Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][OH:16])[N:10]=[CH:9]2)C=CC=CC=1.[F:29][C:30]1[CH:35]=[C:34](O)[CH:33]=[CH:32][C:31]=1[C:37](=[O:39])[CH3:38]>>[F:29][C:30]1[CH:35]=[C:34]([O:16][CH2:15][CH2:14][CH2:13][C:11]2[N:10]=[CH:9][NH:8][CH:12]=2)[CH:33]=[CH:32][C:31]=1[C:37](=[O:39])[CH3:38]
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC(=O)c1ccc(O)cc1F
Product: CC(=O)c1ccc(OCCCc2c[nH]cn2)cc1F

Procedure:
5 mmol of 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanol and 6 mmol of (2-fluoro-4-hydroxyphenyl)ethanone are treated as described in Example 56.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH:13]=[N:12][C:11]2[C:6]1=[N:7][CH:8]=[N:9][C:10]=2[NH2:14].[N-:15]=[N+:16]=[N-:17].[Na+]>CN(C=O)C>[N:15]([CH2:2][CH2:3][CH2:4][N:5]1[CH:13]=[N:12][C:11]2[C:6]1=[N:7][CH:8]=[N:9][C:10]=2[NH2:14])=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1ncnc2c1ncn2CCCCl
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCn1cnc2c(N)ncnc21
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of 9-(3-chloropropyl)adenine and sodium azide in DMF was stirred at 80° C. for 24 hours, cooled to room temperature and filtered. The solid was washed with CH2Cl2. The solvent was removed from the combined filtrates and the residue was taken up in water with sonication. The aqueous layer was extracted with CH2Cl2. After removing the solvent, the crude product was recrystallized from ethanol to give 9-(3-azidopropyl)adenine as a white crystalline solid.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH:11]([C:14]1[N:18]=[C:17]([N:19]2[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]2)[O:16][N:15]=1)([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[CH:11]([C:14]1[N:18]=[C:17]([N:19]2[CH2:20][CH2:21][C:22](=[O:25])[CH2:23][CH2:24]2)[O:16][N:15]=1)([CH3:13])[CH3:12]
Reactant: CC(C)c1noc(N2CCC(O)CC2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)c1noc(N2CCC(=O)CC2)n1
Temperature: -60 °C
Reaction time: 0.33 h
Yield: 88 %

Procedure:
A solution of dimethylsulfoxide (1.07 g, 13.7 mmol) in anhydrous dichloromethane (30 mL) was added dropwise over 10 min to oxalyl chloride (2M in dichloromethane; 5.44 mL, 10.9 mmol) which had been cooled to −60° C. The reaction mixture was stirred at −60° C. for 20 min, and then a solution of crude 1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-ol (from Step 2; 2.00 g, ˜9.5 mmol) in anhydrous dichloromethane (100 mL) was added dropwise over 20 min. The reaction mixture was stirred at −60° C. for 1 h, and then triethylamine (2.68 g, 26.5 mmol) was added. The reaction mixture was stirred at −60° C. for 30 min, then allowed to warm to room temperature and stir for 1 h. Dichloromethane (200 mL) was added, and then the mixture was washed with water (3×150 mL) and brine (150 mL). The organic layer was dried (sodium sulfate), filtered, evaporated, and dried under high vacuum to give 1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-one (1.75 g, 88%) as a light tan solid. Mass spectrum (ES) MH+=209.9.
Reaction SMILES: [Na].Cl[C:3]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][O:5][N:4]=1.[CH2:14]([OH:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[CH2:14]([O:20][C:3]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][O:5][N:4]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCO
Reactant: Clc1nonc1-c1cccnc1
Agent: [Na]
Product: CCCCCCOc1nonc1-c1cccnc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of sodium (100 mg, 4.3 mmol) in 1-hexanol (10 ml) was added 3-(3-chloro-1,2,5-oxadiazol-4-yl)pyridine (180 mg, 1 mmol). The mixture was stirred at 25° C. for 18 h and evaporated. The residue was dissolved in water and extracted with ether. The combined organic phases were dried and evaporated to give the title compound.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH3:12])[C:4]=1[C:13]1[CH:14]=[C:15]([N:19](S(CC)(=O)=O)[S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH:16]=[N:17][CH:18]=1)#[N:2]>CN(C=O)C.CO.[OH-].[Na+].O>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH3:12])[C:4]=1[C:13]1[CH:14]=[C:15]([NH:19][S:20]([CH2:23][CH3:24])(=[O:21])=[O:22])[CH:16]=[N:17][CH:18]=1)#[N:2]
Reactant: CCS(=O)(=O)N(c1cncc(-c2c(C#N)c3ccccc3n2C)c1)S(=O)(=O)CC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: CCS(=O)(=O)Nc1cncc(-c2c(C#N)c3ccccc3n2C)c1

