Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]([C:29]#[CH:30])[CH:26]=[CH:27][CH:28]=1.CS(O)(=O)=O>>[CH3:16][O:15][CH2:14][CH2:13][O:12][C:9]1[CH:10]=[C:11]2[C:2]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[CH:30])[CH:24]=3)=[N:3][CH:4]=[N:5][C:6]2=[CH:7][C:8]=1[O:17][CH2:18][CH2:19][O:20][CH3:21].[ClH:1]
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OCCOC
Reactant: C#Cc1cccc(N)c1
Agent: CS(=O)(=O)O
Product: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(OCCOC)cc23)c1
Product: Cl
Temperature: 27.5 °C
Reaction time: 3 h

Procedure:
5 g of 4-chloro-6,7-bis(2-methoxyethoxy) quinazoline was suspended in 150 ml denatured spirit (SPDS) and 4.6 g of 3-aminophenyl acetylene was charged at 25-30° C. Further 1.0 ml of methane sulphonic acid was added. The reaction mass was stirred at 25-30° C. for 3 hours. Solid obtained was filtered, washed with SPDS and dried under vacuum. This solid was suspended in water, basified with ammonia and stirred for 10 minutes. The resulting erlotinib base was isolated, washed with water and dried under vacuum. The base was suspended in water and acidified to pH 1.0-2.0 using hydrochloric acid. The reaction mixture was stirred for 2 hours, filtered, washed with water and dried at 40-45° C. to obtain 5.8 g of erlotinib hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:10]=[C:11]([C:22]3([C:25]([O:27][CH3:28])=[O:26])[CH2:24][CH2:23]3)[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])=[N:6][C:7]=1[OH:8].[CH2:29]([O:31][CH2:32][C@@H:33]([N:35]=[C:36]=S)[CH3:34])[CH3:30].C(N=C=NC(C)C)(C)C>C(O)C>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[C:13]1[NH:12][C:11]([C:22]2([C:25]([O:27][CH3:28])=[O:26])[CH2:24][CH2:23]2)=[N:10][C:9]=1[C:5]1[N:6]=[C:7]2[O:8][C:36]([NH:35][C@@H:33]([CH3:34])[CH2:32][O:31][CH2:29][CH3:30])=[N:1][C:2]2=[CH:3][CH:4]=1
Reactant: COC(=O)C1(c2nc(-c3ccc(N)c(O)n3)c(-c3ccc(F)cc3F)[nH]2)CC1
Reactant: CCOC[C@H](C)N=C=S
Agent: CC(C)N=C=NC(C)C
Solvent: CCO
Product: CCOC[C@H](C)Nc1nc2ccc(-c3nc(C4(C(=O)OC)CC4)[nH]c3-c3ccc(F)cc3F)nc2o1
Temperature: 85 °C
Reaction time: 16 h
Yield: 22.9 %

Procedure:
A mixture of methyl 1-[4-(5-amino-6-hydroxy-2-pyridyl)-5-(2,4-difluorophenyl)-1H-imidazol-2-yl]cyclopropanecarboxylate (4 g, 10.35 mmol) and (2S)-1-ethoxy-2-isothiocyanato-propane (2.379 g, 15.53 mmol) are dissolved in ethanol (34 mL). The mixture is heated to 85° C. in a sealed flask for 16 h. Diisopropyl carbodiimide (3.21 g, 20.71 mmol) is added dropwise and the mixture is stirred at 85° C. for 16 h, after which time an additional 3 g of diisopropyl carbodiimide is added and the mixture is heated at 85° C. for an additional 4 h. The solvent is evaporated and the residue is purified by normal phase chromatography (120 g silica-gel cartridge, using a hexane-ethanol gradient to afford the title compound (1.180 g, 24%). LC-ES/MS m/z 498.1 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:20]([C:22]#[N:23])=[CH:19][CH:18]=[CH:17][C:16]=3[NH:15][C:14]2=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[CH2:22][NH2:23])[NH:15][CH2:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cccc2c1C1(CCN(Cc3ccccc3)CC1)C(=O)N2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1cccc2c1C1(CCN(Cc3ccccc3)CC1)CN2
Reaction time: 8 h

