Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[N:9]=[C:8]([CH2:10][N:11]([CH3:13])[CH3:12])[N:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:6]=1)=O.[NH3:29]>CO>[ClH:20].[C:21]([C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[N:7]1[C:8]([CH2:10][N:11]([CH3:13])[CH3:12])=[N:9][C:5]([C:3]([NH2:29])=[O:2])=[N:6]1)(=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: N
Reactant: COC(=O)c1nc(CN(C)C)n(-c2ccc(Cl)cc2C(=O)c2ccccc2)n1
Solvent: CO
Product: CN(C)Cc1nc(C(N)=O)nn1-c1ccc(Cl)cc1C(=O)c1ccccc1
Product: Cl
Temperature: 25 °C
Reaction time: 7 h

Procedure:
17.5 g (0.044 mole) of 1-(2-benzoyl-4-chlorophenyl)-5-[(dimethylamino)-methyl]-1H-1,2,4-triazole-3-carboxylic acid methyl ester (see Example 2) is covered over with 850 ml of methanol and 175 ml of concentrated aqueous ammonia solution. The reaction solution is stirred for 7 hours at room temperature, and afterwards concentrated in vacuo to dryness. Water is added to the residue, and extraction is performed twice with methylene chloride. The organic phase is washed twice with water and once with saturated sodium chloride solution; it is dried over sodium sulphate and concentrated in vacuo to dryness. The residue is dissolved in 300 ml of ethyl acetate, and ethereal hydrogen chloride solution is added until the pH-value has reached 2. The crystalline product is filtered with suction and washed with ethyl acetate and ether. After drying in vacuum, there is obtained 1-(2-benzoyl-4-chlorophenyl)-5-[(dimethylamino)-methyl]-1H-1,2,4-triazole-3-carboxamide-hydrochloride, m.p. 250°-255° with decomposition.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C:21]1=[O:26])(=[O:19])=[O:18].[CH2:27]([O:34][C:35]([NH:37][C:38]1[NH:39][C:40](=[O:51])[C:41]2[N:42]=[CH:43][N:44]([CH2:47][C:48](O)=[O:49])[C:45]=2[N:46]=1)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][N:23]([C:48](=[O:49])[CH2:47][N:44]2[CH:43]=[N:42][C:41]3[C:40](=[O:51])[NH:39][C:38]([NH:37][C:35]([O:34][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:36])=[N:46][C:45]2=3)[CH2:22][C:21]1=[O:26])(=[O:19])=[O:18]
Reactant: O=C(O)Cn1cnc2c(=O)[nH]c(NC(=O)OCc3ccccc3)nc21
Reactant: O=C1CNCCN1S(=O)(=O)c1nc2ccccc2s1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1nc2c(ncn2CC(=O)N2CCN(S(=O)(=O)c3nc4ccccc4s3)C(=O)C2)c(=O)[nH]1)OCc1ccccc1

