Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Br:13])[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].[Br:14]NC(=O)CCC(N)=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:3]=[C:2]([Br:1])[C:11]([CH2:12][Br:14])=[C:10]([Br:13])[CH:9]=1
Reactant: NC(=O)CCC(=O)NBr
Reactant: COC(=O)c1cc(Br)c(C)c(Br)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(Br)c(CBr)c(Br)c1
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of methyl 3,5-dibromo-4-methylbenzoate (5 g, 16.24 mmol) in carbon tetrachloride (50 mL) was treated with N-bromosuccinamide (3.6 g, 20.23 mmol) and 2,2′-azobisisobutyronitrile (0.56 g, 3.410 mmol). The reaction mixture was heated to reflux for 24 h. The reaction was cooled to room temperature and concentrated under vacuum. The resulting mixture was absorbed onto silica and was purified by flash chromatography using silica gel eluted with 3:1 hexanes:ethyl acetate. The desired fractions were collected and concentrated under vacuum to afford a solid which was dried under high vacuum to afford 3,5-dibromo-4-bromomethyl-benzoic acid methyl ester (57) (6.22 g, 99%) as a yellow solid; LRMS for C9H7Br3O2 (M+Na) m/z=407. MW=386.8669, Exact Mass=383.7996
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@H:9]2[CH2:13][C@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](Br)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@@H:10]2[O:28][CH:29]2[CH2:32][CH2:31][CH2:30]2)=[O:8])[CH2:5][CH2:4]1)#[N:2].C(C1(NC([C@H]2C[C@H](S(C3C=CC(Br)=CC=3C(F)(F)F)(=O)=O)C[C@@H]2OC2CCOCC2)=O)CC1)#N>>[C:1]([C:3]1([NH:6][C:7]([C@H:9]2[CH2:13][C@H:12]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:24]([F:26])([F:25])[F:27])(=[O:16])=[O:15])[CH2:11][C@@H:10]2[O:28][CH:29]2[CH2:30][CH2:31][CH2:32]2)=[O:8])[CH2:4][CH2:5]1)#[N:2]
Reactant: N#CC1(NC(=O)[C@H]2C[C@H](S(=O)(=O)c3ccc(Br)cc3C(F)(F)F)C[C@@H]2OC2CCC2)CC1
Agent: N#CC1(NC(=O)[C@H]2C[C@H](S(=O)(=O)c3ccc(Br)cc3C(F)(F)F)C[C@@H]2OC2CCOCC2)CC1
Product: N#CC1(NC(=O)[C@H]2C[C@H](S(=O)(=O)c3ccccc3C(F)(F)F)C[C@@H]2OC2CCC2)CC1

Procedure:
The title compound was prepared in analogy to example 175 using (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-cyclobutoxy-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (example 182) instead of (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-(tetrahydro-pyran-4-yloxy)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide. White solid. MS (EI): 455.2 (M−H)−.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][N:10]=2)[CH2:3]1.[F:17][C:18]([F:34])([F:33])[C:19]1[O:23][N:22]=[C:21]([C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27](O)=[O:28])[N:20]=1>>[CH3:1][CH:2]1[N:7]([C:27](=[O:28])[C:26]2[CH:30]=[CH:31][CH:32]=[C:24]([C:21]3[N:20]=[C:19]([C:18]([F:34])([F:33])[F:17])[O:23][N:22]=3)[CH:25]=2)[CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][N:10]=2)[CH2:3]1
Reactant: CC1CN(c2ccc(C#N)cn2)CC(C)N1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: CC1CN(c2ccc(C#N)cn2)CC(C)N1C(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 18 %

Procedure:
This compound was synthesized from 6-(3,5-dimethylpiperazin-1-yl)nicotinonitrile and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (35 mg, yield 18%). 1H NMR (400 MHz, CDCl3) δ 8.42 (d, J=1.8 Hz, 1H), 8.22 (dt, J=7.2 Hz, J=1.7 Hz, 1H), 8.16 (s, 1H), 7.68-7.62 (m, 3H), 6.66 (d, J=9.0 Hz, 1H), 4.46 (m, 2H), 4.29 (d, J=13.8 Hz, 1H), 3.36 (m, 2H), 1.16 (d, J=6.3 Hz, 6H). MS (ESI) m/z: Calculated for C22H19F3N6O2: 456.15. found: 457.2 (M+H)+.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:11]=[C:12]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[CH2:13][NH:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][CH:18]=1)=[O:16].O>C(Cl)Cl>[C:1]1([S:7]([N:32]2[CH2:31][CH2:30][N:29]([C:12](=[O:11])[CH2:13][NH:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:19][CH:18]=3)=[O:16])[CH2:34][CH2:33]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: O
Solvent: ClCCl
Product: O=C(NCC(=O)N1CCN(S(=O)(=O)c2ccccc2)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.3 %

