Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[O:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.Br[CH2:23][CH2:24][S:25][C:26]1[O:27][C:28]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:29]=2[N:30]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:35][C:32]1[CH:33]=[CH:34][C:28]2[O:27][C:26]([S:25][CH2:24][CH2:23][N:13]3[CH2:12][CH2:11][CH:10]([O:9][CH:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)[CH2:15][CH2:14]3)=[N:30][C:29]=2[CH:31]=1
Reactant: Clc1ccc2oc(SCCBr)nc2c1
Reactant: Clc1ccc(C(OC2CCNCC2)c2ccccn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Clc1ccc(C(OC2CCN(CCSc3nc4cc(Cl)ccc4o3)CC2)c2ccccn2)cc1
Reaction time: 6 h
Yield: 53.9 %

Procedure:
After 2.00 g (6.60 mmol) of 4-[(4-chlorophenyl)-2-pyridylmethoxy]piperidine and 2.39 g (8.17 mmol) of 2-(2-bromoethylthio)-5-chlorobenzoxazole were dissolved in 10 ml of dioxane, 1.10 g (7.96 mmol) of potassium carbonate was added to the mixed solution, and the mixture was stirred at an oil bath temperature of 75° to 80° C. for 6 hours. After the reaction, the insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography with a mixed solution of chloroform and methanol in the volume ratio 50:1 as an eluent. The desired fraction was concentrated to give 1.83 g (54%) of 5-chloro-2-[2-[4-[(4-chlorophenyl)-2-pyridylmethoxy]-1-piperidyl]ethylthio]benzoxazole as an oily product.
Reaction SMILES: ClC1C=C(C(OO)=[O:9])C=CC=1.[CH3:12][S:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1.C(=O)(O)[O-].[Na+].[OH2:29]>C(Cl)Cl>[CH3:12][S:13]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1)(=[O:9])=[O:29]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1cccc([N+](=O)[O-])c1
Reactant: O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)Cc1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-Chlorobenzenecarboperoxoic acid (77%; 26.9 g; 120 mmol) was added to a stirred solution of 1-[(methylsulfanyl)methyl]-3-nitrobenzene (10.0 g) in DCM (1305 mL) at 0° C. The batch was stirred at 0° C. for 30 minutes and then 2.5 hours at room temperature. The batch was diluted with water (300 mL) before sodium bicarbonate (11.0 g) was added. The batch was extracted with DCM (2×). The combined organic phases were filtered using a Whatman filter and concentrated. The residue was purified by chromatography (DCM/ethanol 95:5) and finally recrystallized from ethyl acetate to give the desired product (6.2 g; 28.9 mmol).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([Cl:22])[CH:16]=2)[CH2:9]1)(OC(C)(C)C)=O.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29]O)[CH:24]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>ClCCl>[Cl:22][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[O:21][CH2:29][C:25]1[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=1)[CH2:14][C@H:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: OCc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2ccc(O)c(Cl)c2)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: ClCCl
Product: Clc1cc(C[C@@H]2CNCCO2)ccc1OCc1cccnc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
N-BOC-(R)-2-(3-chloro-4-hydroxybenzyl)morpholine, example 7, intermediate (a) (53 mg, 0.16 mmol), was dissolved in dichloromethane (4 mL) with 3-pyridinyl carbinol (35 mg, 0.32 mmol) shaken at room temperature for 20 mins and diisopropylazodicarboxylate (65 mg, 0.32 mmol) added in one portion. dichloromethane (6 mL) was added to solvate the polymer. The reaction mixture was shaken for 24 hrs then filtered. Polymer supported toluenesulfonyl chloride (0.18 g, 2.82 mmol/g) and MP-carbonate (0.39 g, 2.62 mmol/g) were added to the liquor and the mixture shaken for 6 hrs. The reaction was filtered and evaporated under a high flow of nitrogen. The crude residue was dissolved in TFA (20% v/v solution in dichloromethane, 2.0 mL) and shaken for 3 hrs at room temperature. The reaction mixture was added directly to an SCX-2 column (2 g) and washed with dichloromethane (2 mL×2) and methanol (2 mL×2). The SCX-2 column was then washed with ammonia (2N in methanol, 3×2 mL). Combined ammonia washes were concentrated in vacuo and the residue purified by preparative HPLC to yield the desired morpholine example 44 as a colorless oil (9 mg).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11](O)=[O:12])[CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][OH:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:35][CH2:34][CH2:33][O:32][CH2:31][CH2:30][NH:29][C:11]([C:8]1[CH:9]=[CH:10][C:5]2[N:4]=[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:27])([F:28])[F:26])[CH:21]=[CH:20][C:18]=4[N:19]=3)[N:2]([CH3:1])[C:6]=2[CH:7]=1)=[O:12]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2ccc(C(=O)O)cc21
Reactant: NCCOCCO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2ccc(C(=O)NCCOCCO)cc21
Yield: 51.5 %

