Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10].C(N(CC)CC)C.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>C(OCC)(=O)C>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH:2][CH2:3][CH:4]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)CCCCC(CN)c1cccnc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)CCCCC(CNS(=O)(=O)c1ccc(Cl)cc1)c1cccnc1
Reaction time: 2 h

Procedure:
Methyl 7-amino-6-(3-pyridyl)-heptanoate hydrochloride (8.0 g) is suspended in 200 mL of ethyl acetate, 15 mL of triethylamine is added, and then a solution of 10 g of 4-chlorophenylsulfonyl chloride in 100 mL of ethyl acetate is added dropwise over a period of 0.5 hour. The reaction is then stirred for 2 hours and is extracted with 1N aqueous sodium hydroxide, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated. The residue is chromatographed over activated magnesium silicate (Florisil) and eluted with ethyl acetate to yield methyl 7-(p-chlorophenylsulfonamido)-6-(3-pyridyl)-heptanoate as an oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]=[CH:8][CH2:9][CH2:10]O)=[CH:4][CH:3]=1.[OH-:12].[Na+].Cl.[Cl-].[Na+]>O>[CH2:8]([CH:7]1[C:2]([OH:6])([CH3:1])[CH:3]=[CH:4][C:5]1=[O:12])[CH:9]=[CH2:10]
Reactant: Cc1ccc(C=CCCO)o1
Reactant: [OH-]
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: C=CCC1C(=O)C=CC1(C)O
Temperature: 40 °C

Procedure:
In a reaction vessel, water (1 liter) and 5-methyl-2-furylallylcarbinol (25 g) were charged, and the pH value was adjusted to 5.5 with an aqueous 1 N NaOH solution and an aqueous 1 N HCl solution. The temperature was elevated up to 100° C. to reflux, and the mixture was stirred under reflux for 12 hours while maintaining a pH value of 5.0 to 5.5 by the addition of an aqueous 1 N NaOH solution and an aqueous 1 N HCl solution. After cooling to 40° C., the reaction mixture was neutralized with an aqueous 1 N NaOH solution, and sodium chloride (300 g) was added thereto. The mixture was extracted with toluene (100 ml) five times. From the extract, toluene was removed by distillation at 60° C. under reduced pressure to give an oily substance (23 g), which was subjected to distillation under reduced pressure to obtain 2-allyl-3-hydroxy-3-methyl-4-cyclopentenone (21.3 g). Yield, 85.2%. B.P., 77° C./0.1 mmHg. NMR spectrum (CCl4, internal standard TMS, δ ppm, 60 MHz): 7.32 (d, 1H, 4-H); 5.92 (d, 1H, 5-H); 5.81 (complex m, 1H, --CH2 --CH=CHaHb); 5.12 (m, 1H, --CH2 --CH=CHaHb); 4.93 (m, 1H, --CH2 --CH=CHaHb); 4.12 (broad s, 1H, 3-OH); 2.37 (m, 3H, 2-H, s, --CH2 --CH=CHaHb); 1.28 (s, 3H, 3--CH3).
Reaction SMILES: [Br:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([CH:12]=O)=[CH:4][CH:3]=1.[NH2:14][OH:15]>C(O)C>[Br:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([CH:12]=[N:14][OH:15])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)c2ncccc12
Reactant: NO
Solvent: CCO
Product: ON=Cc1ccc(Br)c2ncccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 8-bromo-5-quinolinecarboxaldehyde (i.e. the product from Step B) (1.7 g, 7.1 mmol) in ethanol (30 mL) was added an aqueous solution of hydroxylamine (0.7 mL, 50% in water). After stirring at room temperature for 2 h, the reaction mixture was concentrated under reduced pressure to provide the title compound as a pale yellow solid (1.8 g).
Reaction SMILES: [C:1]1([C:8]2[C:9]([OH:14])=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]([OH:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17]>N1C=CC=CC=1>[C:16](=[O:17])([O:18][CH2:19][CH3:20])[O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:16](=[O:17])[O:18][CH2:19][CH3:20]
Reactant: CCOC(=O)Cl
Reactant: Oc1ccccc1-c1ccccc1O
Solvent: c1ccncc1
Product: CCOC(=O)Oc1ccccc1-c1ccccc1OC(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a round-bottom flask is charged biphenyl-2,2′-diol (7.45 g, 40 mmol) and pyridine (50 mL). The flask is immersed in an ice-water bath and ethyl chloroformate (9.48 mL, 100 mmol) is added dropwise. After gradually warming to room temperature, the mixture is stirred overnight. The volatiles are removed in vacuo, and the residue is suspended in 100 mL of ethyl acetate. After filtration, the filtrate is concentrated and purified by flash chromatography. The product is obtained as a colorless oil. Yield: 5.0 g; 1H NMR (500 MHz, CDCl3, ppm) δ 7.23-7.44 (m, 8H), 4.13 (q, 4H), 1.19 (t, 6H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH3:34][O:35][C:36]1[CH:41]=[C:40]([C@H:42]2[CH2:47][CH2:46][C@H:45]([N:48]3[CH2:53][CH2:52][N:51]([CH2:54][CH2:55][S:56]([CH3:59])(=[O:58])=[O:57])[CH2:50][CH2:49]3)[CH2:44][CH2:43]2)[CH:39]=[CH:38][C:37]=1[NH2:60].Cl.O1CCOCC1.C[O-].[Na+]>FC(F)(F)CO.CO.C(Cl)Cl.CCCCCC>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:60][C:37]3[CH:38]=[CH:39][C:40]([C@H:42]4[CH2:43][CH2:44][C@H:45]([N:48]5[CH2:49][CH2:50][N:51]([CH2:54][CH2:55][S:56]([CH3:59])(=[O:58])=[O:57])[CH2:52][CH2:53]5)[CH2:46][CH2:47]4)=[CH:41][C:36]=3[O:35][CH3:34])[N:7]=2)[CH:18]=1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Reactant: COc1cc([C@H]2CC[C@H](N3CCN(CCS(C)(=O)=O)CC3)CC2)ccc1N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Solvent: OCC(F)(F)F
Product: COc1cc([C@H]2CC[C@H](N3CCN(CCS(C)(=O)=O)CC3)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 175 °C

