Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.[CH2:18]([O:20][C:21]([C:23]1([CH2:29][CH:30]2[CH2:32][CH2:31]2)[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22])[CH3:19].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:18]([O:20][C:21]([C:23]1([CH2:29][CH:30]2[CH2:31][CH2:32]2)[CH2:24][CH2:25][N:26]([C:14]([C:11]2[CH:10]=[CH:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:13][CH:12]=2)=[O:16])[CH2:27][CH2:28]1)=[O:22])[CH3:19]
Reactant: O=C(O)c1ccc(-c2ccc(F)cc2)cc1
Reactant: CCOC(=O)C1(CC2CC2)CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(CC2CC2)CCN(C(=O)c2ccc(-c3ccc(F)cc3)cc2)CC1
Temperature: 25 °C

Procedure:
A mixture of 0.31 g (1.4 mmol) 4′-fluoro-biphenyl-4-carboxylic acid, 0.426 g (1.71 mmol) 4-cyclopropylmethyl-piperidine-4-carboxylic acid ethyl ester, hydrochloride, 0.552 g (1.71 mmol) TBTU and 1.23 mL DIPEA in 25 mL DMF was stirred at room temperature over night. After evaporation to dryness the residue was purified by column chromatography on silica eluting with a gradient formed from ethyl acetate and heptane to yield after evaporation of the product containing fractions 0.51 g (87%) of the title compound as light yellow viscous oil. MS ISP (m/e): 410.3 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[C:4](C)[CH:3]=1.[Cl:12][C:13]1[C:14]([F:21])=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.[CH3:22][O-].[Na+]>CO>[Cl:12][C:13]1[C:14]([F:21])=[C:15](/[CH:16]=[C:6](/[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[C:10]([CH3:22])[CH:9]=2)\[C:7]#[N:8])[CH:18]=[CH:19][CH:20]=1
Reactant: Cc1cc(Cl)ccc1CC#N
Reactant: O=Cc1cccc(Cl)c1F
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(/C(C#N)=C/c2cccc(Cl)c2F)ccc1Cl
Yield: 90.7 %

Procedure:
Step C In a manner similar to the method described in Example 1b, 4-chloro-2-methylbenzyl cyanide (1.2 g, 7.2 mmol) was reacted with 3-chloro-2-fluorobenzaldehyde (1.38 g, 8.7 mmol), methanolic solution (25 wt %) of sodium methoxide (1.82 mL, 8 mmol) in methanol (50 mL) at 50° C. for 3 h to give (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-3-methyl-phenyl)-acrylonitrile as a white solid (2.0 g, 91%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:32]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:18]3[N:19]=[CH:20][N:21]=[C:22]([O:23][C:24]4[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([Cl:31])[CH:25]=4)[C:17]=3[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:41]1[CH:46]=C[CH:44]=[CH:43][CH:42]=1.C(Cl)(=O)[O:48]C1C=CC=CC=1.C1(N)CC1>CN(C)C=O.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:32]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:18]3[N:19]=[CH:20][N:21]=[C:22]([O:23][C:24]4[CH:29]=[CH:28][C:27]([NH:30][C:46]([NH:41][CH:42]5[CH2:44][CH2:43]5)=[O:48])=[C:26]([Cl:31])[CH:25]=4)[C:17]=3[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OCc3ccccc3)cc2)cc2c(Oc3ccc(N)c(Cl)c3)ncnc21
Reactant: c1ccncc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: NC1CC1
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(-c2ccc(OCc3ccccc3)cc2)cc2c(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)ncnc21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
After dissolving 334 mg of the 4-[6-(4-benzyloxyphenyl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-2-chlorophenyl amine synthesized in Production Example 153-5 in 4 ml of dimethylformamide, 0.066 ml (1.4 equivalents) of pyridine and 0.102 ml (1.4 equivalents) of phenyl chlorocarbonate were added, and after stirring at room temperature for 2.5 hours, 0.09 ml (2.2 equivalents) of cyclopropylamine was added and the mixture was stirred overnight. Water was added, liquid separation and extraction were performed with ethyl acetate, and the organic layer was washed with saturated brine, dried over sodium sulfate, concentrated and subjected to silica gel column chromatography (hexane-ethyl acetate) to obtain 330 mg of the title compound.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:15]=[C:16]([CH:37]=[CH:38][CH:39]=2)[C:17]([NH:19][C:20]2[CH:21]=[C:22]([NH:27][C:28]([C:30]3[CH:35]=[CH:34][N:33]=[C:32](Cl)[CH:31]=3)=[O:29])[CH:23]=[CH:24][C:25]=2[CH3:26])=[O:18])[CH2:9][CH2:8]1.CS(C)=O>O>[CH3:6][N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:15]=[C:16]([CH:37]=[CH:38][CH:39]=2)[C:17]([NH:19][C:20]2[CH:21]=[C:22]([NH:27][C:28]([C:30]3[CH:31]=[CH:32][N:33]=[C:34]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:35]=3)=[O:29])[CH:23]=[CH:24][C:25]=2[CH3:26])=[O:18])[CH2:9][CH2:8]1
Reactant: C1CCNC1
Reactant: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1NC(=O)c1cccc(CN2CCN(C)CC2)c1
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(NC(=O)c2ccnc(N3CCCC3)c2)cc1NC(=O)c1cccc(CN2CCN(C)CC2)c1
Temperature: 120 °C
Yield: 2.6 %

