Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:17])[C:3]1[C:12]2[N:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]([C:13]([O:15]C)=[O:14])=[CH:5][CH:4]=1.[OH-].[Na+].O>C(O)C>[F:17][CH:2]([F:1])[C:3]1[C:12]2[N:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]([C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(C(F)F)c2ncccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(C(F)F)c2ncccc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 112 %

Procedure:
0.5 g (2.0 mmol) of methyl 8-difluoromethyl-5-quinolinecarboxylate was dissolved in 5 ml of ethanol, 0.43 g (10.5 mmol) of sodium hydroxide and 1 ml of water were added, and the mixture was stirred at 25° C. for 20 hours. The solvents were subsequently removed, the residue was taken up in water, washed twice with methylene chloride and adjusted to pH 1 using 10 N hydrochloric acid, and the precipitate was filtered off with suction. Drying gave 0.5 g of 8-difluoromethyl-5-quinolinecarboxylic acid (colorless crystals);
Reaction SMILES: [CH:1]1([N:4]2[CH2:10][CH2:9][CH2:8][N:7]([C:11]([C:13]3[N:18]=[C:17]([C:19]#[N:20])[C:16]([O:21][C:22]4[CH:27]=[CH:26][C:25]([S:28][CH3:29])=[CH:24][CH:23]=4)=[CH:15][CH:14]=3)=[O:12])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.N.[OH:31]O>CO.C(Cl)Cl>[CH:1]1([N:4]2[CH2:10][CH2:9][CH2:8][N:7]([C:11]([C:13]3[N:18]=[C:17]([C:19]([NH2:20])=[O:31])[C:16]([O:21][C:22]4[CH:23]=[CH:24][C:25]([S:28][CH3:29])=[CH:26][CH:27]=4)=[CH:15][CH:14]=3)=[O:12])[CH2:6][CH2:5]2)[CH2:2][CH2:3]1
Reactant: OO
Reactant: CSc1ccc(Oc2ccc(C(=O)N3CCCN(C4CC4)CC3)nc2C#N)cc1
Agent: N
Solvent: CO
Solvent: ClCCl
Product: CSc1ccc(Oc2ccc(C(=O)N3CCCN(C4CC4)CC3)nc2C(N)=O)cc1
Reaction time: 1.5 h
Yield: 26 %

Procedure:
A mixture of 6-(4-cyclopropyl-[1,4]diazepane-1-carbonyl)-3-(4-methylsulfanyl-phenoxy)-pyridine-2-carbonitrile (171.0 mg), 28% aq. NH3 (5 mL), and 30% aq. H2O2 (1.0 mL) in MeOH (4.0 mL) was stirred for 1.5 h. The mixture was diluted with DCM and washed with satd. aq. Na2S2O3. The organic layer was dried and concentrated. The residue was purified by reverse-phase HPLC followed by FCC to give the title compound (46.4 mg, 26%). MS (ESI): mass calcd. for C22H26N4O3S, 426.17; m/z found, 427.8 [M+H]+. 1H NMR (d6-acetone): 7.74-7.72 (dd, J=8.5, 2.5 Hz, 1H), 7.55 (br s, 1H), 7.51-7.49 (dd, J=8.5, 1.5 Hz, 1H), 7.33 (d, J=8.5 Hz, 2H), 7.03 (d, J=8.5 Hz, 2H), 6.82 (br s, 1H), 3.71-3.68 (m, 2H), 3.65-3.61 (m, 2H), 2.93-2.88 (m, 2H), 2.85-2.80 (m, 2H), 2.49 (s, 3H), 1.96-1.80 (m, 3H), 0.46-0.44 (m, 1H), 0.42-0.40 (m, 1H), 0.37-0.36 (m, 1H), 0.32-0.30 (m, 1H).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(O)C>CS(C)=O>[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[CH:25]1[CH2:30][CH2:29][N:28]([CH2:3][C@H:2]([OH:1])[CH2:4][O:5][C:6]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:7]=2[CH:8]=[CH:9][NH:10]3)[CH2:27][CH2:26]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: Clc1ccc2[nH]cc(C3CCNCC3)c2c1
Solvent: CS(C)=O
Solvent: CCO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2c[nH]c3ccc(Cl)cc23)CC1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 1 using (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 5-chloro-3-(piperidin-4-yl)-1H-indole using ethanol as the reaction solvent. Yield 0.380 g (42%) as a yellowish foam. mp 109°-114° C. (dec) FDMS m/e=423 (M+ of free base). α[D]589 =+6.5 (c=1.04, dimethylsulfoxide).
Reaction SMILES: [CH2:1]([C:8]1[C:9]([CH3:24])=[N:10][C:11]2[C:16]([C:17]=1[CH3:18])=[CH:15][C:14]([C:19](OCC)=[O:20])=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][NH:26][O:27][CH3:28].Cl.C([Mg]Cl)(C)C>C1COCC1>[CH2:1]([C:8]1[C:9]([CH3:24])=[N:10][C:11]2[C:16]([C:17]=1[CH3:18])=[CH:15][C:14]([C:19]([N:26]([O:27][CH3:28])[CH3:25])=[O:20])=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNOC
Reactant: CCOC(=O)c1ccc2nc(C)c(Cc3ccccc3)c(C)c2c1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)c1ccc2nc(C)c(Cc3ccccc3)c(C)c2c1
Temperature: 0 °C

