Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:27]=[CH:26][C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:24][C:20]=3[C:21](O)=[O:22])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.Cl.[NH2:40][C@H:41]1[CH2:46][CH2:45][CH2:44][CH2:43][C@H:42]1[C:47]([O:49][CH2:50][CH3:51])=[O:48]>>[C:1]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:2]=[CH:3][C:4]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:27]=[CH:26][C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:24][C:20]=3[C:21]([NH:40][C@@H:41]3[CH2:46][CH2:45][CH2:44][CH2:43][C@@H:42]3[C:47]([O:49][CH2:50][CH3:51])=[O:48])=[O:22])=[CH:13][CH:14]=2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1ccc(OCCCc2ccc(OCc3ccc(-c4ccccc4)cc3)cc2)c(C(=O)O)c1
Reactant: CCOC(=O)[C@@H]1CCCC[C@@H]1N
Agent: Cl
Product: CCOC(=O)c1ccc(OCCCc2ccc(OCc3ccc(-c4ccccc4)cc3)cc2)c(C(=O)N[C@@H]2CCCC[C@@H]2C(=O)OCC)c1

Procedure:
The compound is prepared in analogy to the process described in Example 6 from 2-{3-[4-(1,1′-biphenyl-4-ylmethoxy)phenyl]propoxy}-5-(ethoxycarbonyl)benzoic acid and ethyl cis-2-amino-1-cyclohexanecarboxylate hydrochloride.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=CC=C[N:4]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.O.NN.O>C(#N)C>[CH3:1][N:2]1[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][N:4]=[C:3]1[NH2:8]
Reactant: O=C(CBr)c1ccccc1
Reactant: CNc1ncccn1
Agent: NN
Solvent: CC#N
Solvent: O
Product: Cn1c(-c2ccccc2)cnc1N
Temperature: 130 °C

Procedure:
To a microwave vial containing a solution of N-methylpyrimidin-2-amine (90b, 290 mg, 2.7 mmol) in acetonitrile (5 mL) was added 2-bromo-1-phenylethanone (714 mg, 3.6 mmol). The vial was sealed and heated in a microwave reactor at 130° C. for 20 minutes and then cooled to room temperature. The reaction mixture was treated with hydrazine hydrate (0.65 mL, 13.3 mmol) and then heated in a microwave reactor at 100° C. for 5.0 minutes. The solution was poured into water and filtered the precipitate to give 1-methyl-5-phenyl-1H-imidazol-2-ylamine (90c).
Reaction SMILES: [CH2:1]([C:5]1[C:14](=[O:15])[C:13]2[C:8](=[C:9]([Br:16])[CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[C:25]([C:30]([O:32]C)=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)[CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C(O)C>[CH2:1]([C:5]1[C:14](=[O:15])[C:13]2[C:8](=[C:9]([Br:16])[CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[C:25]([C:30]([OH:32])=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:22][CH:23]=2)[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cn(Cc2ccc(-c3ccccc3C(=O)OC)cc2)c2c(Br)cccc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1cn(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2c(Br)cccc2c1=O
Yield: 32.5 %

Procedure:
Using the procedure of Example 2, 380 mg of the product of Example 17 and 10 ml of N sodium hydroxide and 5 ml of ethanol were reacted to obtain 120 mg of the desired product melting at 180° C. after being crystallized from ethyl acetate.
Reaction SMILES: [C:1](C1C=CC(OCC2C=CC(C(C3C=CC=C(C4NN=NN=4)C=3)NC(=O)C)=CC=2)=C(CCC)C=1O)(=[O:3])[CH3:2].[C:38]([C:41]1[CH:65]=[CH:64][C:44]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][C:50]([CH:53]([NH2:63])[C:54]3[CH:55]=[C:56]([CH:60]=[CH:61][CH:62]=3)[C:57]([OH:59])=[O:58])=[CH:49][CH:48]=2)=[C:43]([CH2:66][CH2:67][CH3:68])[C:42]=1[OH:69])(=[O:40])[CH3:39]>>[C:1]([NH:63][CH:53]([C:50]1[CH:49]=[CH:48][C:47]([CH2:46][O:45][C:44]2[CH:64]=[CH:65][C:41]([C:38](=[O:40])[CH3:39])=[C:42]([OH:69])[C:43]=2[CH2:66][CH2:67][CH3:68])=[CH:52][CH:51]=1)[C:54]1[CH:55]=[C:56]([CH:60]=[CH:61][CH:62]=1)[C:57]([OH:59])=[O:58])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCc2ccc(C(NC(C)=O)c3cccc(-c4nnn[nH]4)c3)cc2)ccc(C(C)=O)c1O
Reactant: CCCc1c(OCc2ccc(C(N)c3cccc(C(=O)O)c3)cc2)ccc(C(C)=O)c1O
Product: CCCc1c(OCc2ccc(C(NC(C)=O)c3cccc(C(=O)O)c3)cc2)ccc(C(C)=O)c1O