Procedure:
Pyrrolidine (0.3 g) was added to a stirred mixture of N-{3-[3-(4-methylpiperazin-1-ylmethyl)benzamido]-4-methylphenyl}-2-chloropyridine-4-carboxamide (0.5 g) and DMSO (5 ml) and the mixture was stirred and heated to 120° C. for 16 hours. The resultant solution was cooled to ambient temperature and poured into water and extracted with methylene chloride. The organic phase was evaporated and the residue was purified by column chromatography on an isolute SCX ion exchange column using a 99:1 mixture of methanol and a saturated aqueous ammonium hydroxide solution as eluent. There was thus obtained the title compound (0.014 g); Mass Spectrum: M+H+513.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].Br[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:23][CH:22]=1>CN1CCCC1=O.O>[C:28]([O:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][CH2:19][CH:3]2[C:4]3[C:12]4[CH:11]=[C:10]([CH3:13])[CH:9]=[CH:8][C:7]=4[NH:6][C:5]=3[CH2:14][CH2:15][N:2]2[CH3:1])=[CH:26][CH:25]=1)([CH3:30])([CH3:29])[CH3:31]
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: CC(C)(C)Oc1ccc(CCBr)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc2[nH]c3c(c2c1)C(CCc1ccc(OC(C)(C)C)cc1)N(C)CC3
Temperature: 100 °C
Reaction time: 2 h
Yield: 6.4 %

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.2 g, 0.001 mol) was dissolved in N-methyl 2-pyrolidone (2.0 mL). Powdered potassium hydroxide (0.5 g, 0.0089 mol) was added and heated at 100° C. for 3 h. Reaction mass was cooled to RT and 1-(2-Bromo-ethyl)-4-tert-butoxy-benzene (0.245 g, 0.001 mol) was added at the same temperature and stir for 2 h at RT (TLC showed incomplete reaction). Reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×100 mL). Organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator. The crude was purified through column chromatography (0.5% MeOH:DCM in neutral alumina, Diameter of column—2.5 cm, Height of alumina—approx. 5 inch) then further purified by preparative TLC to provide the desired compound as light yellow oil (0.024 g, 6% yield). 5-[2-(4-tert-Butoxy-phenyl)-ethyl]-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.024 g, 0.000063 mol) was dissolved in THF (1.0 mL), A solution of oxalic acid dihydrate (0.008 g, 0.000063 mol) in THF (1.0 mL) was added and stirred for 30 min at RT. The precipitate was filtered and dried to give oxalate salt as off white solid (0.020 g, 67% yield).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=1.[CH2:9]([Mg]Br)[CH3:10].[Cl-].[NH4+]>C1COCC1.C(OCC)C.CCOC(C)=O>[Br:1][C:2]1[S:3][C:4]([CH:7]([OH:8])[CH2:9][CH3:10])=[CH:5][N:6]=1
Reactant: O=Cc1cnc(Br)s1
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(O)c1cnc(Br)s1
Reaction time: 18 h