Procedure:
A slurry of ethyl 3-benzyl-2,4-dimethylquinoline-6-carboxylate (99.5 mg, 0.312 mmol, Intermediate 34: step b) and N,O-dimethylhydroxylamine.HCl (42.2 mg, 0.433 mmol) in THF (1 mL) was stirred at 0° C. under argon while iPrMgCl (2.01 M in THF, 0.43 mL, 0.864 mmol) was added dropwise. The resulting dark solution was stirred at 0° C. overnight while the ice bath expired. It was then quenched with 5 M aqueous NH4Cl (4 mL) and extracted with EtOAc (2×3 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated, and the residue was flash chromatographed with a heptane to 100% EtOAc gradient to yield the title compound as an amber oil.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([NH2:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>ClCCl.O>[CH2:12]([NH:20][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCN
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCNS(=O)(=O)c1ccc(C)cc1
Reaction time: 0.07 h
Yield: 95 %

Procedure:
A solution of toluene-4-sulfonyl chloride (5.0 g, 0.026 mol) in dry dichloromethane (150 ml) was cooled to 0° C. during the dropwise addition of n-octylamine (9.6 ml, 0.058 mol) with stirring over 4 minutes. The reaction mixture was then allowed to stir for 30 minutes before being diluted with dichloromethane (200 ml) and water (200 ml). The organic layer was separated and washed consecutively with 1 M HCl, 0.5 M Na2CO3 and brine before being dried over anhydrous Na2SO4. The solution was filtered and concentrated in vacuo to a crude solid which was purified by flash chromatography (silica gel, 11% ethyl acetate in hexane) to give the title compound as a white solid (7.0 g, 94%). This material was then used immediately in the next step.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[C:4]([N+:15]([O-])=O)[CH:3]=1.[C:18](O)(=[O:20])[CH3:19]>C(OC(=O)C)(=O)C.[Pd]>[C:18]([NH:15][C:4]1[CH:3]=[C:2]([F:1])[C:7]([F:8])=[CH:6][C:5]=1[CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])(=[O:20])[CH3:19]
Reactant: O=C(O)CCCc1cc(F)c(F)cc1[N+](=O)[O-]
Reactant: CC(=O)O
Agent: [Pd]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc(F)c(F)cc1CCCC(=O)O

