Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CO[C:3]2([CH2:8][CH2:7][C:6](=[CH:9][O:10]C)[CH2:5][CH2:4]2)[O:2]1.C(O)(=O)C>O>[CH:9]([CH:6]1[CH2:7][CH2:8][C:3](=[O:2])[CH2:4][CH2:5]1)=[O:10]
Reactant: COC=C1CCC2(CC1)OCCO2
Solvent: O
Solvent: CC(=O)O
Product: O=CC1CCC(=O)CC1
Temperature: 25 °C
Yield: 86.5 %

Procedure:
A mixture of 28.2 g of 1,1-ethylenedioxy-4-(methoxymethylene)cyclohexane, 770 ml of glacial acetic acid and 385 ml of water was heated to reflux for 1 hour in a round flask while gassing with nitrogen. Thereafter, the yellowish clear solution was cooled to room temperature, diluted with 800 ml of water and extracted three times with 700 ml of methylene chloride each time. The organic phases were washed twice with 500 ml of 10 percent (wt./vol.) sodium carbonate solution each time, dried over sodium sulphate, filtered and concentrated. Chromatographic separation of the brownish liquid obtained (18.5 g) on silica gel with methylene chloride as the eluent finally gave 16.7 g of 4-formylcyclohexanone as a brownish liquid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=2[CH:4]=[N:3]1.[C:12](Cl)(Cl)=[O:13].C(NC(C)C)(C)C.[F:23][C:24]([F:38])([F:37])[C:25]1[CH:30]=[CH:29][N:28]=[C:27]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:26]=1>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:10]2[C:5](=[C:6]([NH:11][C:12]([N:34]3[CH2:35][CH2:36][N:31]([C:27]4[CH:26]=[C:25]([C:24]([F:38])([F:23])[F:37])[CH:30]=[CH:29][N:28]=4)[CH2:32][CH2:33]3)=[O:13])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3]1
Reactant: FC(F)(F)c1ccnc(N2CCNCC2)c1
Reactant: Cn1ncc2c(N)cccc21
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CC(C)NC(C)C
Product: Cn1ncc2c(NC(=O)N3CCN(c4cc(C(F)(F)F)ccn4)CC3)cccc21
Temperature: 25 °C

Procedure:
1-Methyl-1H-indazol-4-amine (560 mg, 3.81 mmol) in toluene (20 mL) was treated with 20% phosgene solution (2.5 mL) and refluxed overnight. The mixture was allowed to cool to ambient temperature and was concentrated under reduced pressure. The residue was taken up in THF (20 mL) and treated with diisopropylamine (5 mL) and 1-[4-(trifluoromethyl)-2-pyridinyl]piperazine (450 mg, 1.95 mmol). The mixture was refluxed overnight, allowed to cool to ambient temperature, and concentrated under reduced pressure. The residue was purified by flash chromatography (97:3 CH2Cl2:CH3OH to 95:5 CH2Cl2:CH3OH) to provide the title compound. The corresponding hydrochloride salt was prepared by treatment with methanolic HCl. 1H NMR (300 MHz, d6-DMSO) δ 8.78 (s, 1H), 8.44 (m, 1H), 8.07 (d, J=1.0 Hz, 1H), 7.83 (m, 1H), 7.19-7.31 (m, 3H), 7.02 (d, 9.2 Hz, 1H), 4.00 (s, 3H), 3.74 (m, 4H), 3.63 (m, 4H); MS (ESI+) m/z 405 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:37])([C:6]([F:36])([F:35])[C:7]([F:34])([F:33])[C:8]([F:32])([F:31])[C:9]([F:30])([F:29])[C:10]([F:28])([F:27])[C:11]([F:26])([F:25])[C:12]([F:24])([F:23])[C:13]([F:22])([F:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])[C:3](Cl)=[O:4].[OH:38][C:39]1[CH:81]=[CH:80][C:42]([C:43]2[CH:48]=[CH:47][C:46]([C:49]3[C:62]4[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=4)[C:56]4[CH:55]=[CH:54][C:53]([C:74]5[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=5)([C:63]5[CH:68]=[CH:67][C:66]([N:69]6[CH2:73][CH2:72][CH2:71][CH2:70]6)=[CH:65][CH:64]=5)[O:52][C:51]=4[CH:50]=3)=[CH:45][CH:44]=2)=[CH:41][CH:40]=1.N1C=CC=CC=1.Cl>C(Cl)Cl.CN(C)C1C=CN=CC=1>[F:1][C:2]([F:37])([C:6]([F:36])([F:35])[C:7]([F:34])([F:33])[C:8]([F:32])([F:31])[C:9]([F:30])([F:29])[C:10]([F:28])([F:27])[C:11]([F:26])([F:25])[C:12]([F:24])([F:23])[C:13]([F:22])([F:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])[C:3]([O:38][C:39]1[CH:40]=[CH:41][C:42]([C:43]2[CH:44]=[CH:45][C:46]([C:49]3[C:62]4[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=4)[C:56]4[CH:55]=[CH:54][C:53]([C:74]5[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=5)([C:63]5[CH:68]=[CH:67][C:66]([N:69]6[CH2:73][CH2:72][CH2:71][CH2:70]6)=[CH:65][CH:64]=5)[O:52][C:51]=4[CH:50]=3)=[CH:47][CH:48]=2)=[CH:80][CH:81]=1)=[O:4]
Reactant: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: Oc1ccc(-c2ccc(-c3cc4c(c5ccccc35)C=CC(c3ccccc3)(c3ccc(N5CCCC5)cc3)O4)cc2)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Oc1ccc(-c2ccc(-c3cc4c(c5ccccc35)C=CC(c3ccccc3)(c3ccc(N5CCCC5)cc3)O4)cc2)cc1)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 45.8 %

