Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[C:12]1(C)C=CC=C[CH:13]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccccc1
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)Cc1ccc(O)cc1
Reaction time: 3 h

Procedure:
A mixed solution comprising 4-hydroxyphenylacetic acid (150.0 g), toluene (250 ml), ethanol (150 ml), and p-toluenesulfonic acid (50 g) was refluxed with stirring for 3 hours. The reaction mixture was washed with aqueous sodium hydrogencarbonate solution, dried over sodium sulfate anhydride, and then concentrated under a vacuum to yield 164.3 g of oily ethyl 4-hydroxyphenylacetate. This material was subjected to a reaction identical to that of Reference Example 1, thereby yielding 138.2 g of oily ethyl 4-hydroxy-3-methallylphenylacetate. In a manner identical to Reference Examples 2 and 3, this material was successively subjected to catalytic reduction, benzylation, and hydrolysis reactions, thereby yielding 70.4 g of 4-benzyloxy-3-isobutylphenylacetic acid. As in the case of Example 3, this material (1.0 g) was subjected to a condensation reaction with 1-isobutylpiperazine (0.48 g), thereby yielding 1.3 g of the aimed compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[O:13]1[CH:15]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:14]1>Cl>[Cl:1][C:2]1[CH:3]=[C:4]([Cl:8])[CH:5]=[CH:6][C:7]=1[CH:18]([CH3:19])[CH2:17][CH2:16][CH2:15][CH2:14][OH:13]
Reactant: CCCCC1CO1
Reactant: Clc1cccc(Cl)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(CCCCO)c1ccc(Cl)cc1Cl
Reaction time: 8 h

Procedure:
A slurry of m-dichlorobenzene, 735 g. (5.0 mole) and anhydrous aluminium chloride, 162 g. (1.1 mole) is cooled to 10° using an ice-water bath and 1,2-epoxyhexane, 100 g. (1.0 mole) is added dropwise over a 1 hour period. The temperature of the reaction is kept below 15°. The reaction mixture is allowed to come to room temperature and stirring is continued overnight. The reaction mixture is then poured into a 4 liter flask containing ice and concentrated hydrochloric acid (50 ml.) with stirring. The aqueous and organic layers are separated and the aqueous layer extracted three times with ether (150 ml). The combined organic extracts are washed twice with water (50 ml) and dried over magnesium sulfate. Solvent is evaporated and vacuum distillation (160°-172°/0.1 mm) gives 114 g. (46%) of product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]([CH3:21])([CH3:20])[CH:5]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]=1.O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:22])[C:4]([CH3:20])([CH3:21])[CH:5]([C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:30][C:31]2[CH:40]=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]=2)=[CH:17][CH:18]=1)[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:30][C:31]2[CH:40]=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]=2)=[CH:8][CH:7]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: COC(=O)C(C)(C)C(c1ccc(O)cc1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)C(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
To a stirred solution in DMF (50 mL) of 2,2-dimethyl-3,3-bis(4-hydroxyphenyl)propionic acid methyl ester (1.1 g, 3.7 mmol), prepared as in step 1, was added Cs2CO3 (2.5 g, 7.7 mmol) and the mixture stirred 0.5 hours at room temperature. 2-Chloromethyquinoline (1.37 g, 7.7 mmol) was added as a solid in small portions. The reaction mixture was stirred overnight at room temperature. The mixture was poured into 300 mL of water and extracted with ether (2×200 mL). Brine was added to the aqueous layer and it was extracted twice with ether. The combined ether extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give a light yellow oil. Chromatography on silica gel (40% ethyl acetate/hexanes) gave 1.68 g (78%) of 2,2-dimethyl-3,3-bis(4-(2-quinolylmethoxy)phenyl)propionic acid methyl ester as a white foam.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]#N)=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=[O:3])[CH3:2].CN(C)C=O.[BH4-].[Na+].C(Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(SC#N)cc1[N+](=O)[O-]
Reactant: BrCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(SCc2ccccc2)cc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
2.37 G. 1-acetamido-2-nitro-4-thiocyanatobenzene in 10 ml. dimethylformamide under nitrogen is treated with 0.38 g. sodium borohydride at 20°-25° C. After one hour 2.4 ml. benzylbromide is added, the mixture left for 2 hours, then diluted with water, filtered, washed with cyclohexane, recrystallized from methanol yielding 1-acetamido-2-nitro-4-benzylthiobenzene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][N:31]1[C:35]([CH3:36])=[CH:34][C:33]([C:37](O)=[O:38])=[N:32]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:37]([C:33]4[CH:34]=[C:35]([CH3:36])[N:31]([CH3:30])[N:32]=4)=[O:38])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1cc(C(=O)O)nn1C
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2cc(C)n(C)n2)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 50 mg, 0.13 mmol) and 1,5-dimethyl-1H-pyrazole-3-carboxylic acid (21 mg, 0.15 mmol).
Reaction SMILES: Cl[C:2]1[C:3]2[C@H:11]([C:12]([F:15])([F:14])[F:13])[CH2:10][C:9](=[O:16])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl.Cl.[NH:19]1[CH2:24][CH2:23][CH:22]([C:25]2[N:26]([CH2:35][CH2:36][OH:37])[CH:27]=[C:28]([CH2:30][C:31]([F:34])([F:33])[F:32])[N:29]=2)[CH2:21][CH2:20]1.CN1CCCC1=O.C(N(C(C)C)CC)(C)C>C(=O)(O)[O-].[Na+]>[OH:37][CH2:36][CH2:35][N:26]1[CH:27]=[C:28]([CH2:30][C:31]([F:32])([F:34])[F:33])[N:29]=[C:25]1[CH:22]1[CH2:21][CH2:20][N:19]([C:2]2[C:3]3[C@H:11]([C:12]([F:15])([F:14])[F:13])[CH2:10][C:9](=[O:16])[NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:24][CH2:23]1
Reactant: O=C1C[C@@H](C(F)(F)F)c2c(Cl)ncnc2N1
Reactant: OCCn1cc(CC(F)(F)F)nc1C1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: O=C1C[C@@H](C(F)(F)F)c2c(ncnc2N2CCC(c3nc(CC(F)(F)F)cn3CCO)CC2)N1
Temperature: 150 °C
Yield: 67.9 %

