Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)[CH:3]1[CH2:7][CH2:6][O:5][C:4]1=[O:8]>C(O)C.[Pd]>[CH3:16][O:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[CH2:2][CH:3]1[CH2:7][CH2:6][O:5][C:4]1=[O:8]
Reactant: COc1cccc(C(O)C2CCOC2=O)c1
Agent: [Pd]
Solvent: CCO
Product: COc1cccc(CC2CCOC2=O)c1
Reaction time: 10 h
Yield: 86.2 %

Procedure:
A mixture of 3-[hydroxy(3-methoxyphenyl)methyl]-2-oxotetrahydrofuran (1.0 g) and 10% Pd/C (0.5 g) in ethanol (20 ml) was stirred under H2 for 10 hours. The catalyst was filtered off and the filtrate was evaporated in vacuo to give 3-(3-methoxybenzyl)-2-oxotetrahydrofuran (0.8 g) MS (m/z): 207 (M+ +1) IR (Neat): 1750 cm-1NMR (CDCl3, δ): 2.0-2.6 (4H, m), 2.7-3.2 (3H, m), 3.79 (3H, s), 4.1-4.4 (2H, m), 6.7-7.1 (3H, m), 7.2-7.4 (1H, m)
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]([C:33]([O:35]CC)=[O:34])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[CH2:29][CH2:28][CH2:27][NH:26][C:25]=3[N:24]=2)=[CH:15][CH:14]=1.C(Cl)Cl.CO.[NH4+].[OH-]>C(O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]([C:33]([OH:35])=[O:34])[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[CH2:29][CH2:28][CH2:27][NH:26][C:25]=3[N:24]=2)=[CH:17][CH:18]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCc2ccc3c(n2)NCCC3)cc1)Nc1nc2ccccc2s1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Solvent: CO
Product: O=C(O)[C@H](Cc1ccc(OCCCc2ccc3c(n2)NCCC3)cc1)Nc1nc2ccccc2s1

Procedure:
The operation is carried out as for 1-6 but starting with 0.15 ml of 2N soda (0.3 mmole) and 80 mg of 2-1 (0.155 mmole) in 5 ml of ethanol. Rf=0.28 (CH2Cl2/MeOH/NH4OH 90/10/1)
Reaction SMILES: [CH:1]1([C:4]2[C:12]3[C:7](=[N:8][CH:9]=[CH:10][C:11]=3[O:13][C:14]3[C:20]([F:21])=[CH:19][C:17]([NH2:18])=[CH:16][C:15]=3[F:22])[NH:6][CH:5]=2)[CH2:3][CH2:2]1.Cl[C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[N:27]=[C:26]([NH2:34])[N:25]=1.Cl.[OH-].[Na+]>O.C(O)C>[CH:1]1([C:4]2[C:12]3[C:7](=[N:8][CH:9]=[CH:10][C:11]=3[O:13][C:14]3[C:15]([F:22])=[CH:16][C:17]([NH:18][C:24]4[CH:29]=[C:28]([C:30]([F:33])([F:31])[F:32])[N:27]=[C:26]([NH2:34])[N:25]=4)=[CH:19][C:20]=3[F:21])[NH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: Nc1nc(Cl)cc(C(F)(F)F)n1
Reactant: Nc1cc(F)c(Oc2ccnc3[nH]cc(C4CC4)c23)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1nc(Nc2cc(F)c(Oc3ccnc4[nH]cc(C5CC5)c34)c(F)c2)cc(C(F)(F)F)n1