Procedure:
A solution of ethanesulfonic acid [5-(3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-yl]-N-ethanesulfonyl-amide in DMF (2 mL), methanol (10 mL) and 5 M NaOH in water (1 mL) is stirred at room temperature for 1 h. The mixture is purified on Xbridge C18 eluting with a 1:9 to 9:1 acetonitrile-water gradient to give ethanesulfonic acid [5-(3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-yl]-amide. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.25 (t, J=7.3 Hz, 3H), 3.24-3.32 (m, 2H), 3.80 (s, 3H), 7.32-7.38 (m, 1H), 7.43 (td, J=7.8, 1.1 Hz, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.75 (d, J=8.3 Hz, 1H), 7.90 (t, J=2.3 Hz, 1H), 8.58-8.62 (m, 2H), 10.42 (s, 1H). HRMS (ESI) m/z 341.1078 [(M+H)+ Calcd for C17H17N4O2S: 341.1072].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[CH3:10][O-:11].[Na+].Cl[C:14](Cl)=[CH:15][C:16]([CH3:21])([CH3:20])[CH2:17][CH2:18][Cl:19]>CN1CCCC1=O.C(Cl)Cl>[Cl:19][C:18]([O:11][C:10]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=1[Cl:8])=[CH:17][C:16]([CH3:21])([CH3:20])[CH2:15][CH2:14][O:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: C[O-]
Reactant: CC(C)(C=C(Cl)Cl)CCCl
Reactant: Oc1ccc(Cl)cc1Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CC(C)(C=C(Cl)Oc1ccc(Cl)cc1Cl)CCOc1ccc(Cl)cc1Cl
Temperature: 200 °C
Reaction time: 6 h
Yield: 90 %

Procedure:
489 g (3 mols) of 2,4-dichlorophenol are dissolved in 1.2 liters of N-methylpyrrolidone, and 600 ml (3 mols) of a 30% strength solution of sodium methylate are added. Methanol and 200 ml of N-methylpyrrolidone are distilled off at 20 mbar. 201 g (1 mol) of 1,1,5-trichloro-3,3-dimethyl-1-pentene are slowly added dropwise at 200° C. and atmospheric pressure. The mixture is then stirred at 200° C. for 6 hours. The solution obtained is diluted with methylene chloride and extracted by shaking several times with dilute sodium hydroxide solution. The dried solution is evaporated and the remaining solvent removed at 0.1 mbar and 150° C. 410 g (90% of theory) of 1-chloro-3,3-dimethyl-1,5-di(2,4-dichlorophenoxy)-1-pentene are obtained as an oil.
Reaction SMILES: [C:1]1([P:7]([O:13]CCCCl)OCCCCl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][NH:19][C:20]([NH:22][CH3:23])=[O:21].[CH:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1(C)C=CC=CC=1>[CH3:18][N:19]1[C:20](=[O:21])[N:22]([CH3:23])[CH:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[P:7]1(=[O:13])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1ccccc1
Reactant: CNC(=O)NC
Reactant: ClCCCOP(OCCCCl)c1ccccc1
Solvent: Cc1ccccc1
Product: CN1C(=O)N(C)P(=O)(c2ccccc2)C1c1ccccc1

