Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][NH:7][C:8]#[N:9].Br[CH2:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].O>CC(=O)CC>[C:13]([C:12]1[O:17][C:8](=[NH:9])[N:7]([CH2:6][C@H:2]2[CH2:3][CH2:4][CH2:5][O:1]2)[CH:11]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)C(=O)CBr
Reactant: N#CNC[C@H]1CCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CC(C)(C)c1cn(C[C@H]2CCCO2)c(=N)o1

Procedure:
A mixture of Example 32A (2.35 g, 18.63 mmol), 1-bromo-3,3-dimethylbutan-2-one (2.52 mL, 18.63 mmol) and potassium carbonate (2.57 g, 18.63 mmol) in 2-butanone (75 mL) was heated to 80° C. overnight. The mixture was poured into water, and extracted with ethyl acetate (2×). The combined organic extracts were dried over Na2SO4, filtered, concentrated under reduced pressure to afford the title compound. MS (ESI) m/z 225 (M+H)+.
Reaction SMILES: CO[C:3]1[CH2:7][CH2:6][CH2:5][N:4]=1.[C:8]1([C:14](=[O:19])[CH2:15][C:16](=[O:18])[CH3:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CCCCCC>[C:8]1([C:14](=[O:19])[C:15](=[C:3]2[CH2:7][CH2:6][CH2:5][NH:4]2)[C:16](=[O:18])[CH3:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: COC1=NCCC1
Solvent: CCCCCC
Product: CC(=O)C(C(=O)c1ccccc1)=C1CCCN1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
9.9 g (0.1 mole) of 2-methoxy-1-pyrroline and 24.4 g (0.15 mole) of 1-phenyl-1,3-butanedione are mixed together and, in a nitrogen atmosphere, heated with stirring for 18 hours in an oil bath at 100°. The dark reaction mixture is cooled to 60° and 500 ml of hexane is added. Upon further cooling to room temperature, the reaction product crystallises out. Recrystallisation from ethyl acetate/hexane yields 1-phenyl-2-(2-pyrrolidinylidene)-1,3-butanedione, m.p. 106°-108°.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1([CH2:16][N:17]2[CH2:22][CH2:21][N:20]([S:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[C:31]([Cl:36])[CH:32]=4)[CH:27]=3)(=[O:25])=[O:24])[CH2:19][C:18]2=[O:37])[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.[CH2:38]([O:41][C:42](OC1C=CC([N+]([O-])=O)=CC=1)=[O:43])[CH2:39][CH3:40].C(N(C(C)C)C(C)C)C.C(OCC)(=O)C>CN(C=O)C>[Cl:36][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[CH:27]=[C:26]([S:23]([N:20]1[CH2:21][CH2:22][N:17]([CH2:16][C:4]3([NH:3][C:42]([O:41][CH2:38][CH2:39][CH3:40])=[O:43])[CH2:9][CH2:8][N:7]([C:10]4[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=4)[CH2:6][CH2:5]3)[C:18](=[O:37])[CH2:19]1)(=[O:24])=[O:25])[CH:35]=[CH:34]2
Reactant: NC1(CN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)CCN(c2ccncc2)CC1
Reactant: CCCOC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCOC(=O)NC1(CN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)CCN(c2ccncc2)CC1
Yield: 47.4 %

Procedure:
A solution of 1-[4-amino-1-(4-pyridyl)-4-piperidylmethyl]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone dihydrochloride (235 mg), O-propoxycarbonyl-4-nitrophenol (270 mg) and N-ethyldiisopropylamine (0.348 ml) in DMF (5 ml) was stirred at 80° C. overnight. To the reaction solution was added ethyl acetate, the mixture was washed successively with a 10% aqueous sodium carbonate solution, an aqueous saturated sodium bicarbonate solution and an aqueous saturated sodium chloride solution, dried, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:10% aqueous ammonia-containing methanol=90:10→80:20), and crystallized from a mixed solution of acetone and ethyl acetate to obtain the pale brown crystalline title compound (114 mg).
Reaction SMILES: O.[OH-].[Li+].[C:4]1([N:14]2[CH:18]=[C:17]([CH3:19])[C:16]([C:20]([O:22]C)=[O:21])=[CH:15]2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][N:5]=1>O1CCCC1.O>[C:20]([C:16]1[C:17]([CH3:19])=[CH:18][N:14]([C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=[CH:6][N:5]=2)[CH:15]=1)([OH:22])=[O:21]
Reactant: COC(=O)c1cn(-c2nccc3ccccc23)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cn(-c2nccc3ccccc23)cc1C(=O)O