Procedure:
330 mg (1.10 mmol) of 4-[(3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluoroaniline and 320 mg (1.64 mmol) of 4-chloro-6-(trifluoromethyl)pyrimidine-2-amine are suspended in 4 ml of water and 2 ml of ethanol. 0.55 ml (2.2 mmol) of 4N hydrochloric acid is added, and the mixture is heated at reflux for 1 h. Another 107 mg (0.55 mmol) of 4-chloro-6-(trifluoromethyl)pyrimidine-2-amine are then added, and the mixture is heated for a further 2 hours. The mixture is made alkaline by addition of 1N aqueous sodium hydroxide solution and extracted with ethyl acetate, and the organic phase is washed with water. The organic phase is dried over sodium sulfate and the solvent is removed under reduced pressure. The product is purified by preparative HPLC.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C1COCC1.[CH2:14]([N:16]1[C:22]2[CH:23]=[C:24]([O:29][CH3:30])[C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N:19][CH2:18][C:17]1=[O:37])[CH3:15].[N+:38]([C:41]1[CH:48]=[CH:47][CH:46]=[CH:45][C:42]=1[CH2:43]Br)([O-:40])=[O:39].O>C1COCC1>[CH3:28][O:27][C:25]1[C:24]([O:29][CH3:30])=[CH:23][C:22]2[N:16]([CH2:14][CH3:15])[C:17](=[O:37])[CH:18]([CH2:43][C:42]3[CH:45]=[CH:46][CH:47]=[CH:48][C:41]=3[N+:38]([O-:40])=[O:39])[N:19]=[C:20]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:21]=2[CH:26]=1
Reactant: CCN1C(=O)CN=C(c2ccccc2)c2cc(OC)c(OC)cc21
Reactant: O=[N+]([O-])c1ccccc1CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCN1C(=O)C(Cc2ccccc2[N+](=O)[O-])N=C(c2ccccc2)c2cc(OC)c(OC)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
To a solution of 920 μl (1.84 mmol) of 2M LDA/THF in 5 ml of anhydrous THF, add dropwise at −78° C. under an inert atmosphere a solution of 300 mg (0.92 mmol) of 1-ethyl-7,8-dimethoxy-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (IIbd) in 2 ml of THF. Allow to equilibrate to room temperature for 30 minutes. Add dropwise at −30° C. a solution of 220 mg (1.01 mmol) of 2-nitrobenzyl bromide in 2 ml of THF. Stir at room temperature for 12 hours. Add 1 ml of H2O. Evaporate the THF. Purify by silica chromatography (AcOEt 1/hexane 4, 1/1, then AcOEt). Recrystallize in EtOH/cHexane. Yield: 35%. M: 158–160° C. 1H-NMR (DMSO, 300 MHz): d 0.87–0.91 (m, 3H, CH3), 3.61–3.99 (m, 10H, NCH+CHCH2+2OCH3), 4.35–4.40 (m, 1H, NCH), 6.60 (s, 1H Ar), 6.82 (s, 1 H Ar), 7.37–7.90 (m, 9H Ar). Mass: (M+H)+=460.88.
Reaction SMILES: ClC1C=CC(OC(F)F)=C(C2C(NC(C3C=NN4C=CC=NC=34)=O)=C[N:10]([CH2:25][C:26]([N:28]3[CH2:35][C@@H:34]4[C@@H:30](CN(C)C4)[CH2:29]3)=O)N=2)C=1.[Cl:41][C:42]1[CH:43]=[CH:44][C:45]([O:69][CH:70]([F:72])[F:71])=[C:46]([C:48]2[C:52]([NH:53][C:54]([C:56]3[CH:57]=[N:58][N:59]4[CH:64]=[CH:63][CH:62]=[N:61][C:60]=34)=[O:55])=[CH:51][N:50]([CH2:65][C:66](O)=[O:67])[N:49]=2)[CH:47]=1.C(N1CCNCC1)C>>[Cl:41][C:42]1[CH:43]=[CH:44][C:45]([O:69][CH:70]([F:71])[F:72])=[C:46]([C:48]2[C:52]([NH:53][C:54]([C:56]3[CH:57]=[N:58][N:59]4[CH:64]=[CH:63][CH:62]=[N:61][C:60]=34)=[O:55])=[CH:51][N:50]([CH2:65][C:66]([N:10]3[CH2:25][CH2:26][N:28]([CH2:29][CH3:30])[CH2:35][CH2:34]3)=[O:67])[N:49]=2)[CH:47]=1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Reactant: CN1C[C@@H]2CN(C(=O)Cn3cc(NC(=O)c4cnn5cccnc45)c(-c4cc(Cl)ccc4OC(F)F)n3)C[C@@H]2C1
Agent: CCN1CCNCC1
Product: CCN1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1