Procedure:
The title compound was synthesized by the reaction of 1-(benzothiazole-2-sulfonyl)-piperazin-2-one trifluoroacetic acid salt with [2-N-(benzyloxycarbonyl)-guanin-9-yl]-acetic acid as per the procedure of Example 52. 1H NMR (500 MHz; DMSO-d6) δ 11.35 (bs, 2H), 8.34 (m, 1H), 8.25 (m, 1H), 7.81 (s, 0.6H), 7.77 (s, 0.4H), 7.71 (m, 2H), 7.45˜7.30 (m, 5H), 5.23 (s, 2H), 5.13 (s, 1.2H), 5.02 (s, 0.8H), 4.51 (s, 0.8H), 4.27 (s, 1.2H), 4.24 (t, 1.2H), 4.08 (t, 0.8H), 4.03 (t, 1.2H), 3.85 (t, 0.8H).
Reaction SMILES: [CH2:1]([C:9]1[N:10]=[C:11]([NH:14][C:15]2[N:20]=[CH:19][C:18]([S:21]CCC(OC)=O)=[CH:17][C:16]=2[O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[S:12][CH:13]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CC([O-])(C)C.[K+].CS(O[CH:46]([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][N:61]=1)[CH:47]1[CH2:52][CH2:51][N:50]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:49][CH2:48]1)(=O)=O>>[CH2:1]([C:9]1[N:10]=[C:11]([NH:14][C:15]2[N:20]=[CH:19][C:18]([S:21][CH:46]([C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][N:61]=3)[CH:47]3[CH2:48][CH2:49][N:50]([C:53]([O:55][C:56]([CH3:57])([CH3:58])[CH3:59])=[O:54])[CH2:51][CH2:52]3)=[CH:17][C:16]=2[O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[S:12][CH:13]=1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)CCSc1cnc(Nc2nc(CCc3ccccc3)cs2)c(Oc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C(OS(C)(=O)=O)c2ccccn2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CCC(C(Sc2cnc(Nc3nc(CCc4ccccc4)cs3)c(Oc3ccccc3)c2)c2ccccn2)CC1

Procedure:
Prepared according to the method of Example 16 from methyl 3-(6-(4-phenethylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)propanoate, potassium 2-methylpropan-2-olate, and tert-butyl 4-((methylsulfonyloxy)(pyridin-2-yl)methyl)piperidine-1-carboxylate.
Reaction SMILES: [CH:1]([NH:3][C@@H:4]1[C:34](=[O:35])[N:6]2[C:7]([C:22]([O:24]CC3C=CC(OC)=CC=3)=[O:23])=[C:8](/[CH:11]=[CH:12]/[CH2:13][N+:14]([CH2:18][C:19](=[O:21])[NH2:20])([CH2:16][CH3:17])[CH3:15])[CH2:9][S:10][C@H:5]12)=[O:2].[I-].[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>C1(OC)C=CC=CC=1>[F:37][C:38]([F:43])([F:42])[C:39]([O-:41])=[O:40].[CH:1]([NH:3][C@@H:4]1[C:34](=[O:35])[N:6]2[C:7]([C:22]([OH:24])=[O:23])=[C:8](/[CH:11]=[CH:12]/[CH2:13][N+:14]([CH2:18][C:19](=[O:21])[NH2:20])([CH2:16][CH3:17])[CH3:15])[CH2:9][S:10][C@H:5]12)=[O:2]
Reactant: CC[N+](C)(C/C=C/C1=C(C(=O)OCc2ccc(OC)cc2)N2C(=O)[C@@H](NC=O)[C@H]2SC1)CC(N)=O
Reactant: O=C(O)C(F)(F)F
Agent: [I-]
Solvent: COc1ccccc1
Product: CC[N+](C)(C/C=C/C1=C(C(=O)O)N2C(=O)[C@@H](NC=O)[C@H]2SC1)CC(N)=O
Product: O=C([O-])C(F)(F)F

Procedure:
In a similar manner as in Example 5, the compound (3.4 g) of Example 25 was suspended in anisole (20 ml), followed by an addition of trifluoroacetic acid (23 ml) to obtain the target compound (2.04 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[CH3:19][C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1)=[O:21]>C(O)CCC>[NH:22]([C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:4][N:3]=2)=[CH:25][CH:24]=1)[C:20]([CH3:19])=[O:21]
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Reactant: CC(=O)Nc1ccc(N)cc1
Solvent: CCCCO
Product: CC(=O)Nc1ccc(Nc2nnc(Cc3ccncc3)c3ccccc23)cc1
Temperature: 110 °C

