Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:12]([N+:22]([O-:24])=[O:23])[CH:11]=1)(=O)C1C=CC=CC=1.C[O-].[Na+]>CO>[CH3:21][O:20][C:18]([CH2:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([OH:9])=[CH:11][C:12]=1[N+:22]([O-:24])=[O:23])=[O:19]
Reactant: COC(=O)COc1ccc(OC(=O)c2ccccc2)cc1[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)COc1ccc(O)cc1[N+](=O)[O-]
Temperature: 20 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
To a stirred suspension of 4-(methoxycarbonylmethoxy)-3-nitrophenyl benzoate (26.2 g, 79 mmol) in methanol (600 mL) at 20° C. was added, dropwise over 0.3 h, a solution of sodium methoxide (4.7 g, 87 mmol) in methanol (300 mL). The resulting mixture was stirred at 20° C. for 2 h then at 50° C. for 1 h. The solution was concentrated to 200 mL in vacuo, then poured into water (1 L) and extracted with diethyl ether-hexane (1:5, 500 mL). The aqueous phase was neutralised with 2 M hydrochloric acid, then extracted with dichloromethane (6×300 mL). The combined dichloromethane extracts were dried (Na2SO4) and evaporated in vacuo to give a semi-solid, which was triturated with ether-hexane (1:3, 2×100 mL) to give the title compound (15.3 g, 85%) as a yellow solid.
Reaction SMILES: CSC.B.[CH3:5][Si:6]([CH3:14])([CH3:13])[CH2:7][CH2:8][CH2:9][C:10](O)=[O:11]>O1CCCC1>[CH3:5][Si:6]([CH3:14])([CH3:13])[CH2:7][CH2:8][CH2:9][CH2:10][OH:11]
Reactant: C[Si](C)(C)CCCC(=O)O
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: C[Si](C)(C)CCCCO
Yield: 71.9 %

Procedure:
1.5 ml (11.4 mmol) of a 1 molar solution of borane dimethylsulfide was added to a cooled (0° C.) solution of 0.61 g (3.8 mmol) of 4-(trimethylsilyl)-butanoic acid in 20 ml of dry tetrahydrofuran. After work-up using the standard procedure (methanol, tetramethylethylene diamine) and flash chromatography purification on silica gel eluted with a 9:1 mixture of hexane and ethyl acetate, 0.4 g of 4-(trimethylsilyl)-1-butanol was obtained as a colorless liquid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:38])=[O:37])[CH:27]=1.Cl.[F:50][C:51]1[CH:56]=[CH:55][C:54]([C@H:57]([NH2:59])[CH3:58])=[CH:53][CH:52]=1>>[Br:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:59][C@@H:57]([C:54]2[CH:55]=[CH:56][C:51]([F:50])=[CH:52][CH:53]=2)[CH3:58])=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:37])=[O:38])[CH:27]=1
Reactant: C[C@@H](N)c1ccc(F)cc1
Reactant: O=C(O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nccnc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: C[C@@H](NC(=O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nccnc12)c1ccc(F)cc1

