Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:15]=[C:14]([NH:16][C:17](=[O:22])[O:18][CH2:19][CH:20]=[CH2:21])[O:13][N:12]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[N+:23]([C:26]1[CH:31]=[CH:30][C:29]([S:32]([N@:35]2[CH2:37][CH:36]2[CH2:38][C:39]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[NH:41][CH:40]=2)(=[O:34])=[O:33])=[CH:28][CH:27]=1)([O-:25])=[O:24].O>CN(C=O)C>[NH:41]1[C:42]2[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:39]([CH2:38][C@H:36]([NH:35][S:32]([C:29]2[CH:28]=[CH:27][C:26]([N+:23]([O-:25])=[O:24])=[CH:31][CH:30]=2)(=[O:33])=[O:34])[CH2:37][N:16]([C:14]2[O:13][N:12]=[C:11]([C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[CH:1]=[N:2][CH:3]=[CH:4]4)[CH:15]=2)[C:17](=[O:22])[O:18][CH2:19][CH:20]=[CH2:21])=[CH:40]1
Reactant: C=CCOC(=O)Nc1cc(-c2ccc3cnccc3c2)no1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)[N@]2CC2Cc2c[nH]c3ccccc23)cc1
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC(=O)N(C[C@H](Cc1c[nH]c2ccccc12)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1cc(-c2ccc3cnccc3c2)no1
Reaction time: 3 h
Yield: 86.6 %

Procedure:
To a 25 mL of round-bottom flask was added allyl 3-(isoquinolin-6-yl)isoxazol-5-ylcarbamate (68 mg, 230 μmol) (prepared as shown for Example 11), 1,8-diazabicyclo(5.4.0)-7-undecene (6.8 μl, 46 μmol) and 2 mL of DMF at room temperature. (S)-3-((1-(4-Nitrophenylsulfonyl)aziridin-2-yl)methyl)-1H-indole (98 mg, 276 μmol) (prepared as described in US Patent Publication No. US 2007/0173506 which is hereby incorporated by reference in its entirety and for all purposes as if specifically set forth herein) in 1 mL of DMF was added to the reaction mixture dropwise. After 3 hours, 10 mL of water was added, and then the reaction mixture was extracted twice with 20 mL of EtOAc. The extracts were combined, concentrated under reduced pressure, and purified by flash chromatography on silica gel (65% EtOAc/hexane) to give allyl(S)-3-(1H-indol-3-yl)-2-(4-nitrophenylsulfonamido)propyl(3-(isoquinolin-6-yl)isoxazol-5-yl)carbamate (130 mg, 86% yield). MS m/z: 653 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][N:17]3[C:20]([CH2:23][CH:24]4[CH2:26][CH2:25]4)=[N:21][N:22]=[C:16]3[C:15]=2[CH3:27])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:24]1([CH2:23][C:20]2[N:17]3[CH:18]=[CH:19][C:14]([CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[C:15]([CH3:27])[C:16]3=[N:22][N:21]=2)[CH2:25][CH2:26]1
Reactant: Cc1c(C2CCN(C(=O)OC(C)(C)C)CC2)ccn2c(CC3CC3)nnc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C2CCNCC2)ccn2c(CC3CC3)nnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.4 %

Procedure:
To a stirred solution of D100 (0.207 g, 0.560 mmol) in dry DCM (3.5 ml), was added trifluoroacetic acid (1.01 ml). The mixture was stirred at r.t. for 2 h and then concentrated in vacuo. The residue was basified with NaOH 50% (aqueous solution) and extracted with DCM. The organic phase was separated, dried (Na2SO4) and concentrated in vacuo to yield intermediate D101 (0.149 g, 99%).
Reaction SMILES: [C:1]([NH:5][C:6]([C@@H:8]1[CH2:17][C@H:16]2[C@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:18]([C@H:21]([C@H:29]1[CH2:33]OS(=O)(=O)[O:30]1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[N+:19]=[N-:20].S(=O)(=O)(O)O.[OH-].[Na+]>O1CCCC1.CO>[N:18]([C@@H:21]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@H:29]([OH:30])[CH2:33][N:9]1[C@H:8]([C:6]([NH:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:17][C@H:16]2[C@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10]1)=[N+:19]=[N-:20]
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1
Reactant: [N-]=[N+]=N[C@@H](Cc1ccccc1)[C@H]1COS(=O)(=O)O1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@H](Cc1ccccc1)N=[N+]=[N-]
Temperature: 25 °C
Yield: 13.3 %