Procedure:
A mixture of 0.511 g (2 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine, 0.901 g (6 mmol) 4-aminoacetanilide and 5 ml 1-butanol is heated for 3 h at 110° C. The reaction mixture is then evaporated under vacuum, the crystalline residue is taken up in a mixture of 20 ml dichloromethane and 10 ml 20% aqueous potassium carbonate solution while stirring, then filtered and the filter residue washed with water and dichloromethane. After recrystallization from dichloromethane/methanol and drying under HV (8 h, 100° C.), title compound is obtained with a methanol content of 1.27%;
Reaction SMILES: [CH3:1][C@H:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1)([O-:31])=[O:30].COCCOC(N=NC(OCCOC)=O)=O>C1(C)C=CC=CC=1.O>[N+:29]([C:32]1[CH:33]=[CH:34][C:35]([C:36]([O:9][C@@H:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:1])=[O:37])=[CH:39][CH:40]=1)([O-:31])=[O:30].[CH3:1][C@H:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CCCCCC[C@H](C)O
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCC[C@@H](C)OC(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 3.5 h

Procedure:
After (S)-2-octanol (300 mg, 2.30 mmol), triphenylphosphine (725 mg, 2.76 mmol), 4-nitrobenzoic acid (463 mg, 2.76 mmol), and toluene (12 ml) were added to a 50 ml flask, azodicarboxylic acid bis(2-methoxyethyl) ester (648 mg, 2.76 mmol) dissolved in toluene (6 ml) was added dropwise thereto at 20° C., and the reaction was allowed to proceed for 3.5 hours. Water (10 mL) was added, and separation was carried out. Then, the aqueous layer was extracted using toluene (10 mL,×1). The resulting organic layer was collectively washed with water (10 mL) and saturated salt water (10 ml), and dehumidified with anhydrous magnesium sulfate. Subsequently, a crude product obtained by concentration was purified by column chromatography (silica gel, 5% ethyl acetate-hexane solution) to give (R)-2-(4-nitrobenzoyloxy)octane as a pale yellow liquid substance (615 mg, yield: 96%/(S)-2-octanol).
Reaction SMILES: [CH3:1][C:2]1[N:6](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:5]=[N:4][C:3]=1/[CH:26]=[CH:27]/[C:28]([C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1)=[O:29].[C:40]([O-:47])(=[O:46])/[CH:41]=[CH:42]\[C:43]([O-:45])=[O:44]>>[C:40]([OH:47])(=[O:46])/[CH:41]=[CH:42]\[C:43]([OH:45])=[O:44].[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH:26]=[CH:27][C:28]([C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1)=[O:29]
Reactant: Cc1c(/C=C/C(=O)c2ccc3ccccc3c2)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C([O-])/C=C\C(=O)[O-]
Product: Cc1[nH]cnc1C=CC(=O)c1ccc2ccccc2c1
Product: O=C(O)/C=C\C(=O)O

Procedure:
The deprotection of (E)-3-(5-methyl-1-(triphenylmethy)-1H-imidazol-4-yl]-1-(2-naphthalenyl)-2-propen-1-one (1.25 g) followed by maleate formation gave the title compound (0.75 g), m.p. 190°-191° (decomp.).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:5]([CH2:14]O)[CH2:4][CH2:3]1.O=S(Cl)[Cl:18]>C(Cl)Cl>[Cl:18][CH2:14][C:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][C:6]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[ClH:18]
Reactant: O=S(Cl)Cl
Reactant: CN1CCC(CO)=C(c2ccccc2)C1
Solvent: ClCCl
Product: CN1CCC(CCl)=C(c2ccccc2)C1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (1-methyl-5-phenyl-1,2,3,6-tetrahydropyridin-4-yl)methanol (130 mg, 0.64 mmol) in DCM (4 mL) was added SOCl2 (1.16 mL, 16 mmol) at room temperature, after stirred at room temperature for 30 min, the mixture was concentrated, dried under high vacuum to give 4-(chloromethyl)-1-methyl-5-phenyl-1,2,3,6-tetrahydropyridine as crude HCl salt.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:17](Br)[CH:18]=[CH2:19]>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][O:11][CH2:19][CH:18]=[CH2:17])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 0 °C