Procedure:
Solid 2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,12-tricosafluorododecanoyl chloride (0.37 g, 0.58 mmol) was added to a solution of 6-[4′-(hydroxy)biphen-4-yl]-3-phenyl-3-(4-pyrrolidinophenyl)-3H-naphtho[2,1-b]pyran (0.33 g, 0.58 mmol) in DCM (100 mL) containing 4-dimethylaminopyridine (0.05 g) and pyridine (2 mL) under N2 with stirring. The mixture was stirred at room temperature for 3 h, poured into HCl (2 M, 100 mL), extracted with EtOAc (3×30 mL), washed with water (100 mL), dried (MgSO4) and the solvent removed under reduced pressure. The residue was filtered through a short plug of silica using DCM (60% in hexanes as eluent), the solvent removed under reduced pressure. Hexane was added and the resulting solid filtered to give the title compound (0.31 g, 46%) as a colourless powder, mp 129-130° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][OH:9])(C)C.C([Li])CCC.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:24]=[O:25].[Cl-].[NH4+]>CCOCC.CCCCCC.C(OCC)(=O)C>[OH:9][CH2:8][C:7]1[CH:10]=[CH:11][CH:12]=[C:5]([O:4][CH3:1])[C:6]=1[CH:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=1)[OH:25]
Reactant: CC(C)Oc1cccc(CO)c1
Reactant: O=Cc1ccccn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COc1cccc(CO)c1C(O)c1ccccn1
Temperature: -20 °C
Reaction time: 2 h
Yield: 25.1 %

Procedure:
To a mixture of 30 g (0.18 mol) of 3-isopropoxybenzyl alcohol in 600 ml of ether cooled to -20° C. was added in portions 38.7 ml (0.387 mol) of n-butyllithium (10M) in hexane over a 20 min period, and the reaction mixture was allowed to warm to room temperature and stirred for 2 hr. The above reaction mixture was cooled to -20° C., 23.1 g (0.216 mol) of pyridine-2-carboxaldehyde was added in one portion to the mixture, and the resulting reaction mixture was allowed to warm to room temperature and stirred for 1 hr. Ammonium chloride solution (200 ml) and 100 ml of ethyl acetate were added to the mixture. The resulting mixture was separated, the aqueous layer was extracted with methylene chloride (2×200 ml), the combined organic layer was washed with brine, dried over sodium sulfate, and concentrated. The diol was purified by chromatography on silica gel eluting with ethyl acetate/hexane (9:1; and 0.05 % TEA). The solvent was concentrated in vacuo, the brown oil was dissolved in methylene chloride/hexane, and removal of methylene chloride in vacuo to 1/2 of its volume afforded 11.1 g (22.6%) of 2-[1-hydroxy-(6'-hydroxymethyl-2'-isopropoxy) -benzyl]pyridine (Formula XIII: R1 =R7 =H; R2 =2'--OCH (CH3)2), as a tan solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:18][CH2:17][C:10]3([NH:14]C(=O)N[C:11]3=[O:16])[CH2:9]2)=[CH:4][CH:3]=1.[OH-:19].[Na+].Cl>O1CCOCC1>[NH2:14][C:10]1([C:11]([OH:19])=[O:16])[CH2:17][CH2:18][C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH2:9]1
Reactant: [OH-]
Reactant: O=C1NC(=O)C2(CC[C@H](c3ccc(Br)cc3)C2)N1
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: NC1(C(=O)O)CC[C@H](c2ccc(Br)cc2)C1
Temperature: 95 °C
Reaction time: 24 h
Yield: 109.5 %