Procedure:
The compound obtained in (3) above (380 mg) was dissolved in a mixed solvent of 5 ml of acetic acid and 10 ml of acetic anhydride. Upon the addition of 60 mg of 10% palladium-on-carbon, the mixture was catalytically hydrogenated. The catalyst was removed by filtration, the solvent was evaporated, and the residue was subjected to silica gel column chromatography using a chloroform-methanol (10:1) mixed solvent as an eluant to obtain fractions containing the target compound. The fractions were concentrated to produce 90 mg of the title compound.
Reaction SMILES: [C:1]([C:3]1[O:4][CH:5]=[CH:6][CH:7]=1)#[N:2].C[O-].[Na+].[C:11](O)(=[O:13])C>CO>[O:4]1[CH:5]=[CH:6][CH:7]=[C:3]1[C:1](=[NH:2])[O:13][CH3:11]
Reactant: N#Cc1ccco1
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=N)c1ccco1
Temperature: 25 °C
Yield: 1844.3 %

Procedure:
2-Cyanofuran (4.50 g, 48.3 mmol) was dissolved in methanol (25 ml), and sodium methoxide (130 mg, 2.4 mmol) was added under ice-cooling. The mixture was stirred while the temperature is slowly raised up to room temperature for 2 hours. After the reaction was completed, acetic acid (0.16 g, 2.6 mmol) was added to neutralize the reaction solution, and the solution was concentrated under reduced pressure. Diethyl ether (100 ml) was added to the concentrated residue, and insolubles were removed by filtration The filtrate was concentrated under reduced pressure to give the crude product of methyl 2-furancarboximidate (6.0 g) as a pale yellow oil.
Reaction SMILES: [C-:1]#[N:2].[K+].O1CCOCCOCCOCCOCCOCC1.Cl[CH2:23][C:24]1[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=1)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>C(#N)C>[C:1]([CH2:23][C:24]1[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=1)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])#[N:2]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)c1cccc(CCl)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)c1cccc(CC#N)c1
Reaction time: 2 h
Yield: 80.6 %

Procedure:
To a mixed liquid of 1.51 g of potassium cyanide and 70 ml of acetonitrile, 6.12 g of 1,4,7,10,13,16-hexaoxacyclooctadecane was added, followed by stirring for 2 hours. Thereafter, a solution of 5.00 g of tert-butyl 3-(chloromethyl)benzoate in 30 ml of acetonitrile was added thereto, followed by stirring at room temperature for 18 hours. The reaction solution was concentrated, diluted with diethyl ether-hexane (1:1), and then washed with water and a saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was evaporated, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain 3.86 g of tert-butyl 3-(cyanomethyl)benzoate as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:28]([CH2:33][CH:34]3[CH2:36][CH2:35]3)[S:29]([CH3:32])(=[O:31])=[O:30])[CH2:18][CH2:17]2)=[O:15])[CH2:10][C:11](O)=[O:12])=[CH:4][CH:3]=1.[N:37]1([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C@H:9]([C:14]([N:16]2[CH2:17][CH2:18][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:28]([CH2:33][CH:34]3[CH2:36][CH2:35]3)[S:29]([CH3:32])(=[O:31])=[O:30])[CH2:20][CH2:21]2)=[O:15])[CH2:10][C:11]([N:40]2[CH2:41][CH2:42][N:37]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:38][CH2:39]2)=[O:12])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CS(=O)(=O)N(CC1CC1)c1ccccc1N1CCN(C(=O)[C@H](CC(=O)O)Cc2ccc(Cl)cc2)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)C[C@H](Cc2ccc(Cl)cc2)C(=O)N2CCN(c3ccccc3N(CC3CC3)S(C)(=O)=O)CC2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 44 %