Procedure:
N-tert-butoxycarbonyl L-serine (27.04 g, 0.1318 mol) was dissolved in DMF (220 mL). The solution was cooled to 0° C. (icebath) before sodium hydride (60% dispersion in mineral oil, 11.59 g, 0.2898 mol) was added slowly under stirring. After gas evolution had ceased allyl bromide (17.54 g, 0.1450 mol) was added dropwise and the reaction mixture stirred for 18 hours at room temperature. The solvent was evaporated and the residue dissolved in H2O (500 mL). The solution was washed with Et2O (2×250 mL), cooled to 0° C. (icebath) and acidified to pH 2.5 by addition of 2M aqueous H2SO4. The resulting solution/suspension was extracted with EtOAc (5×250 mL). The combined organic extracts were dried with anhydrous MgSO4 and the solvent evaporated overnight affording the title compound as a slightly yellow-orange viscous liquid (26.86 g, 83%) with spectral characteristics in accordance with published data;3,4 δH (200 MHz; d6-DMSO) 12.52 (1H, br s, COOH), 6.84 (1H, d, J 8, NH), 5.81 (1H, ddt, J 5, 10 and 17, CH═CH2), 5.20 (1H, ddd, J 1, 3 and 17, CH═CHH), 5.09 (1H, ddd, J 1, 3 and 10, CH═CHH), 4.10 (1H, dt, J 5 and 8, CαH), 3.96-3.92 (2H, dt, J 1 and 5, CH2CH═CH2), 3.56 (2H, d, J 5, CH2), 1.34 (9H, s, (CH3)3); δC (75 MHz; d6-DMSO) 171.9, 155.3, 134.8, 116.5, 78.1, 71.0, 69.1, 53.7, 28.1; m/z (ESI) 268.0 ([M+Na]+)
Reaction SMILES: [C:1]([O:7][CH:8]([CH3:10])[CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH:11](OCC)(OCC)[O:12][CH2:13][CH3:14].C(OC(=O)C)(=O)C>>[CH2:13]([O:12][CH:11]=[CH:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])[CH3:14]
Reactant: CCOC(OCC)OCC
Reactant: CC(=O)CC(=O)OC(C)C
Solvent: CC(=O)OC(C)=O
Product: CCOC=CC(=O)CC(=O)OC(C)C

Procedure:
From isopropyl acetoacetate (28.8 g, 0.20 mol) which can be made by the process described by Lawesson et al., Organic Synthesis, Coll. Vol. V, 155-157 (1973), triethyl orthoformate (29.6 g, 0.20 mol) and acetic anhydride (41 g, 0.40 mol): 14.3 g, 35.7%; bp=85°-90° C. at 0.20 mm Hg; NMR (CDCl3) δ 1.3-1.6 (m, 9H), 2.3-2.6 (d, 3H), 4.1-4.5 (m, 2H), 5.0-5.4 (m, 1H), 7.6-7.8 (d, 1H).
Reaction SMILES: COC(C[CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[N:7]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=O.[OH-:28].[Li+].C1[CH2:34][O:33]CC1.O>>[C:34]([CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([N:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[N:7]1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([OH:33])=[O:28]
Reactant: COC(=O)CC1c2ccccc2N=C(N2CCCCC2)N1c1ccccc1
Reactant: C1CCOC1
Reactant: [OH-]
Agent: [Li+]
Solvent: O
Product: O=C(O)C1c2ccccc2N=C(N2CCCCC2)N1c1ccccc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
The compound (6) (0.235 g, 0.645 mmol) was dissolved in 10 ml of THF/water (1:1) and a hydrate of lithium hydroxide (0.135 g, 3.23 mmol) was added thereto at a room temperature. The reaction mixture was stirred at 60° C. for 2 hours. After the reaction was completed, the pH of the reaction mixture was adjusted to 3˜4 and the reaction mixture was extracted with dichloromethane three times. An organic layer was dried with anhydrous magnesium sulfate and the solvent was removed under reduced pressure to quantitatively obtain the title compound in the form of a white crystal (7) (mp 238° C.).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[CH:7]=[CH:6][C:3]=1[C:4]#N.[OH-:19].[Na+].Cl.[OH2:22]>>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[CH:7]=[CH:6][C:3]=1[C:4]([OH:22])=[O:19]
Reactant: N#Cc1ccc(OCc2cccc(F)c2)cc1F
Reactant: [OH-]
Reactant: O
Agent: Cl
Agent: [Na+]
Product: O=C(O)c1ccc(OCc2cccc(F)c2)cc1F
Temperature: 25 °C
Yield: 53 %

