Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6].[C:11]([O-:14])(=[S:13])[CH3:12].[K+].O>CN(C)C=O>[C:11]([S:13][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])(=[O:14])[CH3:12]
Reactant: C=CCOC(=O)CCCBr
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOC(=O)CCCSC(C)=O
Yield: 96.7 %

Procedure:
Allyl 4-bromobutyrate (19.7 g) was treated with potassium thioacetate (10.9 g) in dimethyl formamide (100 ml) at 20° C. for 2 hours. Water (500 ml) was added and the mixture extracted with diethyl ether. The ethereal solution was washed with dilute aq. HCl, brine, dried (MgSO4) and evaporated to give the title compound as an oil (18.6 g, 97%)
Reaction SMILES: [CH2:1]([O:8][CH:9]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[F:32][C:33]([F:42])([F:41])[C:34]1[CH:35]=[C:36]([CH:38]=[CH:39][CH:40]=1)[NH2:37]>ClCCl.CN(C)C1C=CN=CC=1.O>[CH2:14]([O:13][CH:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:10]([NH:37][C:36]1[CH:38]=[CH:39][CH:40]=[C:34]([C:33]([F:32])([F:41])[F:42])[CH:35]=1)=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)C(OCc1ccccc1)OCc1ccccc1
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1cccc(C(F)(F)F)c1)C(OCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
A stirred solution of dibenzyloxyacetic acid (4.0 g) in dichloromethane (40 ml) was cooled to 0° C. and treated dropwise with, successively, DMF (100 mg) and oxalyl chloride (2.0 g). After 30 min pyrridine (3.52 g), 3-trifluoromethyl aniline (2.64 g) and 4-dimethylaminopyridine (100 mg) were added. The mixture was stirred at 0° C. for a further 30 min then allowed to warm to room temperature. After 3 hours the mixture was poured into water, extracted with ethyl acetate and the extracts washed successively with dilute hydrochloric acid, water, aqueous sodium bicarbonate solution and brine. After drying (MgSO4) the extracts were evaporated under reduced pressure to give the sub-title compound (5.62 g) as an orange gum, sufficiently pure to be used in step d).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.CN.[CH3:17][N:18](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH:18][CH3:17])=[O:8]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Agent: CN
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)c1cc(F)ccc1[N+](=O)[O-]

Procedure:
A solution of 5-fluoro-2-nitrobenzoic acid (0.550 g, 2.97 mmol), methylamine hydrochloride (0.241 g, 3.56 mmol), TBTU (0.954 g, 2.97 mmol), and DIPEA (1.15 g, 8.91 mmol) in DCM (10.0 mL) was stirred at rt for 30 minutes. The reaction was quenched with saturated NaHCO3 (10 mL) and extracted with DCM (15 mL). The organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to yield a yellow semi-solid. 1H NMR (CDCl3, 400 MHz): δ=3.06 (d, J=5.05 Hz, 3H), 7.20-7.26 (m, 1H), 8.16 (dd, J=8.84, 4.55 Hz, 1H). MS (ES+): m/z 199.05 [MH+] (TOF, polar).
Reaction SMILES: [CH2:1]([C:5]1[C:9](/[CH:10]=[CH:11]/[C:12]2[S:13][C:14]([C:18]([OH:20])=O)=[C:15]([CH3:17])[N:16]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:22]1[CH2:26][C@H:25]([OH:27])[C@@H:24]([NH2:28])[CH2:23]1.Cl>>[OH:27][C@H:25]1[CH2:26][CH2:22][CH2:23][C@@H:24]1[NH:28][C:18]([C:14]1[S:13][C:12](/[CH:11]=[CH:10]/[C:9]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=2[CH3:21])=[N:16][C:15]=1[CH3:17])=[O:20]
Reactant: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)O)s1
Reactant: N[C@H]1CCC[C@@H]1O
Agent: Cl
Product: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)N[C@H]2CCC[C@@H]2O)s1
Yield: 65 %

