Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:21][OH:22])[CH:5]=[C:6]([F:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[C:11]([F:19])[CH:10]=1.[H-].[Na+].Cl[C:26]1[CH:27]=[C:28]2[N:35]([CH3:36])[CH2:34][CH2:33][N:29]2[C:30](=[O:32])[N:31]=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:18])[F:16])=[C:11]([F:19])[CH:10]=1)[CH2:21][O:22][C:26]1[CH:27]=[C:28]2[N:35]([CH3:36])[CH2:34][CH2:33][N:29]2[C:30](=[O:32])[N:31]=1
Reactant: OCc1cc(F)c(Oc2ccc(C(F)(F)F)c(F)c2)c(F)c1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCn2c1cc(OCc1cc(F)c(Oc3ccc(C(F)(F)F)c(F)c3)c(F)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using (3,5-difluoro-4-(3-fluoro-4-(trifluoromethyl)phenoxy)phenyl)methanol (122 mg, 0.377 mmol) in DMF (4 mL), sodium hydride (45.3 mg, 1.131 mmol) and 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (70 mg, 0.377 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:42])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33](O)=[O:34])[N:28]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:62][O:63][C:64]([C@@H:66]1[CH2:70][C:69]([F:72])([F:71])[CH2:68][NH:67]1)=[O:65]>CN(C=O)C.C(OCC)(=O)C.C(Cl)CCl>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:42])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33]([N:67]3[CH2:68][C:69]([F:72])([F:71])[CH2:70][C@H:66]3[C:64]([O:63][CH3:62])=[O:65])=[O:34])[N:28]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: COC(=O)[C@@H]1CC(F)(F)CN1
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)O)n(-c3ccccc3)n2)CC1
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)N3CC(F)(F)C[C@H]3C(=O)OC)n(-c3ccccc3)n2)CC1

Procedure:
To a solution of 1.2 g 4-{(S)-4-tert-Butoxycarbonyl-2-[(5-carboxymethoxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester in 35 ml DMF were added 278 mg HOAt, 1.6 g EDC, 1.1 ml DIPEA and 684 mg (S)-4,4-Difluoro-pyrrolidine-2-carboxylic acid methyl ester hydrotrifluoroacetate. After 36 h the mixture was diluted with ethyl acetate and subsequently extracted with aqueous LiCl (4% w/w), 0.1 M HCl and saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. The crude product thus obtained was purified by chromatography on silica using heptan/ethyl acetate 40/60 to 33/67 as eluent.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][C:4]=1[NH:11][C:12]1[N:16]([CH3:17])[C:15]2[CH:18]=[C:19]([N:23]3[CH2:28][CH2:27][CH:26]([C:29]([F:32])([F:31])[F:30])[CH2:25][CH2:24]3)[C:20]([Cl:22])=[CH:21][C:14]=2[N:13]=1.[F:35][C:36]([F:43])([F:42])[CH:37]([CH3:41])[C:38](O)=[O:39].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:34][C:2]([F:33])([F:1])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:38](=[O:39])[CH:37]([CH3:41])[C:36]([F:43])([F:42])[F:35])=[CH:5][C:4]=1[NH:11][C:12]1[N:16]([CH3:17])[C:15]2[CH:18]=[C:19]([N:23]3[CH2:28][CH2:27][CH:26]([C:29]([F:31])([F:32])[F:30])[CH2:25][CH2:24]3)[C:20]([Cl:22])=[CH:21][C:14]=2[N:13]=1
Reactant: Cn1c(Nc2cc(CN)ccc2C(F)(F)F)nc2cc(Cl)c(N3CCC(C(F)(F)F)CC3)cc21
Reactant: CC(C(=O)O)C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C(=O)NCc1ccc(C(F)(F)F)c(Nc2nc3cc(Cl)c(N4CCC(C(F)(F)F)CC4)cc3n2C)c1)C(F)(F)F

Procedure:
The title compound was prepared in analogy to the procedure in Example 94, step (c) using 4-trifluoromethyl-3-[5-chloro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzimidazol-2-ylamino]-benzylamine (110 mg; 0.22 mmol), 3,3,3-trifluoro-2-methylpropanoic acid (31 mg; 0.22 mmol), HBTU (83 mg; 0.22 mmol), TEA (45 mg; 0.44 mmol), DMF (2 mL).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[C:3]([CH:4]=[O:5])=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1Br
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1ccccc1-c1ccc(Cl)cc1