Procedure:
The title compound is prepared in a similar manner to N-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-[3-(1H-tetrazol-5-yl)-phenyl]-methyl}-acetamide employing 3-{[4-(4-Acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-amino-methyl}-benzoic acid to give a white solid (48%). 1H NMR (DMSO-d6) δ 13.01 (bs, 1H), 12.86 (s, 1H), 8.89 (d, 1H), 7.80-7.88 (m, 3H), 7.37-7.57 (m, 6H), 6.72 (d, 1H), 6.20 (d, 1H), 5.25 (s, 2H), 2.57-2.62 (m, 5H), 1.95 (s, 3H), 1.46-1.53 (m, 2H), 0.88 (t, 3H). LCMS M+1 476.
Reaction SMILES: [S:1]([OH:5])(=[O:4])(=[O:3])[CH3:2].[OH:6][CH2:7][CH2:8][N:9]1[CH2:13][CH2:12][N:11]=[C:10]1SC.[NH2:16][NH2:17]>C(O)C.COC(C)(C)C>[S:1]([OH:5])(=[O:4])(=[O:3])[CH3:2].[OH:6][CH2:7][CH2:8][N:9]1[CH2:13][CH2:12][N:11]=[C:10]1[NH:16][NH2:17]
Reactant: CSC1=NCCN1CCO
Reactant: NN
Agent: CS(=O)(=O)O
Solvent: COC(C)(C)C
Solvent: CCO
Product: NNC1=NCCN1CCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(2-Hydroxyethyl)-2-methylthioimidazoline mesylate (35 g, 0.136 mole) is suspended in ethyl alcohol (80 ml) and treated with anhydrous hydrazine (9.3 ml, 0.296 mole). The mixture became clear immediately. The solution is stirred at room temperature overnight and then diluted with t-butyl methyl ether (1 liter). On storage of the mixture in the freezer at -20° C., crystals separated, which are filtered, washed well with t-butyl methyl ether and dried. Recrystallization from isopropyl alcohol and t-butyl methyl ether gives 1-(2-hydroxyethyl)-2-hydrazinoimidazoline mesylate, melting point 85°-88° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].CS(O[CH2:30][CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[CH2:9]([O:8][C:6]([NH:5][C@@H:4]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:30][CH2:31][NH:32][C:33]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:39])=[CH:21][CH:22]=1)[C:3]([O:2][CH3:1])=[O:24])=[O:7])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)[C@H](Cc1ccc(OCCNC(=O)OC(C)(C)C)cc1)NC(=O)OCc1ccccc1
Yield: 46.8 %

Procedure:
In a similar manner to that described in Reference example 25, a reaction was carried out using N-benzyloxycarbonyl-L-tyrosine methyl ester (4.94 g), t-butyl 2-methanesulfonyloxyethylcarbamate (8.97 g) and potassium carbonate (10.4 g) and the reaction mixture was treated to afford the title compound (3.32 g) as colorless crystals.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1>C(Cl)Cl>[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:11][CH:12]=2)=[O:19])=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(CN)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(CNC(=O)c2ccc(Cl)cc2)cc1
Reaction time: 12 h
Yield: 57.3 %

