Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]([O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][OH:17])=[CH:14][CH:13]=1)[CH:9]=[CH2:10].[C:20](O)(=[O:24])[C:21]([CH3:23])=[CH2:22]>COC1C=CC(O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[C:20]([O:17][CH2:16][C:15]1[CH:18]=[CH:19][C:12]([O:11][CH2:8][CH:9]=[CH2:10])=[CH:13][CH:14]=1)(=[O:24])[C:21]([CH3:23])=[CH2:22]
Reactant: C=C(C)C(=O)O
Reactant: C=CCOc1ccc(CO)cc1
Agent: COc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C=CCOc1ccc(COC(=O)C(=C)C)cc1
Yield: 80.4 %

Procedure:
To a 250 ml reaction flask fitted with a Dean-Stark water trap, condenser and magnetic stirrer was added toluene (100 ml), 4allyloxybenzyl alcohol (30.0 g; 0.18 moles), methacrylic acid (15.7 g; 0.18 moles), 4-methoxyphenol (0.6 g) and p-toluene sulfonic acid (0.23 g). The stirred solution was heated under reflux until all of the water was removed (2 hours). The solution was cooled and washed with an equal volume of sodium bicarbonate solution and then with sodium chloride solution. The organic layer was dried over magnesium sulfate and the solvent removed by distillation under reduced pressure to yield 4-allyloxybenzyl methacrylate (33.6 g; 81% yield) as an orange colored viscous liquid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH:9]1([CH2:12][OH:13])[CH2:11][CH2:10]1>>[CH:9]1([CH2:12][O:13][C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)[CH2:11][CH2:10]1
Reactant: OCC1CC1
Reactant: Brc1ccc(Br)nc1
Product: Brc1ccc(OCC2CC2)nc1

Procedure:
Prepared from 2,5-dibromopyridine and cyclopropylmethanol by the method of Example 10 (b).
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([C:12]2[C:17]([CH3:18])=[CH:16][N:15]=[C:14]([NH:19][C:20](=[O:22])[CH3:21])[CH:13]=2)[O:5][C:6]=1[C:7]1[N:11]=[CH:10][NH:9][N:8]=1.CCN(C(C)C)C(C)C.[CH3:32][Si:33]([CH2:36][CH2:37][O:38][CH2:39]Cl)([CH3:35])[CH3:34]>CN(C=O)C>[I:1][C:2]1[N:3]=[C:4]([C:12]2[C:17]([CH3:18])=[CH:16][N:15]=[C:14]([NH:19][C:20](=[O:22])[CH3:21])[CH:13]=2)[O:5][C:6]=1[C:7]1[N:11]=[CH:10][N:9]([CH2:39][O:38][CH2:37][CH2:36][Si:33]([CH3:35])([CH3:34])[CH3:32])[N:8]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC(=O)Nc1cc(-c2nc(I)c(-c3nc[nH]n3)o2)c(C)cn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1cc(-c2nc(I)c(-c3ncn(COCC[Si](C)(C)C)n3)o2)c(C)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.3 %

Procedure:
To a solution of N-{4-[4-iodo-5-(1H-1,2,4-triazol-3-yl)-1,3-oxazol-2-yl]-5-methylpyridin-2-yl}acetamide (6.2 g, 15 mmol) in DMF (60 mL) was added DIEA (4.0 mL, 23.0 mmol). The reaction mixture was allowed to stir at rt for 2 h and then SEM-Cl (4.1 mL, 23.0 mmol) was added. The reaction mixture was allowed to stir at rt overnight and then concentrated. The residue was purified by column chromatography to give N-{4-[4-iodo-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-1,3-oxazol-2-yl]-5-methylpyridin-2-yl}acetamide (2.7 g) plus another SEM regioisomer (1.2 g).
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5]C=CC=1.[OH2:8]>>[CH3:5][CH2:6][CH2:1][CH2:7][O:8][C@H:6]([CH2:5][OH:8])[CH2:1][CH3:7]
Reactant: Cc1ccccc1
Reactant: O
Product: CCCCO[C@@H](CC)CO
Reaction time: 1.5 h