Procedure:
0.63 g (15 mmol) of lithium hydroxide monohydrate is added at a temperature in the region of 20° C. to 1.35 g (5 mmol) of 1-(isoquinol-1-yl)-3-methoxycarbonyl-4-methyl-1H-pyrrole dissolved in 50 mL of tetrahydrofuran and 50 mL of water. After stirring at reflux for 25 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 20 mL of water and then triturated with 15 mL of 1N hydrochloric acid. After filtering off and drying the solid residue at ambient pressure at a temperature in the region of 50° C., 1.1 g of 3-carboxy-1-(isoquinol-1-yl)-4-methyl-1H-pyrrole are obtained in the form of a whitish solid melting at 245° C.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC1(C)[O:25][CH:24]([CH2:26][OH:27])[CH2:23][O:22]1.[OH-].[Na+]>[Cl-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.CCCCCC>[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:22][CH2:23][CH:24]([OH:25])[CH2:26][OH:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OCC(CO)O1
Reactant: BrCCCCCCCCCCCCC1CCCCC1
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: CCCCCC
Product: OCC(O)COCCCCCCCCCCCCC1CCCCC1
Temperature: 80 °C
Reaction time: 10 h
Yield: 24 %

Procedure:
A mixture of 40.8 g (0.123 mole) of 12-cyclohexyldodecyl bromide, 22.7 g (0.172 mole) of 1,2-isopropylideneglycerol, 1.0 g of cetyltrimethylammonium chloride and 27.6 g (0.344 mole) of 50% aqueous sodium hydroxide solution was stirred at 80° C. for 10 hours. To the reaction mixture was added 200 ml of hexane and the resulting mixture was washed with water, dried (MgSO4) and concentrated under reduced pressure. To the residue were added 200 ml of methanol and 4 ml of 6N hydrochloric acid, and the mixture was heated unde reflux for 10 hours. The mixture was cooled and the colorless crystals precipitated were collected by filtration, washed with hexane and dried to give 10.1 g of the above-mentioned compound. The mother liquid was further cooled to obtain 20.8 g of the second crystals. Total yield: 30.9 g (yield: 74%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([CH3:17])[N:14]=[C:13]([NH:18][C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:28]C(C)([O-])C.[K+].CI>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([CH3:17])[N:14]=[C:13]([N:18]([CH3:28])[C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2cc(Nc3c(C)cc(C)cc3C)nc(C)n2)cc1OC
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(-c2cc(N(C)c3c(C)cc(C)cc3C)nc(C)n2)cc1OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 55.8 %

Procedure:
To a solution of 6-(3,4-dimethoxyphenyl)-2-methyl-4-(2,4,6-trimethylphenylamino)pyrimidine (1.0 g) in N,N-dimethylformamide (15 ml) were added potassium tert-butoxide (0.37 g) and methyl iodide (0.34 ml), and the mixture was stirred at ambient temperature for 1.5 hours. Then the mixture was poured into ice-water (200 ml) and stirred for an hour. The precipitates were collected, washed with water, dried in the air, and recrystallized from ethanol to give 6-(3,4-dimethoxyphenyl)-2-methyl-4-[N-methyl-N-(2,4,6-trimethylphenyl)amino]pyrimidine (0.58 g).
Reaction SMILES: [B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.N[CH2:22][N:23]1[C:33](=[O:34])[C:32]2[NH:31][CH:30]=[N:29][C:28]=2[N:26]([CH3:27])[C:24]1=[O:25]>O.B([O-])([O-])[O-]>[N:23]1([C:33](=[O:34])[C:32]2[NH:31][CH:30]=[N:29][C:28]=2[N:26]([CH3:27])[C:24]1=[O:25])[CH3:22]
Reactant: Cn1c(=O)n(CN)c(=O)c2[nH]cnc21
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [O-]B([O-])[O-]
Solvent: O
Product: Cn1c(=O)c2[nH]cnc2n(C)c1=O