Procedure:
To a stirred solution of methyl 4-(aminomethyl)benzoate (75 g, 0.46 mol) and TEA (315 mL, 2.27 mol) in anhydrous DCM (1.5 L) was added a solution of freshly prepared 4-chloro benzoyl chloride (0.91 mol) in DCM (400 mL). The resulting mixture was allowed to stir for 12 hrs. The reaction was quenched with a 10% aqueous solution of sodium hydrogenocarbonate. The organic layer was washed with a 1.5N HCl solution and water. After drying over MgSO4 and evaporation of the solvent in vacuo, a solid was obtained. Recrystallization form MeOH gave the title compound (80 g) in a 60% yield as a white powder.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:30])[NH:21][CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26]C=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CO.C(Cl)Cl>[CH2:22]([NH:21][C:20](=[O:30])[C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:15][CH:16]=1)[C:23]1[CH:24]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)NCCc3ccccc3)cn2)CC1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: O=C(NCc1ccccc1)c1ccc(N2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-(5-phenethylcarbamoyl-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (200 mg) in MeOH (5 ml) was cooled to 0° C. and slowly treated with 4N HCl (2.52 ml). The reaction mixture was stirred at r.t. overnight, then diluted with CH2Cl2 and directly purified by column chromatography (Isolute® SPE flash NH2 column, aminopropyl-functionalized silica; gradient: CH2Cl2→CH2Cl2/MeOH 9:1) to give N-benzyl-6-piperazin-1-yl-nicotinamide as off-white solid. MS (ISP): 297.5 ([M+H]+)
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15].[N:16]1([C:22]2[N:23]=[C:24]3[NH:32][C@H:31]([C:33]([F:36])([F:35])[F:34])[CH2:30][CH2:29][N:25]3[C:26](=[O:28])[CH:27]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.O>CN(C)C=O>[Cl:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][N:32]1[C:24]2=[N:23][C:22]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:27][C:26](=[O:28])[N:25]2[CH2:29][CH2:30][C@H:31]1[C:33]([F:34])([F:35])[F:36]
Reactant: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2
Reactant: Clc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2Cc1ccccc1Cl
Reaction time: 16 h

Procedure:
214 mg of caesium carbonate and 74 mg of 1-(bromomethyl)-2-chlorobenzene are added to a solution of 100 mg of (8S)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one (Example 1e) in 2 ml of dimethylformamide. After 16 hours at a temperature in the region of 20° C., the reaction medium is run into water. The organic phase is separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are concentrated to dryness under reduced pressure. The residue is purified by preparative HPLC/MS (Method C). After evaporation of the acetonitrile and lyophilization, 94 mg of (8S)-9-(2-chloro-benzyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained in the form of an oil, the characteristics of which are the following:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH2:13][CH:14]3[CH2:16][CH:15]3[C:17]([O:19]CC)=[O:18])[CH:12]=2)=[CH:4][C:3]=1[O:22][CH:23]([C:25]1[C:30]([Cl:31])=[CH:29][CH:28]=[C:27]([F:32])[C:26]=1[Cl:33])[CH3:24].[OH-].[Na+]>CO>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH2:13][CH:14]3[CH2:16][CH:15]3[C:17]([OH:19])=[O:18])[CH:12]=2)=[CH:4][C:3]=1[O:22][CH:23]([C:25]1[C:30]([Cl:31])=[CH:29][CH:28]=[C:27]([F:32])[C:26]=1[Cl:33])[CH3:24]
Reactant: CCOC(=O)C1CC1Cn1cc(-c2cnc(N)c(OC(C)c3c(Cl)ccc(F)c3Cl)c2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(Oc1cc(-c2cnn(CC3CC3C(=O)O)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 91.6 %

Procedure:
To a reaction solution of compound (4-6) (377 mg, 0.76 mmol) in 5.0 mL of MeOH at room temperature under N2 was added another solution of 2.0 N NaOH (2) (1.5 mL, 3.04 mmol). The resulting mixture was stirred at 80° C. for 3 hours. The reaction mixture was concentrated by vacuum to remove most of the MeOH and acidified by 2 M HCl to pH 4.0. The mixture was extracted with CH2Cl2 (2×200 mL); the organic layers were washed with brine (50 mL), and dried (Na2SO4) and concentrated by vacuum to give 324 mg of (4-7) as a yellow solid. (92% yield). 1H NMR (400 MHz, DMSO-D6) δ ppm 0.92-1.04 (m, 2H) 1.57-1.72 (m, 2H) 1.76-1.90 (m, 3H) 3.98-4.18 (m, 2H) 6.46 (s, 2H) 6.89-7.02 (m, 1H) 7.29-7.52 (m, 2H) 7.52-7.63 (m, 2H) 7.73 (d, J=1.52 Hz, 1H) 7.94 (s, 1H) 12.19 (s, 1H). LCMS calcd for C21H19Cl2FN4O3(M−H) 463, found 463. HPLC purity 87%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[CH:5]=[CH:4][C:3]=1[C:16](=[N:18]O)[CH3:17].N.[H][H]>CO.[Ni]>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[CH:5]=[CH:4][C:3]=1[CH:16]([NH2:18])[CH3:17]
Reactant: [H][H]
Reactant: CC(=NO)c1ccc(Oc2ccccc2Cl)cc1Cl
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC(N)c1ccc(Oc2ccccc2Cl)cc1Cl
Temperature: 25 °C