Procedure:
A solution of 0.3 mole each of bis(chloropropyl) phenylphosphonite, 1,3-dimethylurea, and benzaldehyde in 100g of toluene is warmed at 105°-110° for 1.5 hr, giving a light yellow reaction mixture in which about half of the phosphorus detectable by nmr had a chemical shift at -25.9 ppm. Stripping to 107°/0.5mm followed by dilution with ether and filtration gives 14.8g of white solid: mp 132°-138° (141.5°-143.5° from tetrahydrofuran-ether); 31P nmr -25.6 ppm; 1H nmr δ 7.3 and 7.6 (m, 10, aryl), 4.6 (d, 1, J = 6Hz, CH), 2.9 (d, 3, J = 8Hz, CH3NP), 2.8 (s, 3, CH3NCH) (phosphorus decoupling converted both doublets to singlets); mass spectrum (70 eV) m/e(rel intensity) intensity) 300(27) (molecular ion), 243(67), 228(35), 166(15), 124(30), 118(100), 77(38), 60(15).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[C:20]([OH:22])=O)=[CH:9][CH:8]=1.[C:23]([C:27]1[O:31][N:30]=[C:29]([NH2:32])[CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>N1C=CC=CC=1.CCOC(C)=O>[C:23]([C:27]1[O:31][N:30]=[C:29]([NH:32][C:20]([C@@H:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:13]2[C:10]2[CH:9]=[CH:8][C:7]([Cl:6])=[CH:12][CH:11]=2)=[O:22])[CH:28]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C(O)[C@@H]1CCCCCN1c1ccc(Cl)cc1
Reactant: CC(C)(C)c1cc(N)no1
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCCN2c2ccc(Cl)cc2)no1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Phosphorus oxychloride (0.21 g, 1.38 mmol) is added drop wise at 0° C. to a solution of (S)-1-(4-chloro-phenyl)-azepane-2-carboxylic acid (0.23 g, 0.92 mmol) and 5-tert-butyl-isoxazol-3-ylamine (0.19 g, 1.38 mol) in pyridine. The reaction mixture is slowly warmed up to room temperature and stirred for three hours. The mixture is diluted with EtOAc and washed twice with saturated NH4Cl solution. The organic phase is washed with 1N HCl, and after drying over anhydrous Na2SO4 the solvent is removed under reduced pressure to afford the crude product that is purified by prep TLC to afford the title compound; m/z 376 [M+H+].
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][O:7][C:8]1[C:9]([CH:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:21][CH2:22]O)=[CH:10][C:11]([O:17][CH3:18])(C)[CH:12]([CH3:15])[C:13]=1[CH3:14].[CH2:30](N(CC)CC)C.[I-:37].[Na+]>ClCCl.O>[I:37][CH2:22][CH2:21][CH2:20][CH:19]([C:9]1[C:10]([CH3:30])=[C:11]([O:17][CH3:18])[C:12]([CH3:15])=[C:13]([CH3:14])[C:8]=1[O:7][CH3:6])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCN(CC)CC
Reactant: COC1=C(C)C(C)C(C)(OC)C=C1C(CCCO)c1ccccc1
Reactant: [I-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1c(C)c(C)c(OC)c(C(CCCI)c2ccccc2)c1C
Reaction time: 0.33 h
Yield: 619 %

