Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2O[C:20](=O)[S:19][N:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([O:27][CH2:28][CH3:29])(=[O:26])[C:24]#[CH:25]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[CH:25]=[C:24]([C:23]([O:27][CH2:28][CH3:29])=[O:26])[S:19][N:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[C:24]([C:23]([O:27][CH2:28][CH3:29])=[O:26])=[CH:20][S:19][N:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCCC(c2nsc(=O)o2)C1
Reactant: C#CC(=O)OCC
Product: CCOC(=O)c1cc(C2CCCN(C(=O)OCc3ccccc3)C2)ns1
Product: CCOC(=O)c1csnc1C1CCCN(C(=O)OCc2ccccc2)C1

Procedure:
A solution of the crude residue from example 131 and ethyl propiolate (2 mL) in xylenes (15 mL) was heated in a sealed tube at 150° C. for 4 hr. Concentration and chromatographic purification (25% ethyl acetate and hexanes) afforded 3-(5-ethoxycarbonyl-isothiazol-3-yl )-piperidine-1-carboxylic acid benzyl ester and 3-(4-ethoxycarbonyl-isothiazol-3-yl )-piperidine-1-carboxylic acid benzyl ester as a 1:1 mixture (1.24 g), MH+( LCMS) 375.1(m/z).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:20][CH:21]([C:23]2[O:24][C:25]([CH2:28][N:29]([CH3:31])[CH3:30])=[CH:26][CH:27]=2)[NH2:22])=[CH:11][C:12]([Cl:19])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[O:39]([CH2:46][C:47](Cl)=[O:48])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>O1CCCC1>[CH2:1]([O:8][C:9]1[C:10]([CH2:20][CH:21]([NH:22][C:47](=[O:48])[CH2:46][O:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:23]2[O:24][C:25]([CH2:28][N:29]([CH3:30])[CH3:31])=[CH:26][CH:27]=2)=[CH:11][C:12]([Cl:19])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)COc1ccccc1
Reactant: CN(C)Cc1ccc(C(N)Cc2cc(Cl)c3cccnc3c2OCc2ccccc2)o1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)Cc1ccc(C(Cc2cc(Cl)c3cccnc3c2OCc2ccccc2)NC(=O)COc2ccccc2)o1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 26.2 %

Procedure:
To a stirring solution of 2-[8-(benzyloxy)-5-chloroquinolin-7-yl]-1-{5-[(dimethylamino)methyl]-2-furyl}ethanamine (0.431 mmol) and triethylamine (0.474 mmol, 1.1 eq.) in tetrahydrofuran (4 mL) at 0° C. was added phenoxyacetyl chloride (0.474 mmol, 1.1 eq.) and the resulting solution was stirred 5 min at 0° C. then warmed to room temperature and stirred 15 min. The reaction was quenched with saturated aqueous sodium bicarbonate solution (15 mL) and the resulting aqueous solution was extracted with ethyl acetate (3×10 mL). The combined organic layers were dried (MgSO4), filtered and concentrated to a white foam that was purified by column chromatography using 10% methanol/dichloromethane to give the final product as a clear oil (0.113 mmol, 26%). MS (ESI) m/z 570.3; HRMS: calcd for C33H32ClN3O4+H+, 570.21541; found (ESI, [M+H]+ Obs'd), 570.2155.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9](=[O:11])[CH3:10].[OH:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.[OH-].[Na+].Cl>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9](=[O:11])[CH:10]=[CH:17][C:16]1[CH:19]=[CH:20][C:13]([OH:12])=[CH:14][CH:15]=1
Reactant: CC(=O)c1c(O)cccc1O
Reactant: O=Cc1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(C=Cc1ccc(O)cc1)c1c(O)cccc1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 22 %