Procedure:
The title compound was prepared in an analogous manner to cis-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid {3-(5-chloro-2-difluoromethoxyphenyl)1-[2-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2-yl)-2-oxoethyl]-1H-pyrazol-4-yl}amide using {3-(5-chloro-2-difluoromethoxy-phenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid and ethyl piperazine to afford the title compound as a white solid. LCMS (Method 5) [M+H]+=559.1, RT=2.89 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.0 Hz), 8.69-8.67 (m, 2H), 8.31 (s, 1H), 7.63 (dd, 1H, J=2.7, 8.8 Hz), 7.56 (d, 1H, J=2.6 Hz), 7.46 (d, 1H, J=9.0 Hz), 7.29 (dd, 1H, J=4.2, 7.1 Hz), 7.25 (t, 1H, J=73.5 Hz), 5.23 (s, 2H), 3.50-3.49 (m, 4H), 2.41-2.32 (m, 6H), 1.02 (t, 3H, J=7.1 Hz).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]1(C)[CH:15]=CC=C[CH:11]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O-]Cl.[Na+]>O>[CH2:1]([OH:9])[CH2:2][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:10]([CH3:15])[CH3:11]
Reactant: Cc1ccccc1
Reactant: O=C(O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Product: CC(C)CCCCCCCO
Temperature: 100 °C
Yield: 98.3 %

Procedure:
2 moles); benzoic acid (250 grams; 2.05 moles), toluene (100 ml) and para toluene sulfonic acid (2 grams) were placed into a glass reaction flask equipped with stirrer, thermometer, heating mantle, 12" column packed with 1/4" glass rings, Dean-Stark water trap, and condenser. The temperature increased from 26° C. to 187° C. as the reaction proceeded with stirring Then the reaction mixture was cooled to 100° C. Soda ash (100 ml; 20% solution) was added to the mixture and was followed by the addition of a mixture of soda ash (50 ml; 20% solution) and chlorox (100 ml) at 81°-100° C. The alkaline bottom layer was separated from the mixture. After the mixture was dried, the toluene was removed by heating the mixture to 178° C. at 45 mmHg. The desired product (515 grams) was obtained after filtration, representing a yield of 98.3%.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]2[N:6]=[C:7]([NH:9][CH3:10])[S:8][C:4]=2[CH:3]=1.[Cl:13][S:14](O)(=[O:16])=[O:15]>>[Cl:1][C:2]1[CH:3]=[C:4]2[S:8][C:7]([NH:9][CH3:10])=[N:6][C:5]2=[C:11]([S:14]([Cl:13])(=[O:16])=[O:15])[CH:12]=1
Reactant: CNc1nc2ccc(Cl)cc2s1
Reactant: O=S(=O)(O)Cl
Product: CNc1nc2c(S(=O)(=O)Cl)cc(Cl)cc2s1

Procedure:
A solution of 6-chloro-N-methylbenzo[d]thiazol-2-amine (500 mg, 2.53 mmol) in chlorosulfonic acid (5 mL) was stirred at 130° C. overnight. The solution was allowed to cool and slowly added to a large excess of ice. The aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by chorography (silica gel) eluting with PE/EA=1:1 to get the title compound. 1H NMR (CHLOROFORM-d) δ: 7.95 (d, J=1.9 Hz, 1H), 7.89 (d, J=2.1 Hz, 1H), 6.70 (br. s., 1H), 3.16 (d, J=4.3 Hz, 3H). LC-MS: m/z 297 (M+H)+
Reaction SMILES: [C:1]1([C@H:7]([N:9]2[C:13]3[CH2:14][O:15][C:16](=[O:17])[C:12]=3[NH:11][C:10]2=[O:18])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CN(C)C=O.[Rh]>[C:1]1([C@H:7]([N:9]2[C@H:13]3[CH2:14][O:15][C:16](=[O:17])[C@H:12]3[NH:11][C:10]2=[O:18])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](c1ccccc1)n1c2c([nH]c1=O)C(=O)OC2
Agent: [Rh]
Solvent: CN(C)C=O
Product: C[C@H](c1ccccc1)N1C(=O)N[C@@H]2C(=O)OC[C@@H]21
Reaction time: 10 h

