Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]Cl.[F:3][C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[NH:6][C:7](=[O:9])[CH3:8]>C(O)(=O)C>[Cl:1][C:12]1[CH:11]=[CH:10][C:5]([NH:6][C:7](=[O:9])[CH3:8])=[C:4]([F:3])[CH:13]=1
Reactant: CC(=O)Nc1ccccc1F
Reactant: ClCl
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(Cl)cc1F
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Seventy-one parts of liquid chlorine were added to a solution of 140 parts of 2'-fluoroacetanilide in 500 parts glacial acetic acid, during one hour, at 25°-27°, with ice-water cooling. While stirring for 4 hours at 25°-27°, 4'-chloro-2'-fluoroacetanilide precipitated. After collecting the product by filtration, the filtrate was poured over 2000 parts ice. The resulting second portion of precipitated product was collected by filtration, combined with the first portion and recrystallized from 700 parts of methanol at -45° to yield 119 parts of 4'-chloro-2'-fluoroacetanilide as white crystals melting at 152°-155°.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:9].[CH:10]1([C:13]([C:15]2[N:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)=[O:14])[CH2:12][CH2:11]1.[Cl-].[NH4+]>O1CCCC1>[CH:10]1([C:13]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:9])([C:15]2[N:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)[OH:14])[CH2:11][CH2:12]1
Reactant: Cc1ccccc1Br
Reactant: Cn1cccc1C(=O)C1CC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccccc1C(O)(c1cccn1C)C1CC1
Reaction time: 8 h
Yield: 96.1 %

Procedure:
To a suspension of magnesium turnings (1.72 g, 0.071 mole) in anhydrous tetrahydrofuran (20 ml), 2-bromotoluene (12.1 g, 0.071 mole) in tetrahydrofuran (100 ml) was added dropwise under nitrogen. The reaction mixture was heated at reflux for 1 h after the initial exotherm had subsided before cyclopropyl-(N-methylpyrrol-2-yl)ketone (7.1 g, 0.047 mole) (J. Org. Chem., (1971), 36, 2897; J.Org.Chem. (1980), 45, 3172) in anhydrous tetrahydrofuran (100 ml) was introduced. After heating the reaction mixture at reflux for 2 h it was left overnight at room temperature. Saturated, aqueous ammonium chloride solution (100 ml) was added, and the mixture was extracted with diethyl ether (3×200 ml). The combined extracts were dried (MgSO4) and the solvents evaporated. The residue was flash chromatografied on silica gel eluting with n-heptane/tetrahydrofuran (19:1) providing the title compound as a solid (10.9 g).
Reaction SMILES: C([O:3][C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][O:21][CH3:22])=[C:15]([O:23][CH2:24][O:25][CH3:26])[CH:14]=2)=[CH:7][CH:6]=1)C.[OH-].[Na+]>CO>[CH3:26][O:25][CH2:24][O:23][C:15]1[CH:14]=[C:13]([CH:12]=[CH:11][C:8]2[CH:7]=[CH:6][C:5]([C:4]([OH:27])=[O:3])=[CH:10][CH:9]=2)[CH:18]=[CH:17][C:16]=1[O:19][CH2:20][O:21][CH3:22]
Reactant: CCOC(=O)c1ccc(C=Cc2ccc(OCOC)c(OCOC)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCOc1ccc(C=Cc2ccc(C(=O)O)cc2)cc1OCOC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-[2-(3,4-bis-methoxymethoxy-phenyl)-vinyl]-benzoic acid ethyl ester (1.0 mmol) in MeOH (20 mL) was added 10% NaOH solution (3 eq). The resulting suspension was vigorously stirred for 8 h at room temperature. The mixture was then quenched by adding saturated NaH2PO4 (50 mL). The mixture was extracted with EtOAc (3×50 mL) and the combined organic layers were dried over Na2SO4. The crude product was purified on a short silica gel column.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]([C:12]([F:15])([F:14])[F:13])=[N:10][N:11]=1)=[O:5])[CH3:2].[C:16](Cl)(Cl)=[O:17]>>[CH2:1]([N:3]1[C:16](=[O:17])[N:11]2[N:10]=[C:9]([C:12]([F:14])([F:15])[F:13])[S:8][C:7]2=[N:6][C:4]1=[O:5])[CH3:2]
Reactant: O=C(Cl)Cl
Reactant: CCNC(=O)Nc1nnc(C(F)(F)F)s1
Product: CCn1c(=O)nc2sc(C(F)(F)F)nn2c1=O