Procedure:
To a stirred solution of 1′-benzyl-2-oxospiro[indoline-3,4′-piperidine]-4-carbonitrile (0.88 g, 2.8 mmol) in THF (20 mL) was added dropwise a solution of 1N LiAlH4 in THF (11 mL, 11 mmol) at about 0° C. under N2. The reaction mixture was allowed to warm to about room temperature and stirred overnight. The reaction was then heated at reflux for 1 h. After cooling, the reaction was quenched by the dropwise addition of water (0.44 mL), followed by 3N NaOH (0.44 mL) and water (1.3 mL) at about 0° C. The mixture was diluted with Ether and stirred for about 10 min. The reaction mixture was filtered through Celite. The filtrate was concentrated to give crude (1′-benzylspiro[indoline-3,4′-piperidine]-4-yl)methanamine, which was carried forward in the next step without further purification. LCMS (APCI+) m/z 308 [M+H]+; Rt=1.96 min.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:19]#[N:20])[C:8]([CH3:18])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]=2[F:11])[N:6]=1.[CH:21]([N:24](C(C)C)[CH2:25]C)(C)C.Cl.[NH:31]1[CH2:34][CH:33]([C:35](C[N-]C)=[O:36])[CH2:32]1>ClCCl>[C:19]([C:7]1[C:5]2[N:6]=[C:2]([N:31]3[CH2:32][CH:33]([C:35]([N:24]([CH3:25])[CH3:21])=[O:36])[CH2:34]3)[O:3][C:4]=2[C:10]([F:11])=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]=1[CH3:18])#[N:20]
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Reactant: CCN(C(C)C)C(C)C
Reactant: C[N-]CC(=O)C1CNC1
Agent: Cl
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)c(F)c2oc(N3CC(C(=O)N(C)C)C3)nc2c1C#N
Yield: 86.9 %