Procedure:
To 3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (50 mg, 0.11 mmol) and [2-(methyloxy)-4-(trans-4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}cyclohexyl)phenyl]amine (Example 93, step H) (43 mg, 0.11 mmol) in 2,2,2-trifluoroethanol (1.0 mL) was added 4 M HCl in dioxane (54 μL, 0.22 mmol). The mixture was stirred and heated on a Biotage microwave at 175° C. for 40 min, then cooled to rt. The mixture was neutralized with 0.5M sodium methoxide in MeOH. The mixture was concentrated under vacuum and the residue purified by silica gel chromatography to give a yellow oil. The oil was dissolved in minimal DCM, then hexane was added until a precipitate was formed. The slurry was cooled at −10° C. for 30 min, then poured through a Teflon filter, washing the solids with cold hexanes. The solids were dried under vacuum to give the title compound (50 mg, 0.06 mmol, 56%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 9.42 (d, 1H, J=6.23 Hz), 8.54 (s, 1H), 8.34 (s, 1H), 8.26 (d, 1H, J=5.31 Hz), 8.06 (d, 1H, J=7.69 Hz), 7.82 (d, 1H, J=7.51 Hz), 7.74 (d, 1H, J=8.97 Hz), 7.59-7.66 (m, 2H), 7.34-7.51 (m, 2H), 7.21 (t, 2H, J=8.06 Hz), 6.98 (t, 1H, J=6.78 Hz), 6.94 (s, 1H), 6.80 (d, 1H, J=8.06 Hz), 6.54 (d, 1H, J=5.13 Hz), 3.82 (s, 3H), 3.24-3.29 (m, 2H), 3.02 (s, 3H), 2.67 (t, 2H, J=6.50 Hz), 2.34-2.60 (m, 12H), 2.18 (s, 1H), 1.91-1.99 (m, 2H), 1.77-1.89 (m, 2H), 1.44-1.60 (m, 4H). MS (ESI): 821 [M+H]+.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:18]=[C:19]([S:28](=[O:31])(=[O:30])[NH2:29])[C:20]=1[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:9][NH:10]CC1C=CC=CC=1)[CH2:2][CH2:3][CH3:4]>COCCO.[Pd]>[CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:18]=[C:19]([S:28](=[O:31])(=[O:30])[NH2:29])[C:20]=1[O:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:9][NH2:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1cc(CNCc2ccccc2)cc(S(N)(=O)=O)c1Oc1ccccc1
Agent: [Pd]
Solvent: COCCO
Product: CCCCNc1cc(CN)cc(S(N)(=O)=O)c1Oc1ccccc1

