Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1)=O.C(NC(C)C)(C)C.C([Li])CCC.ClP(=O)(OCC)[O:31][CH2:32][CH3:33]>CCCCCC.C(N=CC)(C)(C)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=2)=[CH:33][CH:32]=[O:31])[CH:14]=[CH:15][CH:16]=1
Reactant: O=C(c1cccc(Cl)c1)c1cccc(Cl)c1
Reactant: CCOP(=O)(Cl)OCC
Agent: CC=NC(C)(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=CC=C(c1cccc(Cl)c1)c1cccc(Cl)c1

Procedure:
The compound was prepared according to the procedure described in Example 84. The following reagents were used: 3,3'-dichlorobenzophenone (25.1 g), diisopropylamine (32.2 mL), 1.6M n-butyl lithium in hexane (144 mL), acetaldehye N-tert-butylimine (14.75 mL), diethyl chlorophosphonate (16.6 mL) and tetrahydrofurane (200 mL). The usual work up furnished 24.0 g of essentially pure 3,3-bis(3-chlorophenyl)-2-propenal as an orange oil.
Reaction SMILES: C1N=C(N)C2N=CN([C@@H:10]3[O:14][C@H:13](COP(OP(OC[C@H:26]4[O:30][C@@H:29](N5C=C(C(N)=O)CC=C5)[C@H:28](O)[C@@H:27]4O)(O)=O)(O)=O)[C@@H:12](O)[C@H:11]3OP(O)(O)=O)C=2N=1.C=CC=C.OO>>[CH2:26]1[O:30][CH:29]1[CH:28]=[CH2:27].[CH:13](=[O:14])/[CH:12]=[CH:11]/[CH3:10]
Reactant: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: C=CC=C
Agent: OO
Product: C/C=C/C=O
Product: C=CC1CO1

Procedure:
Elfarra et al. (1991 Arch. Bioch. Biophy. 286, 244-251) has demonstrated the NADPH-dependent oxidation of 1,3-butadiene by mouse liver microsomes and the hydrogen peroxide-dependent oxidation of 1,3 butadiene by chloroperoxidase. Both oxidations yielded butadiene monoxide and crotonaldehyde.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:13][CH:12]=2)=[C:9]([C:24]2[CH:29]=[C:28]([CH2:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:27]([O:38]CC3C=CC=CC=3)=[CH:26][C:25]=2[O:46]CC2C=CC=CC=2)[O:8][N:7]=1)=[O:5])[CH3:2].B(Cl)(Cl)[Cl:55]>ClCCl>[ClH:55].[CH2:1]([NH:3][C:4]([C:6]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([CH2:17][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[CH:15][CH:16]=2)=[C:9]([C:24]2[CH:29]=[C:28]([CH2:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:27]([OH:38])=[CH:26][C:25]=2[OH:46])[O:8][N:7]=1)=[O:5])[CH3:2]
Reactant: ClB(Cl)Cl
Reactant: CCNC(=O)c1noc(-c2cc(CCc3ccccc3)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1ccc(CN2CCOCC2)cc1
Solvent: ClCCl
Product: CCNC(=O)c1noc(-c2cc(CCc3ccccc3)c(O)cc2O)c1-c1ccc(CN2CCOCC2)cc1
Product: Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 24 %

