Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]O)=[CH:4][C:3]=1[O:10][CH3:11].S(Cl)([Cl:14])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][Cl:14])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: COc1cc(CO)ccc1Cl
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1cc(CCl)ccc1Cl

Procedure:
4-chloro-3-methoxybenzyl alcohol (5 g, 1 equiv) in 15 mL of DCM was treated with thionyl chloride (5 mL, 3 equiv) at reflux for 2 hours. Evaporation of volatiles gave 4-chloro-3-methoxybenzyl chloride.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:22][C:23]#[N:24])[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])(=[O:14])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2]>CO.CC(O)=O.O=[Pt]=O>[CH2:1]([O:3][C:4]([C:6]1([CH2:22][CH2:23][NH2:24])[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])(=[O:14])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(CC#N)CCN(S(=O)(=O)c2ccccc2Cl)CC1
Agent: O=[Pt]=O
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)C1(CCN)CCN(S(=O)(=O)c2ccccc2Cl)CC1

Procedure:
1-(2-Chloro-benzenesulfonyl)-4-cyanomethyl-piperidine-4-carboxylic acid ethyl ester (8.5 g) dissolved in MeOH/AcOH (1:1, 250 ml) was hydrogenated over PtO2 (2.6 g) for 4 h at atmospheric pressure until full conversion (control by thin layer chromatography). The catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in AcOEt and washed with 1M aqueous NaOH then with brine. The organic layer was dried over magnesium sulphate, the solvent removed in vacuo to give the desired product, crude light yellow oil (7.09 g), as a mixture together with some already spirocyclised amide. MS (ESI): 375.1 MH+). The crude material was directly used as such in the subsequent ring closure reaction.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:23][CH:12]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH:11]3[CH2:10]2)[C:5]([Cl:24])=[CH:4][N:3]=1.[CH:25]1([CH2:28][N:29]2[CH:33]=[C:32]([NH2:34])[CH:31]=[N:30]2)[CH2:27][CH2:26]1.FC(F)(F)C(O)=O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[Cl:24][C:5]1[C:6]([NH:8][CH:9]2[CH2:23][CH:12]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH:11]3[CH2:10]2)=[N:7][C:2]([NH:34][C:32]2[CH:31]=[N:30][N:29]([CH2:28][CH:25]3[CH2:27][CH2:26]3)[CH:33]=2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CC2CC(Nc3nc(Cl)ncc3Cl)CC2C1
Reactant: Nc1cnn(CC2CC2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC2CC(Nc3nc(Nc4cnn(CC5CC5)c4)ncc3Cl)CC2C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 271.2 %

Procedure:
To a solution of tert-butyl 5-[(2,5-dichloropyrimidin-4-yl)amino]-hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1.10 g, 2.95 mmol) and 1-(cyclopropylmethyl)pyrazol-4-amine (38.5 mg, 0.28 mmol) in dioxane (10 mL) was added 2,2,2-trifluoroacetic acid (61.8 mg, 0.54 mmol). The reaction mixture was stirred at 100° C. overnight, then adjusted to pH=10 with a saturated Na2CO3 solution, and extracted with EtOAc (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/2) to give the title compound as a pale yellow solid (0.36 g, 26%).
Reaction SMILES: F[P-](F)(F)(F)(F)F.C([O+:10]([CH2:13][CH3:14])[CH2:11][CH3:12])C.O=[C:16]1[NH:21]CC[N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1>>[CH2:13]([O:10][C:11]1[CH2:12][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17][CH2:16][N:21]=1)[CH3:14]
Reactant: CC[O+](CC)CC
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: F[P-](F)(F)(F)(F)F
Product: CCOC1=NCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Triethyloxonium hexafluorophosphate (3.20 g, 28.0 mmol) was added to a solution of tert-butyl 3-oxopiperazine-1-carboxylate (2.54 g, 12.7 mmol) in CH2CL2 (31.7 mL) at 0° C., and the resulting solution was stirred at room temperature for 18 hours. The reaction mixture was washed with saturated NaHCO3, dried (Na2SO4), and concentrated to give tert-butyl 3-ethoxy-5,6-dihydropyrazine-1(2H)-carboxylate as an oil. LCMS (APCI+) M+H-t-Bu: 173 (40%); rt=3.14 minutes.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([CH:15]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]1)#[N:14].Br[CH2:27][F:28]>C1COCC1>[C:13]([C:15]1([CH2:27][F:28])[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]1)#[N:14]
Reactant: FCBr
Reactant: CC(C)(C)OC(=O)N1CC(C#N)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)N1CC(C#N)(CF)C1
Temperature: 0 °C
Yield: 88.6 %

