Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[O:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C.CS(O[CH2:35][CH2:36][CH2:37][N:38]1[C:42]2[CH:43]=[C:44]([Cl:48])[C:45]([Cl:47])=[CH:46][C:41]=2[NH:40][C:39]1=[O:49])(=O)=O>O>[Cl:47][C:45]1[C:44]([Cl:48])=[CH:43][C:42]2[N:38]([CH2:37][CH2:36][CH2:35][N:14]3[CH2:15][CH2:16][CH:11]([C:9](=[O:10])[C:6]4[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=4)[CH2:12][CH2:13]3)[C:39](=[O:49])[NH:40][C:41]=2[CH:46]=1
Reactant: CS(=O)(=O)OCCCn1c(=O)[nH]c2cc(Cl)c(Cl)cc21
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: O=C(c1ccc(F)cc1)C1CCN(CCCn2c(=O)[nH]c3cc(Cl)c(Cl)cc32)CC1
Yield: 25 %

Procedure:
A mixture of 4.4 parts of (4-fluorophenyl) (4-piperidinyl) methanone hydrochloride, 6 parts of sodium carbonate and 160 parts of 4-methyl-2-pentanone is stirred and refluxed for 30 minutes with water-separator. After cooling, 6.2 parts of 3-(5,6-dichloro-2,3-dihydro-2-oxo-1H-benzimidazol-1yl)propyl methanesulfonate are added and the whole is stirred and refluxed overnight. The reaction mixture is cooled, water is added and the layers are separated. The 4-methyl-2-pentanone-phase is dried, filtered and evaporated. The solid residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 10% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The solid residue is stirred in trichloromethane. The product is filtered off, stirred in methanol, filtered off again and dried, yielding 2 parts (25%) of 5,6-dichloro-1-{3-[4-(4-fluorobenzoyl)-1-piperidinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 198°-202° C.
Reaction SMILES: C[Mg]I.[Mg].[CH3:5]I.[C:7]1([CH:17]=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.Cl>CCOCC>[C:7]1([CH:17]([OH:18])[CH3:5])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CI
Reactant: O=Cc1cccc2ccccc12
Agent: C[Mg]I
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CC(O)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
To a solution of methylmagnesium iodide in ether which was prepared from magnesium turning (1.08 g, 44.4 mmol) and methyl iodide (2.75 ml, 44.2 mmol) in 100 ml of ether, were added a solution of 1-naphthaldehyde (1) (5.75 g, 36.8 mmol) in 10 ml of ether with cooling in an ice-water bath, then the resulting reaction mixture was stirred for 2 hours at room temperature. To this mixture was added 25 ml of 2N hydrochloric acid and then the organic layer was separated from the aqueous layer. The organic layer was washed with 50 ml of brine and dried over sodium sulfate. Evaporation of the solvent in vacuo gave 6.20 g (97%) of 2 as a viscous oil.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:11][C:12]1[C:21]([Cl:22])=[CH:20][CH:19]=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]1)=[N:17]2>>[Cl:22][C:21]1[C:12]([NH:11][C:8](=[O:10])[CH2:7][CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([N:23]1[CH2:24][CH2:25][CH:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:27][CH2:28]1)[CH:15]=[CH:14]2
Reactant: CCOC(=O)C1CCN(c2ccc3c(N)c(Cl)ccc3n2)CC1
Reactant: O=C(O)CCC1CCCC1
Product: CCOC(=O)C1CCN(c2ccc3c(NC(=O)CCC4CCCC4)c(Cl)ccc3n2)CC1

Procedure:
Prepared according to the method of example 62(a), using cyclopentanepropanoic acid (256 mg) and 1-(5-amino-6-chloro-2-quinolinyl)-4-piperidinecarboxylic acid, ethyl ester Example 77(a)) (200 mg), to afford the sub-titled compound (240 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[CH:4]=1.[C:10]([O:14][C:15](=[O:26])[NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=1)([CH3:13])([CH3:12])[CH3:11].C([O-])([O-])=O.[K+].[K+].[I-].[K+]>CN(C)C=O>[C:10]([O:14][C:15](=[O:26])[NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[CH:4]=2)[CH:20]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)NCCc1cccc(O)c1
Reactant: Fc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCc1cccc(OCc2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
2.87 g (19.8 mmol) of 1-chloromethyl-3-fluoro-benzene in 5 ml of dry dimethylformamide were added to a suspension of 4.66 g (19.6 mmol) of [2-(3-hydroxy-phenyl)-ethyl]-carbamic acid tert-butyl ester, 4 g of K2CO3 and 0.3 g of potassium iodide in 50 ml of dry dimethylformamide. The reaction was first stirred at room temperature overnight, then was heated up to 50° C. for 6 hours. After evaporation of the solvent, water was added to the residue and the product was extracted with ethyl acetate. 7 g of crude oil were obtained. Purification by flash chromatography using a mixture of ethyl acetate/hexane (1:9→2:8 gradient) gave 5.9 g (86% yield) of the title product as a colourless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1)([O-:3])=[O:2].Br[CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=1)[O:13][CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])([O-:3])=[O:2]
Reactant: CCOC(=O)C(C)Br
Reactant: O=[N+]([O-])c1ccccc1Oc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)Oc1cccc(Oc2ccccc2[N+](=O)[O-])c1
Yield: 101.2 %

