Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Se](=O)=O.C[C@H]1[C@H](O)C(=O)O[CH2:31][C@:23]23[C@H:28]([O:29][C@H:20]4[C@:21]5(O[CH2:38]5)[C@:22]2([CH3:37])[C@@H:18]([CH2:19]4)OC(=O)C=CC=CC(=O)OCC1)[CH:27]=[C:26]([CH3:30])[CH2:25][CH2:24]3>>[CH3:38][CH:21]1[C@@:22]2([CH3:37])[C@:23]3([CH3:31])[C@H:28]([O:29][C@@H:20]1[CH2:19][CH2:18]2)[CH:27]=[C:26]([CH3:30])[CH2:25][CH2:24]3
Reactant: CC1=C[C@H]2O[C@@H]3C[C@H]4OC(=O)C=CC=CC(=O)OCC[C@@H](C)[C@H](O)C(=O)OC[C@@]2(CC1)[C@]4(C)[C@]31CO1
Agent: CC1=C[C@H]2O[C@@H]3C[C@H]4OC(=O)/C=C\C=C\C(=O)OCC[C@@H](C)[C@H](O)C(=O)OC[C@@]2(CC1)[C@]4(C)[C@]31CO1
Agent: O=[Se]=O
Product: CC1=C[C@H]2O[C@@H]3CC[C@@](C)(C3C)[C@@]2(C)CC1

Procedure:
The trichothecene therapeutic agent 16-oxo verrucarin A is prepared by selenium dioxide oxidation of verrucarin A. The MAb hydrazide is then reacted with 16-oxo verrucarin A at 4C overnight with agitation, thereby yielding a unique Schiff base-linked targeting substance conjugate having the following structure: ##STR22##
Reaction SMILES: C(OC([N:11]1[C:16]2[CH:17]=[C:18](Cl)[CH:19]=[C:20]([N:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)[C:15]=2[O:14][CH2:13][CH2:12]1)=O)C1C=CC=CC=1>C(O)C.[Pd]>[C:30]([O:29][C:27]([N:24]1[CH2:25][CH2:26][N:21]([C:20]2[C:15]3[O:14][CH2:13][CH2:12][NH:11][C:16]=3[CH:17]=[CH:18][CH:19]=2)[CH2:22][CH2:23]1)=[O:28])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(Cl)cc3c2OCCN3C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3c2OCCN3)CC1
Yield: 83 %

Procedure:
A solution of 8-(4-tert-butoxycarbonyl-piperazin-1-yl)-6-chloro-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid benzyl ester (640 mg, 1.32 mmol) in ethanol (10 mL) was hydrogenated at 50 psi in the presence of palladium on carbon for 12 hours. The catalyst was removed by filtration, and the filtrate was concentrated to give 4-(3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-piperazine-1-carboxylic acid tert-butyl ester as a light yellow solid (350 mg, 84%). MS: MH+=320.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH2:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC(CN)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(CNC(=O)OCc2ccccc2)C1

Procedure:
A solution of 3-aminomethylpiperidine-1-carboxylic acid tert-butyl ester (2.20 g, 10.3 mmol) in dichloromethane (40 mL) was treated with triethylamine (1.90 mL, 13.3 mmol) and stirred on an ice bath. A solution of benzyl chloroformate (1.90 mL, 13.3 mmol) in dichloromethane (10 mL) was added over 5 minutes. The mixture was stirred at room temperature for 70 hours. It was washed with 0.1 N aqueous hydrochloric acid, dried over sodium sulfate, and concentrated under vacuum to provide a colorless gum (3.58 g, quantitative) which was used without further purification. 1H NMR (300 MHz, CDCl3) δ7.37 (m, 5H), 5.11 (s, 2H), 3.75 (m, 2H), 3.18 (m, 1H), 3.05 (m, 2H), 2.83 (m, 1H), 1.9-1.6 (m, 4H), 1.46 (s, 9H), 1.27 (m, 1H).
Reaction SMILES: [C:1]([CH:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:12]([OH:14])=O)[C:6]=2[CH2:5][CH2:4]1)#[N:2].S(Cl)([Cl:17])=O>>[C:1]([CH:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:12]([Cl:17])=[O:14])[C:6]=2[CH2:5][CH2:4]1)#[N:2]
Reactant: O=S(Cl)Cl
Reactant: N#CC1CCc2c(C(=O)O)cccc21
Product: N#CC1CCc2c(C(=O)Cl)cccc21
Reaction time: 15 h