Procedure:
The dye I (1,1'-(4-sulfobutyl)-3,3,3',3'-tetramethyl-6-carboxymethylindotricarbocyanine) was synthesized according to P. L. Southwick et al., Cytometry, 11 (1990) 418, dye XVIII. This dye is a water-soluble and reactive derivative of the dye HITC used in the previous examples. The absorption maximum in water was at 746 nm. The dye I was activated with TSTU (O-(N-succinimidyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, Fluka, Switzerland) and dissolved in borate buffer (pH 8.5, 0.1M borate) containing aminotheophylline (8-(3-aminopropyl)theophylline). The reaction yielded a clear solution. Thin layer chromatography confirmed that the aminotheophylline was completely used up. The absorption spectrum of the reaction mixture was similar to that of pure dye I. In subsequent experiments, the reaction mixture was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([S:14]([OH:17])(=O)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.CN(C=O)C.C1(C)C=CC=CC=1.S(Cl)([Cl:32])=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([S:14]([Cl:32])(=[O:17])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)(O)c1ccccc1-c1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=S(=O)(Cl)c1ccccc1-c1ccc(F)cc1

Procedure:
4′-Fluorobiphenyl sulfonic acid (3 g) was refluxed in thionyl chloride (30 mL) with a catalytic quantity of DMF (0.5 mL) for 4 hours. Toluene was added and the solvents evaporated under vacuum to give the title compound as an amorphous solid.
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:3])=[O:2].C(O)(C(F)(F)F)=O.[CH2:19]([N:26]([CH2:30][Si](C)(C)C)[CH2:27]OC)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[CH2:19]([N:26]1[CH2:30][CH:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:4]([N+:1]([O-:3])=[O:2])[CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=[N+]([O-])/C=C/c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])C1CN(Cc2ccccc2)CC1c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (E)-(2-nitrovinyl)benzene (110 g, 0.738 mol) and TFA (8.42 g, 0.073 mol) in DCM (500 mL) was added N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methan-amine (351.4 g, 1.476 mol) in DCM (500 mL) drop-wise at 0° C. for a period of 30 min. Then the reaction mixture was stirred at room temperature for 48 h. After completion of the reaction, the mixture was concentrated in vacuo, dissolved in water, and extracted into EtOAc (×2, 1.0 L). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified via flash chromatography (20-80% petroleum ether/EtOAc) to afford (3S and R,4R and S)-1-benzyl-3-nitro-4-phenylpyrrolidine. MS ESI calc'd. For C17H18N2O2 [M+1]+ 283. found 283.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.CC(C)([O-])C.[K+].[N+]([C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=1)([O-])=O>CN(C)C=O>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Oc2ccc(Oc3ccccc3)cc2)cc1
Temperature: 25 °C
Yield: 82 %

Procedure:
Methyl 4-(4-phenoxyphenoxy)benzoate is synthesized as follows. A mixture of 15.00 g (80.6 mmoles) of 4-phenoxyphenol, 130 ml of N,N-dimethylformamide and 75 ml of toluene is agitated under nitrogen atmosphere. Potassium t-butoxide (9.32 g, 80.6 mmoles) is added with vigorous stirring and the mixture is heated to reflux. An azeotrope of t-butanol and toluene (85 ml) is collected at temperatures of 120° C. to 135° C. and is discarded. The mixture is cooled to ambient temperature, and a solution of 14.59 g (80.6 mmoles) of methyl 4-nitrobenzoate in 30 ml of N,N-dimethylformamide is added over a period of 15 minutes with cooling in a water bath. The mixture is heated at 100° C. for 14 hours, cooled to 20° C., and quenched with 1500 ml of ice water. The precipitate is filtered, dried in air and dissolved in 500 ml of acetone. The solution is filtered to remove insolubles, and the filtrate is concentrated by evaporation and cooled to precipitate methyl 4-(4-phenoxyphenoxy)benzoate. The recovered product weighs 21.23 g (82 percent yield) and has a melting point of 114° C. as determined by DSC.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[Si:10]([O:17][C@H:18]1[CH2:27][C:26]([CH3:29])([CH3:28])[CH2:25][C:24]2[N:23]=[C:22]([CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[C:21]([C@H:35]([C:37]3[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=3)O)=[C:20]([CH:47]3[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]3)[C:19]1=2)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Si:10]([O:17][C@H:18]1[CH2:27][C:26]([CH3:29])([CH3:28])[CH2:25][C:24]2[N:23]=[C:22]([CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[C:21]([C@@H:35]([F:7])[C:37]3[CH:38]=[CH:39][C:40]([C:43]([F:44])([F:46])[F:45])=[CH:41][CH:42]=3)=[C:20]([CH:47]3[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]3)[C:19]1=2)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC1(C)Cc2nc(C3CCCC3)c([C@@H](O)c3ccc(C(F)(F)F)cc3)c(C3CCCCC3)c2[C@@H](O[Si](C)(C)C(C)(C)C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC1(C)Cc2nc(C3CCCC3)c([C@@H](F)c3ccc(C(F)(F)F)cc3)c(C3CCCCC3)c2[C@@H](O[Si](C)(C)C(C)(C)C)C1
Reaction time: 1 h