Procedure:
TEA (62.57 mg, 062 mmol) followed by benzenesulphonyl chloride (54.6 mg, 0.31 mmol) were added at to 0° C. to biphenyl-4-carboxylicacid (2-oxo-2-piperazin-1-yl-ethyl)-amide (100 mg, 0.31 mmol) in DCM (4 mL). The resulting mixture was stirred at room temperature overnight. Cold water was then added and the product extracted with DCM. The organic layer was separated, washed with 10% HCl solution, saturated NaHCO3 solution and brine, dried over sodium sulphate and concentrated. The resulting residue was purified by column chromatography (using 60-120 mesh silica gel and 30% EtOAc in hexane as eluent) to afford 45 mg (31.4% yield) of biphenyl-4-carboxylicacid {2-[4-benzene sulfonyl-piperazin-1-yl]-2-oxo-ethyl}-amide, LC-MS purity: 98.75%, 1H NMR: (DMSO) δ 8.76 (t, 1H), 7.92 (d, 2H), 7.8-7.6 (m, 9H), 7.54-7.44 (t, 2H), 7.44-7.36 (t, 1H), 4.1 (d, 2H), 3.6 (s, 4H), 3.0-2.86 (d, 4H).
Reaction SMILES: [N+](C1C=CC(COC([N:12]=[CH:13][N:14]2[CH2:18][CH2:17][C@H:16]([NH:19][C:20]([C@@H:22]3[CH2:26][C@H:25]([S:27][C:28]4[C@H:29]([CH3:52])[C@@H:30]5[C@@H:47]([C@H:48]([OH:50])[CH3:49])[C:46](=[O:51])[N:31]5[C:32]=4[C:33]([O:35]CC4C=CC([N+]([O-])=O)=CC=4)=[O:34])[CH2:24][N:23]3C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)=[O:21])[CH2:15]2)=O)=CC=1)([O-])=O>O1CCCC1.O>[CH:13]([N:14]1[CH2:18][CH2:17][C@@H:16]([NH:19][C:20]([C@@H:22]2[CH2:26][C@H:25]([S:27][C:28]3[C@H:29]([CH3:52])[C@@H:30]4[C@@H:47]([C@H:48]([OH:50])[CH3:49])[C:46](=[O:51])[N:31]4[C:32]=3[C:33]([OH:35])=[O:34])[CH2:24][NH:23]2)=[O:21])[CH2:15]1)=[NH:12]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N[C@H]4CCN(C=NC(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)N[C@@H]4CCN(C=N)C4)C3)[C@H](C)[C@H]12
Yield: 51 %

Procedure:
205 mg of 4-nitrobenzyl (1R, 5S, 6S)-2-{(2S, 4S)-2-[(3S)-1-(N-4-nitrobenzyloxycarbonylformimidoyl)pyrrolidin-3-ylaminocarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] were dissolved in 12 ml of 1:1 by volume mixture of tetrahydrofuran and water, and the mixture was hydrogenated by bubbling hydrogen through it at room temperature for 2 hours in the presence of 160 mg of 10% w/w palladium-on-charcoal. At the end of this time, the reaction mixture was worked up and purified by the same procedure as described in Example 23(b), to give 50 mg of the title compound as a powder.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[N:5]1([C:10]2[CH:20]=[CH:19][CH:18]=[CH:17][C:11]=2[O:12][CH2:13][CH:14]2[O:16][CH2:15]2)[CH:9]=[CH:8][CH:7]=[CH:6]1>C(O)(C)C>[CH:1]([NH:4][CH2:15][CH:14]([OH:16])[CH2:13][O:12][C:11]1[CH:17]=[CH:18][CH:19]=[CH:20][C:10]=1[N:5]1[CH:9]=[CH:8][CH:7]=[CH:6]1)([CH3:3])[CH3:2]
Reactant: c1ccc(-n2cccc2)c(OCC2CO2)c1
Reactant: CC(C)N
Solvent: CC(C)O
Product: CC(C)NCC(O)COc1ccccc1-n1cccc1

