Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[C:21]([CH2:22]Br)=[CH:20][C:19]3[C:18]([CH3:25])([CH3:24])[CH2:17][CH2:16][C:15]([CH3:27])([CH3:26])[C:14]=3[CH:13]=2)=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:35]([SH:39])[CH2:36][CH2:37][CH3:38]>CN(C)C=O.O>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[C:21]([CH2:22][S:39][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:20][C:19]3[C:18]([CH3:25])([CH3:24])[CH2:17][CH2:16][C:15]([CH3:27])([CH3:26])[C:14]=3[CH:13]=2)=[CH:6][CH:5]=1
Reactant: CCCCS
Reactant: COC(=O)c1ccc(/C=C/c2cc3c(cc2CBr)C(C)(C)CCC3(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCSCc1cc2c(cc1/C=C/c1ccc(C(=O)OC)cc1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 58.4 %

Procedure:
A solution of 445 mg (1 mmol) of Methyl-4-[(E)-2-(3-Bromomethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoate, 418 mg (3 mmol) of potassium carbonate and 180 mg (2 mmol) of 1-butanethiol in 10 mL dimethylformamide was heated to reflux. After 40 minutes, the reaction mixture was cooled to room temperature, then diluted with water. The mixture was extracted with ethyl acetate, the organic extracts washed with brine, dried over sodium sulfate, then concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (5% ethyl acetate/hexane) to give 263 mg (58%) of Methyl-4-[(E)-2-(3-Butylthiomethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoate.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][CH2:19][CH2:20][CH3:21])=[N:6][C:5]=2[N:4]([CH2:22][CH2:23][CH3:24])[N:3]=1.[Cl:25][S:26](O)(=[O:28])=[O:27]>>[Cl:25][S:26]([C:16]1[CH:15]=[CH:14][C:13]([O:18][CH2:19][CH2:20][CH3:21])=[C:12]([C:7]2[NH:8][C:9](=[O:11])[C:10]3[C:2]([CH3:1])=[N:3][N:4]([CH2:22][CH2:23][CH3:24])[C:5]=3[N:6]=2)[CH:17]=1)(=[O:28])=[O:27]
Reactant: CCCOc1ccccc1-c1nc2c(c(C)nn2CCC)c(=O)[nH]1
Reactant: O=S(=O)(O)Cl
Product: CCCOc1ccc(S(=O)(=O)Cl)cc1-c1nc2c(c(C)nn2CCC)c(=O)[nH]1

Procedure:
The title compound was prepared from 3-methyl-6-(2-n-propoxyphenyl)-1-n-propyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 21; 0.5 g, 0.0017 mol) and chlorosulphonic acid (3 ml), by the same procedure as Preparation 3, and was obtained as a white powder (0.587 g, 90%), m.p. 148-150° C. Found: C, 50.88; H, 4.67; N, 13.30. C18H21ClN4O4S requires C, 50.88; H, 4.98; N, 13.19%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:13]2[C@H:22]3[C:23]([O:25][CH2:26][C@@H:21]3[C@@H:20]([OH:27])[C:19]3[CH:18]=[C:17]4[O:28][CH2:29][O:30][C:16]4=[CH:15][C:14]2=3)=[O:24])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9]C.NC(C(O)=O)CCSC.O>FC(F)(F)C(O)=O.CS(O)(=O)=O>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C@H:13]2[C@H:22]3[C:23]([O:25][CH2:26][C@@H:21]3[C@H:20]([OH:27])[C:19]3[CH:18]=[C:17]4[O:28][CH2:29][O:30][C:16]4=[CH:15][C:14]2=3)=[O:24])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[OH:9]
Reactant: COc1cc([C@@H]2c3cc4c(cc3[C@H](O)[C@H]3COC(=O)[C@H]23)OCO4)cc(OC)c1OC
Agent: CS(=O)(=O)O
Agent: CSCCC(N)C(=O)O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc([C@@H]2c3cc4c(cc3[C@@H](O)[C@H]3COC(=O)[C@H]23)OCO4)cc(OC)c1O
Temperature: 0 °C
Yield: 95.2 %