Procedure:
200 ml of an acidic ion-exchange resin (Bio-Rad 50W-X2) was added to the mixture and it was stirred for 1.5 hours. 200 ml of toluene was added to the mixture and water was removed by azeotropic distillation. The product was filtered to remove the resin, and the solvent was removed under reduced pressure. The resulting diol (482 g) had a hydroxyl number of 67 mg KOH/g.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C@@H:4]([CH:5]=[C:6]([CH3:8])[CH3:7])[C@@H:3]1[C:9](O)=[O:10].S(Cl)([Cl:15])=O>CCCCCC>[CH3:1][C:2]1([CH3:12])[C@@H:4]([CH:5]=[C:6]([CH3:8])[CH3:7])[C@@H:3]1[C:9]([Cl:15])=[O:10]
Reactant: CC(C)=C[C@H]1[C@H](C(=O)O)C1(C)C
Reactant: O=S(Cl)Cl
Solvent: CCCCCC
Product: CC(C)=C[C@H]1[C@H](C(=O)Cl)C1(C)C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
In a 300 ml flask, there were charged (-)-trans-2,2-dimethyl-3-isobutenylcyclopropane-1-carboxylic acid (50.0 g) and n-hexane (50 g), and thionyl chloride (41.0 g) was added thereto from a dropping funnel over a period of 30 minutes with stirring under reflux. After completion of the addition, stirring was continued for an additional 2.5 hours, and then the solvent and excess of the thionyl chloride were removed by distillation. The residue was distilled to obtain (-)-trans-2,2-dimethyl-3-isobutenylcyclopropane-1-carboxylic acid chloride (54.0 g) having a boiling point of 50° C./0.5 mmHg to 56° C./0.6 mmHg.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](C)[CH:10]=2)[NH:5][C:4](=O)[N:3]=1.F[C:15](F)(F)C1C=C(C=CC=1)N>C(O)C>[CH3:15][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][N:3]=[C:2]2[Cl:1]
Reactant: Cc1ccc2[nH]c(=O)nc(Cl)c2c1
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: CCO
Product: Cc1cccc2c(Cl)ncnc12

Procedure:
0.45 g of 4-chloro 6-methyl quinazolone and 0.405 g, of m-trifluoromethylaniline in 20 ml ethanol were refluxed 1 hour. Treatment with aqueous Na2CO3 and extraction with CH2Cl2 gave 0.2 g of P15 as a white solid, mp-215° C., as the free base. NMR CDCl3 δ 8.78 (1H,S), 8.06 (2H,m), 7.86(1H,d,J=7.6 Hz), 7.65 (2H,m), 7.54(1H,t,J=8.0 Hz), 7.42 (1H,m), 2.58 (3H,S).
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[C:12]([O:13][CH:14]([F:16])[F:15])=[CH:11][CH:10]=[CH:9][C:8]=2/[CH:17]=[CH:18]/[C:19]2[N:20]=[C:21]3[N:25]([C:26]=2[C:27](O)=[O:28])[CH:24]=[CH:23][S:22]3)[CH2:4][CH2:3][CH2:2]1.[CH:30]1([C:33]2[N:34]=[C:35]([NH2:38])[S:36][CH:37]=2)[CH2:32][CH2:31]1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C1COCC1.CN(C=O)C>[CH:1]1([CH2:5][O:6][C:7]2[C:12]([O:13][CH:14]([F:16])[F:15])=[CH:11][CH:10]=[CH:9][C:8]=2/[CH:17]=[CH:18]/[C:19]2[N:20]=[C:21]3[N:25]([C:26]=2[C:27]([NH:38][C:35]2[S:36][CH:37]=[C:33]([CH:30]4[CH2:32][CH2:31]4)[N:34]=2)=[O:28])[CH:24]=[CH:23][S:22]3)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(O)c1c(/C=C/c2cccc(OC(F)F)c2OCC2CCC2)nc2sccn12
Reactant: Nc1nc(C2CC2)cs1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Nc1nc(C2CC2)cs1)c1c(/C=C/c2cccc(OC(F)F)c2OCC2CCC2)nc2sccn12