Procedure:
3-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-benzoimidazole-5-carboxylic acid [2-(2-hydroxy-ethoxy)-ethyl]-amide (50 mg) was prepared by following General Procedure F starting from 3-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-benzoimidazole-5-carboxylic acid (80 mg), 2-(2-amino-ethoxy)-ethanol (24 mg), HBTU (80 mg), and DIEA (70 uL) in DMF (1 mL). LC/MS: m/z 495.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[CH:16]=[CH2:17]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][CH:16]=[CH2:15])=[CH:4][CH:3]=1
Reactant: C=CCBr
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCOc1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 86.5 %

Procedure:
To a solution of 4-chlorophenol (30 g, 233 mmol) in acetonitrile (100 ml) was added potassium carbonate (48.1 g, 349 mmol, 1.5 eq) and allyl bromide (36.28 g, 299.9 mmol, 1.3 eq) dropwise with stirring for 5 hours at 50° C. in an oil bath. The solids were filtered out and the liquid was concentrated under vacuum to afford 1-chloro-4-(prop-2-en-1-yloxy)benzene as yellow oil (34 g, 86%); 1H NMR (300 MHz, CDCl3): δ 7.20-7.25 (m, 2H), 6.81-6.86 (m, 2H), 5.96-6.09 (m, 1H), 5.27-5.44 (m, 2H), 4.49-4.51 (m, 2H).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([C@@H:11]2[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]3[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:21][CH:20]=3)=[O:17])[CH2:12]2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[CH3:32][C:33]([O:36][C:37]([NH:39][C:40](=[N:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[NH:41][C:42]1[CH:50]=[CH:49][C:45]([C:46](O)=[O:47])=[CH:44][CH:43]=1)=[O:38])([CH3:35])[CH3:34]>>[CH3:58][C:55]([O:54][C:52]([NH:51][C:40](=[N:39][C:37]([O:36][C:33]([CH3:35])([CH3:34])[CH3:32])=[O:38])[NH:41][C:42]1[CH:50]=[CH:49][C:45]([C:46]([N:14]2[CH2:15][C@@H:11]([N:8]3[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH2:7]3)[CH2:12][C@H:13]2[C:16]([NH:18][C:19]2[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])=[CH:21][CH:20]=2)=[O:17])=[O:47])=[CH:44][CH:43]=1)=[O:53])([CH3:56])[CH3:57]
Reactant: CC(C)(C)OC(=O)c1ccc(NC(=O)[C@@H]2C[C@H](N3CCN(S(C)(=O)=O)CC3)CN2)cc1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)Nc1ccc(C(=O)O)cc1
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)Nc1ccc(C(=O)N2C[C@@H](N3CCN(S(C)(=O)=O)CC3)C[C@H]2C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)cc1