Procedure:
As described for example 104, 2-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid (153 mg, 0.5 mmol) was converted, using trans-(1S,2S)-2-aminocyclopentanol hydrochloride instead of rac-2-amino-1-butanol, to the title compound (127 mg, 65%) which was obtained as an off white solid after purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) and recrystallization from ethyl acetate/heptane. MS: m/e=390.3 [M+H]+.
Reaction SMILES: [K:1].[K].[OH:3][C:4]1[CH:16]=[CH:15][C:14]([CH:17]=[CH:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([OH:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[CH:13][C:5]=1[C:6]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[O:7].[C:29](O)(=[O:31])[CH3:30].C(OC(=O)C)(=O)C.S(=O)(=O)(O)O>C(OCC)C>[K:1].[C:29]([O:3][C:4]1[CH:16]=[CH:15][C:14]([CH:17]=[CH:18][C:19]2[CH:20]=[CH:21][C:22]([S:25]([OH:28])(=[O:26])=[O:27])=[CH:23][CH:24]=2)=[CH:13][C:5]=1[C:6]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[O:7])(=[O:31])[CH3:30]
Reactant: CC(=O)O
Reactant: CC(C)COC(=O)c1cc(C=Cc2ccc(S(=O)(=O)O)cc2)ccc1O
Agent: O=S(=O)(O)O
Agent: [K]
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: CC(=O)Oc1ccc(C=Cc2ccc(S(=O)(=O)O)cc2)cc1C(=O)OCC(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Isobutyl 2-hydroxy-5-[2-(4-sulfophenyl)ethenyl]benzoate dipotassium salt (37.2 g, 0.09 mol) was added to a boiling solution of acetic acid (20 ml) and acetic anhydride (80 ml). Sulfuric acid (8 ml) was added cautiously and the mixture refluxed until the major part of the solids had dissolved, and then more acetic anhydride (80 ml) was added. After boiling for 1 h, the mixture was cooled to room temperature. Diethyl ether (350 ml) was added and the suspension filtered and washed with diethyl ether. Yield 36.1 g (88%).
Reaction SMILES: Cl.Cl.[CH3:3][C@@:4]1([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[O:8][C:7]2=[N:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][N:6]2[CH2:5]1.C(=O)([O-])[O-].[K+].[K+].[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH2:36][CH2:37][N:38]([C:41](Cl)=[O:42])[CH2:39][CH:40]=2)=[CH:31][CH:30]=1.O>CN(C=O)C>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH2:40][CH2:39][N:38]([C:41]([N:19]3[CH2:18][CH2:17][N:16]([CH2:15][C@:4]4([CH3:3])[O:8][C:7]5=[N:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][N:6]5[CH2:5]4)[CH2:21][CH2:20]3)=[O:42])[CH2:37][CH:36]=2)=[CH:31][CH:30]=1
Reactant: C[C@]1(CN2CCNCC2)Cn2cc([N+](=O)[O-])nc2O1
Reactant: O=C(Cl)N1CC=C(c2ccc(Cl)cc2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@]1(CN2CCN(C(=O)N3CC=C(c4ccc(Cl)cc4)CC3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52 %

Procedure:
A mixture of (S)-2-methyl-6-nitro-2-(piperazin-1-ylmethyl)-2,3-dihydroimidazo[2,1-b]oxazole dihydrochloride prepared in Example 408 (401 mg, 1.5 mmol), DMF (8 ml) and potassium carbonate (750 mg, 5.4 mmol) was stirred at room temperature for 10 minutes. To the reaction mixture, a solution of 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine-1-carbonylchloride (400 mg, 1.56 mmol) in DMF (3 ml) was added slowly with cooling on ice-bath followed by stirring at room temperature overnight. To the reaction mixture, water was added, and the solution was extracted with ethyl acetate. The organic phase was washed with water three times and a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethanol to afford (S)-[4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl]-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]methanone (380 mg, yield 53%) as a light yellow powder.
Reaction SMILES: BrCC1C=CC(C(OC)=O)=CC=1.N1N=C(S)NC=1.N1N=C(SCC2C=CC(C(OC)=O)=CC=2)NC=1.[N:36]1[N:37]=[C:38]([S:41]([CH2:43][C:44]2[CH:53]=[CH:52][C:47]([C:48]([O:50]C)=[O:49])=[CH:46][CH:45]=2)=[O:42])[NH:39][CH:40]=1.[N:54]1[N:55]=[C:56]([S:59]([CH2:62][C:63]2[CH:72]=[CH:71][C:66]([C:67]([O:69]C)=[O:68])=[CH:65][CH:64]=2)(=[O:61])=[O:60])[NH:57][CH:58]=1>>[N:36]1[N:37]=[C:38]([S:41]([CH2:43][C:44]2[CH:53]=[CH:52][C:47]([C:48]([OH:50])=[O:49])=[CH:46][CH:45]=2)=[O:42])[NH:39][CH:40]=1.[N:54]1[N:55]=[C:56]([S:59]([CH2:62][C:63]2[CH:72]=[CH:71][C:66]([C:67]([OH:69])=[O:68])=[CH:65][CH:64]=2)(=[O:61])=[O:60])[NH:57][CH:58]=1
Reactant: COC(=O)c1ccc(CS(=O)(=O)c2nnc[nH]2)cc1
Reactant: COC(=O)c1ccc(CS(=O)c2nnc[nH]2)cc1
Agent: COC(=O)c1ccc(CBr)cc1
Agent: COC(=O)c1ccc(CSc2nnc[nH]2)cc1
Agent: Sc1nnc[nH]1
Product: O=C(O)c1ccc(CS(=O)(=O)c2nnc[nH]2)cc1
Product: O=C(O)c1ccc(CS(=O)c2nnc[nH]2)cc1

