Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1.C(O)C.[C:15](=S)=[S:16].[OH-].[Na+]>O>[SH:16][C:15]1[NH:11][C:6]2[CH:5]=[C:4]([O:3][CH3:2])[CH:9]=[CH:8][C:7]=2[N:10]=1
Reactant: COc1ccc(N)c(N)c1
Reactant: S=C=S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc2nc(S)[nH]c2c1
Yield: 59 %

Procedure:
A mixture of 2.6 g of 4-methoxy-o-phenylenediamine hydrochloride, 70 ml of ethanol, 15 ml of carbon disulfide and an aqueous solution containing 1.5 g of sodium hydroxide and 5 ml of water was refluxed for 4 hours. Then, the reaction mixture was condensed under reduced pressure. The residue was recrystallized from a mixture of water and methanol (70:30 by volume) to obtain 1.3 g of 2-mercapto-5-methoxybenzimidazole (Compound (III-15)) having a melting point of 254° to 255° C. (yield: 59%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH:12][NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=O)=[S:11])=[CH:5][CH:4]=1.[O-]CC.[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:14]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)=[N:13][NH:12][C:10]2=[S:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(NC(=S)NNC(=O)c2cccs2)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-n2c(-c3cccs3)n[nH]c2=S)cc1
Yield: 63.7 %

Procedure:
N1-(4-Methoxyphenylaminothiocarbonyl)-N2-(thien-2-carbonyl)hydrazine (1 g) and 0.2 g of sodium ethoxide in 10 mL of ethanol are refluxed for 6 hours. The mixture is cooled and the precipitate collected by vacuum filtration and dried to give 0.6 g of the title compound as an off-white solid. 4-(4-Methoxyphenyl)-5-(thien-2-yl)-1,2,4-triazol-3-thione (0.5 g) and 0.4 g of 2-bromo-5-nitrothiazole in 50 mL of acetonitrile are refluxed for 6 hours. The solvent is concentrated to give crude product which is collected by vacuum filtration. The crude product is crystallized from ethanol and dried to give 0.6 g of the desired triazole compound as an off-white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[N:8]([C:9](=[O:34])[CH:10]=[C:11]([C:16]([NH:18][CH2:19][C@H:20]([NH:24][S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:21]([OH:23])=[O:22])=[O:17])[CH:12]=2)[CH:7]=1.FC(F)(F)C(O)=O.NCCCOC1C=CC2N(C(=O)C=C(C(NC[C@H](NS(C3C=CC=CC=3)(=O)=O)C(O)=O)=O)C=2)C=1.C(N(C(C)C)CC)(C)C.[ClH:85].[N:86]1([C:91](N)=[NH:92])C=CC=N1>CN(C=O)C.O>[ClH:85].[C:28]1([S:25]([NH:24][C@@H:20]([CH2:19][NH:18][C:16]([C:11]2[CH:12]=[C:13]3[N:8]([C:9](=[O:34])[CH:10]=2)[CH:7]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:1][C:91]([NH2:92])=[NH:86])[CH:15]=[CH:14]3)=[O:17])[C:21]([OH:23])=[O:22])(=[O:27])=[O:26])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: NCCCOc1ccc2cc(C(=O)NC[C@H](NS(=O)(=O)c3ccccc3)C(=O)O)cc(=O)n2c1
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)NCCCOc1ccc2cc(C(=O)NC[C@H](NS(=O)(=O)c3ccccc3)C(=O)O)cc(=O)n2c1
Temperature: 60 °C
Reaction time: 7 h