Procedure:
A solution of 237 mg (1 mmol) of N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide and 300 mg (1.1 mmol) of 4(S)-[1(S)-azido-2-phenylethyl]-1,3,2-dioxathiolane 2,2-dioxide in 10 ml of tetrahydrofuran was stirred at room temperature under an argon atmosphere for 2 days, during which time some white solid deposits formed. The mixture was evaporated to give a white powder which was taken up in a 10% solution of sulphuric acid in 70% aqueous methanol and heated under reflux for 30 minutes. After cooling to room temperature the solution was adjusted to pH 10 with 10% aqueous sodium hydroxide solution and extracted three times with ethyl acetate. The ethyl acetate extracts were combined, washed with sodium chloride solution, dried over anhydrous magnesium sulphate and evaporated. Purification of the crude product by flash chromatography on silica gel using n-hexane/ethyl acetate (4:1) for the elution gave 57 mg of 2-[3(S)-azido-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide; MS: m/e 428 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][SH:12])=[CH:9][C:4]=2[O:3][CH2:2]1.Br[CH2:14][C:15]([OH:17])=[O:16].[OH-].[Na+]>C(O)C.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][S:12][CH2:14][C:15]([OH:17])=[O:16])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: SCCc1ccc2c(c1)OCO2
Reactant: O=C(O)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CSCCc1ccc2c(c1)OCO2
Yield: 93.2 %

Procedure:
100 g of 2-(1,3-benzodioxol-5-yl)ethanethiol and 75.1 g of bromoacetic acid were dissolved in 1 l of ethanol. A solution of 44 g of sodium hydroxide in 125 ml of water and then 2 l of ethanol were added thereto. The mixture was heated under reflux for 3 h. The reaction mixture was concentrated under reduced pressure. 2.5 l of water was added thereto. The mixture was made alkaline with a 1N sodium hydroxide solution, washed with 35% hydrochloric acid, extracted with ethyl acetate, washed with water four times and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain 121 g of [{2-(1,3-benzodioxol-5-yl)ethyl}thio]acetic acid in the form of a faint yellow oil.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:23][CH:24]=[CH:25][C:26]#[C:27][C:28]([CH3:31])([CH3:30])[CH3:29]>CN(C)C=O>[CH3:29][C:28]([CH3:31])([CH3:30])[C:27]#[C:26]/[CH:25]=[CH:24]\[CH2:23][N:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:1]
Reactant: CNCc1ccccc1-c1ccccc1
Reactant: CC(C)(C)C#CC=CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C/C=C\C#CC(C)(C)C)Cc1ccccc1-c1ccccc1
Reaction time: 16 h