Procedure:
500 mg of methyl 4-(bromomethyl)benzoate was reacted with 4H-1,2,4-triazole-3-thiol via Procedure Q. 542 mg of methyl 4-((4H-1,2,4-triazol-3-ylthio)methyl)benzoate was subsequently reacted via Procedure R to give an approximate 1:9 mixture of methyl 4-((4H-1,2,4-triazol-3-ylsulfinyl)methyl)benzoate and methyl 4-((4H-1,2,4-triazol-3-ylsulfonyl)methyl)benzoate. The mixture of 467 mg was hydrolyzed via Procedure M to give 4-((4H-1,2,4-triazol-3-ylsulfinyl)methyl)benzoic acid and 4-((4H-1,2,4-triazol-3-ylsulfonyl)methyl)benzoic acid. 107 mg of the mixture of 4-((4H-1,2,4-triazol-3-ylsulfinyl)methyl)benzoic acid and 4-((4H-1,2,4-triazol-3-ylsulfonyl)methyl)benzoic acid was coupled to 75 mg of 4-chloro-3-(pyridin-2-yl)aniline via Procedure G. The mixture was seperated on reverse phase HPLC to give 4-((4H-1,2,4-triazol-3-ylsulfinyl)methyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. MS (Q1) 438.1 (M)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].Br[C:12](Br)([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:5]([C:4]1[CH:7]=[CH:8][C:9]2[O:10][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])([C:18]([O:20][CH2:21][CH3:22])=[O:19])[O:1][C:2]=2[CH:3]=1)=[O:6]
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: CCOC(=O)C(Br)(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C1(C(=O)OCC)Oc2ccc(C=O)cc2O1

Procedure:
One equivalent of 3,4-dihydroxybenzaldehyde, 1.1 equivalents of diethyl dibromomalonate and powdered potassium carbonate is stirred in acetonitrile at room temperature for 18 hours. The reaction mixture is filtered, evaporated in vacuo, and distilled to give diethyl 5-formyl-1,3-benzodioxole-2,2-dicarboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]=1[C:16]([CH3:22])([CH3:21])[C:17]([O:19][CH3:20])=[O:18])[C:6]([O:8]C(C)(C)C)=[O:7].C(O)(C(F)(F)F)=O.C(Cl)[Cl:31]>>[ClH:31].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]=1[C:16]([CH3:22])([CH3:21])[C:17]([O:19][CH3:20])=[O:18])[C:6]([OH:8])=[O:7]
Reactant: COC(=O)C(C)(C)c1ccc(C(=O)OC(C)(C)C)cc1OC
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(C)(C)c1ccc(C(=O)O)cc1OC
Product: Cl
Reaction time: 2 h

Procedure:
To the crude tert-butyl 3-methoxy-4-(1-methoxy-2-methyl-1-oxopropan-2-yl)benzoate from Step 2 was added DCM (1 mL) followed by TFA (540 μL, 7.0 mmol). The reaction was allowed to stir for 2 h before it was concentrated in vacuo. The residue was dissolved in DMF, filtered and was purified by prep-HPLC (MeOH:H2O, 1-99% in an HCl modifier) to give 3-methoxy-4-(1-methoxy-2-methyl-1-oxopropan-2-yl)benzoic acid. ESI-MS m/z calc. 252.1, found 253.2 (M+1)+; Retention time: 2.45 minutes (4 min run).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[C:18]([C:19](OC)=[O:20])[C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH3:23]>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([NH2:23])=[O:20])[C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: N
Reactant: COC(=O)c1cccc2[nH]c(-c3ccc([N+](=O)[O-])cc3)nc12
Product: NC(=O)c1cccc2[nH]c(-c3ccc([N+](=O)[O-])cc3)nc12