Procedure:
A suspension of 2-fluoro-4-(3-fluoro-benzyloxy)-benzonitrile (24.5 g, 100 mmol) and sodium hydroxide (30 g, 750 mmol) in water (300 mL) was heated under reflux for 16 h. After cooling to room temperature the suspension was acidified to pH 2 with concentrated hydrochloric acid. The resulting mixture was diluted with water (100 mL) and extracted with ether (3×400 mL). The combined organic extracts were then washed with water and brine and then dried over sodium sulfate. Filtration and half evaporation of the filtrate resulted in the formation of a white precipitate which was filtered off to afford the title compound (14 g, 53%) as white crystals after recrystallisation from cyclohexane: ethyl acetate. MS: m/e=263.1 (M−H−)
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:20]3[CH:25]=[CH:24][N:23]=[C:22](S(C)=O)[N:21]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13](S(C)=O)[N:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([NH:36][C:2]1[N:7]2[N:8]=[C:9]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:36][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:21]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:36][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NCc1ccccc1
Reactant: CS(=O)c1nccc(-c2nn3c(Cl)cccc3c2-c2ccnc(S(C)=O)n2)n1
Product: c1ccc(CNc2nccc(-c3nn4c(NCc5ccccc5)cccc4c3-c3ccnc(NCc4ccccc4)n3)n2)cc1

Procedure:
N-Benzyl-2,3-bis[2-(benzylamino)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-7-amine was prepared by treating 7-chloro-2,3-bis[2-(methylsulfinyl)pyrimidin-4-yl]pyrazolo[1,5-a]pyridine with benzylamine as described in Example 7. 1H NMR, (400 MHz, CDCl3): δ 8.37 (d, 1H), 8.02 (d, 1H), 7.16–7.40 (m, 16H), 7.12 (t, 1H), 7.02 (bs, 1H), 6.63 (d, 1H), 6.48 (t, 1H), 5.96 (d, 1H), 5.58 (bs, 1H), 5.46 (1H), 4.65 (d, 2H), 4.38–4.62 (m, 4H); MS m/z 590 (M+1).
Reaction SMILES: O1CCOCC1.Cl[C:8]1[CH:13]=[C:12]([CH:14]([S:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[C:11]([Cl:31])=[CH:10][N:9]=1.[NH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1>CO>[Cl:31][C:11]1[C:12]([CH:14]([S:23][C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])=[CH:13][C:8]([NH:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)=[N:9][CH:10]=1
Reactant: NCCc1ccncc1
Reactant: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(Cl)ncc2Cl)c1
Solvent: C1COCCO1
Solvent: CO
Product: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(NCCc3ccncc3)ncc2Cl)c1
Temperature: 25 °C
Yield: 43 %