Procedure:
50 ml of isopropylamine are added to a solution of 26.9 g of 1-[o-(pyrrol-1-yl)-phenoxy]-2,3-epoxy-propane in 250 ml of isopropanol and the mixture is heated to the boil under reflux for 1 1/2 hours. The oil which remains after evaporating off the volatile constituents in vacuo is distilled in a bulb tube under a high vacuum and gives 1-iso-propylamino-3[o-(pyrrol-1-yl)-phenoxy]-2-propanol as a colourless oil of boiling point 125°-135° C/0.04 mm Hg. The distillate which crystallises can be recrystallised from ether/petroleum ether and gives crystals of melting point 80°-81° C and is in every respect identical with the product obtained in Example 3.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][C:3]=1[CH3:15].O.[NH2:17][NH2:18]>Cl.C(O)C>[NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][C:3]=1[CH3:15].[NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]2[CH2:8][CH2:9][C:10](=[O:11])[NH:17][N:18]=2)=[CH:4][C:3]=1[CH3:15]
Reactant: NN
Agent: Cc1cc(C(=O)CCC(=O)O)ccc1N
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1cc(C2=NNC(=O)CC2)ccc1N

Procedure:
There are obtained from 70 g of N-acetyl-1,2-toluidine, with 47 g of succinic anhydride and 234 g of aluminium chloride in 2000 ml of tetrachloroethane, by the customary method, 50 g of 3-(3-methyl-4-acetamido-benzoyl)-propionic acid, m.p. 150°-160° C., as crude product. From this are obtained, by hydrolysis in 18% hydrochloric acid, 28 g of crude 3-(4-amino-3-methyl-benzoyl)-propionic acid. And from 6 g of 3-(4-amino-3-methyl-benzoyl)-propionic acid are obtained, with 1.7 ml of hydrazine hydrate in 70 ml of ethanol, in a manner analogous to that in Example 1, 2.6 g of 6-(4-amino-3-methyl-phenyl)-4,5-dihydro-3(2H)-pyridazinone having a melting point of 215°-225° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[C:14]1[CH2:18][NH:17][CH:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]=1.C(N(CC)CC)C>ClCCl>[F:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[C:14]1[CH2:18][N:17]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]=1
Reactant: CS(=O)(=O)Cl
Reactant: Fc1ccc(F)c(C2=CC(c3ccccc3)NC2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CC(c2cc(F)ccc2F)=CC1c1ccccc1
Reaction time: 16 h

Procedure:
Methanesulfonyl chloride (40 μL, 0.51 mmol, 1.00 equiv) was added to a solution of 4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrole (2-4, 130 mg, 0.505 mmol, 1 equiv) and triethylamine (350 μL, 2.52 mmol, 5.00 equiv) in dichloromethane (30 mL) at 23° C., and the resulting reaction mixture was stirred for 16 hours. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution (50 mL) and ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by reverse-phase LC (H2O/CH3CN gradient w/0.1% TFA present) to provide 4-(2,5-difluorophenyl)-1-(methylsulfonyl)-2-phenyl-2,5-dihydro-1H-pyrrole (6-1) as a tan solid. 1H NMR (300 MHz, CDCl3) δ 7.39-7.30 (m, 5H), 7.09 (td, 1H, J=9.8, 4.6 Hz), 7.01 (m, 2H), 6.36 (br s, 1H), 5.76 (m, 1H), 4.84 (br d, 1H, J=13.2 Hz), 4.64 (ddd, 1H, J=13.2, 5.6, 2.0 Hz), 2.55 (s, 3H). LRMS m/z (M+H) 336.0 found, 336.1 required.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[OH:11]O>>[CH3:1][C:2]1[C:3](=[O:10])[C:4]([CH3:9])=[CH:5][C:6](=[O:11])[C:7]=1[CH3:8]
Reactant: OO
Reactant: Cc1ccc(C)c(O)c1C
Product: CC1=CC(=O)C(C)=C(C)C1=O

Procedure:
The method according to claim 6, wherein 2,3,6-trimethylphenol is reacted with hydrogen peroxide to obtain 2,3,6-trimethylbenzoquinone.
Reaction SMILES: [C:1]1([C:7]2[CH:19]=[CH:18][C:10]([C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:12])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]1COCC1.C[Mg]I.[NH4+].[Cl-]>CCOCC>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:19]=[CH:18][C:10]([C:11]([OH:12])([CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][CH:8]=1
Reactant: CCOC(=O)C(=O)c1ccc(-c2ccccc2)cc1
Reactant: C1CCOC1
Agent: C[Mg]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCOC(=O)C(C)(O)c1ccc(-c2ccccc2)cc1
Temperature: -25 °C