Procedure:
To an ice-bath cooled solution of 5-(2,4-bis-benzyloxy-5-phenethyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide (0.109 g, 0.15 mmol) in dichloromethane (4 mL) under a nitrogen atmosphere was added a 1.0M solution of Boron trichloride in dichloromethane (0.45 mL; 0.45 mmol). The reaction mixture was stirred at 0° C. for 20 minutes then at ambient temperature for 3.5 hours. The reaction mixture was re-cooled to 0° C. and quenched by the addition of saturated aqueous sodium hydrogen carbonate solution (5 mL). After stirring for 5 minutes the dichloromethane was removed in vacuo and the residue was partitioned between ethyl acetate (20 mL) and water (20 mL). The phases were separated and the organic phase was washed with water (20 mL), saturated aqueous sodium chloride solution (20 mL) then dried over sodium sulphate. The mixture was filtered and the filtrate solvents were removed in vacuo to afford a light-brown oil which was purified by adsorption onto silica gel then flash chromatography on silica gel (10 g IST) eluting with 0 to 5% methanol in ethyl acetate. This affords a colourless oil which was triturated with 1.0M HCl in diethyl ether solution (5 mL) to afford 5-(2,4-dihydroxy-5-phenethyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide hydrochloride (0.019 g; 24%). LCMS: [M+H]+ 528. 1H NMR (400 MHz, d6-DMSO) □ 1.08 (t, 3H), 2.60 (m, 4H), 2.90-3.30 (m, 6H), 3.67 (m, 2H), 3.87 (m, 2H), 4.30 (s, 2H), 6.46 (s, 1H), 6.84 (s, 1H), 7.05-7.49 (m, 5H), 7.40-7.68 (m, 4H), 8.90 (brs, 1H), 9.67 (s, 1H), 9.89 (s, 1H), 10.75 (brs, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])O1.[CH2:11](Cl)[CH:12](C)[CH3:13].Cl[CH2:17]Cl>N1C=CC=CC=1>[CH3:11][CH:12]([CH3:13])[C:4](=[O:5])[CH2:6][C:7]([O:9][C:2]([CH3:1])([CH3:10])[CH3:17])=[O:8]
Reactant: ClCCl
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CC(C)CCl
Solvent: c1ccncc1
Product: CC(C)C(=O)CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a mixture of 85 ml of dichloromethane and 40 ml of pyridine was dissolved 33.8 g of meldrum's acid. Under cooling with ice, 25.0 g of isobutyl chloride was added dropwise to the solution, followed by stirring under room temperature for 1 hour. The solvent was removed under reduced pressure and to the residue was added water. The mixture was extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was dissolved in 100 ml of tert-butanol, followed by reflux under heating for 4 hours. The solvent was removed under reduced pressure. The residue was subjected to distillation under reduced pressure to yield 32.5 g of the oily titled compound.
Reaction SMILES: C([N+](CCC)(CCC)CCC)CC.CO.[OH:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]2[C:22](=[O:32])[C:23]3[C:28]([C:29]=2[N:30]=1)=[CH:27][CH:26]=[C:25]([Br:31])[CH:24]=3>C(Cl)Cl.C(OCC)(=O)C>[CH:17]([C:18]1[CH:19]=[CH:20][C:21]2[C:22](=[O:32])[C:23]3[C:28]([C:29]=2[N:30]=1)=[CH:27][CH:26]=[C:25]([Br:31])[CH:24]=3)=[O:16]
Reactant: O=C1c2cc(Br)ccc2-c2nc(CO)ccc21
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=Cc1ccc2c(n1)-c1ccc(Br)cc1C2=O
Reaction time: 0.25 h

Procedure:
150 mg of finely powdered 3 Å molecular sieves, 350 mg (3 mM) of N-methylmorpholine n-oxide, and 70 mg (0.2) of tetrapropylammonium perrhuthenate are added. To a solution of 576 mg (2 mM) of the carbinol, 3-hydroxymethyl-7-bromo-4-aza-9-fluorenone, prepared as described in Example 38, in 20 mL of dry methylene chloride under nitrogen at R.T. the reaction mixture is stirred 15 minutes, diluted with 20 mL of ethyl acetate and filtered through a bed of silica gel, which is washed further with ethyl acetate 5 times. The combined filtrates are concentrated to give the desired aldehyde as yellow solid.
Reaction SMILES: [CH3:1][S-:2].[Na+].[Cl:4][C:5]1[N:10]=[C:9](Cl)[CH:8]=[CH:7][N:6]=1>C1COCC1.C(OCC)(=O)C>[Cl:4][C:5]1[N:10]=[C:9]([S:2][CH3:1])[CH:8]=[CH:7][N:6]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: C[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSc1ccnc(Cl)n1
Reaction time: 8 h
Yield: 70.5 %