Procedure:
, and having a melting point of about 173°-175° C., from 1.9 g. of 1-ethyl-3-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)urea and phosgene.
Reaction SMILES: [BH4-].[Li+].[Cl:3][C:4]1[CH:29]=[CH:28][C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:22][C:23](OCC)=[O:24])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[C:6]([F:30])[CH:5]=1>C1COCC1>[Cl:3][C:4]1[CH:29]=[CH:28][C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:22][CH2:23][OH:24])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[C:6]([F:30])[CH:5]=1
Reactant: CCOC(=O)COc1cc2ncnc(Nc3ccc(Cl)cc3F)c2cc1OC
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCO
Reaction time: 1.5 h
Yield: 27.5 %

Procedure:
Lithium borohydride (150 μl of a 2M solution in THF, 0.15 mmol) was added to a solution of 4-(4-chloro-2-fluoroanilino)-7-(ethoxycarbonylmethoxy)-6-methoxyquinazoline (150 mg, 0.3 mmol) in THF (1 ml) and the mixture stirred for 1.5 hours. The reaction mixture was quenched with aqueous amonium chloride solution and extracted with ethyl acetate. The combined extracts were washed with water, dried (MgSO4) and concentrated by evaporation. Hexane was added, the mixture was cooled and the precipitated solid was collected by filtration to give 4-(4-chloro-2-fluoroanilino)-7-(2-hydroxyethoxy)-6-methoxyquinazoline (30 mg, 23%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[N:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3I)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH:22]1[CH2:26][CH2:25][C@H:24]2[CH2:27][N:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:29][C@@H:23]12.C(=O)([O-])[O-].[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:33]([O:32][C:30]([N:28]1[CH2:27][C@H:24]2[C@H:23]([N:22]([C:15]3[CH:16]=[CH:17][CH:18]=[C:19]4[C:14]=3[N:13]=[CH:12][C:11]([S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)(=[O:10])=[O:9])=[CH:20]4)[CH2:26][CH2:25]2)[CH2:29]1)=[O:31])[CH3:34]
Reactant: CCOC(=O)N1C[C@@H]2CCN[C@@H]2C1
Reactant: O=S(=O)(c1cccc(F)c1)c1cnc2c(I)cccc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1C[C@@H]2CCN(c3cccc4cc(S(=O)(=O)c5cccc(F)c5)cnc34)[C@@H]2C1
Yield: 93.5 %

Procedure:
0.255 of g 3-(3-fluorophenylsulfonyl)-8-iodoquinoline (0.617 mmol), 0.114 g of (3aS,6aS)-ethyl hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate (0.617 mmol), 0.404 g of cesium carbonate (1.234 mmol), 0.014 g of palladium acetate (0.062 mmol) and 0.029 g of X-Phos (2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 0.062 mmol) in 5 mL toluene were stirred at 90° C. for 8 h. The reaction mixture was directly purified via silica gel chromatography (eluent toluene/methanol 10/1 +2.5% triethylamine). Fractions containing the product were combined and the solvent was evaporated to yield 0.271 g of the desired product which was used in example 26 without additional purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([CH3:13])=[C:5]([C:9]([CH3:12])=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].C[Si](/N=C(/O[Si](C)(C)C)\C(F)(F)F)(C)C.CCN(CC)CC.[C:36](Cl)(=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38]>C1COCC1>[CH3:13][C:4]1[C:3]([CH2:2][NH:1][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:11][CH:10]=[C:9]([CH3:12])[C:5]=1[C:6]([OH:8])=[O:7]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1ccc(CN)c(C)c1C(=O)O
Agent: C[Si](C)(C)/N=C(/O[Si](C)(C)C)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(CNC(=O)C(C)(C)C)c(C)c1C(=O)O
Temperature: 0 °C
Reaction time: 18 h
Yield: 69.5 %