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 10 (200 mg, 0.476 mmol) with 4-cyclopropyl-1,3-thiazol-2-amine (73 mg, 0.523 mmol) in the presence of EDCI hydrochloride (182 mg, 0.952 mmol) and DMAP (53 mg, 0.476 mmol) in a mixture of THF and DMF (1:1, 4 mL) to give 120 mg of the product as an off-white solid; 1H NMR (300 MHz, CDCl3) δ 0.80-0.86 (m, 2H), 0.88-0.96 (m, 2H), 1.23-1.29 (m, 1H), 1.85-1.94 (m, 4H), 2.00-2.10 (m, 2H), 2.72-2.80 (m, 1H), 3.98 (d, J=6.6 Hz, 2H), 6.36 (s, 1H), 6.58 (t, J=75.3 Hz, 1H), 6.95 (d, J=4.5 Hz, 1H), 7.00-7.10 (m, 2H), 7.48-7.53 (m, 1H), 7.62 (d, J=15.6 Hz, 1H), 7.82 (d, J=15.6 Hz, 1H), 8.24-8.30 (m, 1H); APCI-MS (m/z) 543.31 (MH)+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([CH2:16][CH3:17])[N:13]=[C:12]([NH2:18])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[C:20]1[S:21][C:22]([C:25]#[N:26])=[CH:23][N:24]=1.[H-].[Na+].O>C1COCC1>[Si:1]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([CH2:16][CH3:17])[N:13]=[C:12]([NH:18][C:20]2[S:21][C:22]([C:25]#[N:26])=[CH:23][N:24]=2)[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCc1cc(CO[Si](C)(C)C(C)(C)C)cc(N)n1
Reactant: N#Cc1cnc(Cl)s1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCc1cc(CO[Si](C)(C)C(C)(C)C)cc(Nc2ncc(C#N)s2)n1
Temperature: 75 °C
Reaction time: 8.5 h

Procedure:
4-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-6-ethylpyridin-2-amine 12-1 (0.159 g, 0.60 mmol) was dissolved in 2 mL THF. 2-Chloro-1,3-thiazole-5-carbonitrile (0.103 g, 0.72 mmol) and sodium hydride (60% dispersion in mineral oil) (0.057 g, 2.38 mmol) were added and the solution was heated to 75° C. After 4 hours more 2-chloro-1,3-thiazole-5-carbonitrile (0.043 g, 0.30 mmol) and sodium hydride (0.014 g, 0.60 mmol) were added. After 5.5 hours more 2-chloro-1,3-thiazole-5-carbonitrile (0.086 g, 0.60 mmol) and sodium hydride (0.029 g, 1.19 mmol) were added. After 8.5 hours the solution was allowed to cool to room temperature. H2O was added and the reaction was concentrated in vacuo (to remove THF). 1N HCl was added to adjust to neutral pH. The resulting precipitate was filtered and washed with water to afford the desired compound 12-2 as a yellow solid. 1H NMR (DMSO-d6) δ 12.23 (s, 1H), 8.25 (s, 1H), 6.70 (s, 1H), 6.83 (s, 1H), 4.73 (bs, 2H), 2.79 (q, 2H, J=7.63 Hz), 1.32 (t, 3H, J=7.63 Hz), 0.94 (s, 9H), 0.10 (s, 6H).
Reaction SMILES: [CH2:1]([C:3]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12])[CH3:2].Cl[CH2:15][CH2:16][O:17]C1CCCCO1>>[CH2:1]([C:3]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:15][CH2:16][OH:17])[C:4]1=[O:12])[CH3:2]
Reactant: CCC1(C)C(=O)Nc2ccccc21
Reactant: ClCCOC1CCCCO1
Product: CCC1(C)C(=O)N(CCO)c2ccccc21

Procedure:
Prepared from 3-ethyl-3-methyl-1,3-dihydro-2H-indol-2-one (prepared by the method of Endler and Becker; Organic Syntheses Coll. vol. 4 page 657) and 2-(2-chloroethoxy) tetrahydro-2H-pyran.
Reaction SMILES: [CH:1]1([C:8](Cl)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:11]([O:13][C:14]#[CH:15])[CH3:12].C(N(CC)CC)C>C(OCC)C>[CH2:11]([O:13][CH:14]1[C:1]2([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8](=[O:9])[CH2:15]1)[CH3:12]
Reactant: C#COCC
Reactant: O=C(Cl)C1CCCCCC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC1CC(=O)C12CCCCCC2
Temperature: 25 °C
Reaction time: 120 h
Yield: 87.1 %