Procedure:
Sodium thiomethoxide (5.18 g, 73.8 mmol) was added slowly portion-wise via powder addition funnel to a stirring solution of 2,4-dichloropyrimidine (10 g, 67.1 mmol) in THF (150 mL) at room temperature. After stirring overnight, the reaction was taken up in ethyl acetate, washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with ethyl acetate and hexanes to give 2-chloro-4-(methylsulfanyl)pyrimidine (10.127 g, 47.3 mmol, 70.4%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[N:5]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21]C(=O)C)=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:3]=1>[OH-].[Na+]>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([NH:11][C:4]2[CH:3]=[C:2]([Cl:1])[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[N:5]=2)(=[O:13])=[O:14])=[CH:16][CH:17]=1
Reactant: CCNc1nc(Cl)cc(NS(=O)(=O)c2ccc(NC(C)=O)cc2)n1
Agent: [Na+]
Agent: [OH-]
Product: CCNc1nc(Cl)cc(NS(=O)(=O)c2ccc(N)cc2)n1

Procedure:
2.88 g (0.0075 mol) of N-[4-(6-chloro-2-ethylamino-pyrimidin-4-ylsulfamoyl)-phenyl]-acetamide were dissolved in 76 ml of 1N NaOH and boiled at reflux for 3 hours. The mixture was extracted with ethyl acetate, the aqueous phase was saturated with sodium chloride and the residual ethyl acetate was distilled on a rotary evaporator. Then, the aqueous phase was made acid with 3N HCl and the precipitate which separated was filtered off under suction. After drying there were obtained 2.2 9 (90%) of 4-amino-N-(6-chloro-2-ethylamino-pyrimidin-4-yl)-benzenesulfonamide as white crystals; m.p.: 172-173° C.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=2[O:2]1.Br[C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[O:9]1[C:8]2[CH:7]=[CH:6][C:5]([C:14]3[CH:15]=[C:16]([NH2:17])[CH:18]=[CH:19][CH:20]=3)=[CH:4][C:3]=2[O:2][CH2:1]1
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: Nc1cccc(Br)c1
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: COCCOC
Product: Nc1cccc(-c2ccc3c(c2)OCO3)c1
Temperature: 25 °C
Yield: 58 %

Procedure:
3,4-methylenedioxyphenyl boronic acid (0.115 g, 0.693 mmol) and 3-bromoaniline (0.05 mL, 0.462 mmol) were combined in DME (2 mL) in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.485 mL, 0.970 mmol) and Pd(PPh3)4 (0.017 g, 0.014 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in H20 and extracted with CH2Cl2. The organic phase was dried over MgSO4 and concentrated under vacuum. The crude product was purified by silica column chromatography (0-20% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.057 g in 58% yield.
Reaction SMILES: [O:1]=[C:2]([CH3:10])[CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[CH3:11][Mg+].[Br-].Cl>C(OCC)C>[OH:1][C:2]([CH3:11])([CH3:10])[CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: C[Mg+]
Reactant: CC(=O)CN1CCOCC1
Agent: Cl
Agent: [Br-]
Solvent: CCOCC
Product: CC(C)(O)CN1CCOCC1
Temperature: 0 °C
Yield: 33 %

Procedure:
A solution of N-(2-oxopropyl)morpholine (82 g, 0.57 mmol) in diethyl ether (400 ml) was added to a solution of 3M CH3MgBr (500 ml, 1.5 ml) in anhydrous diethyl ether (21) and stirred at 0° C. under an argon atmosphere. The mixture was stirred at ambient temperature for 16 hours, treated with 12N HCl (50 ml) and extracted with ethyl acetate. The product was purified by flash column chromatography eluting with ethyl acetate to give N-(2-hydroxy-2-methylpropyl)morpholine.
Reaction SMILES: [C:1]1([Mg]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C[CH2:16][Mg:17][Cl:18])C=CC=CC=1.C1(CC[Mg]Br)C=CC=CC=1.C1(CCC[Mg]Br)C=CC=CC=1.C[Mg]Cl>>[CH2:16]([Mg:17][Cl:18])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cl[Mg]c1ccccc1
Reactant: Cl[Mg]CCc1ccccc1
Agent: Br[Mg]CCCc1ccccc1
Agent: Br[Mg]CCc1ccccc1
Agent: C[Mg]Cl
Product: Cl[Mg]Cc1ccccc1