Procedure:
To a solution of 7.6 grams (0.05 mole) of 2',6'-dihydroxyacetophenone and 6.1 gram (0.05 mole) p-hydroxybenzaldehyde in ethanol was added 100 ml. of 60% aqueous sodium hydroxide. The mixture was stirred at room temperature for 18 hours and then acidified with 6 N hydrochloric acid. The resulting orange solid was collected by filtration and washed with water. The solid was chromatographed on silica gel (200 g., 2.25 l., 20% acetone-Skellysolve "B") and 150 ml. fractions taken. Fractions 6-12 were combined and crystallized from methanol-methylene chloride giving fine orange needles, 28 g., m.p. 190°-192° C., resolidified and melted 210°-212° C., 22% yield).
Reaction SMILES: [S:1]([O-:6])(O[O-])(=O)=[O:2].[K+].[K+].[C:9]([NH:12][C:13]1[S:14][C:15]([C:34]([NH:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41](SC)=[CH:40][CH:39]=2)=[O:35])=[C:16]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:22][CH:21]=2)[N:17]=1)(=[O:11])[CH3:10].[CH2:46]1COCC1>O>[C:9]([NH:12][C:13]1[S:14][C:15]([C:34]([NH:36][CH2:37][C:38]2[CH:39]=[CH:40][C:41]([S:1]([CH3:46])(=[O:6])=[O:2])=[CH:42][CH:43]=2)=[O:35])=[C:16]([CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:24][CH:25]=2)[N:17]=1)(=[O:11])[CH3:10]
Reactant: CSc1ccc(CNC(=O)c2sc(NC(C)=O)nc2CCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1
Reactant: C1CCOC1
Reactant: O=S(=O)([O-])O[O-]
Agent: [K+]
Solvent: O
Product: CC(=O)Nc1nc(CCc2ccc(NC(=O)OC(C)(C)C)cc2)c(C(=O)NCc2ccc(S(C)(=O)=O)cc2)s1
Temperature: 25 °C

Procedure:
Potassium peroxymonosulfate (264 mg) was suspended in water (1 ml) and THF (1 ml), and then tert-butyl (4-{2-[2-(acetylamino)-5-({[4-(methylthio)benzyl]amino}carbonyl)-1,3-thiazol-4-yl]ethyl}phenyl)carbamate (155 mg) in THF (2 ml) was added dropwise to the suspension at 0° C. The reaction mixture was stirred at r.t. for an hour, and then water was added to the suspension. The solution was extracted with AcOEt (twice). The combined organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo to give tert-butyl (4-{2-[2-(acetylamino)-5-({[4-(methylsulfonyl)benzyl]amino}carbonyl)-1,3-thiazol-4-yl]ethyl}phenyl)carbamate (140.6 mg) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C-]#N.[K+].[N:13]1C(C)=CC=C[C:14]=1C.O.[C:22]([O:25]C(=O)C)(=[O:24])[CH3:23]>C(Cl)Cl.[V]>[C:22]([OH:25])(=[O:24])[CH3:23].[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]([OH:5])[C:14]#[N:13]
Reactant: Cc1cccc(C)n1
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1ccccc1Cl
Agent: [V]
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CC(=O)O
Product: N#CC(O)c1ccccc1Cl
Reaction time: 7 h

Procedure:
o-Chlorobenzaldehyde (2.0 g, 1.62 ml, 14.23 mmol) was added via syringe to an agitated mixture of potassium cyanide (2.793 g, 43.8 mmol) and a vanadium catalyst* of Formula (7) (90 mg, 14.23×10−2 mmol) in CH2Cl2 (55 ml), followed by 2,6-lutidine (0.147 g, 0.16 ml, 1.37 mmol) and water (0.25 g, 0.25 ml, 13.66 mmol). The slurry was cooled to a temperature of −6° C. and acetic anhydride (3.08 g, 2.85 ml, 30.17 mmol) was added via a syringe. The slurry was agitated at a temperature of −5° C. to 0° C. Analysis by G.C. showed that the reaction had gone to 51% conversion (62% e.e.) after 4 hrs and to 61% conversion (53% e.e.) after 7 hrs. The excess potassium cyanide was filtered off and the product was washed with dichloromethane before the filtrates were reduced in vacuo. The residues were dissolved in 10:2 v/v hexane:ethyl acetate and the catalyst was removed by passing the mixture through a bed of silica and washing with 10:1 v/v hexane:ethyl acetate.
Reaction SMILES: N#N.[CH3:3][O:4][CH2:5][C:6]1[S:7][C:8]([CH2:11][OH:12])=[CH:9][N:10]=1.CCN(CC)CC.[S:20](Cl)([CH3:23])(=[O:22])=[O:21]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:23][S:20]([O:12][CH2:11][C:8]1[S:7][C:6]([CH2:5][O:4][CH3:3])=[N:10][CH:9]=1)(=[O:22])=[O:21]
Reactant: COCc1ncc(CO)s1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCc1ncc(COS(C)(=O)=O)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (2-(methoxymethyl)thiazol-5-yl)methanol (319 mg, 2.00 mmol) in dry CH2Cl2 (15.0 mL) was treated at 0° C. with Et3N (0.36 mL, 2.59 mmol) followed by DMAP (25 mg, 0.20 mmol) and Ms-Cl (0.20 mL, 2.53 mmol). After stirring at 0° C. for 30 min, the reaction was quenched with water (10 mL). The org. layer was dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give 469 mg (quant.) of crude (2-(methoxymethyl)thiazol-5-yl)methyl methanesulfonate as an yellow oil: TLC: rf (1:4 hept-EA)=0.39. A solution of this crude material (469 mg) in DMF (4.5 mL) was added to a solution of 4-nitro-2H-[1,2,3]triazole (2.35 g of a 9.6% solution in DMF, 1.98 mmol) in DMF (4.5 mL) pre-treated for 30 min with DIPEA (0.68 mL, 3.96 mmol) and the reaction mixture was stirred for 4 days at 50° C. Water (10 mL), followed by EA (10 mL) were added. The aq. layer was extracted with EA (10 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (1:1 hept-EA) gave the title compound as a yellow oil: TLC: rf (1:1 hept-EA)=0.33. LC-MS-conditions 07: tR=0.72 min, [M+H]+=255.95.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]2=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:16]=[CH:17][N:13]2[N:12]=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:25]#[N:26].[Na+]>CN(C=O)C>[CH2:1]([NH:8][C:9]1[C:14]2=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:16]=[CH:17][N:13]2[N:12]=[C:11]([C:25]#[N:26])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nc(NCc2ccccc2)c2c(-c3ccccc3)ccn2n1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1nc(NCc2ccccc2)c2c(-c3ccccc3)ccn2n1
Temperature: 100 °C
Yield: 41.3 %