Procedure:
N-methyl-2-phenylbenzylamine (2.57 g) was dissolved in 17 ml of N,N-dimethylformamide (DMF), followed by the addition of 1.39 g of sodium carbonate. While stirring the resulting mixture under ice cooling, a solution of 2.5 g of 1-bromo-6,6-dimethyl-2-hepten-4-yne in DMF was added dropwise. The temperature of the mixture was allowed to rise to room temperature, at which a reaction was allowed to proceed for 16 hours. After the reaction mixture was concentrated under reduced pressure, water and diethyl ether were added to subject the resulting concentrate to liquid-liquid extraction. The organic layer was collected and then dried over magnesium sulfate. The solvent was then distilled off. The residue was purified by chromatography on a silica gel (eluent:hexane/ethyl acetate=10/1), whereby trans-N-(6,6-dimethyl-2-hepten-4-yn-1-yl)-N-methyl-2-phenylbenzylamine (Compound 5) and cis-N-(6,6-dimethyl-2-hepten-4-yn-1-yl)-N-methyl-2-phenylbenzylamine (Compound 6) were obtained in amounts of 2.15 g (yield: 54.5%) and 0.73 g (yield: 18.5%), respectively. The followings are their NMR spectrum data:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[C:21]4[CH2:22][CH2:23][CH2:24][C:20]=4[N:19]=[C:18](Cl)[N:17]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[N:26]1([S:31]([C:34]2[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=2)(=[O:33])=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27]1>C(O)(C)C>[CH3:1][O:2][C:3]([C:5]1([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[C:21]4[CH2:22][CH2:23][CH2:24][C:20]=4[N:19]=[C:18]([NH:40][C:37]4[CH:38]=[CH:39][C:34]([S:31]([N:26]5[CH2:30][CH2:29][CH2:28][CH2:27]5)(=[O:33])=[O:32])=[CH:35][CH:36]=4)[N:17]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(c2ccc(Nc3nc(Cl)nc4c3CCC4)cc2)CCC1
Reactant: Nc1ccc(S(=O)(=O)N2CCCC2)cc1
Solvent: CC(C)O
Product: COC(=O)C1(c2ccc(Nc3nc(Nc4ccc(S(=O)(=O)N5CCCC5)cc4)nc4c3CCC4)cc2)CCC1
Reaction time: 45 h
Yield: 51.1 %

Procedure:
1-[4-(2-chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino)-phenyl]cyclobutanecarboxylic acid methyl ester (0.36 g, 1 mmol) was added to a solution of 4-(pyrrolidine-1-sulfonyl)-phenylamine (0.24 g, 1.06 mmol) in anhydrous isopropanol (10 mL) and the mixture was stirred at a temperature in the range of 60° C. to 110° C. for 40 to 50 hours. The reaction was cooled to a temperature in the range of 15° C. to 25° C. The precipitated solid was filtered, washed with ether, and dried in vacuo to afford the title compound as a white solid (0.28 g, 54% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8](Cl)(=O)=O)=[CH:6][C:5]([C:12]2[C:13](=[O:23])[N:14]([CH3:22])[C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)=[C:4]([F:24])[CH:3]=1.II.[C:27](O)(=[O:29])[CH3:28]>>[C:27]([S:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([F:24])=[C:5]([C:12]2[C:13](=[O:23])[N:14]([CH3:22])[C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[CH:6]=1)(=[O:29])[CH3:28]
Reactant: Cn1c(C(F)(F)F)ccc(-c2cc(S(=O)(=O)Cl)c(Cl)cc2F)c1=O
Reactant: CC(=O)O
Agent: II
Product: CC(=O)Sc1cc(-c2ccc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Yield: 98 %

Procedure:
To 50 ml of acetic acid, 3.1 g (7.7 mmol) of 3-(4-chloro-5-chlorosulfonyl-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2(1H)-pyridone, 1.2 g (38 mmol) of red phosphorus and 0.12 g (0.47 mmol) of iodine were added, followed by heating and refluxing for 1 hour. After cooling, insoluble substances were filtered off, and majority of acetic acid was distilled off. Then, the obtained residue was poured into water and extracted with ethyl acetate. After washing with water and a saturated sodium hydrogencarbonate aqueous solution, the organic layer was washed with anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 2.8 g (yield: 98%) of the desired product. Melting point: 91-92° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:7][C:6]2[CH:10]=[CH:2][CH:3]=[CH:4][CH:5]=2)=[C:6]([CH:10]=1)[C:7]([O:9][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:8]
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cc(Cl)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-chloro-2-hydroxybenzoic acid (2.03 g, 11.8 mmol), benzyl bromide (2.79 ml, 23.5 mmol) and potassium carbonate (4.87 g, 35.3 mmol) in DMF (20 ml) was stirred at room temperature overnight then heated at 60° C. for 1 hour. Cooled, diluted with water (150 ml) and extracted with ethyl acetate (×3). The organics were washed with water (×2) and brine, dried (MgSO4), and concentrated in vacuo to yield the crude title compound as a yellow oil which was used immediately without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH:7]([CH2:11][S:12](Cl)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]1[CH2:28][NH:29][CH2:30][CH2:31][C:22]2=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6](=[O:16])[CH:7]([CH2:11][S:12]([N:29]1[CH2:30][CH2:31][C:22]2[C:21]3[C:25](=[CH:26][CH:27]=[C:19]([O:18][CH3:17])[CH:20]=3)[NH:24][C:23]=2[CH2:28]1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C(CS(=O)(=O)Cl)C(=O)OC(C)(C)C
Reactant: COc1ccc2[nH]c3c(c2c1)CCNC3
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2[nH]c3c(c2c1)CCN(S(=O)(=O)CC(C(=O)OC(C)(C)C)C(C)C)C3
Reaction time: 0.33 h
Yield: 64.5 %

