Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[C:28](=[O:29])[CH:27]=[C:26]([CH2:30][OH:31])[O:25][CH:24]=1)=[CH:13][CH:12]=[C:11]([C:32]([F:35])([F:34])[F:33])[CH:10]=2)=[O:5])[CH3:2].C(N(CC)CC)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[C:28](=[O:29])[CH:27]=[C:26]([CH2:30][O:31][S:44]([CH3:43])(=[O:46])=[O:45])[O:25][CH:24]=1)=[CH:13][CH:12]=[C:11]([C:32]([F:34])([F:33])[F:35])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1OCCCCCOc1coc(CO)cc1=O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1OCCCCCOc1coc(COS(C)(=O)=O)cc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of 4-[5-(6-hydroxymethyl-4-oxo-4H-pyran-3-yloxy)-pentyloxy]-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester 13 (330 mg, 0.67 mmol) in CH2Cl2 (15 mL) was added at 0° C. triethylamine (37 μL, 0.26 mmol), methanesulfonyl chloride (62 μL, 0.80 mmol). The solution was stirred at RT for 1 h. Dichloromethane (50 mL) was added and the solution was washed with water (2×100 mL), dried over MgSO4, filtered and evaporated. The crude product was purified by column chromatography on silica using as eluent CH2Cl2:MeOH=95:15. (5-(5-(6-(Trifluoromethyl)quinolin-4-yloxy)pentyloxy)-4-oxo-4H-pyran-2-yl)methylmethanesulfonate 18 was obtained (246 mg, 65% yield) as a pale yellow oil.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[CH:14]=1)[C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=O.[S-:20][C:21]#[N:22].[K+]>CN(C=O)C.O>[Cl:19][C:15]1[CH:14]=[C:13]([C:3]2[NH:2][C:21](=[S:20])[NH:22][C:4]=2[C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=2)[CH:18]=[CH:17][N:16]=1
Reactant: N#C[S-]
Reactant: NC(C(=O)c1ccc(F)cc1)c1ccnc(Cl)c1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(-c2[nH]c(=S)[nH]c2-c2ccnc(Cl)c2)cc1

Procedure:
With gentle heating, 23a (2.9 g; about 9.6 mmol) was dissolved in absolute DMF (75 ml). Potassium thiocyanate (1.9 g; 19.6 mmol) was introduced into the clear orange-red solution: immediate opalescence and a lighter color. The reaction mixture was stirred under reflux for 1.5 h. The suspension was cooled to room temperature and, with H2O cooling, diluted dropwise with H2O (about 140 ml). The yellow precipitate was filtered off, washed with H2O and dried under reduced pressure over CaCl2.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([CH2:20][CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24])[C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.CO.[IH:33]>C(OCC)(=O)C>[IH:33].[IH:33].[N:11]1([C:15]2[N:19]([CH2:20][CH2:21][CH2:22][C:23]([F:26])([F:24])[F:25])[C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[N:16]=2)[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCCC(F)(F)F)CC1
Agent: I
Solvent: CCOC(C)=O
Solvent: CO
Product: FC(F)(F)CCCn1c(N2CCCNCC2)nc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
Treat a solution of 4-[1-(4,4,4-trifluoro-butyl)-1H-benzoimidazol-2-yl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester (1.80 g, 4.22 mmol) and methanol (15 mL) at 0° C. with 57% hydroiodic acid (3.79 g, 16.9 mmol). Stir at room temperature for 30 minutes, heat to 50° C. for two hours and then stir at room temperature overnight. Thin layer analysis (silica gel, ethyl acetate) indicates the presence of starting material. Add 57% hydroiodic acid (1.12 mL) and heat at 50° C. for two hours. Concentrate in vacuo to remove the methanol, dissolve the residue in methanol (10 mL) and add ether (total of 200 mL) to afford a white tacky precipitate. Decant the supernatant, add ether (200 mL) and stir to afford a cream colored solid. Collect the solid by vacuum filtration under nitrogen and dry in vacuo at 82° C. (0.2 Torr) overnight to afford 2.25 g of 2-[1,4]diazepan-1-yl-1-(4,4,4-trifluoro-butyl)-1H-benzoimidazole dihydroiodide, m.p. 206-208° C. Elemental Analysis: Calculated for C16H21F3N4.2HI: 33.01%C, 3.98%H, 9.62%N; Found 33.15%C, 3.87%H, 9.41%N.