Procedure:
To a solution of 2,6-dimethyl-3-((2,2,2-trifluoroacetamido)methyl)benzoic acid (3.2 g) in THF (15 mL) was added 1N HCl (15 mL) and the reaction mass was heated at reflux for 3 h. The reaction mixture was concentrated and the crude was co-distilled with toluene to afford 2.0 g of the 3-(aminomethyl)-2,6-dimethylbenzoic acid which was used in the next step without further purification. To a solution of 3-(aminomethyl)-2,6-dimethylbenzoic acid (500 mg, 2.46 mmol) in THF was added N,O-bis(trimethylsilyl)trifluoroacetamide (948 mg, 3.69 mmol) and the reaction mass was heated at reflux for 20 minutes. The reaction mass was cooled to 0° C. and Et3N (1.77 mL, 9.85 mmol) was added, followed by pivaloyl chloride (0.44 mL, 3.69 mmol). The reaction mixture was stirred at rt for 18 h before it was quenched with water and was extracted with chloroform. The organic layer was separated, dried, filtered and concentrated to afford 450 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 13.15 (br s, 1H), 7.93 (br t, 1H), 7.08-7.01 (m, 2H), 4.19 (d, J=5.7 Hz, 2H), 2.21 (s, 3H), 2.17 (s, 3H), 1.12 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.Cl.[F:14][C:15]1[CH:16]=[C:17]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:18]=[C:19]([F:21])[CH:20]=1>C(N(CC)CC)C>[F:21][C:19]1[CH:18]=[C:17]([N:22]2[CH2:27][CH2:26][N:25]([CH2:8][C:7]3[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:24][CH2:23]2)[CH:16]=[C:15]([F:14])[CH:20]=1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: Fc1cc(F)cc(N2CCNCC2)c1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(CN2CCN(c3cc(F)cc(F)c3)CC2)cc1

Procedure:
In the manner given in Example 1A, p-nitrobenzyl chloride is reacted with 4-(3,5-difluorophenyl)piperazine dihydrochloride in the presence of triethylamine to give 1-(3,5 -difluorophenyl)-4-(p-nitrobenzyl)piperazine
Reaction SMILES: [CH2:1]([SnH:5]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[C:14]1([C:20]#[CH:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N(C(C)(C)C#N)=NC(C)(C)C#N>[CH2:10]([Sn:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:6][CH2:7][CH2:8][CH3:9])/[CH:21]=[CH:20]/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:11][CH2:12][CH3:13]
Reactant: C#Cc1ccccc1
Reactant: CCCC[SnH](CCCC)CCCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCC[Sn](/C=C/c1ccccc1)(CCCC)CCCC
Temperature: 50 °C
Reaction time: 24 h
Yield: 87 %

