Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl.[C:37]1([CH:43]([OH:46])[CH2:44][CH3:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:26](=[O:28])[O:46][CH:43]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:44][CH3:45])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: CCC(O)c1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCC(OC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C)c1C)c1ccccc1
Yield: 69.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-phenyl-1-propanol (31 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (52 mg, yield 66%).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:14]>[Pd].CO>[NH2:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([CH3:15])([CH3:1])[C:3](=[O:14])[NH:4]2)=[CH:9][CH:8]=1
Reactant: CC1(C)C(=O)Nc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CO
Product: CC1(C)C(=O)Nc2cc(N)ccc21
Reaction time: 10 h
Yield: 68.5 %

Procedure:
A mixture of 3,3-dimethyl-6-nitroindolin-2-one (1.2 g, 5.8 mmol) (Mertens et al, J. Med. Chem. 30:1279, 1987), 10% Pd—C (100 mg), and MeOH (100 mL) was stirred under hydrogen atmosphere (1 atm) for 10 h. The catalyst was filtered out and the filtrate was concentrated. The residue was purified by column to give an off-white solid (700 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:31][CH3:32])[C:12]([NH:17][C@H:18]2[C@@H:22]([O:23][CH2:24][CH3:25])[CH2:21][N:20]([C:26]3[S:27][CH:28]=[CH:29][N:30]=3)[CH2:19]2)=[N:13][C:14]=1[CH2:15][CH3:16].ClC1C=[C:38]([O:40]C)C=CC=1C1N=C(CC)C(N[C@H]2[C@@H](OCC)CNC2)=NC=1CC>>[Cl:1][C:2]1[CH:7]=[C:6]([O:40][CH3:38])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:31][CH3:32])[C:12]([NH:17][C@H:18]2[C@@H:22]([O:23][CH2:24][CH3:25])[CH2:21][N:20]([C:26]3[S:27][CH:28]=[CH:29][N:30]=3)[CH2:19]2)=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2Cl)nc1CC
Reactant: CCO[C@H]1CN(c2nccs2)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCO[C@H]1CN(c2nccs2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(3R,4S)-4-ethoxy-1-(1,3-thiazol-2-yl)pyrrolidin-3-yl}-3,6-diethylpyrazin-2-amine but starting with 5-(2-chloro-4-methoxyphenyl)-N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine provided the title compound as an amorphous solid. 1H NMR (CDCl3) δ 1.17, 1.25˜1.35, 2.50, 2.72, 3.45, 3.58, 3.75, 3.86, 4.04, 4.27, 4.93, 5.26, 6.55, 6.90, 7.02, 7.24; IR (diffuse reflectance) 2970, 2351 (w), 2337 (w), 2063 (w), 1604, 1568, 1549 (s), 1537 (s), 1482 (s), 1397, 1359, 1286, 1228, 1199, 1043 cm−1 HRMS (ESI) calcd for C24H30N5O2SCl+H1 488.1887. found 488.1880.
Reaction SMILES: [CH:1]1([NH:7][C:8](SC)=[C:9]([C:15]#[N:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:19][CH2:20][CH:21]1[O:26][CH2:25][CH2:24][N:23]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH2:22]1>>[CH:1]1([NH:7][C:8]([NH:19][CH2:20][CH:21]2[O:26][CH2:25][CH2:24][N:23]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:22]2)=[C:9]([C:15]#[N:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCC1CN(Cc2ccc(F)cc2)CCO1
Reactant: CCOC(=O)C(C#N)=C(NC1CCCCC1)SC
Product: CCOC(=O)C(C#N)=C(NCC1CN(Cc2ccc(F)cc2)CCO1)NC1CCCCC1
Yield: 10 %

Procedure:
This compound was synthesized as a yellow oily substance from ethyl 3-cyclohexylamino-3-methylthio-2-cyanoacrylate and 2-aminomethyl-4-(p-fluorobenzyl)morpholine according to the same procedure as in Example 8. Yield=10%.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:32]=[CH:31][C:25]([C:26]([O:28]CC)=[O:27])=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1.[OH-].[Na+].O1CCCC1.[ClH:40]>C(O)C.O>[ClH:40].[ClH:40].[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:31][CH:32]=3)[CH2:18][CH2:17]2)=[CH:14][CH:15]=1
Reactant: CCOC(=O)c1ccc(N2CCN(c3ccc(OCCCCCCOC)cc3)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COCCCCCCOc1ccc(N2CCN(c3ccc(C(=O)O)cc3)CC2)cc1