Procedure:
A dioxane (1.5 ml) solution of the 2,5-dichloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]pyridine (220 mg, 0.528 mmol) obtained in Example 54 and 4-(2-aminoethyl)pyridine (400 μl) was heated at 120° C. for 3 days in a sealed tube. The reaction mixture was cooled to room temperature and then, concentrated under reduced pressure. Water was added to the residue thus obtained, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography. The fraction obtained from the methanol:methylene chloride=1:30 eluate was concentrated under reduced pressure to give the title compound (114 mg, 0.227 mmol, 43%) as a colorless oil.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11]1[CH:16]=[C:15]([C:17]([CH3:21])([CH3:20])[CH2:18][OH:19])[CH:14]=[CH:13][C:12]=1[I:22])[CH3:9].[C]=[O:24].C[CH2:26][O:27][CH2:28]C>CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:8]([O:10][C:11]1[CH:16]=[C:15]([C:17]([CH3:21])([CH3:20])[CH2:18][OH:19])[CH:14]=[CH:13][C:12]=1[C:26]([O:27][CH3:28])=[O:24])[CH3:9].[CH2:8]([O:10][C:11]1[CH:16]=[C:15]([C:17]([CH3:21])([CH3:20])[CH2:18][OH:19])[CH:14]=[CH:13][C:12]=1[I:22])[CH3:9]
Reactant: CCOCC
Reactant: [C]=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCOc1cc(C(C)(C)CO)ccc1I
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOc1cc(C(C)(C)CO)ccc1C(=O)OC
Yield: 48 %

Procedure:
Triethylamine (3.5 mL, 25.1 mmol) was added to a solution 2-ethoxy-4-(2-hydroxy-1,1-dimethylethyl)iodobenzene (4.0 g, 12.5 mmol) in methanol (20 mL) under an atmosphere of nitrogen. The reaction was purged twice with carbon monoxide, and palladium (II) acetate (0.2 g, 0.9 mmol) was added. The reaction was stirred at 80° C. for 18 h under a positive pressure of carbon monoxide. The reaction was diluted with ether, washed with 10% hydrochloric acid, aqueous sodium bicarbonate, brine, dried over anhydrous magnesium sulfate and concentrated. Purification of the crude residue by flash chromatography over silica gel using 20-75% ethyl acetate in hexanes gave methyl 2-ethoxy-4-(2-hydroxy-1,1-dimethylethyl)benzoate (1.5 g, 48%) as a yellow oil and 0.91 g of unreacted 2-ethoxy-4-(2-hydroxy-1,1-dimethylethyl)iodobenzene.
Reaction SMILES: CNCCNCCNC.CNC.[CH3:13][N:14]([CH3:22])[P:15]([N:19]([CH3:21])[CH3:20])[N:16]([CH3:18])[CH3:17]>>[CH3:13][N:14]1[CH2:22][CH2:21][N:19]2[P:15]1[N:16]([CH3:18])[CH2:17][CH2:20]2
Reactant: CN(C)P(N(C)C)N(C)C
Agent: CNC
Agent: CNCCNCCNC
Product: CN1CCN2CCN(C)P12
Temperature: 125 °C
Yield: 94.8 %

Procedure:
A mixture of 5.00 g of 1,7-dimethyldiethylenetriamine and 6.22 g of hexamethylphosphorous triamide is heated to 80° C., at which temperature dimethylamine begins to be evolved. Evolution of dimethylamine continues for about 1 hour, during which time the temperature is gradually raised to 125° C. The mixture is distilled to give 5.75 g (95%) of 2,8-dimethyl-2,5,8-triaza-1-phosphabicyclo[3.3.0]octane as a clear, colorless liquid, which boils at 55°-65° C. at 0.30 mm. The nuclear magnetic-resonance spectrum (C6D6 /TMS) of the product shows a highly split pattern from δ 2.0 to 4.5 and has the expected sharp doublet for the --CH3 groups at δ2.55, J = 10 Hz. The infrared absorption spectrum (neat) has absorptions at 3.5, 6.83, 6.91, 7.65, 7.80, 8.20, 8.68, 9.20, 9.70, 10.15, 10.4, 10.7, and 11.5 μ.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-:20].[Na+].[O:22]1[CH:26]=[CH:25][C:24]([C:27]([CH:29]=[CH2:30])=O)=[CH:23]1.[H][H]>>[O:22]1[CH:26]=[CH:25][C:24]([CH:27]=[CH:29][CH2:30][OH:20])=[CH:23]1
Reactant: [OH-]
Reactant: [H][H]
Reactant: C=CC(=O)c1ccoc1
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: OCC=Cc1ccoc1
Yield: 3804 %