Procedure:
The title compound was prepared from the HATU-mediated coupling of 4-bromo-2-(quinoxaline-5-sulfonylamino)benzoic acid (EXAMPLE 1, Step G) and (R)-1-(4-fluorophenyl)ethylamine hydrochloride (EXAMPLE 7, Step C) and purified as described in EXAMPLE 1, Step K. MS (ESI): mass calculated for C23H18BrFN4O3S, 528.0; m/z found, 527/529 [M−H]−. HPLC (reverse phase): RT=10.03 min. 1H NMR (500 MHz, CDCl3): 11.34 (s, 1H), 8.85 (d, J=1.8 Hz, 1H), 8.78 (d, J=1.8 Hz, 1H), 8.57 (dd, J=7.4, 1.4 Hz, 1H), 8.32 (dd, J=7.4, 1.4 Hz, 1H), 7.92 (d, J=1.8 Hz, 1H), 7.87 (dd, J=8.4, 7.4 Hz, 1H), 7.30-7.25 (m, 2H), 7.15 (d, J=8.4 Hz, 1H), 7.10-7.00 (m, 2H), 6.91 (dd, J=8.4, 2.0 Hz, 1H), 6.13 (br d, J=6.5 Hz, 1H), 5.25-5.15 (m, 1H), 1.53 (d, J=7.0 Hz, 3H).
Reaction SMILES: [Li]CCCC.[CH3:6][C:7](=[N:9][OH:10])[CH3:8].CCCC.C[O:16][C:17](=O)[C@@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH3:23].Cl>CCCCCC.C1COCC1>[CH3:23][N:19]1[CH2:20][CH2:21][CH2:22][C@H:18]1[C:17](=[O:16])[CH2:6][C:7](=[N:9][OH:10])[CH3:8]
Reactant: CC(C)=NO
Reactant: COC(=O)[C@@H]1CCCN1C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(CC(=O)[C@@H]1CCCN1C)=NO
Temperature: 0 °C
Reaction time: 20 h

Procedure:
To n-BuLi (Aldrich, 2.5M in hexane, 61 4 mL, 1.53 mol, 4.4 eq.), diluted to 1.6M with hexane (342 mL), under argon at 0° C. was added a solution of acetone oxime (Aldrich, 56.15 g, 768 mmol, 2.2 eq.; recrystallized 1x hexanes) in THF (500 mL) dropwise over a 90 minute period (butane evolved!). After an additional 2 hours at 0° C. a solution of N-methyl proline methyl ester (50.0 g, 349 mmoL, 1.0 eq., the product of step 1b above) in THF (75 mL) was added over a 90 minute period. After stirring an additional 20 hours at 0° C. the reaction mixture was slowly cannulated into a vigorously stirred solution of 10% aq. HCl (1700 mL, cooled to 0° C.) over a 40 minute period. The layers were separated and the aqueous layer was washed with ether (1000 mL), then adjusted to pH ~9-10 with NaHCO3 /Na2CO3 (solid) and extracted with methylene chloride (4×800 mL). The combined methylene chloride layers were dried (MgSO4) and concentrated to afford the crude product as a pale yellow oil, (53.62 g), along with 10-20% of the N-oxide byproduct (by NMR integration). MS (Cl, DCl/N H3) m/e 185 (M+H)+. 1NMR (CDCl3) δ: 1.57-1.91 (br.m., 4H); 2.02 (s, 3H); 2.42-2.52 (m, 1H); 2.53 (s, 3H); 2.75 (dd, 1H); 2.80 (d, 2H); 3.15 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]([CH3:15])[C:12]([F:16])=[CH:11][C:3]=1[C:4]([NH:6][S:7]([CH3:10])(=[O:9])=[O:8])=[O:5].[Br:17]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>ClCCCl>[Br:17][CH2:15][C:13]1[C:12]([F:16])=[CH:11][C:3]([C:4]([NH:6][S:7]([CH3:10])(=[O:8])=[O:9])=[O:5])=[C:2]([F:1])[CH:14]=1
Reactant: Cc1cc(F)c(C(=O)NS(C)(=O)=O)cc1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCCl
Product: CS(=O)(=O)NC(=O)c1cc(F)c(CBr)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
A stirred mixture of 2,5-difluoro-4-methyl-N-(methylsulfonyl)benzamide (Preparation 244, 5.07 g, 20.3 mmol), N-bromosuccinimide (freshly recrystallised and dried, 4.71 g, 26.4 mmol) and azobisisobutyronitrile (0.05 g, 0.30 mmol) in 1,2-dichloroethane (100 mL) was heated at reflux under nitrogen whilst being irradiated with light from a lamp. After 2 hours, additional azobisisobutyronitrile (0.05 g, 0.30 mmol) was added and the reaction heated under reflux for 2 hours more. The reaction mixture was cooled to room temperature and evaporated in vacuo. The resulting residue was partitioned between brine (200 mL) and EtOAc (2×150 mL). The combine organic extracts were dried over magnesium sulphate and concentrated in vacuo to yield a pale yellow oil which solidified on standing (7.88 g). The solid was purified by silica gel chromatography eluting with 0 to 30% EtOAc in heptane to afford the title compound as a white solid (3.71 g, 56%):
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([CH:13]=[CH:14][CH2:15]Cl)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[S:21][C:22]2[CH2:23][CH2:24][NH:25][CH2:26][CH2:27][C:28]=2[N:29]=1.CCOCC>C(Cl)(Cl)Cl>[NH2:19][C:20]1[S:21][C:22]2[CH2:23][CH2:24][N:25]([CH2:15][CH:14]=[CH:13][C:12]3[CH:17]=[CH:18][C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:10][CH:11]=3)[CH2:26][CH2:27][C:28]=2[N:29]=1
Reactant: ClCC=Cc1ccc(OCc2ccccc2)cc1
Reactant: Nc1nc2c(s1)CCNCC2
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: Nc1nc2c(s1)CCN(CC=Cc1ccc(OCc3ccccc3)cc1)CC2
Yield: 13 %