Procedure:
The same procedures as described In Preparation Example 1 were repeated using phenyl magnesium chloride, 2-phenylethyl magnesium chloride, 2-phenylethyl magnesium bromide, 3-phenylpropyl magnesium bromide and methyl magnesium chloride, respectively, in place of benzyl magnesium chloride to obtain functionalized amines. Each compound obtained in Preparation Examples 4 to 7 and physical properties thereof are given below in table 4.
Reaction SMILES: [Cl-].[Cl-].[CH2:3]([C:7]1([Zr+2:12]C2(CCCC)C=CC=C2)[CH:11]=[CH:10][CH:9]=[CH:8]1)[CH2:4][CH2:5][CH3:6].[C:22]([OH:30])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:22]([O-:30])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[C:22]([O-:30])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[C:22]([O-:30])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH2:3]([C:7]1([Zr+3:12])[CH:11]=[CH:10][CH:9]=[CH:8]1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCC1([Zr+2]C2(CCCC)C=CC=C2)C=CC=C1
Reactant: O=C(O)c1ccccc1
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCC1([Zr+3])C=CC=C1
Product: O=C([O-])c1ccccc1
Yield: 84 %

Procedure:
To a solution of bis (n-butylcyclopentadienyl)zirconium dichloride (1.001 g, 2.477 mmol ) and benzoic acid (0.900 g, 7.371 mmol ) in toluene (40 ml) at 25° C. was added triethylamine (0.871 g, 8.610 mmol ) with stirring. A white precipitate formed immediately which was removed by filtration. The title compound was isolated as a dark yellow oil in 84% yield by evaporating the solvent under vacuum. The title compound such prepared exhibit purity above 95% based on NMR results. 1H NMR (toluene-d8) δ 8.08 (s,6H), 7.01 (m,9H), 6.47 (m,2H), 6.22 (m, 2H), 2.80(t,J=7.6 Hz, 2H), 1.54 (m, 2H), 1.26 (m, 2H), 0.84 (t, J=7.2 Hz 3H).
Reaction SMILES: [OH:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C@@H:9]2[CH2:13][C@H:12]([S:14][C:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][N:10]2[C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=2)=[O:35])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:54][S:55](Cl)(=[O:57])=[O:56]>ClCCl>[CH3:54][S:55]([O:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C@@H:9]2[CH2:13][C@H:12]([S:14][C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:11][N:10]2[C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=2)=[O:35])[CH2:4][CH2:3]1)(=[O:57])=[O:56]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CN1CCN(O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)ON1CCN(C[C@@H]2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 1 h

Procedure:
To a solution of (2S,4S)-2-[(4-hydroxypiperizin-1-yl)methyl]-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (5.4 g) and triethylamine (1.54 ml) in dichloromethane (60 ml) was added methanesulfonyl chloride (0.72 ml) under ice-cooling and the mixture was stirred under the same condition for 1 hour. The reaction mixture was washed successively with aqueous sodium hydrogen carbonate and aqueous sodium chloride, dried over magnesium sulfate, and evaporated in vacuo to give (2S,4S)-2-[(4-methanesulfonyloxypiperizin-1-yl)methyl]-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (6.06 g).
Reaction SMILES: [C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[CH2:25]([OH:32])[C@@H:26]([C@@H:28]([CH2:30][OH:31])O)[OH:27].[C:33]1([CH3:40])[C:34]([CH3:39])=[CH:35][CH:36]=[CH:37][CH:38]=1.S(=O)(=O)(O)O>O>[C:1]([O:24][C@H:28]([C@@H:26]([CH2:25][OH:32])[O:27][C:1](=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:39][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:33][CH3:40])[CH2:30][OH:31])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Reactant: Cc1ccccc1C
Reactant: OC[C@@H](O)[C@@H](O)CO
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)O[C@@H](CO)[C@@H](CO)OC(=O)CCCCCCCCCCCCCCCCCCCCC
Temperature: 145 °C
Reaction time: 2 h

