Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH2:4][OH:5])[CH2:2][NH2:3].[CH3:6][O:7][C:8]([CH2:10][C:11]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=O)=[O:9].Br[CH2:19][C:20](C)=O.[Cl-].[Na+]>O>[OH:5][CH2:4][CH2:1][CH2:2][N:3]1[CH:20]=[CH:19][C:10]([C:8]([O:7][CH3:6])=[O:9])=[C:11]1[CH2:13][C:14]([O:16][CH3:17])=[O:15]
Reactant: NCCCO
Reactant: COC(=O)CC(=O)CC(=O)OC
Reactant: CC(=O)CBr
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COC(=O)Cc1c(C(=O)OC)ccn1CCCO
Temperature: 40 °C

Procedure:
To a solution of propanolamine in water there is added dimethyl 1,3-acetonedicarboxylate. The resultant mixture is rapidly cooled to -10° C. and treated dropwise, over a 15 minute period, with stirring, with 1-bromoacetone, whilst maintaining the reaction mixture at a temperature not higher than 40° C. When the addition is completed the dark reaction mixture is stirred for an additional hour at room temperature, and then poured into a mixture of hydrochloric acid-ice, saturated with solid sodium chloride and extracted with ethyl acetate (3×100 ml.). The combined organic extract is washed with cold water to neutrality, dried with anhydrous sodium sulfate and evaporated to dryness under reduced pressure. Chromatography of the residue on silica gel, using hexane:ethyl acetate as eluant, affords methyl N-(3-hydroxypropyl)-3-carbomethoxy-4-methylpyrrole-2-acetate (IV, R=CH3, n=1).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:21](=[O:37])[CH:22]([N:24]2[CH2:29][CH2:28][C:27]([OH:36])([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:26][CH2:25]2)[CH3:23])[CH:7]=[CH:8][C:9]=1[O:10][Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13]>C(O)C>[F:3][C:4]1[CH:5]=[C:6]([C@@H:21]([OH:37])[C@H:22]([N:24]2[CH2:25][CH2:26][C:27]([OH:36])([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:28][CH2:29]2)[CH3:23])[CH:7]=[CH:8][C:9]=1[O:10][Si:11]([CH:18]([CH3:19])[CH3:20])([CH:12]([CH3:13])[CH3:14])[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C(=O)c1ccc(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c1)N1CCC(O)(c2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)[Si](Oc1ccc([C@@H](O)[C@@H](C)N2CCC(O)(c3ccccc3)CC2)cc1F)(C(C)C)C(C)C
Reaction time: 0.17 h
Yield: 9.9 %

Procedure:
A mixture of sodium borohydride (0.12 g, 3.17 mmol) and ethanol (5 mL) was stirred 10 min and then 1-(3-fluoro-4-triisopropylsilyloxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-propan-1-one (1.41 g, 2.82 mmol in 25 mL of ethanol) was added. The reaction was stirred at ambient temperature overnight. The white precipitate which formed was collected by filtration to afford 0.14 g (10%) of (1R*,2R*)-1-(3-fluoro-4-triisopropylsilyloxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-propan-1-ol which had: mp 140-141 ° C. Analysis calculated for C29H44FNO3Si: C, 69.42; H, 8.84; N, 2.79. Found: C, 69.30; H. 9.06; N, 2.84. The filtrate was quenched with water and stirred overnight. The resulting precipitate was collected, washed with water and air dried (1.5 g). This material was recrystallized from ethanol to afford 0.72 g of additional product for a total yield of 0.86 g (61%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([O:10][C:11]3[C:16]([Cl:17])=[CH:15][C:14]([NH:18][S:19]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=4[Cl:32])(=[O:21])=[O:20])=[CH:13][C:12]=3[Cl:33])=[N:7][C:6]=2[CH:34]=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>>[Cl:32][C:23]1[CH:24]=[C:25]([C:28]([F:29])([F:30])[F:31])[CH:26]=[CH:27][C:22]=1[S:19]([NH:18][C:14]1[CH:15]=[C:16]([Cl:17])[C:11]([O:10][C:8]2[S:9][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:34][C:6]=3[N:7]=2)=[C:12]([Cl:33])[CH:13]=1)(=[O:21])=[O:20]
Reactant: Nc1ccc2sc(Oc3c(Cl)cc(NS(=O)(=O)c4ccc(C(F)(F)F)cc4Cl)cc3Cl)nc2c1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)Nc1ccc2sc(Oc3c(Cl)cc(NS(=O)(=O)c4ccc(C(F)(F)F)cc4Cl)cc3Cl)nc2c1