Procedure:
To (7S)-7-(4-bromophenyl)-1,3-diazaspiro[4.4]nonane-2,4-dione (I-1B, 13.9 g, 45.0 mmol) in 1,4-dioxane (40 mL) in a round bottom flask was added aqueous NaOH (2N, 100 mL, 200 mmol). The mixture was heated to 95° C. and stirred for 24 hours. Additional NaOH (25 mL, 50 mmol) was added and heating continued for another two days. The solution was cooled with an ice-bath, neutralized with 5N HCl to approximately pH 7 resulting in the formation of a white precipitate. The solids were collected by filtration and dried under high vacuum for 2 days to provide 14 g of (3S)-1-amino-3-(4-bromophenyl)cyclopentanecarboxylic acid as a white solid which was used as such for the subsequent step without further purification. HPLC retention time=0.64 min (Condition G) LC/MS M+1=284/286.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([N:13]([CH:22]([CH3:24])[CH3:23])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[O:12])[C:6]2[CH:25]=[CH:26][CH:27]=[CH:28][C:5]=2[N:4](CC2C=CC(OC)=CC=2)[C:3]1=[O:38].[N+]([O-])([O-])=O.[NH4+]>C(#N)C.O>[NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([N:13]([CH:22]([CH3:24])[CH3:23])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[O:12])[C:6]2[CH:25]=[CH:26][CH:27]=[CH:28][C:5]=2[NH:4][C:3]1=[O:38]
Reactant: COc1ccc(CN2C(=O)C(N)C(=O)N(CC(=O)N(c3ccc(OC)cc3)C(C)C)c3ccccc32)cc1
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(N(C(=O)CN2C(=O)C(N)C(=O)Nc3ccccc32)C(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
To a stirred solution of 2-[3-Amino-5-(4-methoxybenzyl)-2,4-dioxo-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(4-methoxyphenyl)-acetamide (2.63 g, 5.09 mmol) in acetonitrile/H2O (9:1, 70 mL) at ambient temperature was added cerric ammonium nitrate (10.05 g, 18.3 mmol) portionwise over one hour. The solution was stirred overnight at room temperature. The solution was concentrated in vacuo, chased with toluene (2×50 mL) and the residue was extracted with CH2Cl2 (3×50 mL), filtered and concentated to an orange glass. The crude product was purified by flash chromatography on silica gel (100 g) eluting successively with CH2 Cl2 /CH3OH (15:1, 1.5 L) and CH2Cl2 /CH3OH (10:1, 1.3 L). Appropriate fractions were combined and concentrated under reduced pressure to give the title compound (1.97 g, 4.97 mmol) as a brown foam: 1H NMR (300 MHz, DMSO-d6): d 10.68 (br s, 1H), 7.39-6.98 (m, 8H), 5.75 (s, 1H), 4.76 (m, 1H), 4.16-3.92 (m, 4H), 3.7 (s, 3H), 3.15 (m, 2H), 0.97 (m, 6H); TLC (CH2Cl2 /CH3OH (13:1)): Rf =0.21.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([CH2:20][C:21](OCC)=[O:22])[N:9]=1.OCC[NH:29][CH2:30][CH2:31][NH:32][CH2:33][CH2:34][OH:35].[CH2:36]([OH:38])[CH3:37]>>[OH:38][CH2:36][CH2:37][N:32]([CH2:33][CH2:34][OH:35])[CH2:31][CH2:30][NH:29][C:21](=[O:22])[CH2:20][N:10]1[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])=[N:12][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[OH:1])=[N:9]1
Reactant: CCOC(=O)Cn1nc(-c2ccccc2O)nc1-c1ccccc1O
Reactant: OCCNCCNCCO
Reactant: CCO
Product: O=C(Cn1nc(-c2ccccc2O)nc1-c1ccccc1O)NCCN(CCO)CCO