Procedure:
To a flame dried 500 mL flask flushed with N2, was added 24 g (100 mmol) of ethyl 4-phenylbenzoylformate and 300 mL of anhydrous THF. The solution was cooled with stirring to -25° C. and 37 mL (110 mmol) of a 3.0M solution of methylmagnesium iodide was added at a rate to maintain the reaction temperature below -10° C. The reaction progress was monitored by TLC and upon disappearance of starting material, 100 mL of saturated NH4Cl solution and 200 mL of ether were added. The organic layer was separated and washed with 2×50 mL of brine, dried (MgSO4) and concentrated leaving racemic ethyl 2-[(1,1'-biphenyl)-4-yl]-2-hydroxypropionate as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13](Cl)=[O:14])=[CH:8][C:7]=2[CH:16]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41])[C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH:28]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:27]1)=[O:25].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13]([N:29]3[CH2:30][CH2:31][N:26]([C:24](=[O:25])[C:23]4[CH:22]=[C:21]([O:20][CH3:19])[C:39]([O:40][CH3:41])=[C:38]([O:42][CH3:43])[CH:37]=4)[CH2:27][CH:28]3[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:14])=[CH:8][C:7]=2[CH:16]=1
Reactant: CCOC(=O)C1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1
Reactant: COc1cc2c(cc1OC)CCCC(C(=O)Cl)=C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1C(=O)C1=Cc2cc(OC)c(OC)cc2CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.8 %

Procedure:
A solution of 2,3-dimethoxy-6,7-dihydro-5H-benzocycloheptene-8-carbonyl chloride (0.53 g) in dichloromethane (8 ml) is added dropwise, while stirring at 0° C. for 3 minutes, to a mixture of ethyl 4-(3,4,5-trimethoxybenzoyl)piperazine-2-carboxylate (0.7 g), triethylamine (0.5 g) and dichloromethane (15 ml). The reaction mixture is stirred for 2 hours at room temperature, and then poured into ice-water, followed by extraction with dichloromethane. The organic layer is washed with dilute hydrochloric acid, an aqueous solution of sodium hydrogencarbonate and water, successively, and dried, then the solvent is distilled off under reduced pressure. Crystals obtained from the residue are recrystallized from ethyl acetate and hexane to give ethyl 1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl) -4-(3,4,5-trimethoxybenzoyl)piperazine-2-carboxylate as colorless crystals (0.9 g), m.p. 108-110° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:12]1[C:20]2[C:15](=[N:16][C:17]([CH:21]=[CH2:22])=[CH:18][CH:19]=2)[CH2:14][O:13]1.[OH:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(N(CC)CC)C>O1CCOCC1.CC(O)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:12]1[C:20]2[C:15](=[N:16][C:17]([CH2:21][CH2:22][N:27]3[CH2:28][CH2:29][CH:24]([OH:23])[CH2:25][CH2:26]3)=[CH:18][CH:19]=2)[CH2:14][O:13]1
Reactant: OC1CCNCC1
Reactant: C=Cc1ccc2c(n1)COC2=C1C(=O)Nc2ccc(F)cc21
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C1Nc2ccc(F)cc2C1=C1OCc2nc(CCN3CCC(O)CC3)ccc21
Temperature: 100 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
A solution of 5-fluoro-3-(2-vinyl-7H-furo[3,4-b]pyridin-5-ylidene)-1,3-dihydro-indol-2-one (50 mg, 0.17 mmol) in dioxane (10 mL) is treated with 4-hydroxypiperidine (260 mg, 2.57 mmol) and 10 drops of glacial AcOH. The reaction is stirred at 100° C. for 1 h and then cooled to room temperature. The reaction mixture is treated with triethylamine (2 mL) and is loaded onto silica gel. Purification by chromatography (silica gel) gave the title compound (57 mg, 85%).
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].CS(O[CH:11]1[CH2:20][CH2:19][C:14]2([O:18][CH2:17][CH2:16][O:15]2)[CH2:13][CH2:12]1)(=O)=O>CS(C)=O.[Cl-].[Na+].O>[C:1](=[S:3])([O:4][CH:11]1[CH2:20][CH2:19][C:14]2([O:18][CH2:17][CH2:16][O:15]2)[CH2:13][CH2:12]1)[CH3:2]
Reactant: CS(=O)(=O)OC1CCC2(CC1)OCCO2
Reactant: CC([O-])=S
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=S)OC1CCC2(CC1)OCCO2
Temperature: 40 °C
Yield: 64.8 %