Procedure:
A solution of 8.98 (36.8 mmol) of 1-[(R)-(1-phenylethyl)]-1H-furo[3,4-d]-imidazol-2,4(3H,6H)-dione in 90 ml of dimethylformamide was placed in a 250-ml autoclave and 0.90 g of RH/Al2O3 (5 percent) is added. Then the autoclave was flushed twice successively with hydrogen, and filled to 40 bars. The mixture was stirred for 10 hours. Then the catalyst was filtered off. The solvent was evaporated at 13.3 mbar and the residue was crystallized with 10 ml of ethyl acetate. (3aS,6aR)-1-[(R)-(1-phenylethyl)]-dihydro-1H-furo[3,4-d]-imidazol-2,4(3H,3aH)-dione was obtained as a white crystalline product in a yield of 4.89 g =54 percent. Concerning the product:
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([N:9]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([N:23]4CCCC[CH2:24]4)=[O:22])=[CH:17][CH:16]=3)[C:10]2=[O:29])=[N:6][C:5]=1[CH3:30])(=O)C.C([C:34]1SC(N2CCN(CC3C=CC(C(NC)=O)=CC=3)C2=O)=[N:36][C:35]=1[CH3:56])(=O)C.COC(OC)([N:61](C)C)C.O.NN>>[CH3:24][NH:23][C:21](=[O:22])[C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:9]([C:7]3[S:8][C:4]([C:1]4[NH:61][N:36]=[C:35]([CH3:56])[CH:34]=4)=[C:5]([CH3:30])[N:6]=3)[C:10]2=[O:29])=[CH:16][CH:17]=1
Reactant: COC(C)(OC)N(C)C
Reactant: CNC(=O)c1ccc(CN2CCN(c3nc(C)c(C(C)=O)s3)C2=O)cc1
Reactant: CC(=O)c1sc(N2CCN(Cc3ccc(C(=O)N4CCCCC4)cc3)C2=O)nc1C
Agent: NN
Solvent: O
Product: CNC(=O)c1ccc(CN2CCN(c3nc(C)c(-c4cc(C)n[nH]4)s3)C2=O)cc1
Yield: 80 %

Procedure:
Following the procedure as described in Example 40, making variations as required to replace 1-(5-acetyl-4-methylthiazol-2-yl)-3-(4-(piperidine-1-carbonyl)benzyl)imidazolidin-2-one with 4-((3-(5-acetyl-4-methylthiazol-2-yl)-2-oxoimidazolidin-1-yl)methyl)-N-methylbenzamide to react with N,N-dimethylacetamide dimethyl acetal and further with hydrazine monohydrate, the title compound was obtained as a colorless solid in 80% yield: mp 236-238° C. (ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ 8.40 (d, J=4.2 Hz, 1H), 7.79 (d, J=8.1 Hz, 2H), 7.35 (d, J=8.1 Hz, 2H), 6.16 (s, 1H), 4.44 (s, 2H), 4.03-3.93 (m, 2H), 3.45-3.40 (m, 2H), 2.67 (d, J=4.2 Hz, 3H), 2.34 (s, 3H), 2.22 (s, 3H): 13C NMR (75 MHz, DMSO-d6) δ 166.7, 155.8, 144.0, 142.3, 140.1, 134.1, 128.0, 127.8, 102.7, 102.6, 47.1, 42.4, 42.3, 42.2, 26.7, 16.9.: MS (ES+) m/z 411.1 (M+1).
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][C:10]([CH:12]=O)=[CH:11][C:6]=2[O:5][CH2:4][CH2:3][CH2:2]1.[CH3:14][CH:15]([CH3:19])[C:16](=[O:18])[CH3:17].[OH-].[Na+]>CO>[O:1]1[C:7]2[CH:8]=[CH:9][C:10]([CH:12]=[CH:17][C:16](=[O:18])[CH:15]([CH3:19])[CH3:14])=[CH:11][C:6]=2[O:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)C(C)C
Reactant: O=Cc1ccc2c(c1)OCCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)C(=O)C=Cc1ccc2c(c1)OCCCO2
Reaction time: 24 h