Procedure:
1.8 g (6.08 mmol) of 1-[2-chloro-4-(2-chloro-phenoxy)-phenyl]-ethanone-oxime was dissolved in 50 mL methanol and 50 mL 7M methanolic ammonia were added, followed by 400 mg Raney nickel. The mixture was shaken at RT and 50 psi hydrogen pressure. The catalyst was suction filtered and the filtrate was evaporated down. The residue was purified by chromatography (silica gel column, dichloromethane:methanol=50:1 to 9:1)
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[C:4]([CH2:21][CH3:22])[CH:3]=1.[CH3:23][O-:24].[Na+].O>CO>[CH2:21]([C:4]1[CH:3]=[C:2]([O:24][CH3:23])[N:7]=[N:6][C:5]=1[CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[CH3:22]
Reactant: C[O-]
Reactant: CCc1cc(Cl)nnc1Cn1ccnc1-c1cccc(F)c1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCc1cc(OC)nnc1Cn1ccnc1-c1cccc(F)c1

Procedure:
A solution of 6-chloro-4-ethyl-3-[2-(3-fluoro-phenyl)-imidazol-1-ylmethyl]-pyridazine (73.3 mg, 0.23 mmol) and sodium methoxide (40 mg, 0.74 mmol) in methanol (5 mL) is heated under N2 for 5 hours. After cooling, water (10 mL) is added, followed by extraction with ethyl acetate (3×30 mL). The solvent is removed in vacuo and PTLC separation gives the title compound. LC-MS (M+1) 313.1 (retention time: 0.99 min).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8](O)=[O:9])=[CH:4][CH:3]=1.[ClH:13].[NH:14](C1C=C(C=CC=1)C([Cl:23])=O)[C:15](N)=[NH:16]>>[ClH:23].[NH:1]([C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([Cl:13])=[O:9])=[CH:4][CH:3]=1)[C:15]([NH2:16])=[NH:14]
Reactant: Nc1ccc(C=CC(=O)O)cc1
Reactant: N=C(N)Nc1cccc(C(=O)Cl)c1
Agent: Cl
Product: N=C(N)Nc1ccc(C=CC(=O)Cl)cc1

Procedure:
The 4-guanidinocinnamoyl chloride hydrochloride was prepared from 4-aminocinnamic acid according to the procedure of Example XII for preparing 3-guanidinobenzoyl chloride hydrochloride.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C:9]2[CH:10]=[CH:11][C:12]([CH3:35])=[C:13]([C:15]3[CH:16]=[CH:17][C:18]4[O:22][C:21]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=5)=[C:20]([C:30]([NH:32][CH3:33])=[O:31])[C:19]=4[CH:34]=3)[CH:14]=2)=[O:8])[CH2:5][CH2:4]1)#[N:2].Cl.[NH2:37][OH:38].CCN(CC)CC>C(O)C>[F:29][C:26]1[CH:25]=[CH:24][C:23]([C:21]2[O:22][C:18]3[CH:17]=[CH:16][C:15]([C:13]4[CH:14]=[C:9]([C:7](=[O:8])[NH:6][C:3]5([C:1](=[NH:2])[NH:37][OH:38])[CH2:4][CH2:5]5)[CH:10]=[CH:11][C:12]=4[CH3:35])=[CH:34][C:19]=3[C:20]=2[C:30]([NH:32][CH3:33])=[O:31])=[CH:28][CH:27]=1
Reactant: NO
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(C#N)CC4)ccc3C)cc12
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(C(=N)NO)CC4)ccc3C)cc12
Temperature: 115 °C

Procedure:
To a mixture of 5-(5-(1-cyanocyclopropylcarbamoyl)-2-methylphenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (43.5 mg, 0.093 mmol) in ethanol (1.5 mL) at r.t. under N2 was added hydroxylamine hydrochloride (12.93 mg, 0.186 mmol), followed by Et3N (0.039 mL, 0.279 mmol). The mixture was stirred at reflux (115° C.) for about 4 hours. The mixture was cooled to r.t. and evaporated. The residue was used for the next step without further purification. LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters MICROMASS®. HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column: PHENOMENEX® Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)+=501.13, HPLC Rt=1.385 min.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:19](=[O:20])[N:18]([CH:21]([F:23])[F:22])[C:17]([CH3:24])=[N:16]2)=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6](O)=[O:7].[C:25]1([CH3:37])[CH:30]=[CH:29][C:28]([S:31]([N:34]=C=O)(=[O:33])=[O:32])=[CH:27][CH:26]=1>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[CH3:37][C:25]1[CH:26]=[CH:27][C:28]([S:31]([NH:34][C:6](=[O:7])[CH:5]([O:4][C:3]2[CH:10]=[C:11]([N:15]3[C:19](=[O:20])[N:18]([CH:21]([F:23])[F:22])[C:17]([CH3:24])=[N:16]3)[C:12]([F:14])=[CH:13][C:2]=2[Cl:1])[CH3:9])(=[O:33])=[O:32])=[CH:29][CH:30]=1
Reactant: Cc1nn(-c2cc(OC(C)C(=O)O)c(Cl)cc2F)c(=O)n1C(F)F
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)NC(=O)C(C)Oc2cc(-n3nc(C)n(C(F)F)c3=O)c(F)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.2 %