Procedure:
To a solution of (3S)-3-[(4-chlorophenyl)methyl]-4-(4-{2-[(cyclopropylmethyl)(methylsulfonyl)amino]phenyl}-piperazinyl)-4-oxobutanoic acid (Step 6) (0.63 g, 0.97 mmol), tert-butyl piperazinecarboxylate (0.272 g, 1.46 mmol), HOBt (0.131 g, 0.97 mmol) and TEA (0.135 mL, 0.97 mmol) in 10 mL of CH2Cl2 at 0° C. was added EDC (0.28 g, 1.46 mmol). The reaction was warmed to RT and stirred for 12 h. The reaction was quenched with satd. NaHCO3, and extracted with 50 mL of EtOAc. The organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude compound was further purified by silica gel column chromatography (EtOAc) to afford tert-butyl 4-[(3S)-3-[(4-chlorophenyl)methyl]-4-(4-{2-[(cyclopropylmethyl)(methylsulfonyl)amino]-phenyl}piperazinyl)-4-oxobutanoyl]piperazinecarboxylate as a white foam (0.3 g). MS (ESI, pos. ion) m/z: 702.5 (M+1). Calc'd for C35H48ClN5O6S: 701.30. Anal. Calc'd for C35H48ClN5O6S.0.5H2O: C, 59.10; H, 6.94; N. 9.85; Cl, 4.98. Found: C, 59.32; H, 6.94; N, 9.81; Cl, 5.17.
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][CH:42]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34](O)=[O:35])=[O:30])[CH:11]=1)=[O:9].C[N:46]([CH2:90][CH2:91][N:92]1[CH2:97][CH2:96][O:95][CH2:94][CH2:93]1)[C:47](=O)[C:48]1[CH:88]=[CH:87][CH:86]=[C:50](C(NC2C=CC(N3CCCCC3)=CC=2C2C=C(C(=O)NCC3C=CC=C(C(F)(F)F)C=3)C=CN=2)=O)[CH:49]=1.C(NCCN1CCOCC1)C1C=CC=CC=1>>[CH2:47]([N:46]([CH2:90][CH2:91][N:92]1[CH2:93][CH2:94][O:95][CH2:96][CH2:97]1)[C:34](=[O:35])[C:33]1[CH:37]=[CH:38][CH:39]=[C:31]([C:29]([NH:28][C:17]2[CH:18]=[CH:19][C:20]([N:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)=[CH:21][C:16]=2[C:12]2[CH:11]=[C:10]([C:8](=[O:9])[NH:7][CH2:6][C:5]3[CH:40]=[CH:41][CH:42]=[C:3]([C:2]([F:43])([F:44])[F:1])[CH:4]=3)[CH:15]=[CH:14][N:13]=2)=[O:30])[CH:32]=1)[C:48]1[CH:88]=[CH:87][CH:86]=[CH:50][CH:49]=1
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: O=C(O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: c1ccc(CNCCN2CCOCC2)cc1
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(C(=O)N(CCN3CCOCC3)Cc3ccccc3)c2)c1