Procedure:
The MeOH (5 mL) solution of 3,4-dihydro-2H-1,5-benzodioxepine-7-carbaldehyde (445 mg) and 3-methyl-2-butanone (195 mg) was treated with aq. sodium hydroxide (1N, 1 ml) and the mixture was stirred for 24 hours. The reaction was partitioned between 10 ml water and 40 ml ethyl acetate. The organic layer was then sequentially washed with aq. hydrochloric acid (1N, 20 ml), water (20 ml), and Brine (20 ml) and then concentrated under reduced pressure. The residue was purified with flash chromatography on silica (33% ethyl acetate in hexane) to give the desired product as a white crystal.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[O:12]=[C:13]([CH2:20][CH3:21])[CH2:14][C:15](OCC)=[O:16]>C1(C)C=CC=CC=1>[O:12]=[C:13]([CH2:20][CH3:21])[CH2:14][C:15]([O:9][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][CH:10]=1)=[O:16]
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Reactant: CCOC(=O)CC(=O)CC
Solvent: Cc1ccccc1
Product: CCC(=O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 98.4 %

Procedure:
A suspension of 55.3 g (0.36 mole) of 4-nitrobenzyl alcohol and 56.2 g (0.39 mole) of ethyl 3-oxopentanoate in 360 ml of toluene was heated to boiling. About 300 ml of toluene were distilled out over the course of 10 h, then the mixture was cooled and another 200 ml were added and this procedure was repeated. After cooling, the mixture was filtered through kieselguhr, which was washed with toluene, and the filtrate solution was evaporated in vacuo. 89 g (98%) of the title compound were obtained as an oil, Rf: 0.42 (toluene:ethyl acetate 4:1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[CH3:22][O:23][CH2:24][CH2:25][CH2:26][CH2:27]O>>[CH3:22][O:23][CH2:24][CH2:25][CH2:26][CH2:27][O:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: COCCCCO
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Product: COCCCCOc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1

Procedure:
Mitsunobu reaction of phenol 58 with 4-methoxybutanol gave 2-(3-(3-(4-methoxybutoxy)phenyl)propyl)isoindoline-1,3-dione as yellow oil. Yield (0.840 g, 66%): 1H NMR (400 MHz, CDCl3) δ 7.80-7.85 (m, 2H), 7.68-7.72 (m, 2H), 7.11-7.17 (m, 1H), 6.72-6.79 (m, 2H), 6.65 (dd, J=8.2, 2.4 Hz, 1H), 3.95 (t, J=6.2 Hz, 2H), 3.75 (t, J=6.8 Hz, 2H), 3.44 (t, J=6.4 Hz, 2H), 3.35 (s, 3H), 2.65 (t, J=7.2 Hz, 2H), 1.98-2.06 (m, 2H), 1.70-1.86 (m, 4H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:22]=[C:21]([C:23]([OH:25])=O)[CH:20]=[N:19]2)=[C:14]([F:26])[CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.[N:34]1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)CC)C.N>ClCCl.C(O)C>[NH2:34][C:23]([C:21]1[CH:20]=[N:19][N:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:13][C:14]=2[F:26])[CH:22]=1)=[O:25]
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: O=C(Nc1ccc(-n2cc(C(=O)O)cn2)c(F)c1)OCc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: ClCCl
Product: NC(=O)c1cnn(-c2ccc(NC(=O)OCc3ccccc3)cc2F)c1
Reaction time: 1 h
Yield: 74.7 %