Procedure:
To a solution of 2-bromo-thiazole-5-carbaldehyde (1.00 g, 5.21 mmol) in THF (10 mL) was added a 3 M solution of ethylmagnesium bromide (5.00 mL, 15.0 mmol) in diethyl ether. The mixture was stirred for 18 hours. The reaction was poured into saturated aqueous ammonium chloride (100 mL) containing crushed ice and diluted with EtOAc (100 mL). The organic phase was separated, washed with saturated aqueous sodium bicarbonate solution (100 mL), dried over sodium sulfate, filtered and concentrated. The compound was purified by silica gel chromatography eluting with a gradient of 0-100% ethyl acetate in hexanes provided 1-(2-bromo-thiazol-5-yl)-propan-1-ol.
Reaction SMILES: C[C@@H]1N(S(O)(=O)=O)C(=[O:5])[C@H]1NC(/C(/C1N=C(N)SC=1)=N\OC(C(O)=O)(C)C)=O.C(N(CCCC)CCCC)CCC.OC1C2N=NNC=2C=CC=1.CN(C1C=CC=CN=1)C.[CH:61]1([N:67]=[C:68]=[N:69][CH:70]2[CH2:75][CH2:74][CH2:73][CH2:72][CH2:71]2)[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62]1>CN(C)C=O>[C:68]([NH:67][CH:61]1[CH2:62][CH2:63][CH2:64][CH2:65][CH2:66]1)([NH:69][CH:70]1[CH2:75][CH2:74][CH2:73][CH2:72][CH2:71]1)=[O:5]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: C[C@H]1[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)O)c2csc(N)n2)C(=O)N1S(=O)(=O)O
Agent: CN(C)c1ccccn1
Agent: Oc1cccc2[nH]nnc12
Solvent: CCCCN(CCCC)CCCC
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 0.5 h
Yield: 44.8 %

Procedure:
To a solution of aztreonam (2.29 g, 5.27 mmol) in 35 ml dimethylformamide were added tributylamine (0.97 g, 5.27 mmol), hydroxybenzotriazole (0.78 g, 5.79 mmol), dimethylaminopyridine (0.064 g, 0.53 mmol) and dicyclohexylcarbodiimide (1.19 g, 5.79 mmol). After stirring for 30 minutes, the resulting dicyclohexylurea (0.47 g, 40.1%) was filtered off and solution (a) was added to the filtrate. After stirring overnight at room temperature, the mixture was filtered (yielding 0.53 g, 45% of dicyclohexylurea) and evaporated. The residue was taken up in acetone, filtered, and 9.0 ml of 10% potassium perfluorobutane sulfonic acid in acetone were added. The resulting precipitate was filtered off (1.70 g), dissolved in water and chromatographed on XAD under MPLC conditions with a water - acetonitrile gradient. The sample-containing fractions were collected and freeze-dried to give 250 mg (6.9%) of Example 3.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.[Br:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=1[CH3:32].O>C(Cl)(Cl)Cl>[Br:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=1[CH2:32][Br:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(Br)c(C)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(Br)c(CBr)c1
Temperature: 70 °C
Reaction time: 48 h

Procedure:
NBS (46.6 g, 262 mmol) and AIBN (0.72 g, 4.4 mmol) were added in one portion into a solution of methyl 4-bromo-3-methylbenzoate (50.0 g, 218 mmol) in CHCl3 (1 L) under N2. The mixture was stirred at 70° C. for 2 days. The reaction mixture was cooled to RT and water (500 mL) was added. The organic layer was washed with a saturated solution of NaHCO3 (50 mL), water (350 mL) and brine (500 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was washed with pentane (2×500 mL) affording the title compound as a yellow solid. HPLC (Method A), Rt 4.9 min (Purity: 98.2%). 1H NMR (DMSO-d6, 300 MHz) δ 8.24 (d, J=1.9 Hz, 1H), 7.85 (m, 2H), 4.87 (s, 2H), 3.91 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:27]=[CH:26][C:17]([C:18]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[O:19])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.Cl[C:31]1[CH:36]=[CH:35][N:34]=[C:33]([O:37][CH3:38])[CH:32]=1.C(N(CC)CC)C>C(O)CO>[CH3:38][O:37][C:33]1[CH:32]=[C:31]([N:23]2[CH2:24][CH2:25][N:20]([C:18](=[O:19])[C:17]3[CH:26]=[CH:27][C:14]([NH:13][C:7]4[C:6]5[C:11](=[CH:12][C:3]([C:2]([F:1])([F:28])[F:29])=[CH:4][CH:5]=5)[N:10]=[CH:9][CH:8]=4)=[CH:15][CH:16]=3)[CH2:21][CH2:22]2)[CH:36]=[CH:35][N:34]=1
Reactant: COc1cc(Cl)ccn1
Reactant: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCNCC1
Solvent: OCCO
Solvent: CCN(CC)CC
Product: COc1cc(N2CCN(C(=O)c3ccc(Nc4ccnc5cc(C(F)(F)F)ccc45)cc3)CC2)ccn1