Procedure:
To 2-bromobenzaldehyde (2.3 ml) and tetrakis(triphenylphosphine)palladium(O) (0.35 g) in toluene (50 mL), was added 4-chlorophenylboronic acid (4.0 g) and 2M Na2CO3 (70 ml). The mixture was heated under reflux for one hour. The reaction was cooled, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine and the combined aqueous layers back-extracted with ethyl acetate. The combined organic layers were dried over Na2SO4. The crude material was purified by flash chromatography using 97.5/2.5 hexane/ethyl acetate.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([NH:11][CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:8]=[CH:9][CH:10]=1.[F:23][C:24]([F:31])([F:30])[CH2:25][S:26](Cl)(=[O:28])=[O:27]>>[CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([N:11]([CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[S:26]([CH2:25][C:24]([F:31])([F:30])[F:23])(=[O:28])=[O:27])[CH:8]=[CH:9][CH:10]=1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: Cc1ccccc1Oc1cccc(NCc2cccnc2)c1
Product: Cc1ccccc1Oc1cccc(N(Cc2cccnc2)S(=O)(=O)CC(F)(F)F)c1

Procedure:
Using the method of Example 342 using N-(3-(2-methylphenoxy)phenyl)pyridin-3-ylmethylamine and 2,2,2-trifluoroethanesulfonyl chloride and purifying via radial chromatography eluting with 40:60 to 50:50 THF/hexanes gave the title compound. Anal Calcd for C21H19F3N2O3S.0.1H2O: C, 57.55; H, 4.42; N, 6.39. Found: C, 57.28; H, 4.15; N, 6.33. MS found 437.2 [M+H]+
Reaction SMILES: Br[C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@H:25]([CH2:28][OH:29])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[C:12]([F:21])[CH:11]=1)=[O:8].[F:30][C:31]1[CH:32]=[N:33][CH:34]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:36]=1>>[F:30][C:31]1[CH:36]=[C:35]([C:2]2[C:3]([N:23]3[CH2:27][CH2:26][C@H:25]([CH2:28][OH:29])[CH2:24]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:18])([F:19])[F:20])=[C:12]([F:21])[CH:11]=3)=[O:8])[CH:22]=2)[CH:34]=[N:33][CH:32]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)c(F)c1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
Product: O=C(Nc1ccc(OC(F)(F)F)c(F)c1)c1cnc(N2CC[C@H](CO)C2)c(-c2cncc(F)c2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 185 using (S)-5-bromo-N-(3-fluoro-4-(trifluoromethoxy)phenyl)-6-(3-(hydroxymethyl)pyrrolidin-1-yl)nicotinamide (Stage 201.1) and 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine to afford a white powder. HPLC (Condition 4) tR=5.4 min, UPLC-MS (Condition 3) tR=1.07 min, m/z=495.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.46-1.64 (m, 1H) 1.73-1.92 (m, 1H) 2.11-2.27 (m, 1H) 2.85-3.03 (m, 1H) 3.11-3.39 (m, 5H) 4.60 (t, J=1.00 Hz, 1H) 7.41-7.64 (m, 2H) 7.74-7.87 (m, 1H) 7.91-8.00 (m, 1H) 8.04 (d, J=2.35 Hz, 1H) 8.50 (s, 1H) 8.58 (d, J=2.74 Hz, 1H) 8.76 (d, J=1.00 Hz, 1H) 10.29 (s, 1H).
Reaction SMILES: [C:1]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([NH:16][C:17]([C:19]2[CH:38]=[CH:37][C:22]3[N:23]([CH3:36])[C:24]([CH2:26][CH2:27][C:28]4[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=4)=[N:25][C:21]=3[CH:20]=2)=[O:18])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[C:1]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([NH:16][C:17]([C:19]2[CH:38]=[CH:37][C:22]3[N:23]([CH3:36])[C:24]([CH2:26][CH2:27][C:28]4[CH:33]=[CH:32][C:31]([CH2:34][NH2:35])=[CH:30][CH:29]=4)=[N:25][C:21]=3[CH:20]=2)=[O:18])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c(CCc2ccc(C#N)cc2)nc2cc(C(=O)NN3CCC(NC(=O)c4ccccc4)CC3)ccc21
Solvent: CO
Product: Cn1c(CCc2ccc(CN)cc2)nc2cc(C(=O)NN3CCC(NC(=O)c4ccccc4)CC3)ccc21