Procedure:
This compound was prepared from 3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)benzoic acid 4.1e using the procedure described for the preparation of N1-methyl-N1-(2-morpholinoethyl)-N3-(4-(piperidin-1-yl)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)isophthalamide 4.8. N-benzyl-2-morpholinoethanamine was used as the amine component in this coupling. MS (ES, m/z): 805 [M+H]+
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH2:13])(=[O:12])=[O:11])=[N:7][C:6]=2[CH:14]=1.C(N(CC)CC)C.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](Cl)=[O:31])=[CH:25][CH:24]=1.Cl>CN(C)C1C=CN=CC=1.CN(C)C=O>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([O:1][C:2]2[CH:3]=[CH:4][C:5]3[S:9][C:8]([S:10](=[O:12])(=[O:11])[NH2:13])=[N:7][C:6]=3[CH:14]=2)=[O:31])=[CH:25][CH:24]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: NS(=O)(=O)c1nc2cc(O)ccc2s1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1nc2cc(OC(=O)Cc3ccc(Cl)cc3)ccc2s1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 5-hydroxy-2-benzothiazolesulfonamide 1.15 g., 0.005 mole) triethylamine (0.7 ml, 0.005 mole) and 4-dimethylaminopyridine (5 mg, catalyst) in dimethylformamide (10 ml) is added 2-(4-chlorophenyl)acetyl chloride (0.8 ml). The reaction mixture is stirred for 2 hours, poured into ice water, acidified with hydrochloric acid and extracted with ether. The organic extract is washed with water and dried over magnesium sulfate. The ether is distilled at reduced pressure and the residue chromatographed on silica gel as eluant (130 g, 70-230 mesh) using ethylacetatehexane (1:1) to give 2-sulfamoyl-5-benzothiazolyl 2-(4-chlorophenyl)acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:20][C:19](=O)[C:11]3[C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][O:14][C:10]=3[CH2:9]2)=[CH:4][CH:3]=1.[C:22]([NH:25][NH2:26])([NH2:24])=[NH:23].[ClH:27].Cl>C(O)C>[ClH:27].[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:20]/[C:19](=[N:26]\[NH:25][C:22]([NH2:24])=[NH:23])/[C:11]3[C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][O:14][C:10]=3[CH2:9]2)=[CH:4][CH:3]=1
Reactant: N=C(N)NN
Reactant: O=C1CC(c2ccc(F)cc2)Cc2occ(C(F)(F)F)c21
Agent: Cl
Solvent: CCO
Product: N=C(N)N/N=C1\CC(c2ccc(F)cc2)Cc2occ(C(F)(F)F)c21
Temperature: 90 °C
Reaction time: 4 h
Yield: 61.1 %

Procedure:
To a mixture of 6-(4-fluorophenyl)-3-trifluoromethyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.25 g) and aminoguanidine hydrochloride (93 mg) were ethanol (20 ml) and 6N hydrochloric acid (0.072 ml), and the mixture was stirred at 90° C. for 4 hours and cooled. The reaction solution was concentrated under reduced pressure, and the residue was washed with ethanol, ethyl acetate and isopropylether, and dried to give (E)-6-(4-fluorophenyl)-4-guanidinoimino-3-trifluoromethyl-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 51) (0.20 g).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([CH2:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:12][C@H:11]([CH2:32][P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])[C:10]1=[N:41][OH:42])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:49][C:50](OC(C)=O)=[O:51]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:50]([O:42][N:41]=[C:10]1[C@@H:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([CH2:23][O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[O:12][C@@H:11]1[CH2:32][P:33](=[O:40])([O:34][CH2:35][CH3:36])[O:37][CH2:38][CH3:39])(=[O:51])[CH3:49]
Reactant: CCOP(=O)(C[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)C1=NO)OCC
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOP(=O)(C[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)C1=NOC(C)=O)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
To a solution of diethyl (((2S,4R,5S,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-3-(hydroxyimino)tetrahydro-2H-pyran-2-yl)methyl)phosphonate (2.0 g, 3.35 mmol, 1.0 equiv) in dry DCM (40 mL) was added catalytic DMAP, pyridine (2.1 mL, 26.8 mmol, 8.0 equiv) and Ac2O (1.26 mL, 13.4 mmol, 4.0 equiv) slowly. The mixture was stirred at room temperature for 16 hours and then the concentrated in vacuo. The product thus obtained was then purified by silica gel chromatography, eluting with MeOH:acetone:chloroform:petroleum ether (0.5:0.5:1:8), to give diethyl (((2 S,4R,5 S,6R)-3-(acetoxyimino)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)methyl)phosphonate as a colorless oil (1.5 g, 70%). 1H NMR (400 MHz, CDCl3) δ 7.32 (dddd, J=21.0, 10.3, 8.1, 6.0 Hz, 13H), 7.20 (ddq, J=8.2, 5.4, 3.0 Hz, 2H), 5.48-5.38 (m, 1H), 4.90 (d, J=11.6 Hz, 1H), 4.72 (d, J=11.5 Hz, 1H), 4.62-4.44 (m, 5H), 4.18-4.02 (m, 4H), 3.95-3.83 (m, 2H), 3.63 (qd, J=10.1, 4.8 Hz, 2H), 2.61-2.46 (m, 1H), 2.26-2.15 (m, 4H), 1.32 (td, J=7.1, 1.9 Hz, 6H). MS ESI (M+1) 639.8; calc for C34H42NO9P 639.3.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][CH2:7][S:8]([O-:11])(=O)=[O:9])[C:2]#[CH:3].[Na+].S(Cl)([Cl:15])=O>ClCCl>[CH2:1]([O:4][CH2:5][CH2:6][CH2:7][S:8]([Cl:15])(=[O:11])=[O:9])[C:2]#[CH:3]
Reactant: C#CCOCCCS(=O)(=O)[O-]
Reactant: O=S(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Product: C#CCOCCCS(=O)(=O)Cl
Yield: 95.6 %