Procedure:
2-Chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (0.21 g, 0.73 mmol), (diisopropylethylamine (0.28 ml, 1.65 mmol) and azetidine-3-carbonyldimethylamide hydrochloride (I-145) (0.25 g) were dissolved in dichloromethane (10 ml). After heated under reflux for 3 hours, this was diluted with dichloromethane, washed with water, then dried over anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane to dichloromethane:methanol=100:1) to obtain a colorless oil (0.24 g, 86%)
Reaction SMILES: [S:1]([CH2:11][N+:12]#[C-:13])([C:4]1[CH:10]=[CH:9][C:7](C)=[CH:6][CH:5]=1)(=[O:3])=[O:2].[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH:19]=[O:20].[C-:21]#N.[Na+]>CCO>[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C@@H:19]1[O:20][CH:13]=[N:12][C@@H:11]1[S:1]([C:4]1[C:5]([CH3:21])=[CH:6][CH:7]=[CH:9][CH:10]=1)(=[O:2])=[O:3]
Reactant: O=Cc1cccs1
Reactant: [C-]#N
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Solvent: CCO
Product: Cc1ccccc1S(=O)(=O)[C@H]1N=CO[C@H]1c1cccs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tosylmethylisocyanide (0.75 g, 3.84 mmol), 2-thiophenecarboxaldehyde (0.37 mL, 3.96 mmol) and sodium cyanide (0.02 g, 0.40 mmol) in EtOH (10 mL) was stirred at room temperature for 2 h. The solvent was removed to give the desired compound as a tan solid. This material was used without further purification. MS(ES+) m/z 614.8 (2M+H+).
Reaction SMILES: [CH3:1][C:2]1([C:8]([OH:24])=[C:9]([N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[CH2:7][O:6][CH2:5][O:4][CH2:3]1.N1C=CN=C1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>>[CH3:1][C:2]1([CH:8]([O:24][C:30](=[O:32])[CH3:31])[C:9]([N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[CH2:7][O:6][CH2:5][O:4][CH2:3]1
Reactant: CC1(C(O)=C(Cc2ccc(Cl)c(Cl)c2)n2cncn2)COCOC1
Reactant: CC(=O)OC(C)=O
Agent: c1c[nH]cn1
Product: CC(=O)OC(C(=Cc1ccc(Cl)c(Cl)c1)n1cncn1)C1(C)COCOC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
A mixture of 14 g (0.0378 mole) of 1-(5-methyl-1,3-dioxan-5-yl)-2-(1,2,4-triazol-1-yl)-3-(3,4-dichlorophenyl)-propen-1-ol (Example 25), 1 g of imidazole and 80 g of acetic anhydride is stirred for 8 hours at 70° C. and then concentrated under reduced pressure. The residue is taken up in 300 ml of ether and stirred for half an hour with 100 ml of 6% strength sodium bicarbonate solution. The organic phase is dried over sodium sulfate and concentrated under reduced pressure, finally at 50° C. under 0.1 mbar. 10.8 g (69.3% of theory) of 1-(5-methyl-1,3-dioxan-5-yl)-1-acetoxy-2-(1,2,4-triazol-1-yl)-3-(3,4-dichlorophenyl)-prop-2-ene are obtained as a pale yellow resin.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[CH2:4][NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)(=[O:8])=[O:7].[H-].[Na+].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br.C(OCC)(=O)C>CN(C=O)C>[CH3:17][O:16][CH:3]([O:2][CH3:1])[CH2:4][N:5]([CH2:25][C:24]1[CH:27]=[CH:28][CH:29]=[C:22]([O:21][CH3:20])[CH:23]=1)[S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)(=[O:8])=[O:7]
Reactant: COC(CNS(=O)(=O)c1ccc(C)cc1)OC
Reactant: COc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cccc(CN(CC(OC)OC)S(=O)(=O)c2ccc(C)cc2)c1
Reaction time: 0.17 h

Procedure:
13.0 g (50 mmol) of N-(2,2-dimethoxyethyl)-4-methylbenzenesulfonamide was dissolved in 40 ml of DMF. 2.01 g (50 mmol) of sodium hydride was added to the obtained solution at room temperature. After stirring for 10 minutes, 9.18 g (46 mmol) of 3-methoxybenzyl bromide was added to the obtained mixture, and they were stirred for 2 hours. After the treatment with ethyl acetate as the extraction solvent in an ordinary manner, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[NH:22][C@@:16]2([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:17][C@H:18]3[CH:23]=O)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:33](=O)([O-])[O-].[K+].[K+].[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-]>CO>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[NH:22][C@@:16]2([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:17][C@@H:18]3[C:23]#[CH:33])[CH:4]=[C:3]([C:2]([F:32])([F:1])[F:31])[CH:8]=1
Reactant: O=C[C@@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C([O-])[O-]
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Product: C#C[C@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.4 %