Procedure:
To a solution of (3-n-butylamino-4-phenoxy-5-sulfamylbenzyl)benzylamine (8.8 g; prepared as described in Example 136) in 2-methoxyethanol (90 ml), palladium (10%) on carbon (4.0 g) is added and the mixture is hydrogenated. After about 5 hours the theoretical amount of hydrogen has been absorbed, and the mixture is heated on a steam-bath and filtered to remove the catalyst. The filtrate is evaporated in vacuo and the residue triturated with water to yield crude 3-n-butylamino-4-phenoxy-5-sulfamylbenzylamine. The crude amine is dissolved in formic acid (50 ml), whereafter the solution is evaporated in vacuo. The residue is recrystallized from a mixture of ethanol and 2-methoxyethanol to yield, after filtration and drying, 3-n-butylamino-4-phenoxy-5-sulfamylbenzylamine formate hemihydrate with a melting point of 224°-226° C.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]([N:9]1[C:17]2[C:12](=[C:13]([O:21][CH:22]([CH2:28][O:29]C(=O)C)[CH2:23][O:24]C(=O)C)[CH:14]=[CH:15][C:16]=2[N+:18]([O-:20])=[O:19])[CH2:11][CH2:10]1)=[O:8])=[N+:2]=[N-:3].[OH-].[Na+]>CO.O>[N:1]([CH2:4][CH2:5][CH2:6][C:7]([N:9]1[C:17]2[C:12](=[C:13]([O:21][CH:22]([CH2:28][OH:29])[CH2:23][OH:24])[CH:14]=[CH:15][C:16]=2[N+:18]([O-:20])=[O:19])[CH2:11][CH2:10]1)=[O:8])=[N+:2]=[N-:3]
Reactant: CC(=O)OCC(COC(C)=O)Oc1ccc([N+](=O)[O-])c2c1CCN2C(=O)CCCN=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: [N-]=[N+]=NCCCC(=O)N1CCc2c(OC(CO)CO)ccc([N+](=O)[O-])c21
Yield: 78.9 %

Procedure:
A solution of 26 (0.76 g, 1.7 mmol) in MeOH (85 mL), water (8.5 mL) and 1 M aq. NaOH (4.1 mL, 4.1 mmol) was stirred at room temperature for 2 min, quenched with 1 M citric acid (8.5 mL) and concentrated under reduced pressure to ˜20 mL. The solution was diluted with water (30 mL), washed with EtOAc (3×50 mL) and the combined organic washings were washed with saturated aq. NaHCO3 and brine, dried and evaporated to a brown viscous oil which after trituration with Et2O gave 27 (0.49 g, 78%) as yellow needles, mp 78-79° C. (EtOAc-hexanes); 1H NMR (500 MHz) δ 7.70 (d, J=9.2 Hz, 1H), 6.76 (d, J=9.2 Hz, 1H), 4.57 (quintet, J=4.8 Hz, 1H), 4.25 (d, J=8.1 Hz, 2H), 3.95 (dd, J=11.9, 4.8 Hz, 2H), 3.92 (dd, J=11.9, 4.8 Hz, 2H), 3.43 (t, J=6.4 Hz, 2H), 3.14 (t, J=8.0 Hz, 2H), 2.57 (t, J=6.9 Hz, 2H), 2.03 (t, J=7.6 Hz, 2H), 2.02 (quintet, J=6.4 Hz, 2H); HRMS (ESI) (m/z): Calcd for (C15H19N5O6+H)+, 366.1408. Found: 366.1427.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.O.C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:26]2[CH:34]=[C:33]3[C:29]([C:30]([NH:43][C:44](=[O:48])[CH2:45][CH2:46][CH3:47])=[N:31][N:32]3[CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])=[CH:28][CH:27]=2)O1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:26]2[CH:34]=[C:33]3[C:29]([C:30]([NH:43][C:44](=[O:48])[CH2:45][CH2:46][CH3:47])=[N:31][N:32]3[CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:40])[CH3:41])=[CH:28][CH:27]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(B3OC(C)(C)C(C)(C)O3)ccc12
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc([N+](=O)[O-])cc3)ccc12
Yield: 65.7 %