Procedure:
To a stirred solution of N-benzyl-2-chloro-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-amine (0.500 g, 1.49 mmol) dissolved in DMF (5 mL) was added sodium cyanide (0.366 g, 7.47 mmol). The reaction mixture was heated to 100° C. for 24 h and cooled. Reaction was quenched by adding ice cold water (100 mL) and was extracted with EtOAc (50×3 mL). The organic layer was separated and dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography using CombiFlash (REDISEP®, silica gel, 24 g, 10% EtOAc/hexanes) to afford 4-(benzylamino)-5-phenylpyrrolo[2,1-f][1,2,4]triazine-2-carbonitrile (0.200 g, 41.2%). LCMS Condition B-45: retention time 2.95 min, [M−1]=324.2. HPLC Condition B-2: retention time 25.49 min, Purity 98.76%. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.68 (s, 2H), 6.92-6.96 (m, 2H), 7.26 (m, 10H), 7.86 (d, J=2.8 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[O:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1.C1CCC(N=C=NC2CCCCC2)CC1.[CH3:26][S:27]([O:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[C:36]([C:41](=[NH:43])[NH2:42])[CH:37]=2)[CH:32]=1)(=[O:29])=[O:28]>N1C=CC=CC=1>[CH3:26][S:27]([OH:30])(=[O:29])=[O:28].[CH3:1][O:2][C:3]1[O:7][C:6]([C:8]([O:10][C:31]2[CH:40]=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[C:36]([C:41](=[NH:42])[NH2:43])[CH:37]=3)[CH:32]=2)=[O:9])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)O)o1
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Oc2ccc3cc(C(=N)N)ccc3c2)o1
Product: CS(=O)(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 10 ml of dry pyridine was dissolved 1.4 g of 5-methoxy-furan-2-carboxylic acid. To the resulting solution was added 2.5 g of DCC and the reaction mixture was stirred for 30 minutes at room temperature. To the reaction mixture was added with stirring and cooling in ice 2.8 g of 6-amidino-2-naphthol methanesulfonate. The reaction mixture was stirred overnight at room temperature. The precipitate was collected by filtration, washed with dry pyridine, added to DMF and stirred. The insolubles were filtered off and ethyl ether was added to the filtrate. The precipitate was collected by filtration and washed with acetone to obtain 2.7 g of 6-amidino-2-naphthyl 5-methoxy-furan-2-carboxylate methanesulfonate.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:22]([OH:24])=O)[CH2:10][CH2:11][C:12]([O:14]CC1C=CC=CC=1)=[O:13])=[O:7])([CH3:4])[CH3:3].ClC(OCC)=O.C([N:33](CC)CC)C.N.[H][H]>O1CCCC1.[Pd].CO>[C:2]([O:5][C:6]([NH:8][C@H:9]([C:22](=[O:24])[NH2:33])[CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:1]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Reactant: [H][H]
Agent: [Pd]
Agent: CCOC(=O)Cl
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(N)=O