Procedure:
2.0 g (4.1 mmol) 2-[2-(4-Cyanophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylic acid-(4-benzamido-piperidinyl)-amide are hydrogenated in 30 ml of methanol in the presence of about 2 g of methanol-moist Raney Nickel at room temperature and standard pressure. The catalyst is filtered off and washed with methanol, and the solvent is distilled off under vacuum. The residue is hydrogenated over silica gel (acetic ester:methanol:ammonia, 80:20:1) and then chromatographed over an RP-18 column (gradient acetonitrile:water: 0-2 min. 90% water over 11 min. of 90 to 5% water, 5 min. 5% water). Yield: 0.4 g (20%); MPt.: 165-167° C.,
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:24])=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:25](O)=[O:26])#[N:2].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1.C(N(C(C)C)CC)(C)C>CN(C)C=O.ClCCl>[Cl:23][C:22]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:24])[C:17]=1[CH2:16][O:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[N:6]([CH2:5][CH2:4][CH2:3][C:1]#[N:2])[C:7]([C:25]([N:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1)=[O:26])=[CH:8]2
Reactant: N#CCCCn1c(C(=O)O)cc2cc(OCc3c(Cl)cccc3Cl)ccc21
Reactant: C1COCCN1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#CCCCn1c(C(=O)N2CCOCC2)cc2cc(OCc3c(Cl)cccc3Cl)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.1 %

Procedure:
1-(3-Cyanopropyl)-5-(2,6-dichlorobenzyloxy)-1H-indole-2-carboxylic acid (0.10 g, 0.25 mmol) was dissolved in dimethylformamide (15 mL). PyBroP (bromo-tris-pyrrolidino-phosphonium hexafluorophosphate) (0.13 g, 0.27 mmol) was added followed by morpholine (0.065 g, 0.74 mmol), diisopropylethylamine (0.13 g, 0.99 mmol), and a catalytic amount of N,N-dimethylaminopyridine. The reaction mixture was stirred for 18 h under argon at ambient temperature. The solution was diluted with dichloromethane and washed with water (3×) and brine. The organic layer was dried over MgSO4, filtered, and the solvent removed under reduced pressure. Purification by flash chromatography (silica gel, 25% acetone/chloroform) yielded an off-white solid (0.11 g, 95%). MS(ES) m/e 472.2 [M +H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.B(F)(F)F.[CH3:23]COCC.CS(Cl)(=O)=O>CN(C=O)C>[OH:8][C:6]1[CH:7]=[C:2]2[C:3]([C:9](=[O:18])[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)=[CH:23][O:1]2)=[CH:4][CH:5]=1
Reactant: CCOCC
Reactant: O=C(Cc1ccc(O)cc1)c1ccc(O)cc1O
Agent: CS(=O)(=O)Cl
Agent: FB(F)F
Solvent: CN(C)C=O
Product: O=c1c(-c2ccc(O)cc2)coc2cc(O)ccc12
Temperature: 50 °C

Procedure:
In a solution of 1-(2,4-dihydroxyphenyl)-2-(4-hydroxyphenyl)-ethanone (2 mmol) in DMF (6 mL), freshly distilled BF3.OEt2 (6.3 mL) was added under argon. The mixture was heated at 50° C., and a solution of methanesulphonyl chloride (1 mL) in dry DMF (1.5 mL) was added slowly. After reaction at 80° C. for 1 h, the mixture was cooled to rt and poured into a large volume of ice cold aq. sodium acetate (12 g/100 mL), then extracted with EtOAc, and the organic layer was dried and concentrated. The residue was purified by column chromatography on silica gel using a mixture of DCM and MeOH to give 7-hydroxy-3-(4-hydroxyphenyl)-chromen-4-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.Cl[CH2:18][CH2:19][CH2:20][O:21][C:22]1[C:23]2[CH:24]=[CH:25][NH:26][C:27]=2[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:11]1[CH2:16][CH2:15][N:14]([CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:23]=2[CH:24]=[CH:25][NH:26]3)[CH2:13][CH2:12]1
Reactant: ClCCCOc1cccc2[nH]ccc12
Reactant: Clc1cccc2c(C3CCNCC3)c[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Clc1cccc2c(C3CCN(CCCOc4cccc5[nH]ccc45)CC3)c[nH]c12