Procedure:
Following the procedure described in Example 8, the compound prepared in Example 6 was treated with the compound prepared in Example 10 to give the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1([C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=2)[CH2:5][O:4][CH2:3]1.[H-].[Na+].[CH3:16]I>CN(C=O)C.O>[CH3:16][O:1][C:2]1([C:6]2[CH:7]=[CH:8][C:9]([C:10]#[N:11])=[CH:12][CH:13]=2)[CH2:3][O:4][CH2:5]1
Reactant: CI
Reactant: N#Cc1ccc(C2(O)COC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC1(c2ccc(C#N)cc2)COC1

Procedure:
To a solution of 4-(3-hydroxyoxetan-3-yl)benzonitrile (Step 1 of Intermediate O, 600 mg, 3.43 mmol) in DMF (12.5 mL) was added sodium hydride (60% suspension in mineral oil, 151 mg, 3.77 mmol) at a temperature of ˜5° C. The reaction mixture was allowed to stirr for 1 h at this temperature, before methyl iodide (256 μL, 4.11 mmol) was added. Stirring was continued at rt over night. The mixture was diluted with water and extracted with diethyl ether. The organic extract was dried with anhydrous magnesium sulfate and filtered. After evaporation of the solvent, the crude product was purified by MPLC (silica, cyclohexane/ethyl acetate 20:1→4:1) to afford the title compound in pure form (566 mg, 87%): 1H NMR (500 MHz, DMSO-d6) δ 7.93 (d, 2H), 7.68 (d, 2H), 4.81 (d, 2H), 4.73 (d, 2H), 3.05 (s, 3H); ES-MS m/z 190 (MH)+; HPLC RT (Method E) 1.22 min.
Reaction SMILES: [O:1]1[CH2:6][C@@:2]1([C:7]([F:10])([F:9])[F:8])[C:3]([OH:5])=[O:4].Cl.[Cl-].[Na+]>ClCCl.CO>[F:8][C:7]([F:10])([F:9])[C@:2]([OH:1])([CH3:6])[C:3]([OH:5])=[O:4]
Reactant: O=C(O)[C@]1(C(F)(F)F)CO1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: C[C@](O)(C(=O)O)C(F)(F)F
Temperature: -80 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
Into a 500 ml three-necked round-bottomed flask equipped with a stirrer, a 1.0 M aluminum diisobutyl hydride/hexane solution (2400 ml, 2.40 mol) was charged in a nitrogen atmosphere. This solution was cooled to −80° C. A dichloromethane (600 g) solution of (S)-2,3-epoxy-2-trifluoromethylpropionic acid (149.82 g, 0.96 mol) was added over a period of two hours from a dropping funnel. After stirring at −70° C. for one hour, stirring was carried out at −50° C. for 6 hours. The reaction solution was cooled to −80° C., and a mixed solution of methanol (100 g) and dichloromethane (100 g) was dropwise added over a period of two hours to terminate the reaction. The reaction solution was dropwise added over a period of two hours to 1800 ml of a 18% HCl aqueous solution cooled to 0° C., and then, 160 g of sodium chloride was added. The mixture was extracted twice with 500 ml of diethyl ether, and the solvent was distilled off to obtain (S)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (98.6 g) (yield: 65%). This was recrystallized twice from toluene (400 ml) to obtain (S)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (51.6 g) having an optical purity of 99.9 ee % (yield: 34%). This product shows the same 1H and 13C-NMR and IR spectrum data as the already reported (S)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid and therefore was determined to be (S)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[F:17][C:18]1[C:26]([F:27])=[CH:25][C:21]([C:22](O)=O)=[C:20]([O:28][CH3:29])[CH:19]=1>>[F:17][C:18]1[C:26]([F:27])=[CH:25][C:21]([C:22]2[O:14][C:13]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:15][N:16]=2)=[C:20]([O:28][CH3:29])[CH:19]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Reactant: COc1cc(F)c(F)cc1C(=O)O
Product: COc1cc(F)c(F)cc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 49 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was converted using 4,5-difluoro-2-methoxybenzoic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 0:80:20, 168 mg, 49%) which was obtained as a white solid. MS: m/e=340.2 [M+H]+.
Reaction SMILES: O1[CH2:6][CH2:5][CH2:4][O:3][O:2]1.[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.C(O[BH-](O[C:30](=[O:32])[CH3:31])OC(=O)C)(=O)C.[Na+].O>ClCCl>[C:11]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[CH:9][C:8]([NH:7][CH:18]2[CH2:6][CH2:5][C:4]3([O:3][O:2][CH:31]([C:14]([C:11]4[CH:12]=[CH:13][CH:8]=[CH:9][CH:10]=4)=[CH2:15])[CH2:30][O:32]3)[CH2:16][CH2:17]2)=[CH:13][CH:12]=1
Reactant: Nc1ccc(-c2ccccc2)cc1
Reactant: C1COOOC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C=C(c1ccccc1)C1COC2(CCC(Nc3ccc(-c4ccccc4)cc3)CC2)OO1
Temperature: 25 °C
Yield: 70.5 %