Procedure:
340 g (1 mol) behenic acid and 61 g (0.5 mol) erythritol were added into a 2 L three-neck flask which was equipped with a stirrer, a condenser and an addition funnel. To the flask was added 1 L xylene as a water carrier, followed by addition of a reaction catalyst sulfuric acid (32 g, 8 wt %). The mixture was refluxed at 145±2° C. for 22 hours. When the reaction was ended, the reaction system was allowed to cool to room temperature and stand for 2 hours. The solid was removed by filtration, and the liquid phase was washed with a saturated sodium bicarbonate aqueous solution and petroleum ether in sequence. 260 g solid product was obtained after drying by rotary evaporation. The product was erythritol 2,3-dibehenate as characterized by 1H NMR, and the purity was 91% as characterized by HPLC.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:31])[C:14]=2[C@H:15]2[O:21][CH2:20][C@@H:19]([F:22])[C@H:18]([NH:23]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[F:32][C:33]1[C:38]([O:39][CH3:40])=[CH:37][CH:36]=[C:35]([F:41])[C:34]=1B(O)O>>[NH2:23][C@H:18]1[C@H:19]([F:22])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:31])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:34]3[C:35]([F:41])=[CH:36][CH:37]=[C:38]([O:39][CH3:40])[C:33]=3[F:32])[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: COc1ccc(F)c(B(O)O)c1F
Reactant: Cn1ncc(NC(=O)c2csc(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: COc1ccc(F)c(-c2nc(C(=O)Nc3cnn(C)c3[C@@H]3CC[C@@H](N)[C@H](F)CO3)cs2)c1F

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3S,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 99), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2,6-difluoro-3-methoxyphenyl)boronic acid gave 229. 1H NMR (400 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.63 (s, 1H), 7.78 (s, 1H), 7.40 (td, J=9.3, 5.1 Hz, 1H), 7.27 (td, J=9.5, 1.9 Hz, 1H), 4.81 (dd, J=10.9, 3.6 Hz, 1H), 4.37 (d, J=47.9 Hz, 1H), 4.24-4.10 (m, 1H), 4.10-3.92 (m, 1H), 3.90 (s, 3H), 3.78 (s, 3H), 3.29-3.19 (m, 1H), 2.11-2.01 (m, 1H), 1.87-1.77 (m, 1H), 1.75-1.66 (m, 2H). LCMS (ES+) m/z 482 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:16]2=[N:17][CH:18]=[N:19][C:20](O)=[C:15]2[CH:14]=[N:13]1.O=P(Cl)(Cl)[Cl:24].CN(C)C1C=CC=CC=1>>[Cl:24][C:20]1[N:19]=[CH:18][N:17]=[C:16]2[N:12]([C:3]3[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:7][C:2]=3[F:1])[N:13]=[CH:14][C:15]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(O)ncnc32)c(F)c1
Solvent: CN(C)c1ccccc1
Product: CS(=O)(=O)c1ccc(-n2ncc3c(Cl)ncnc32)c(F)c1
Yield: 95.2 %

Procedure:
1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol (0.774 g, 2.51 mmol) was suspended in POCl3 (23 mL, 251 mmol) and dimethylaniline (0.69 mL) and the mixture brought to reflux for 18 h. The solvent was concentrated under reduced pressure and the residue loaded to a column of silica gel. The product was eluted using 5% ethyl acetate/dichloromethane. Removal of solvent afforded 4-chloro-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine as a white solid (0.781 g, 95%). 1H NMR (400 MHz DMSO-d6) δ (ppm): 9.14 (s, 1H); 9.07 (s, 1H); 8.34 (d, 1H); 8.24 (m, 1H); 8.20 (m, 1H); 3.55 (s, 3H). Exact mass calculated for C12H8ClFN4O2S 326, found 327.2 (MH+, 100%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([Br:24])[CH:9]=[C:10]([CH:11]3CCN(C(OC(C)(C)C)=O)C[CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.NC1C2=CC=C(CC[OH:37])N2N=CN=1>>[NH2:1][C:2]1[C:7]2=[C:8]([Br:24])[CH:9]=[C:10]([CH2:11][CH2:12][OH:37])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Nc1ncnn2c(CCO)ccc12
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(Br)c3c(N)ncnn23)CC1
Product: Nc1ncnn2c(CCO)cc(Br)c12