Procedure:
A stirred mixture of 0.78 g (0.0021 mole) of 2-[2-chloro-4-fluoro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenoxy]propionic acid, 0.42 g (0.0021 mole) of p-toluenesulfonyl isocyanate and 0.05 g (0.0004 mole) of 4-dimethylaminopyridine in 50 mL of toluene was heated at reflux for approximately 18 hours. The mixture was allowed to cool to room temperature and was stirred for 24 hours. The solvent was removed by evaporation at reduced pressure to leave a residue. This residue was purified by column chromatography on silica gel, eluting with toluene:ethyl acetate (1:1). The appropriate fractions were combined and evaporated under reduced pressure to yield 0.7 g of N-(4-methylphenylsulfonyl)-2-[2-chloro-4-fluoro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenoxy]propionamide as a solid, Compound C10.
Reaction SMILES: [OH:1][C:2]1([CH2:15][CH:16]=O)[CH2:14][CH2:13][C:5]2([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]2)[CH2:4][CH2:3]1.[C:18]1([C@@H:24]([NH2:26])[CH3:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:11][C:8]1([CH3:12])[CH2:9][O:10][C:5]2([CH2:13][CH2:14][C:2]([CH2:15][CH2:16][NH:26][C@H:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:25])([OH:1])[CH2:3][CH2:4]2)[O:6][CH2:7]1
Reactant: CC1(C)COC2(CCC(O)(CC=O)CC2)OC1
Reactant: C[C@H](N)c1ccccc1
Product: C[C@H](NCCC1(O)CCC2(CC1)OCC(C)(C)CO2)c1ccccc1
Yield: 62 %

Procedure:
The title compound is prepared from (9-hydroxy-3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-yl)-acetaldehyde and (S)-1-phenyl-ethylamine following a procedure analogous to that described in Step 3 of Intermediate 2. Yield: 62% of theory; LC (method 6): tR=1.10 min; Mass spectrum (ESI+): m/z=348 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7](O)[CH3:8])[CH:2]=1.[CH3:10][C:11]1[C:17]([CH3:18])=[C:16]([OH:19])[C:15]([CH3:20])=[CH:14][C:12]=1[OH:13].FC(F)(F)S(O)(=O)=O>ClC(Cl)C>[CH3:20][C:15]1[C:16](=[O:19])[C:17]([CH3:18])=[C:11]([CH3:10])[C:12](=[O:13])[C:14]=1[CH:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH3:8]
Reactant: CC(O)c1cccnc1
Reactant: Cc1cc(O)c(C)c(C)c1O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: CC1=C(C)C(=O)C(C(C)c2cccnc2)=C(C)C1=O
Temperature: 0 °C
Yield: 61.5 %

Procedure:
To a solution of 4.0 g (32.5 mmol) of 1- (3-pyridyl)ethanol in 25 ml of dichloroethane, 4.96 g (32.6 mmol) of 2,3,5-trimethylhydroquinone and 4.5 ml (50.9 mmol) of trifluoromethanesulfonic acid were added and refluxed by heating for 20 hours in argon atomosphere. After cooling, ice water was added, washed with ethyl acetate to eliminate neutral substances, and made weakly alkaline with a saturated solution of sodium hydrogen carbonate. The resultant substance was extracted with ethyl acetate, and the extract was washed with water, dried, oxidized with air and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (isopropyl ether-ethyl acetate (1:2)), to give 5.1 g of 3,5,6-trimethyl-2-[1-(3-pyridyl)ethyl]-1,4-benzoquinone (yield 61%). Physical data of this compound are shown in Table 1.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:21])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[N:7]=1.[CH3:22][P:23]([C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[C:28]([F:33])[CH:27]=1)([CH3:25])=[O:24].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CC(O)C.ClCCl>[Cl:21][C:5]1[N:4]=[N:3][C:2]([NH:30][C:29]2[CH:31]=[CH:32][C:26]([P:23]([CH3:22])([CH3:25])=[O:24])=[CH:27][C:28]=2[F:33])=[N:7][C:6]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16]
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nnc1Cl
Reactant: CP(C)(=O)c1ccc(N)c(F)c1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Nc2ccc(P(C)(C)=O)cc2F)nnc1Cl
Temperature: 25 °C