Procedure:
The synthesis was carried out according to the methods described in (a) Labadie, J. W.; Tueting, D.; Stille, J. K. J. Org. Chem. 1983, 48, 4634 and (b) Lappert, M. F.; Jones, K. J. Organomet. Chem. 1965, 3, 295. A mixture of tributyltin hydride (5.82 g, 20.0 mmole), phenylacetylene (1.95 g, 19.0 mmole), and 2,2′-azobis(isobutyronitrile) (0.14 g, 0.085 mmole) was slowly heated to 50° C., followed by stirring for 24 hours. Next, the mixture was cooled to room temperature and filtered by a Celite pad to remove the white precipitate. The filtrate was distilled to obtain 6.50 g of tributyl[(E)-2-phenyl-1-ethenyl]stannane. Yield: 84%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[O:10][C:9](=[O:11])[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:5]2=[N:6][CH:7]=1.BrC1[CH:21]=[C:22]2[O:28]C(=O)N(C)C2=NC=1>>[CH2:12]([N:8]1[C:5]2=[N:6][CH:7]=[C:2]([C:22](=[O:28])[CH3:21])[CH:3]=[C:4]2[O:10][C:9]1=[O:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cn1c(=O)oc2cc(Br)cnc21
Reactant: O=c1oc2cc(Br)cnc2n1Cc1ccccc1
Product: CC(=O)c1cnc2c(c1)oc(=O)n2Cc1ccccc1

Procedure:
The method of operation is the same as that used for the synthesis of the compound of Example 1 (coupling with 1-ethoxy-1-(trimethylstannyl)ethylene), 6-bromo-3-benzyloxazolo[4,5-b]pyridin-2(3H)-one from Preparation 13 being used instead of 6-bromo-3-methyloxazolo[4,5-b]pyridin-2(3H)-one. The yield obtained is 75%. ##STR47##
Reaction SMILES: O=[CH:2][CH2:3][O:4][CH2:5][CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([N:23]([CH3:36])[CH2:24][CH2:25][CH2:26][N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:22])=[CH:17][CH:16]=1>>[C:30]([O:29][C:28]([N:27]([CH3:35])[CH2:26][CH2:25][CH2:24][N:23]([CH3:36])[C:21]([C:18]1[CH:19]=[CH:20][C:15]([NH:14][CH2:2][CH2:3][O:4][CH2:5][CH2:6][C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])=[CH:16][CH:17]=1)=[O:22])=[O:34])([CH3:32])([CH3:31])[CH3:33]
Reactant: CC(C)(C)OC(=O)CCOCC=O
Reactant: CN(CCCN(C)C(=O)c1ccc(N)cc1)C(=O)OC(C)(C)C
Product: CN(CCCN(C)C(=O)c1ccc(NCCOCCC(=O)OC(C)(C)C)cc1)C(=O)OC(C)(C)C
Yield: 82.6 %

Procedure:
The compound (87 mg, 0.461 mmol) obtained in Example 28b and the compound (150 mg, 0.461 mmol) obtained in Example 28d were used to give the title compound (188 mg; yield, 83%) as a colorless oily substance according to the method described in Example 18b.
Reaction SMILES: C(N[C:4]1[N:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:26]=[C:25]([CH3:27])[C:18]([O:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])=[C:17]([CH3:28])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:29])[N:5]=1)C.[CH:30]([O:33]C1N=C(C(O)=O)C=C(C)N=1)([CH3:32])[CH3:31]>>[CH:30]([O:33][C:4]1[N:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:26]=[C:25]([CH3:27])[C:18]([O:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])=[C:17]([CH3:28])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:29])[N:5]=1)([CH3:32])[CH3:31]
Reactant: CCNc1nc(C)cc(-c2nc(-c3cc(C)c(OCC(O)CO)c(C)c3)no2)n1
Reactant: Cc1cc(C(=O)O)nc(OC(C)C)n1
Product: Cc1cc(-c2nc(-c3cc(C)c(OCC(O)CO)c(C)c3)no2)nc(OC(C)C)n1