Procedure:
A mixture of ethyl 4-[4-[4-(6-methoxyhexyloxy)phenyl]piperazin-1-yl]benzoate (3.00 g) in ethanol (30 ml) was treated with 1N-sodium hydroxide aqueous solution (6.81 ml) then the mixture was refluxed for 24 hours, during which period tetrahydrofuran (20 ml) and 1N-sodium hydroxide aqueous solution (6.81 ml) was added. After cooling, water was added to the mixture, and the acidity of the mixture was adjusted to pH 1 with 1N-hydrochloric acid. The resulting precipitate was filtered, washed with water and dried under reduced pressure to give 4-[4-[4-(6-methoxyhexyloxy)phenyl]piperazin-1-yl]benzoic acid dihydrochloride (2.25 g) as an ocher solid.
Reaction SMILES: [NH:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH3:7].[CH3:8][N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10](Cl)=[O:11]>C1C=CC=CC=1>[CH3:8][N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([N:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH3:7])=[O:11]
Reactant: CN1CCCC1=N
Reactant: CN(C(=O)Cl)c1ccccc1
Solvent: c1ccccc1
Product: CN1CCCC1=NC(=O)N(C)c1ccccc1
Temperature: 25 °C

Procedure:
The hydrochloride salt of 2-imino-1-methylpyrrolidine (13.46 g.; 0.1 mole) is converted to free base by adding 10 ml. of 50% NaOH and extracting into benzene. After drying over K2CO3, the benzene layer is stirred at room temperature and 8.48 g. (0.05 mole) of N-methyl-phenylcarbamoyl chloride (prepared according to the method of J. A. Aeschlimann, U.S. Pat. No. 2,449,440), dissolved in anhydrous benzene, is added dropwise to this solution. Cloudiness occurs and then solid precipitates from solution. The mixture is stirred at room temperature overnight and then filtered. The filtrate is taken to dryness in vacuo to an oily residue which is dissolved in hot hexane and filtered hot. Cooling and scratching yields crystals which are collected and recrystallized from hexane to give the pure product, 1-methyl-3-(1-methyl-2-pyrrolidylidene)-1-phenylurea, 27.5°-30° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([CH:15]=[C:16]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:17]=3)[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[C:24]([C:26]1([C:29]2[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=2)[C:32](O)=[O:33])[CH2:28][CH2:27]1)#[N:25].C(Cl)(=O)C(Cl)=O.O1CCCC1>CN(C)C=O.CN(C)C(=O)C>[C:24]([C:26]1([C:29]2[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=2)[C:32]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([S:8][C:9]3[CH:10]=[CH:11][C:12]4[N:13]([CH:15]=[C:16]([NH:18][C:19]([CH:21]5[CH2:22][CH2:23]5)=[O:20])[N:17]=4)[N:14]=3)[CH:3]=2)=[O:33])[CH2:27][CH2:28]1)#[N:25]
Reactant: N#CC1(c2cccc(C(=O)O)c2)CC1
Reactant: Nc1cccc(Sc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Sc4ccc5nc(NC(=O)C6CC6)cn5n4)c3)c2)CC1
Yield: 80.1 %

Procedure:
Using N-{6-[(3-aminophenyl)sulfanyl]imidazo[1,2-b]pyridazin-2-yl}cyclopropanecarboxamide (130 mg, 0.399 mmol), 3-(1-cyanocyclopropyl)benzoic acid (89 mg, 0.479 mmol), oxalyl chloride (70 μL, 0.799 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (3 mL) and N,N-dimethylacetamide (3 mL) as starting materials and in the same manner as in Example 412, the title compound (158 mg, 80%) was obtained as a pale-brown powder.
Reaction SMILES: [CH2:1]([O:5][CH:6]([O:8][NH:9][C:10]([C:12]1[S:16][C:15]2[CH:17]=[C:18]([CH:21]=O)[CH:19]=[CH:20][C:14]=2[CH:13]=1)=[O:11])[CH3:7])[CH:2]([CH3:4])[CH3:3].[CH:23]1([O:28][C:29](=[O:48])[C@@H:30]([NH:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([CH2:46][NH2:47])=[CH:42][CH:41]=2)[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl.C(O)(=O)C>[CH:23]1([O:28][C:29](=[O:48])[C@@H:30]([NH:38][CH2:39][C:40]2[CH:41]=[CH:42][C:43]([CH2:46][NH:47][CH2:21][C:18]3[CH:19]=[CH:20][C:14]4[CH:13]=[C:12]([C:10](=[O:11])[NH:9][O:8][CH:6]([O:5][CH2:1][CH:2]([CH3:3])[CH3:4])[CH3:7])[S:16][C:15]=4[CH:17]=3)=[CH:44][CH:45]=2)[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: NCc1ccc(CN[C@@H](Cc2ccccc2)C(=O)OC2CCCC2)cc1
Reactant: CC(C)COC(C)ONC(=O)c1cc2ccc(C=O)cc2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)COC(C)ONC(=O)c1cc2ccc(CNCc3ccc(CN[C@@H](Cc4ccccc4)C(=O)OC4CCCC4)cc3)cc2s1
Reaction time: 3 h
Yield: 17.9 %