Procedure:
100 g (0.24 mol) of podophyllotoxin I are dissolved in 186 ml of trifluoroacetic acid with stirring. After cooling the reaction mixture to 0° C., a solution of 198 g (1.32 mol) of D,L-methionine in 500 ml of methanesulfonic acid is introduced, the reaction mixture being maintained between 10 and 20° C. 200 ml of methanesulfonic acid are added to the mixture, which is kept stirring for 1 h at this temperature. The reaction mixture is poured with stirring onto 4 l of water and of ice and the product precipitates. It is extracted with ethyl acetate (3×1 l ). The combined organic phases are washed with an NaHCO3 solution and then dried over Na2SO4, filtered and evaporated under reduced pressure in order to obtain 91.5 g (Yd 94%) of crude 4'-demethylepipodophyllotoxin.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.Br[CH2:14][CH2:15][CH2:16][C:17]#[N:18]>C(#N)C>[O:10]1[CH2:11][CH2:12][N:7]([CH2:14][CH2:15][CH2:16][C:17]#[N:18])[CH2:8][CH2:9]1
Reactant: C1COCCN1
Reactant: N#CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 94.2 %

Procedure:
To a suspension of K2CO3 (8.28 g, 60 mmol) and morpholine (4.35 g, 50 mmol) in acetonitrile (50 mL) was added 4-bromobutyronitrile (7.40 g, 50 mmol) dropwise at rt under N2. The mixture was stirred at rt for 6 h, filtered and concentrated in vacuo to give the title compound (7.26 g, 94.2%).
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]2[CH:9]=[C:8]([CH:10]3[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]3)[CH:7]=[CH:6][C:5]=12.C(O)(C(F)(F)F)=O>ClCCl>[NH:13]1[CH2:12][CH2:11][CH:10]([C:8]2[CH:7]=[CH:6][C:5]3[N:4]([CH:3]=[N:2][N:1]=3)[CH:9]=2)[CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3nncn3c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc2nncn2cc1C1CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 749.1 %

Procedure:
To a solution of tert-Butyl 4-([1,2,4]triazolo[4,3-a]pyridin-6-yl)piperidine-1-carboxylate (compound 36.1, 0.05 g, 0.165 mmol) in dichloromethane (2 mL) was added TFA (0.2 mL). The mixture was stirred at room temperature for 3 hours. The solvents were removed under reduced pressure. The residue was purified by prep-TLC (10% MeOH in dichloromethane+˜0.5% NH4OH) to give 0.25 g (76%) of the title compound as a light brown oil. m/z (ES+) 203 (M+H)+.
Reaction SMILES: C[O-].[Na+].[CH2:4]=[CH:5][C:6](=[O:10])[CH2:7][CH2:8][CH3:9].[N+:11]([CH3:14])([O-:13])=[O:12]>CO>[N+:11]([CH2:14][CH2:4][CH2:5][C:6](=[O:10])[CH2:7][CH2:8][CH3:9])([O-:13])=[O:12]
Reactant: C[N+](=O)[O-]
Reactant: C=CC(=O)CCC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCC(=O)CCC[N+](=O)[O-]
Temperature: -10 °C

Procedure:
A solution of sodium methoxide in MeOH is added to a solution of 1-hexen-3-one and nitromethane in MeOH at −30° C. The reaction mixture is then warmed to −10° C. for 1.5 h, quenched with half saturated ammonium chloride solution, and then extracted with dichloromethane. The combined organics are dried over sodium sulfate concentrated and then stripped from toluene and MeOH to provide 7-nitro-heptan-4-one.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:26][CH:25]=2)=[O:21])=[CH:16][CH:15]=1.I[CH3:38]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]([N:22]([CH3:38])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:26][CH:25]=2)=[O:21])=[CH:18][CH:19]=1
Reactant: CI
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4ccc(Oc5ccccc5)cc4)cc3)c2)o1
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)N(C)Cc4ccc(Oc5ccccc5)cc4)cc3)c2)o1