Procedure:
Potassium thioacetate (21.39 g, 187 mmol) was added to a stirred mixture of 1,4-dioxaspiro[4.5]dec-8-yl methanesulfonate (29.5 g, 125 mmol) in DMSO (31.2 ml) and the mixture was heated at 40° C. for 24 h. The mixture was cooled, brine was added and the mixture was extracted with ethyl acetate. The combined organic fractions were washed with brine, dried, and evaporated. The residue was purified by column chromatography on silica gel using a Biotage 65i cartridge, eluting with EtOAc/isohexane to give 1,4-dioxaspiro[4.5]dec-8-yl ethanethioate (17.5 g, 81 mmol, 64.8% yield) as a red oil. 1H NMR (500 MHz, CDCl3): δ 3.92 (4H, s), 3.53 (1H, s), 2.29 (3H, s), 2.00-1.93 (2H, m), 1.77-1.63 (6H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[NH:8][C:9]1[N:13]([CH3:14])[C:12]2[C:15]3[CH2:16][C:17]([CH3:26])([CH3:25])[O:18][C:19]=3[C:20]([C:22]([OH:24])=O)=[CH:21][C:11]=2[N:10]=1.[CH:28]1([CH2:31][NH2:32])[CH2:30][CH2:29]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN(C=O)C>C1COCC1>[CH:28]1([CH2:31][NH:32][C:22]([C:20]2[C:19]3[O:18][C:17]([CH3:26])([CH3:25])[CH2:16][C:15]=3[C:12]3[N:13]([CH3:14])[C:9]([NH:8][C:7]4[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=4[Cl:27])=[N:10][C:11]=3[CH:21]=2)=[O:24])[CH2:30][CH2:29]1
Reactant: NCC1CC1
Reactant: Cn1c(Nc2c(Cl)cncc2Cl)nc2cc(C(=O)O)c3c(c21)CC(C)(C)O3
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cn1c(Nc2c(Cl)cncc2Cl)nc2cc(C(=O)NCC3CC3)c3c(c21)CC(C)(C)O3
Yield: 18.6 %

Procedure:
The title compound was prepared following the procedure described for Example-1 by using 2-((3,5-dichloropyridin-4-yl)amino)-1,7,7-trimethyl-7,8-dihydro-1H-benzofuro[4,5-d]imidazole-5-carboxylic acid (Intermediate-61, 0.100 g, 0.245 mmol), cyclopropylmethanamine (0.025 g, 0.363 mmol), TBTU (0.157 g, 0.49 mmol), DMF (5 mL), THF (3 mL) to afford 0.021 g of the desired product. 1HNMR (DMSO-d6): δ 0.22 (d, J=4.2 Hz, 2H), 0.44 (d, J=6.6 Hz, 2H), 1.02 (m, 1H), 1.54 (s, 6H), 3.19 (m, 2H), 3.44 (s, 2H), 3.56 (s, 3H), 7.22 (s, 1H), 7.80 (m, 1H), 8.45 (s, 2H), 10.79 (s, 1H); MS [M+]+: 459.03.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]([C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:18]=1)[CH:14]=O)([CH3:10])([CH3:9])[CH3:8].CC(C)=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[C:7]([C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:18]=1)[CH:14]=[CH2:1])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: C=Cc1cc(C(C)(C)C)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
Dry tetrahydrofuran (80 ml) was added to a mixture of potassium t-butoxide (6.740 g, 60.06 mmoles) and methyltriphenylphosphonium bromide (24.276 g, 60.06 mmoles) and stirred at room temperature for 30 minutes. A solution of 3,5-di-t-butylbenzaldehyde (10.087 g, 46.20 mmoles) in dry tetrahydrofuran (30 ml) was then added and the reaction mixture was stirred at room temperature for 17 hours. Acetone (50 ml) was then added and then all of the solvent was removed under vacuum. Pet. ether (60-80, 150 ml) was then added to the residue and the mixture was stirred vigorously for 30 minutes. The solution was then filtered through silica, rinsing thoroughly with pet. ether (60-80) and the solvent removed under vacuum to give 3,5-di-t-butylstyrene (9.302 g, 93%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][NH:16]C(OC(C)(C)C)=O)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].CCO.Cl.O1CCOCC1>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][CH:9]1[CH2:10][CH2:11][CH:12]([CH2:15][NH2:16])[CH2:13][CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC1CCC(CNC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CC(C)(C)OC(=O)NCC1CCC(CN)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 46.7 %