Procedure:
6-formyl-benzo[b]thiophene-2-carboxylic acid (1-isobutoxy-ethoxy) amide (Scheme 7) (220 mg, 0.68 mmol) and (S)-2-(4-Aminomethyl-benzylamino)-3-phenyl-propionic acid cyclopentyl ester (263 mg, 0.75 mmol) were dissolved in DCE (10 mL) under an atmosphere of N2. Sodium triacetoxyborohydride (430 mg, 2.04 mmol) and acetic acid (50 μL) were added and the reaction stirred at r.t for 3 h. Sodium hydrogen carbonate (20 mL) was added and the reaction mixture extracted with dichloromethane (3×50 mL). The organic layers were combined and concentrated. The residue was purified by column chromatography (50%-100% EtOAc/heptane) to give the protected compound (80 mg, 21%). m/z 658 [M++H]+
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([O:14][CH2:15][CH:16]1[O:18][CH2:17]1)(=[O:13])[C:10]([CH3:12])=[CH2:11].N(C(C)(C)C#N)=NC(C)(C)C#N.[C:31]1(=[O:37])[O:36][C:34](=[O:35])[CH:33]=[CH:32]1>C(C(C)=O)C.N(C(C)(C)C#N)=NC(C)(C)C#N.CO>[CH2:15]([O:14][C:9](=[O:13])[C:10]([CH3:12])=[CH2:11])[CH:16]1[O:18][CH2:17]1.[CH:1]([C:32]1=[CH:33][C:34]([O:36][C:31]1=[O:37])=[O:35])=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: O=C1C=CC(=O)O1
Agent: C=C(C)C(=O)OCC1CO1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCC(C)=O
Solvent: CO
Product: O=C1C=C(C=Cc2ccccc2)C(=O)O1
Temperature: 70 °C
Reaction time: 10 h
Yield: 516.1 %

Procedure:
A monomer mixture comprising 600 g of styrene (hereinafter referred to as "St") and 70 g of glycidyl methacrylate (hereinafter referred to as "GMA") was dissolved in 1000 g of methyl ethyl ketone (hereinafter referred to as "MEK") in a four -necked flask fitted with a dropping funnel, a nitrogen inlet tube, a thermometer, a condenser and a stirrer and the solution was heated to 70° C. Another monomer mixture comprising 15 g of azobisisobutyronitrile (hereinafter referred to as "AIBN") as the polymerization initiator, 260 g of St, 70 g of maleic anhydride (hereinafter referred to as "MAH") and 280 g of MEK was stepwise dropped thereinto to initiate polymerization. After 10 h, the flask was cooled to room temperature arid the reaction mixture was immediately poured into a large quantity of methanol. The polymer thus precipitated was recovered by decantation, dried under reduced pressure in a vacuum drier axed Finely pulverized to give 870 g of styrene-maleic anhydride glycidyl methacrylate copolymer (3). According to GPC, the copolymer (3) had a number-average molecular weight (in terms of polystyrene ) of 15,000. The infrared absorption spectrum of the copolymer (3) is given in FIG. 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:26])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][N:13]=[C:12]2[NH:19][C:20]1[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=1.CS(O[CH:32]1[CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33]1)(=O)=O>>[ClH:1].[NH:34]1[CH2:35][CH:32]([O:26][C:4]2[CH:3]=[C:2]([Cl:1])[C:7]([O:8][C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][CH:18]=3)[N:15]=[CH:14][N:13]=[C:12]4[NH:19][C:20]3[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=3)=[N:6][CH:5]=2)[CH2:33]1
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Reactant: Cn1ccc(Nc2ncnc3ccc(Oc4ncc(O)cc4Cl)cc23)n1
Product: Cl
Product: Cn1ccc(Nc2ncnc3ccc(Oc4ncc(OC5CNC5)cc4Cl)cc23)n1