Procedure:
To 6.0 g. of 1-cyanoindan-4-carboxylic acid is added 96 ml. of thionyl chloride and the mixture is allowed to stand at room temperature for 15 hours. The excess thionyl chloride is removed under reduced pressure. To 1-cyanoindan-4-carbonyl chloride, which is thus obtained as the residue, are added 50 ml. of anisole, 50 ml. of methylene chloride and 6.0 g. of anhydrous aluminum chloride powder. The mixture is stirred at room temperature for 90 minutes. After cooling, the product is poured into ice-hydrochloric acid and extracted with ether. The extract is washed with 1N hydrochloric acid and a saturated aqueous solution of sodium chloride, followed by drying. The solvent is distilled under reduced pressure and the residue obtained is purified by chromatography on a column of silica gel (700 g. silica gel; eluted with chloroform). The procedure gives 4-(p-methoxybenzoyl)indan-1-carbonitrile as crystals melting at 109°-112° C.
Reaction SMILES: O[CH2:2][C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1.S(Cl)([Cl:12])=O>ClCCl>[Cl:12][CH2:2][C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ncccc1CO
Solvent: ClCCl
Product: Cc1ncccc1CCl
Reaction time: 2 h
Yield: 47 %

Procedure:
Prepared essentially according to the procedure of I. M. Bell et al., J. Med. Chem. 41, 2146–2163 (1998). To a stirred solution of the 3-hydroxymethyl-2-methyl-pyridine of Step A (2.5 g, 20.3 mmol) in dichloromethane (100 mL) was added thionyl chloride (15 mL, 206 mmol). After stirring for 2 hours, the reaction mixture was concentrated in vacuo. The residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The aqueous layer was repeatedly extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 1.35 g of the title compound as an orange oil which was immediately used in the next step.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=O)[CH:8]=[CH:9][CH:10]=1.[Cl-].[CH2:16]([O:23][C:24]1[CH:49]=[CH:48][CH:47]=[CH:46][C:25]=1[CH2:26][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N12CCCN=C1CCCCC2>C(#N)C>[CH2:16]([O:23][C:24]1[CH:49]=[CH:48][CH:47]=[CH:46][C:25]=1[CH:26]=[CH:13][CH:12]=[CH:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH2:3][O:2][CH3:1])[CH:6]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COCOc1cccc(C=CC=O)c1
Reactant: c1ccc(COc2ccccc2C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COCOc1cccc(C=CC=Cc2ccccc2OCc2ccccc2)c1
Yield: 88.6 %

Procedure:
Following a procedure similar to that described in the first part of Preparation 3, 7.00 g of 3-(3-methoxymethoxyphenyl)-2-propenal and 18 g of 2-benzyloxybenzyltriphenylphosphonium chloride (prepared as described in Preparation 1) were dissolved in 200 ml of acetonitrile, with heating, and 5.54 g of 1,8-diazabicyclo[5,4,0]undec-7-ene were added to the mixture and reacted. The crude product, extracted as described in Preparation 3, was purified as described in Preparation 3, to give 12.0 g of 1-(2-benzyloxyphenyl)-4-(3-methoxymethoxyphenyl)butadiene as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]=[CH:28][C:29]([O:31][CH3:32])=[O:30])[C:8]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)([CH3:13])[CH2:9][S:10]2)=[CH:5][CH:4]=1.[BH4-].[Na+].O.CCCCCC>CO.O1CCCC1.[Ni].C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:8]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)([CH3:13])[CH2:9][S:10]2)=[CH:5][CH:4]=1
Reactant: COC(=O)C=CCCCCCC1c2ccc(OC)cc2SCC1(C)c1ccc(OC)cc1
Agent: [Ni]
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COC(=O)CCCCCCCC1c2ccc(OC)cc2SCC1(C)c1ccc(OC)cc1
Reaction time: 2 h
Yield: 76 %