Procedure:
A solution of 1.37 g (10×1.2 mmole) of methanesulfonyl chloride in dichloromethane (10 ml) was added dropwise to 3.28 g (10.0 mmole) of 4-(2,5-dimethoxy-3,4,5-trimethylphenyl)-4-phenylbutan-1-ol and 2.10 ml (10×1.5 mmole) of triethylamine dissolved in dichloromethane (30 ml) at -5° C. over the period of 30 minutes, and the reaction was continued for 20 minutes under stirring, with ice cooling. The reaction was stopped by adding cold water to the reaction solution, and the dichloromethane layer was separated out, washed with cold dilute hydrochloric acid and aqueous sodium chloride solution successively, dried (magnesium sulfate) and evaporated. The residue was dissolved in acetone (50 ml), and 4.5 g (10×3 mmole) of sodium iodide was added to the solution, followed by stirring at 50° C. for 2 hours. The acetone was distilled off, and isopropyl ether and water were added to the residue to extract the product. The isopropyl ether layer was separated out, washed with aqueous sodium chloride solution, and evaporated, and the residual solution was chromatographed on a silica gel column to perform purification (elution with hexane/isopropyl ether) to thereby give 4.07 g (93%) of 1-iodo-4-(2,5-dimethoxy-3,4,6-trimethylphenyl)-4-phenylbutane. Its typical physical properties and nuclear magnetic resonance spectrum data are shown in Table 14.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[NH2:11][CH2:12][C:13]([N:15]1[C@@H:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][CH2:24][C@H:16]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:14]>O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:10])[NH:11][CH2:12][C:13]([N:15]2[C@@H:26]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:25][CH2:24][C@H:16]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CC[C@H](c2ccccc2)N1C(=O)CN
Reactant: Cc1cccc(N=C=O)c1
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)NCC(=O)N2[C@@H](c3ccccc3)CC[C@H]2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.05 cm3 of 3-methylphenyl isocyanate is added to a solution of 0.08 g of tert-butyl (2S,5R)-1-(2-aminoacetyl)-5-phenylprolinate in 10 cm3 of anhydrous tetrahydrofuran. The reaction mixture is stirred for 3 hours at a temperature in the vicinity of 25° C., the solvent is then evaporated under reduced pressure at 45° C. The crude product obtained is purified by chromatography on silica [eluent: dichloromethane/methanol (98/2 by volume)]. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure. 0.04 g of tert-butyl (2S,5R)-1-{2-[3-(3-methylphenyl)ureido]acetyl}-5-phenylprolinate is thus obtained, the analytical data for which are in agreement with those for the dextrorotatory enantiomer prepared by chiral stationary phase chromatography of the racemic product, ([α]D20 =±35.6°±0.8° (C=0.11%; MeOH)).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH:6]2[C:15](=O)[C:14]3[C:13]([C:17]([O:19]CC)=O)=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][CH:7]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:2]1.O.[NH2:29][NH2:30]>CO>[O:1]1[CH:5]=[CH:4][C:3]([CH:6]2[C:15]3=[N:29][NH:30][C:17](=[O:19])[C:13]4[CH:12]=[CH:11][CH:10]=[C:9]([C:14]=43)[NH:8][CH:7]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:2]1
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ccoc1)C(c1ccccc1)N2
Solvent: O
Solvent: CO
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ccccc1)C2c1ccoc1
Temperature: 45 °C
Reaction time: 8 h
Yield: 7 %

Procedure:
A mixture of ethyl 3-(furan-3-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (80 mg) in 85% hydrazine monohydrate (10 mL) and methanol (10 mL) was stirred at 45° C. overnight. Methanol was removed under reduced pressure. The crude product was purified by prep-HPLC to give 9-(furan-3-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (5 mg, yield 7%). 1H-NMR (400 MHz, CD3OD) δ (ppm): 4.19 (d, J=8.0 Hz, 1H), 4.67 (d, J=8.0 Hz, 1H), 6.26 (s, 1H), 7.07-7.21 (m, 7H), 7.30 (s, 1H), 7.27 (m, 1H), 7.41 (d, 1H), 7.51 (m, 1H); LC-MS (ESI) m/z: 330 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[N:9][C:10]([O:12][Si](C)(C)C)=[CH2:11])[CH:5]=[CH:6][CH:7]=1.C1(C)C=CC=CC=1.[Cl:24][C:25]1[CH:33]=[C:32]2[C:28](/[C:29](=[CH:35]/[CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])/[C:30](=[O:34])[NH:31]2)=[CH:27][CH:26]=1>CO>[Cl:24][C:25]1[CH:33]=[C:32]2[NH:31][C:30](=[O:34])[C:29]3([CH:35]([CH2:36][C:37]([CH3:39])([CH3:38])[CH3:40])[CH2:12][C:10](=[O:11])[NH:9][CH:8]3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:28]2=[CH:27][CH:26]=1
Reactant: C=C(N=Cc1cccc(Cl)c1)O[Si](C)(C)C
Reactant: CC(C)(C)C/C=C1\C(=O)Nc2cc(Cl)ccc21
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)(C)CC1CC(=O)NC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 110 °C
Yield: 34.8 %