Procedure:
At −55° C. and under argon, 3.21 ml of diethylaminosulphur trifluoride (24.3 mmol, 1.5 eq.) are added dropwise to a solution of 9.96 g (16.2 mmol) of the compound from Example 5A in 300 ml of dry toluene. The mixture is stirred at this temperature for 1 h and then at room temperature for a further 2 h. For work-up, 120 ml of a saturated sodium bicarbonate solution are added carefully. The mixture is extracted three times in total with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product is purified by filtration through silica gel (mobile phase: cyclohexane/ethyl acetate 9:1).
Reaction SMILES: [C:1]1([S:7][CH2:8]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:10][SiH:11]([Cl:13])[Cl:12]>[Cl-].C([P+](CCCC)(CCCC)CCCC)CCC>[C:1]1([S:7][CH2:8][Si:11]([Cl:13])([Cl:12])[Cl:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCSc1ccccc1
Reactant: Cl[SiH](Cl)Cl
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Product: Cl[Si](Cl)(Cl)CSc1ccccc1
Reaction time: 12 h
Yield: 44.6 %

Procedure:
As in Example 1, phenylthiomethyl chloride (2.97 g, 0.0187 mol)), trichlorosilane (7.61 g, 0.0562 mol) and tetrabutylphosphonium chloride (2.97 g, 0.0187 mol) were put in a 50 mL stainless steel tube under nitrogen atmosphere. The reaction chamber was closed with a cover and the reaction was carried out at 120° C. for 12 hours. This reaction mixture was distilled under low pressure to give 2.15 g of (phenylthiomethyl)trichlorosilane in 44.5% yield.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:12](=[C:13](Cl)[CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][C:7]([CH2:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:16]([OH:18])=[O:17])[CH2:6][C:5]2=1.ClC1C=C(Cl)C=CC=1NN>>[C:22]1([CH2:21][CH2:20][CH2:19][C:7]2([C:16]([OH:18])=[O:17])[CH2:6][C:5]3[C:4]4[C:12](=[CH:13][CH:14]=[CH:2][CH:3]=4)[NH:11][C:10]=3[CH2:9][CH2:8]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(O)C1(CCCc2ccccc2)CCc2[nH]c3c(Cl)cc(Cl)cc3c2C1
Agent: NNc1ccc(Cl)cc1Cl
Product: O=C(O)C1(CCCc2ccccc2)CCc2[nH]c3ccccc3c2C1

Procedure:
39 mg of 6,8-dichloro-2,3,4,9-tetrahydro-3-(3-phenylpropyl)-1H-carbazole-3-carboxylic acid 275 is produced analogously with use of 2,4-dichlorophenylhydrazine.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH-].[Na+].Cl[CH2:15]/[CH:16]=[CH:17]\[CH2:18]Cl>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH3:11][C:1]1[CH:2]=[CH:3][C:4]([S:7]([N:10]2[CH2:18][CH:17]=[CH:16][CH2:15]2)(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: ClC/C=C\CCl
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)N2CC=CC2)cc1
Temperature: 0 °C
Yield: 66.9 %