Procedure:
A solution of 2-chlorosulfonylmethyl-3-methylbutyric acid tert-butyl ester (WO 99/24399) (470 mg) in dichloromethane (10 ml) was added to a mixture of 6-methoxy-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole (350 mg) and triethylamine (0.72 ml) in dichloromethane (10 ml) at room temperature under nitrogen. The mixture was stirred for 20 minutes before being evaporated to dryness and the residue chromatographed (SiO2, 1:1 heptane-ethyl acetate) to give the title compound (487 mg, 66%) as a white solid.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:4]([O:6][CH3:7])=[O:5].[C:19]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[OH:1][CH2:2][C@H:3]([N:8]([CH3:19])[S:9]([C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1)(=[O:11])=[O:10])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)[C@H](CO)NS(=O)(=O)c1ccc(C)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CO)N(C)S(=O)(=O)c1ccc(C)cc1
Temperature: 50 °C

Procedure:
A solution of 2E (2 g, 7.35 mmol) in DMF (15 mL) was added with an .K2CO3 (1.5 mol eq, 1.52 g) and, after few minutes, iodomethane (1.2 mol eq, 0.81 ml) was added and the mixture was heated at 50° C. overnight. The solvent was removed under reduced pressure, water was added to the residue (120 mL) and the aqueous phase was extracted with EtOAc (3×50 mL). The combined organic phases were dried over Na2SO4 and evaporated under reduced pressure to afford 3E as a pale yellow oil (2.1 g, quantitative yield). 1HNMR (DMSO, 200 MHz) δ 2.38 (s, 3H), 2.87 (s, 3H), 3.64 (s, 3H), 3.70 (t, 2H), 4.58 (t, 1H), 5.11 (t, 1H), 7.40 (d, 2H, J=8), 7.61 (d, 2H, J=8).
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([OH:14])=[O:13].O[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C1(C)C=CC=CC=1>S(=O)(=O)(O)O.O>[N:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH2:21][O:13][C:12](=[O:14])[CH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[NH:4][C:3]1[C:15]([Cl:19])=[CH:16][CH:17]=[CH:18][C:2]=1[CH3:1]
Reactant: OCc1ccccn1
Reactant: Cc1cccc(Cl)c1Nc1ccccc1CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cccc(Cl)c1Nc1ccccc1CC(=O)OCc1ccccn1
Temperature: 5 °C