Procedure:
In the manner given in Example 5, a mixture of 4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine, 4-chloro-2-methoxypyridine and triethylamine is heated in ethylene glycol at 80° C. to give 1-(2-methoxypyridin-4-yl)-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine.
Reaction SMILES: [C:1]1(O)C=CC=CC=1.[13CH4].[C:9]([C:17]1[CH:27]=[CH:26][C:20]([O:21][CH:22](C)[CH2:23][OH:24])=[CH:19][CH:18]=1)([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:11])[CH3:10]>>[C:9]([C:17]1[CH:18]=[CH:19][C:20]([O:21][CH2:22][CH:23]([OH:24])[CH3:1])=[CH:26][CH:27]=1)([CH2:12][C:13]([CH3:14])([CH3:15])[CH3:16])([CH3:10])[CH3:11]
Reactant: CC(CO)Oc1ccc(C(C)(C)CC(C)(C)C)cc1
Reactant: Oc1ccccc1
Agent: [13CH4]
Product: CC(O)COc1ccc(C(C)(C)CC(C)(C)C)cc1

Procedure:
A 250 mL 2-neck flask was charged with 20.6 g (0.10 mol) of 4-tert-octylphenol obtained from Aldrich Chemical Co., a catalytic amount of dry, ground potassium carbonate (1.38 g, 0.010 mol) obtained from EM Science, Inc., a stir bar, and 95%. ethanol (70 mL) under argon. The side arm was then stoppered, and a condenser with an argon inlet was attached to the center neck. Stirring was commenced to dissolve the phenol, then cold propylene oxide (8.4 mL, 7.0 g, 0.12 mol) obtained from Aldrich Chemical Co. was added. The reaction was refluxed 3 hours, allowed to cool, and the ethanol was removed by rotary evaporation. The colorless oil was dissolved in 120 mL ethyl ether, and washed twice successively with 5% aqueous sodium hydroxide, followed by water. After drying over anhydrous MgSO4, the ether was evaporated off to give 25.3 g of crude product, which contained about 22 mol % unreacted phenol, and about 7 mol % of the 2-(4-tert-octyl-phenoxy)-1-propanol isomer. The product was purified by dissolving in 100 mL hexanes, and extracting with 4×50 mL 5% NaOH in 15:85 v/v water/methanol. The methanol layers were back-extracted with 50 mL hexanes obtained from EM Science, Inc. The hexanes layers were dried over anhydrous MgSO4, and the hexanes removed under vacuum to afford a combined yield of 13.3 g (50%) of material that contained less than 1% unreacted phenol. The structure of the compound was corroborated by proton (1H) and carbon-13 NMR spectrometry. Proton NMR revealed the material to contain about 7 mol % of the 2-(4-tert-octyl-phenoxy)-1-propanol isomer.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10]#[N:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][OH:21])=[CH:14][CH:13]=2)[C:7]([C:22]#[N:23])=[C:6]([SH:24])[N:5]=1)[CH3:2].Cl[CH2:26][C:27]1[N:28]=[C:29]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[S:30][CH:31]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[Cl:38][C:35]1[CH:34]=[CH:33][C:32]([C:29]2[S:30][CH:31]=[C:27]([CH2:26][S:24][C:6]3[C:7]([C:22]#[N:23])=[C:8]([C:12]4[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][OH:21])=[CH:14][CH:13]=4)[C:9]([C:10]#[N:11])=[C:4]([O:3][CH2:1][CH3:2])[N:5]=3)[N:28]=2)=[CH:37][CH:36]=1
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Reactant: CCOc1nc(S)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N

Procedure:
100 mg (0.293 mmol) of 2-ethoxy-4-[4-(2-hydroxyethoxy)phenyl]-6-sulphanylpyridine-3,5-dicarbonitrile together with 78 mg (0.322 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole and 98 mg (1.172 mmol) of sodium bicarbonate are stirred in 2 ml of DMF at room temperature overnight. The reaction mixture is purified by preparative HPLC (acetonitrile/water: 10:90→95:5). This gives 77 mg (47% of theory) of the target compound.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][N:8]=1)[CH3:2]>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[O:14])=[CH:9][N:8]=1)[CH3:2]
Reactant: CCOCCOc1ccc(CO)cn1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CCOCCOc1ccc(C=O)cn1