Procedure:
(1R*,2R*,5S*,6R*)-2-{(3,5-Bis(trifluoromethyl)phenyl]methoxy}-6-formyl-1-phenyl-8-azabicyclo[3.2.1]octane (Example 47; 165 mg, 0.3 mmol) in methanol (3 ml) at 0° C. was treated with potassium carbonate (83 mg, 0.6 mmol) and dimethyl 1-diazo-2-oxopropylphosphonate (81 mg, 0.5 mmol) and stirred for 18 hours at room temperature. The reaction mixture was concentrated in vacuo. The residue was partitioned between water and hexane. The organics were collected, dried (MgSO4), filtered and concentrated in vacuo to afford the title compound as a white crystalline solid (123 mg, 75%).
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][CH:20]([NH:23][C:24]5[N:29]=[C:28]([NH2:30])[C:27]([N+:31]([O-])=O)=[CH:26][N:25]=5)[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([O-])=O.[NH4+]>C(OCC)(=O)C.CO.[Pd]>[CH:11]1[C:12]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][CH:20]([NH:23][C:24]5[N:29]=[C:28]([NH2:30])[C:27]([NH2:31])=[CH:26][N:25]=5)[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:5]4[C:14]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: Nc1nc(NC2CCN(CC34CC(c5ccccc53)c3ccccc34)CC2)ncc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1cnc(NC2CCN(CC34CC(c5ccccc53)c3ccccc34)CC2)nc1N
Temperature: 25 °C
Reaction time: 28 h
Yield: 69.6 %

Procedure:
2-[1-(9,10-Dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidylamino]-4-amino-5-nitropyrimidine (1.000 g, 2.3 mmol, prepared as described in Example 97), 0.2 weight equivalents of 10% Pd/C, and ammonium formate (1.000 g, 15.9 mmol) were combined in 20 mL 50% ethyl acetate/methanol and stirred under a nitrogen atmosphere at room temperature for 28 hours. The reaction mixture was filtered through celite and concentrated on a rotary evaporator to give the title compound as a tan glassy solid (0.643 g, 1.6 mmol, 69%), mp 138°-140° C.; MS(CI): 413 (M+H); NMR (250 MHz, DMSO-d6): 7.29-7.18(m, 5H), 6.98-6.87(m, 4H), 6.33(s, 2H), 5.75-5.72(br m, 1H), 4.32(s, 1H), 3.56(br m, 1H), 3.36(br m, 2H), 2.99-2.94(d, J=11.3 Hz, 2H), 2.47(s, 2H), 2.32-2.23(m, 2H), 1.80-1.75(m, 2H), 1.41-1.37(m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([CH:18]=1)[CH2:7][N:8]1[C:12]([CH:13]([F:15])[F:14])=[N:11][N:10]([CH3:16])[C:9]1=[O:17].[CH2:20]([C:22]([O:27][CH3:28])([CH2:25][CH3:26])[C:23]#[CH:24])[CH3:21].C(N(CC)CC)C.C(#N)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COC(C)(C)C>[F:14][CH:13]([F:15])[C:12]1[N:8]([CH2:7][C:6]2[CH:18]=[C:2]([C:21]#[C:20][C:22]([CH2:25][CH3:26])([O:27][CH3:28])[CH2:23][CH3:24])[CH:3]=[CH:4][C:5]=2[CH3:19])[C:9](=[O:17])[N:10]([CH3:16])[N:11]=1
Reactant: C#CC(CC)(CC)OC
Reactant: Cc1ccc(Br)cc1Cn1c(C(F)F)nn(C)c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COC(C)(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCC(C#Cc1ccc(C)c(Cn2c(C(F)F)nn(C)c2=O)c1)(CC)OC
Temperature: 25 °C
Yield: 84.5 %

Procedure:
332 mg (1.00 mmol) of 4-(5-bromo-2-methylbenzyl)-5-difluoromethyl-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (Compound 40), 378 mg (3.00 mmol) of 3-ethyl-3-methoxy-1-pentine, 14 mg (0.020 mmol) of PdCl2(PPh3)2, 9.5 mg (0.050 mmol) of copper iodide (I), 15.7 mg (0.060 mmol) of triphenylphosphine and 0.5 ml of triethylamine were added to 4.0 ml of acetonitrile, and the mixture was heated under reflux for 5 hours in nitrogen atmosphere. After cooling to room temperature, t-butyl methyl ether was added to the reaction solution, and the mixture was washed with water and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluant: hexane/ethyl acetate=2/1 (v/v)), to obtain 319 mg of 5-difluoromethyl-4-{5-(3-ethyl-3-methoxy-1-pentynyl)-2-methylbenzyl}-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (Compound 277).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C@H:6]1[CH2:9][C@H:8]([O:10]C(=O)C2C=CC([N+]([O-])=O)=CC=2)[CH2:7]1)=[O:4].O.C1COCC1.C([O-])([O-])=O.[K+].[K+]>CO>[CH3:1][O:2][C:3](=[O:4])[CH2:5][C@H:6]1[CH2:9][C@H:8]([OH:10])[CH2:7]1
Reactant: COC(=O)C[C@H]1C[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C[C@H]1C[C@H](O)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 86.7 %