Procedure:
A mixture of 1.0 g of [o-(2-methyl-6-chloro-anilino)-phenyl]-acetic acid, 15 ml of 2-hydroxymethyl-pyridine and 15 ml of anhydrous toluene is treated with 2 drops of concentrated sulphuric acid. The solution is heated to 130°C for 1 hour, during which the resulting water is distilled off azeotropically with the toluene. A further 20 ml of anhydrous toluene are added and again distilled off. The solution is then poured onto 150 g of ice. The mixture is twice extracted with 50 ml of ether at a time. The combined ether extracts are shaken with 15 ml of 2 N-hydrochloric acid at 5°C. The hydrochloric acid solution is separated off and rendered alkaline with 2 N-sodium hydroxide solution at 5°C. The suspension is extracted with 50 ml of ether and the ether solution is separated off, washed with 10 ml of water, dried over magnesium sulphate and evaporated to dryness under 0.1 mm Hg at 40°C. The residue is crystallised from ether-petroleum ether. [o-(2-methyl-6-chloro-anilino)-phenyl]-acetic acid (2-pyridyl)-methyl ester melts at 80°-82°C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4]/[C:5](=N\C(=O)C)/[N:6]([CH:8]([F:10])[F:9])[CH:7]=1.[OH:15]S([O-])(=O)=O.[K+]>CC#N.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:15])[N:6]([CH:8]([F:10])[F:9])[CH:7]=1
Reactant: O=S(=O)([O-])O
Reactant: CC(=O)/N=c1\ccc(Br)cn1C(F)F
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=c1ccc(Br)cn1C(F)F
Yield: 52 %

Procedure:
To a stirred solution of the crude N-[5-Bromo-1-difluoromethyl-1H-pyridin-(2E)-ylidene]-acetamide (1 g) in 10 ml CH3CN was added 1% KHSO4 in water (10 ml). The reaction mixture was heated at reflux for 3 hrs. The reaction mixture was cooled down and the solvent was removed under reduced pressure. Without any workup this crude was purified by column chromatography using 10% ethyl acetate in hexane to get 5-Bromo-1-difluoromethyl-1H-pyridin-2-one (550 mg, 52%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2[CH2:18][CH:17]([CH2:19][NH:20][C:21](=O)[CH3:22])[O:16][N:15]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][S:11][CH2:10][CH2:9]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1.ClCCl>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([C:14]2[CH2:18][CH:17]([CH2:19][NH:20][C:21](=[S:33])[CH3:22])[O:16][N:15]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][S:11][CH2:10][CH2:9]1
Reactant: CC(=O)NCC1CC(c2ccc(N3CCSCC3)c(F)c2)=NO1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=S)NCC1CC(c2ccc(N3CCSCC3)c(F)c2)=NO1
Temperature: 80 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
1.0 g (3.0 mmole) of N-({3-[3-fluoro-4-(4-thiomorpholinyl)phenyl]-4,5-dihydro-5-isoxazolyl}methyl)acetamide is suspended in 12 ml dioxane in a 50 ml one neck round bottom flask under nitrogen. The suspension is treated with Lawesson's Reagent (1.27 g, 3.15 mmole) and the reaction is stirred at 80° C. for 1 hour. The mixture is cooled to room temperature, brought to homogeneity with dichloromethane and is treated with 10 g silica gel (230-400 mesh) and is concentrated to dryness. The plug is loaded onto a SIM and the material is chromatographed twice over 40 g silica gel (BIOTAGE), eluting with 7% acetone/dichloromethane while collecting 25 ml fractions. Fractions 6-13 are combined and concentrated to afford 902 mg (85%) of the title compound as a solid. mp=219-220° C.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.[NH2:16][C@H:17]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C@@H:18]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[C:26]([Cl:31])[CH:25]=1)[CH2:19][CH2:20][C:21]([OH:23])=O.[CH3:39][C:40]([CH3:42])=O.ClC(Cl)C>CN(C=O)C>[Cl:31][C:26]1[CH:25]=[C:24]([C@@H:18]2[C@@H:17]([C:32]3[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=3)[N:16]([CH:40]([CH3:42])[CH3:39])[C:21](=[O:23])[CH2:20][CH2:19]2)[CH:29]=[CH:28][C:27]=1[F:30]
Reactant: N[C@H](c1ccc(Cl)cc1)[C@H](CCC(=O)O)c1ccc(F)c(Cl)c1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Product: CC(C)N1C(=O)CC[C@H](c2ccc(F)c(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium triacetoxyborohydride (1.796 g, 8.48 mmol) was added to a solution of (4R,5S)-5-amino-4-(3-chloro-4-fluorophenyl)-5-(4-chlorophenyl)pentanoic acid hydrochloride (2.56 g, 6.52 mmol; Example 390, Step B) and acetone (0.491 mL, 6.68 mmol) in anhydrous DMF (6.52 mL) at rt. The reaction mixture was stirred at rt for 16 hours. Dichloroethane (25 mL) was added followed by 3 Å molecular sieves. The reaction mixture was heated to 70° C. for 22 hours, filtered and concentrated in vacuo. Purification by flash chromatography on silica gel using a 220 g column and eluting with 30 to 100% EtOAc/hexanes provided the desired product as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:5]([O:7][CH3:8])=[O:6].[Cu][C:17]#[N:18].C(OCC)(=O)C>CN1CCCC1=O>[C:17]([C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:5]([O:7][CH3:8])=[O:6])#[N:18]
Reactant: COC(=O)c1ccc(OC(C)C)c(Br)c1
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(OC(C)C)c(C#N)c1