Procedure:
1010 mg (3.0 mmol) of Boc-Glu (OBzl)-OH, 316 μl (3.3 mmol) of ethyl chloroformate and 460 μl (3.3 mmol) of triethylamine were suspended in 12.0 ml of tetrahydrofuran, to which 2.0 ml of a concentrated aqueous ammonia solution was added. Following agitation at room temperature overnight, the resultant was subjected to extraction with ethyl acetate/water. The organic layer was washed with saturated saline and then sodium sulfate was added for drying. The organic layer was subjected to vacuum condensation, and the resulting residue was added with 100 mg of 10% Pd/C and 12.0 ml of methanol and stirred at room temperature overnight in a hydrogen atmosphere under a normal pressure. After the reaction, the catalyst was filtrated away and the solvent was distilled away to obtain a crude purified substance of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1>ClCCl.CO.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CNc2ccc(F)cc2N1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CO
Solvent: ClCCl
Product: O=c1cnc2ccc(F)cc2[nH]1
Yield: 47.7 %

Procedure:
A solution of 7-fluoro-3,4-dihydro-2(1H)-quinoxalinone (15.65 g, 92.88 mmol) in dichloromethane/methanol (1:1, 600 mL) was stirred with manganese dioxide (78.25 g) at room temperature for 1.5 h. The mixture was filtered through kieselguhr, washing through several times with 10% methanol/dichloromethane (˜1 L), and the filtrate was evaporated to give the product (7.27 g). Extraction of the residual filtration solids several times with dimethylformamide at 60-70° C., followed by filtration and evaporation of the extracts, gave more product (6.66 g), the total yield being 13.93 g (91.5%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][N:16]=[C:17]([C:22](=[O:26])[CH2:23][O:24][CH3:25])[C:18]([O:20][CH3:21])=[O:19])=[C:11]([F:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28]OC(OC)N(C)C>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:28]=[C:23]([O:24][CH3:25])[C:22](=[O:26])[C:17]([C:18]([O:20][CH3:21])=[O:19])=[N:16]2)=[C:11]([F:27])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: COCC(=O)C(=NNc1ccc(OCc2ccccc2)cc1F)C(=O)OC
Product: COC(=O)c1nn(-c2ccc(OCc3ccccc3)cc2F)cc(OC)c1=O
Temperature: 25 °C
Yield: 93 %

Procedure:
A solution of methyl 2-{[4-(benzyloxy)-2-fluorophenyl]hydrazono}-4-methoxy-3-oxobutanoate (8.46 g, 22.6 mmol) in N,N-dimethylformamide dimethyl acetal (80 mL) was refluxed for 3 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was diluted with AcOEt, washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with THF and recrystallized from hexane/THF to give the title compound (8.12 g, 93% yield) as a white solid: mp 143-144° C.; 1H NMR (300 MHz, CDCl3): δ ppm 3.89 (3H, s), 3.96 (3H, s), 5.12 (2H, s), 6.83-6.91 (2H, m), 7.33-7.44 (5H, m), 7.48-7.54 (1H, m), 7.69 (1H, d, J=2.3 Hz). Anal. Calcd for C20H17FN2O5: C, 62.50; H, 4.46; N, 7.29. Found: C, 62.40; H, 4.59; N, 7.26.
Reaction SMILES: [Cl-].Cl[CH2:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][NH+:5]=1.[SH:14][C:15]1[NH:19][C:18]2[CH:20]=[CH:21][C:22]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:23][C:17]=2[N:16]=1>C(O)C.[OH-].[Na+]>[CH3:11][O:10][C:8]1[C:7]([O:12][CH3:13])=[CH:6][N:5]=[C:4]([CH2:3][S:14][C:15]2[NH:19][C:18]3[CH:20]=[CH:21][C:22]([O:24][C:25]([F:28])([F:26])[F:27])=[CH:23][C:17]=3[N:16]=2)[CH:9]=1
Reactant: COc1c[nH+]c(CCl)cc1OC
Reactant: FC(F)(F)Oc1ccc2[nH]c(S)nc2c1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cnc(CSc2nc3cc(OC(F)(F)F)ccc3[nH]2)cc1OC
Temperature: 20 °C
Reaction time: 2 h