Procedure:
In 120 ml of acetone were dissolved 8.0 g of 3-(2-nitrophenoxy)phenol and 7.5 g of ethyl 2-bromopropionate followed by addition of 7.2 g of potassium carbonate. The mixture was refluxed for 5 hours and, after cooling, the insoluble matter was filtered off. The filtrate was concentrated to give 11.6 g of the title compound as a light brown oil.
Reaction SMILES: [ClH:1].[CH3:2][S:3]([NH:6][C:7]1[CH:20]=[CH:19][C:10]([C:11]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=1)(=[O:5])=[O:4].C(=O)([O-])O.[Na+].Cl.[Cl:27][CH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1.[I-].[K+]>CN(C)C=O>[ClH:27].[ClH:1].[CH3:2][S:3]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([CH:13]2[CH2:18][CH2:17][N:16]([CH2:28][CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)[CH2:15][CH2:14]2)=[O:12])=[CH:19][CH:20]=1)(=[O:4])=[O:5]
Reactant: ClCCCc1ccncc1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)C2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1ccc(C(=O)C2CCN(CCCc3ccncc3)CC2)cc1
Temperature: 85 °C
Reaction time: 0.67 h
Yield: 65.6 %

Procedure:
0.295 g (0.926 mmol) of 4-(4-methylsulfonylaminobenzoyl)piperidine hydrochloride and 0.380 g (4.52 mmol) of sodium hydrogencarbonate were suspended in 4 ml of dimethylformamide and the suspension was stirred at 85° C. for 40 min. 0.20 g (1.04 mmol) of 4-(3-chloropropyl)pyridine hydrochloride and 0.31 g (1.87 mmol) of potassium iodide were added to the suspension and the mixture was stirred at 85° C. for 1.5 h. The liquid reaction mixture was filtered and the filtrate was concentrated. The obtained residue was purified according to silica gel column chromatography (chloroform:methanol:aqueous ammonia=96:4:0.4). The purified product was converted into its hydrochloride with ethanolic hydrogen chloride and recrystallized from ethanol to obtain 0.288 g (66%) of the intended compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][Sn:5]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9].C(N(CC)CC)C.[C:25](Cl)(=[O:27])[CH3:26]>C1COCC1>[C:25]([NH:1][CH2:2][CH2:3][S:4][Sn:5]([CH2:6][CH2:7][CH2:8][CH3:9])([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH2:12][CH3:13])(=[O:27])[CH3:26]
Reactant: CC(=O)Cl
Reactant: CCCC[Sn](CCCC)(CCCC)SCCN
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC[Sn](CCCC)(CCCC)SCCNC(C)=O
Temperature: 0 °C
Yield: 85 %

Procedure:
(2-Aminoethylthio)tri-n-butyltin (6.8 mmol, 2.5 g) and triethylamine (6.8 mmol, 687 mg) were dissolved in THF (75 ml). This mixture was cooled to 0° C. and acetyl chloride was added dropwise, and the resultant mixture stirred at 22° C. for 16 h. The solvent was evaporated, the residue was suspended in ether (50 ml), and the precipitated triethylamine hydrochloride was removed by filtration. The salt was washed with ether (20 ml), and the combined organic phases were washed with water (25 ml), dried and evaporated to leave the crude product which was purified by column chromatography leaving the pure amide (13) as a colourless oil (2.35 g, 85%). All spectroscopic and analytical data were consistent with the proposed structure.
Reaction SMILES: Cl[C:2]([C:7]1(C)[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][CH3:13])([CH2:5][CH3:6])[CH2:3][CH3:4].[CH3:15][NH:16][CH3:17]>C(O)C>[CH3:15][N:16]([CH3:17])[CH:7]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH3:13])[C:2]1([CH2:5][CH3:6])[CH2:3][CH3:4]
Reactant: CCN1CCCC1(C)C(Cl)(CC)CC
Reactant: CNC
Solvent: CCO
Product: CCN1CCCC(N(C)C)C1(CC)CC
Temperature: 40 °C
Reaction time: 44 h