Procedure:
rac-3-{4-[5-(2-Isopropoxy-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propane-1,2-diol is prepared in analogy to rac-3-{4-[5-(2-ethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propane-1,2-diol using 2-isopropoxy-6-methyl-pyrimidine-4-carboxylic acid; LC-MS: tR=0.86 min*; [M+H]+=415.09.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[C:19]2[C:18](=[O:20])[C:17]([C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])=[CH:16][N:15]([CH2:26][C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])[C:14]=2[S:13][C:12]=1[C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-])=O)=[CH:37][CH:36]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.Cl.C(=O)([O-])O.[Na+]>O.[Fe].C(OCC)(=O)C>[NH2:41][C:38]1[CH:37]=[CH:36][C:35]([C:12]2[S:13][C:14]3[N:15]([CH2:26][C:27]4[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=4[F:34])[CH:16]=[C:17]([C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[C:18](=[O:20])[C:19]=3[C:11]=2[CH2:10][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH3:9])=[CH:40][CH:39]=1
Reactant: CC(C)C(=O)c1cn(Cc2c(F)cccc2F)c2sc(-c3ccc([N+](=O)[O-])cc3)c(CN(C)Cc3ccccc3)c2c1=O
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CC(C)C(=O)c1cn(Cc2c(F)cccc2F)c2sc(-c3ccc(N)cc3)c(CN(C)Cc3ccccc3)c2c1=O
Reaction time: 2 h
Yield: 103 %

Procedure:
3-(N-Benzyl-N-methylaminomethyl)-7-(2,6-difluorobenzyl)-4,7-dihydro-5-isobutyryl-2-(4-nitrophenyl)-4-oxothieno[2,3-b]pyridine (33 g), iron powder (12.3 g) and ethanol (132 ml) were mixed and treated dropwise with concentrated hydrochloric acid (55.5 g) diluted with water (19 ml) over a period of 2 hours with cooling on ice, and the reaction mixture was stirred as it was for 2 hours. The reaction mixture was poured into a solution of sodium hydrogencarbonate (55.3 g) in water (450 ml) and the mixture was stirred for 1 hour together with ethyl acetate (825 ml), and filtered through a Hyflo Super Cell to remove insoluble materials. The aqueous layer was extracted with ethyl acetate (500 ml) and then the organic layers were combined, and washed with a saturated saline (1000 ml), dried over anhydrous magnesium sulfate (35 g) and then concentrated into dryness to obtain a crude product of 2-(4-aminophenyl)-3-(N-benzyl-N-methylaminomethyl)-7-(2,6-difluorobenzyl)-4,7-dihydro-5-isobutyryl-4-oxothieno[2,3-b]pyridine (32.3 g). This was dissolved in methanol (200 ml) and admixed with a solution of fumaric acid (6.56 g) in methanol (200 ml) and the mixture was concentrated under reduced pressure to about 150 g. The precipitated suspension thus obtained was diluted with ethyl acetate (300 ml) and the mixture was stirred at room temperature for 1 hour and then the crystal was recovered by a filtration. After washing with ethyl acetate (200 ml) followed by drying in vacuo at 50° C. for 3 hours, the title compound (33.38 g, 88.5%) was obtained.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([N:7]2[CH:12]([OH:13])[CH2:11][CH2:10][N:9]([CH3:14])[C:8]2=[O:15])=[N:4][N:3]=1.[CH3:16][N:17]=[C:18]=[O:19]>C(N(CC)CC)C>[CH3:1][C:2]1[S:6][C:5]([N:7]2[CH:12]([O:13][C:18](=[O:19])[NH:17][CH3:16])[CH2:11][CH2:10][N:9]([CH3:14])[C:8]2=[O:15])=[N:4][N:3]=1
Reactant: CN=C=O
Reactant: Cc1nnc(N2C(=O)N(C)CCC2O)s1
Solvent: CCN(CC)CC
Product: CNC(=O)OC1CCN(C)C(=O)N1c1nnc(C)s1
Reaction time: 1 h