Procedure:
Methyl 3-bromo-4-iso-propoxybenzoate (2.0 g, 7.3 mmol) and copper(I)cyanide in N-methyl pyrrolidone (50 ml) was heated under vigorous reflux for 4 h. Work-up with ethyl acetate gave the title compound (1.0 g).
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH:8]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][C:10]([OH:12])=[O:11])=[CH:3][CH:2]=1.[CH3:27][C:28](O)([CH3:30])[CH3:29].CCN=C=NCCCN(C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:1]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:2]=[CH:3][C:4]([CH2:7][CH:8]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15])[CH2:9][C:10]([O:12][C:28]([CH3:30])([CH3:29])[CH3:27])=[O:11])=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NC(CC(=O)O)Cc1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC(Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 62 h
Yield: 38 %

Procedure:
A solution of 4-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)butanoic acid (250 mg, 0.703 mmol), tBuOH (0.135 ml, 1.407 mmol), EDCI (270 mg, 1.407 mmol) and 4-dimethylaminopyridine (86.0 mg, 0.704 mmol) in DCM (7 ml) is allowed to stir at room temperature under nitrogen for 62 hours. The reaction is quenched with water, and the organic layer is separated and concentrated. The residue is purified by flash column chromatography on silica gel to give tert-butyl 4-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)butanoate (110 mg); HPLC retention time=1.77 minutes (condition B); MS (ES+)=412.1 (m+1) 300.0 (m-tBux2+3; 100%); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.41 (s, 9 H) 1.47 (s, 9 H) 2.36 (A of ABX, Jab=15.5 Hz, Jax=6.2 Hz, 1 H) 2.44 (B of ABX, Jab=15.5 Hz, Jbx=5.6 Hz) 2.82-2.94 (m, 2 H) 4.11-4.17 (m, 1 H) 5.08-5.10 (m, 1 H) 7.25-7.34 (m, 3H) 7.41-7.44 (m, 2 H) 7.51-7.58 (m, 4 H).
Reaction SMILES: O.Cl.[NH2:3][C@H:4]([C:7]([OH:9])=[O:8])[CH2:5][SH:6].CCO.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O.CCO>O>[C:14]1([C@@H:13]2[NH:3][CH:4]([C:7]([OH:9])=[O:8])[CH2:5][S:6]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: N[C@@H](CS)C(=O)O
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C(O)C1CS[C@H](c2ccccc2)N1
Reaction time: 2.5 h
Yield: 102.5 %

Procedure:
To the suspension of L-cysteine hydrochloride monohydrate (99.24 g, 565.1 mmol) in H2O (535 mL) were added EtOH (420 mL) and benzaldehyde (83.1 mL, 818 mmol) under stirring. After a few minutes, the mixture became a thick cream, which could not be stirred. Enough H2O/EtOH (3:2) solution was added to assist in stiffing the mixture. After 2.5 hrs, the mixture was filtered and the solid was washed with H2O and hexane successively. Upon drying under high vacuum, white powder (121.19 g) was obtained, which was used in the next step without further purification.