Procedure:
Prepared from 4-benzyloxy-cinnamyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H- thiazolo[5,4-d]azepine in chloroform for one hour at 50° C. Yield: 13% of theory, Melting point: 135°-140° C. (ether).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:8]([Cl:16])[CH:7]=1)=O.Cl.[CH:19]1([O:25][NH2:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>CO>[CH3:1][O:2][C:3](=[O:17])/[C:4](/[C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:8]([Cl:16])[CH:7]=1)=[N:26]/[O:25][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COC(=O)C(=O)c1ccc(S(C)(=O)=O)c(Cl)c1
Reactant: NOC1CCCCC1
Agent: Cl
Solvent: CO
Product: COC(=O)/C(=N/OC1CCCCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
(3-Chloro-4-methanesulfonyl-phenyl)-oxo-acetic acid methyl ester (prepared as in Example 1, 1.2 g, 4.34 mmol) was stirred in methanol (9 mL) and warmed in a 70° C. oil bath. O-Cyclohexyl-hydroxylamine hydrochloride (0.811 g, 5.43 mmol) was added. After 2 h, the reaction mixture was allowed to cool and concentrated in vacuo. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 20% ethyl acetate/hexanes to 50% ethyl acetate/hexanes) afforded (E)-(3-chloro-4-methanesulfonyl-phenyl)-cyclohexyloxyimino-acetic acid methyl ester as a white solid (552 mg, 34%): H1-NMR (400 MHz, CDCl3) δ=1.34 (3H, m), 1.51 (3H, m), 1.68 (2H, m), 1.96 (2H, m), 3.31 (3H, s), 3.91 (3H, s), 4.39 (1H, m), 7.51 (1H, dd, J=8.1 Hz, J=1.5 Hz), 7.62 (1H, d, J=1.5 Hz), 8.18 (1H, d, J=8.1 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.C([Li])CCC.CN(C)[CH:16]=[O:17].[BH4-].[Na+]>C1(C)C=CC=CC=1.O1CCCC1.O>[F:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:16][OH:17])=[N:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: Fc1ccc(Br)nc1
Agent: [BH4-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: OCc1ccc(F)cn1
Reaction time: 0.5 h
Yield: 35.7 %