Procedure:
A solution of cycloheptyl carbonyl chloride (10.0 g, 0.062 mol) and ethoxyacetylene (40% w/w solution in hexanes, 6.0 g, 0.083 mol, 12 ml) in diethylether (50 ml) was treated dropwise with triethylamine (20 ml, 0.14 mol) and the reaction stirred for 5 d at room temperature. Filtration and concentration of the filtrate in vacuo followed by chromatography (SiO2, 5:1 EtOAc:hexanes) gave the title compound as a pale yellow oil (10.5 g, 0.054 mol, 87%). δH (CDCl3, 300K) 4.78 (1H, s), 4.20 (2H, q J 7.1 Hz), 1.94-1.87 (2H, m), 1.83-1.77 (2H, m), 1.71-1.66 (2H, m), 1.63-1.52 (6H, m), 1.45 (3H, t J 7.1 Hz); m/z (ES+, 70V) 194.9 (MH+).
Reaction SMILES: [OH:1][CH:2]([C:10]1[CH:19]=[CH:18][C:13]2[C:14](=[O:17])[O:15][CH2:16][C:12]=2[C:11]=1[CH3:20])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[F:21][C:22]1[CH:29]=[C:28]([CH:30]2[CH2:32][O:31]2)[CH:27]=[CH:26][C:23]=1[C:24]#[N:25]>>[F:21][C:22]1[CH:29]=[C:28]([CH:30]([OH:31])[CH2:32][N:7]2[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[C:10]3[CH:19]=[CH:18][C:13]4[C:14](=[O:17])[O:15][CH2:16][C:12]=4[C:11]=3[CH3:20])[CH2:5][CH2:6]2)[CH:27]=[CH:26][C:23]=1[C:24]#[N:25]
Reactant: N#Cc1ccc(C2CO2)cc1F
Reactant: Cc1c(C(O)CN2CCNCC2)ccc2c1COC2=O
Product: Cc1c(C(O)CN2CCN(CC(O)c3ccc(C#N)c(F)c3)CC2)ccc2c1COC2=O

Procedure:
2-fluoro-4-(1-hydroxy-2-{4-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile was prepared in a similar fashion to that described for the synthesis of EXAMPLES 2C and 28-29 starting from 5-(1-hydroxy-2-piperazin-1-ylethyl)-4-methyl-2-benzofuran-1(3H)-one and 2-fluoro-4-oxiran-2-ylbenzonitrile. 1H NMR (500 MHz, DMSO-d6), δ 7.98 (m, 1H), 7.74 (m, 1H), 7.71 (m, 1H), 7.60 (d, J=10.5 Hz, 1H), 7.52 (d, J=7.9 Hz, 1H), 5.56 (d, J=7.7 Hz, 1H), 5.42 (dd, J=8.3 Hz, 2H), 5.38 (bs, 1H), 3.95-3.42 (m, 6H), 3.40-3.18 (m, 6H), 2.36 (s, 3H); LC/MS (M+1)+=440.02.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15](N1C=CN=C1)(N1C=CN=C1)=[S:16]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]=[C:15]=[S:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(N=C=S)CC1
Temperature: -15 °C
Reaction time: 14 h
Yield: 94.1 %

Procedure:
4-Aminopiperidine-1-carboxylic acid tert-butyl ester (5.0 g, 25 mmol) (Astatech, Inc) was dissolved in dimethylformamide (120 mL) and cooled to −15° C. Thiocarbonyidiimidazole (4.8 g, 27 mmol) (Aldrich) in dimethylformamide (100 mL) was added slowly at below −10° C. The mixture was stirred at room temperature for 14 h. All solvent was removed under vacuum and the residue was dissolved in methylene chloride (200 mL) and washed 2× water. The solvent was removed and the residue was triturated with hexane. This was filtered and the solution treated with Norite and filtered through celite. Removal of solvent gave 4-isothiocyanatopiperidine-1-carboxylic acid tert-butyl ester (5.7 g, 94% yield) as oil. LR-MS-EI(+): Compatible with 242 MW.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C@@H:11]1([NH2:18])[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]1[NH2:17]>>[NH2:1][C:2]1[CH:9]=[C:8]([NH:17][C@@H:12]2[CH2:13][CH2:14][CH2:15][CH2:16][C@@H:11]2[NH2:18])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N[C@@H]1CCCC[C@@H]1N
Reactant: N#Cc1ccc(F)cc1N
Product: N#Cc1ccc(N[C@@H]2CCCC[C@@H]2N)cc1N
Temperature: 120 °C
Reaction time: 48 h