Procedure:
2′-Methyl-N-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(4-phenoxybenzyl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(4-phenoxybenzyl)-1,1′-biphenyl-4-carboxamide and iodomethane using method L. NMR; δH [2H6]—DMSO 7.89,(1H, d), 7.76,(1H, s), 7.55-7.48,(5H, m), 7.40-7.36,(3H, m), 7.23,(1H, b), 7.13,(1H, t), 7.01,(4H, m), 4.684.52,(2H, m), 2.91,(3H, s), 2.55,(3H, s), 2.32,(3H, s). LCMS; retention time 3.85 min, MH+ 490.
Reaction SMILES: C([O:3][C:4](=[O:27])[C:5]1[CH:10]=[C:9]([NH:11][C:12]2[N:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[CH:14][N:13]=2)[CH:8]=[N:7][C:6]=1[CH3:26])C.CO.O.[Li+].[OH-]>C1COCC1>[CH3:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([C:15]2[CH:14]=[N:13][C:12]([NH:11][C:9]3[CH:8]=[N:7][C:6]([CH3:26])=[C:5]([CH:10]=3)[C:4]([OH:27])=[O:3])=[N:17][CH:16]=2)=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1cc(Nc2ncc(-c3ccc(OC)cc3)cn2)cnc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-c2cnc(Nc3cnc(C)c(C(=O)O)c3)nc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a suspension of the 5-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-2-methyl-nicotinic acid ethyl ester 9 (0.9 mmol) in THF:MeOH:H2O=3:2:1 (7 mL), is added 6M LiOH (2.7 mmol). The reaction mixture is stirred at rt for 12 h. After this time the solvent is removed under vacuum, the residue is diluted with H2O (6 mL) and the pH neutralized with 6M HCl. The solid formed is filtered, washed with water and dried in a vacuum oven for 12 h to afford 5-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-2-methyl-nicotinic acid 10 as off white solid, which is used in the next step without further purification. MS (m/z) (M+1)+: 337.2.
Reaction SMILES: Cl.[CH3:2][NH:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:13]([O-:15])=[O:14])[CH:10]=2)[CH2:5]1.[N+:16]([C:19]1[CH:27]=[CH:26][C:22]([CH2:23][CH2:24]Br)=[CH:21][CH:20]=1)([O-:18])=[O:17].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:2][N:3]([CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:13]([O-:15])=[O:14])[CH:10]=2)[CH2:5]1)[CH2:24][CH2:23][C:22]1[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:27][CH:26]=1
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: CNC1Cc2ccc([N+](=O)[O-])cc2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCc1ccc([N+](=O)[O-])cc1)C1Cc2ccc([N+](=O)[O-])cc2C1

Procedure:
2-Methylamino-5-nitroindane hydrochloride (0.45 g), 4-nitrophenethyl bromide (0.46 g) and potassium carbonate (2 g) were heated under reflux in acetonitrile (30 ml) for 3 days. The reaction mixture was then filtered, the filtrate evaporated in vacuo, and the residue purified by column chromatography on silica eluting with methylene chloride containing methanol (0% up to 1%). The product-containing fractions were combined and evaporated in vacuo to give a gum which was crystallised from ethanol affording the title compound, yield 0.16 g, m.p. 138°-141°.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23]>CN(C=O)C>[O:23]=[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:21][N:11]1[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]1
Reactant: O=C(CBr)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CC(=O)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A one liter three necked round bottom flask was charged with Boc-piperazine (20 g), dry potassium carbonate (44.5 g) and dry DMF (150 ml) under nitrogen atmosphere. The reaction mixture was cooled to 0° C. and bromoacetophenone (23.5 g) was added into the reaction mixture very slowly. The reaction mixture was stirred at room temperature for overnight. The progress of reaction was monitored by TLC. After consumption of starting material, ice-cold water (200 ml) was added to reaction mixture. The precipitated white solid was filtered, washed with water (4×50 ml) and dried to afford tert-butyl 4-(2-oxo-2-phenylethyl)piperazine-1-carboxylate as pure product.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[C:5]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][CH:4]=1)([CH3:9])([CH3:6])[CH3:4]
Reactant: O=C(O)c1ccc(O)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(O)cc1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 131.4 %