Procedure:
790 mg of 4-bromonitrobenzene, 10 cm3 of water, 646 mg of sodium carbonate and 190 mg of tetrakis(triphenylphosphine)palladium are added to 1 g of N-[6-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, prepared as described in Example 56, in 50 cm3 of dioxane. The reaction medium is then refluxed for 18 hours and is allowed to return to room temperature, 75 cm3 of ethyl acetate are then added and the organic phase is washed with 2×50 cm3 of distilled water and then with 50 cm3 of saturated aqueous sodium chloride solution. After drying over magnesium sulphate, filtering and concentrating to dryness under reduced pressure (2 kPa; 45° C.), the residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a cyclohexane/ethyl acetate mixture (80/20 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). 650 mg of N-[6-(4-nitrophenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide are obtained in the form of a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].C(OCC)(=O)C.CCCCCC>C(COC)OC.O.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>[Cl:1][C:2]1[CH:7]=[C:6]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[F:9])[N:5]=[CH:4][N:3]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: OB(O)c1ccccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: Fc1ccccc1-c1cc(Cl)ncn1

Procedure:
4,6-dichloropyrimidine (5.1 g, 34.1 mmol), 2-fluorophenyl boronic acid (5.0 g, 35.7 mmol, 1.05 equiv), Na2CO3 (6.9 g, 65.0 mmol, 1.8 equiv) and Pd(PPh3)2Cl2 (0.3 g, 0.4 mmol, 0.01 equiv) were refluxed in dimethoxyethane-water (204:69 mL) mixed solvent system for 4 h. Reaction was monitored by tlc (using ethyl acetate-hexane, 1:9). Reaction mixture was cooled and the subject compound was extracted using dichloromethane. Subject compound was purified by flash chromatography (2.5% ethyl acetate in n-hexane) to yield 3.7 g (Yield=52.0%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH:10]1(CC(C2C=CC=CN=2)O)C[CH2:11]1>>[CH3:1][C:2]1[N:7]=[C:6]([CH:8]([OH:9])[CH2:10][CH3:11])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(C=O)n1
Reactant: OC(CC1CC1)c1ccccn1
Product: CCC(O)c1cccc(C)n1