Procedure:
To a solution of 2-bromo-5-fluoropyridine (3.67 g, 20.8 mmol) in toluene (100 mL) was added dropwise n-butyl lithium (15.6 mL, 1.6 M hexane solution, 25.0 mmol) under nitrogen atmosphere at −78° C., which was stirred for 30 minutes. N,N-Dimethylformamide (8.05 mL, 104.0 mmol) was added dropwise to this solution at −78° C., and stirred for 20 minutes at 0° C. This reaction solution was vigorously stirred after addition of water and tetrahydrofuran. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and filtered. Sodium borohydride (1.58 g, 41.8 mmol) was added to the filtrate at 0° C., and stirred for 1 hour at room temperature. This reaction solution was partitioned by addition of water and tetrahydrofuran. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under a reduced pressure. The resulting residue was purified by NH silica gel column chromatography (hexane:diethyl ether=1:2) to obtain the title compound (945 mg, 36%).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:21])=[CH:8][C:9]=2[NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[S:4][C:3]=1[C:22]1[CH:23]=[N:24][N:25](C(OC(C)(C)C)=O)[CH:26]=1.[N:34]1([C:39]2[CH:40]=[N:41][CH:42]=[C:43](B3OC(C)(C)C(C)(C)O3)[CH:44]=2)[CH2:38][CH2:37][CH2:36][CH2:35]1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.CN(C=O)C>[CH3:21][C:7]1[N:6]=[C:5]2[S:4][C:3]([C:22]3[CH:23]=[N:24][NH:25][CH:26]=3)=[C:2]([C:43]3[CH:42]=[N:41][CH:40]=[C:39]([N:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)[CH:44]=3)[C:10]2=[C:9]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:8]=1
Reactant: Cc1cc(NS(=O)(=O)c2ccccc2)c2c(Br)c(-c3cnn(C(=O)OC(C)(C)C)c3)sc2n1
Reactant: CC1(C)OB(c2cncc(N3CCCC3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(NS(=O)(=O)c2ccccc2)c2c(-c3cncc(N4CCCC4)c3)c(-c3cn[nH]c3)sc2n1
Temperature: 120 °C
Yield: 98.4 %

Procedure:
A mixture of 1,1-dimethylethyl 4-{3-bromo-6-methyl-4-[(phenylsulfonyl)amino]thieno[2,3-b]pyridin-2-yl}-1H-pyrazole-1-carboxylate (Description 71) (200 mg, 0.364 mmol), 3-(1-pyrrolidinyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Description 79) (399 mg, 0.73 mmol), potassium carbonate (151 mg, 1.09 mmol), tetrakis(triphenylphosphine)palladium(0) (42.1 mg, 0.036 mmol) and bis(triphenylphosphine)palladium(II) chloride (25.5 mg, 0.036 mmol) were weighed into a microwave vial. 1,4-Dioxane (3 mL), DMF (1.5 mL) and water (0.75 mL) were added and the mixture heated in a microwave at 120° C. for 30 min. At this point, all three reaction mixtures were combined and concentrated. The residue was passed through an SCX cartridge, eluting with MeOH (150 mL) and then with 2M NH3 in MeOH (200 mL). The basic methanolic solution was concentrated and purified by normal phase chromatography, eluting with 0-100% ethyl acetate in DCM, followed by trituration with DCM (10 mL×3), to give the title compound (185 mg). LCMS (A) m/z: 517 [M+1]+, Rt 0.76 min (acidic).
Reaction SMILES: [NH:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[SH:4](=[O:17])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:3]1.C(N(CC)CC)C.[C:25]1([CH2:31][C:32](Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)(Cl)Cl>[C:25]1([CH2:31][C:32]([N:1]=[C:2]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[SH:4](=[O:17])([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:3]2)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: N=C1N[SH](=O)(c2ccccc2)c2ccccc21
Reactant: O=C(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(Cc1ccccc1)N=C1N[SH](=O)(c2ccccc2)c2ccccc21

Procedure:
2.4 g. 3-imino-1-phenyl-3H-1,2-benzisothiazole-1-oxide are boiled for 1 hour with 1.32 g. triethylamine and 1.6 g. phenylacetyl chloride in 50 cc. chloroform. After working up in the usual manner, there is obtained 3-(phenylacetylimino)-1-phenyl-3H-1,2-benzisothiazole-1-oxide in the form of yellow crystals which, after recrystallisation from ethyl acetate, melt at 120°C.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[O:8][C@@](CCC[C@@H](CCC[C@@H](CCCC(C)C)C)C)(C)C[CH2:11][C:6]=2[C:5]([CH3:29])=[C:4]([O:30]C(C)=O)[C:3]=1C.CC1C(=O)C(C)=C(C)C(=O)C=1>[Pd].[Pt]>[CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH3:11])[C:5]([CH3:29])=[C:4]([CH:3]=1)[OH:30]
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Agent: [Pd]
Agent: [Pt]
Agent: CC1=CC(=O)C(C)=C(C)C1=O
Product: Cc1cc(O)c(C)c(C)c1O