Reaction SMILES: Br[C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[C:8]3[CH:29]=[CH:28][CH:27]=[CH:26][C:9]=3[S:10][C:11]=2[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1.CN([CH:40]=[O:41])C>>[N:32]1([C:40]([C:2]2[CH:3]=[CH:4][C:5]([CH2:6][C:7]3[C:8]4[CH:29]=[CH:28][CH:27]=[CH:26][C:9]=4[S:10][C:11]=3[C:12]3[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][N:21]4[CH2:22][CH2:23][CH2:24][CH2:25]4)=[CH:16][CH:17]=3)=[CH:30][CH:31]=2)=[O:41])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: C1CCNC1
Reactant: CN(C)C=O
Reactant: Brc1ccc(Cc2c(-c3ccc(OCCN4CCCC4)cc3)sc3ccccc23)cc1
Product: O=C(c1ccc(Cc2c(-c3ccc(OCCN4CCCC4)cc3)sc3ccccc23)cc1)N1CCCC1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
3-(4-Bromobenzyl)-2-[4-[2-(1-pyrrolidinyl)ethoxy]-phenyl]benzo[b]thiophene (178 mg, 0.36 mmol) was dissolved in DMF (2.0 mL) and treated with pyrrolidine (0.3 mL). The solution was purged with carbon monoxide for 5 min at 80° C. before the catalyst dichlorobis(triphenylphosphine)pallidium (10 mg) was added. The reaction mixture was allowed to stir under a balloon of carbon monoxide at 80° C. for 4 h, then diluted with brine (30 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were dried with sodium sulfate and concentrated. Chromotography with Et3N:MeOH:EtOAc (5:5:90) afforded the product (16 mg) along with recovered starting material (140 mg). FDMS m/e: found 511 (M+H+); 1H NMR (CDCl3): δ 7.97 (d, 1H), 7.57 (m, 1H), 7.55 (d, 2H), 7.50 (m, 1H), 7.40 (m, 1H), 7.39 (d, 2H), 7.24 (d, 2H), 7.03 (d, 2H), 4.40 (s, 2H), 4.28 (t, 2H), 3.76 (t, 2H), 3.57 (t, 2H), 3.10 (t, 2H), 2.82 (m, 4H), 2.01 (m, 4H), 1.98 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@H:10]2[C@@H:14]([NH:15][C:16](=[O:30])[C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]4=[O:29])=[CH:19][CH:18]=3)[CH2:13][C@H:12]([C:31](O)=[O:32])[CH2:11]2)=[O:8])=[CH:4][CH:3]=1.CCN(CC)CC.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1.CCOC(C)=O>[OH:32][CH2:31][C@@H:12]1[CH2:11][C@@H:10]([NH:9][C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:8])[C@@H:14]([NH:15][C:16](=[O:30])[C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]3=[O:29])=[CH:19][CH:18]=2)[CH2:13]1
Reactant: O=C(N[C@H]1C[C@H](C(=O)O)C[C@H]1NC(=O)c1ccc(Cl)s1)c1ccc(-n2ccccc2=O)cc1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1C[C@H](CO)C[C@H]1NC(=O)c1ccc(Cl)s1)c1ccc(-n2ccccc2=O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The product from Example 94 (0.22 g, 0.45 mmol) was stirred in THF (10 mL) at 0° C., Et3N (0.095 mL, 0.68 mmol, 1.5 eq) was added followed by dropwise addition of ClCOOEt (0.051 mL, 0.54 mmol, 1.2 eq). The mixture was stirred at 0° C. for 1 h. It was filtered and rinsed with THF (10 mL). The THF solution was stirred at 0° C. MeOH (5 mL) was added followed by addition of NaBH4 (0.25 mg, 6.6 mmol). The resulting mixture was stirred at 0° C. for 1 h. LC/MS showed completion of the reaction. EtOAc was added, it was washed with NH4Cl, H2O, and brine. The organic layer was concentrated, and purified by reverse phase HPLC (MeOH/H2O in 0.1% TFA) to give pure title compound. LC-MS (ESI) 472.12, 474.04 (M+H), 488.06 (M+Na), tR=2.54 min (10–90% MeOH in H2O with 0.1% TFA in a 4-min run).