Procedure:
To an oven-dried 25 mL round bottom flask equipped for stirring was added diisopropylamine (0.659 mL, 4.66 mmol) under nitrogen. THF (5 mL) was added and the colorless solution was cooled to 0° C. To this solution was added n-BuLi (2.92 mL, 4.66 mmol) and the solution was stirred at 0° C. for 30 min. The solution was cooled to -78° C. and a solution of tert-butyl 3-cyanoazetidine-1-carboxylate (0.5 g, 2.74 mmol) in THF (3 mL) was added and the solution was stirred at −78° C. for 30 min. Bromofluoromethane (0.403 g, 3.57 mmol) was added at −78° C. dropwise. The reaction mixture was stirred for 30 min and then allowed to warm to 25° C. and stirred for 16 h. The reaction mixture was quenched at 0° C. with aqueous NH4Cl (5 mL) and extracted with DCM (3×). The extracts were dried over Na2SO4. Purification by silica column chromatography (MeOH/DCM, 0-5%) afforded the title compound as a yellow oil (0.52 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:11][C:12]2[CH:13]=[C:14]([C:18](=O)[CH3:19])[CH:15]=[CH:16][CH:17]=2)[CH2:9][CH3:10])=[CH:4][C:3]=1[CH3:21].[NH:22]1[CH2:25][CH:24]([C:26]([OH:28])=[O:27])[CH2:23]1.CC(O)=O.[BH3-]C#N.[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:11][C:12]2[CH:13]=[C:14]([CH:18]([N:22]3[CH2:25][CH:24]([C:26]([OH:28])=[O:27])[CH2:23]3)[CH3:19])[CH:15]=[CH:16][CH:17]=2)[CH2:9][CH3:10])=[CH:4][C:3]=1[CH3:21]
Reactant: O=C(O)C1CNC1
Reactant: CC[C@@H](Nc1cccc(C(C)=O)c1)c1ccc(Cl)c(C)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC[C@@H](Nc1cccc(C(C)N2CC(C(=O)O)C2)c1)c1ccc(Cl)c(C)c1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a solution of INT 11 (213 mg, 0.71 mmol) and azetidine-3-carboxylic acid (75 mg, 0.74 mmol) in MeOH (7 mL) was added HOAc (0.040 mL, 0.71 mmol) followed by NaCNBH3 (44 mg, 0.71 mmol). The reaction mixture was stirred at room temperature for 40 hours. More azetidine-3-carboxylic acid (10 mg, 0.099 mol) and NaCNBH3 (10 mg, 0.16 mmol) were added and the mixture was stirred at room temperature for an additional 4 hours. The mixture was concentrated. The residue was taken up in CH2Cl2 and washed with brine. The aqueous layer was extracted with CH2Cl2 and EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by preparative HPLC (H2O/CH3CN) to afford the title compound Example 6.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[CH2:16]([O:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1B(O)O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[F:30][C:28]1[CH:27]=[CH:26][C:25]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][C:3]=2[C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)=[C:24]([O:23][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:29]=1
Reactant: OB(O)c1ccc(F)cc1OCc1ccccc1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(F)cc1OCc1ccccc1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile (PREPARATION 2) and 2-benzyloxyl-4-fluorophenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C23H17FN4O, 385. Found, 385.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[CH2:11]([N:14]=[C:15]([NH2:29])[NH:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH2:28])[N:18]=1)[CH2:12][CH3:13]>CCO.C(N(CC)CC)C>[CH2:11]([N:14]=[C:15]([NH2:29])[NH:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=2)[N:18]=1)[CH2:12][CH3:13]
Reactant: O=C(Cl)c1cccnc1
Reactant: CCCN=C(N)Nc1ccnc(CCCCCN)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCN=C(N)Nc1ccnc(CCCCCNC(=O)c2cccnc2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 5.4 %