Procedure:
Referring to FIG. 16, a slurry of sodium 3-(propargyloxy)propyl sulfonate (5.0 g, 25.0 mmol, 1.0 equiv.) and thionyl chloride (25 mL, 344 mmol, 13.8 equiv.) was heated to 100° C. under N2 for three hours. The mixture was concentrated to a thick oil, diluted with 50 mL benzene, and concentrated again by rotavap to obtain a waxy solid. The material was slurried in 50 mL dichloromethane and filtered. The solids were discarded and the mother liquor concentrated on rotavap to obtain product as an orange oil (4.7 g, 95%). 1H NMR (300 MHz. CDCl3) δ 4.17 (d, 2H), 3.82 (t, 2H), 3.70 (t, 2H). 2.47 (t, 1H), 2.34 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:17]12[CH2:22][CH:21]1[CH2:20][N:19]([CH2:23][C:24]1[S:25][CH:26]=[C:27](Br)[N:28]=1)[CH2:18]2.C(O)C>C1(C)C=CC=CC=1>[CH:17]12[CH2:22][CH:21]1[CH2:20][N:19]([CH2:23][C:24]1[S:25][CH:26]=[C:27]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:28]=1)[CH2:18]2
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Brc1csc(CN2CC3CC3C2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Clc1ccc(-c2csc(CN3CC4CC4C3)n2)cc1
Temperature: 97.5 °C
Yield: 79.8 %

Procedure:
(4-chlorophenyl) boronic acid (0.34 g, 2.17 mmol) and potassium carbonate (0.63 g, 4.53 mmol) were added to a solution of 2-(3-azabicyclo[3.1.0]hexan-3-ylmethyl)-4-bromothiazole (Step-1 of compound 102, 0.47 g, 1.81 mmol) in a mixture of toluene:ethanol (5:15 ml) in a tube at 25° C. Nitrogen gas was bubbled through the reaction mixture for 15 minutes. Tetrakis(triphenylphosphine)(0)palladium (0.10 g, 0.09 mmol) was then added to the reaction mixture under nitrogen atmosphere and the tube was sealed. The reaction mixture was heated at 95-100° C. for 18 hr under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25° C. and filtered through celite. The celite cake was washed with ethanol (20 ml). The combined filtrate was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography using 5% ethyl acetate in hexanes as an eluent to obtain the title compound (0.42 g, 79.0%). MS: m/z 291 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11])[CH:6]=[O:7].[C:14]([Si:18]([CH3:21])([CH3:20])Cl)([CH3:17])([CH3:16])[CH3:15].N1C=CN=C1>CN(C)C=O>[Si:18]([O:11][C:10]1[C:9]([O:12][CH3:13])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:2][CH3:1])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1cc(C=O)cc(OC)c1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1cc(C=O)cc(OC)c1O[Si](C)(C)C(C)(C)C