Procedure:
The title compound was prepared from 6-methyl-2-pyridinecarboxaldehyde (purchased from Tokyo Chemical Industry Co. Ltd.) using a procedure similar to the one described above for the synthesis of 2-cyclopropyl-1-(pyridin-2-yl)ethanol (Example 232, Step A). Mass Spectrum (ESI) m/z=151.4 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][O:5][C:6]1[CH:33]=[CH:32][CH:31]=[CH:30][C:7]=1[CH2:8][CH2:9][N:10]([CH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=1)[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17]C)=[O:16].O.[OH-].[Na+]>CO>[C:15]([CH2:14][CH2:13][CH2:12][CH2:11][N:10]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:28][CH:29]=1)[CH2:9][CH2:8][C:7]1[CH:30]=[CH:31][CH:32]=[CH:33][C:6]=1[O:5][CH2:4][C:3]1[CH:34]=[CH:35][CH:36]=[CH:37][C:2]=1[Cl:1])([OH:17])=[O:16]
Reactant: COC(=O)CCCCN(CCc1ccccc1OCc1ccccc1Cl)Cc1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCCN(CCc1ccccc1OCc1ccccc1Cl)Cc1ccc(C(=O)O)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
124.8 mg (0.238 mmol) of methyl 4-{[{2-[(2-chlorobenzyl)-oxy]phenethyl}(5-methoxy-5-oxopentyl)amino]methyl}benzoate from Ex. 1 are initially charged in 0.3 ml of methanol and 0.17 ml of water and admixed with 0.2 ml of a 40% strength sodium hydroxide solution. The mixture is stirred at 60° C. for one hour and then cooled, and the methanol is distilled off under reduced pressure. The aqueous phase is adjusted to pH 4 by addition of a citric acid/aqueous sodium hydroxide solution buffer and the resulting precipitate is separated off. Tituration with boiling cyclohexane gives a finely crystalline product.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([N:9]2[C:13](C)=[C:12]([C:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH:20]=3)[N:11]=[N:10]2)=[CH:7][CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.Cl[C:29]([O:31][CH2:32][CH2:33][O:34][CH3:35])=[O:30]>ClCCl>[Cl:2][C:3]1[C:8]([N:9]2[CH:13]=[C:12]([C:15]3[CH2:16][CH2:17][N:18]([C:29]([O:31][CH2:32][CH2:33][O:34][CH3:35])=[O:30])[CH2:19][CH:20]=3)[N:11]=[N:10]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COCCOC(=O)Cl
Reactant: Cc1c(C2=CCNCC2)nnn1-c1cccnc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCOC(=O)N1CC=C(c2cn(-c3cccnc3Cl)nn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-Chloro-3-[5-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)-[1,2,3]triazol-1-yl]-pyridine hydrochloride (3.0 mg) prepared in Example 42-1 was dissolved in 1.0 ml of dichloromethane and 0.02 ml of triethylamine and 0.02 ml of 2-methoxyethyl chloroformate were added thereto followed by stirring at room temperature for 10 minutes. The solvent was evaporated in vacuo and the residue was separated and purified by a thin-layer chromatography (ethyl acetate) to give 1.36 mg of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:16]([OH:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:33][C:34]1[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:35]=1[C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58]O)=[CH:43][CH:42]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:26]([O:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:16]([O:18][CH2:58][CH2:57][CH2:56][CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][O:47][C:44]1[CH:43]=[CH:42][C:41]([C:35]2[CH:36]=[CH:37][CH:38]=[C:39]([F:40])[C:34]=2[F:33])=[CH:46][CH:45]=1)=[O:17])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(O)C(CCCCCCOCc1ccccc1)CCCCCCOCc1ccccc1
Reactant: OCCCCCCCCCCCOc1ccc(-c2cccc(F)c2F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(OCCCCCCCCCCCOc1ccc(-c2cccc(F)c2F)cc1)C(CCCCCCOCc1ccccc1)CCCCCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
First, 3.0 g of 2,2-bis(6-benzyloxyhexyl)acetic acid, 2.8 g of 2,3-difluoro-4'-[11-hydroxyundecyl]oxybiphenyl, 2.2 g of triphenylphosphine, and 50 ml of tetrahydrofuran were placed in a 100 ml flask. Then, 1.4 g of diethyl azodicarboxylate was added dropwise to the mixture at 5° C. The resultant mixture was allowed to warm to room temperature and stirred for 8 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/9) to obtain 5 g of 11-[2,3-difluorobiphenyl-4'-yl]oxyundecyl 2,2-bis(6-benzyloxyhexyl)acetate (Y: 92.6%). The compound thus obtained had a purity of 98% by HPLC.
Reaction SMILES: [CH3:1][C@H]1OC(=O)C2C(O)=CC(O)=C(Cl)C=2CC(=O)C=CC=C[C@H]2O[C@H]2C1.C(O)(=O)CCCCCCCCCCCC.[CH:41]1([N:47]=[C:48]=[N:49][CH:50]2[CH2:55][CH2:54][CH2:53]CC2)CCCCC1>O1CCCC1>[CH3:1][N:47]([C:48]1[CH:53]=[CH:54][CH:55]=[CH:50][N:49]=1)[CH3:41]
Reactant: C[C@@H]1C[C@@H]2O[C@@H]2C=CC=CC(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCCCCCCCCCCCC(=O)O
Agent: C[C@@H]1C[C@@H]2O[C@@H]2/C=C\C=C\C(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Solvent: C1CCOC1
Product: CN(C)c1ccccn1