Procedure:
To a solution of methyl 8-[7-Methoxy-3-(4-methoxyphenyl)-3-methylthiochroman-4-yl]-2-octenate (160 mg, 0.34 mmol) in methanol (3 ml) and tetrahydrofuran (1 ml) were added sodium borohydride (129 mg, 3.40 mmol) and nickel (1 ml) chloride hexahydrate (16 mg, 0.068 mmol) at 0° C., which was then stirred at the same temperature for 2 hours. After the reaction was completed, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. This crude product thus obtained was subjected to silica gel column chromatography (n-hexane:ethyl acetate=4:1) to give the title compound (118 mg, yield: 73%; (3RS,4RS):(3RS,4SR)=4:1).
Reaction SMILES: [NH:1]1C2(CCCCC2)[NH:4][CH2:3][C:2]1=[O:11].[O:12]1[CH2:22][CH:13]1[CH2:14][C:15]([O:17]CC(C)C)=O>C(#N)C>[CH2:14]1[C:15](=[O:17])[N:4]([CH2:3][C:2]([NH2:1])=[O:11])[CH2:22][CH:13]1[OH:12]
Reactant: CC(C)COC(=O)CC1CO1
Reactant: O=C1CNC2(CCCCC2)N1
Solvent: CC#N
Product: NC(=O)CN1CC(O)CC1=O
Reaction time: 30 h

Procedure:
1 g of 2,2-dimethyl-4-imidazolidinone ((5); R4 =R5 =CH3) (8.76 mmoles) is dissolved in 5 ml acetonitrile. 1 g 2-methylpropyl 3,4-epoxybutanoate ((4); X=isobutyl) (6.32 mmoles) is added and the mixture is boiled for 30 h with stirring. The mixture is cooled, the solvent is decanted off, the resulting dark solid mass is taken up in ethanol, and the solid oxiracetam obtained is filtered off, m.p. 167°-70° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])[CH2:7][CH2:6][C:5]2=[N:22][OH:23].C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[S:32]([OH:34])(=[O:21])(=[O:33])[CH3:31].[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])[CH2:7][CH2:6][C:5]2=[N:22][OH:23]
Reactant: CS(=O)(=O)Cl
Agent: O=C(c1ccc(Cl)cc1Cl)N1CCC(=NO)c2cc(Cl)ccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O

Procedure:
To a mixture of 6-chloro-1-(2,4-dichlorobenzo-yl)-2,3-dihydro-4(1H)-quinolinone-4-oxime (10.0 g), triethylamine (4.1 g) and dichloromethane (150 ml) was added dropwise methanesulfonyl chloride (3.5 g) at -20° C. with stirring. The mixture was stirred at -20° C. for 30 minutes and dichloromethane (300 ml) was added. The reaction mixture was sequentially washed with 1 N HCl, saturated aqueous sodium bicarbonate solution, then with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. Solvent was removed in vacuo and the residue was recrystallized with ether and n-hexane to obtain 6-chloro-1-(2,4-dichlorobenzoyl)-2,3-dihydro-4(1H)-quinolinone-4-oxime mesylate (yield 11 g) as white crystal.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:10](OC)=[O:11])=[CH:4][CH:3]=1.[Li]Cl.O.[BH4-].[Na+]>C(O)C.C1COCC1>[C:18]([O:17][C:15](=[O:16])[NH:14][CH:9]([CH2:10][OH:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)([CH3:19])([CH3:21])[CH3:20]
Reactant: COC(=O)C(Cc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li]Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(CO)Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
To a solution of compound 3e (15 g, 42 mmol) in ethanol (50 mL) and THF (50 mL) was added LiCl.H2O (10 g, 170 mmol) and NaBH4 (6.3 g, 170 mmol) at 0° C. The mixture was stirred at rt overnight. LCMS analysis indicated the total consumption of compound 3e. The precipitate was removed by filtration and the filtrate was concentrated in vacuo to give 3f as a white solid (13 g, 94% yield).
Reaction SMILES: [C:1]([O:7][C@H:8]1[C@H:20]([O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[C@H:19]([O:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[C@H:18]([CH3:35])[O:17][C@@H:9]1[S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C1C=C(Cl)C=C(C(OO)=[O:44])C=1.CSC>C(Cl)Cl>[C:1]([O:7][C@H:8]1[C@H:20]([O:21][C:22](=[O:27])[C:23]([CH3:24])([CH3:25])[CH3:26])[C@H:19]([O:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[C@H:18]([CH3:35])[O:17][C@@H:9]1[S:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:44])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C[C@@H]1O[C@H](Sc2ccccc2)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Solvent: ClCCl
Solvent: CSC
Product: C[C@@H]1O[C@H](S(=O)c2ccccc2)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Temperature: -15 °C
Yield: 66.1 %