Procedure:
A four-necked pear-shaped flask (500 mL) was charged with 14.04 g (0.07 mol) of 2-(1-chloro-1-ethylpropyl)methyl-1-ethylpyrrolidine, 54.26 g (0.48 mol) of a 40% aqueous dimethylamine solution, and 100 mL of ethanol, and the mixture was stirred at 40° C. for 44 hours.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:39]=[C:38]([N:40]4[CH2:45][CH2:44][N:43]([CH2:46][C:47]5[CH2:48][C:49]6([CH2:54][CH2:55][C:56]=5[C:57]5[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=5)OCC[O:50]6)[CH2:42][CH2:41]4)[CH:37]=[CH:36][C:12]=3[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][CH2:26][CH:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[C:21]([N+:33]([O-:35])=[O:34])[CH:20]=3)(=[O:18])=[O:17])=[O:14])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CC(C)=O.O.ClCCl>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:39]=[C:38]([N:40]4[CH2:41][CH2:42][N:43]([CH2:46][C:47]5[CH2:48][C:49](=[O:50])[CH2:54][CH2:55][C:56]=5[C:57]5[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=5)[CH2:44][CH2:45]4)[CH:37]=[CH:36][C:12]=3[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][CH2:26][CH:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[C:21]([N+:33]([O-:35])=[O:34])[CH:20]=3)(=[O:18])=[O:17])=[O:14])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(NS(=O)(=O)c1ccc(NCC2CCOCC2)c([N+](=O)[O-])c1)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC4(C3)OCCO4)CC2)cc1Oc1ccc2[nH]ccc2c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: O
Solvent: CC(C)=O
Product: O=C1CCC(c2ccc(Cl)cc2)=C(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NCC5CCOCC5)c([N+](=O)[O-])c4)c(Oc4ccc5[nH]ccc5c4)c3)CC2)C1

Procedure:
A mixture of EXAMPLE 249E (20 mg) and pyridinium p-toluenesulfonate (16.8 mg) in acetone/H2O (1:1, 3 mL) was heated in a microwave to 135° C. for 8 minutes. The mixture was diluted with dichloromethane (100 mL), washed with water and brine, and dried over Na2SO4. Filtration and evaporation of solvent gave the product.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:34]([C:36]1([O:39]C(=O)C)[CH2:38][CH2:37]1)=[O:35]>>[OH:39][C:36]1([C:34]([NH:1][C@@H:2]2[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]3[C:15]4[N:16]=[CH:17][N:18]=[C:19]([C:20]5[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=5[O:28][CH2:29][CH:30]5[CH2:31][CH2:32]5)[C:14]=4[NH:13][CH:12]=3)=[O:10])[CH2:4][CH2:3]2)=[O:35])[CH2:38][CH2:37]1
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c[nH]c23)c1
Reactant: CC(=O)OC1(C(=O)Cl)CC1
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)C5(O)CC5)CC4)c[nH]c23)c1

Procedure:
Starting from cis-4-(2-cyclopropylmethoxy-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A154) and acetic acid 1-chlorocarbonyl-cyclopropyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:27])[C@:4]1([O:24]C=O)[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.C(=O)(O)[O-].[K+]>CO.O>[Cl:1][CH2:2][C:3](=[O:27])[C@:4]1([OH:24])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@]2(OC=O)C(=O)CCl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CO
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CCl
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
At room temperature, 1.6 g of 21-chloro-17-formyloxy-4-pregnene-3,20-dione is stirred in a mixture of 60 ml of methanol and 9 ml of water with 500 mg of potassium bicarbonate. After one hour, the reaction mixture is stirred into ice water. The thus-precipitated product is suctioned off, washed with water, and dried over sodium sulfate, yielding 1.3 g of 21-chloro-17-hydroxy-4-pregnene-3,20-dione; mp 239.4° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH2:11][CH:12]3[NH:16][CH:15]([C:5]2=1)[CH2:14][CH2:13]3.C1(C=CC(O)=CC=1)O.[Na].[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]=[CH2:34])=[CH:29][N:28]=1>CS(C)=O.O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:34][CH2:33][C:30]1[CH:29]=[N:28][C:27]([CH3:26])=[CH:32][CH:31]=1)[C:6]1[CH2:11][CH:12]3[NH:16][CH:15]([C:5]2=1)[CH2:14][CH2:13]3
Reactant: Cc1ccc2[nH]c3c(c2c1)C1CCC(C3)N1
Reactant: C=Cc1ccc(C)nc1
Agent: Oc1ccc(O)cc1
Agent: [Na]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CC2CCC1N2
Temperature: 100 °C
Reaction time: 48 h