Procedure:
Tetrahydro-1-(5-methyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole) and methyl isocyanate (3.5 ml; 0.06 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer. The mixture is stirred and triethylamine (1 drop) is added thereto. After the addition is completed the reaction mixture is allowed to stand for a period of about 1 hour. The mixture is then washed with hexane and is dried to yield the desired product tetrahydro-1-(5-methyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-(N-methylcarbamoyloxy)-2(1H)-pyrimidinone.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[ClH:15]>C(O)C>[ClH:15].[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[C:6]([CH2:7][NH2:8])[CH:9]=1
Reactant: N#Cc1cc(F)ccc1-n1cncn1
Agent: Cl
Solvent: CCO
Product: NCc1cc(F)ccc1-n1cncn1
Reaction time: 6 h
Yield: 98 %

Procedure:
A solution of intermediate 96, 5-fluoro-2-(1H-1,2,4-triazol-1-yl)benzonitrile (2.94 g, 15.59 mmol) in ethanol (100 mL) and 1N HCl (50 mL) was degassed by bubbling N2. Then, 10%Pd/C was added, the flask evacuated and vented to H2 three times and left on a Parr shaker under a H2 atmosphere (40 psi). After 6 h, the reaction mixture was filtered, concentrated and the aqueous solution lyophilized to afford the title compound (4.07 g, 98%) as a white powder. LCMS (M+H) calcd for C9H10FN4: 193.09; found: 193.15.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][CH:24]([C:38]1[CH:39]=[N:40][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:42][CH:43]=1)[CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1>C(Cl)Cl>[F:47][C:44]([F:45])([F:46])[C:41]1[CH:42]=[CH:43][C:38]([C:24]([CH:25]2[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:36])([CH3:37])[CH3:35])=[O:32])[CH2:29][CH2:30]2)=[O:23])=[CH:39][N:40]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(O)c2ccc(C(F)(F)F)nc2)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccc(C(F)(F)F)nc2)CC1

Procedure:
Dess-Martin periodinane reagent (30.0 g, 70.8 mmol) was added to a solution of tert-butyl 4-(hydroxy(6-(trifluoromethyl)pyridin-3-yl)methyl)piperidine-1-carboxylate (Intermediate 56: step a, 17.8 g, 49.5 mmol) in DCM (354 mL) at room temperature and the mixture was stirred for 2 hours. The reaction mixture was diluted with DCM and washed with saturated aqueous solution of NaHCO3. The organic phase was dried (MgSO4), filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (silica gel, 0-60% EtOAc-hexanes) to provide the title compound that was 90% pure by NMR and was carried on to the next step.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27][CH3:28])=[CH:23][CH:22]=2)=[O:20])(=O)=O)C=CC=CC=1.[Mg].Br[CH2:31][CH:32]1[CH2:35][CH2:34][CH2:33]1.II>O1CCCC1.[Cl-].[Na+].O>[CH:32]1([CH2:31][C:19]([C:21]2[CH:22]=[CH:23][C:24]([S:27][CH3:28])=[CH:25][CH:26]=2)([C:11]2[NH:10][C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=2)[OH:20])[CH2:35][CH2:34][CH2:33]1
Reactant: CSc1ccc(C(=O)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: BrCC1CCC1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: CSc1ccc(C(O)(CC2CCC2)c2cc3cccnc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 18.1 %