Procedure:
The title compound was prepared in a fashion similar to that described in Example 192 from 7-chloro-3-(piperidin-4-yl)-1H-indole (0.34 g, 1.25 mmol), 1-chloro-3-(1H-indole-4-oxy)propane (0.275 g, 1.32 mmol) and potassium carbonate (0.41 g, 3.0 mmol). The product was isolated as a white foam. Yield 240 mg (47%). mp 178°-182° C. FDMS m/e=407 (M+ of free base). HRMS: calc., 408.184265; found, 408.184300
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][CH2:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1.C([O-])([O-])=O.[K+].[K+].[CH2:25](I)[CH3:26].C(C1C2NC(CC)=NC=2C=CC=1)C>CN(C=O)C>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:25][CH3:26])[CH:13]=1
Reactant: Oc1cccc(CCc2nc3ccccc3[nH]2)c1
Reactant: CCI
Agent: CCc1nc2cccc(CC)c2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cccc(CCc2nc3ccccc3[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.3 %

Procedure:
A 100 mL flask fitted with a stir-bar and septum with an Ar inlet was charged with benzimidazole 69 (2.00 g, 8.39 mmol), K2CO3 (1.74 g, 12.6 mmol), and DMF (20 mL). Ethyl iodide (1.44 g, 0.74 mL, 9.23 mmol) was added, and the mixture stirred at rt overnight. Analysis by HPLC showed a mixture of approximately 1:3:2 starting material:product:diethylbenzimidazole. The solids were filtered off and rinsed with EtOAc (60 mL). The filtrate was washed with saturated aqueous NH4Cl (2×50 mL), H2O (2×50 mL), 1% aqueous LiOH (4×50 mL), and brine (25 mL). The solution was filtered through phase separation paper and concentrated to 1.85 g of a yellow oil. The crude oil was chromatographed on silica gel with the product eluting with 25-35% EtOAc in hexanes. The product fractions were concentrated in vacuo to a white solid that was collected with hexanes. The material was dried to give 855 mg of 70 as a white solid (38%). 1H NMR (60 MHz, CDCl3): δ 7.8-7.5 (m, 2H), 7.5-7.0 (m, 3H), 6.9-6.6 (m, 3H), 3.8 (qt, 2H), 3.3-2.9 (m, 4H), 1.3 (t, 3H) ppm. HPLC analysis (15:10:75 H2O:A1:MeOH) showed a purity of 99% with a retention time of 3.6 min.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].Cl[CH2:11][CH2:12][C:13]([OH:15])=[O:14]>O>[O:7]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: O=C(O)CCCl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCOc1ccccc1
Temperature: 25 °C

Procedure:
Phenol (203 g, 2.16 moles) is added to a solution of potassium hydroxide (112 g, 2.0 mole) in water (100 ml) at 70° C. The resulting solution is maintained at a temperature of 70° C and small portions of 3-chloropropionic acid (101 g, 0.93 mole) in water (100 ml) and potassium hydroxide (44 g, 0.81 mole) in water (50 ml) are added alternately over a period of 0.5 hour. The reaction solution is heated at reflux temperature for 10 min., cooled to room temperature and washed with ether. The aqueous phase is acidified with hydrochloric acid and extracted with ether. The combined ethereal extracts are shaken with sodium carbonate solution. The aqueous part is acidified with hydrochloric acid and extracted with ether. The combined organic extracts are dried, evaporated and crystallized from ether-petroleum ether to give the title compound, m.p. 95°-97° C [lit. m.p. 97°-98° C as reported by S. G. Powell, J. Amer. Chem. Soc., 45, 2711 (1923)].
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][C:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([CH3:15])[CH3:14])/[C:8]([OH:10])=[O:9])[N:6]=1.C(N(CC)CC)C.[C:30]1([C:36]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)Cl)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[C:19]([O:18][C:16]([C:13]([O:12]/[N:11]=[C:7](/[C:5]1[N:6]=[C:2]([NH:1][C:36]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[S:3][CH:4]=1)\[C:8]([OH:10])=[O:9])([CH3:14])[CH3:15])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)O)c1csc(N)n1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 22.5 °C
Reaction time: 6 h