Procedure:
Add (R)-4-chloro-5-(trifluoromethyl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (0.70 g, 2.78 mmol), 2-(2-(piperidin-4-yl)-4-(2,2,2-trifluoroethyl)-1H-imidazol-1-yl)ethanol dihydrochloride (1.17 g, 1.2 eq), N-methylpyrrolidinone (10 mL) and diisopropylethylamine (2.20 mL, 5.7 eq) in a microwave tube. Seal with crimp cap. Heat in a microwave reactor at 150° C. for one hour. Dilute the reaction mixture with saturated aqueous sodium bicarbonate and extract with ethyl acetate. Dry the organics over anhydrous sodium sulfate, filter, and concentrate in vacuo. Purify by normal phase chromatography, eluting with 5% methanol/dichloromethane to 10% methanol/dichloromethane to 10% 2 M ammonia in methanol/dichloromethane, to give (R)-4-(4-(1-(2-hydroxyethyl)-4-(2,2,2-trifluoroethyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(trifluoromethyl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (0.93 g, 68%). MS (ES) m/z=493 [M]+.
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:17])=[N:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:12]([CH3:13])[C@@H:10]([OH:11])[C@H:8]1[OH:9].C[Si](Cl)(C)C.Cl[C:24]([O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:25]>N1C=CC=CC=1>[CH:27]1([O:26][C:24]([NH:17][C:3]2[C:2]([F:1])=[CH:15][N:6]([C@@H:7]3[O:14][C@H:12]([CH3:13])[C@@H:10]([OH:11])[C@H:8]3[OH:9])[C:5](=[O:16])[N:4]=2)=[O:25])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: O=C(Cl)OC1CCCCC1
Reactant: C[C@H]1O[C@@H](n2cc(F)c(N)nc2=O)[C@H](O)[C@@H]1O
Agent: C[Si](C)(C)Cl
Solvent: c1ccncc1
Product: C[C@H]1O[C@@H](n2cc(F)c(NC(=O)OC3CCCCC3)nc2=O)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
5'-Deoxy-5-fluorocytidine (2.5 g) was dissolved in dry pyridine (20 ml). To the mixture, trimethylsilyl chloride (3.4 ml) was added dropwise at 0° C., and stirred for 30 min at room temperature. To the reaction mixture, cyclohexyl chloroformate (2.0 ml) was added in one portion at 0° C. After stirring of the mixture for 1 hour at room temperature, pyridine was evaporated under reduced pressure. The residue was then partitioned between saturated aqueous NaHCO3 and ether. The organic layer was washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. To the residue were added citric acid (2.0 g) and methanol (50 ml). The mixture was stirred at room temperature overnight. After removal of the solvent under reduced pressure, the residue was dissolved in CH2Cl2 /MeOH (95:5) and neutralized by aqueous NaOH. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography using CH2Cl2 /MeOH (20:1) as an eluent, followed by recrystallization from ethyl acetate to give N4 -(cyclohexyloxycarbonyl)-5'-deoxy-5-fluorocytidine (3.47 g:92% yield):mp. 134°-136° C., FAB-MS m/z 372 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[N:9][OH:10])=[N:6][CH:7]=1.[CH2:11]([OH:14])[CH:12]=[CH2:13]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:13][CH:12]([CH2:11][OH:14])[O:10][N:9]=2)=[N:6][CH:7]=1
Reactant: ON=Cc1ccc(Br)cn1
Reactant: C=CCO
Solvent: C1CCOC1
Product: OCC1CC(c2ccc(Br)cn2)=NO1
Reaction time: 4 h