Procedure:
1.57 g of 2-chloromethyl-4,5-dimethoxypyridinium chloride are added to a solution of 1.64 g of 2-mercapto-5-trifluoromethoxy-1H-benzimidazole in 40 ml of ethanol and 20 ml of 1N sodium hydroxide solution, the mixture is stirred at 20° C. for 2 hours and then at 40° C. for a further hour, the ethanol is distilled off on a rotary evaporator (10 mbar/40° C.) and the colorless precipitate which thereby separates out is filtered off over a suction filter, rinsed with 1N sodium hydroxide solution and water and dried. 2.15 g (79% of theory) of the title compound of m.p. 92°-93° C. are obtained.
Reaction SMILES: [F:1][CH2:2][CH2:3]O.FC(F)(F)C([O-])=O.[C:12]([C:15]1[C:16]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[N:17][N:18]([C:20]2([CH2:26][C:27]#[N:28])[CH2:25][CH2:24][NH2+:23][CH2:22][CH2:21]2)[CH:19]=1)(=[O:14])[NH2:13].C(O)(C(F)(F)F)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.CN(C=O)C>[C:27]([CH2:26][C:20]1([N:18]2[CH:19]=[C:15]([C:12]([NH2:13])=[O:14])[C:16]([NH:29][C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)=[N:17]2)[CH2:25][CH2:24][N:23]([CH2:3][CH2:2][F:1])[CH2:22][CH2:21]1)#[N:28]
Reactant: N#CCC1(n2cc(C(N)=O)c(Nc3ccc(F)cc3)n2)CC[NH2+]CC1
Reactant: OCCF
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])C(F)(F)F
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: N#CCC1(n2cc(C(N)=O)c(Nc3ccc(F)cc3)n2)CCN(CCF)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a sealed vial was added 2-fluoroethanol (0.0090 g, 0.14 mmol), PS-IBX (0.28 g, 0.28 mmol, 1.0 mmol/g) suspended in DCE (1.0 mL). The vial was capped and shaken at RT for 16 hours. The reaction was passed though a syringe filter and the eluent was collected into a reaction vial. To the reaction vial was added 4-(4-carbamoyl-3-((4-fluorophenyl)amino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidin-1-ium 2,2,2-trifluoroacetate (Intermediate #38-5) (0.020 g, 0.058 mmol), TFA (0.020 mL, 0.26 mmol), Na(OAc)3BH (0.037 g, 0.18 mmol) suspended in DMF (0.50 mL). The reaction vial was capped and heated to 50° C. for 4 hours. The completed reaction was concentrated in vacuo and the residue taken up in DMF (1.0 mL). The crude reaction was passed through a syringe filter and the eluent was directly purified by reverse phase preparative HPLC (using a gradient elution of 0-95% ACN/water with 0.1% v/v TFA modifier). The collected HPLC fraction was concentrated in vacuo and the residue was taken up in MeOH and passed through a Si-Carbonate SPE cartridge. The eluent was collected and evaporated to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[F:8].[H-].[Na+].Br[CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:15][CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH2:10][NH2:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N#CCc1ccc(F)c(F)c1
Reactant: BrCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NCC(CCOC1CCCCO1)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.7 %

Procedure:
A solution of 50 g of 3,4-difluorophenyl acetonitrile in 50 ml of THF is added dropwise at 20° C. to a suspension of 14.4 g of 60% sodium hydride in oil in 250 ml of THF, and the reaction mixture is left tirring for three hours at RT. It is cooled in an ice bath, a solution of 68.2 g of 1-bromo-2-(tetrahydro-2-pyranyloxy)ethane in 50 ml of THF is added dropwise and the reaction mixture is left stirring overnight at RT. It is acidified by adding a pH 2 buffer solution, and the THF is then evaporated off under vacuum. The aqueous phase is extracted with ether, the organic phase is washed twice with a pH 4 buffer solution, with water and with saturated NaCl solution and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica, eluting with toluene and then with a toluene/AcOEt (100:3; v/v) mixture. 50 g of the expected product are obtained.
Reaction SMILES: C12(COC3C(I)=CC(C(O)=O)=C(F)C=3)CC3CC(CC(C3)C1)C2.[CH:24]1([CH2:29][O:30][C:31]2[C:39]([CH:40]3[CH2:42][CH2:41]3)=[CH:38][C:34]([C:35]([OH:37])=O)=[C:33]([F:43])[CH:32]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1.N1(S(N)(=O)=O)CCC1.[CH:52]1([S:55]([NH2:58])(=[O:57])=[O:56])[CH2:54][CH2:53]1>C(OCC)C>[CH:24]1([CH2:29][O:30][C:31]2[C:39]([CH:40]3[CH2:42][CH2:41]3)=[CH:38][C:34]([C:35]([NH:58][S:55]([CH:52]3[CH2:54][CH2:53]3)(=[O:57])=[O:56])=[O:37])=[C:33]([F:43])[CH:32]=2)[CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: O=C(O)c1cc(C2CC2)c(OCC2CCCC2)cc1F
Reactant: NS(=O)(=O)C1CC1
Agent: NS(=O)(=O)N1CCC1
Agent: O=C(O)c1cc(I)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Solvent: CCOCC
Product: O=C(NS(=O)(=O)C1CC1)c1cc(C2CC2)c(OCC2CCCC2)cc1F