Procedure:
Nicotinoyl chloride hydrochloride (0.2 g.) was added at 0° to a stirred solution of 4-(2-propylguanidino)-2-(5-aminopentyl)pyrimidine (0.2 g.) in EtOH (5 ml.) and triethylamine (2 ml.). The mixture was stirred at room temperature for 16 hours and evaporated to dryness. The residue was partitioned between 2N aqueous HCl and EtOAc and the aqueous phase was then basified with 10N aqueous NaOH and extracted with EtOAc. The extract was dried (MgSO4) and evaporated to dryness. The residual gum was purified twice by preparative thin layer chromatography on Merck 60 F-254 plates using EtOAc/MeOH/aqueous ammonia (s.g. 0.88) 6:1:1 v/v/v as developing solvent. The appropriate zone of the chromatogram was extracted with MeOH/aqueous ammonia (s.g. 0.88) 10:1 v/v and the solvent was evaporated. The residual gum was dissolved in EtOAc, filtered and treated with an excess of a saturated solution of maleic acid in EtOAc. The precipitated gum was washed with EtOAc to give N-[5-(4-[2-propylguanidino]-pyrimid-2-yl)pentyl]nicotinamide (0.015 g.) as a straw coloured gum. The n.m.r. spectrum in d4MeOH using tetramethylsilane as standard included the following resonances (δ): 1.0 (3H, triplet), 1.7 (8H, multiplet), 2.9 (2H, triplet), 3.6 (2H, triplet), 6.8 (1H, doublet), 7.6 (1H, multiplet), 8.3 (2H, multiplet) and 8.8 (2H, complex).
Reaction SMILES: [C:1]([NH2:4])(=[O:3])[CH3:2].[C:5]([N:10]=[C:11]=[O:12])(=[O:9])[C:6]([CH3:8])=[CH2:7]>ClCCCl>[C:5]([NH:10][C:11]([NH:4][C:1](=[O:3])[CH3:2])=[O:12])(=[O:9])[C:6]([CH3:8])=[CH2:7]
Reactant: CC(N)=O
Reactant: C=C(C)C(=O)N=C=O
Solvent: ClCCCl
Product: C=C(C)C(=O)NC(=O)NC(C)=O
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 95.8 %

Procedure:
To a solution of acetamide (0.59 g; 10 mmol) in 1,2-dichloroethane (20 ml), a solution of methacryloyl isocyanate (1.11 g; 10 mmol) in 1,2-dichloroethane (5 ml) was dropwise added at room temperature, and the reaction mixture was stirred at 80° C. for 3.5 hours. After cooling, 1,2-dichloroethane was evaporated under reduced pressure to give 1-methacryloyl-3-acetylurea (1.63 g), which was recrystallized from a mixture of benzene-and hexane to give colorless needles. M.P., 92°-94° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[N:19]=[C:18]([CH:27]([CH3:29])[CH3:28])[CH:17]=2)=[CH:12][CH:11]=1.O>CN(C=O)C>[Br:1][C:17]1[C:18]([CH:27]([CH3:29])[CH3:28])=[N:19][N:20]([C:21]2[N:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[C:16]=1[C:13]1[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=1
Reactant: CC(C)c1cc(-c2ccc(F)cc2)n(-c2ncccn2)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1nn(-c2ncccn2)c(-c2ccc(F)cc2)c1Br
Temperature: 25 °C
Yield: 82.6 %