Procedure:
A mixture of (S)-3-{[7-(3-amino-propoxy)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-2-benzenesulfonylamino-propionic acid trifluoroacecic acid salt (compound XIV)(15 mg, 0.025 mmol), diisopropylethylamine (13 μl, 0.075 mmol) and 1H-pyrazole-1-carboxamidine hydrochloride (6 mg, 0.038 mmol) in DMF (0.5 ml) and water (0.5 ml) was stirred at 60° C. for 7 hours. It was then concentrated and the residue was flash chromatographed (ethanol:NH4OH:water; 8:1:1) and lyophilized in a (1:1) mixture of 0.1N HCl and water to afford 11.4 mg of pure desired product as a yellow solid which was characterized by 1HNMR (400 MHz, CD3OD) δ: 2.14-2.21 (m, 2H), 3.44-3.48 (m,2H), 3.49-3.54 (dd, J=13.5 and 9.0 Hz, 1H), 3.77-3.82 (dd, J=13.5 and 5.0 Hz, 1H), 4.23-4.28 (m, 3H), 6.94 (d, J=1.5 Hz, 1H), 7.37 (s, 1H), 7.43-7.56 (m, 4H), 7.85-7.86 (m, 2H), 7.91 (d, J=9.5 Hz, 1H), 8.7 (s, 1H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:23][C:24]1[N:25]=[CH:26][NH:27][CH:28]=1)[C:3]([NH:5][C@@H:6]([CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C@@H:7]([OH:15])[CH2:8][C@@H:9]([CH:12]([CH3:14])[CH3:13])[CH:10]=[CH2:11])=[O:4]>CO.[Pd]>[NH2:1][C@@H:2]([CH2:23][C:24]1[N:25]=[CH:26][NH:27][CH:28]=1)[C:3]([NH:5][C@@H:6]([CH2:16][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1)[C@@H:7]([OH:15])[CH2:8][C@@H:9]([CH:12]([CH3:14])[CH3:13])[CH2:10][CH3:11])=[O:4]
Reactant: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@@H](N)Cc1c[nH]cn1)C(C)C
Agent: [Pd]
Solvent: CO
Product: CC[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@@H](N)Cc1c[nH]cn1)C(C)C

Procedure:
50 mg of (S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamide were dissolved in 3 ml of methanol and hydrogenated at room temperature for 3 hours at normal pressure in the presence of 7 mg of palladium-on-carbon. Thereafter, the catalyst was filtered off and rinsed with methanol. The alcoholic solution was then evaporated under reduced pressure, to obtain (S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]imidazole-4-propionamide as a colorless foam. MS: 393 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]([OH:12])=[O:11])=[C:8]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[C:7]([F:21])=[C:6]([F:22])[CH:5]=1)(=O)[CH3:2].Cl.[NH2:24]O>CO.O.CCOC(C)=O>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[NH:13][C:8]1[C:9]2[C:10](=[O:11])[O:12][N:24]=[C:1]([CH3:2])[C:4]=2[CH:5]=[C:6]([F:22])[C:7]=1[F:21]
Reactant: NO
Reactant: CC(=O)c1cc(F)c(F)c(Nc2ccccc2Cl)c1C(=O)O
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1noc(=O)c2c(Nc3ccccc3Cl)c(F)c(F)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.4 %

Procedure:
To a solution of 6-acetyl-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid (50 mg, 0.15 mmol) and hydroxylamine hydrochloride (11 mg, 0.15 mmol) in MeOH-H2O (1 mL/0.5 mL) was added TEA (0.022 mL, 0.15 mmol) at room temperature. The resulting mixture was stirred for 16 hours at room temperature. The reaction mixture was diluted with EtOAc and washed with water. The organic layer was dried over MgSO4, filtered and concentrated in vacuo to give the crude material that was purified by silica gel flash column chromatography (100% CH2Cl2) to afford the desired product (26.8 mg, 54%).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[CH:15]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][CH3:30])[CH:23]=1)[NH:14][CH:13]=[C:12]2[CH:31]=[O:32])(=[O:3])[CH3:2]>C(Cl)(Cl)Cl.[O-2].[Mn+4].[O-2]>[C:1]([O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[C:15]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][CH3:30])[CH:23]=1)=[N:14][CH:13]=[C:12]2[CH:31]=[O:32])(=[O:3])[CH3:2]
Reactant: CCOc1cccc(CC2NC=C(C=O)c3cc(OCCCOC(C)=O)c(OC)cc32)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CCOc1cccc(Cc2ncc(C=O)c3cc(OCCCOC(C)=O)c(OC)cc23)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 101.6 %

Procedure:
To a stirred solution of 6-(3-acetoxy-propoxy)-7-methoxy-1-(3-ethoxy-benzyl)-1,2-dihydro-isoquinoline-4-carbaldehyde (120 mg, 0.27 mmol) in chloroform (3 mL) was addend manganese (IV) oxide (279 mg, 2.7 mmol). The reaction mixture was stirred at room temperature for 15 hrs, filtered through a celite pad®, and washed with chloroform. The filtrate was concentrated in vacuo to afford 6-(3-acetoxy-propoxy)-7-methoxy-1-(3-ethoxy-benzyl)-isoquinoline-4-carbaldehyde (120 mg, 99% yield). The crude product was used without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@H:2]1[C:10]([OH:12])=[O:11].S(Cl)(Cl)=O.[CH:17](O)([CH3:19])[CH3:18]>>[CH:17]([O:11][C:10]([C@@H:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1]1)=[O:12])([CH3:19])[CH3:18]
Reactant: O=C(O)[C@@H]1Cc2ccccc2N1
Reactant: CC(C)O
Solvent: O=S(Cl)Cl
Product: CC(C)OC(=O)[C@@H]1Cc2ccccc2N1
Yield: 89 %