Procedure:
A mixture of 2-amino-4-fluorobenzonitrile (5.0 g, 37 mmol) and cis-cyclohexane-1,2-diamine (12.6 g, 111 mmol) was heated to 120° C. After 48 hours, the reaction mixture was cooled to ambient temperature and purified directly via silica gel chromatography (1-5% methanol/dichloromethane, linear gradient) to afford rel-2-amino-4-{[(1R,2S)-2-aminocyclohexyl]amino}benzonitrile. MS ESI calc'd. for C13H19N4 [M+H]+ 231. Found 231. 1H NMR (400 MHz, CDCl3) δ 7.13 (d, J=8.8 Hz, 1H), 6.01 (d, J=9.6 Hz, 1H), 5.85 (s, 1H), 4.68 (d, J=9.6 Hz, 1H), 4.22 (br s, 2H), 3.39-3.34 (m, 1H), 3.14-3.11 (m, 1H), 1.70-1.35 (m, 10H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.[CH3:11][Sn:12](Cl)([CH3:14])[CH3:13].[Cl-].[NH4+]>CCOCC.CCCCCC>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][C:7]([Sn:12]([CH3:14])([CH3:13])[CH3:11])=[CH:8][C:4]=2[CH:3]=1
Reactant: C[Sn](C)(C)Cl
Reactant: Cc1ccc2sccc2c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Product: Cc1ccc2sc([Sn](C)(C)C)cc2c1
Reaction time: 0.5 h

Procedure:
A solution of 7.411 g of 5-methylbenzo[b]thiophene (Maybridge, Chemical Co. Ltd., 11-78) in 35 ml of ether is added dropwise at 0° to a mixture of 40 ml of 1.5N butylithium in hexane and 40 ml of ether. After 30 minutes, a solution of 9.963 g of trimethyltin chloride in 50 ml of ether is also added dropwise at 0°. After stirring for 1 hour at 0°, 50 ml of 5% ammonium chloride solution are added. The product is obtained by extracting with 100 ml and 150 ml of ether. Distillation at 0.15 mbar and 100-106° yields 5-methyl-2-trimethylstannylbenzo[b]thiophene.
Reaction SMILES: [F:1][C:2]([F:46])([F:45])[C:3]([C:41]([F:44])([F:43])[F:42])=[CH:4][C:5]([NH:7][C@:8]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[C:32]([O:37][CH:38]([CH3:40])[CH3:39])[CH:31]=1)([C:16]1[CH:21]=[C:20]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:19]=[C:18]([F:29])[CH:17]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6].C1(C2C=C[N+]([O-:59])=CC=2)C=CC=CC=1.[O-]Cl.[Na+]>C(#N)C>[F:36][C:33]1[CH:34]=[CH:35][C:30]([C@@:8]([NH:7][C:5]([CH:4]2[C:3]([C:41]([F:43])([F:44])[F:42])([C:2]([F:1])([F:45])[F:46])[O:59]2)=[O:6])([C:16]2[CH:21]=[C:20]([O:22][C:23]([F:27])([F:28])[CH:24]([F:26])[F:25])[CH:19]=[C:18]([F:29])[CH:17]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:31][C:32]=1[O:37][CH:38]([CH3:40])[CH3:39]
Reactant: CC(C)Oc1cc([C@@](Cc2ccccc2)(NC(=O)C=C(C(F)(F)F)C(F)(F)F)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Reactant: [O-][n+]1ccc(-c2ccccc2)cc1
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC#N
Product: CC(C)Oc1cc([C@@](Cc2ccccc2)(NC(=O)C2OC2(C(F)(F)F)C(F)(F)F)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 74 %