Procedure:
To a solution of phenyl 6-deoxy-2,3,4-tri-O-pivaloyl-1-thio-β-L-galactopyranoside 4 (2.47 g, 5.22 mmol) in 65 mL of CH2Cl2 at -78° C. is added mCPBA (1.53 g, 8.84 mmol). The reaction mixture is allowed to warm to -15° C. and then quenched with methyl sulfide (5.3 mL, 4.48 g, 17.4 mmol) and allowed to warm to room temperature. The reaction mixture is then diluted with 50 mL CH2Cl2, extracted with H2O (100 mL), saturated NaHCO3 (100 mL), saturated NaCl (100 mL), dried over Na2SO4, filtered and concentrated to afford a white solid. The sulfoxide is purified using flash chromatography (15% EtOAc/petroleum ether) to afford 1.81 g (66%) of 1,6-dideoxy-2,3,4-tri-O-pivaloyl-1-(phenylsulfinyl)-β-L-galactopyranose 5 as a mixture of diastereomers: Rf 0.05 and 0.13 (15% EtOAc/petroleum ether).
Reaction SMILES: Br[C:2]1[C:3]([O:17][CH3:18])=[C:4]2[O:8][C:7]([CH:9]3[CH2:11][CH2:10]3)=[N:6][C:5]2=[C:12]([C:15]#[N:16])[C:13]=1[CH3:14].C([Sn](CCCC)(CCCC)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)CCC.C(C1(C)C(O)=C(C(C)(C)C)C=CC1)(C)(C)C>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.O1CCOCC1>[CH:9]1([C:7]2[O:8][C:4]3[C:5](=[C:12]([C:15]#[N:16])[C:13]([CH3:14])=[C:2]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:3]=3[O:17][CH3:18])[N:6]=2)[CH2:11][CH2:10]1
Reactant: COc1c(Br)c(C)c(C#N)c2nc(C3CC3)oc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)C1=C(O)C(C)(C(C)(C)C)CC=C1
Solvent: C1COCCO1
Product: COc1c(-c2ccccc2)c(C)c(C#N)c2nc(C3CC3)oc12
Temperature: 100 °C
Reaction time: 15 h
Yield: 97.7 %

Procedure:
Under argon atmosphere, bis(triphenylphosphine)palladium(II) dichloride (777 mg, 1.11 mmol) was added to a 1,4-dioxane (110 ml) solution of 6-bromo-2-cyclopropyl-7-methoxy-5-methyl-1,3-benzoxazole-4-carbonitrile (I-83) (3.40 g, 11.1 mmol), tributylphenyltin (5.28 g, 14.4 mmol) and 2,6-di-tert-butylcresol (488 mg, 2.21 mmol), followed by stirring in an oil bath at 100° C. for 15 hours. The reaction liquid was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, and washed with water and saturated brine. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, and the residue obtained by concentration was washed with diethyl ether to obtain the entitled compound (3.30 g, 98%) as a pale gray solid.
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1)=[O:5].C[Mg+].[Br-].[C:21](O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[C:4]([CH:6]1[CH2:7][N:8]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:9]1)(=[O:5])[CH3:21]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CON(C)C(=O)C1CN(C(=O)OC(C)(C)C)C1
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 70 %

Procedure:
To a solution of tert-butyl 3-(methoxy(methyl)carbamoyl)azetidine-1-carboxylate (7.0 g, 28.7 mmol) in THF (150 mL) was added CH3MgBr (43 mL, 43 mmol) at 0° C., then slowly warmed to RT for about 2 hr. 10% aqueous of citric acid (30 mL) was added to the mixture, and extracted with EA (50 mL×3), the combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography on silica gel (200-300 mesh, PE/EA=2/1), to give the crude product (4.0 g, 70%) as a colorless oil. MS (ESI) m/e [M−55]+ 144.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[NH2:5].C(N(CC)CC)C.[C:18](OC(=O)C)(=[O:20])[CH3:19]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:18](=[O:20])[CH3:19])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(N)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(NC(C)=O)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.8 %