Procedure:
Using 5-chloro-6-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)pyridin-3-ol obtained in Example 22 and tert-butyl 3-[(methylsulfonyl)oxy]azetidine-1-carboxylate, and in the same manner as in Example 6-4) and 6-5) and Example 10-2), or according to a method similar to it or according to a combination thereof with an ordinary method, the entitled compound (86 mg) was obtained as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[S:14][N:13]=[C:12]([CH3:15])[N:11]=1.Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([OH:27])[CH:25]=2)[N:20]=[CH:19][N:18]=1>>[F:8][C:7]1[C:2]([O:27][C:24]2[CH:25]=[C:26]3[C:21](=[CH:22][CH:23]=2)[N:20]=[CH:19][N:18]=[C:17]3[NH:9][C:10]2[S:14][N:13]=[C:12]([CH3:15])[N:11]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccc2ncnc(Cl)c2c1
Reactant: Cc1nsc(N)n1
Reactant: Fc1cccnc1Cl
Product: Cc1nsc(Nc2ncnc3ccc(Oc4ncccc4F)cc23)n1

Procedure:
The compound of Example 87 was manufactured by the same method as in Example 95, by a similar method thereto or by a combination of such a method with a conventional method using 2-chloro-3-fluoropyridine, 5-amino-3-methyl-[1,2,4]-thiadiazole and 4-chloro-6-hydroxy-quinazoline.
Reaction SMILES: [C:1]([CH2:4][N:5]([C:10]1[CH:15]=[C:14]([O: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][CH2:33][CH3:34])[CH:13]=[C:12]([N+:35]([O-])=O)[CH:11]=1)[CH2:6][C:7]([OH:9])=[O:8])([OH:3])=[O:2].[H][H]>[Pd].C1COCC1.CN(C=O)C>[C:1]([CH2:4][N:5]([C:10]1[CH:15]=[C:14]([O: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][CH2:33][CH3:34])[CH:13]=[C:12]([NH2:35])[CH:11]=1)[CH2:6][C:7]([OH:9])=[O:8])([OH:3])=[O:2]
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(N(CC(=O)O)CC(=O)O)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOc1cc(N)cc(N(CC(=O)O)CC(=O)O)c1
Reaction time: 4 h
Yield: 44.2 %

Procedure:
A mixture of 0.6 g of N-(carboxymethyl)-N-[3-nitro-5-(octadecyloxy)phenyl]glycine and 0.2 g of 10% palladium on carbon in 170 ml of THF and 10 ml of DMF was stirred in a hydrogen atmosphere at room temperature until uptake ceased after 4 hours. The reaction mixture was heated to dissolve the precipitated product and the catalyst was removed by filtration. The filtrate was concentrated at reduced pressure and the solid residue was dissolved in THF and the solution was passed through a SEP-PAK silica cartridge (Waters Associates). The eluent was concentrated at reduced pressure to a solid which was triturated with ethyl acetate and filtered to give 0.25 g (44% yield, mp 185°-195°) of N-(carboxymethyl)-N-[3-amino-5-(octadecyloxy)phenyl]glycine. The structure was confirmed by nmr and mass spectra.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5](/[C:17](/[CH2:29][CH3:30])=[CH:18]\[CH:19]=[CH:20]\[C:21](\[CH3:28])=[CH:22]\[C:23]([O:25]CC)=[O:24])=[CH:6][C:7]2[C:8]([CH3:16])=[CH:9][CH2:10][C:11]([CH3:15])([CH3:14])[C:12]=2[CH:13]=1)[CH3:2].[OH-].[Na+].Cl>C(O)C.C1COCC1>[CH2:1]([O:3][C:4]1[C:5](/[C:17](/[CH2:29][CH3:30])=[CH:18]\[CH:19]=[CH:20]\[C:21](\[CH3:28])=[CH:22]\[C:23]([OH:25])=[O:24])=[CH:6][C:7]2[C:8]([CH3:16])=[CH:9][CH2:10][C:11]([CH3:15])([CH3:14])[C:12]=2[CH:13]=1)[CH3:2]
Reactant: CCOC(=O)/C=C(C)/C=C/C=C(/CC)c1cc2c(cc1OCC)C(C)(C)CC=C2C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1cc2c(cc1/C(=C\C=C\C(C)=C\C(=O)O)CC)C(C)=CCC2(C)C
Temperature: 50 °C
Reaction time: 5 h