Procedure:
2-Chloro-N-[3,5-dichloro-4-(5-methanesulfonylamino-benzothiazol-2-yloxy)-phenyl]-4-trifluoromethyl-benzenesulfonamide was synthesized from N-[4-(5-Amino-benzothiazol-2-yloxy)-3,5-dichloro-phenyl]-2-chloro-4-trifluoromethyl-benzenesulfonamide (456) and methanesulfonyl chloride (Aldrich) in a similar manner as described in Examples 70-91.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](#[N:11])[CH:9]=[CH2:10]>>[C:2]1([NH:1][CH2:10][CH2:9][C:8]#[N:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: C=CC#N
Product: N#CCCNc1ccccc1
Temperature: 25 °C
Reaction time: 144 h
Yield: 78.3 %

Procedure:
Silica was activated by heating it above 100° C. in vacuum and was then allowed to cool to room temperature under nitrogen. To the activated silica (10 g) was absorbed aniline (1.86 g, 20 mmol) and acrylonitrile (2.65 g, 50 mmol) and the flask was capped tightly. The contents were then stirred with a magnetic stirrer for 6 days at 60° C. After this time the mixture was cooled to room temperature and extracted with MeOH. The extracts were evaporated to dryness and the residue was Kugelrohr-distilled under high vacuum to give the product 3-(phenylamino)propanenitrile (2.29 g, 78.4%) as an oil which crystallised on standing; bp 120-150° C./1-2 Torr (lit bp 120° C.1 Torr), mp 50.5-52.5° C.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:21]1[CH2:25][CH2:24][CH2:23][N:22]1[C:26](=[O:45])[CH2:27][C@@H:28]([O:43][CH3:44])[C@@H:29]([N:34]([CH3:42])[C:35](=[O:41])[C@H:36]([CH:38]([CH3:40])[CH3:39])[NH2:37])[C@@H:30]([CH3:33])[CH2:31][CH3:32])[C@@H:4]([CH3:20])[C:5]([NH:7][C@H:8]([C:16]([O:18][CH3:19])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[S:6].[CH:46]1[C:58]2[CH:57]([CH2:59][O:60][C:61]([N:63]([CH3:70])[C:64]([CH3:69])([C:66](O)=[O:67])[CH3:65])=[O:62])[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[C:50]=2[CH:49]=[CH:48][CH:47]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>ClCCl>[CH:55]1[C:56]2[CH:57]([CH2:59][O:60][C:61]([N:63]([CH3:70])[C:64]([CH3:65])([C:66]([NH:37][C@H:36]([C:35]([N:34]([C@@H:29]([C@@H:30]([CH3:33])[CH2:31][CH3:32])[C@H:28]([O:43][CH3:44])[CH2:27][C:26]([N:22]3[CH2:23][CH2:24][CH2:25][C@H:21]3[C@H:3]([O:2][CH3:1])[C@@H:4]([CH3:20])[C:5]([NH:7][C@@H:8]([CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:16]([O:18][CH3:19])=[O:17])=[S:6])=[O:45])[CH3:42])=[O:41])[CH:38]([CH3:39])[CH3:40])=[O:67])[CH3:69])=[O:62])[C:58]3[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:51]=2[CH:52]=[CH:53][CH:54]=1
Reactant: CN(C(=O)OCC1c2ccccc2-c2ccccc21)C(C)(C)C(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=S)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](N)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=S)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)N(C)C(=O)OCC1c2ccccc2-c2ccccc21)C(C)C