Procedure:
4-Hydroxy-benzoic acid (3 g, 21.7 mmol) was stirred in toluene (35 ml, dried over mol. sieves). The solution was heated to 80° C. under N2, and N,N′-dimethylformamide di-tert-butyl acetal (10.42 mL, 43.4 mmol) was added over ca. 5 min. The mixture was stirred at 80° C. for 1 h 10 min., and cooled to rt. The solution was washed with water, twice with sat. NaHCO3 and sat. NaCl (15 mL each), dried over MgSO4, and concentrated to yield a yellow oil (2.77 g). The product was purified by flash chromatography (380 g silica, eluant: 4:6 AcOEt/heptane (2 L) and 1:1 AcOEt/heptane 700 mL) to yield white crystals (2.07 g, 49% yield).
Reaction SMILES: C(OC(=O)[N:7]([CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([F:29])[CH:24]=3)[CH:20]=[CH:19][C:18]=2[O:30][CH3:31])[CH2:11][CH2:10]1)[CH3:8])(C)(C)C.[Cl:33][C:34]1[C:35]2[C:45]([F:46])=[CH:44][CH:43]=[C:42]([F:47])[C:36]=2[S:37][C:38]=1[C:39](Cl)=[O:40]>>[F:29][C:25]1[CH:24]=[C:23]([C:21]2[CH:20]=[CH:19][C:18]([O:30][CH3:31])=[C:17]([CH:22]=2)[CH2:16][N:15]([CH:12]2[CH2:11][CH2:10][CH:9]([NH:7][CH3:8])[CH2:14][CH2:13]2)[C:39]([C:38]2[S:37][C:36]3[C:42]([F:47])=[CH:43][CH:44]=[C:45]([F:46])[C:35]=3[C:34]=2[Cl:33])=[O:40])[CH:28]=[CH:27][N:26]=1
Reactant: COc1ccc(-c2ccnc(F)c2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Product: CNC1CCC(N(Cc2cc(-c3ccnc(F)c3)ccc2OC)C(=O)c2sc3c(F)ccc(F)c3c2Cl)CC1

Procedure:
Following the synthetic protocol described in Method D′; 3-Chloro-4,7-difluoro-benzo[b]thiophene-2-carboxylic acid [5-(2-fluoro-pyridin-4-yl)-2-methoxy-benzyl]-(4-methylamino-cyclohexyl)-amide is prepared starting from {4-[5-(2-Fluoro-pyridin-4-yl)-2-methoxy-benzylamino]-cyclohexyl}-methyl-carbamic acid tert-butyl ester and 3-Chloro-4,7-difluoro-benzo[b]thiophene-2-carbonyl chloride. The desired product is isolated in 52%.
Reaction SMILES: N1C=CC=CC=1.[C:7]([O:12][CH2:13][CH2:14][O:15][CH:16](O)[C:17]([Cl:20])([Cl:19])[Cl:18])(=[O:11])[C:8]([CH3:10])=[CH2:9].O=CC(Cl)(Cl)[Cl:25].CC(C(OCCO)=O)=C>C(OCC)C.S(Cl)(Cl)=O>[C:7]([O:12][CH2:13][CH2:14][O:15][CH:16]([Cl:25])[C:17]([Cl:20])([Cl:19])[Cl:18])(=[O:11])[C:8]([CH3:10])=[CH2:9]
Reactant: C=C(C)C(=O)OCCOC(O)C(Cl)(Cl)Cl
Reactant: O=CC(Cl)(Cl)Cl
Agent: C=C(C)C(=O)OCCO
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: C=C(C)C(=O)OCCOC(Cl)C(Cl)(Cl)Cl
Temperature: 20 °C