Procedure:
To a solution of (1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-(4-methylsulfanyl-phenyl)-methanone (0.6 g, 1.47 mmol) in anhydrous tetrahydrofuran (5 mL) at 0° C. was added a solution of freshly prepared Grignard reagent [To a suspension of magnesium turnings (0.14 g, 5.88 mmol) in anhydrous tetrahydrofuran (5 mL) was added (bromomethyl)cyclobutane (0.44 g, 2.94 mmol) at room temperature. After initiation by iodine, the resulting solution was refluxed for 30 min, and then cooled to room temperature] dropwise. After stirring for 3 h at 0° C., the mixture was poured into brine (10 mL), extracted with ethyl acetate (3×20 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo. The residue was purified by flash column chromatography (silica gel from QingDao, 200-300 mesh, 25% ethyl acetate/hexanes) afforded 2-cyclobutyl-1-(4-methylsulfanyl-phenyl)-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)-ethanol (90 mg, 18%) as a white solid: LC/MS m/e calcd for C20H22N2OS [M+H]+ 339.48, observed 339.0.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:11]([OH:13])=O.Cl.[CH3:15][NH:16][O:17][CH3:18].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl>C(N(CC)CC)C.CN(C)C=O>[CH3:18][O:17][N:16]([CH3:15])[C:11]([C:3]1[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2]=1[CH3:1])=[O:13]
Reactant: CNOC
Reactant: Cc1c(C(=O)O)oc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1oc2ccccc2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
To a mixture of 3-methyl-1-benzofuran-2-carboxylic acid (15.0 g), N,O-dimethylhydroxyamine hydrochloride (9.95 g), 1-hydroxybenzotriazole-monohydrate (15.6 g), triethylamine (14.2 mL) and N,N-dimethylformamide (150 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (19.6 g), and the mixture was stirred overnight at room temperature. In addition, N,O-dimethylhydroxyamine hydrochloride (4.16 g), 1-hydroxybenzotriazole-monohydrate (6.52 g), triethylamine (5.94 mL) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (8.17 g) were added, and the mixture was stirred at room temperature for 4 hr. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:7, volume ratio) to give the title object compound (16.2 g, 87%) as a colorless oil.
Reaction SMILES: O[C:2]1[CH:11]=[C:10]2[C:5](C=CC=C2CCNC(C2CC2)=O)=[CH:4][CH:3]=1.[OH:20][C:21]1[CH:30]=[C:29]2[C:24]([CH:25]=[CH:26][CH:27]=[C:28]2[CH2:31][CH2:32][NH:33][C:34]([CH:36]2[CH2:39][CH2:38][CH2:37]2)=[O:35])=[CH:23][CH:22]=1>>[CH:2]1[CH2:11][CH2:10][CH2:5][CH:4]([O:20][C:21]2[CH:30]=[C:29]3[C:24]([CH:25]=[CH:26][CH:27]=[C:28]3[CH2:31][CH2:32][NH:33][C:34]([CH:36]3[CH2:39][CH2:38][CH2:37]3)=[O:35])=[CH:23][CH:22]=2)[CH:3]=1
Reactant: O=C(NCCc1cccc2ccc(O)cc12)C1CC1
Reactant: O=C(NCCc1cccc2ccc(O)cc12)C1CCC1
Product: O=C(NCCc1cccc2ccc(OC3C=CCCC3)cc12)C1CCC1

Procedure:
Using the procedure described in Example 25, but replacing the compound obtained in Example 24 by the compound obtained in Example 41, N-{2-[7-(cyclohexen-3-yl)oxy-1-naphthyl]ethyl}cyclobutanecarboxamide is obtained.
Reaction SMILES: [C:1]1([CH:11]([C:17](OCC)=[O:18])[C:12](OCC)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].Cl.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O1CCOCC1.O>[C:1]1([CH:11]([CH2:12][OH:13])[CH2:17][OH:18])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1cccc2ccccc12
Agent: Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [BH4-]
Solvent: C1COCCO1
Solvent: O
Product: OCC(CO)c1cccc2ccccc12
Reaction time: 8 h

Procedure:
50 g (175 mmol) of diethyl 2-(naphthalen-1-yl)propanedioate in 310 ml of dioxane and 300 ml of water are stirred at ambient temperature; an excess (2.2 mol, or 84 g) of sodium borohydride is then added in portions; the mixture is stirred for 8 h, and the products are left in contact for 2 days. The mixture is then hydrolysed, with stirring, while introducing crushed ice and 3N hydrochloric acid until an acidic pH is obtained. The mixture is extracted with diethyl ether, the organic phase is evaporated, and the residual oil is purified by chromatography on a silica gel column eluted with ethyl acetate. After evaporation and drying at 40° C. in the presence of phosphorus pentoxide, 18.5 g (91 mmol) of product are isolated. Melting point: 58-60° C.