Procedure:
According to general procedure D, from #77 (399 mg, ≦0.52 mmol, 1 eq.), N-[(9H-fluoren-9-ylmethoxy)carbonyl]-N,2-dimethylalanine (213 mg, 0.628 mmol, 1.2 eq.), dichloromethane (5 mL, 0.1 M), HATU (239 mg, 0.628 mmol, 1.2 eq.) and diisopropylethylamine (282 μL, 1.62 mmol, 3.1 eq.) was synthesized the crude desired material, which was purified by silica gel chromatography (Gradient: 0% to 50% acetone in heptane), providing #78 (231 mg, 46% over two steps). LC-MS: m/z 970.7 [M+H+], 992.6 [M+Na+], retention time=1.11 minutes; HPLC (Protocol C): retention time=9.260 minutes; 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ [10.19 (d, J=7.4 Hz) and 10.47 (d, J=7.8 Hz), total 1H], 7.89 (d, J=7.4 Hz, 2H), 7.61-7.67 (m, 2H), 7.41 (br dd, J=7.4, 7.4 Hz, 2H), 7.14-7.36 (m, 8H), [5.20 (ddd, J=11, 7, 5 Hz) and 5.38 (ddd, J=11, 8, 4 Hz), total 1H], [4.41 (dd, J=8.6, 8.4 Hz) and 4.46 (dd, J=8.2, 8.2 Hz), total 1H], 3.65 and 3.68 (2 s, total 3H), 3.23 and 3.24 (2 s, total 3H), 3.13 (br s, 3H), 2.88 and 2.93 (2 br s, total 3H), 2.84 and 2.85 (2 s, total 3H), 1.31 and 1.32 (2 s, total 3H), [1.15 (d, J=6.6 Hz) and 1.18 (d, J=6.4 Hz), total 3H].
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].C(N(CC)CC)C.[C:17](Cl)(Cl)=[O:18].ClC(OC(Cl)(Cl)Cl)=O>O1CCCC1>[O:18]=[C:17]1[O:1][CH2:2][C:3]2[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=2[NH:5]1
Reactant: O=C(Cl)Cl
Reactant: Nc1ccccc1CO
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2CO1

Procedure:
To a mixture of 2-hydroxymethylaniline (25 g), triethylamine (32 ml) and tetrahydrofuran (250 ml) was introduced phosgene generated from trichloromethyl chloroformate (12.2 ml) and active carbon at room temperature with stirring. After stirring for 1 hour at room temperature, the reaction mixture was filtered off and the filtrate was concentrated. The resulting residue was recrystallized from diethyl ether-n-hexane to give 4H-1,2-dihydro-2-oxo-[3,1]benzoxazine (22.3 g).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([N:13]=[N+:14]=[N-:15])[C@H:9]1[C:16](=[O:27])[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[F:26])=O)(C)(C)C.[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29].CO>C(Cl)Cl>[F:31][C:30]([F:33])([F:32])[C:28]([OH:34])=[O:29].[Cl:25][C:21]1[C:20]([F:26])=[C:19]([CH:24]=[CH:23][CH:22]=1)[CH2:18][NH:17][C:16]([C@@H:9]1[C@H:10]([N:13]=[N+:14]=[N-:15])[CH2:11][CH2:12][NH:8]1)=[O:27]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N=[N+]=[N-])[C@H]1C(=O)NCc1cccc(Cl)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: [N-]=[N+]=N[C@@H]1CCN[C@@H]1C(=O)NCc1cccc(Cl)c1F
Reaction time: 8 h

Procedure:
To a solution of (2S,3R)-3-azido-2-(3-chloro-2-fluoro-benzylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butylester (87 mg, 0.22 mmol) in CH2Cl2 (6 mL) was added TFA at RT, and stirring was continued overnight at RT. Methanol was added to the reaction mixture and volatiles were removed under reduced pressure. The residue was taken up in MeOH and concentrated in vacuo to afford the crude title compound as a colorless wax. The product was used in the next reaction step without further purification. MS (LC/MS): 298 [M+H]+; tR (HPLC conditions b): 2.71 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.Cl.[N:19]1([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1.[CH3:36][OH:37]>C(Cl)Cl>[C:31]([OH:33])(=[O:32])[C:36]([OH:2])=[O:37].[N:19]1([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([CH2:31][C:10]3[C:11]4[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=4[S:13][C:9]=3[C:6]3[CH:7]=[CH:8][C:3]([O:2][CH2:1][C@@H:20]4[CH2:21][CH2:22][C:36](=[O:37])[NH:19]4)=[CH:4][CH:5]=3)=[CH:29][CH:28]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CO
Reactant: O=C(O)c1ccc(OCCN2CCCC2)cc1
Reactant: COc1ccc(-c2cc3ccccc3s2)cc1
Agent: Cl
Solvent: ClCCl
Product: O=C(O)C(=O)O
Product: O=C1CC[C@@H](COc2ccc(-c3sc4ccccc4c3Cc3ccc(OCCN4CCCC4)cc3)cc2)N1
Yield: 59 %