Procedure:
Pyridine (75 ml) in 500 ml of diethyl ether and 65 ml of thionyl chloride are mixed while being stirred and cooled by an ice-water bath in a flask provided with a mechanical stirrer, a reflux condenser and a dropping funnel. A solution of 220 g of crystalline 2-(1-hydroxy-2,2,2-trichloroethoxy)ethyl methacrylate (m.p. 44-45° C; prepared by the addition of chloral to glycol monomethacrylate) in 500 ml of diethyl ether is slowly added to the mixture during continuous stirring and cooling. After all of the hydroxy compound has been added into the reactor, the reaction mixture is stirred and cooled for further 2 hours. It is then warmed to the temperature 20° C, the precipitated pyridine hydrochloride is filtered off and ether is removed by distillation. The distillation residue is heated in the presence of 20 g of powdered copper to the temperature 80° C at the pressure 15 Torr for 2 hrs and then it is rectified through an effective column. By a repeated fraction distillation, 180 g of 2-(1,2,2,2-tetrachloroethoxy)ethyl methacrylate was obtained, having b.p. 96 - 97° C 0.1 Torr and refractive index nD25 1.4900. Elemental analysis: found C 32.20%, H 3.58%, Cl 47.35%; calculated C 32.46%, H 3.40%, Cl 47.90%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:12][S:13](O)(=[O:15])=[O:14]>>[Cl:12][S:13]([C:8]1[C:9]([F:11])=[CH:10][C:2]([F:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])(=[O:15])=[O:14]
Reactant: O=C(O)c1ccc(F)cc1F
Reactant: O=S(=O)(O)Cl
Product: O=C(O)c1cc(S(=O)(=O)Cl)c(F)cc1F
Temperature: 155 °C
Yield: 94 %

Procedure:
A mixture of chlorosulfonic acid (200 mL) and 2,4-difluorobenzoic acid (40 g, 253 mmol, 1 equiv) was heated to 155° C. for 3 h. The reaction was cooled to RT and poured slowly over ice. The product was extracted into ether and the organics dried over MgSO4, filtered and concentrated to give 5-(chlorosulfonyl)-2,4-difluorobenzoic acid 6a as brown solid (61 g, 94% yield).
Reaction SMILES: Cl[CH:2]([C:8]([CH3:10])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(=O)([O-])O.[Na+].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([SH:23])=[CH:19][CH:18]=1.O>COCCOC>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([S:23][C:20]1[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=1)[C:8](=[O:9])[CH3:10])[CH3:7]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: Sc1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(Sc1ccc(Cl)cc1)C(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.9 %

Procedure:
To a solution of ethyl 2-chloroacetoacetate (1.58 g, 9.61 mmol) in ethylene glycol dimethyl ether (30 mL) was added sodium hydrogencarbonate (ca. 15 g) and 4-chlorothiophenol (1.39 g, 9.61 mmol). The suspension was heated to reflux and stirred for 3 hours. The reaction mixture was allowed to cool to room temperature, and water (100 mL) was added. The mixture was extracted with ethyl ether (75 mL), and the organic extract was washed with brine (150 mL). The organic phase was dried (magnesium sulfate), filtered, and concentrated to afford a yellow oil. Flash chromatography over silica (ethyl acetate/hexanes) provided 1.44 g (55%) of the product as a colorless oil: 1H NMR (CDCl3) δ 13.8 (s, 1H), 7.26–7.21 (m, 2H), 7.06–7.04 (m, 2H), 4.21 (q, J=7.1 Hz, 2H), 2.33 (s, 3H), 1.20 (t, J=7.1 Hz, 3H).
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][C:5]([C:10](O)=[O:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[N:2]12[CH2:9][CH2:8][C:5]([CH2:10][OH:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2
Reactant: O=C(O)C12CCN(CC1)CC2
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: OCC12CCN(CC1)CC2
Yield: 92289.4 %