Procedure:
A 1.0 l stirred vessel having a bottom discharge valve is charged with 51.3 g (0.3 mol) of p-toluenesulphonamide, 200 ml (1.2 mol) of 6N sodium hydroxide, 400 ml of toluene and 4.44 g (15 mmol) of tetrabutyl-ammonium chloride and, at an internal temperature of 60° C., 37.5 g (0.3 mol) of cis-1,4-dichloro-2-butene are added dropwise with vigorous stirring over a period of 20 minutes, whereupon the internal temperature rises by 2° C. The mixture is stirred for another hour at 60° C. and another 2 hours at 80° C., the aqueous phase is then separated off and the organic phase is washed at 60° C. with 100 ml of 1N sulphuric acid and 2×200 ml of water. The organic phase is filtered through a fluted filter moistened with toluene into a crystallisation vessel. Upon cooling to 0° C., 44.8 g of product, melting point 128° to 130° C., are obtained. From the concentrated mother liquor (approx. 20 g), recrystallisation from 100 ml of isopropanol or 60 ml of toluene affords a further 12 to 15 g of product, melting point: 125° to 127° C. Yield: 85 to 90% of theory.
Reaction SMILES: C1(C(C(C2C=CC=CC=2)=O)=O)C=CC=CC=1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH:26]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)[OH:27])=[O:25])=[CH:20][CH:19]=1>O.N1C=CC=CC=1>[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]([C:26]([C:28]2[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=2)=[O:27])=[O:25])=[CH:22][CH:23]=1
Reactant: Cc1ccc(C(=O)C(O)c2ccc(C)cc2)cc1
Agent: O=C(C(=O)c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(C(=O)C(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4,4′-Dimethylbenzil was prepared on the basis of a known method for benzil (L. F. Tietze, Th. Eicher, Reaktionen und Synthesen[Reactions and Syntheses], R. Stierlein, Chem. Ber. 22/1 (1889) 37). 420 g of CuSO4·5H2O (1.68 mol) were dissolved in a mixture of 350 ml of water and 400 ml of pyridine bases while heating. 190 g (0.79 mol) of crude 4,4′-dimethylbenzoin were added to the still warm solution, and refluxing was effected for 4 hours. After cooling to room temperature, the crude product was filtered off and washed with water. The filter residue was taken up in ether, filtered and dried with Na2SO4. After the solution had been evaporated down to about 500 ml, 4,4′-dimethylbenzil crystallized out in the form of pale yellow crystals. Depending on their use, they were recrystallized from ethanol (yield 119.9 g (64%, based on crude 4,4′-dimethylbenzoin used); m.p.: 104° C., literature: 104-105° C. The IR spectrum of 4,4′-dimethylbenzil is shown in FIG. 9.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[Cl:7][C:8]1[C:13]([F:14])=[C:12](B(O)O)[CH:11]=[CH:10][N:9]=1.[Cl:18][C:19]1[N:24]=[C:23](Cl)[CH:22]=[CH:21][N:20]=1.B(O)O>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1.O>[Cl:18][C:19]1[N:24]=[C:23]([C:12]2[CH:11]=[CH:10][N:9]=[C:8]([Cl:7])[C:13]=2[F:14])[CH:22]=[CH:21][N:20]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: OB(O)c1ccnc(Cl)c1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Fc1c(-c2ccnc(Cl)n2)ccnc1Cl
Temperature: 80 °C
Reaction time: 4.5 h
Yield: 72.1 %