Procedure:
Process for the preparation of ∝-tocopherol acetate, comprising: in a first stage, a hydrogenation of trimethylbenzoquinone in a solvent chosen from alkyl acetates comprising 2 to 4 carbon atoms in the alkyl chain is carried out with a supported hydrogenation catalyst chosen from palladium and platinum to form trimethylhydroquinone, in a second stage, after filtration to remove the catalyst of the first stage, the trimethylhydroquinone obtained in the first stage is subjected to a condensation reaction with a phytol in a polar solvent of the ester type and in the presence of a Bronsted acid and of a zinc halide, wherein the condensation reaction is carried out in the presence of an amount of water of between 0.7 molar eq. and 2 molar eq. with respect to the number of moles of zinc halide used and in the presence of an amount of zinc halide of greater than 0.3 molar equivalent with respect to the phytol, said condensation reaction resulting in a second stage reaction medium containing α-tocopherol, in a third stage, the zinc halide is extracted from the second stage reaction medium with water to form an aqueous solution containing the zinc halide and an organic phase containing the α-tocopherol, the aqueous solution is then concentrated under warm conditions so as to leave remaining only at most two moles of water per mole of zinc halide before the aqueous solution is recycled to the second stage of the process, in a fourth stage, the organic phase is concentrated to dryness, so as to remove the polar solvent and its possible byproducts from the α-tocopherol, said α-tocopherol then being acetylated neat under warm conditions by forming an acetylation reaction medium comprising, the ∝-tocopherol, acetic anhydride, and either an inorganic acid chosen from sulphuric acid or phosphoric acid or an alkaline acetate, said acetylation reaction medium containing no solvent.
Reaction SMILES: O[CH2:2][CH2:3][C:4]([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)=[O:5].C(N(CC)CC)C.CS(Cl)(=O)=O>C(OCC)(=O)C>[CH:10]1[N:9]=[CH:8][N:7]2[CH2:2][CH2:3][C:4](=[O:5])[C:6]=12
Reactant: O=C(CCO)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C1CCn2cncc21
Temperature: 0 °C
Yield: 45.7 %

Procedure:
3-Hydroxy-1-(1-trityl-1H-imidazol-4-yl)-1-propanone (129 g) was dissolved in ethyl acetate (2 L). While stirring under ice-cooling (ice-salt), triethylamine (65.8 ml) was added and then a solution of methanesulfonyl chloride (34.2 ml) in ethyl acetate (50 ml) was added. The mixture was stirred at the same temperature for 1 h and ice water (0.8 L) was added to the reaction mixture, which was followed by partitioning. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in acetonitrile (2.36 L) and the mixture was stirred at 70° C. for 3 h. The reaction mixture was allowed to assume room temperature. Methanol (0.8 L) and triethylamine (61 ml) were added and the mixture was stirred again at 70° C. for 1.5 h. The solvent was evaporated under reduced pressure and ethyl acetate (200 ml) was added to the resulting residue. The insoluble material was filtered off. The solvent was evaporated and the residue was purified by silica gel column chromatography (eluent; methanol/ethyl acetate; 1/24–1/9). The eluate was recrystallized from methanol/ethyl acetate to give the title compound (18.84 g) as pale brown crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:13]([C:22]#[N:23])=[CH:12]2)=[CH:7][C:6]=1[NH2:24])[CH3:2].C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl>[CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:13]([C:22]#[N:23])=[CH:12]2)=[CH:7][C:6]=1[NH:24][S:34]([CH3:33])(=[O:36])=[O:35])[CH3:2]
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c(-c3ccccc3)c2)cc1N
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc(-n2cc(C#N)c(-c3ccccc3)c2)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 24.3 %