Procedure:
Quinuclidine-4-carboxylic acid hydrochloride (6.0 g, 0.031 mmoles) in tetrahydrofuran (300 ml) was treated with lithium aluminum hydride (5.0 g, 0.137 mmoles) at ambient temperature for 18 hours. Water (20 ml) and 10% aqueous sodium hydroxide (7.5 ml) was added carefully and the mixture filtered, washing with diethyl ether. The combined filtrates were evaporated to dryness to give the title compound as a white solid 4.04 g, (91%): MS (+ve ion electrospray) m/z 142 (MH+, 100%)
Reaction SMILES: [OH-].[K+].C(OC([N:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[O:12][CH2:11][CH2:10][CH2:9]1)=O)C>O.COCCO>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]2[O:12][CH2:11][CH2:10][CH2:9][NH:8][C:14]=2[CH:15]=1)([O-:21])=[O:20]
Reactant: CCOC(=O)N1CCCOc2ccc([N+](=O)[O-])cc21
Agent: [K+]
Agent: [OH-]
Solvent: COCCO
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)NCCCO2
Temperature: 110 °C
Yield: 78.9 %

Procedure:
1.00 M of Potassium hydroxide in Water (25 mL) was added to 2-Nitro-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid ethyl ester (2.84 g, 10.7 mmol) in 2-Methoxyethanol (50 mL) and the reaction was heated at 110° C. After overnight heating, the mixture was cooled, extracted with DCM (2×50 mL); the combined organics were washed with water (50 mL) and brine (50 mL), dried and conc. in vacuo. The residue was chromatographed (120 g SiO2, ISCO, 0-20% EtOAc:Hex) to afford 2-Nitro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene as an orange solid (1.64 g, 79%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[N:11]1([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[CH:15]=[N:14][CH:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:22][C:19]2[CH:18]=[CH:17][C:16]([N:11]3[CH:15]=[N:14][CH:13]=[N:12]3)=[CH:21][CH:20]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: Oc1ccc(-n2cncn2)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccc(-n3cncn3)cc2)cc1
Temperature: 25 °C
Yield: 37 %

Procedure:
A mixture of 1-fluoro-4-nitrobenzene (0.17 mL, 1.6 mmol), 4-{[1,2,4]triazol-1-yl}phenol (0.26 g, 1.58 mmol), and potassium carbonate (1.69 g, 12.2 mmol) in DMF was refluxed overnight. The reaction was cooled to room temperature, then partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with an aqueous sodium hydroxide solution (2N), water (2 times), dried over sodium sulfate, filtered, and evaporated under reduced pressure to give a yellow solid. Purification by column chromatography (silica gel; 1:1 hexane/ethyl acetate) and recrystallization from chloroform/hexane afforded 165 mg (37%) of the title compound as a yellow solid, mp 131-132° C. 1H-NMR (CDCl3): δ 8.55 (s, 1H), 8.25 (d, J=9 Hz, 2H), 8.12 (s, 1H), 7.75 (d, J=9 Hz, 2H), 7.24 (d, J=9 Hz, 2H), 7.08 (d, J=9 Hz, 2H).
Reaction SMILES: C([O:4][CH2:5][C@@H:6]1[CH2:8][C@:7]1([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1)[CH2:9][O:10]S(C1C=CC(C)=CC=1)(=O)=O)(=O)C.[CH3:28][C:29]1[N:34]=[C:33]([CH3:35])[C:32](O)=[CH:31][N:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[Na+]>C(#N)C.CC(OC)(C)C.CCOC(C)=O.CCCCCCC>[CH3:28][C:29]1[N:34]=[C:33]([CH3:35])[C:32]([O:10][CH2:9][C@@:7]2([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=3)[CH2:8][C@H:6]2[CH2:5][OH:4])=[CH:31][N:30]=1
Reactant: CC(=O)OC[C@@H]1C[C@@]1(COS(=O)(=O)c1ccc(C)cc1)c1cccc(F)c1
Reactant: Cc1ncc(O)c(C)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: COC(C)(C)C
Product: Cc1ncc(OC[C@@]2(c3cccc(F)c3)C[C@H]2CO)c(C)n1
Temperature: 67.5 °C