Procedure:
A mixture of 3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine (prepared as in Example 106: 0.7 mmol), 4-(Dimethylphosphoryl)-2-fluoroaniline (0.7 mmol) and camphorsulfonic acid (0.7 equiv.), is refluxed for 20-48 hours in 2-propanol. The reaction mixture is allowed to cool to room temperature, dissolved in dichloromethane and washed with an aqueous solution of Na2CO3. The dichloromethane extract is dried over MgSO4 and evaporated. The crude product is purified by Prep-HPLC.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5].S(=O)(=O)(O)O.C(Cl)(Cl)Cl.[CH2:24](O)[CH3:25]>>[OH:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([O:10][CH2:24][CH3:25])=[O:9])=[O:5]
Reactant: CCO
Reactant: O=C(O)CCC(=O)c1ccccc1O
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCC(=O)c1ccccc1O
Temperature: 0 °C

Procedure:
A solution of 3-(o-hydroxybenzoyl)propionic acid (18.8 g.) in ethanol (120 ml.) was treated with concentrated sulphuric acid (1 ml.) and the mixture heated at reflux temperature for 12 hours. It was cooled, poured into ice-water (350 ml.) and the oily solid isolated with chloroform. It (18.6 g.) was purified by distillation at reduced pressure and had bp 112°-113° C at 0.1 mm; nD24.5 = 1.5301.
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[CH3:8]CCCCC.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([OH:25])[C:22]([OH:24])=[O:23])=[CH:17][CH:16]=1.CO>C1C=CC=CC=1>[CH3:8][O:23][C:22](=[O:24])[CH:21]([C:18]1[CH:17]=[CH:16][C:15]([Br:14])=[CH:20][CH:19]=1)[OH:25]
Reactant: O=C(O)C(O)c1ccc(Br)cc1
Reactant: CCCCCC
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)C(O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 93.2 %

Procedure:
A solution of trimethylsilyldiazomethane in hexane (2 M, 1.4 mL, 2.8 mmol) was added to a solution of 4-bromo-phenyl-hydroxy-acetic acid (506 mg, 2.19 mmol) in benzene (2.1 mL)-methanol (1.0 mL) under cooling with ice, and the mixture was stirred at room temperature for five minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=3/1) to give the title compound (500 mg, 93%).
Reaction SMILES: P([O-])(O)(O)=O.[Na+].Cl([O-])=O.[Na+].[OH:11]O.[CH3:13][O:14][C:15]1[C:16]([CH3:44])=[C:17]([C:35]([O:42][CH3:43])=[C:36]([O:40][CH3:41])[C:37]=1[O:38][CH3:39])[CH2:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[C:21]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:20]=1>O.C(#N)C>[CH3:13][O:14][C:15]1[C:16]([CH3:44])=[C:17]([C:35]([O:42][CH3:43])=[C:36]([O:40][CH3:41])[C:37]=1[O:38][CH3:39])[CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]([OH:11])=[O:24])=[C:21]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:20]=1
Reactant: OO
Reactant: COc1c(C)c(Cc2ccc(C=O)c(OCc3ccccc3)c2)c(OC)c(OC)c1OC
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC#N
Product: COc1c(C)c(Cc2ccc(C(=O)O)c(OCc3ccccc3)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
An aqueous solution (2 ml) of sodium dihydrogenphosphate (157 mg, 1.31 mmol), an aqueous solution (7 ml) of sodium chlorite (795 mg, 80%, 7.07 mmol) and aqueous hydrogen peroxide (0.5 ml, 30%) were added to an acetonitrile solution (5 ml) of 4-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-benzyloxybenzaldehyde (735 mg, 1.69 mmol) and the resulting solution was stirred at room temperature for 16 hours. The reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with an aqueous 10% sodium hydrosulfite (Na2S2O4) solution and saturated brine, then dried and concentrated to obtain the titled compound (603 mg, 1.33 mmol, 79%).