Procedure:
Following a procedure similar to that described in Example 12, but using 400 mg of radicicol, 588 mg of tridecanoic acid, 6 ml of dry tetrahydrofuran, 566 mg of dicyclohexylcarbodiimide and a catalytic amount of dimethylaminopyridine, 688 mg of the title compound were obtained.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[N:13][C:12]([CH3:15])=[N:11]1)[C:5]#[N:6].[CH3:16][O-:17].[Na+]>CN(C=O)C>[CH3:16][O:17][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[N:13][C:12]([CH3:15])=[N:11]1)[C:5]#[N:6]
Reactant: C[O-]
Reactant: Cc1ncn(-c2ccc(C#N)cc2F)n1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C#N)ccc1-n1cnc(C)n1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a mixture of 3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)benzonitrile (0.51 g) in DMF (10 mL) was added sodium methoxide (5M methanol solution, 1.51 mL) at room temperature, and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was added to ice water, and the precipitated solid was collected by filtration, and washed with water to give the title compound (0.34 g).
Reaction SMILES: [C:1]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[CH:22].[OH2:29].[OH-].[Na+].OO>C1COCC1.C(OCC)(=O)C>[OH:29][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]
Reactant: O
Reactant: C#CCCCCCCCCCCCCCCCCCCCC(=O)OC(C)(C)C
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCCCCO
Reaction time: 1 h
Yield: 54 %

Procedure:
A solution of the acetylene (33) (0.4 g, 1.02 mmol) in dry THF (5 ml) at room temperature under nitrogen was treated with borane-dimethyl sulphide complex (1.04 ml of a 2M solution in THF, 2.08 mmol) and the resulting solution stirred for 1 hour, after which time no starting material was present on tlc. The reaction was then treated sequentially with water (2 ml), 2N aqueous sodium hydroxide (1 ml) and 30% hydrogen peroxide (1 ml). The resulting solution was left a further 15 minutes, then ethyl acetate added and the organic layer separated. The aqueous layer was re-extracted with ethyl acetate, the organic layers combined, dried (MgSO4) and evaporated. The crude product obtained in this manner was purified on silica (5 g). Elution with 10% ethyl acetate in petrol gave tert.-butyl 22-hydroxydocosanoate (34) as a white solid (0.23 g, 54%).
Reaction SMILES: C([N:4]1[CH2:8][CH2:7][N:6]=[C:5]1[NH:9][C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[N:13]=[C:12]([CH3:22])[CH:11]=1)(=O)C.Cl>CO>[CH3:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N:14]1[C:10]([NH:9][C:5]2[NH:6][CH2:7][CH2:8][N:4]=2)=[CH:11][C:12]([CH3:22])=[N:13]1
Reactant: CC(=O)N1CCN=C1Nc1cc(C)nn1-c1ccccc1C
Agent: Cl
Solvent: CO
Product: Cc1cc(NC2=NCCN2)n(-c2ccccc2C)n1

Procedure:
1-Acetyl-2-[1-(2-methylphenyl)-3-methyl-5-pyrazolyl] amino-2-imidazoline (7.0 g.) was treated with HCl in methanol as described in Example II to give 4.6 g. of product, mp 168°-169°.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=1)(=[O:3])[CH3:2].Br[CH:14]([CH3:17])[CH:15]=O>>[C:1]([O:4][CH2:5][C:6]1[C:7]2[N:8]([C:14]([CH3:17])=[CH:15][N:12]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1cccnc1N
Reactant: CC(Br)C=O
Product: CC(=O)OCc1cccn2c(C)cnc12
Yield: 37.5 %

Procedure:
A mixture of 5.0 g (30 mmole) of 3-(acetoxymethyl)-2-pyridinamine and 4.8 g (35 mmole) of 2-bromopropanal spontaneously heated upon mixing. After cooling, the mixture was partitioned between aqueous potassium carbonate and dichloromethane. The organic phase was separated, washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel (using ethanol-dichloromethane as eluent) yielded 2.3 g of 8-(acetoxymethyl)-3-methylimidazo[1,2-a]pyridine, as confirmed by the nmr and infrared spectra and by elemental analysis. [Calcd. for C11H12N2O2 : C, 64.69; H, 5.92; N, 13.72. Found: C, 63.70; H, 5.85; N, 14.24). A mixture of 2.3 g (11 mmole) of 8-(acetoxymethyl)-3-methylimidazo[1,2-a]pyridine and 1.65 g (11 mmole) of 2-mercaptobenzimidazole in 40 ml of 15% hydrogen bromide in acetic acid was heated on a steam bath. After being cooled to room temperature, the mixture was partitioned between 5% aqueous sodium hydroxide and dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated to an oil. Chromatography yielded 2.1 g of the title compound. Structure assignment was supported by the nmr and infrared spectra.