Procedure:
To a solution of [4-(tert-butoxycarbonylamino-methyl)-cyclohexylmethyl]-carbamic acid tert-butyl ester (11.00 g, 32 mmol) dissolved in 2:1 CHCl3:EtOH at room temperature was added 4.0 M HCl/dioxane (16.1 mL). The mixture was stirred at room temperature for 4 h then concentrated in vacuo to provide a crude white solid. The crude material was purified by silica gel chromatography using a gradient elution of 10-50% (2% NH4OH, 18% MeOH, 80% CH2Cl2)/CH2Cl2. The product-containing fractions were combined and concentrated in vacuo to provide (4-aminomethyl-cyclohexylmethyl)-carbamic acid tert-butyl ester as a white powder 3.62 g, 47%, m/z calculated for C13H26N2O2: 242.4, found: 243.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:16]=[C:15]([CH:17]3[CH2:19][CH2:18]3)[NH:14][N:13]=2)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(O)(C)C>[CH2:20]([NH:27][C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:16]=[C:15]([CH:17]3[CH2:19][CH2:18]3)[NH:14][N:13]=2)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Clc1nc(Nc2cc(C3CC3)[nH]n2)c2occc2n1
Reactant: NCc1ccccc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(C)(C)O
Product: c1ccc(CNc2nc(Nc3cc(C4CC4)[nH]n3)c3occc3n2)cc1
Temperature: 100 °C
Yield: 5.1 %

Procedure:
To a vial was added 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)furo[3,2-d]pyrimidin-4-amine (0.20 g, 0.73 mmol), benzyl amine (0.79 mL, 7.3 mmol), X-Phos (0.02 g, 0.04 mmol) K2CO3 (0.50 g, 3.6 mmol), and Pd2dba3 (0.04 g, 0.04 mmol). To the vial was added t-BuOH (3.6 mL) and tube was sealed. The tube was evacuated, purged with nitrogen three times and stirred over night at about 100° C. To the mixture was added additional benzyl amine (0.79 mL, 7.3 mmol), X-Phos (0.02 g, 0.04 mmol), and Pd2dba3 (0.04 g, 0.04 mmol). The mixture was stirred at about 100° C. for about 26 h. The mixture was filtered, the filter pad was washed with DCM and then the solvent was removed in vacuo. The crude material was added to a silica gel column and was eluted with EtOAc/DCM (50% to 100% gradient) followed by 2.0 M NH3 in EtOH/DCM (2%) to give N2-benzyl-N4-(5-cyclopropyl-1H-pyrazol-3-yl)furo[3,2-d]pyrimidine-2,4-diamine (0.013 g, 5%). LC/MS Rt=1.30 min; MS m/z 347.29 (M+H)+. Syk IC50=B.
Reaction SMILES: [CH2:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14].[C:15](Cl)(=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>ClC(Cl)C>[CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:14][C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCC(=O)Cl
Reactant: NC1CCc2oc3ccccc3c2C1
Solvent: CC(Cl)Cl
Product: CCCCCC(=O)Nc1ccc2oc3c(c2c1)CCCC3
Yield: 43.8 %

Procedure:
Following the procedure of Example 23, tetrahydro-dibenzofuran-2-ylamine (0.15 g, 0.80 mmol), hexanoyl chloride (0.11 mL, 0.80 mmol), and poly(vinylpyridine) (0.5 g) in dichloroethane (8 mL) provided N-(6,7,8,9-tetrahydrodibenzo[b,d]furan-2-yl)hexanamide (0.10 g). MS (ESI) m/z286.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1>CCO>[Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Solvent: CCO
Product: Nc1c(Cl)ncnc1Cl
Temperature: 25 °C

Procedure:
The mixture of 4,6-dichloro-5-nitropyrimidine (A-1) (20.0 g, 104 mmol) and stannous chloride dihydrate (117.7 g, 520 mmol) in EtOH (300 mL) is stirred at reflux for 2 h. The reaction mixture is allowed to cool to RT and then concentrated in vacuo. The residue is poured into ice water (300 mL) and neutralized with saturated NaHCO3 aqueous solution to adjust the pH to 5-6. The resulting mixture is stirred at RT for 30 min and then extracted with ethyl acetate (3×200 mL). The combined organic layers are washed with brine, dried over Na2SO4 and filtered. The filtrate is concentrated in vacuo to afford the product, 4,6-dichloropyrimidine-5-amine (A-2).