Procedure:
At 0° C. to a solution of (R)-4,4,4-trifluoro-N-(1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)but-2-enamide (Example 291, 130 mg, 0.19 mmol) and 4-phenyl pyridine N-oxide (26 mg, 0.15 mmol) in acetonitrile (5 mL) was added NaOCl solution (206 μL, chlorine wt % 10−3%, 0.58 mmol). The reaction mixture was stirred at 0° C. for 10 min, then at rt for 1 h. The solvents were removed under reduced pressure and the residue was diluted with EtOAc (30 mL), washed with saturated Na2SO3 (30 mL), dried over MgSO4, filtered and concentrated. The resulting residue was right away purified by ISCO chromatography (40 g column, flow rate 25 mL/min) using hexanes/EtOAc (0-10% over 30 min) to give N—((R)-1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3,3-bis(trifluoromethyl)oxirane-2-carboxamide as a diastereomer mixture at a retention time of 26 min (97 mg, 74% yield). The diastereomer mixture was separated by Chiral preparative HPLC chiralpak AD 20μ column, 5×50 cm, eluting with 5% IPA/Heptane with flow rate 50 mL/min.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[N:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:16](=O)[NH:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:28]>>[Cl:28][C:16]1[N:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[C:13]2=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]2[N:17]=1
Reactant: O=c1[nH]c2ccc(OCc3ccccc3)nc2n1-c1ccccc1Cl
Reactant: O=P(Cl)(Cl)Cl
Product: Oc1ccc2nc(Cl)n(-c3ccccc3Cl)c2n1
Reaction time: 0.25 h
Yield: 0.7 %

Procedure:
5-(Benzyloxy)-3-(2-chlorophenyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (905 mg, 2.58 mmol) and POCl3 (1965 μl, 21.08 mmol) was heated in microwave at 100° C. for 1 h. The mixture was concentrated. The residue was dissolved in EtOAc and saturated NaHCO3. The organics were separated, washed with brine, dried over MgSO4, filtered, and concentrated. The residue was dissolved in DCM (2.5 mL) and H2SO4 (6 drops) was added. The mixture was stirred vigorously for 15 minutes. DCM was removed by gentle heating. The residue was dissolved in MeOH and purified by preparative HPLC to give the title compound (5.0 mg). LCMS m/z=280.2, [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 6.63 (d, J=8.6 Hz, 1H), 7.63 (dd, J1=7.6, J2=1.6 Hz, 1H), 7.66 (td, J1=7.6, J2=1.8 Hz, 1H), 7.79 (m, 2H), 7.98 (d, J=8.6 Hz, 1H), 11.10 (broad s, 1H).
Reaction SMILES: [CH:1]1([C:5]2[C:6]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:20][C:21]1([CH2:27][C:28]([NH2:30])=[O:29])[CH2:24][S:23](=[O:26])(=[O:25])[CH2:22]1>>[NH2:30][C:28](=[O:29])[CH2:27][C:21]1([NH:20][C:11]([C:8]2[CH:7]=[C:6]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:5]([CH:1]3[CH2:2][CH2:3][CH2:4]3)=[CH:10][N:9]=2)=[O:13])[CH2:22][S:23](=[O:25])(=[O:26])[CH2:24]1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CCC2)cn1
Reactant: NC(=O)CC1(N)CS(=O)(=O)C1
Product: NC(=O)CC1(NC(=O)c2cc(OCC(F)(F)F)c(C3CCC3)cn2)CS(=O)(=O)C1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclobutyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (example 108f) and 2-(3-amino-1,1-dioxo-thietan-3-yl)acetamide (example 160d) as starting materials and isolated (16.5 mg, 21%); MS (ESI, m/z): 436.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:22]([NH2:24])=[O:23])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][OH:20])=[CH:14][CH:13]=3)[C:6]=2[CH:21]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27].O>ClCCl>[CH3:25][S:26]([O:20][CH2:19][CH2:18][C:15]1[CH:14]=[CH:13][C:12]([N:7]2[C:6]3[CH:21]=[C:2]([Cl:1])[C:3]([C:22]([NH2:24])=[O:23])=[CH:4][C:5]=3[N:9]=[C:8]2[CH2:10][CH3:11])=[CH:17][CH:16]=1)(=[O:28])=[O:27]
Reactant: CCc1nc2cc(C(N)=O)c(Cl)cc2n1-c1ccc(CCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CCc1nc2cc(C(N)=O)c(Cl)cc2n1-c1ccc(CCOS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 49.7 %