Procedure:
A suspension of 2-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole (170 mg, 0.80 mmol; Example 4A), hydroquinone (9 mg, 0.08 mmol), and -32% sodium in paraffin (79 mg, 1.1 mmol; Aldrich) in anhydrous dimethyl sulfoxide (800 μL) was sealed in a septum-capped reaction tube. After thoroughly evacuating and purging the vessel with nitrogen, 2-methyl-5-vinylpyridine (143 mg, 1.2 mmol, International Publication No. WO2001/017968) was added, and the reaction was stirred at 100° C. for 48 hours. The thick mixture was cooled to room temperature, poured into water (5 mL), and extracted with ethyl acetate (3×). The combined organic phases were washed with water, filtered through diatomaceous earth, dried (Na2SO4), concentrated, and purified by chromatography on silica (0-5% gradient of concentrated aqueous ammonium hydroxide in acetonitrile). The resulting material was purified further by reverse-phase HPLC [Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 5-95% gradient of acetonitrile in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.10-1.26 (m, 1H), 1.84-2.06 (m, 4H), 2.40 (s, 3H), 2.43 (s, 3H), 2.86 (dd, J=16, 4.6, 1H), 2.97 (ddd, J=14, 5.4, 5.4, 1H), 3.09 (ddd, J=14, 9.0, 6, 1H), 3.75-3.86 (m, 1H), 4.14 (ddd, J=15, 9.0, 5.4, 1H), 4.30 (ddd, J=15, 6, 5.4, 1H), 4.44 (d, J=4.6, 1H), 6.90 (d, J=8.3, 1H), 7.10 (d, J=7.9, 1H), 7.17 (d, J=8.3, 1H), 7.20-7.25 (m, 2H), 7.75 (d, J=2.1, 1H); MS (ESI) m/z 332 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17]([C:22](O)=[O:23])=[CH:16]3)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:25](N1C=CN=C1)([N:27]1C=CN=[CH:28]1)=O.CNC.Cl>O1CCCC1.C(OCC)(=O)C>[CH3:25][N:27]([CH3:28])[C:22]([C:17]1[NH:18][C:19]2[C:15]([CH:16]=1)=[CH:14][C:13]([NH:12][S:9]([C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1)(=[O:10])=[O:11])=[CH:21][CH:20]=2)=[O:23]
Reactant: O=C(O)c1cc2cc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)ccc2[nH]1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1cc2cc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)ccc2[nH]1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
55 mg 5-(3,5-dichloro-phenylsulphonylamino)-1H-indole-2-carboxylic acid are dissolved in 2 ml of tetrahydrofuran, combined with 25 mg carbonyldiimidazole, stirred for 3 hours at ambient temperature and for 1 hour at 40° C. Then the mixture is combined with 300 μl dimethylamine (2 M in tetrahydrofuran) and stirred overnight. The solvent is eliminated in vacuo and the residue is divided between ethyl acetate and 0.5 N hydrochloric acid. The organic phase is washed with water and saturated sodium chloride solution and dried on magnesium sulphate. After elimination of the solvents in vacuo the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10 to 30:70).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][C:4]=1[F:12])[CH3:2].[Br:13]Br>O1CCOCC1>[Br:13][CH2:10][C:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[C:4]([F:12])[CH:5]=1)=[O:11]
Reactant: CCc1ccc(C(C)=O)cc1F
Reactant: BrBr
Solvent: C1COCCO1
Product: CCc1ccc(C(=O)CBr)cc1F

Procedure:
To a stirred solution of 1-(4-ethyl-3-fluoro-phenyl)-ethanone (166 mg, 1 mmol) in 1,4-dioxane (5 mL), bromine was added dropwise at room temperature. After the addition, the solvent was removed and the residue was chromatographed (dichloromethane/hexanes) to give a solid. 77 mg, 31%. 1H NMR(CDCl3, 300MHz), σ 1.22 (t, 3H), 2.73 (q, 2H), 4.40 (s, 2H), 7.735 (t, 1H), 7.56-7.75 (dd, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][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]([N:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[C:46]1([CH2:52][C:53]([N:55]=[C:56]=[S:57])=[O:54])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>C(O)C.C1(C)C=CC=CC=1>[CH3:28][N:25]1[CH2:24][CH2:23][N:22]([CH:19]2[CH2:18][CH2:17][N:16]([C:14]([NH:13][C:9]3[CH:8]=[C:7]([O:6][C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:56]([NH:55][C:53](=[O:54])[CH2:52][C:46]5[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=5)=[S:57])=[CH:30][CH:29]=4)[CH:12]=[CH:11][N:10]=3)=[O:15])[CH2:21][CH2:20]2)[CH2:27][CH2:26]1
Reactant: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4)ccn3)CC2)CC1
Reactant: O=C(Cc1ccccc1)N=C=S
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Solvent: Cc1ccccc1
Product: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4)ccn3)CC2)CC1
Reaction time: 3 h
Yield: 26 %