Procedure:
A mixture of 3-fluoro-4-methoxyaniline (56.4 g; 400 mmol) and triethylamine (56 ml; 400 mmol) in dichloromethane (400 ml) is cooled down using an ice bath. Acetic anhydride (57 ml; 600 mmol) is added dropwise and the reaction mixture is agitated for 3 hours at ambient temperature. The reaction medium is then washed successively with water, with an aqueous solution of 10% sodium bicarbonate then with an aqueous solution saturated in sodium chloride. The organic fraction is dried over sodium sulphate and concentrated under reduced pressure. The residue is recrystallized from an ethyl acetate/pentane mixture in order to produce 66.5 g (91%) of a white solid, m.p. 120° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[C:17]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:16][CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11].[CH2:22](Br)[CH:23]=[CH2:24].O>CN(C)C=O>[CH3:20][CH:19]([O:18][C:17]1[C:8]([O:7][CH2:24][CH:23]=[CH2:22])=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])[CH3:21]
Reactant: C=CCBr
Reactant: COC(=O)c1cccc(OC(C)C)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1c(OC(C)C)cccc1C(=O)OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79 %

Procedure:
Cesium carbonate (2.05 g, 6.2 mmol) was added to a solution of methyl 2-hydroxy-3-(propan-2-yloxy)benzoate (123c, 539 mg, 2.40 mmol) in N,N-dimethylformamide (9.6 mL), causing a thick paste to form. Allyl bromide (0.25 mL, 3.0 mmol) was added and the mixture stirred at room temperature for 1.5 hours. Deionized water (15 mL) was added, and the solution extracted with ethyl acetate (2×20 mL). The combined organic extracts were dried over magnesium sulfate, filtered, concentrated under vacuum, and purified by column chromatography (ethyl acetate/heptane) to give methyl 3-(propan-2-yloxy)-2-(prop-2-en-1-yloxy)benzoate (123d, 474.5 mg, 79% yield) as a colorless oil.
Reaction SMILES: [Li+].[OH-].[CH3:3][C:4](=[CH2:34])[C:5]#[C:6][C@@H:7]([N:13]1[CH2:18][CH2:17][C@@H:16]([CH2:19][C:20]([O:22]C)=[O:21])[CH2:15][C@H:14]1[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1)[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11].Cl>O.C1COCC1>[CH3:34][C:4](=[CH2:3])[C:5]#[C:6][C@@H:7]([N:13]1[CH2:18][CH2:17][C@@H:16]([CH2:19][C:20]([OH:22])=[O:21])[CH2:15][C@H:14]1[C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=1)[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: C=C(C)C#C[C@H](CCC(C)C)N1CC[C@@H](CC(=O)OC)C[C@H]1c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=C(C)C#C[C@H](CCC(C)C)N1CC[C@@H](CC(=O)O)C[C@H]1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.5 %