Procedure:
To the solution of (2S)-2,3-dihydroindole-2-carboxylic acid (163 mg, 1.0 mmol) in isopropyl alcohol (40 mL), was added thionyl chloride (0.1 mL) slowly. The reaction mixture was heated at reflux for 4 hr with stirring. After cooling, all volatiles were removed under reduced pressure. To the residue saturated aqueous solution of NaHCO3 (10 mL) was added, which was extracted with ethyl acetate (10 mL×3). The extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) to give the desired compound (182 mg, 89%).
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][CH2:19][OH:20])[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2].[N+:21]([C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1)([O-:23])=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C=O)C>[CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][CH2:19][O:20][C:27]3[CH:28]=[CH:29][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=3)[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(C)c1noc(N2CCC([C@H]3C[C@H]3CCO)CC2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)c1noc(N2CCC([C@H]3C[C@H]3CCOc3ccc([N+](=O)[O-])cc3)CC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-{(1S,2R)-2-[1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl]cyclopropyl}ethanol (367 mg, 0.943 mmol) in DMF (3 ml) at room temperature under nitrogen was added 4-nitrophenol (144 mg, 1.037 mmol), followed by cesium carbonate (614 mg, 1.886 mmol) and the resulting mixture stirred at room temperature overnight. Ethyl acetate (50 mL) was added and washed with water followed by brine. The organic layer was then dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to afford the crude product which was used for the next reaction without further purification. LCMS: retention 1.24 min/2.0 minute run: (ESI) m/z 401 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[CH2:11][CH2:10][CH2:9][C:8](=[O:15])[C:7]2=1.CCCCC.[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH2:23]([N:13]1[C:12]2[CH2:11][CH2:10][CH2:9][C:8](=[O:15])[C:7]=2[C:6]2[C:14]1=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=2)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C1CCCc2[nH]c3c(F)cccc3c21
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCC
Product: O=C1CCCc2c1c1cccc(F)c1n2Cc1ccccc1
Reaction time: 0.33 h
Yield: 69.7 %

Procedure:
8-Fluoro-1,2,3,9-tetrahydro-4H-carbazol-4-one (2.23 g, 0.011 mol) is added to a slurry of pentane-washed NaH (0.59 g, 0.015 mol) in DMF (18 mL) and after stirring for 20 min, benzyl bromide (1.7 mL, 0.014 mol) is added. The mixture is stirred for 1 h at which time the mixture is partitioned between water and ethyl acetate. The combined organic layers are dried over sodium sulfate and concentrated to dryness. The resulting residue is chromatographed on silica gel (200 mL) using methanol/dichloromethane (1/99). The solids are then recrstallized from ethyl acetate/dichloromethane/hexane to give 2.25 g (70%) of the title compound; mp 183-184° C.; MS (ESI−) for C19H16FNO m/z 292.1 (M−H)−; IR (drift) 1639, 1631, 1495, 1459, 1434, 1359, 1246, 1219, 1193, 1125, 798, 789, 736, 730, 698 cm−1; 1H NMR (CDCl3) δ2.23, 2.58, 2.87, 5.51, 6.92, 7.03, 7.16, 7.29, 8.07. Anal. Calcd for C19H16FNO: C, 77.80; H, 5.50; N, 4.78. Found: C, 77.58; H, 5.59; N, 4.79.
Reaction SMILES: [Cl-].[C:2]([C:6]1[CH:7]=[C:8]([CH:16]=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[OH:19])[CH2:9][N+]1C=CC=CC=1)([CH3:5])([CH3:4])[CH3:3].[N+:24]([CH:27]([CH3:29])[CH3:28])([O-:26])=[O:25]>>[CH3:28][C:27]([CH3:29])([N+:24]([O-:26])=[O:25])[CH2:9][C:8]1[CH:7]=[C:6]([C:2]([CH3:4])([CH3:5])[CH3:3])[C:18]([OH:19])=[C:17]([C:20]([CH3:21])([CH3:22])[CH3:23])[CH:16]=1
Reactant: CC(C)(C)c1cc(C[n+]2ccccc2)cc(C(C)(C)C)c1O
Reactant: CC(C)[N+](=O)[O-]
Agent: [Cl-]
Product: CC(C)(C)c1cc(CC(C)(C)[N+](=O)[O-])cc(C(C)(C)C)c1O