Reaction SMILES: C([Si]([O:8]/[C:9](/[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=1)=[CH:10]\[CH3:11])(C)C)(C)(C)C.CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:40]C)C=C4)N(CC2)C1.CS(N)(=O)=O>C(O)(C)(C)C.O>[Br:18][C:14]1[CH:13]=[C:12]([C:9](=[O:8])[C@H:10]([OH:40])[CH3:11])[CH:17]=[CH:16][CH:15]=1
Reactant: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: C/C=C(\O[Si](C)(C)C(C)(C)C)c1cccc(Br)c1
Agent: CS(N)(=O)=O
Solvent: CC(C)(C)O
Solvent: O
Product: C[C@@H](O)C(=O)c1cccc(Br)c1
Yield: 87.3 %

Procedure:
Compound 10d was synthesized by a procedure similar to that described for (R)-10a using (Z)-tert-butyl(1-(3-bromophenyl)prop-1-enyloxy)dimethylsilane, (9d, 1.15 g, 0.0035 mol), AD-mix-β (4.9 g), and CH3SO2NH2 (334 mg, 3.5 mmol) in tert-butyl alcohol-water (17.5 mL. 17.5 mL). The reaction was quenched with sodium sulfite (3.5 g). After purification by column chromatography on silica gel, 0.700 g (88%) of the desired product was isolated: [α]20D +61.1° (c 1.3, CHCl3); 1H NMR (CDCl3) δ 8.09-8.04 (m, 1H), 7.87-7.81 (m, 1H), 7.78-7.72 (m, 1H), 7.39 (t, 1H, J=8.0 Hz), 5.18-5.05 (m, 1H), 3.66 (d, 1H, J=6.4 Hz), 1.45 (d, 3H, J=7.2 Hz); 13C NMR (CDCl3) δ 201.2, 136.8, 135.2, 131.6, 130.4, 127.1, 123.3, 69.5, 22.1. C9H9BrO2.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]2[N:23]=[CH:22][C:21]3[CH2:20][CH2:19][C:18]4[C:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:25][N:26]([CH3:27])[C:17]=4[C:16]=3[N:15]=2)[CH2:9]1)=O)(C)(C)C.C1(NC2N=CC3C=CC4C(C(N)=O)=NN(C)C=4C=3N=2)CCCCC1>>[CH2:28]([O:30][CH2:31][CH3:32])[CH3:24].[CH3:27][N:26]1[C:17]2[C:16]3[N:15]=[C:14]([NH:13][CH:10]4[CH2:11][CH2:12][NH:8][CH2:9]4)[N:23]=[CH:22][C:21]=3[CH2:20][CH2:19][C:18]=2[C:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:25]1
Reactant: CCOC(=O)c1nn(C)c2c1CCc1cnc(NC3CCN(C(=O)OC(C)(C)C)C3)nc1-2
Agent: Cn1nc(C(N)=O)c2ccc3cnc(NC4CCCCC4)nc3c21
Product: CCOC(=O)c1nn(C)c2c1CCc1cnc(NC3CCNC3)nc1-2
Product: CCOCC
Yield: 829.5 %

Procedure:
A solution of 110 mg (0.27 mmol) of ethyl 8-{[1-(tert-butoxycarbonyl)pyrrolidin-3-yl]amino}-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate in a mixture dichoromethane-trifluoroacetic acid 9/1 was stirred at room temperature for 6 hours. The solvent was then removed in vacuo and the resulting oil taken up with dichloromethane and washed with aqueous NaHCO3. The organic layer was dried over Na2SO4 and evaporated. The residue was triturated with diethylether giving 83 mg (60% yield) of the title compound.