Procedure:
5-Bromo-pyridine-2-carbaldehyde oxime (60 g, 298.5 mmol) and allyl alcohol (49.7 ml) were added to tetrahydrofuran (200 ml) and then bleach (2016 ml) was added. The reaction was stirred for four hours followed by extraction with tetrahydrofuran (2×200 ml). The organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to give the desired product (38.8 g).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)[CH:18]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:37][C:38]1[CH:46]=[C:45]([Cl:47])[CH:44]=[C:43]([Cl:48])[C:39]=1[C:40](Cl)=[O:41]>C(Cl)Cl>[Cl:37][C:38]1[CH:46]=[C:45]([Cl:47])[CH:44]=[C:43]([Cl:48])[C:39]=1[C:40]([N:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[CH:10][CH:11]=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH:18]=1)=[O:41]
Reactant: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Reactant: c1cc(CNc2ccc(OCCN3CCCC3)cc2)cc(OC2CCCCO2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1c(Cl)cc(Cl)cc1Cl)N(Cc1cccc(OC2CCCCO2)c1)c1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-[3-(tetrahydro-pyran-2-yloxy)-benzyl]-amine (0.050 g, 0.13 mmol) in 0.5 mL methylene chloride was added triethylamine (0.035 mL, 0.25 mmol), 2,4,6-trichlorobenzoyl chloride (0.061 g, 0.25 mmol), and catalytic N,N-dimethylaminopyridine (DMAP). The reaction mixture was stirred overnight at room temperature. The reaction was concentrated to give the title compound of Step A which was used in Step B without further purification. MS 605.4 (M+1)+
Reaction SMILES: [CH3:1][O:2][CH:3]([O:7][CH3:8])[C:4]([CH3:6])=O.[CH2:9]([NH2:12])[CH:10]=[CH2:11].[BH4-].[Na+]>C(O)C>[CH2:9]([NH:12][CH:4]([CH3:6])[CH:3]([O:7][CH3:8])[O:2][CH3:1])[CH:10]=[CH2:11]
Reactant: COC(OC)C(C)=O
Reactant: C=CCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C=CCNC(C)C(OC)OC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
20 g of molecular sieve are added to 12 g (0.1 mol) of 1,1-dimethoxyacetone in 100 ml of ethanol and 7 g (0.12 mol) of allylamine are then added dropwise. The mixture is allowed to stand overnight at room temperature, decanted from the molecular sieve and cooled in an ice-bath to 0° C., and 4 g (0.1 mol) of sodium borohydride are added in small portions. The mixture is stirred overnight at room temperature and concentrated, the residue is taken up in 100 ml of water, and the mixture is saturated with potassium carbonate and extracted five times with 100 ml of chloroform each time. The extracts are dried over potassium carbonate and concentrated, and the residue is distilled.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[C:8]([C:18]([N:20]([CH2:43][CH:44]([CH3:46])[CH3:45])[C@H:21]2[CH2:26][C@@H:25]([NH:27][C:28](OCC(Cl)(Cl)Cl)=[O:29])[CH2:24][N:23]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:22]2)=[O:19])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[NH:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1>CN(C)C(=O)C.Cl>[C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[C:8]([C:18]([N:20]([CH2:43][CH:44]([CH3:46])[CH3:45])[C@H:21]2[CH2:26][C@@H:25]([NH:27][C:28]([N:56]3[CH2:61][CH2:60][O:59][CH2:58][CH2:57]3)=[O:29])[CH2:24][N:23]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:22]2)=[O:19])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)[C@H]1C[C@@H](NC(=O)OCC(Cl)(Cl)Cl)CN(C(=O)OC(C)(C)C)C1
Reactant: C1COCCN1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)[C@H]1C[C@@H](NC(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
tert-Butyl (3S,5R)-3-[({2-tert-butyl-4-[(furan-2-ylmethyl)amino]pyrimidin-5-yl}carbonyl)(2-methylpropyl)amino]-5-{[(2,2,2-trichloroethoxy)carbonyl]amino}piperidine-1-carboxylate (98.0 mg) and N,N-diisopropylethylamine (120 μl) were dissolved in N,N-dimethylacetamide (3 ml), morpholine (20 μl) was added, and the mixture was stirred at 80° C. for 1 day. The reaction mixture was diluted with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (10:90-100:0) was concentrated under reduced pressure to give the object compound (12.7 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C@H:20]2[CH2:22][O:21]2)=[C:13](C(=O)C)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=[C:26]([C:30]([O:32]O)=[O:31])C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C@H:20]2[CH2:22][O:21]2)=[C:13]([O:32][C:30](=[O:31])[CH3:26])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cc(OCc2ccccc2)ccc1OC[C@H]1CO1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)Oc1cc(OCc2ccccc2)ccc1OC[C@H]1CO1
Temperature: 25 °C
Reaction time: 72 h
Yield: 52.1 %