Procedure:
3,5-Di-tert alkyl-4-hydroxybenzylpyridinium salts are reacted under basic conditions with compounds containing active methylene groups to form phenolic antioxidants. For example, 3,5-di-tert.butyl-4-hydroxybenzylpyridinium chloride is reacted with 2-nitropropane to produce 1,1-dimethyl-2-(3,5-di tert.butyl-4-hydroxyphenyl)-1-nitroethane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([C:17]#[N:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CC([O-])(C)C.[K+].Br[CH2:26][CH2:27][CH2:28][Cl:29]>CN(C)C=O>[Cl:29][CH2:28][CH2:27][CH2:26][C:4]1[C:3]([O:2][CH3:1])=[C:8]([O:9][CH3:10])[CH:7]=[CH:6][C:5]=1[CH:11]([C:17]#[N:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(C#N)c1ccc(OC)c(OC)c1
Reactant: ClCCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C#N)c1ccc(OC)c(OC)c1CCCCl

Procedure:
124.5 g (0.5 mol) of ethyl 3,4-dimethoxyphenylcyanoacetate in 160 ml of abs. dimethylformamide were added at 15°-20° while stirring to a suspension of 84.5 g (0.753 mol) of potassium tert-butylate in 300 ml of abs. dimethylformamide. After one hour 83.5 ml of 1-bromo-3-chloropropane were slowly added dropwise, whereby the temperature amounted to 15°-20°. After 16 hours the reaction mixture was evaporated in a high vacuum. The residue was partitioned between ether and an aqueous saturated ammonium chloride solution. The combined organic extracts were dried and evaporated under reduced pressure. The oily residue was distilled in a high vacuum, whereby 145.7 g of ethyl [γ-chloropropyl-3,4-dimethoxyphenyl]cyanoacetate were obtained, b.p. 195°-201°/80 Pa.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][C:7]([OH:9])=O)[C:2]([NH2:4])=[O:3].[CH:10]1([NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[N:24]=[C:25]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][C@@H:33]4[CH3:38])[C:26]4[CH2:31][NH:30][CH2:29][C:27]=4[N:28]=3)=[CH:19][CH:18]=2)=[O:15])[CH2:12][CH2:11]1>>[CH:10]1([NH:13][C:14]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[N:24]=[C:25]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][C@@H:33]4[CH3:38])[C:26]4[CH2:31][N:30]([C:7](=[O:9])[CH2:6][CH2:5][NH:1][C:2]([NH2:4])=[O:3])[CH2:29][C:27]=4[N:28]=3)=[CH:21][CH:22]=2)=[O:15])[CH2:11][CH2:12]1
Reactant: NC(=O)NCCC(=O)O
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CNC2
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CN(C(=O)CCNC(N)=O)C2

Procedure:
Method as example 127 using 3-ureidopropanoic acid and (S)-1-cyclopropyl-3-(4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (example 3) as starting materials to afford a white solid (22.3 mg, 0.044 mmol, 16%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH2:10]([O:12][C:13]([CH:15]=[C:16]1[NH:20][N:19]=[C:18]([C:21]2[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=2)[NH2:24])[O:17]1)=[O:14])[CH3:11]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:24][C:23]2[CH:25]=[CH:26][CH:27]=[C:21]([C:18]3[O:17][C:16](=[CH:15][C:13]([O:12][CH2:10][CH3:11])=[O:14])[NH:20][N:19]=3)[CH:22]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CCOC(=O)C=C1NN=C(c2cccc(N)c2)O1
Product: CCOC(=O)C=C1NN=C(c2cccc(Nc3nc(Cl)ncc3F)c2)O1