Procedure:
N-Bromosuccinimide (9.97 g, 0.056 mol) was added to a solution of 2-[5-(4-fluorophenyl)-3-(l-methylethyl)-1H-pyrazol-1-yl]pyrimidine (15.8 g, 0.056 mol) in DMF at 0° C. The resulting mixture was allowed to warm to room temperature over 24 hours. This was then poured into 500 mL water. The white solid which precipitated was collected by filtration and dried to yield 16.7 g of 2-[4-bromo-5-(4-fluorophenyl)-3-(1-methylethyl)-1H-pyrazol-1-yl]pyrimidine (3), mp 130°-133° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7].[CH:13]([Mg]Br)=[CH2:14].[Cl-].[NH4+]>O1CCCC1>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:4]=[C:5]([CH:6]([OH:7])[CH:13]=[CH2:14])[CH:8]=[CH:9][CH:10]=1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-trifluoromethylbenzaldehyde (6.7 mL) in tetrahydrofuran (40 mL) was stirred on an ice bath and treated dropwise over 25 min with a solution of vinylmagnesium bromide in tetrahydrofuran (1.0 M, 60 mL). The mixture was stirred for 2 h while allowing to warm slowly to room temperature, then was treated with saturated aqueous ammonium chloride. The mixture was extracted with ether, and the organic extracts were washed with water and brine, then dried over sodium sulfate and concentrated under vacuum. Purification by flash column chromatography, eluting with 10% ethyl acetate in hexane, provided 1-(3-trifluoromethylphenyl)prop-2-en-1-ol (2.33 g) as a colorless oil. MS found: (M+H−H2O)+=185.19.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.F[C:12]1[CH:20]=[N:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:17]2[CH:18]=[N:19][CH:20]=[CH:12][C:13]=2[C:14]([OH:16])=[O:15])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccncc1F
Reactant: COc1ccc(CN)cc1
Product: COc1ccc(CNc2cnccc2C(=O)O)cc1
Yield: 26 %

Procedure:
The title compound was prepared in 26% yield from 4-methoxybenzylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 8.17 (s, 1H), 7.81 (d, 1H, J=5.0 Hz), 7.56 (d, 1H, J=5.0 Hz), 7.29 (d, 2H, J=8.5 Hz), 6.91 (d, 2H, J=8.5 Hz), 4.47 (s, 2H), 3.73 (s, 3H). [M+H] calc'd for C14H14N2O3, 259. found 259.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:9])[CH:4]=[CH:5][C:6](=[O:8])[CH:7]=1.[SH:10][CH2:11][CH2:12][OH:13]>C(O)C>[OH:13][CH2:12][CH2:11][S:10][C:4]1[C:3](=[O:9])[C:2]([CH3:1])=[CH:7][C:6](=[O:8])[CH:5]=1
Reactant: OCCS
Reactant: CC1=CC(=O)C=CC1=O
Solvent: CCO
Product: CC1=CC(=O)C=C(SCCO)C1=O
Temperature: 0 °C

Procedure:
Methyl-p-benzoquinone 12.2 g, 0.1 mole) and 2-mercaptoethanol (3.9 g, 0.05 mole) are mixed in absolute ethanol (70 ml) under nitrogen and with stirring. The temperature rises to 50° C. The mixture is cooled in a bath of ice-water and left to stand, with stirring, for 2 hours at ambient temperature. The solution is concentrated under vacuum and the oil obtained is chromatographed on Silica 60 (eluent: dichloromethane). According to 1H and 13C NMR, a first fraction (3 g) is a 50/50 mixture of two products: 2-hydroxyethylthio-5-methyl-1,4-benzoquinone and 2-hydroxyethylthio-6-methyl-1,4-benzoquinone. A second fraction gives the expected product:
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([F:12])([F:11])[F:10])=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].[Cl:15][C:16]1[CH:27]=[C:26]([F:28])[C:25]([N:29]=[C:30]=[O:31])=[CH:24][C:17]=1[C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19]>CCCCCC.CN(C)C=O>[Cl:15][C:16]1[CH:27]=[C:26]([F:28])[C:25]([NH:29][C:30]([NH:1][C:2]([C:9]([F:10])([F:11])[F:12])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:31])=[CH:24][C:17]=1[C:18]([O:20][CH:21]([CH3:22])[CH3:23])=[O:19]
Reactant: CC(C)OC(=O)c1cc(N=C=O)c(F)cc1Cl
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCOC(=O)C=C(NC(=O)Nc1cc(C(=O)OC(C)C)c(Cl)cc1F)C(F)(F)F
Reaction time: 0.5 h