Procedure:
To a mixture of trioxane 3a (0.40 g, 1.45 mmol) and 4-aminobiphenyl (0.30 g, 1.82 mmol) in dichloromethane (20 ml) acetic acid (1 ml) was added and reaction mixture was stirred at room temp for half an hour. Sodium triacetoxyborohydride (0.46 g, 3.63 mmol) was added slowly and it was stirred for 3 h at room temperature. Reaction mixture was then poured into water and extracted with CH2Cl2 (2×20 ml). Combined organic layer was dried over anhyd. Na2SO4, concentrated under vacuum and crude product was chromatographed over silica gel using benzene-hexane (50:50) as eluant to furnish amino functionalized 1,2,4-trioxane 4ad as an inseparable mixture of diastereomers (0.44 g, 70.5% yield), m.p. 118–120° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[C:5](Cl)=[O:6])[CH3:2].[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([NH:18][C:5](=[O:6])[CH:4]([O:8][CH2:9][CH3:10])[O:3][CH2:1][CH3:2])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(OCC)C(=O)Cl
Reactant: NCc1ccccc1
Product: CCOC(OCC)C(=O)NCc1ccccc1

Procedure:
Ethyl diethoxyacetate (Ex. Fluka) (25 g) was added to sodium hydroxide (5.68 g) in ethanol (60 ml) and water (30 ml). After heating under reflux for 5 hours the solvents were removed at reduced pressure and the residue dried in vacuo to give sodium diethoxyacetate (23.2 g). The salt was then converted to diethoxyacetyl chloride and reacted with benzylamine to give N-benzyl diethoxyacetamide which was cyclised with conc. sulphuric acid according to Fukumi and Hideshi, Heterocycles, 9, 1197 (1978) to give 3-hydroxyisoquinoline.
Reaction SMILES: [CH2:1]([S:3]([NH:6][C@@H:7]([CH:11]([CH3:13])[CH3:12])[C:8]([OH:10])=O)(=[O:5])=[O:4])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[OH:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][NH2:39])=[CH:33][C:32]=1[O:40][CH3:41].Cl>O1CCCC1>[OH:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][NH:39][C:8](=[O:10])[C@@H:7]([NH:6][S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH:11]([CH3:13])[CH3:12])=[CH:33][C:32]=1[O:40][CH3:41]
Reactant: COc1cc(CCN)ccc1O
Reactant: CCS(=O)(=O)N[C@H](C(=O)O)C(C)C
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCS(=O)(=O)N[C@H](C(=O)NCCc1ccc(O)c(OC)c1)C(C)C
Temperature: -20 °C