Procedure:
Into a stainless steel autoclave equipped with a glass inner tube, Cu(NO3)(PPh3)2 (11.7 mg, 0.018 mmol) and triphenylphosphine (28.3 mg, 0.108 mmol) were introduced. The inside of the autoclave was then replaced with nitrogen. To the autoclave, an ethanolic solution of sodium hydroxide (0.03 M) (6.0 mL, 0.18 mmol) and 3-furylacrolein (1.24 g, 9 mmol) were added, and stirring was performed at a hydrogen pressure of 5 MPa at 50° C. for 16 hours. The hydrogen was released with great care, and the conversion was analyzed by GC (91%). The contents were concentrated, and then purified by silica gel chromatography. Thus, 850 mg of the 3-furylallyl alcohol was obtained (yield: 67%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12](=O)[CH2:13][CH2:14][C:5]=3[C:4]=2[CH:3]=1.[NH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>C(#N)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:11][N:7]1[C:8]2[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][C:4]=2[C:5]2[CH2:14][CH2:13][C:12](=[N:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:6]1=2
Reactant: Cn1c2c(c3cc(O)ccc31)CCC2=O
Reactant: NCCN1CCOCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CC#N
Product: Cn1c2c(c3cc(O)ccc31)CCC2=NCCN1CCOCC1
Reaction time: 2 h
Yield: 9.6 %

Procedure:
To a stirred solution of 7-hydroxy-4-methyl-1,4-dihydrocyclopent[b]indol-3-one (8.00 g) in acetonitrile (125 ml) under nitrogen were added 4-(2-aminoethyl)morpholine (10.35 g) and titanium isopropoxide (22.60 g). The reaction was monitored by TLC and after two hours additional equivalents of 4-(2-aminoethyl)morpholine (5.17 g) and titanium isopropoxide (1 1.30 g) were added. Fourteen hours later the reaction was quenched with water (200 ml). EtOAc (200 ml) was added and the mixture stirred for fifteen minutes and filtered. The layers were separated, the aqueous layer was extracted with ethyl acetate, and the combined organics were dried (Na2SO4) and concentrated in vacuo. The resulting yellow solid was dried yielding 6.65 g. of product. A 2 g sample of the solid was further purified by crystallization from CH2Cl2 /hexane to afford 1.2 g of 4-methyl-3-[2-(4-morpholinyl)ethyl]imino-1,2,3,4-tetrahydrocyclopent[b]indol-7-ol.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH2:24][C:25]#[N:26])(=[O:23])=[O:22])=[CH:17][CH:16]=1.O>C(O)C>[C:1]([C:5]1[CH:6]=[C:7](/[CH:8]=[C:24](/[S:21]([C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=2)(=[O:23])=[O:22])\[C:25]#[N:26])[CH:10]=[CH:11][C:12]=1[OH:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#CCS(=O)(=O)c1ccc(F)cc1
Reactant: CC(C)(C)c1cc(C=O)ccc1O
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(/C=C(\C#N)S(=O)(=O)c2ccc(F)cc2)ccc1O
Yield: 82.2 %

Procedure:
The reaction mixture of 178.0 mg of 3-t-butyl-4-hydroxybenzaldehyde and 219.0 mg of (4-fluorobenzenesulphonyl)acetonitrile in 2.0 mL of ethanol containing 0.01 mL piperidine was refluxed for 4 h and cooled down. To the above reaction mixture was added water and then the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. The resulting residue was purified on silica gel column eluting with ethyl acetate-hexane (1:6) to give 295.0 mg of the titled compound.