Procedure:
A total of 16 g of manganese dioxide is added in portions to a boiling solution of 8 g (40.6 mmol) of [2-(2-ethoxyethoxy)-5-pyridyl]-methanol in 200 ml of toluene within two hours. The mixture is then filtered hot and evaporated. Pale yellow oil, yield 7.1 g (90% of theory).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH:21]3[CH2:25][CH2:24][N:23](CC4C=CC=CC=4)[CH2:22]3)[CH:18]=2)[NH:13][C:12]=1[CH3:33])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:34]C(OC(Cl)C)=O.CCCCCC.C(OCC)(=O)C>ClCCCl>[ClH:34].[CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH:21]3[CH2:25][CH2:24][NH:23][CH2:22]3)[CH:18]=2)[NH:13][C:12]=1[CH3:33])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1[nH]c2ccc(OC3CCN(Cc4ccccc4)C3)cc2c1C(=O)OCc1ccccc1
Reactant: CC(Cl)OC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCCl
Product: Cc1[nH]c2ccc(OC3CCNC3)cc2c1C(=O)OCc1ccccc1
Product: Cl
Reaction time: 2 h

Procedure:
5-(1-benzyl-pyrrolidin-3-yloxy)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (0.118 g, 0.268 mmol, 1.0 eq.) was dissolved in dry 1,2-dichloroethane (5 mL) and treated with α-chloroethyl chloroformate (0.035 mL, 0.32 mmol, 1.2 eq.). The reaction was heated to reflux and followed by TLC (hexane/ethyl acetate 1/1). After 2 hours, the reaction was concentrated in vacuo, redissolved in methanol (5 mL), and heated to reflux. After 4 hours, the crude hydrochloride salt was precipitated from methanol/ethyl acetate/hexane to afford a brown solid, which was carried directly to the next step.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])=[O:4].[CH3:13][C:14]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:15]=1[O:16][CH2:17][CH:18]([OH:21])[CH2:19]O.CC1C=CC(S(O)(=O)=O)=CC=1.C(O)CCC>O.C1C=CC=CC=1>[Br:1][CH2:2][C:3]1([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=2[Cl:12])[O:21][CH:18]([CH2:17][O:16][C:15]2[CH:22]=[C:23]([CH3:26])[CH:24]=[CH:25][C:14]=2[CH3:13])[CH2:19][O:4]1
Reactant: Cc1ccc(C)c(OCC(O)CO)c1
Reactant: O=C(CBr)c1ccc(Cl)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Solvent: O
Solvent: c1ccccc1
Product: Cc1ccc(C)c(OCC2COC(CBr)(c3ccc(Cl)cc3Cl)O2)c1

Procedure:
A mixture of 13.6 parts of 2-bromo-1-(2,4-dichlorophenyl)-1-ethanone, 12 parts of 3-(2,5-dimethylphenoxy)-1,2-propanediol, 3 parts of 4-methylbenzenesulfonic acid, 80 parts of butanol and 180 parts of benzene is stirred and refluxed for 24 hours with water-separator. The reaction mixture is evaporated and the residue is dissolved in trichloromethane. The solution is stirred with silicagel for 30 minutes. The latter is filtered off and the filtrate is evaporated, yielding A + B 2-(bromomethyl)-2-(2,4-dichlorophenyl)-4-(2,5-dimethylphenoxymethyl)-1,3-dioxolane as a residue.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][C:9]1[CH:10]=[C:11]([N:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])[CH:12]=[CH:13][CH:14]=1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[CH3:1][S:2]([O:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])[CH:10]=1)(=[O:4])=[O:3]
Reactant: O=C1CCCN1c1cccc(CCO)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1cccc(N2CCCC2=O)c1
Reaction time: 2 h
Yield: 93 %