Procedure:
Following standard procedure C, methyl 2-(4′-nitrophenyl)-1-H-benzimidazole-4-carboxylate was dissolved in liquid ammonia and heated under constant volume in a pressure vessel. The product was purified by column chromatography from dichloromethane/methanol 99:1 and recrystallised from methanol. mp >310° C.; δH 7.48-7.56 (1H, t), 7.90-7.94 (1H, d), 8.00 (1H, s, NH), 8.00-8.04 (1H, d), 8.52-8.56 (2H, d, J=8.8), 8.60-8.64 (2H, d, J=8.8), 9.3-9.4 (1H, br s, NH), 13.8-14.0 (1H, br s, NH)
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:14])=O>CN(C=O)C.C(Cl)Cl>[I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: O=C(O)c1ccccc1I
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccccc1I

Procedure:
2-Iodobenzoic acid (65.92 g, 0.266 mol), oxalyl chloride (40.5 g, 0.319 mol) , CH2Cl2 (200 mL) and DMF (10 drops) were stirred at RT overnight. The reaction solution was concentrated, toluene was added and the solution concentrated to afford the crude 2-iodobenzoyl chloride.
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:33])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[Br:34]Br>C(Cl)(Cl)Cl>[CH2:1]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:33])[CH:23]([Br:34])[C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: BrBr
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)Cc2ccc([N+](=O)[O-])cc2)cc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)C(Br)c2ccc([N+](=O)[O-])cc2)cc1
Yield: 94.9 %

Procedure:
80 g (0.18 mol) of p-n-tetradecyloxy-ω-(p-nitrophenyl)acetophenone prepared as described above was dissolved in 400 cc of chloroform and to the solution 28 g (0.18 mol) of bromine dissolved in 50 cc of chloroform was gradually added dropwise while refluxing with heating. The mixture was washed with water and dried with anhydrous sodium sulfate. Chloroform was distilled off under reduced pressure and 91 g of p-n-tetradecyloxy-ω-bromo-ω-(p-nitrophenyl)acetophenone was obtained after recrystallization from n-hexane. Yield: 95%, Melting Point: 55° to 56° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH2:16])=[CH:4][CH:3]=1.[N:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:32][CH2:31][CH:27]([C:28]([Cl:30])=[O:29])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1>>[ClH:30].[N:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:25][CH2:26][CH:27]([C:28]([NH:16][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[O:17])=[O:29])[CH2:31][CH2:32]2)=[CH:20][CH:19]=1
Reactant: Nc1ccccc1C(=O)Nc1ccc(F)cc1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Product: Cl
Product: O=C(Nc1ccc(F)cc1)c1ccccc1NC(=O)C1CCN(c2ccncc2)CC1
Yield: 34.9 %

Procedure:
Using the procedure described in Example 138, N-(4-fluorophenyl)-2-aminobenzamide (0.92 mmol) and N-(4-pyridyl)isonipecotoyl chloride (1.8 mmol), purifying with RPHPLC Method A, yielded 146 mg (35%) of the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([CH3:7])(=[O:6])=[O:5].[CH3:8][N:9]([CH3:28])[C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([N:25]([CH3:27])[CH3:26])[C:19]=1[N:20]([CH3:24])[C:21](=[O:23])[CH3:22])[C:13](OC)=[O:14]>CS(C)=O>[CH3:27][N:25]([CH3:26])[C:18]1[CH:17]=[C:12]([C:13](=[O:14])[CH2:3][S:4]([CH3:7])(=[O:6])=[O:5])[CH:11]=[C:10]([N:9]([CH3:28])[CH3:8])[C:19]=1[N:20]([CH3:24])[C:21](=[O:23])[CH3:22]
Reactant: COC(=O)c1cc(N(C)C)c(N(C)C(C)=O)c(N(C)C)c1
Reactant: CS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)N(C)c1c(N(C)C)cc(C(=O)CS(C)(=O)=O)cc1N(C)C
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A suspension of 0.77 g. of sodium hydride (50% suspension in oil) and 2.28 g. of dimethylsulfone in 28 ml. of dimethylsulfoxide was stirred with the exclusion of moisture and under nitrogen for 2 hours at 50° C. 2 G. of methyl 3,5-bis(dimethylamino)-4-(N-methylacetamido)benzoate were then added, the mixture heated to 70° C. for a short time and stirred for a further 2 hours without heating. The solution was diluted with 100 ml. of ice water, washed with 100 ml. of low-boiling petroleum ether, the product extracted with ethyl acetate, the ethyl acetate solution dried over sodium sulfate and evaporated. After purification of the residue over aluminum oxide with benzene and recrystallization from ethyl acetate/petroleum ether, there was obtained 2'.6'-bis(dimethylamino)-N-methyl-4'-[(methylsulfonyl)acetyl]acetanilide having a melting point of 130° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[O:12]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(=O)c1ccc(F)cc1
Product: O=C(C=Cc1ccc(Cl)cc1)c1ccc(F)cc1