Procedure:
By essentially following the procedure detailed in Example 1, Part D, but using thionyl chloride in refluxing dichloromethane to form the benzoyl choride, the title compound was prepared from 2-(4-methoxyphenyl)-benzo[b]thiophene and 4-[2-(1-pyrrolidinyl)ethoxy]benzoic acid hydrochloride in 59% yield as an oil following radial chromatography (SiO2; gradient of 2-5% MeOH in CH2Cl2).
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([CH2:22][N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:30])[CH:3]=1.[C:31]1([CH2:37][C:38]([N:40]=[C:41]=[O:42])=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C)C=O.CCCCCC.C(OCC)C>[F:30][C:4]1[CH:3]=[C:2]([NH:1][C:41]([NH:40][C:38](=[O:39])[CH2:37][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:42])[CH:29]=[CH:28][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][N:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)[CH2:18][CH2:17]2)=[O:15])[CH:8]=1
Reactant: O=C=NC(=O)Cc1ccccc1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCC(CN4CCCC4)CC3)c2)c(F)c1
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1)NC(=O)Nc1ccc(Oc2ccnc(NC(=O)N3CCC(CN4CCCC4)CC3)c2)c(F)c1
Reaction time: 64.5 h

Procedure:
4-(Pyrrolidin-1-ylmethyl)piperidine-1-carboxylic acid [4-(4-amino-2-fluorophenoxy)pyridin-2-yl]amide (50 mg) was dissolved in N,N-dimethylformamide (1.5 ml) under a nitrogen atmosphere, and then 0.25 M phenylacetyl isocyanate in hexane (1.45 ml) was added, followed by stirring for 64.5 hrs. The reaction mixture was partitioned between ethyl acetate (100 ml) and a saturated aqueous solution of sodium hydrogencarbonate (50 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (50 ml), water (50 ml) and brine (50 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate). Fractions containing the target compound were concentrated to give a residue, which was then suspended in diethyl ether (3 ml) and hexane (3 ml). The solid was filtered off, and dried under aeration to provide the titled compound (49.6 mg) as white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[CH:4]=O.[Cl:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([NH:18][NH2:19])=[O:17])=[CH:14][CH:13]=1.O>CCO>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[CH:4]=[N:19][NH:18][C:16](=[O:17])[C:15]1[CH:14]=[CH:13][C:12]([Cl:11])=[CH:21][CH:20]=1
Reactant: O=Cc1c(O)cccc1Cl
Reactant: NNC(=O)c1ccc(Cl)cc1
Solvent: O
Solvent: CCO
Product: O=C(NN=Cc1c(O)cccc1Cl)c1ccc(Cl)cc1
Temperature: 60 °C
Yield: 95.5 %

Procedure:
A suspension of 2-chloro-6-hydroxybenzaldehyde (0.10 g, 0.64 mmol) and 4-chlorobenzoic acid hydrazide (0.10 g, 0.61 mmol) in EtOH (3 mL) was agitated and heated to 60° C. for 16 h. The reaction mixture was cooled to room temperature and H2O (1-2 mL) was added portionwise to precipitate the product. The solid was collected via suction filtration and rinsed with ethanol to furnish the title compound as an off-white solid (0.18 g, 95%): mp 273-277° C.; 1H NMR (400 MHz, DMSO-d6) δ 12.53 (s, 1H), 12.51 (s, 1H), 9.04 (s, 1H), 8.03-7.95 (m, 2H), 7.71-7.63 (m, 2H), 7.34 (t, J=8.2 Hz, 1H), 7.07 (dd, J=7.9, 0.9 Hz, 1H), 6.96 (d, J=8.2 Hz, 1H); ESIMS m/z 309 ([M+H]+), 307 ([M−H]−).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[O:19]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH2:31])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1C=CC=CC=1>[O:19]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCCCCCOc1ccccc1
Reactant: Clc1ncnc2ccccc12
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: c1ccc(OCCCCCNc2ncnc3ccccc23)cc1
Yield: 19.5 %