Procedure:
To a solution of trans-4-nitro-benzoic acid 3-methoxycarbonylmethyl-cyclobutyl ester (540 mg, 1.84 mmol) in MeOH (20 mL) is added H2O (2.4 mL), THF (10 mL), and K2CO3 (255 mg, 1.84 mmol) at room temperature. The mixture is stirred at room temperature for 45 minutes. The solvent is removed under reduced pressure. Water is added to the obtained residue, and the mixture is extracted with dichloromethane. The organic layer is concentrated under reduced pressure then purified by silica gel column chromatography to give trans-(3-hydroxy-cyclobutyl)-acetic acid methyl ester (230 mg, 87%); TLC (hexane/AcOEt, 1:1) Rf 0.40, 1H NMR (400 MHz, chloroform-) δ ppm 1.69-1.70 (m, 1H), 2.07-2.19 (m, 4H), 2.44-2.46 (d, 2H), 2.41-2.69 (m, 1H), 3.66 (s, 3H), 4.39-4.47 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([CH3:17])(C(O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:20]([CH2:23]C)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:32])C=CC=CC=1.O>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([N:20]=[C:23]=[O:32])([CH3:17])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCC(C)(C(=O)O)C1
Reactant: CCN(CC)CC
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(N=C=O)CCCN(C(=O)OC(C)(C)C)C1
Temperature: 90 °C

Procedure:
To a suspension of 727 mg (3.0 mmol) rac-3-methyl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester (CAS: 534602-47-6) in 8 ml toluene was added at ambient temperature 0.42 ml (3.0 mmol) triethylamine. To the resulting solution was added under stirring 0.72 ml (3.3 mmol) diphenylphosphoryl azide and the mixture heated to 90° C. (gas evolution) for 90 min. The reaction mixture was poured onto iced water and extracted 3 times with tert-butyl methyl ether. The combined extracts were washed with brine, dried over sodium sulfate, filtered and evaporated. The title compound was obtained as slightly yellow oil which was used without purification in the next step. MS (m/e): 240 (M).
Reaction SMILES: C([O:8][C@@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([CH3:31])[O:11][C@H:10]1[O:32][C@@H:33]1[C@@H:42]([O:43][C@H:44]2[O:73][C@H:72]([CH2:74][O:75][CH2:76][C:77]3[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=3)[C@@H:63]([O:64][CH2:65][C:66]3[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=3)[C@H:54]([O:55][CH2:56][C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[C@H:45]2[O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@H:41]([CH3:83])[O:40][C@@H:35]([O:36][CH2:37][CH:38]=[CH2:39])[C@@H:34]1[O:84][C:85](=[O:92])[C:86]1[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=1)(=O)CCC(C)=O.NN.CC(C)=O>N1C=CC=CC=1.C(O)(=O)C>[CH2:16]([O:15][C@@H:14]1[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([CH3:31])[O:11][C@@H:10]([O:32][C@@H:33]2[C@@H:42]([O:43][C@H:44]3[O:73][C@H:72]([CH2:74][O:75][CH2:76][C:77]4[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=4)[C@@H:63]([O:64][CH2:65][C:66]4[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=4)[C@H:54]([O:55][CH2:56][C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)[C@H:45]3[O:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C@H:41]([CH3:83])[O:40][C@@H:35]([O:36][CH2:37][CH:38]=[CH2:39])[C@@H:34]2[O:84][C:85](=[O:92])[C:86]2[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=2)[C@@H:9]1[OH:8])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C=CCO[C@@H]1O[C@@H](C)[C@H](O[C@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@@H](O[C@@H]2O[C@@H](C)[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@H]2OC(=O)CCC(C)=O)[C@H]1OC(=O)c1ccccc1
Agent: NN
Solvent: CC(C)=O
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: C=CCO[C@@H]1O[C@@H](C)[C@H](O[C@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@@H](O[C@@H]2O[C@@H](C)[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@H]2O)[C@H]1OC(=O)c1ccccc1
Reaction time: 0.33 h
Yield: 94 %