Procedure:
A solution of LiOH (67 mg, 2.8 mmol) in H2O (1 ml) was added to a stirred solution of methyl {(2S,4R)-1-[(1S)-4-methyl-1-(3-methylbutyl)pent-4-en-2-yn-1-yl]-2-[4-(trifluoromethyl)phenyl]piperidin-4-yl}acetate (Step 1, 250 mg, 0.56 mmol) in THF (2 ml) at RT. The mixture was stirred at RT for 18 hrs, then at 60° C. for 3 hrs. After cooling to RT 2N HCl was added and the THF was removed in vacuo. The residue was partitioned between CH2Cl2/H2O. The pH of the aqueous layer was adjusted to ˜pH7 with saturated aqueous NaHCO3. The aqueous layer was extracted with CH2Cl2 (×3). The combined extracts were dried (Na2SO4) filtered and evaporated. The residue was purified by chromatography (silica, 4% MeOH/CH2Cl2) to give the acid (228 mg) as a colourless foam. 1H NMR (500 MHz, CD3OD): δ 0.83 (6H, d, J 6.6), 1.12-1.20 (2H, m), 1.33-1.43 (3H, m), 1.58 (2H, q, J 7.8), 1.80 (1H, dd, J 2.8, 12.8), 1.85-1.91 (5H, s), 2.18-2.26 (2H, m), 2.48 (1H, t, J 11.1), 2.98-3.04 (1H, m), 3.16 (1H, t, J 7.6), 3.55 (1H, dd, J 2.5, 11.3), 5.21 (1H, s), 5.24 (1H, s), 7.53 (2H, d, J 7.6), 7.62 (2H, d, J 8.2); M/Z (ES+) 436 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([CH:26]2[CH2:28][CH2:27]2)[OH:25])=[CH:4][CH:3]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[F:60][CH:61]([F:64])[CH2:62]O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([CH:26]2[CH2:28][CH2:27]2)[O:25][CH2:62][CH:61]([F:64])[F:60])=[CH:4][CH:3]=1
Reactant: OCC(F)F
Reactant: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(O)C4CC4)c23)c(Cl)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(OCC(F)F)C4CC4)c23)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.6 %

Procedure:
To a solution of [9-chloro-1-(2-chloro-4-methoxyphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl](cyclopropyl)methanol (120 mg, 0.26 mmol), 1,1′-(azodicarbonyl)dipiperdine (131 mg, 0.52 mmol) in tetrahydrofuran (5.0 mL) was added tri(n-butyl)phosphine (0.130 mL, 0.52 mmol) at room temperature. After the mixture was stirred at room temperature for 10 min under nitrogen atmosphere, 2,2-difluoroethanol (0.165 mL, 2.61 mmol) was added to the reaction mixture. The mixture was stirred at 50° C. for 16 hr under nitrogen atmosphere. The mixture was concentrated in vacuo and diethyl ether was added to the residue. The solid was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture and recrystallization from ethyl acetate/n-hexane to give the title compound (72.8 mg, 0.155 mmol, 58%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([O:13][CH2:14][CH3:15])[C:6]([CH3:12])=[N:7]2.[NH2:16][C:17]1[N:22]=[C:21]([O:23][CH2:24][CH3:25])[CH:20]=[CH:19][CH:18]=1>Cl>[ClH:1].[CH2:14]([O:13][C:5]1[C:6]([CH3:12])=[N:7][C:8]2[C:3]([CH:4]=1)=[C:2]([NH:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([O:23][CH2:24][CH3:25])[N:22]=1)[CH:11]=[CH:10][N:9]=2)[CH3:15]
Reactant: CCOc1cc2c(Cl)ccnc2nc1C
Reactant: CCOc1cccc(N)n1
Agent: Cl
Product: CCOc1cccc(Nc2ccnc3nc(C)c(OCC)cc23)n1

Procedure:
A mixture of 5-chloro-3-ethoxy-2-methyl-1,8 naphthyridine (0.98 g), 6-amino-2-ethoxypyridine (0.6 g), IMS (25 ml) and concentrated hydrochloric acid (2 drops) was boiled under reflux for 18 hours. The mixture was cooled and filtered to give 3-ethoxy-5-(6-ethoxy-2-pyridylamino)-2-methyl-1,8-naphthyridine hydrochloride, m.p. >250° C. Active (1/1) at 30 mg/kg.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:5]#[N:6].C(N(CC)CC)C.N1C=CC=CC=1.[SH2:26]>O>[CH3:1][O:2][CH2:3][CH:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:5]([NH2:6])=[S:26]
Reactant: COCC(C#N)c1ccccn1
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: O
Product: COCC(C(N)=S)c1ccccn1
Temperature: 100 °C

Procedure:
Two grams of 3-methoxy-2-(2-pyridyl)propionitrile is dissolved in 1.5 g. of triethylamine and 2 g. of dry pyridine, saturated with hydrogen sulfide. The mixture is heated at 100° C. in a sealed bomb for 15 hours. The mixture is cooled, diluted with water and extracted with ether. The organic phase is dried, the solvent is removed and the residue is recrystallized from benzene-petroleum ether to give 3-methoxy-2-(2-pyridyl)thiopropanamide.