Procedure:
To a solution of 1.7 g (0.01 mol) of 4-chloroquinazoline in 50 ml of benzene were added 1.0 g (0.01 mol) of triethylamine and 1.8 g (0.01 mol) of 5-phenoxypentylamine, and the mixture was refluxed for 3 hours. After completion of the reaction, the benzene was evaporated under reduced pressure to leave crystals, which were washed with water, collected by filtration and recrystallized from aqueous ethanol, giving 0.6 g of 4-(5-phenoxypentyl)aminoquinazoline in the form of colorless flakes.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[N:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1.[CH2:19]1[S:21][CH2:20]1>C1C=CC=CC=1.O.CCOCC>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([O-:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[SH:21][CH2:20][CH2:19][N+:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1
Reactant: Cc1ccncc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C1CS1
Solvent: CCOCC
Solvent: O
Solvent: c1ccccc1
Product: Cc1cc[n+](CCS)cc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a suspension of p-toluenesulfonic acid (1.72 g, 0.01 mol) in benzene (6.5 mL) was added 4-picoline (1.17 mL, 0.012 mL). The resulting mixture was stirred under a nitrogen atmosphere at 23° C. for 30 min, treated with ethylenesulfide (0.65 mL, 0.011 mol) and stirred at 75° for 24 h. More ethylenesulfide (0.65 mL, 0.011 mol) was added and the stirring was continued at 75° C. for 24 h more. The reaction mixture was cooled to 23° C. and diluted with water (5 mL) and ether (8 mL). The aqueous layer was separated and washed with ether (3×8 mL). The traces of organic solvents were removed under vacuum and the compound was chromatographed on μ-bondapak C-18 with water as eluting solvent to give 2.94 g (90%) of the title compound as a colorless syrup; ir (film) νmax : 2510 (SH) 1640 (pyridinium), 1595, 1582, 1475, 1200 (sulfonate), 1031, 1010, 818 cm-1, 1Hmr (DMSO, d6) δ: 2.29 (3H, s, CH3 on pyridinium), 2.61 (s, CH3Ph), 2.4-2.8 (4H, SH, CH3Ph), 3.03 (2H, m[addition of D2O gave a t, J=6.4 Hz, at 3.04], CH2S), 4.68 (2H, t, J=6.4 Hz, CH2N+), 7.11, 7.49 (4H, 2d, J=7.9 Hz, Phenyl), 8.00 (2H, d, J=6.5 Hz, Hm of pyridinium), 8.89 (2H, d, J=6.5 Hz, Ho of pyridinium), uv (H2O) λmax : 256 (ε4315), 222 (ε17045) mμ.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][C@H:9]1[C:19]([OH:21])=O)=[O:7])(C)(C)C.[O:22]=[C:23]1[C:28](C(Cl)=O)=[CH:27][CH:26]=[C:25]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[O:24]1.[CH3:37][O:38][CH2:39][CH2:40][NH2:41]>>[C:15]([O:14][N:13]=[C:11]1[CH2:12][N:8]([C:6]([C:28]2[C:23](=[O:22])[O:24][C:25]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:26][CH:27]=2)=[O:7])[C@H:9]([C:19]([NH:41][CH2:40][CH2:39][O:38][CH3:37])=[O:21])[CH2:10]1)([CH3:16])([CH3:17])[CH3:18]
Reactant: CCCCCc1ccc(C(=O)Cl)c(=O)o1
Reactant: COCCN
Reactant: CC(C)(C)ON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CCCCCc1ccc(C(=O)N2CC(=NOC(C)(C)C)C[C@H]2C(=O)NCCOC)c(=O)o1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(tert-butoxyimino)-2-pyrrolidinecarboxylic acid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and 2-methoxyethylamine the title compound was obtained in 75% purity by LC/MS. MS(ESI+): m/z=450.2.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]([C:11]3[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)[C:7]([CH2:9]Cl)=[N:8][C:4]=2[CH:3]=1.[CH3:21][S:22]([C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][N:26]=1)(=[O:24])=[O:23]>>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]([C:11]3[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)[C:7]([CH2:9][N:27]3[C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:25]([S:22]([CH3:21])(=[O:23])=[O:24])=[N:26]3)=[N:8][C:4]=2[CH:3]=1
Reactant: COc1ccc(-n2c(CCl)nc3cc(Cl)ccc32)cn1
Reactant: CS(=O)(=O)c1n[nH]c2ccccc12
Product: COc1ccc(-n2c(Cn3nc(S(C)(=O)=O)c4ccccc43)nc3cc(Cl)ccc32)cn1