Procedure:
To a mixture of 1-(3-chlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (0.25 g, 1 mmol) prepared in example 1b, and toluene (4 mL) was added E/Z-6-chloro-3-(3,3-dimethyl-butylidene)-1,3-dihydro-indol-2-one (0.25 g, 1 mmol) prepared in example 1a. The reaction mixture was heated in a sealed tube under nitrogen at 110° C. for 18 h. The mixture was cooled to room temperature, and methanol (10 mL) was added. The mixture was concentrated and the residue was purified by chromatography (EtOAc/hexanes=2:1) to give racemic (2′S,3S,4′S)-6-chloro-2′-(3-chlorophenyl)-4′-(2,2-dimethylpropyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a brown solid (Yield 0.15 g, 35%).
Reaction SMILES: [O:1]=[C:2]([OH:11])[CH2:3][N:4]([CH2:8][CH2:9][OH:10])[CH2:5][CH2:6][OH:7].[C:12]([OH:35])(=O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].[C:36](Cl)(=[O:40])[C:37](Cl)=O.Cl.[Cl-].[Na+]>C(Cl)(Cl)Cl.N1C=CC=CC=1>[C:36]([O:10][CH2:9][CH2:8][N:4]([CH2:3][C:2]([OH:11])=[O:1])[CH2:5][CH2:6][O:7][C:12](=[O:35])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])(=[O:40])[CH2:37][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CN(CCO)CCO
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)OCCN(CCOC(=O)CCCCCCCCCCCCCCCCCCCCC)CC(=O)O
Yield: 61 %

Procedure:
Bicine (0.95 g, 5.82×10−3 mol, Aldrich®, 99+%) was added to chloroform (30 mL, anhydrous, Aldrich®, 99+%). A concentrate of docosanoyl chloride, prepared by the reaction of docosanoic acid (4.12 g, 1.14×10−2 mol, Aldrich®) with excess oxalyl chloride (Sigma) in chloroform, was added dropwise to the suspension. After stirring for a few minutes, excess pyridine (1.5 mL, anhydrous, Aldrich®, 99+%) was added to the flask. The flask was refluxed overnight. The reaction mixture was acidified with dilute HCl saturated with sodium chloride (Mallinckrodt, AR®). The aqueous phase was separated. Any remaining volatiles were removed from the organic phase under reduced pressure with mild heating. The glassy product was recrystallized from ethanol (Mallinckrodt, AR®). The product was recovered by filtration as an amorphous white solid. The product weighed 2.86 g after vacuum drying for a 61% yield; mp 73-75° C.; Rf=0.23 (silica gel, 10:1; chloroform-methanol). 1H NMR (CDCl3, 99.8% D, 1% TMS, Aldrich): 0.880 ppm (t,); 1.254 ppm (s); IR (paraffin oil) OH 3,100 cm−1; CO 1,760 and 1,700 cm−1 C—O 1,180 cm−1.
Reaction SMILES: Cl[C:2]([Cl:12])=[CH:3][C:4]([CH2:10][CH3:11])([CH3:9])[CH2:5][CH2:6][CH2:7][CH3:8].[C:13]1([O-:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Na+]>CN(C)C=O.C(Cl)Cl>[Cl:12][CH:2]=[C:3]([O:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]([CH2:10][CH3:11])([CH3:9])[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: [O-]c1ccccc1
Reactant: CCCCC(C)(C=C(Cl)Cl)CC
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCC(C)(CC)C(=CCl)Oc1ccccc1
Yield: 65.3 %