Procedure:
2.0 g of ethyl [3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]acetate (Example 2) and 1.0 g of bis(2-hydroxyethyl)ethylenediamine are boiled under reflux for 24 h in 8 ml of ethanol. The mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is chromatographed on silica gel. After concentration and drying, N-{2-[bis(2-hydroxyethyl)amino]ethyl}-2-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]acetamide remains as a colorless foam. Rf value: 0.35 (silica gel 60, methylene chloride/methanol=9/1). 1H-NMR (DMSO-d6): 2.5 (m, 6H), 3.1 (m, 2H), 3.4 (m, 4H), 4.2 (bs, 2H), 4.9 (s, 2H), 7.0 (m, 4H), 7.4 (m, 3H), 7.95 (d, 1H), 8.1 (t, 1H), 11.0 ppm (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@H:9]([OH:16])[CH2:10][NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)Cl.[N+:35]([C:38]1[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=1)([O-:37])=[O:36]>O>[C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C@H:9]([OH:16])[CH2:10][N:11]([S:44]([C:41]1[CH:40]=[CH:39][C:38]([N+:35]([O-:37])=[O:36])=[CH:43][CH:42]=1)(=[O:45])=[O:46])[CH2:12][CH:13]([CH3:14])[CH3:15])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)CNC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 42.5 °C
Yield: 93.5 %

Procedure:
[(1S,2R)-3-[(2-methylpropyl)amino]-2-hydroxy-1-(phenyl methyl)propyl]carbamic acid tert-butyl ester (4, 100 gm) and triethylamine (39.04 g) was added to methylenedichloride (1200 mL) and the temperature was raised to 40° C. p-nitro benzene sulfonyl chloride solution (72.3 g of p-NBSC dissolve in 300 mL methylenedichloride) was added slowly at 40-45° C. for 2-3 hrs. The reaction was maintained for 3 hours at 40-45° C. After completion of the reaction, water (500 mL) was added, separated the organic layer and distilled out methylene dichloride at atmospheric pressure. Finally, strip out the methylene dichloride by using isopropyl alcohol (200 mL). Isopropyl alcohol (1000 mL) was added to the distillate and maintained the stirring for 60 minutes at 70-80° C. Cooled the mass to 30-35° C., filtered and washed with Isopropyl alcohol to get title compound 3 (yield 145 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[C:6](Br)[CH:7]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.O>C1COCC1.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]>[Cl:9][C:3]1[C:2]([NH2:1])=[CH:7][C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:5][N:4]=1
Reactant: C1COCCN1
Reactant: Nc1cc(Br)cnc1Cl
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: O
Solvent: C1CCOC1
Product: Nc1cc(N2CCOCC2)cnc1Cl
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
A mixture of 3-amino-5-bromo-2-chloropyridine (2.0 g, 9.7 mmol), morpholine (1.3 mL, 14.9 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′,-triisopropyl-biphenyl, (X-Phos) (0.37 g, 0.8 mmol), and tris(dibenzylideneacetone)dipalladium (0) (0.36 g, 0.39 mmol) in dry THF (15.0 mL) was degassed by nitrogen. To this mixture was added 1.0M lithium bis(trimethylsilyl)amide in THF (25 mL) dropwise, and the resulting reaction was heated to 60° C. After 2.5 h, the reaction was cooled to rt then poured into water. After extracting twice with EtOAc and twice with DCM, the combined organic layers were dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on basic alumina (0-20% EtOAc in hexanes) to afford an off-white solid as 2-chloro-5-morpholinopyridin-3-amine. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.35 (1H, d, J=2.7 Hz), 6.67 (1H, d, J=2.7 Hz), 5.33 (2H, s), 3.79 (4H, m), 3.11 (4H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10]([OH:12])=O.[K+].[CH3:14][O:15][C:16](=[O:21])[CH2:17]C([O-])=O>>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[CH2:9][C:10](=[O:12])[CH2:17][C:16]([O:15][CH3:14])=[O:21]
Reactant: COC(=O)CC(=O)[O-]
Reactant: O=C(O)Cc1c(F)cccc1F
Agent: [K+]
Product: COC(=O)CC(=O)Cc1c(F)cccc1F