Reaction SMILES: Cl[C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[C:13]1([C:19]2[CH:24]=[CH:23][C:22]([SH:25])=[CH:21][CH:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[N+:10]([C:3]1[CH:4]=[C:5]([C:7](=[O:9])[CH3:8])[S:6][C:2]=1[S:25][C:22]1[CH:21]=[CH:20][C:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:24][CH:23]=1)([O-:12])=[O:11]
Reactant: Sc1ccc(-c2ccccc2)cc1
Reactant: CC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Product: CC(=O)c1cc([N+](=O)[O-])c(Sc2ccc(-c3ccccc3)cc2)s1

Procedure:
Prepared according to the procedure described for example 1 from 1-(5-Chloro-4-nitro-2-thienyl)ethanone (82 mg, 0.4 mmol) and 4-phenylbenzenthiol (74 mg, 0.4 mmol). The title compound was obtained as a solid (30 mg, 21% yield). 1H NMR (400 MHz, CDCl3) δ: 8.09 (1H, s), 7.74 (2H, m) 7.65 (2H, m), 7.52 (2H, m), 7.44 (2H, m), 2.49 (3H, s). MS m/z: 355.9 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:33]=[CH:32][C:12]([O:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]3[CH:24]=[N:25][CH:26]=[C:27]([CH:31]=3)[C:28]([OH:30])=[O:29])=[O:21])[CH2:16][CH2:15]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[C].[Pd].C1COCC1>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]3[CH:24]=[N:25][CH:26]=[C:27]([CH:31]=3)[C:28]([OH:30])=[O:29])=[O:21])[CH2:16][CH2:15]2)=[CH:32][CH:33]=1
Reactant: [H][H]
Reactant: O=C(O)c1cncc(OC(=O)N2CCC(Oc3ccc(OCc4ccccc4)cc3)CC2)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(O)c1cncc(OC(=O)N2CCC(Oc3ccc(O)cc3)CC2)c1
Yield: 34.4 %

Procedure:
10% Palladium-carbon (catalytic amount) was added to a THF (10 ml) solution containing 5-[({4-[4-(benzyloxy)phenoxy]piperidin-1-yl}carbonyl)oxy]nicotinic acid (200 mg), and in a hydrogen gas atmosphere, this was stirred at room temperature under normal pressure for 3 hours. The catalyst was removed by filtration, and the resulting filtrate was concentrated under reduced pressure to obtain 5-[({4-[4-(hydroxy)phenoxy]piperidin-1-yl}carbonyl)oxy]nicotinic acid (55 mg).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:9]=[C:10]([C@H:15]([CH2:27][CH2:28][OH:29])[CH2:16][N:17]([CH3:26])[C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:11]=[CH:12][C:13]=1[Cl:14].C(N(CC)CC)C>ClCCl.CS(C)=O>[Cl:7][C:8]1[CH:9]=[C:10]([C@H:15]([CH2:27][CH:28]=[O:29])[CH2:16][N:17]([CH3:26])[C:18](=[O:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: CN(C[C@@H](CCO)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CN(C[C@@H](CC=O)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
To a solution of oxalyl chloride (4.5 ml) in dichloromethane (100 mL) at −78° C., dimethylsulfoxide (7.4 mL) in dichlororomethane (40 mL) was added. After the addition was complete, the solution was stirred for another 30 minutes at −78° C. A solution of (S)—N-[2-(3,4-dichloro-phenyl)-4-hydroxy-butyl]-N-methyl-benzamide (14.6 g) in dichloromethane (35 mL) and dimethylsulfoxide (7 ml) was then added drop wise. The solution was stirred at −78° C. for one hour. Triethylamine (29 mL) was added drop wise to the reaction and after 20 minutes the ice bath was removed and the solution was stirred at ambient temperature for 30 minutes. The reaction mixture was diluted with dichloromethane (200 mL), and washed with dilute aqueous hydrochloric acid (150 mL), water (150 mL), and aqueous sodium bicarbonate (150 mL). The separated organic layer was dried and evaporated then dissolved in ether. The white precipitate that formed, was filtered and dried giving the title compound (9.1 g). Rf=0.41 methylene chloride:methanol (95:5).