Procedure:
In like manner to the preparation of 2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 3-(2-ethoxycarbonylmethylene-1,3,4-oxadiazol-5-yl)aniline gave 2-chloro-N4-[3-(2-ethoxycarbonylmethylene-1,3,4-oxadiazol-5-yl)phenyl]-5-fluoro-4-pyrimidineamine. 1H NMR (CD3OD): δ 8.42 (t, 1H, J=1.8 Hz), 8.19 (d, 1H, J=3.3 Hz), 7.99 (dt, 1H, J=1.2 and 8.1 Hz), 7.82 (dt, 1H, J=1.2 and 8.1 Hz), 7.58 (t, 1H, J=9 Hz), 4.24 (q, 2H, J=3.9 Hz), 4.17 (s, 2H), 1.28 (t, 3H, J=7.2 Hz); LCMS: purity: 85%; MS (m/e): 379 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([NH2:16])=[C:11]([NH2:17])[CH:10]=1.[O:18]1[C:22]2([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:21][C:20]([CH:28]=O)=[N:19]1.O>CN(C=O)C>[CH3:15][C:13]1[C:12]2[NH:16][C:28]([C:20]3[CH2:21][C:22]4([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]4)[O:18][N:19]=3)=[N:17][C:11]=2[CH:10]=[C:9]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=2[F:8])[CH:14]=1
Reactant: O=CC1=NOC2(CCCCC2)C1
Reactant: Cc1cc(-c2c(F)cccc2F)cc(N)c1N
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-c2c(F)cccc2F)cc2nc(C3=NOC4(CCCCC4)C3)[nH]c12
Temperature: 100 °C
Yield: 38 %

Procedure:
2′,6′-Difluoro-5-methyl-biphenyl-3,4-diamine (186 mg, 0.792 mmol, as prepared in the previous step) was placed in an 8 mL vial equipped with a stir bar, and dry DMF (2 mL) was added. 1-Oxa-2-aza-spiro[4.5]dec-2-ene-3-carbaldehyde (122 mg, 0.730 mmol, as prepared in step B of this Example) was added as a solution in DMF (2 mL). Solid Na2S2O5 (153 mg, 0.803 mmol) was added, and the mixture was heated to 100° C. for 4 h. The cooled mixture was poured into water (100 mL) and extracted three times with EtOAc (50 mL). The combined organic extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. The residue was purified by column chromatography using a 4-g SiO2 pre-packed column eluting with EtOAc/hexanes, 0:1 to 3:17, v/v over 30 min, yielding 105 mg (38%) of the title compound. 1H-NMR (400 MHz, d6-DMSO) δ: 7.43-7.55 (m, 2H), 7.15-7.30 (m, 3H), 3.35 (s, 2H), 2.61 (s, 3H), 1.63-1.83 (m, 6H), 1.34-1.57 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C22H21F2N3O: 382.2 (M+H). found: 382.2.
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[O:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][CH2:15]1.CN(C)[CH:25]=[O:26]>CCCCCC.O>[CH:25]([C:19]1[C:18]2[O:14][CH2:15][CH2:16][C:17]=2[CH:22]=[CH:21][CH:20]=1)=[O:26]
Reactant: CN(C)C=O
Reactant: c1ccc2c(c1)CCO2
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Product: O=Cc1cccc2c1OCC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35 %

Procedure:
108 ml of an n-butyllithium solution (2.1M) in hexane and 26.7 g (230 mmol) of tetramethylethylenediamine (TMEDA) are introduced into a 1 liter round-bottomed flask. The mixture is stirred at room temperature for 15 minutes and 23 g (190 mmol) of 2,3-dihydrobenzofuran are added. The mixture is stirred for 4 hours at 35° C., cooled to -78° C. and 13.9 g (190 mmol) of dimethylformamide are added. The temperature is allowed to return to 20° C., 500 ml of water are added and extraction is carried out with ethyl acetate (3×200 ml). The organic phases are combined, dried and concentrated under vacuum. The residue is purified by silica flash chromatography (elution: 5% ethyl acetate in petroleum ether). 9.85 g (Yield: 35%) of 7-formyl-2,3-dihydrobenzofuran are obtained--M.p.: 55° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][OH:6]>CC(C)=O.O=[Mn]=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=[O:6]
Reactant: OCc1ccc(Cl)c(Br)c1
Agent: O=[Mn]=O
Solvent: CC(C)=O
Product: O=Cc1ccc(Cl)c(Br)c1
Reaction time: 72 h
Yield: 62.4 %

Procedure:
A solution of 3-bromo-4-chlorobenzyl alcohol (3.24 g, 14.6 mmol) in acetone (100 mL) was treated with MnO2 (16.2 g, 73 mmol) and the mixture stirred for 3 days then filtered over diatomaceous earth. The filtrate was concentrated under reduced pressure to afford 2.0 g of title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[C:19]([O:23][C:24]([N:26]1[CH2:36][CH2:35][C:29]2([O:34][CH2:33][CH2:32][NH:31][CH2:30]2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:19]([O:23][C:24]([N:26]1[CH2:27][CH2:28][C:29]2([O:34][CH2:33][CH2:32][N:31]([CH2:11][C:9]3[S:10][C:5]4[C:4]([N:13]5[CH2:18][CH2:17][O:16][CH2:15][CH2:14]5)=[N:3][C:2]([Cl:1])=[N:7][C:6]=4[CH:8]=3)[CH2:30]2)[CH2:35][CH2:36]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCCO2
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(Cc1cc3nc(Cl)nc(N4CCOCC4)c3s1)CCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.1 %