Procedure:
A solution of ethyl 7-(3-ethoxy-5,5,8-trimethyl-5,6-dihydronaphthalen-2-yl)-3-methyl-nona-2E,4E,6Z-trienoate (Compound A-13, 0.82 g, 2.01 mmol) in ethanol (5 mL) and THF (5 mL) was treated with 2M NaOH (5 mL, 10 mmol) and then stirred at 50° C. for 5 h. The mixture was cooled to room temperature, acidified with 10% HCl, and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by recrystallization from acetonitrile to yield the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]=[CH2:11])=[N:7][C:6]=2[CH:12]=1.[C:13]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)#[N:14].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.O1CCCC1>CCCCCC>[CH:10]([C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([C:18]3[CH:19]=[CH:20][C:15]([C:13]#[N:14])=[CH:16][CH:17]=3)=[CH:12][C:6]=2[N:7]=1)=[CH2:11]
Reactant: C=Cc1nc2cc(Br)ccc2o1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=Cc1nc2cc(-c3ccc(C#N)cc3)ccc2o1
Temperature: 23 °C
Reaction time: 24 h
Yield: 78 %

Procedure:
A mixture of 224 mg (1 mmol) of 5-bromo-2-vinyl-benzooxazole, 191 mg (1.3 mmol) of 4-cyanophenylboronic acid, 55 mg (0.03 mmol) of tris-(dibenzylidineacetone)dipalladium (0) (CAS #52409-22-0), 0.2 mL (0.06 mmol) of a 10% solution of tri-tert-butylphosphine in hexane, and 1.5 mL of tetrahydrofuran was stirred at 23° C. for 24 hours. It was then heated at 65° C. for 0.5 hour, then cooled. The mixture was suction filtered to remove particulates, then partitioned between 80 mL of water and a mixture of 30 mL of ethyl acetate and 10 mL of hexane. The organic phase was collected, dried over Na2SO4, and purified by flash chromatography on silica gel (eluting with 1:1 hexane:dichloromethane) to give 4-(2-vinyl-benzooxazol-5-yl)-benzonitrile (192 mg, 78%) as a white solid: mp 143–144° C.; 1H NMR (300 MHz, CDCl3) δ 7.90 (d, J=1.8 Hz, 1 H), 7.76 (d, J=8.4 Hz, 2 H), 7.70 (d, J=8.4 Hz, 2 H), 7.62 (d, J=7.5 Hz, 1 H), 7.55 (dd, J=7.5, 1.8 Hz, 1 H), 6.79 (dd, J=17.4, 10.5 Hz, 1 H), 6.52 (d, J=17.4 Hz, 1 H), 5.91 (d, J=10.5 Hz, 1 H); Mass spectrum: [M+H]+ 247.1.
Reaction SMILES: O[C:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:10])([CH:4]=[CH2:5])[CH3:3].C(OCC)C.P(Br)(Br)[Br:23].C(=O)(O)[O-].[Na+]>O.N1C=CC=CC=1>[CH2:5]([Br:23])[CH:4]=[C:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:10])[CH3:3]
Reactant: C=CC(C)(O)CCC=C(C)CCC=C(C)C
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)=CCCC(C)=CCCC(C)=CCBr
Reaction time: 12 h
Yield: 240.4 %