Procedure:
The trisaccharide 215 (200 mg, 0.16 mmol) was treated with 0.4 mL of a solution 1 M of hydrazine (100 mg) diluted in a mixture of pyridine (1.6 mL) and acetic acid (0.4 mL) at rt. The solution was stirred during 20 min. Acetone (1.2 mL) was added and the solution was concentrated. The residue was eluted from a column of silica gel with 98.5:1.5 DCM-EtOAc to give 216 (174 mg) as a foam. Although, contaminated with hydrazine salts, the 1H NMR spectrum showed that compound 216 had NMR data identical to that of a reference compound. (F. Bélot, K. Wright, C. Costachel, A. Phalipon, L. A. Mulard, J. Org. Chem. 2004, 69, 1060-1074)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:10][CH3:11])[CH3:9])[C:5]([Cl:12])=[CH:4][N:3]=1.[N+:13]([C:16]1[C:21]([CH3:22])=[CH:20][C:19]([OH:23])=[C:18]([CH3:24])[CH:17]=1)([O-:15])=[O:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:12][C:5]1[C:6]([N:8]([CH2:10][CH3:11])[CH3:9])=[N:7][C:2]([O:23][C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N+:13]([O-:15])=[O:14])=[CH:17][C:18]=2[CH3:24])=[N:3][CH:4]=1
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1O
Reactant: CCN(C)c1nc(Cl)ncc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(C)c1nc(Oc2cc(C)c([N+](=O)[O-])cc2C)ncc1Cl

Procedure:
A solution of 16.8 g (40 mmol) 2,5-dichloro-N-ethyl-N-methylpyrimidin-4-amine, 7.35 g 4-nitro-2,5-dimethylphenol (44 mmol) and 8.29 g potassium carbonate (60 mmol) in 70 ml DMF were stirred for 20 hrs at 100° C. After adding the mixture to 150 ml water the resulting suspension was extracted twice with 50 ml dichloromethane. The combined organic layers were washed with aqueous solution of sodium hydroxide. The organic layer was dried over magnesium sulfate, concentrated in vacuo and column chromatography (dichloromethane) yielded 8.3 g (47%) with a purity of 76%; log P (pH=2.3)=4.07.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl[S:11]([N:14]([CH3:16])[CH3:15])(=[O:13])=[O:12].CCOC(C)=O>CN(C1CCCCC1)C>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][S:11](=[O:13])(=[O:12])[N:14]([CH3:16])[CH3:15])=[CH:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(O)cc1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: CN(C)C1CCCCC1
Solvent: CCOC(C)=O
Product: CN(C)S(=O)(=O)Oc1ccc(C=O)cc1
Temperature: 92.5 °C