Procedure:
By a procedure similar to that of example 1.59.1, starting from 4-chlorobenzaldehyde and commercial 4-fluoroacetophenone, 3-(4-chlorophenyl)-1-(4-fluorophenyl)prop-2-en-1-one was obtained as yellowish solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:17][O:18][C:19](=[O:30])[C:20]1[CH:25]=[C:24]([CH2:26]Br)[CH:23]=[CH:22][C:21]=1[O:28][CH3:29].[C:31](=O)([O-])[O-].[K+].[K+]>C(C(CC(C)C)=O)C>[CH2:17]([O:18][C:19](=[O:30])[C:20]1[CH:25]=[C:24]([CH2:26][N:14]2[CH2:15][CH2:16][CH:11]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[NH:8][CH:7]=3)[CH2:12][CH2:13]2)[CH:23]=[CH:22][C:21]=1[O:28][CH3:29])[CH3:31]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(CBr)ccc1OC
Reactant: Fc1ccc2c(C3CCNCC3)c[nH]c2c1
Agent: CCC(=O)CC(C)C
Agent: [K+]
Product: CCOC(=O)c1cc(CN2CCC(c3c[nH]c4cc(F)ccc34)CC2)ccc1OC
Temperature: 90 °C

Procedure:
A suspension containing 0.5 g (2.2 mmol) of 6-fluoro-3-piperidin-4-yl-1H-indole, 0.8 g (2.7 mmol) of 5-bromomethyl-2-methoxy-benzoic acid methyl ester and 0.6 g (4.3 mmol) of potassium carbonate in 10 ml of ethyl isobutylketone was heated at 90° C. for 16 hours. The inorganic solid was filtrated and the solvent was removed under reduced pressure. 0.91 g (97% of yield) of the expected product was obtained.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[C:10]([N:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]3=[O:20])[CH:11]=[CH:12][C:5]=2[N:4]=1)[CH3:2].[F:21][C:22]([F:31])([F:30])[C:23]1[S:27][CH:26]=[C:25]([CH2:28]O)[CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCCOC)=O)=NC(OCCOC)=O>C1COCC1.O>[CH2:1]([C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[C:10]([N:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:28][C:25]4[CH:24]=[C:23]([C:22]([F:31])([F:30])[F:21])[S:27][CH:26]=4)=[CH:15][C:14]3=[O:20])[CH:11]=[CH:12][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccc(-n3ccc(O)cc3=O)cc2n1C
Reactant: OCc1csc(C(F)(F)F)c1
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc2ccc(-n3ccc(OCc4csc(C(F)(F)F)c4)cc3=O)cc2n1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 14.5 %

Procedure:
To a solution of 1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (300 mg), (5-(trifluoromethyl)-3-thienyl)methanol (352 mg) and triphenylphosphine (877 mg) in THF (10 ml) was added bis(2-methoxyethyl) azodicarboxylate (783 mg), and the mixture was stirred at room temperature for 3 h. The mixture was poured into water and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated and purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH). The resulting solid was recrystallized from IPA-IPE to give the title compound (70.0 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]([O:11]CC(C)=C)=[CH:9][C:8]([CH3:16])=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[CH:17]=[O:18].[CH3:19][C:20]1[CH:28]=C(CC(C)=C)C(C)=C2[C:21]=1C=CN2C=O>CN(C)C1C=CC=CC=1.CCCCCC>[OH:11][C:10]1[C:2]([CH3:1])=[C:3]2[C:7](=[C:8]([CH3:16])[C:9]=1[CH2:21][C:20]([CH3:28])=[CH2:19])[N:6]([CH:17]=[O:18])[CH2:5][CH2:4]2
Reactant: C=C(C)COc1cc(C)c2c(c1C)CCN2C=O
Reactant: C=C(C)Cc1cc(C)c2ccn(C=O)c2c1C
Solvent: CN(C)c1ccccc1
Solvent: CCCCCC
Product: C=C(C)Cc1c(C)c2c(c(C)c1O)CCN2C=O
Temperature: 220 °C
Reaction time: 7 h
Yield: 91 %