Procedure:
Sodium carbonate (2.13 g, 20.1 mmol) was added to 2-chloro-3-fluoropyridin-4-ylboronic acid (1.41 g, 8.05 mmol) and 2,4-dichloropyrimidine (1.0 g, 6.71 mmol) in 4:1 dioxane/water (50 mL), and the mixture was sparged with argon. PdCl2(dppf)*DCM (0.274 g, 0.336 mmol) was added, and the mixture was heated at 80° C. under argon. After 4.5 hours, more boronic acid (approximately 0.2 g) was added and heating continued for a total of 8.5 hours. The reaction mixture was diluted with water, and the resulting solid was collected by vacuum filtration to afford the desired 2-chloro-4-(2-chloro-3-fluoropyridin-4-yl)pyrimidine (1.18 g, 4.84 mmol, 72.0% yield) with minor impurities.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:45]=[CH:46][CH:47]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[C:23]([O:33][CH3:34])[CH:22]=4)[CH:19]=3)[N:14]([S:35]([C:38]3[CH:44]=[CH:43][C:41]([CH3:42])=[CH:40][CH:39]=3)(=[O:37])=[O:36])[CH:13]=2)[CH:9]=[N:8]1.[CH3:48][C@H:49]1[CH2:51][O:50]1.CCN(C(C)C)C(C)C>C(O)C>[F:2][C:3]1[CH:4]=[C:5]([CH:45]=[CH:46][CH:47]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:28][CH2:29][N:30]([CH2:48][C@@H:49]([OH:50])[CH3:51])[CH2:31][CH2:32]5)=[C:23]([O:33][CH3:34])[CH:22]=4)[CH:19]=3)[N:14]([S:35]([C:38]3[CH:39]=[CH:40][C:41]([CH3:42])=[CH:43][CH:44]=3)(=[O:36])=[O:37])[CH:13]=2)[CH:9]=[N:8]1
Reactant: C[C@H]1CO1
Reactant: COc1cc(-c2cnc3c(c2)c(-c2cnn(Cc4cccc(F)c4)c2)cn3S(=O)(=O)c2ccc(C)cc2)ccc1N1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COc1cc(-c2cnc3c(c2)c(-c2cnn(Cc4cccc(F)c4)c2)cn3S(=O)(=O)c2ccc(C)cc2)ccc1N1CCN(C[C@H](C)O)CC1
Yield: 68.1 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(3-methoxy-4-(piperazin-1-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine hydrochloride (100 mg. 0.148 mmol) was alkylated using (S)-2-methyloxirane (26 mg, 0.445 mmol), DIPEA (115 mg, 0.891 mmol) and ethanol (5 mL) to get crude 70 mg of the titled compound. MS: m/z=695.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C@H:13]([CH3:22])[CH2:14][CH2:15][C@@H:16]([C:18]([O:20]C)=[O:19])[CH2:17][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[C@H:13]([CH3:22])[CH2:14][CH2:15][C@@H:16]([C:18]([OH:20])=[O:19])[CH2:17][C:11]=3[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H]1CC[C@@H](C)c2c(-c3ccc(Cl)cc3)noc2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H]1CC[C@@H](C(=O)O)Cc2onc(-c3ccc(Cl)cc3)c21
Yield: 80.5 %

Procedure:
0.36 g (1.13 mmol) of methyl trans-3-(4-chlorophenyl)-5,6,7,8-tetrahydro-4-methyl-4H-cyclohept[d]isoxazole-7-carboxylate in 35 ml of dioxane was stirred at room temperature for 1 hour with 15 ml of 1N aqueous sodium hydroxide solution. Water was added and the solution was partially evaporated. Additional water was added to give a solution which was then acidified with 1N hydrochloric acid. The precipitate was filtered off, washed with water and dried to give 0.278 g of trans-3-(4-chlorophenyl)-5,6,7,8-tetrahydro-4-methyl-4H-cyclohept[d]isoxazole-7-carboxylic acid of melting point 154°-155° C.
Reaction SMILES: C([Li])CCC.[Br:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11].CN([CH:19]=[O:20])C.O>C1COCC1>[Br:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:9]2[C:8]=1[CH:19]([OH:20])[O:11][C:10]2=[O:12]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cccc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C1OC(O)c2c(Br)cccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.3 %

Procedure:
To a stirred solution of n-butyllithium 1.6 M in hexanes (17.5 mL, 28.1 mmol) was added at −20° C. under argon 2,2,6,6-tetramethylpiperidine (4.7 mL, 28.1 mmol) in anhydrous THF (40 mL). After cooling (−50° C.), 3-bromobenzoic acid (2.54 g, 12.8 mmol) in anhydrous THF (10 mL) was added dropwise and the mixture was stirred for 1 h. The mixture was then treated with an excess of DMF (3.7 g, 50.4 mmol). The resulting solution was allowed to warm up to ambient temperature, after which water was added. The aqueous layer was washed with diethyl ether, and then acidified with 4M HCl. The mixture was diluted with diethyl ether and the organic layer was separated and dried with MgSO4. The residue was purified by crystallization using with EtOAc/PE to give the crude title product (1.18 g, yield: 41%).