C(=O)Cl)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
(R)-tert-butyl 3-((R)-(3-methoxypropoxy)(phenyl)methyl)piperidine-1-carboxylate (219 mg, 0.603 mmol) was dissolved in 4M HCl in 1,4-dioxane (20 mL, 80 mmol) and stirred for 30 min. LC-MS showed removal of the Boc protecting group. The reaction mixture was concentrated and redissolved dry CH2Cl2 (5 mL). Pyridine (122 μL, 1.51 mmol, 2.5 equiv) was added. This solution was added dropwise under N2 to a solution of triphosgene (188 mg, 0.63 mmol, 1.05 equiv) in dry CH2Cl2 (5 mL) at −78° C. After 10 min, the reaction mixture was warmed to rt and stirred for 2 h. LC-MS showed the reaction was complete. 5% aq HCl (15 mL) was added and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2×30 ml). The combined organic layers were washed with satd aq NaHCO3 and brine, and dried over Na2SO4. Concentration afforded (R)-3-((R)-(3-methoxypropoxy)(phenyl)-methyl)piperidine-1-carbonyl chloride (188 mg, 96%) as a yellow oil. LC-MS (3 min) tR=1.83 min, m/z 344 (M+H2O). The crude product was used for the next step without further purification.
Reaction SMILES: [NH2:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:20]([O:24][C:25](ON=C(C1C=CC=CC=1)C#N)=[O:26])([CH3:23])([CH3:22])[CH3:21]>CC(C)=O.O>[C:20]([O:24][C:25]([NH:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Reaction time: 8 h

Procedure:
To a suspension of D-phenylalanine (33.0 g, 0.2 mol) in acetone (120 ml) and water (120 ml) was added triethylamine (41.8 ml, 1.5 eq) followed by 2-(t-butoxycarbonyloxyimino)-2-phenylacetonitrile (54.2 g, 1.1 eq). The resulting mixture was stirred overnight and then diluted with water (250 ml). The aqueous fraction was extracted twice with ether and the ether fractions were discarded. The aqueous fraction was acidified with 0.5M citric acid and extracted with ethyl acetate (2×500 ml). The ethyl acetate fractions were combined and washed with water and brine. After drying over anhydrous magnesium sulfate, the solvent was removed to give the title compound as a viscous yellow oil: 52.2 g.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:18][CH3:19])=[CH:11][C:12](Br)=[C:13]([O:15][CH3:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[B:25](OCC)([O:29]CC)[O:26]CC>C1COCC1>[CH2:1]([O:8][C:9]1[C:10]([CH2:18][CH3:19])=[CH:11][C:12]([B:25]([OH:29])[OH:26])=[C:13]([O:15][CH3:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOB(OCC)OCC
Reactant: CCc1cc(Br)c(OC)cc1OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cc(B(O)O)c(OC)cc1OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 71.6 %

Procedure:
Under a nitrogen atmosphere, 16.70 g (52.00 mmol) of 5-benzyloxy-2-bromo-4-ethyl-1-methoxybenzene (4) was added to 110 mL of anhydrous THF. The solution was cooled to −78° C., and 22.88 mL (57.19 mmol) of a 2.5 M solution of butyl lithium was added dropwise while maintaining the temperature below −70° C. The reaction mixture was stirred at −78° C. for 45 minutes. 9.73 mL (57.19 mmol) of triethyl borate was then added, and the reaction was allowed to stir at −78° C. for an additional 2 hours. The reaction mixture was then allowed to warm to 23° C. over a 30 minute period and was quenched with 100 mL of saturated NH4Cl. The pH was adjusted to 5.0 with 1M HCl, and the resultant solution was extracted with ethyl acetate (2×200 mL). The combined extracts were washed with brine (1×100 mL), dried over sodium sulfate, filtered and concentrated in vacuo to yield crude product as a greenish-tan solid. The crude product was triturated with hexane and filtered to afford 10.65 g (64%) of 4-benzyloxy-5-ethyl-2-methoxy-phenylboronic acid (5) as an off-white solid.