Procedure:
A solution of 3.55 g of ethyl 3-amino-4,4,4-trifluorocrotonate in 50 ml of n-hexane is added dropwise with stirring and at 0°-3° C. during 15 minutes to 0.85 g of a 55% sodium hydride dispersion in 50 ml of dimethylformamide, and the mixture is stirred for a further 30 minutes. Then a solution of 5.0 g of isopropyl 2-chloro-4-fluoro-5-isocyanatobenzoate in 100 ml of n-hexane is added dropwise during 5 minutes with stirring and cooling. The temperature of the reaction mixture rises to 10° C., and the mixture is thereafter stirred for one hour at room temperature. The isopropyl 2-chloro-4-fluoro-5-{3-[2-(ethoxycarbonyl)-1-trifluoromethyl-vinyl]ureido}-benzoate which is formed as an intermediate is not isolated.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:8]=2[C:9](O)=[O:10])=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+]>C1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:8]=2[CH2:9][OH:10])=[CH:17][CH:18]=1
Reactant: Cc1ccc(Oc2ccc(C)cc2C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: Cc1ccc(Oc2ccc(C)cc2CO)cc1

Procedure:
A solution of 121 g. of 2-(4-methyl-phenoxy)-5-methyl-benzoic acid in 600 ml. of tetrahydrofuran is slowly added dropwise, with cooling in an icebath, to 420 ml. of a 70% solution of sodium dihydro-bis(1-methoxyethoxy)aluminate in benzene and stirred for an additional hour at room temperature. To the obtained clear solution, 800 ml. of 20% aqueous sodium hydroxide solution are carefully added dropwise. Then, the organic phase is separated. The aqueous phase is extracted three additional times with ether. The organic extracts are washed with saturated sodium chloride solution and the latter dried over sodium sulfate. After evaporation of the ether, there is obtained 2-(4-methyl-phenoxy)-5-methyl-benzyl alcohol as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][C@@H:15]([OH:18])[CH2:14][CH2:13]2)=[O:10])=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].Cl[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:25]=1.CC(C)([O-])C.[K+]>C1COCC1>[C:33]([O:32][C:30]([C:26]1[CH:25]=[C:24]([O:18][C@H:15]2[CH2:14][CH2:13][C@@H:12]([NH:11][C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:19]([F:20])([F:21])[F:22])[CH:4]=3)=[O:10])[CH2:17][CH2:16]2)[CH:29]=[CH:28][N:27]=1)=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)ccn1
Reactant: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)N[C@H]1CC[C@@H](O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cc(O[C@H]2CC[C@@H](NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)CC2)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of cis-1-(4-chloro-3-trifluoromethyl-phenyl)-3-(4-hydroxy-cyclohexyl)-urea (0.38 g, 1.13 mmol) and tert-butyl 4-chloropicolinate (0.24 g, 1.13 mmol) in THF (12 mL) was added 1.0 M potassium tert-butoxide solution in THF (3.4 mL, 3.4 mmol) at 0° C. The reaction mixture was allowed to slowly warm to room temperature and then stirred overnight. The reaction was quenched by adding water and the resulting white precipitates were collected and washed with water. Purification by column chromatography (6:4 Hexanes-EtOAc) gave the title compound, 0.32 g (55%) as a yellowish powder. 1H NMR (300 MHz, DMSO-d δ 8.78 (s, 1H), 8.48 (d, J=6 Hz, 1H), 8.09-8.06 (m, 1H), 7.55-7.50 (m, 2H), 7.46 (d, J=2 Hz, 1H), 7.21 (dd, J=6 and 2 Hz, 1H), 6.48 (d, J=8 Hz, 1H), 4.82-4.67 (m, 1H), 3.75-3.59 (m, 1H), 1.91-1.47 (m, 17H).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].Cl[C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[C:13]([C:20]3[NH:28][C:27]4[CH2:26][CH2:25][NH:24][C:23](=[O:29])[C:22]=4[CH:21]=3)[CH:14]=[CH:15][CH:16]=2)[N:11]=1>>[OH:2][C:1]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[O:5][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[C:13]([C:20]3[NH:28][C:27]4[CH2:26][CH2:25][NH:24][C:23](=[O:29])[C:22]=4[CH:21]=3)[CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Reactant: Oc1cccc(O)c1
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(Oc5cccc(O)c5)nc34)cc21
Temperature: 90 °C
Yield: 77.4 %