Procedure:
2,3-Dihydro-5-hydroxy group-4,7-dimethyl-6-(2-methyl-2-propenyl)-1H-indole-1-carbaldehyde 2,3-Dihydro-4,7-dimethyl-5-[(2-methyl-2-propenyl)oxy]-1H-indole-1-carbaldehyde (6.00 g, 24.4 mmol) was suspended in N,N-dimethylaniline (25 ml) and stirred under argon atmosphere at 220° C. for 7 hours. The reaction mixture was cooled and diluted with hexane (50 ml) and stirred for 30 minutes. The precipitated crystals were filtered and washed with hexane to obtain 5.45 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Br:8].[CH3:9][S:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1>>[Br:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:14]1[CH:15]=[CH:16][C:11]([S:10][CH3:9])=[CH:12][CH:13]=1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: Brc1ccccc1Br
Product: CSc1ccc(-c2ccccc2Br)cc1
Yield: 88 %

Procedure:
Following the general procedure outlined in Synthetic Scheme IV, 33 g (140 mmol) of 1,2-dibromobenzene was reacted with 12 g (70 mmol) of 4-methylthiophenylboronic acid (Example 1, Step 2). Purification by silica gel chromatography with hexane gave 17.2 g (89%) of 1-bromo-2-[4-(methylthio)phenyl]benzene as a colorless oil: NMR (CDCl3) δ 2.53 (s, 3H), 7.16-7.23 (m, 1H), 7.28-7.39 (m, 6H), 7.66 (d, J=8 Hz, 1H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:7]([C:13]([F:16])([F:15])[F:14])=[C:6](Cl)[CH:5]=1)[CH3:2].C[O-].[Na+].[CH3:21][O:22]NC1C=CC=CC=1>CO>[CH2:1]([NH:3][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:7]([C:13]([F:16])([F:15])[F:14])=[C:6]([O:22][CH3:21])[CH:5]=1)[CH3:2]
Reactant: CONc1ccccc1
Reactant: CCNc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCNc1cc(OC)c(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 119 °C

Procedure:
A solution of 14.0g. (0.052 mole) of N-ethyl-3-chloro-6-nitro-4-trifluoromethylaniline and 16.98g. (0.057 mole) of 18.23% methanolic sodium methoxide in 25 ml. of anhydrous methanol was sealed in a glass tube and heated at 119°C. for 88 hours. Removal of the solvent by distillation left a yellow solid residue which was triturated with hot chloroform. Filtration and evaporation of chloroform from the filtrate gave a crude solid residue. Crystallization of the residue from ethanol gave 12.4g. of yellow crystalline product, m.p. 140.5°-141.5°C. shown by its nmr spectrum to be the desired methoxyaniline.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Br:11][C:12]1[N:13]([CH2:25][C:26]#[C:27][CH3:28])[C:14]([C:21]([O:23][CH3:24])=[O:22])=[C:15]([C:17](OC)=[O:18])[N:16]=1.Cl.O>O1CCCC1>[Br:11][C:12]1[N:13]([CH2:25][C:26]#[C:27][CH3:28])[C:14]([C:21]([O:23][CH3:24])=[O:22])=[C:15]([CH:17]=[O:18])[N:16]=1
Reactant: CC#CCn1c(Br)nc(C(=O)OC)c1C(=O)OC
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CC#CCn1c(Br)nc(C=O)c1C(=O)OC
Temperature: -70 °C
Reaction time: 4 h

Procedure:
43 ml of a 1 M solution of diisobutylaluminium hydride in tetrahydrofuran are added dropwise within 20 minutes to a solution of 13.5 g of dimethyl 2-bromo-1-(2-butyn-1-yl)-1H-imidazole-4,5-dicarboxylate in 220 ml of tetrahydrofuran under an argon atmosphere at −70° C. The mixture is stirred for a further four hours at −70° C., then 20 ml of a mixture of 1 M hydrochloric acid and tetrahydrofuran are added dropwise. After heating to ambient temperature approx. 200 ml of water are added and the mixture is extracted three times with 70 ml of ethyl acetate. The combined extracts are dried and evaporated down. The crude product thus obtained is purified by column chromatography through silica gel with petroleum ether/ethyl acetate (4:1->1:1) as eluant.