Procedure:
To a solution of 2-amino-4-(3-cyano-4-phenylpyrrole-1-yl)benzoic acid ethyl ester (0.050 g) and triethylamine (0.046 g) in dichloromethane (2 mL) was added methane sulfonylchloride (0.043 g) under ice-cooling, and this mixture was stirred at room temperature for 3 days. This reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=75/25) to give the title compound (0.015 g).
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5]2[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[CH:8][C:6]=2[N:7]=1.[NH:18]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[CH3:13][O:12][C:11]1[C:5]2[NH:4][C:3]([CH2:2][N:18]3[CH2:24][CH2:23][CH2:22][N:21]([CH2:2][C:3]4[NH:4][C:5]5[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[CH:8][C:6]=5[N:7]=4)[CH2:20][CH2:19]3)=[N:7][C:6]=2[CH:8]=[C:9]([O:16][CH3:17])[C:10]=1[O:14][CH3:15]
Reactant: C1CNCCNC1
Reactant: COc1cc2nc(CCl)[nH]c2c(OC)c1OC
Product: COc1cc2nc(CN3CCCN(Cc4nc5cc(OC)c(OC)c(OC)c5[nH]4)CC3)[nH]c2c(OC)c1OC

Procedure:
2-Chloromethyl-4,5,6-trimethoxybenzimidazole (200 mg) and homopiperazine (30 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:10][C@@H:11]1[O:15][C:14]([CH3:17])([CH3:16])[N:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@H:12]1[CH2:28][C:29]1[CH:34]=[CH:33][C:32](OC(=O)C(F)(F)F)=[CH:31][CH:30]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[Cl-].C([Sn](CCCC)(CCCC)[C:56]1[N:61]=[C:60]([O:62][CH3:63])[CH:59]=[CH:58][CH:57]=1)CCC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[CH2:10][C@@H:11]1[O:15][C:14]([CH3:16])([CH3:17])[N:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@H:12]1[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:56]2[CH:57]=[CH:58][CH:59]=[C:60]([O:62][CH3:63])[N:61]=2)=[CH:33][CH:34]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1Cc1ccc(OC(=O)C(F)(F)F)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(OC)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COc1cccc(-c2ccc(C[C@H]3[C@H](C[C@H](Cc4ccccc4)NC(=O)OC(C)(C)C)OC(C)(C)N3C(=O)OCc3ccccc3)cc2)n1
Yield: 52 %

Procedure:
A solution containing the product from Example 23I (0.20 g, 0.28 mmol) in DMF (3 mL) was treated with LiCl (0.119 g, 2.8 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.060 g, 0.085 mmol), and the product from Example 113A (0.338 g, 0.85 mmol), heated at 85° C. for 64 hours, cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 20% ethyl acetate in hexanes to give the title compound (0.097 g, 51% yield).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[C:4](=[O:9])[NH:5][CH:6]=[CH:7][CH:8]=1.CC(C)([O-])C.[K+].F[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=1[CH3:28]>CS(C)=O.O>[CH3:28][C:20]1[CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=[CH:24][C:19]=1[N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[C:4]1=[O:9]
Reactant: O=c1[nH]cccc1C(F)(F)F
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])ccc1-n1cccc(C(F)(F)F)c1=O
Temperature: 80 °C

Procedure:
2.5 g (15.3 mmol) of 3-(trifluoromethyl)pyridin-2(1H)-one are dissolved in 40 ml of dimethyl sulfoxide and admixed at room temperature with 2.58 g (22.9 mmol) of potassium tert-butoxide. The suspension is stirred at room temperature for 30 min, before 2.6 g (16.9 mmol) of 1-fluoro-2-methyl-4-nitrobenzene are added and the reaction solution is heated to 80° C. for 20 h. It is diluted cautiously with water. The solution is extracted repeatedly with dichloromethane. The combined organic extracts are washed with water and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is dissolved in acetonitrile and purified by preparative HPLC with a gradient of water and acetonitrile. The product fractions are combined and concentrated to dryness under reduced pressure. This affords 1.87 g (41% of theory) of the desired product.