Reaction SMILES: C([Li])CCC.Cl[C:7]1[S:8][CH:9]=[CH:10][N:11]=1.[CH2:12]([N:15]=[C:16]=[O:17])[CH2:13][CH3:14].O>CCCCCC.O1CCCC1>[CH2:12]([NH:15][C:16]([C:9]1[S:8][CH:7]=[N:11][CH:10]=1)=[O:17])[CH2:13][CH3:14]
Reactant: Clc1nccs1
Reactant: CCCN=C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCNC(=O)c1cncs1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 68.9 %

Procedure:
Butyl lithium (2.4 M, 50 ml) in hexane was added to a solution of 2-chlorothiazole (12.43 g, 0.104 mol) in tetrahydrofuran (400 ml) at -78° C. under at atmosphere of nitrogen. The resultant solution was stirred for 5 minutes before propyl isocyanate (11.25 ml, 0.12 mol) was added and the reaction mixture was then stirred for a further 10 minutes before being hydrolysed with water (100 ml). The solvent was removed under reduced pressure and the residue extracted with ethyl acetate (2×400 ml). The combined organic extract was then washed with saturated sodium chloride solution, dried over magnesium sulphate and the solvent evaporated. Acetic acid (110 ml) was added to the residue and the solution warmed to about 100° C. whereupon zinc dust (11.8 g) was added and the mixture was refluxed for 1 hour. On cooling, the reaction mixture was made basic with ammonium hydroxide and then extracted into ethyl acetate (4×250 ml). The combined organic extract was washed with saturated sodium chloride solution, dried (MgSO4) and then concentrated. Flash chromatography of the residue on a silica gel column using ethyl acetate as eluant gave N-propylthiazole-5-carboxamide (12.2 g) as a pale yellow solid, m.pt. 86° C.
Reaction SMILES: [CH2:1]([OH:6])[C:2]#[C:3][CH2:4][OH:5].C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1.C(N(CC)CC)C>O1CCCC1>[O:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[O:5][CH2:4][C:3]#[C:2][CH2:1][OH:6]
Reactant: OCC#CCO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: OCC#CCOC1CCCCO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 90 g (1.07 mol) of 2-butyne-1,4-diol and 9 g of p-toluenesulfonic acid in 1000 ml of tetrahydrofuran, cooled to 0° C., there were added dropwise 104.88 ml (96.69 g, 1.15 mol) of dihydropyran, and thereafter the reaction mixture was stirred for 3 hours at room temperature. It was then neutralized with triethylamine and evaporated in vacuo. The residue was purified by silica gel column chromatography (2000 g) using hexane-ethyl acetate (80:20) as eluant, to yield 2-butyne-1,4-diol monotetrahydropyranyl ether and a small amount of the bis-tetrahydropuranyl ether.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)([CH3:4])[CH3:3].[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[S:28][C:27]([S:29](Cl)(=[O:31])=[O:30])=[CH:26][CH:25]=1>>[CH3:4][C:2]([CH3:1])([O:5][C:6]([NH:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][S:29]([C:27]2[S:28][C:24]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=3)=[CH:25][CH:26]=2)(=[O:30])=[O:31])=[CH:14][CH:15]=1)=[O:17])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccn2)s1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(N)cc1
Product: CC(C)(C)OC(=O)NCCc1ccc(NS(=O)(=O)c2ccc(-c3ccccn3)s2)cc1

Procedure:
In a manner analogous to that of Example 5, the title compound was prepared from the Boc amine from Example 4 and 5-(pyridin-2-yl)-2-thiophenesulfonyl chloride: 1H NMR (400 MHz, CD3OD) 8.48 (d, 1, H, J=5.2 Hz), 7.81 (m, 2H), 7.54 (d, 1H, J=4.1 Hz), 7.41 (m, 1H), 7.30 (m, 1H), 7.11 (s, 4H), 3.18 (t, 2H, J=7.1 Hz), 2.67 (t, 2H, J=7.1 Hz), 1.38 (s, 9H). FAB MS m/z 460 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:16][CH3:17])[CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1.[Cl:18][C:19]1[C:20]([Cl:33])=[CH:21][C:22]2[O:27][CH2:26][CH2:25][N:24]([CH2:28][C:29]([OH:31])=O)[C:23]=2[CH:32]=1.CN([P+]([O:44]N1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([N:16]([CH3:17])[C:29](=[O:31])[CH2:28][N:24]2[C:23]3[CH:32]=[C:19]([Cl:18])[C:20]([Cl:33])=[CH:21][C:22]=3[O:27][CH2:26][C:25]2=[O:44])[CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CN1CCOc2cc(Cl)c(Cl)cc21