Procedure:
626 g (3 moles) of 1,1-dichloro-3-ethyl-3-methyl-1-heptene and 696 g (6 moles) of sodium phenolate are heated under reflux in 3 L of dimethylformamide for 16 hours. The mixture is diluted with methylene chloride and extracted by shaking several times with 2 N aqueous sodium hydroxide solution. After drying and evaporating on a rotary evaporator, 666 g of crude product remain. Distillation at boiling point0.1 100°-110° C. gives 523 g (65% of theory) of 1-chloro-3-ethyl-3-methyl-2-phenoxy-hept-1-ene. NMR (CDCl3): δ 0.7-1.6 (m, 17 H), 5.8 and 5.85 (2 s, 1 H) and 6.8-7.4 (m, 5 H). ##STR60##
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH2:8].[Cl:9][CH2:10][C:11]([N:14]=[C:15]=[O:16])([CH3:13])[CH3:12].CO>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:9][CH2:10][C:11]([NH:14][C:15]([NH:8][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[CH3:1])=[O:16])([CH3:13])[CH3:12]
Reactant: CC(C)(CCl)N=C=O
Reactant: Cc1ccncc1N
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1ccncc1NC(=O)NC(C)(C)CCl
Temperature: 25 °C
Reaction time: 72 h
Yield: 97.1 %

Procedure:
4-Methyl-pyridin-3-ylamine (1.98 g, 18.33 mmol) was added to solution of 1-chloro-2-isocyanato-2-methyl-propane (I-200c: 3 g, 20.40 mmol) in toluene (30 mL). The resulting mixture was stirred at room temperature for 3 days. The reaction was monitored by TLC (5% MeOH in CHCl3). The reaction mixture was filtered and the residue was dried to afford 4.3 g of the product (87.75% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[CH2:8][Si:9]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12].C(N)CN>>[NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:14]([O:13][Si:9]([CH2:8][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)([O:16][CH2:17][CH3:18])[O:10][CH2:11][CH3:12])[CH3:15]
Reactant: CCO[Si](CCl)(OCC)OCC
Solvent: C1COCCN1
Solvent: NCCN
Product: CCO[Si](CN1CCOCC1)(OCC)OCC
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
82 g of dry morpholine (pKb 5.67) were heated to 120° C. in a 500 ml four-necked flask having a reflux condenser, KPG stirrer and thermometer and 80 g of chloromethyltriethoxysilane were added in the course of 180 min with stirring. After the end of the addition, the temperature was reduced to 105° C. and 226.6 g of ethylenediamine (pKb 4.07) were added to the mixture in the course of 10 min with stirring, phase separation occurring. At constant temperature, stirring was effected for a further 30 min and the heavier ethylenediamine hydrochloride phase was then separated off. The upper phase was subjected to fractional distillation without a distillation column. 37 g (45% recovery) of morpholine having a purity of 89.7% and 73.5 g (yield 74.2%) of 4-(triethoxysilylmethyl)-tetrahydro-1,4-oxazine were obtained, the purity of which was determined as 97.3%.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[N:15]=[C:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:17]=[C:18](Cl)[C:13]=3[CH:12]=[C:11]2[C:26]([O-:28])=[O:27])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH:30][CH:31](O)[CH2:32][CH2:33][NH2:34].Cl.CS(C)=[O:39]>O>[C:1]1([S:7]([N:10]2[C:14]3[N:15]=[C:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:17]=[C:18]([NH:34][CH2:33][C@H:32]([OH:39])[CH2:31][OH:30])[C:13]=3[CH:12]=[C:11]2[C:26]([OH:28])=[O:27])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C([O-])c1cc2c(Cl)nc(-c3ccccc3)nc2n1S(=O)(=O)c1ccccc1
Reactant: CS(C)=O
Reactant: NCCC(O)O
Agent: Cl
Agent: [Li+]
Solvent: O
Product: O=C(O)c1cc2c(NC[C@H](O)CO)nc(-c3ccccc3)nc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 93 %