Procedure:
The title compound was prepared from 2-(2,6-difluorophenyl)acetic acid and 3-methoxy-3-oxopropanoic acid potassium salt according to the procedure for the preparation of Example 170, part A. 1H NMR (300 MHz, CDCl3): δ 3.56 (2H, s), 3.75 (3H, s), 3.92 (2H, s), 6.89-6.93 (2H, m), 7.22-7.27 (1H, m).
Reaction SMILES: [CH2:1]([C:4]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[ClH:22].O1CCOCC1>O1CCOCC1>[ClH:22].[CH2:1]([C:4]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: C=CCC1(C(=O)OCC)CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an ice-cold solution of 1-tert-butyl 4-ethyl 4-allylpiperidine-1,4-dicarboxylate (2 g, 6.70 mmol) in 1,4-dioxane (10 mL) was added HCl-dioxane (4.0 M, 15 mL) solution and the mixture stirred at rt for 30 min. After completion of reaction (by TLC), the solvent was evaporated to obtain a brownish solid material (1.30 g) that was carried forward to the next step without further purification. MS: 198.28 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:12][CH:13]1OC(C)OC(C)O1.O.[C:22](OC(=O)C)(=O)[CH3:23]>I.[PH2](O)=O>[CH3:1][C:2]1[NH:3][C:4]([CH2:22][CH3:23])=[C:5]([CH2:12][CH3:13])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cc[nH]c1C
Reactant: CC1OC(C)OC(C)O1
Reactant: CC(=O)OC(C)=O
Agent: I
Agent: O=[PH2]O
Solvent: O
Product: CCOC(=O)c1c(C)[nH]c(CC)c1CC
Reaction time: 0.5 h

Procedure:
A solution of 612 mg of 2-methyl-3-carbethoxy-pyrrole in 10 ml of hydriodic acid, 10 ml of acetic anhydride and 2 ml of hypophosphorous acid was stirred while 0.35 ml of paraldehyde was dropped in. Stirring was contined for 1/2 h and the solution was then poured into water. For analysis, the pale yellow micro crystals which separated (0.45 g, 53%, m.p. 104°-106°) were recrystallized from aqueous ethanol. Anal Calc. for C12H19NO2 : C, 68.86; H, 9.15; N, 6.67. Found: C, 68.73; H, 9.09; N, 6.85.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].Br[CH2:11][CH2:12][CH2:13][CH2:14]Cl.[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17]>>[CH2:16]([N:18]([CH2:19][CH3:20])[CH2:11][CH2:12][CH2:13][CH2:14][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH3:17]
Reactant: ClCCCCBr
Reactant: CCNCC
Reactant: N#Cc1ccc(O)cc1
Product: CCN(CC)CCCCOc1ccc(C#N)cc1

Procedure:
According to a similar manner as that in Reference Example 78 except that 4-cyanophenol, 1-bromo-4-chlorobutane, and diethylamine were used, 4-[4-(diethylamino)butoxy]benzonitrile (quantitative) was obtained as a crude product.
Reaction SMILES: C(OC([N:11]1[CH2:15][C:14](=[CH2:16])[N:13]=[C:12]1[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25])=O)C1C=CC=CC=1.[N:26]1[C:35]2[C:30](=[N:31][C:32](C=O)=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1.N1CCCCC1.CC([OH:47])C>>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][NH:17][C:12]1[NH:13][C:14](=[CH:16][C:32]2[CH:33]=[CH:34][C:35]3[C:30](=[CH:29][CH:28]=[CH:27][N:26]=3)[N:31]=2)[C:15](=[O:47])[N:11]=1
Reactant: CC(C)O
Reactant: O=Cc1ccc2ncccc2n1
Reactant: C=C1CN(C(=O)OCc2ccccc2)C(NCc2ccccc2Cl)=N1
Solvent: C1CCNCC1
Product: O=C1N=C(NCc2ccccc2Cl)NC1=Cc1ccc2ncccc2n1