Procedure:
Following the procedure reported by G. Pala et al. in Helv. Chim. Acta., 53, 1827- 1832 (1970), a mixture of 666 g of nerolidol (cis:trans= 40:60 ), 2,000 ml of diethyl ether and 20 ml of pyridine was cooled at -5° - -10° C. Thereto, 300 g of phosphorus tribromide was added dropwise slowly at the same temperature. Thereafter, the reaction was completed by further stirring of the mixture for 12 hours at the same temperature. The reaction mixture was poured into water and neutralized with sodium bicarbonate. The ether layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off in vacuo at room temperature to give 760 g of farnesyl bromide which showed orange color and irritating odor. As this substance was relatively unstable, it was brought to the following reaction without further purification or kept in a cold place.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH:21]1([CH2:26][C:27](Cl)=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22]1>O1CCCC1>[CH:21]1([CH2:26][C:27]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)CC1CCCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)CC2CCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of methyl 4-aminobenzoate (0.25 g, 1.654 mmol) in tetrahydrofuran (8.27 ml) was treated with diisopropylethylamine (0.433 ml, 2.481 mmol) and 2-cyclopentylacetyl chloride (0.279 g, 1.902 mmol) and the reaction mixture was stirred at ambient temperature for 2 hours. Concentration and normal phase chromatography provided the title compound.
Reaction SMILES: [CH3:1][C:2]([NH:4][CH:5]1[C:15]2[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:14]=2[C:13]2[C:8](=[CH:9][C:10]([O:25][CH3:26])=[C:11]([O:23][CH3:24])[C:12]=2[O:21][CH3:22])[CH2:7][CH2:6]1)=[O:3].Cl[C:28](OC1C=CC([N+]([O-])=O)=CC=1)=[O:29].C(N(CC)CC)C.[NH2:47][CH2:48][CH2:49][CH2:50][CH2:51][N:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1>ClCCl>[O:55]1[CH2:54][CH2:53][N:52]([CH2:51][CH2:50][CH2:49][CH2:48][NH:47][C:28](=[O:29])[O:20][C:17]2[CH:18]=[CH:19][C:14]3[C:13]4[C:12]([O:21][CH3:22])=[C:11]([O:23][CH3:24])[C:10]([O:25][CH3:26])=[CH:9][C:8]=4[CH2:7][CH2:6][C@H:5]([NH:4][C:2](=[O:3])[CH3:1])[C:15]=3[CH:16]=2)[CH2:57][CH2:56]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCCCCN1CCOCC1
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(O)cc1C(NC(C)=O)CC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(c(OC)c1OC)-c1ccc(OC(=O)NCCCCN3CCOCC3)cc1[C@@H](NC(C)=O)CC2
Reaction time: 4 h
Yield: 24 %

Procedure:
A solution of N-acetyl-colchicinol (0.357 g; 1 mmol), 4-nitrophenyl chloroformate (0.262 g; 1.3 mmol) and triethylamine (182 μl; 1.3 mmol) in dichloromethane (10 ml) was stirred, under argon atmosphere, at ambient temperature for 90 minutes. 4-(4-Aminobutyl)morpholine (0.237 g; 1.5 mmol) was then added and the mixture was further stirred for 4 hours. After evaporation to dryness the residue was purified by flash chromatography eluting with a gradient of 0–12% ethanol/dichloromethane to give (5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl N-(4-morpholinobutyl)carbamate as a white foam.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][C:13](=O)[C:14]([F:17])([F:16])[F:15])=[CH:7][C:6]=1[C:20]([F:23])([F:22])[F:21].[NH2:26][C:27]1[C:31]([C:32]2[CH:37]=[C:36]([CH3:38])[N:35]=[C:34]([CH3:39])[CH:33]=2)=[CH:30][NH:29][N:28]=1>>[F:1][C:2]([F:25])([F:24])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]([C:14]([F:17])([F:16])[F:15])[N:28]3[N:29]=[CH:30][C:31]([C:32]4[CH:37]=[C:36]([CH3:38])[N:35]=[C:34]([CH3:39])[CH:33]=4)=[C:27]3[N:26]=2)=[CH:7][C:6]=1[C:20]([F:23])([F:22])[F:21]
Reactant: Cc1cc(-c2c[nH]nc2N)cc(C)n1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(OCC(F)(F)F)c(C(F)(F)F)c1
Product: Cc1cc(-c2cnn3c(C(F)(F)F)cc(-c4ccc(OCC(F)(F)F)c(C(F)(F)F)c4)nc23)cc(C)n1
Yield: 61.8 %

Procedure:
Reaction of 1-[4-(2,2,2-trifluoroethoxy)-3-trifluoromethyl-phenyl]-4,4,4-trifluoro-butane-1,3-dione (191 mg, 0.5 mmol), prepared from 4-(2,2,2-trifluoroethoxy)-3-trifluoromethyl-acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A, and 3-amino-4-(2,6-dimethyl-4-pyridinyl)-pyrazole [prepared from 4-cyanomethyl-2,6-dimethyl-pyridine, CAS No. 130138-46-4, see part synthesis of amino-pyrazole derivatives] (94 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (165 mg, 62%). MS (ISP) 535.5 [(M+H)+]; mp 229° C.