Procedure:
27 (126 mg) and dihydroxypropyl amine (273 mg) were stirred in anhydrous DMSO (2 mL) at 80° C. under nitrogen for 4 h. The reaction mixture was cooled to rt and diluted with water (10 mL). The resulting mixture was acidified with 0.5N HCl until a white solid formed (pH≈3.5-4.0). The solid was collected by filtration, washed with cold water, and dried in vacuo. A white solid (131 mg) was obtained in 93% yield. 1H-NMR (200 MHz, DMSO-d6): δ=3.30-3.33 (m, 2H), 3.57-3.60 (m, 2H), 3.65-6.71 (m, 1H), 3.82-3.97 (m, 2H), 7.32 (s, 1H), 7.46-7.50 (m, 3H), 7.55-7.68 (m, 3H), 8.38-8.49 (m, 4H). MS (ES): 468.9 (M++1).
Reaction SMILES: CN.[NH2:3][C:4]1[C:9]([C:10]2[O:11][C:12]3[C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:8][C:7]([C:22]2[CH:23]=[N:24][N:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)[CH:26]=2)=[CH:6][N:5]=1.F[P-](F)(F)(F)(F)F.[CH3:47][N:48](C(=[O+]N1C2=NC=CC=C2N=N1)N(C)C)C>CO.CN(C=O)C>[NH2:3][C:4]1[N:5]=[CH:6][C:7]([C:22]2[CH:23]=[N:24][N:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)[CH:26]=2)=[CH:8][C:9]=1[C:10]1[O:11][C:12]2[C:18]([C:19](=[O:20])[NH:48][CH3:47])=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1
Reactant: CN(C)C(=[O+]n1nnc2cccnc21)N(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4nc5cccc(C(=O)O)c5o4)c3)cn2)CC1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Product: CNC(=O)c1cccc2nc(-c3cc(-c4cnn(C5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc3N)oc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 75.8 %

Procedure:
A 2M solution of methylamine in methanol (0.535 ml) was added to a mixture of 2-[2-amino-5-[1-(1-tert-butoxycarbonyl-4-piperidyl)pyrazol-4-yl]-3-pyridyl]-1,3-benzoxazole-7-carboxylic acid (270 mg) and bis(dimethylamino)methylene-(triazolo[5,4-b]pyridin-3-yl)oxonium hexafluorophosphate (285 mg) dissolved in DMF (1 ml). The resulting solution was heated at 25° C. for 1 day. A 2N solution of methylamine (0.535 ml) in methanol was added and the mixture was stirred at 25° C. in a sealed tube for 3 days. The mixture was evaporated to dryness and adsorbed on silica gel. The crude product was purified by flash chromatography on silica gel eluting with 20 to 50% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford tert-butyl 4-[4-[6-amino-5-[7-(methylcarbamoyl)-1,3-benzoxazol-2-yl]-3-pyridyl]pyrazol-1-yl]piperidine-1-carboxylate (210 mg) as a pale yellow solid. NMR Spectrum: (DMSOd6) 1.43 (s, 9H), 1.80 (dd, 1H), 1.85 (dd, 1H), 2.01-2.11 (m, 2H), 2.94 (bs, 2H), 2.96 (d, 3H), 4.00-4.13 (m, 2H), 4.36-4.46 (m, 1H), 7.51 (dd, 1H), 7.65 (bs, 2H), 7.82 (dd, 1H), 7.93 (s, 1H), 7.98 (dd, 1H), 8.30 (s, 1H), 8.43 (q, 1H), 8.54 (d, 1H), 8.57 (d, 1H); Mass spectrum: M+H+ 518.