Procedure:
1-(4-{[Benzyloxycarbonyl]amino}-2-fluorophenyl)-1H-pyrazole-4-carboxylic acid (1.1 g, 3.1 mmol) (Intermediate 41) and benzotriazole-1-yl-oxy-trispyrrolidinophosphonium hexafluorophosphate (PyBob) (1.61 g, 3.1 mmol) were slurried in dichloromethane (25 ml), and triethylamine (0.43 ml, 3.1 mmol) was added. Excess ammonia solution in ethanol (2M) was added and the resulting mixture was stirred for 1 hour. The solvent removed under reduced pressure and the residue was taken up in water. It was basified by adding 1M sodium hydroxide solution, and then extracted with ethyl acetate, dried over magnesium sulfate and concentrated under vacuum. Chromatography on silica gel with 0-1% methanol in ethyl acetate gave the title compound (0.82 g).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][C:11](Br)=[CH:12][CH:13]=1)(=[O:3])[CH3:2].[O:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[CH:29]=[C:28]1B(O)O>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][C:11]([C:28]2[O:27][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[CH:29]=2)=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1cc2ccccc2o1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(Br)nc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(-c2cc3ccccc3o2)nc1

Procedure:
By carrying out the operation analogously to example 1, starting from 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, and 2-benzofuranboronic acid, the desired product is obtained in the form of an ecru solid (yield=65%).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[NH:8][C:7](=O)[CH:6]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[CH:4]=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:7]1[CH:6]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[CH:4]=[C:3]([C:2]([F:21])([F:20])[F:1])[N:8]=1
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cc2)cc(C(F)(F)F)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1ccc(-c2cc(Cl)nc(C(F)(F)F)c2)cc1

Procedure:
The title compound was prepared from 6-trifluoromethyl-4-(4-trifluoromethylphenyl)-1H-pyridin-2-one (23.7 g, 77 mmol) and phosphoryl chloride (35.2 mL, 386 mmol) according to the general procedure Ia to d preparation of chlorides. Obtained as an off-white solid (16.5 g, 66%). MS (ISP) 326.1 [(M+H)+] and 328 [(M+2+H)+].
Reaction SMILES: NC(N)=S.[CH3:5][N:6]([CH3:19])[S:7]([C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=1[OH:18])(=[O:9])=[O:8].[F:20][C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=1[N:28]=[C:29]=[S:30]>>[Cl:16][C:15]1[CH:14]=[CH:13][C:12]([NH:17][C:29]([NH:28][C:22]2[CH:23]=[CH:24][CH:25]=[C:26]([Cl:27])[C:21]=2[F:20])=[S:30])=[C:11]([OH:18])[C:10]=1[S:7]([N:6]([CH3:19])[CH3:5])(=[O:9])=[O:8]
Reactant: Fc1c(Cl)cccc1N=C=S
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc(N)c1O
Agent: NC(N)=S
Product: CN(C)S(=O)(=O)c1c(Cl)ccc(NC(=S)Nc2cccc(Cl)c2F)c1O
Yield: 66.5 %

Procedure:
Following the general procedure for thiourea formation outlined in example 12, N,N-dimethyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide (500 mg, 2 mmol) and 2-fluoro-3-chlorophenylisothiocyanate (374 mg, 2 mmol) were coupled to form the desired thiourea (583 mg, 67%). EI-MS m/z 438.2(M+).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11]2)[C:6]([C:19]([OH:21])=O)=[CH:5][N:4]=1.C(Cl)CCl.[OH-].[NH4+:27].O>CN(C=O)C>[CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11]2)[C:6]([C:19]([NH2:27])=[O:21])=[CH:5][N:4]=1
Reactant: [NH4+]
Reactant: CSc1ncc(C(=O)O)c(NC2(c3ccccc3)CC2)n1
Agent: [OH-]
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ncc(C(N)=O)c(NC2(c3ccccc3)CC2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98.5 %