Procedure:
To a stirred solution of 1-[5-benzyloxy-2-((R)-1-oxiranylmethoxy)phenyl]ethanone (1.0 g, 3.36 mmol) in DCM (20 ml) was added m-chloroperbenzoic acid (1.24 g) and solid NaHCO3 (3.24 g). The mixture was stirred at RT for 3 d. The mixture was filtered and the filtrate washed once with 10% NaHSO4 solution and then twice with NaHCO3 solution. The organic layer was washed with water and brine and dried with Na2SO4. The solvent was removed under reduced pressure. The residue was triturated with ether to give the title compound (0.55 g) as a white solid, which was used without purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]=[O:9].[Na+].[C:11]1([S:17]([O-:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CN1CCCC1=O>C(OCC)(=O)C.[Cu]I>[C:11]1([S:17]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[CH:8]=[O:9])(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1cnccc1Br
Reactant: O=S([O-])c1ccccc1
Agent: [Cu]I
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: O=Cc1cnccc1S(=O)(=O)c1ccccc1
Temperature: 60 °C
Yield: 158.8 %

Procedure:
A mixture of 4-bromopyridine-3-carbaldehyde (0.90 g), benzenesulfinic acid sodium salt (4.0 g), copper (I) iodide (4.6 g) and 1-methyl-2-pyrrolidinone (50 mL) was heated at 60° C. for 2 hours. The mixture was cooled to room temperature, diluted with ethyl acetate and filtered through Celite. The filtrate was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (1:0 to 0:1 by volume) to afford the title compound as a yellow oil (1.9 g).
Reaction SMILES: [H-].[Na+].C([O:5][C:6](=O)[CH:7]([Cl:11])[C:8]([CH3:10])=[O:9])C.C([Li])CCC.[CH:18]1([C:23](=[O:28])[CH2:24][CH2:25][C:26]#[CH:27])[CH2:22][CH2:21][CH2:20][CH2:19]1>C1COCC1>[CH2:24]([C:23]1([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[O:28][C:6](=[O:5])[CH:7]([Cl:11])[C:8](=[O:9])[CH2:10]1)[CH2:25][C:26]#[CH:27]
Reactant: C#CCCC(=O)C1CCCC1
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCCC1(C2CCCC2)CC(=O)C(Cl)C(=O)O1
Temperature: -40 °C
Yield: 76.3 %

Procedure:
To a slurry of sodium hydride (480 mg, 60% suspension in mineral oil, 12 mmol) in THF (30 mL) cooled to −10° C. was added ethyl-2-chloroacetoacetate (1.66 mL, 12 mmol). The reaction was stirred until all gas evolution ceased. The reaction was then cooled to −40 ° C. and a solution of butyl lithium (4.8 mL, 2.5 M in ether, 12 mmol) was added. The reaction was stirred for 10 minutes, and then 1-cyclopentyl-pent-4-yn-1-one (0.60 g, 4 mmol) was added as a solution in THF (10 mL). The reaction was stirred for 1 hour, and then quenched with 40 mL saturated ammonium chloride. The solution was acidified further with 5 mL of 6 N HCl. The layers were separated, and the aqueous was extracted with ethyl acetate. The organics were combined and washed with water and then saturated sodium chloride. The organic phase was dried over sodium sulfate, filtered, and then concentrated. The crude product was then dissolved in toluene (13 mL) and bis(dibutylchlorotin) (1.027 g) was added. The solution was heated to reflux for one hour. The reaction was then concentrated and chromatographed (40 g silica gel, 2% MeOH in CH2Cl2) to yield the title compound (0.820 g, 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([N:18]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[N:19]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH3:25])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:29]([O:31][CH2:32][CH2:33][O:34][CH3:35])=[O:30].O>CN(C)C=O>[CH3:35][O:34][CH2:33][CH2:32][O:31][C:29](=[O:30])[N:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:9]1[N:17]=[C:16]([N:18]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[N:19]2)[N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[CH3:25]
Reactant: Cc1cc(C)n(-c2nc(Nc3ccc(Cl)cc3)c3ncn(C)c3n2)n1
Reactant: COCCOC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOC(=O)N(c1ccc(Cl)cc1)c1nc(-n2nc(C)cc2C)nc2c1ncn2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.9 %