Procedure:
5.1 g of (S)-2-(ethylsulfonylamino)-3-methyl-butyric acid and 5.7 ml of N-methylmorpholine in 200 ml of tetrahydrofuran are cooled, with stirring, to −20° C. 3.15 ml of isobutyl chloroformate are added dropwise thereto. When the addition is complete, the reaction mixture is stirred at −10° C. for 40 minutes. The mixture is again cooled to −20° C. 5.0 g of solid 2-(4-hydroxy-3-methoxy-phenyl)-ethylamine hydrochloride are introduced into the reaction mixture. The reaction mixture is stirred, without cooling, for a further 24 hours, the internal temperature gradually rising to room temperature. The reaction mixture is introduced into 300 ml of 2N hydrochloric acid. Extraction is carried out twice using 500 ml of ethyl acetate each time. The organic phases are washed twice using 100 ml of saturated sodium chloride solution each time, dried over magnesium sulfate and concentrated. The residue is purified by flash chromatography on silica gel with a mixture of ethyl acetate/n-hexane 3: 1, yielding (S)-2-(ethylsulfonylamino)-3methyl-butyric acid N-[2-(4-hydroxy-3-methoxyphenyl)-ethyl]-amide in the form of a colourless oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[CH2:16]([O:23][C:24]1[CH:40]=[CH:39][CH:38]=[CH:37][C:25]=1[CH2:26][S:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][NH:1][C:32](=[O:33])[C:31]2[CH:30]=[CH:29][C:28]([S:27][CH2:26][C:25]3[CH:37]=[CH:38][CH:39]=[CH:40][C:24]=3[O:23][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:36][CH:35]=2)[CH:4]=1
Reactant: O=C(Cl)c1ccc(SCc2ccccc2OCc2ccccc2)cc1
Reactant: NCc1cccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCc1cccnc1)c1ccc(SCc2ccccc2OCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a stirred mixture of 3-aminomethylpyridine (324 mg) and triethylamine (1.51 g) in dichloromethane (20 ml) at 0° C. was added 4-[2-benzyloxybenzylthio]benzoylchloride in CH2Cl2 (10 ml) (3 mmol). The mixture was allowed to warm to ambient temperature, washed with saturated aqueous NaHCO3 (3×20 ml), dried (MgSO4), filtered and evaporated. The residue was triturated with diethyl ether (20 ml) and crystallised from ethyl acetate to give N-(3-pyridylmethyl)-4-[2-benzyloxybenzylthio]benzamide (220 mg).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[C:8]([Cl:15])=[C:7]([Cl:16])[CH:6]=1)=[O:4].[N:17]1[CH2:22][CH2:21][CH2:20][NH:19][C:18]=1[SH:23]>>[ClH:1].[Cl:16][C:7]1[CH:6]=[C:5]([C:3]2([OH:4])[N:19]3[CH2:20][CH2:21][CH2:22][N:17]=[C:18]3[S:23][CH2:2]2)[CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[C:8]=1[Cl:15]
Reactant: SC1=NCCCN1
Reactant: NS(=O)(=O)c1cc(C(=O)CCl)cc(Cl)c1Cl
Product: Cl
Product: NS(=O)(=O)c1cc(C2(O)CSC3=NCCCN32)cc(Cl)c1Cl

Procedure:
was obtained in a manner analogous to the method described in Example 1 d from 2,3',4'-trichloro-5'-sulfamoyl-acetophenone and 2,35 g of 3,4,5,6-tetrahydro-2-pyrimidine-thiol. M.p. 188° C (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[C:54]([NH:57][C:58]1[S:59][C:60]([S:64](Cl)(=[O:66])=[O:65])=[C:61]([CH3:63])[N:62]=1)(=[O:56])[CH3:55]>>[CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:64]([C:60]1[S:59][C:58]([NH:57][C:54](=[O:56])[CH3:55])=[N:62][C:61]=1[CH3:63])(=[O:65])=[O:66])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(NC(C)=O)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester (510 mg) was reacted with 2-acetylamino-4-methyl-thiazole-5-sulfonyl chloride to yield (S)-2-({(3S,8S)-7-(2-acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (526 mg) according to General Procedure E. The title compound (32 mg) was prepared by the hydrolysis of (S)-2-({(3S,8S)-7-(2-acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (LCMS m/z=968) (40 mg) according to General Procedure B. LCMS (m/z): 952.
Reaction SMILES: [C:1]1([C:7]2[C:9](=[O:10])[C:8]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:24]=1[C:25]#[N:26])#[N:18]>ClC1C=CC=CC=1>[OH:10][C:9]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:8]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:21]2[C:22]=1[CH:23]=[C:24]([C:25]#[N:26])[C:19]([C:17]#[N:18])=[CH:20]2
Reactant: N#Cc1ccncc1C#N
Reactant: O=c1c(-c2ccccc2)c1-c1ccccc1
Solvent: Clc1ccccc1
Product: N#Cc1cc2c(O)c(-c3ccccc3)c(-c3ccccc3)n2cc1C#N
Temperature: 130 °C
Reaction time: 2 h