Procedure:
To a suspension of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (100 mg, 0.352 mmol) in dichloroethane (10 mL) were added 1-oxa-4,9-diaza-spiro[5.5]undecane-9-carboxylic acid tert-butyl ester (110 mg, 0.376 mmol) and sodium triacetoxyborohydride (113 mg, 0.533 mmol) and the resulting solution stirred at RT for 3 h. The reaction was quenched with water and loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH. The resulting residue was then purified by column chromatography to give the title compound as a white solid (98 mg, 53%) [M+H]+ 524.3
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][O:25]C(=O)C.O>CN(C=O)C.CCOC(C)=O.CO>[OH:25][CH2:24][CH2:23][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)OCCBr
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2ccc(OCCO)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To a solution of 4′-hydroxy-4-biphenylcarbonitrile (1.014 g, 5.19 mmol) in 10 mL DMF was added potassium carbonate (2.15 g, 15.6 mmol, 3 eq.) and 2-bromoethylacetate. After two hours at 50° C., the reaction mixture was cooled to room temperature, diluted with 50 mL EtOAc, washed with H2O (3×10 mL), dried (Na2SO4), filtered, and concentrated to provide a white solid. The solid was dissolved in 20 mL MeOH and 5 mL H2O and potassium carbonate (2.15 g, 15.6 mmol) were added. After 30 minutes, the MeOH was evaporated and the crude reaction was taken up in EtOAc and washed with H2O (10 mL×3), dried (Na2SO4), filtered, concentrated, and purified on silica gel to provide 0.967g (78%) of the desired compound.
Reaction SMILES: C(OC1C=C(C(C)(C)O)C=C(C(C)(C)O)C=1)C1C=CC=CC=1.C([O:30][C:31]1[CH:32]=[C:33]([C:43]([CH2:47][CH3:48])([CH2:45][CH3:46])O)[CH:34]=[C:35]([C:37]([CH2:41][CH3:42])([CH2:39][CH3:40])O)[CH:36]=1)C1C=CC=CC=1>>[CH2:45]([CH:43]([C:33]1[CH:32]=[C:31]([OH:30])[CH:36]=[C:35]([CH:37]([CH2:39][CH3:40])[CH2:41][CH3:42])[CH:34]=1)[CH2:47][CH3:48])[CH3:46]
Reactant: CCC(O)(CC)c1cc(OCc2ccccc2)cc(C(O)(CC)CC)c1
Agent: CC(C)(O)c1cc(OCc2ccccc2)cc(C(C)(C)O)c1
Product: CCC(CC)c1cc(O)cc(C(CC)CC)c1

Procedure:
The procedure (including reaction and treatment) of Example 2 was repeated, except that 5-benzyloxy-α,α,α′,α′tetramethyl-1,3-benzenedimethanol was replaced by 5-benzyloxy-α,α,α′,α′-tetraethyl-1,3-benzenedimethanol, to thereby yield the above-described target as colorless needles.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][C:6]([CH2:7][O:8][N:9]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][CH2:20][C:21]([O:23]CC)=[O:22])=[CH:15][CH:14]=2)[CH2:11][CH3:12])=[CH:5][CH:4]=1.[OH-].[Li+]>C1COCC1.O>[F:1][C:2]([F:28])([F:29])[C:3]1[CH:27]=[CH:26][C:6]([CH2:7][O:8][N:9]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:15][CH:14]=2)[CH2:11][CH3:12])=[CH:5][CH:4]=1
Reactant: CCOC(=O)CNc1ccc(C(CC)=NOCc2ccc(C(F)(F)F)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCC(=NOCc1ccc(C(F)(F)F)cc1)c1ccc(NCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
To a solution of the product of step 3 (2.2 g, 5.39 mmoles) in THF (10 ml), a solution of lithium hydroxide (0.45 g, 10.77 mmoles) in water (10 mL) was added and the reaction mixture was stirred at 25° C. for 3 hours. The solvents were evaporated under reduced pressure. The residue was dissolved in water and neutralized to pH 6 with 1N HCl. Solid seperated was filtered, washed with water and dried over CaCl2 under vacuum to give 1.64 g (82%) of title product.