Procedure:
To a suspension of (Z)-2-(2-aminothiazol-4-yl)-2-(2-tert-butoxycarbonylprop-2-oxyimino) acetic acid (monoblocked acid) (100 g) prepared as in Example 1 in methylene chloride (1.74 lt) is added triethylamine (33.76 g) slowly at 5-10° to obtain a clear solution. Add triphenylchloromethane (118.5 g) at 5-10° and then mass temperature is raised to 36-38°. The resulting reaction mixture is stirred for 6 hours. It is then cooled to 20-25° and washed with DM water. The organic layer is concentrated and toluene is added to the residue. The resulting slurry is cooled to 20-25° C., the product is filtered, washed with toluene and dried under reduced pressure at 40-45° C. Yield 171 g (98.5% of theory), water <0.2% w/w, assay 96-97% w/w, methylene chloride 2-2.5% w/w and toluene 1-2% w/w.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.Br[CH2:11][CH:12]([OH:15])[CH2:13][OH:14].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:1]1([CH:13]([OH:14])[CH:12]([OH:15])[CH3:11])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: OCC(O)CBr
Reactant: c1ccc2[nH]cnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(O)C(O)n1cnc2ccccc21
Yield: 68.7 %

Procedure:
Benzimidazole (590 mg, 5.0 mmol) and 3-bromo-1,2-propanediol (0.52 mL, 6.0 mmol) were dissolved in anhydrous acetonitrile (50 mL) and dry potassium carbonate (2.07 g, 15 mmol) was added. The solution was then heated to reflux for 3 days. Upon cooling the mixture was filtered and the filtrates were concentrated, giving the desired N-benzimidazolyl-1,2-propanediol (0.66 g, 69%) as a pale yellow solid. 1H NMR (CDCl3) δ3.60 (m, 2H), 3.78 (m, 2H), 4.17 (m, 1H), 4.27 (m, 2H), 7.25 (m, 2H), 7.42 (d, 1H, J=6 Hz), 7.67 (d, 1H, J=6 Hz), 7.87 (s, 1H).
Reaction SMILES: CO[CH:3](OC)[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][O:14][CH2:15][CH3:16])=[C:8]([CH3:17])[C:7]=1[CH3:18].S(O)(O)(=O)=O.[NH2:26][OH:27].S(=O)(=O)(O)O.[OH-].[Na+]>>[CH3:18][C:7]1[C:8]([CH3:17])=[C:9]([CH2:12][CH2:13][O:14][CH2:15][CH3:16])[CH:10]=[CH:11][C:6]=1[O:5][CH2:4][CH:3]=[N:26][OH:27]
Reactant: CCOCCc1ccc(OCC(OC)OC)c(C)c1C
Reactant: NO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCOCCc1ccc(OCC=NO)c(C)c1C
Temperature: 70 °C
Reaction time: 10 h
Yield: 93 %

Procedure:
A mixture of 2.1 liters of methanolic solution of 760 g of 1-(2,2-dimethoxyethoxy)-4-(2-ethoxyethyl)-2,3-dimethylbenzene and 2 1 liters of aqueous solution of 466 g of hydroxylamine sulfate was heated to 70° C. To the mixture added was 12 N sulfuric acid until the pH became 0.5, and the mixture was stirred vigorously. Since the pH is lowers with the progress of the reaction, an aqueous 12 N sodium hydroxide solution was added dropwise so as to maintain pH at 0.5. The reaction was monitored by HPLC, and when the conversion exceeded 95%, the reaction mixture was cooled to around room temperature. Generally, the reaction requires about 10 hours. After pH was adjusted to 6.5 with 12 N-NaOH, the solid formed was filtered The filtered product was washed with 1.0 liter of warm water, and dried under reduced pressure to obtain the title product. m.p. 102°-105° C., amount obtained 676 g, purity 93%, yield 93%.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:7][C:6]=2[CH:18]=1.N.[CH3:20][N:21]1CCCC1=O>[C-]#N.[Zn+2].[C-]#N>[O:11]([CH2:10][C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([C:20]#[N:21])=[CH:18][C:6]=2[CH:7]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CN1CCCC1=O
Reactant: Ic1ccc2oc(COc3ccccc3)cc2c1
Agent: N
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc2oc(COc3ccccc3)cc2c1
Temperature: 130 °C
Reaction time: 3 h
Yield: 15 %