Procedure:
Diphenylcyclopropenone (0.319 g, 1.55 mmol) and 3,4-dicyanopyridine (0.200 g, 1.55 mmol) were mixed in a dry, argon filled reaction flask. Chlorobenzene (2.5 mL) (oxygen free) was added, and the reaction was heated to 130° C. After 2 h the heating was stopped and the reaction was allowed to reach room temperature. Petroleum ether 40°-60° C. (2.5 mL) was added in order to obtain a complete precipitate of the product. The solvent was filtered off and the precipitate was washed with petroleum ether. The crude product was stirred with chloroform (30 mL) for 1 h. The dark chloroform solution was filtered off leaving the title product as a yellow precipitate.
Reaction SMILES: [O:1]=[O+][O-].[F:4][C:5]1[C:14]([CH:15]=C)=[N:13][CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[F:4][C:5]1[C:14]([CH:15]=[O:1])=[N:13][CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: C=Cc1nccc(C(=O)OC)c1F
Reactant: O=[O+][O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccnc(C=O)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ozone was bubbled through a solution of methyl 3-fluoro-2-vinylisonicotinate (1.4 g, 7.73 mmol, from Step 2) in methylene chloride (100 mL) at −78° C. until the blue color of excess ozone persisted. Nitrogen was bubbled through the solution for 1 minute to purge excess ozone and then triphenylphosphine (3.9 g, 15 mmol) was added and the solution was warmed to room temperature and stirred overnight. The compound was dry loaded onto silica gel. Flash chromatography eluting with 40% ethyl acetate in hexanes afforded product (0.8 g, 57%) as an off-white crystalline solid. 1H NMR (300 MHz, CDCl3): δ 10.27 (s, 1H), 8.73 (d, 1H), 8.01 (dd, 1H), 4.01 (s, 3H).
Reaction SMILES: I(C1C=CC=CC=1C(O)=O)(=O)=[O:2].[C:13]12(O)[CH2:21][CH:17]([C:18]1([CH3:20])[CH3:19])[CH2:16][CH2:15][C:14]2([OH:23])[CH3:22].C([O-])([O-])=O.[Na+].[Na+]>CS(C)=O.C1COCC1>[OH:23][C:14]1([CH3:22])[C:15](=[O:2])[CH2:16][CH:17]2[CH2:21][CH:13]1[C:18]2([CH3:20])[CH3:19]
Reactant: O=C(O)c1ccccc1I(=O)=O
Reactant: CC1(O)CCC2CC1(O)C2(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC1(O)C(=O)CC2CC1C2(C)C
Yield: 86 %

Procedure:
o-Iodoxybenzoic acid I (420 mg; 1.5 mmol) was added under stirring in one portion to a solution of pinanediol (170 mg; 1 mmol) in DMSO (3.4 ml) and THF (2.9 ml) at 0° C. After 3 h the reaction was poured in 20 ml of a solution of Na2CO3 (10%) and extracted with diethyl ether (3×10 ml). The combined organic layers were dried over sodium sulfate. The organic solvent was distilled under vacuum. The residue was purified by chromatography (SiO2, dichloromethane) to give after trituration with n-hexane, 145 mg (86%) of 2-hydroxy-pinanone, mp 30°-32° C.