Procedure:
To a mixture of 2-(2-chloro-benzylamino)-4-methylene-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester (62.0 mg, 0.17 mmol), 1,5-naphthyridine-6-carboxaldehyde (31.6 mg, 0.2 mmol) and iPrOH (5.0 mL) in a 25-mL round bottom flask was added piperidine (0.05 mL) and the suspension was then heated under refluxing for 3.5 hrs to give a suspension. The reaction mixture was concentrated to give a brown solid which was washed with MeOH and ether. The solid was collected by filtration to give 2-(2-chloro-benzylamino)-5-[1,5]-naphthyridin-2-ylmethylene-1,5-dihydro-imidazol-4-one as a brown solid, (10.1 mg, 16.3%). HR-ES (+) m/e calcd. for C19H14ClN5OS: (M+H)+ 364.0960. Found: 364.0959.
Reaction SMILES: [C:1]1([C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[S:27](Cl)(=[O:29])=[O:28].[OH-].[Na+]>O1CCCC1.C(Cl)Cl>[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[S:27]([OH:29])(=[O:8])=[O:28].[C:1]1([C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: O=C(c1ccccc1)C(O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=S(=O)(O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.1 mole of benzoin and 0.12 mole of β-naphthalenesulfonyl chloride are dissolved at room temperature in 500 ml of tetrahydrofuran. After addition of 0.15 mole of 30% sodium hydroxide solution the mixture is stirred for 8 hours at room temperature. The reaction solution is diluted with 200 ml of methylene chloride and the organic phase is washed once with NaHCO3 solution and once with water. The organic solution is dried over MgSO4, dried and concentrated by evaporation. The residue is crystallised from hexane/ethyl acetate. The resultant sulfonate melts at 107°-109° C.
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)C=CN=1.[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]([C:46]([CH3:49])([CH3:48])[CH3:47])=[N:43][C:42]=2[C:50]2[C:51]([F:58])=[C:52]([NH2:57])[CH:53]=[CH:54][C:55]=2[F:56])[CH:38]=[CH:37][N:36]=1.[F:59][C:60]1[CH:61]=[C:62]([S:66](Cl)(=[O:68])=[O:67])[CH:63]=[CH:64][CH:65]=1>>[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]([C:46]([CH3:49])([CH3:48])[CH3:47])=[N:43][C:42]=2[C:50]2[C:51]([F:58])=[C:52]([NH:57][S:66]([C:62]3[CH:63]=[CH:64][CH:65]=[C:60]([F:59])[CH:61]=3)(=[O:68])=[O:67])[CH:53]=[CH:54][C:55]=2[F:56])[CH:38]=[CH:37][N:36]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: CC(C)(C)c1nc(-c2c(F)ccc(N)c2F)c(-c2ccnc(Cl)n2)s1
Agent: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Product: CC(C)(C)c1nc(-c2c(F)ccc(NS(=O)(=O)c3cccc(F)c3)c2F)c(-c2ccnc(Cl)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using {3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}amine (500 mg, 1.313 mmol) and 3-fluorobenzenesulfonyl chloride (0.210 mL, 1.575 mmol), the title compound was obtained as an yellow foam (690 mg, 98% yield).
Reaction SMILES: [F:1][CH:2]([F:17])[C:3]([CH3:16])([CH3:15])[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9](Br)[CH:8]=1.[C:18]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+].COCCOCCN(CCOCCOC)CCOCCOC>C(OCC)(=O)C.CN(C)C=O>[F:1][CH:2]([F:17])[C:3]([CH3:16])([CH3:15])[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([N:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18](=[O:20])[CH3:19])[CH:8]=1
Reactant: CC(C)(COCc1ccc(F)c(Br)c1)C(F)F
Reactant: CC(=O)Nc1ccccc1
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)N(c1ccccc1)c1cc(COCC(C)(C)C(F)F)ccc1F
Yield: 38.6 %

Procedure:
A mixture of 1,1-difluoro-2,2-dimethyl-3-(3-bromo-4-fluorobenzyloxy)propane (1.5 g), acetanilide (0.716 g), cuprous chloride (0.1 g); potassium carbonate (0.67 g), dry N,N-dimethylformamide (10 cm3) and tri[2-(2-methoxyethoxy)ethyl]amine (catalytic quantity) was heated at 158° C. for 4 days under an atmosphere of nitrogen; the mixture was then stood at the ambient temperature for 1 week. The combined organic extracts were washed with water and brine and dried over anhydrous magnesium sulphate. Evaporation of the solvent under reduced pressure gave a dark oil which was subjected to flash column chromatography on a silica gel support, eluting firstly with petroleum ether (boiling range 40°-6° C.) containing 2% by volume ethyl acetate (to give starting materials and a small amount of the deacylated product) and secondly with petroleum ether (boiling range 40°-60° C.) containing 50% by volume ethyl acetate, to give the title compound as a dark oil (0.68 g).