Procedure:
The title compound was prepared in analogy to Example 3-1 by using 5-chloro-2-chloromethyl-1-(6-methoxy-pyridin-3-yl)-1H-benzoimidazole and 3-methanesulfonyl-1H-indazole instead of 5-chloro-2-chloromethyl-1-(4,4,4-tri fluoro-butyl)-1H-benzoimidazole and 3-methanesulfonyl-1H-indazole.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([SH:14])=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)=[O:4].Cl[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)=[CH:19][CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+].CCOCC>C(#N)C.O>[F:30][C:29]([F:31])([F:32])[C:26]1[CH:25]=[CH:24][C:23]([C:20]2[CH:21]=[CH:22][C:17]([CH2:16][S:14][C:11]3[CH:12]=[CH:13][C:8]([C:5]4([C:3]([OH:2])=[O:4])[CH2:7][CH2:6]4)=[CH:9][CH:10]=3)=[CH:18][CH:19]=2)=[CH:28][CH:27]=1.[CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:9]=[CH:10][C:11]([S:14][CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:7]1)=[O:4]
Reactant: COC(=O)C1(c2ccc(S)cc2)CC1
Reactant: FC(F)(F)c1ccc(-c2ccc(CCl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: O
Solvent: CC#N
Product: COC(=O)C1(c2ccc(SCc3ccc(-c4ccc(C(F)(F)F)cc4)cc3)cc2)CC1
Product: O=C(O)C1(c2ccc(SCc3ccc(-c4ccc(C(F)(F)F)cc4)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 134917.3 %

Procedure:
Compound 36C (416 mg, 2.0 mmol) was dissolved in acetonitrile (50 mL) with example 36E (568 mg, 2.1 mmol) and Cs2CO3 (1.3 g, 4.0 mmol). The reaction mixture was stirred at RT overnight. Ether (50 mL) and H2O were added and stirring was continued for another 5 min. The layers were separated and the aqueous layer was extracted with ether (2×100 mL). The combined organics was dried over MgSO4 and concentrated to an oil. The crude product was purified by column chromatography eluted with EtOAc and hexanes to give the desired product, compound 36F as a thick yellow oil (597 g, 68%). MS: 443 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5](=[CH:7][CH:8]=1)[OH:6].[C:10](=O)([O-])[O-].[Cs+].[Cs+].ClCCl>CN(C)C=O>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]2[O:6][CH2:10][O:9][C:4]=2[CH:3]=1
Reactant: Cc1ccc(O)c(O)c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc2c(c1)OCO2
Temperature: 110 °C
Yield: 303.8 %

Procedure:
4-methylcatechol (15 g, 120.9 mmol) was added to a suspension of cesium carbonate (50 g, 154 mmol) in dimethylformamide (60 mL). The mixture was put under vacuum and purged with nitrogen three times. At ambient temperature, dichloromethane (15.4 g, 181.3 mmol) was added, and then the reaction mixture was heated at about 110° C. for about 2 hours. After cooling to ambient temperature, the reaction was quenched with water (500 mL) and extracted with ether-pentane (1:1 ratio, 3×500 mL). The combined organic layers were washed with water (3×1000 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford the desired product (50 g, 30%). 1H NMR (300 MHz, CDCl3) δ 6.71-6.59 (m, 3H), 5.88 (s, 2H), 2.27 (s, 3H); GC-MS: m/z=136 (MH)+.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].[Br:8][C:9]1[CH:14]=[CH:13]C(C)=[CH:11][C:10]=1[F:16].S(=O)(=O)(O)O.[C:22](O)(=[O:24])[CH3:23]>[O-2].[O-2].[O-2].[Cr+6]>[C:1]([O:4][CH:5]([O:7][C:22](=[O:24])[CH3:23])[C:6]1[CH:13]=[CH:14][C:9]([Br:8])=[C:10]([F:16])[CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: Cc1ccc(Br)c(F)c1
Reactant: CC(=O)OC(C)=O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Product: CC(=O)OC(OC(C)=O)c1ccc(Br)c(F)c1
Reaction time: 0.5 h

Procedure:
A mixture of acetic acid (108 ml), acetic anhydride (0.58 ml) and 4-bromo-3-fluorotoluene (20 g) was cooled to -10° when concentrated sulphuric acid (22.5 mls) was added dropwise, such that the temperature did not exceed -5°. When the addition was complete, chromium trioxide (31.3 g) was added portionwise at such a rate that the temperature did not exceed 5°. The resulting mixture was stirred for 30 minutes and then poured onto ice (300 g). The reaction mixture was then extracted with diethyl ether and the combined ethereal extracts were washed with 2M sodium hydroxide and brine before drying over anhydrous magnesium sulphate and evaporation in vacuo. Recrystallisation from hexane gave 4-bromo-3-fluorobenzylidene diacetate (15 g).