Procedure:
A mixture of 6-chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-carboxamide (Example 111, step 4, 500 mg, 1.45 mmol), triethylamnine (293 mg, 2.90 mmol) and methansulfonyl chloride (322 mg, 2.9 mmol) in dichloromethane (20 ml) was stirred at room temperature for 6 h. The reaction mixture was poured into water, and extracted with dichloromethane (50 ml). The organic layer was washed with brine (50 ml), then dried (Na2SO4). After removal of solvent, the crude product was purified by TLC with hexane/ethyl acetate (1:1) to afford 304 mg (50%) of the title compound as white solids.
Reaction SMILES: [CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[O:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C([O-])(O)=O.[Na+].O.[Br:24]Br>ClCCl>[Br:24][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[O:10][CH:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:17]2
Reactant: CCCCCCCCC1Cc2ccccc2O1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCC1Cc2cc(Br)ccc2O1
Temperature: 0 °C
Yield: 96.3 %

Procedure:
In a 50 ml-three-necked flask, 2.00 g (8.61 mM) of 2-octylcoumaran and 3.2 ml of dichloremethane were placed and mixed to obtain a solution. To the solution, 0.73 (8.69 mM) of NaHCO3 and 3.2 ml of water were added. To the mixture, a solution of 0.44 ml (0.54 mM) of bromine in 1 ml of dichloromethane were added dropwise in 17 minutes under stirring on an ice bath, followed by stirring for 3 hours and 25 minutes at room temperature. After the reaction, the reaction mixture was poured into ice water and subjected to extraction with dichloromethane, followed by two times washing with a common salt aqueous solution and drying with mirabilite. The resultant mixture was concentrated under reduced pressure to obtain 2.58 g of 5-bromo-2-octylcoumaran (Yield: 96.3%).
Reaction SMILES: Cl[CH2:2][S:3][C:4]1[S:8][C:7]([CH3:9])=[N:6][N:5]=1.[I-:10].[Na+]>CC(C)=O.O>[I:10][CH2:2][S:3][C:4]1[S:8][C:7]([CH3:9])=[N:6][N:5]=1
Reactant: Cc1nnc(SCCl)s1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1nnc(SCI)s1
Temperature: 55 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
To a solution of 5-chloromethylthio-2-methyl-1,3,4-thiadiazole (730 mg: 4 mMol.) in acetone (6 ml) is added sodium iodide (1.2 g: 2.0 equivalents: 8 mMol.), and the mixture is stirred at 55° C. for 2 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is washed with water, dried over sodium sulfate and concentrated to give 5-iodomethylthio-2-methyl-1,3,4-thiadiazole (1.05 g) as yellow oil.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:36]1[N:37]=[C:38]([NH:41][C:42]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[S:39][CH:40]=1)\[C:5]([NH:7][CH:8]1[C:34](=[O:35])[N:10]2[C:11]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:12](CI)[CH2:13][S:14](=[O:15])[C@H:9]12)=[O:6].Br.[OH:62][C:63]1[CH:64]=[C:65]2[C:69](=[CH:70][CH:71]=1)[CH2:68][NH:67][CH2:66]2.C(N(CC)CC)C>CN(C)C=O>[CH3:1][O:2]/[N:3]=[C:4](/[C:36]1[N:37]=[C:38]([NH:41][C:42]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[S:39][CH:40]=1)\[C:5]([NH:7][CH:8]1[C:34](=[O:35])[N:10]2[C:11]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:19])=[C:12]([N:67]3[CH2:66][C:65]4[C:69](=[CH:70][CH:71]=[C:63]([OH:62])[CH:64]=4)[CH2:68]3)[CH2:13][S:14](=[O:15])[C@H:9]12)=[O:6]
Reactant: Oc1ccc2c(c1)CNC2
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS(=O)[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Br
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(N3Cc4ccc(O)cc4C3)CS(=O)[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
2.4 g (2.53 mmol) of the powder obtained in Example 1 (B) was dissolved in 20 ml of N,N-dimethylformamide, and 0.77 g (3.56 mmol) of 5-hydroxyisoindoline hydrobromide and 0.6 ml (4.3 mmol) of triethylamine were added thereto. The mixture was stirred at room temperature for 1 hour. The dimethylformamide was distilled off under reduced pressure. The residue was subjected to silica gel flush column chromatography (ethyl acetate/n-hexane =3/1 to 1/0) to obtain 2.1 g (yield: 87%) of the above-identified compound.