Procedure:
To a solution of 2-(methylthio)-4-(1-phenylcyclopropylamino)pyrimidine-5-carboxylic acid (646 mg, 2.15 mmol) and HOBtH2O (395 mg, 2.58 mmol) in DMF (3.5 mL), EDC (515 mg, 2.69 mmol) was added. The mixture was stirred at room temperature for 20 min. Ammonium hydroxide (244 mg, 4.30 mmol) was added. It was stirred at room temperature for 1 h. Water was added to induce precipitation, the solids were collected by filtration to give 2-(methylthio)-4-(1-phenylcyclopropylamino) pyrimidine-5-carboxamide (636 mg). MS 301.2 (M+H).
Reaction SMILES: Br[CH2:2][C:3]1([CH3:16])[CH2:7][C:6]2[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)[NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:21][CH:20]=1>>[NH2:14][C:9]1[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]2[O:4][C:3]([CH2:2][N:30]3[CH2:31][CH2:32][CH:27]([NH:26][CH:25]([C:22]4[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=4)[C:33]4[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=4)[CH2:28][CH2:29]3)([CH3:16])[CH2:7][C:6]=2[C:8]=1[CH3:15]
Reactant: COc1ccc(C(NC2CCNCC2)c2ccc(OC)cc2)cc1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CBr)O2
Product: COc1ccc(C(NC2CCN(CC3(C)Cc4c(C)c(N)c(C)c(C)c4O3)CC2)c2ccc(OC)cc2)cc1
Yield: 43 %

Procedure:
Starting with 2-bromomethyl-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine and N-[bis(4-methoxyphenyl)methyl]-4-piperidinamine, the procedure of Example 53 was otherwise repeated to provide the title compound. Yield 43%.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)C.[C:8]1([CH3:16])[C:9]([CH:14]=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=1>CCCCCC.C1COCC1.CS(C)=O>[CH3:16][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]1[O:15][CH2:4]1
Reactant: Cc1ccccc1C=O
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Cc1ccccc1C1CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
Sodium hydride (57%) (4.84 g., 0.115 mole) previously washed with hexane was stirred with dry dimethylsulfoxide (70 ml) at 65°-70° for 2 hours under argon. The mixture was diluted with dry THF (70 ml), cooled to -5° and trimethylsulfonium iodide (23.5 g, 0.115 mole) in 100 ml of dry DMSO was added over a period of 3 minutes. After stirring for one minute o-tolualdehyde (11.5 g, 0.0926 mole) was added at a moderate rate while keeping the reaction mixture at 0° to -5°. The mixture was stirred at 0° for 5 minutes and at room temperature for 1 hour, diluted with 500 ml of ice water and extracted three times with ether. The ether solution was washed with saturated sodium chloride, dried with sodium sulfate and evaporated to an oil which was distilled under reduced pressure (~0.25-0.50 mm) to give 10.25 g (83 %) of o-methylstyrene oxide as a clear liquid (b.p. 35°-38°).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](OC)=[O:8].[H-]>>[Cl:1][C:2]1[CH:11]=[C:6]([CH2:7][OH:8])[CH:5]=[N:4][C:3]=1[O:12][CH2:13][C:14]([F:15])([F:16])[F:17]
Reactant: COC(=O)c1cnc(OCC(F)(F)F)c(Cl)c1
Agent: [H-]
Product: OCc1cnc(OCC(F)(F)F)c(Cl)c1
Yield: 78 %

Procedure:
The title compound is prepared in 78% yield (210 mg, a white solid) from methyl 5-chloro-6-(2,2,2-trifluoroethoxy)nicotinate (300 mg, 1.1 mmol, Step-1) and diisobutylalminium hydride (1.0 M in hexane, 2.4 mL, 2.4 mmol) by the similar manner in Step-3 of Amine-4.