Procedure:
To a 1-methyl-2-pyrrolidinone (10 mL) solution of 5-iodo-2-phenoxymethyl-benzofuran (250 mg, 0.714 mmol) described in Production Example 75-1-1 were added zinc cyanide (168 mg, 1.43 mmol) and tetraquis(triphenylphosphine) palladium (0) (165 mg, 0.143 mmol). This mixture was stirred at 130° C. for 3 hours. After adding ice water and concentrated aqueous ammonia to the reaction mixture and stirring, the reaction mixture was extracted with ethyl acetate. The organic layer was separated followed by washing with sat. NaCl, drying over anhydrous magnesium sulfate and concentrating under a reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain the title compound (27 mg, 15%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:24]=[CH:23][C:12]([O:13][C@H:14]2[CH2:17][C@H:16]([C:18](OCC)=[O:19])[CH2:15]2)=[CH:11][CH:10]=1.O.Cl>CCOCC>[CH3:7][O:8][C:9]1[CH:24]=[CH:23][C:12]([O:13][C@H:14]2[CH2:17][C@H:16]([CH2:18][OH:19])[CH2:15]2)=[CH:11][CH:10]=1
Reactant: CCOC(=O)[C@H]1C[C@H](Oc2ccc(OC)cc2)C1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: COc1ccc(O[C@H]2C[C@H](CO)C2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of lithium aluminum hydride (389 mg, 10.0 mmol) in ether (413 ml) was added a solution of ethyl trans-3-(4-methoxyphenoxy)cyclobutanecarboxylate (1.97 g, 7.9 mmol) in ether (10 ml) at 0° C. and the mixture stirred for 1 h at room temperature. Water (3 ml) was carefully added to the reaction mixture at 0° C. and the whole allowed to warm to room temperature. 1 N aqueous hydrochloric acid (50 ml) was added, the ether phase separated and the aqueous phase extracted with ethyl acetate (100 ml). The combined organic phase was dried (MgSO4) and concentrated in vacuo to provide 1.99 g (quant.) of {trans-3-(4-methoxyphenoxy)-cyclobutyl }methanol as white solids. The product was used without further purification: 1H NMR δ6.88-6.70 (m, 4H), 4.75-4.62 (m, 1H), 3.76 (s, 3H), 3.71 (d, J=6.6 Hz, 2H), 2.62-2.46 (m, 1H), 2.35-2.28 (m, 4H), 1.59 (s, 1H).
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7]Br)[C:3](Cl)=[O:4].[CH:9]1([NH2:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[OH-].[Na+].[H-].[Na+]>C(Cl)(Cl)Cl.O>[Br:1][CH:2]1[CH2:6][CH2:7][N:15]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:3]1=[O:4]
Reactant: NC1CCCCC1
Reactant: O=C(Cl)C(Br)CCBr
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C1C(Br)CCN1C1CCCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 40.2 %

Procedure:
Dissolve 2,4-dibromo-butyryl chloride (17.0 g, 64.3 mmol) in chloroform (3 ml) and add to a mixture of cyclohexylamine (7.65 g, 77.2 mmol) in chloroform (20 mL) and H2O (3 mL) at 0° C. Add sodium hydroxide (5.92 g, 147.9 mmol) slowly while keeping the reaction temperature below 10° C. Stir for 1 hour. Wash the organic layer with 0.5M hydrochloride and brine. Dry over sodium sulfate, filter, and concentrate. Place the residue in THF (200 mL) and cool to 0° C. Add sodium hydride (1.02 g, 42.6 mmol) and stir for two days. Add additional sodium hydride (1.02 g, 42.6 mmol) and stir for 3 days. Pour onto water and ice and extract with methylene chloride. Dry over sodium sulfate, filter, and concentrate to yield 6.36 g (34%) of the title compound: NMR (CDCl3) δ 4.41 (dd, 1H), 3.94 (m, 1H), 3.48 (m, 1H), 3.33 (m, 1H), 2.51 (m, 1H), 2.30 (m, 1H), 1.82 (m, 3H), 1.70 (m, 2H), 1.38 (m, 4H), 1.11 (m, 1H).