Procedure:
(4-Chloro-phenyl)-[2-(3,5-dimethyl-pyrazol-1-yl)-9-methyl-9H-purin-6-yl]-amine (520 mg, 1.5 mmol) was dissolved in N,N-dimethylformamide (5 mL). Sodium hydride (60% in mineral oil, 90 mg, 2.2 mmol) was added and mixture was stirred at room temperature for 30 minutes. 2-Methoxyethyl chloroformate (0.26 mL, 2.2 mmol) was added and stirring was continued at room temperature over night. Water was added and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulphate, filtrated and concentrated in vacuo. The crude product was purified by flash chromatography (ethyl acetate/methanol as eluent) to give (4-chloro-phenyl)-[2-(3,5-dimethyl-pyrazol-1-yl)-9-methyl-9H-purin-6-yl]-carbamic acid 2-methoxy-ethyl ester (280 mg, 42%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:28]=[CH:27][C:5]([O:6][C@@H:7]([CH2:25][CH3:26])[C@H:8]([O:17][Si](C(C)(C)C)(C)C)[CH2:9][CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33](Br)=[CH:32][C:31]=1[S:37]([NH2:40])(=[O:39])=[O:38].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:25]([C@@H:7]([C@H:8]([OH:17])[CH2:9][CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[O:6][C:5]1[CH:4]=[CH:3][C:2]([C:33]2[CH:34]=[CH:35][C:30]([F:29])=[C:31]([S:37]([NH2:40])(=[O:39])=[O:38])[CH:32]=2)=[CH:28][CH:27]=1)[CH3:26]
Reactant: NS(=O)(=O)c1cc(Br)ccc1F
Reactant: CC[C@H](Oc1ccc(Br)cc1)[C@@H](CCc1cccnc1)O[Si](C)(C)C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC[C@H](Oc1ccc(-c2ccc(F)c(S(N)(=O)=O)c2)cc1)[C@H](O)CCc1cccnc1
Temperature: 90 °C
Yield: 73.1 %

Procedure:
Prepared according to the method described in Example 12b) from from (3R,4S)-3-[4-(4-Bromophenoxy)-3-(t-butyldimethylsilanyloxy)hexyl]pyridine (0.20 g, Example 88b)), 2-fluoro-5-bromophenylsulfonamide (0.177 g, Example 35a)), 2M aqueous sodium carbonate (0.54 ml) and tetrakis(triphenylphosphine)palladium (0) (0.014 g) in ethanol (3 ml) with heating at 90 ° C. for 4 hours. The residue was purified by column chromatography over silica eluting with ethyl acetate to give the title compound as a foam (0.14 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O>>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1
Reactant: COc1ccccc1B(O)O
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Product: COc1ccccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 25, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 2-methoxyphenylboronic acid (CAS RN 5720-06-9). Off-white solid (45%). MS (ESI): m/z=455.4 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[N:5][C:6]([S:9][C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:7][CH:8]=1.[Cl:19]N1C(=O)CCC1=O>CO>[CH3:1][O:2][C:3]1[N:4]=[N:5][C:6]([S:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[Cl:19])=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:7][CH:8]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc(Sc2cc3ccccc3[nH]2)nn1
Solvent: CO
Product: COc1ccc(Sc2[nH]c3ccccc3c2Cl)nn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
A mixture of 3-methoxy-6-(indole-2-sulfenyl)-pyridazine) (2.92 mmol, 750 mg), N-chloro-succinimide (2.92 mmol, 390 mg) and methanol (15 mL) was stirred overnight at room temperature. Excess methanol was removed and the residue was extracted with EtOAc (3×10 mL). The EtOAc extract was collected, dried, filtered and evaporated to dryness to obtain a residue, which was purified by silica gel chromatography (eluent: hexanes:EtOAc:19:5) to yield 3-methoxy-6-(3-chloro-indole-2-sulfenyl)-pyridazine (40%, 338 mg).