Reactant: CNC(CN1CCOCC1)c1cccc(Br)c1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C(=O)CN1C(=O)COc2cc(Cl)c(Cl)cc21)C(CN1CCOCC1)c1cccc(Br)c1
Yield: 55.8 %

Procedure:
A mixture of [1-(3-bromophenyl)-2-(4-morpholinyl)ethyl]methylamine (3.06 g, 10.2 mmol) and (6,7-dichloro-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetic acid (2.82 g, 10.2 mmol) was dissolved in a mixture of dichloromethane and DMF (1:1, 100 mL). BOP Reagent (7.16 g, 16.6 mmol) was added followed by triethylamine (4.36 g, 43.2 mmol). The resultant mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (150 mL) and extracted with 5% NaHCO3 (150 mL) and brine (150 mL). The organic layer was dried over MgSO4, and concentrated. The residue was recrystallized in ether, and the crystal was collected by filtration to give the title compound as a white solid (3.17 g, 56%). MS (ESI): 556.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:24][CH2:25][O:26][CH3:27])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[CH2:28][CH2:29][CH3:30])[CH:5]=[CH:4][N:3]=1.O.Cl.O1CCOC[CH2:34]1>CCCCCCC.C[Al](C)C>[F:17][C:16]([F:19])([F:18])[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:34])[CH:7]=2)=[C:10]([CH2:28][CH2:29][CH3:30])[CH:11]=1)([O:24][CH2:25][O:26][CH3:27])[C:20]([F:23])([F:22])[F:21]
Reactant: C1COCCO1
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccnc(Cl)c1
Agent: C[Al](C)C
Agent: Cl
Solvent: CCCCCCC
Solvent: O
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccnc(C)c1
Yield: 94 %

Procedure:
To a solution of 2-chloro-4-(4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylphenoxy) pyridine (867 mg, 559 μmol) in 1,4-dioxane, trimethylaluminum heptane solution (2 mol/L, 1.13 mL) and tetrakis triphenylphosphine palladium complex (218 mg) were added at room temperature under an argon atmosphere, and then the resultant mixture was heated at 80° C. After completion of the reaction, the reaction solution was neutralized by adding water and 2 mol/L of hydrochloric acid, extracted with ethyl acetate, and then concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate) and the title compound (780 mg, yield 94%) was obtained as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:42]=[C:43]([CH:50]=[CH:51][CH:52]=2)[CH2:44][O:45]S(C)(=O)=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:53]1[CH2:57][CH2:56][CH2:55][CH2:54]1.C1C[O:61]CC1>>[CH:44]([OH:45])=[O:61].[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:52]=[CH:51][CH:50]=[C:43]([CH2:44][N:53]3[CH2:57][CH2:56][CH2:55][CH2:54]3)[CH:42]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C1CCNC1
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(COS(C)(=O)=O)c4)c4ccccc43)cn12
Reactant: C1CCOC1
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(CN5CCCC5)c4)c4ccccc43)cn12
Product: O=CO
Temperature: 50 °C
Reaction time: 24 h
Yield: 22 %

Procedure:
To a solution of Intermediate 167b (0.16 mmol) in THF (2 mL) was added pyrrolidine (273 μL, 3.27 mmol) and the reaction stirred at 50° C. for 24 h. The crude reaction mixture was cooled and partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-10% (2M NH3 in MeOH) in DCM, followed by MDAP (Method 7) purification, to give the title compound (26 mg, 22%). LCMS (Method 5): Rt 3.64 min, m/z 702 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.86 (3H, d, J=6.2 Hz), 1.23 (9H, s), 1.42-1.50 (2H, m), 1.58-1.66 (6H, m), 1.70-1.84 (3H, m), 1.84-1.92 (1H, m), 1.95-2.12 (2H, m), 2.36-2.42 (4H, m), 2.86 (1H, ddd, J=12.7, 9.0, 3.9 Hz), 3.12 (1H, dt, J=11.9, 4.1 Hz), 3.58 (2H, s), 4.77 (1H, td, J=8.4, 5.7 Hz), 5.46 (1H, t, J=4.2 Hz), 6.28 (1H, s), 7.01 (1H, d, J=8.6 Hz), 7.15 (1H, dd, J=9.8, 2.1 Hz), 7.20-7.25 (2H, m), 7.26-7.34 (4H, m), 7.35 (1H, s), 7.39 (1H, t, J=7.8 Hz), 7.59 (1H, d, J=10.0 Hz), 7.64 (1H, d, J=1.8 Hz), 8.07 (1H, s), 8.19 (0.7H, s).