Procedure:
((1R,2S)-2-(3-fluorophenyl)-2-((tosyloxy)methyl)cyclopropyl)methyl acetate (8, 11.05 g, 0.028 mol, 1.0 equiv.), 2,4-dimethylpyrimidin-5-ol (3.74 g, 0.030 mol, 1.07 equiv.), and cesium carbonate (22.94 g, 1.8 equiv.) were dissolved in ACN (110.5 mL), under nitrogen. The solution was stirred vigorously and heated to 65-70° C. for 2-3 hours. The reaction was monitored by HPLC and TLC (EtOAc/Heptane=1/1). Once complete, aqueous 1 N NaOH solution (71.82 mL) was added to the reaction mixture. The reaction mixture was stirred at 20-25° C. for 10-16 h, and was monitored by HPLC and TLC (EtOAc/Heptane=1/1). Once the hydrolysis reaction was complete, the reaction mixture was diluted with MTBE (110.50 mL) and stirred for at least 15 min. The aqueous layer was back extracted once with MTBE (55.25 mL). The organic layers were combined and washed once with saturated aqueous NaCl solution (33.15 mL), The solvent was removed under reduced pressure to afford the title compound; ((1R,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)cyclopropyl)methanol: (11, 8.51 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])/[CH:4]=[CH:5]/[CH3:6].CN(C)C(=N)N(C)C.[N+:16]([CH3:19])([O-:18])=[O:17]>C(OC(=O)CC(C)=O)C>[CH3:1][O:2][C:3](=[O:7])[CH2:4][CH:5]([CH3:6])[CH2:19][N+:16]([O-:18])=[O:17]
Reactant: C/C=C/C(=O)OC
Reactant: C[N+](=O)[O-]
Agent: CN(C)C(=N)N(C)C
Solvent: CCOC(=O)CC(C)=O
Product: COC(=O)CC(C)C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 576 h
Yield: 78.9 %

Procedure:
3 g (29.9 mmol) of trans-2-butenoic acid methyl ester and 0.69 g (5.99 mmol) of tetramethylguanidine and 9.14 g (149 mmol) of nitromethane were mixed. The resulting mixture was stirred at room temperature for 24 days. 100 mL of ethylacetoacetate was added to the solution and the reaction solution was washed with water, then an organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, then the residue was purified by column chromatography to give 5.7 g (23.6 mmol) of the title compound in a yield of 100%.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:18][CH2:19][CH3:20])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[CH:8][C:7]([OH:17])=[CH:6][CH:5]=2.[CH2:21]([O:23][C:24](=[O:29])[C:25](Br)([CH3:27])[CH3:26])[CH3:22]>>[CH2:21]([O:23][C:24](=[O:29])[C:25]([CH3:27])([O:17][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]([CH2:18][CH2:19][CH3:20])[C:2]([CH3:1])=[C:10]2[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)[CH3:26])[CH3:22]
Reactant: CCCn1c(C)c(-c2ccncc2)c2cc(O)ccc21
Reactant: CCOC(=O)C(C)(C)Br
Product: CCCn1c(C)c(-c2ccncc2)c2cc(OC(C)(C)C(=O)OCC)ccc21

Procedure:
The above compound was prepared from 2-methyl-1-propyl-3-(4-pyridyl)-1H-indole-5-ol and 2-bromo-2-methylpropanoic acid ethylester using a procedure analogous to that of Example 10.