Procedure:
Methanesulfonyl chloride (0.124 mL) was added dropwise to a stirred solution of 1-[3-(2-hydroxyethyl)phenyl]-2-pyrrolidinone (0.30 g) and triethylamine (0.42 mL) in dichloromethane (10 mL) at room temperature under an inert atmosphere. The solution was stirred for 2 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL), aqueous hydrochloric acid (1N, 2×50 mL), a saturated aqueous solution of sodium hydrogencarbonate (50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel, eluting with ethyl acetate-cyclohexane (50:50) to afford the title compound in 93% yield (0.384 g).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:34])[NH:13][C:14](=[O:33])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25]CCOS(C)(=O)=O)[CH:17]=2)=[CH:3]1.[S:35]1[CH:39]=[CH:38][CH:37]=[C:36]1CC([O-])=O.[K+].CS(C)=[O:47]>O>[C:36]([S:35][CH2:39][CH2:38][CH2:25][N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([C:15]2[C:14](=[O:33])[NH:13][C:12](=[O:34])[C:11]=2[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)=[CH:17]1)(=[O:47])[CH3:37]
Reactant: Cn1cc(C2=C(c3cn(CCCOS(C)(=O)=O)c4ccccc34)C(=O)NC2=O)c2ccccc21
Reactant: O=C([O-])Cc1cccs1
Reactant: CS(C)=O
Agent: [K+]
Solvent: O
Product: CC(=O)SCCCn1cc(C2=C(c3cn(C)c4ccccc34)C(=O)NC2=O)c2ccccc21
Reaction time: 3 h

Procedure:
838 mg of the product of Example 58 in 15 ml of DMSO were treated with 600 mg of potassium thiolacetate. The solution was stirred for 3 hours and then diluted with water. The solution was extracted with ethyl acetate and the ethyl acetate extracts were dried. Concentration and chromatography on silica gel with ethyl acetate gave 723 mg of 3-[1-[3-(acetylthio)propyl]-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione, m.p. 210°-213° C.
Reaction SMILES: [CH:1]1([C:4](=[O:16])[CH2:5][C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][N:9]=2)=[O:7])[CH2:3][CH2:2]1.CC(C)C(O)=O.[CH3:23][N:24]([CH3:27])[CH:25]=O>O1CCOCC1>[CH:1]1([C:4](=[O:16])[C:5](=[CH:23][N:24]([CH3:27])[CH3:25])[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][N:9]=2)=[O:7])[CH2:3][CH2:2]1
Reactant: CN(C)C=O
Reactant: CSc1ccc(C(=O)CC(=O)C2CC2)nc1
Solvent: CC(C)C(=O)O
Solvent: C1COCCO1
Product: CSc1ccc(C(=O)C(=CN(C)C)C(=O)C2CC2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-cyclopropyl-1-[5-(methylsulphenyl)-pyrid-2-yl] propan-1,3-dione (2.9g), dimethylformamide dimethyl acetate and dioxane was stirred at room temperature overnight. It was evaporated to dryness and the residue was triturated with ether and filtered to give 3-cyclopropyl-2-(N,N-dimethylaminomethylene)-1-[5-(methylsulphenyl)-pyrid-2-yl ]propan-1,3-dione (3.24 g) as a brown solid which was used without further characterization.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([CH3:14])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[Br:16]N1C(=O)CCC1=O>C(#N)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([CH2:14][Br:16])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc(C)c1C(=O)OC
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COC(=O)c1cccc(CBr)c1C(=O)OC
Temperature: 70 °C
Yield: 83.6 %

Procedure:
A stirred mixture of 3-methyl-phthalic dimethyl ester (12.1 g, 57.9 mmol) and N-bromosuccinimide (12.4 g, 69.5 mmol) in acetonitrile (150 mL) was heated at 70° C. (oil bath), while a 200 W light bulb situated 2 cm away was shining on the reaction mixture overnight. The resulting mixture was cooled and concentrated. The residue was dissolved in ethyl acetate (150 mL), washed with water (3×50 mL) and brine (50 mL), and dried (MgSO4). Solvent was removed in vacuo, and the residue was purified by flash chromatography (SiO2, Hexane:EtOAc 8:2) to give 3-bromomethyl-phthalic dimethyl ester (13.9 g, 83%) as a solid: 1H NMR (CDCl3) δ 7.94-7.90 (dd, J=1.1 and 7.9 Hz, 1H), 7.65-7.62 (dd, J=1.0 and 6.9 Hz, 1H), 7.47 (t, J=7.8H, 1H), 4.54 (s, 2H), 3.97 (s, 3H), 3.90 (s, 3H).