Procedure:
This compound was prepared in a manner similar to the bromination procedure described for the preparation of tert-butyl 4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate, using 2-(4-amino-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-ethanol as the starting material. 1H NMR (300 MHz, DMSO-d6) δ 7.83 (s, 1H), 6.64 (s, 1H), 4.75 (t, 1H), 3.65 (q, 2H), 2.96 (t, 2H); ES-MS m/z 257.3/259.2 [M+H]+, RT (min) 0.35.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)(=O)=O)[N:3]=1.[CH3:19][O:20][CH2:21][CH2:22][OH:23].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:23][CH2:22][CH2:21][O:20][CH3:19])[N:3]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: COCCO
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: COCCOc1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, 2-methoxyethanol and DBU in DME. ES-MS m/e (%): 283 (M+Na+, 15), 261 (M+H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]2[N:7]=[C:8]([C:10]3[CH:19]=[CH:18][C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH:11]=3)[S:9][C:5]=2[C:4]=1[N+:22]([O-])=O.[H][H]>CO.C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]2[N:7]=[C:8]([C:10]3[CH:19]=[CH:18][C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH:11]=3)[S:9][C:5]=2[C:4]=1[NH2:22]
Reactant: [H][H]
Reactant: COc1ccc2nc(-c3ccc4ccccc4c3)sc2c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc2nc(-c3ccc4ccccc4c3)sc2c1N
Yield: 52.8 %

Procedure:
1.06 g (3.15 mmol) of 6-methoxy-2-(2-naphthyl)-7-nitro-1,3-benzothiazole are put into suspension in 50 ml of methanol and 5 ml of acetic acid. 105 mg (10%) of palladium on carbon is added to the reaction mixture which is maintained under stirring under 2.5 bars of hydrogen for 24 hours. The catalyst is filtered, then the solvents are evaporated under reduced pressure. 0.51 g (yield=53%) of 6-methoxy-2-(2-naphthyl)-1,3-benzothiazol-7-amine is obtained and used in the following stage without other purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[O:12])=[O:9])=[CH:4][C:3]=1I.[C:30]([C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)#[CH:31].C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O.[Cu]I>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[O:12])=[O:9])=[CH:4][C:3]=1[C:31]#[C:30][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1
Reactant: C#Cc1ccc(N)cc1
Reactant: COC(=O)CCCCS(=O)(CCCCC(=O)OC)=NC(=O)c1cnc(N)c(I)c1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)CCCCS(=O)(CCCCC(=O)OC)=NC(=O)c1cnc(N)c(C#Cc2ccc(N)cc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95.9 %

Procedure:
To the degassed mixture of dimethyl 5,5′-{N-[(6-amino-5-iodopyridin-3-yl)carbonyl]sulfonimidoyl}dipentanoate (234 mg, 0.434 mmol, 1.0 equiv.), 4-ethynylaniline (76.3 mg, 0.651 mmol, 1.5 equiv.), and triethylamine (0.242 mL, 1.736 mmol, 4.0 equiv.) in anhydrous DMF (2 mL) under nitrogen atmosphere was added CuI (16.5 mg, 0.087 mmol, 0.2 equiv.) and PdCl2(Ph3P)2 (30.5 mg, 0.043 mmol, 0.1 equiv.). The reaction mixture was stirred at room temperature for 15 minutes. The reaction was then diluted with EtOAc, washed with sat. aq. NaHCO3, aq. NH4Cl, and brine, and lastly dried with anhydrous Na2SO4. The solution was decanted, concentrated, and the oily residue was subject to a gradient column chromatography (from EtOAc-Hex 1:3 to EtOAc) yielding dimethyl 5,5′-[N-({6-amino-5-[(4-aminophenyl)ethynyl]pyridin-3-yl}carbonyl)sulfonimidoyl]dipentanoate as brown oil (220 mg).