Procedure:
Following the procedure as described in Example 299 Step 2 and making variations as required to replace 4-(adamantan-1-ylmethoxy)-2-fluoro-5-iodobenzoic acid with 4-(cyclopentylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid and to replace azetidine-1-sulfonamide with cyclopropane-sulfonamide, the title compound was obtained as a colorless solid (0.039 g, 12%) after trituration in diethyl ether followed by trituration in methanol: 1H NMR (300 MHz, DMSO-d6) δ 11.81 (br s, 1H), 7.12 (d, J=8.3 Hz, 1H), 6.96 (d, J=13.1 Hz, 1H), 3.97 (d, J=6.8 Hz, 2H), 3.13-3.02 (m, 1H), 2.41-2.26 (m, 1H), 2.08-1.95 (m, 1H), 1.85-1.72 (m, 2H), 1.68-1.49 (m, 4H), 1.44-1.31 (m, 2H), 1.15-1.07 (m, 4H), 0.93-0.85 (m, 2H), 0.71-0.64 (m, 2H); MS (ES−) m/z 380.2 (M−1).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([C@H:12]1[O:16][C:15](=[O:17])[C@H:14]([CH2:18][CH3:19])[CH2:13]1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29].O>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C@@H:10]([O:11][S:28]([CH3:27])(=[O:30])=[O:29])[C@@H:12]1[CH2:13][C@@H:14]([CH2:18][CH3:19])[C:15](=[O:17])[O:16]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H]1C[C@@H]([C@H](O)COCc2ccccc2)OC1=O
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@@H]1C[C@@H]([C@@H](COCc2ccccc2)OS(C)(=O)=O)OC1=O
Reaction time: 3 h
Yield: 96.2 %

Procedure:
A solution of 25.0 g of (3R,5S)-5-[(R)-2-benzyloxy-1-hydroxyethyl]-3-ethyldihydrofuran-2-one obtained in Example (106c) (94.7 mmol) in methylene chloride (600 ml) was cooled in an ice bath. Then, 28.7 g of triethylamine (284 mmol) and 15.9 g of methanesulfonyl chloride (139 mmol) were added thereto, and the mixture was stirred at the same temperature for three hours. 500 ml of water was added to the reaction mixture, followed by extraction with methylene chloride. Then, the organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:n-hexane/ethyl acetate=4/1-1/1) to obtain 31.2 g of the title compound (yield: 96%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[NH:7][C:6]([C:13]([OH:15])=O)=[CH:5]2.[CH3:16][CH:17]([NH:19][C:20]1[C:21]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:22][CH:23]=[CH:24][CH:25]=1)[CH3:18].N=C=N>>[CH3:18][CH:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[N:26]1[CH2:27][CH2:28][N:29]([C:13]([C:6]2[NH:7][C:8]3[C:4](=[CH:3][C:2]([F:1])=[C:10]([O:11][CH3:12])[CH:9]=3)[CH:5]=2)=[O:15])[CH2:30][CH2:31]1)[CH3:16]
Reactant: COc1cc2[nH]c(C(=O)O)cc2cc1F
Reactant: CC(C)Nc1cccnc1N1CCNCC1
Agent: N=C=N
Product: COc1cc2[nH]c(C(=O)N3CCN(c4ncccc4NC(C)C)CC3)cc2cc1F

Procedure:
Following the general procedure of EXAMPLE 16A and making non-critical variations but starting with 5-fluoro-6-methoxyindole-2-carboxylic acid (PREPARATION 92, 0.30 g), 1-[3-(1-methylethylamino)-2-pyridinyl]piperazine (0.32 g) and 1-(ethyl)-3-dimethylaminopropyl) carbodiimide (0.33 g), the title compound is obtained, mp 193°-194°.