Procedure:
A stirred solution of 4-hydroxybenzaldehyde (1.0 g, 8.02 mmol) in N,N-dimethylcyclohexylamine (7 mL) was heated to 90-95° C. and at this temperature ClSO2NMe2 (0.87 mL, 8.02 mL) was added dropwise. The reaction mixture was then heated at 90-95° C. for 3 h. After cooling to room temperature, EtOAc (100 mL) was added and the organic layer was washed with 1M hydrochloric acid (2×100 mL) and then brine (3×50 mL), dried (Na2SO4), filtered and evaporated to give a yellow oil which solidified to a yellow wax upon storage in the refrigerator (1.82 g, 99%); 1H (270 MHz, CDCl3) 3.08 (6H, s), 7.46 (2H AA′BB′), 7.94 (2H AA′BB′) and 10.0 (1H, s).
Reaction SMILES: [CH2:1]([C:5]1([CH:9]([OH:30])/[CH:10]=[CH:11]/[C@H:12]2[C@H:16](C)[O:15][C:14](=[O:18])[N:13]2[CH2:19][CH2:20][S:21][C:22]2[S:23][CH:24]=[C:25]([C:27]([OH:29])=[O:28])[N:26]=2)CC[CH2:6]1)[CH2:2][CH2:3][CH3:4].[C:31]([O-])(=O)[CH3:32].[Na+].[CH2:36](O)C>>[OH:30][C@@H:9]([C:5]([CH3:6])([CH3:36])[CH2:1][CH2:2][CH2:3][CH3:4])/[CH:10]=[CH:11]/[C@H:12]1[CH2:16][O:15][C:14](=[O:18])[N:13]1[CH2:19][CH2:20][S:21][C:22]1[S:23][CH:24]=[C:25]([C:27]([O:29][CH2:31][CH3:32])=[O:28])[N:26]=1
Reactant: CCO
Reactant: CC(=O)[O-]
Reactant: CCCCC1(C(O)/C=C/[C@H]2[C@H](C)OC(=O)N2CCSc2nc(C(=O)O)cs2)CCC1
Agent: [Na+]
Product: CCCCC(C)(C)[C@H](O)/C=C/[C@H]1COC(=O)N1CCSc1nc(C(=O)OCC)cs1
Temperature: 25 °C

Procedure:
To a solution of ethyl ester of the compound 34-4 (175 mg) in ethanol (3 mL) was added p-toluenesulfonylhydrazide (6 g) and the solution was dissolved at 90° C. Sodium acetate (4.5 g) was added thereto and the solution was stirred for 10 Hours. After standing to cool to room temperature, the reaction solution was concentrated. Ethyl acetate and water was added thereto and the solution was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, an aqueous saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (Fuji-silysia, FL60D, 60 mL, n-hexane:ethyl acetate=9:11). The title compound having the following physical data was obtained by the same procedure by the same procedure as the reaction of example 8 using the obtained residue instead of the compound 7.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][C:7]([CH3:12])([CH3:11])[C:8](=[O:10])[CH3:9].[Cl:18][CH2:19][CH2:20][CH:21](O)O.[OH2:24]>C1(C)C=CC=CC=1>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][C:7]([C:8]1([CH3:9])[O:24][CH:20]([CH2:19][Cl:18])[CH2:21][O:10]1)([CH3:12])[CH3:11]
Reactant: O
Reactant: CC(=O)C(C)(C)Oc1cccc(C(F)(F)F)c1
Reactant: OC(O)CCCl
Solvent: Cc1ccccc1
Product: CC(C)(Oc1cccc(C(F)(F)F)c1)C1(C)OCC(CCl)O1
Yield: 65 %

Procedure:
12.3 g (0.5 mol) of 3-(3-trifluoromethyl-phenoxy)-3-methyl-butan-2-one are heated under reflux together with 110 g (1 mol) of 3-chloropropanediol and 10 g of acid ion exchanger (Lewasorb A10) in 600 ml of toluene over a water separator for 14 hours. The cooled reaction mixture is filtered and the filtrate is dried over sodium sulphate and concentrated. The residue is distilled under a high vacuum. 109 g (65% of theory) of 2-[2-(3-trifluoromethyl-phenoxy)-prop-2-yl]-2-methyl-4-chloromethyl-1,3-dioxolane of boiling point 163° C. under 0.2 mbar are obtained.