Procedure:
To a solution of 4-(4-aminophenoxy)-2-{[4-(1-methylpiperazin-4-yl)piperidin-1-yl]carbonylamino}pyridine (130 mg) and (+)-10-camphorsulfonic acid (138 mg) in ethanol (3.0 ml) was added a solution of 2-phenylacetyl isothiocyanate in toluene (0.25 M, 2.5 ml) at room temperature, followed by stirring for 3 hours. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine in this order, 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, then ethyl acetate:methanol=98:2) to provide the titled compound (48.5 mg, 26%) as white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH3:15][C:16]1([CH3:19])[CH2:18][O:17]1>CN(C)C=O.O>[CH3:15][C:16]([OH:17])([CH3:19])[CH2:18][N:6]1[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]1
Reactant: CC1(C)CO1
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1ccc([N+](=O)[O-])n1
Temperature: 100 °C
Yield: 53.4 %

Procedure:
A solution of 3-nitro-1H-pyrazole (200 mg, 1.77 mmol) in N,N-dimethylformamide (5 mL) was treated with solid potassium carbonate (352 mg, 2.55 mmol) and 2,2-dimethyl-oxirane (3.14 mL, 3.54 mmol) and placed in a sealed tube and heated at 100° C. for 1 h in an oil bath. After this time the reaction was cooled to 25° C. and diluted with water (10 mL) and extracted with ethyl acetate (3×10 mL). The organic layers were then combined and dried over sodium sulfate, filtered and concentrated in vacuo. Purification by AnaLogix Intelliflash system (12 g column, 50% ethyl acetate/hexanes to 60% ethyl acetate/hexanes) afforded 2-methyl-1-(3-nitro-pyrazol-1-yl)-propan-2-ol (175 mg, 54%) as a clear colorless oil: ES-HRMS m/z calculated for C7H11N3O3 [M+H]+ 186.0873, observed 186.0873; 1H NMR (300 MHz, CDCl3) δ ppm 1.25 (s, 6H), 2.11 (br. s., 1H), 4.18 (s, 2H), 6.92 (d, J=2.4 Hz, 1H), 7.60 (d, J=2.4 Hz, 1H).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46](O)[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2].C(N(C(C)C)CC)(C)C.[N+:65]([C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][C:69]=1[S:74](Cl)(=[O:76])=[O:75])([O-:67])=[O:66]>C(Cl)Cl>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([S:74]([C:69]3[CH:70]=[CH:71][CH:72]=[CH:73][C:68]=3[N+:65]([O-:67])=[O:66])(=[O:75])=[O:76])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(S(=O)(=O)c4ccccc4[N+](=O)[O-])C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a cooled solution (0° C.) of 17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (787mg) in dry methylene chloride (15 ml) is added diisopropylethyl amine (492.4 mg) followed by o-nitrobenzenesulfonyl chloride (281 mg) and a catalytic amount of N,N-dimethylaminopyridine. The yellow solution is stirred at room temperature under a nitrogen atmosphere for 3 hr., and then quenched with sat'd aqueous sodium bicarbonate. Organic layer is washed (water, sat'd NaHCO3, sat'd NaCl), dried (anhydrous Na2SO4) and the solvent is removed in vacuo. Chromatography on silica gel gives the title compounds.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>CN(C)C=O.O>[Si:16]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: N#CCc1ccc(O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC#N)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.6 %

Procedure:
A solution of (4-hydroxyphenyl)acetonitrile (6.01 g, 45.1 mmol) in N,N-dimethylformamide (60 ml) was treated with imidazole (3.819, 58.6 mmol), tert-butyldimethylsilyl chloride (7.49 g, 49.6 mmol) and N,N-dimethylaminopyridine (20 mg) and the resulting solution left to stir at room temperature under a nitrogen atmosphere for 16 hours. The reaction mixture was diluted with water (200 ml) and extracted with ethyl acetate (200 ml×2). The combined organic extracts were washed with sat. aq. sodium chloride (200 ml), dried (sodium sulfate) and the solvent removed in vacuo. Purification by column chromatography on silica gel eluting with ethyl acetate:pentane (0:100 changing to 10:90) gave the title compound as a pale yellow oil (9.44 g).