Procedure:
Using the conditions described in Example 14c 2.05 g of 3,5-dimethoxy-4-hydroxybenzaldehyde were reacted with 2.05 g of tertbutyldimethylchlorosilane in the presence of 0.91 g of imidazole and 15 ml of absolute dimethylformamide. The crude product was purified by chromatography on silica gel [Kieselgel 60 (0.063-0.200 mm)] with petroleum ether/ether (1:1) whereupon 2.91 g of the title compound were obtained in the form of crystals melting at 68° C.
Reaction SMILES: [H-].[K+].[C:3]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[CH:11][C:10]=1[C:19]1[NH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][C:24]([O:28][CH3:29])=[C:23]([O:30][CH3:31])[CH:22]=2)(=[O:5])[CH3:4].[CH3:32]OS(OC)(=O)=O.O>CS(C)=O>[C:3]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[CH:11][C:10]=1[C:19]1[N:20]([CH3:32])[C:21]2[C:26]([CH:27]=1)=[CH:25][C:24]([O:28][CH3:29])=[C:23]([O:30][CH3:31])[CH:22]=2)(=[O:5])[CH3:4]
Reactant: COc1cc(CCNC(C)=O)c(-c2cc3cc(OC)c(OC)cc3[nH]2)cc1OC
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(CCNC(C)=O)c(-c2cc3cc(OC)c(OC)cc3n2C)cc1OC
Reaction time: 0.17 h
Yield: 84.6 %

Procedure:
In dimethyl sulfoxide was slowly suspended 480 mg of 35% potassium hydride, and 1.37 g of 2-[2-(2-acetamidoethyl)-4,5-dimethoxyphenyl]-5,6-dimethoxyindole was added to the suspension, followed by stirring for 10 minutes. To the mixture was further added 700 mg of dimethylsulfate, followed by stirring for 30 minutes. The reaction mixture was poured into water and extracted with methylene chloride. The extract was washed successively with water and a saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. Recrystallization of the residue from ethanol yielded 1.20 g of the title compound.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([CH3:23])=[C:5]([C:9]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2F)(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])[CH3:2].C(N(CC)CC)C.[CH2:31]([N:33]([CH2:38][CH3:39])[CH2:34][CH2:35][CH2:36][NH2:37])[CH3:32]>C(#N)C>[CH2:31]([N:33]([CH2:38][CH3:39])[CH2:34][CH2:35][CH2:36][NH:37][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[S:13]([NH:12][C:9]1[C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:23])[C:3]([CH2:1][CH3:2])=[CH:11][CH:10]=1)(=[O:15])=[O:14])[CH3:32]
Reactant: CCc1ccc(NS(=O)(=O)c2ccccc2F)c(C(=O)O)c1C
Reactant: CCN(CC)CCCN
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCc1ccc(NS(=O)(=O)c2ccccc2NCCCN(CC)CC)c(C(=O)O)c1C
Yield: 10.8 %

Procedure:
A solution of Example 230C (40 mg, 0.12 mmol), triethylamine (0.1 mL), and N,N-diethyl-1,3-propanediamine (0.1 mL) in acetonitrile (1.0 mL) was heated to 200° C. for 1 hour on a Personal Chemistry microwave instrument. The mixture was then purified by reverse phase HPLC to provide the desired product (5.8 mg, 10.8%). 1H NMR (DMSO-d6) δ 1.07 (t, 3H), 1.12 (t, 6H), 2.19 (s, 3H), 2.53 (q, 2H), 3.05-3.12 (m, 8H), 6.02 (br s, 1H), 6.62-6.66 (m, 2H), 6.84 (d, 1H), 7.03 (d, 1H), 7.40 (t, 1H), 7.52 (d, 1H), 8.98 (br s, 1H), 9.50 (br s, 1H); MS (ESI(+)) m/e 448 (M+H)+.