Procedure:
Prepared according to Example 103 using resorcinol (125.5 mg, 1.140 mmol) and 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 50.0 mg, 0.168 mmol), heating at 90° C. for 18 h. Chromatographic purification (silica gel, 0-10% MeOH/DCM) furnished 2-(2-(3-hydroxyphenoxy)-quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (48.4 mg, 0.130 mmol, 78% yield) as a light-yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.20 (1H, br. s.), 9.86 (1H, s), 8.47 (1H, d, J=8.8 Hz), 8.14 (1H, d, J=7.6 Hz), 7.78 (1H, d, J=7.2 Hz), 7.47 (1H, t, J=7.7 Hz), 7.35-7.42 (2H, m), 6.98 (1H, d, J=2.2 Hz), 6.94 (1H, br. s.), 6.83 (1H, m, J=7.8, 1.8 Hz), 6.79 (1H, dd, J=7.9, 1.7 Hz), 6.74 (1H, t, J=2.2 Hz), 3.31-3.37 (2H, m), 2.47-2.49 (2H, obsc. m). m/z (ESI, +ve) 372.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH2:16][F:17])[C@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[C:19]([C:21]1[CH:22]=[CH:23][C:24]([C:27](O)=[O:28])=[N:25][CH:26]=1)#[N:20]>>[NH2:15][C:10]1[O:11][CH2:12][C@@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:27]([C:24]3[CH:23]=[CH:22][C:21]([C:19]#[N:20])=[CH:26][N:25]=3)=[O:28])[CH:3]=[CH:4][C:5]=2[F:18])([CH2:16][F:17])[N:9]=1
Reactant: NC1=N[C@](CF)(c2cc(N)ccc2F)[C@H](F)CO1
Reactant: N#Cc1ccc(C(=O)O)nc1
Product: N#Cc1ccc(C(=O)Nc2ccc(F)c([C@@]3(CF)N=C(N)OC[C@H]3F)c2)nc1

Procedure:
The condensation of (4S,5S)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-fluoromethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (A8.6) and 5-cyano-pyridine-2-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=390.4 [M+H]+.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[Br:11][C:12]1[N:17]=[C:16]([CH2:18][NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=2[O:29][CH3:30])[CH:15]=[CH:14][CH:13]=1>O1CCCC1>[Br:11][C:12]1[N:17]=[C:16]([CH2:18][N:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=2[O:29][CH3:30])[CH:1]=[O:3])[CH:15]=[CH:14][CH:13]=1
Reactant: COc1ccc(CNCc2cccc(Br)n2)c(OC)c1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Solvent: C1CCOC1
Product: COc1ccc(CN(C=O)Cc2cccc(Br)n2)c(OC)c1
Temperature: 55 °C
Reaction time: 0.75 h

Procedure:
To acetic anhydride (0.703 mL) was added dropwise formic acid (0.349 mL) under ice-cooling, and the mixture was stirred at 55° C. for 45 min. The mixture was allowed to be cooled to room temperature, and tetrahydrofuran (10 mL) was added thereto. A solution of 1-(6-bromopyridin-2-yl)-N-(2,4-dimethoxybenzyl)methanamine obtained in Reference Example 19 (930 mg) in tetrahydrofuran (10 mL) was added dropwise thereto over 3 min under ice-cooling, and the reaction mixture was stirred at room temperature for 30 min. The reaction solution was concentrated under reduced pressure, the obtained colorless oil was subjected to azeotropy with toluene, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (932 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][C:3]=1[OH:14].[CH3:15][NH:16][C:17]([C:19]1[CH:24]=[C:23](Cl)[CH:22]=[CH:21][N:20]=1)=[O:18]>C(Cl)Cl>[CH3:15][NH:16][C:17]([C:19]1[CH:24]=[C:23]([O:14][C:3]2[CH:4]=[C:5]([N+:11]([O-:13])=[O:12])[C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[CH3:1])[CH:22]=[CH:21][N:20]=1)=[O:18]
Reactant: Cc1cc([N+](=O)[O-])c([N+](=O)[O-])cc1O
Reactant: CNC(=O)c1cc(Cl)ccn1
Solvent: ClCCl
Product: CNC(=O)c1cc(Oc2cc([N+](=O)[O-])c([N+](=O)[O-])cc2C)ccn1
Temperature: 170 °C

Procedure:
2-Methyl-4,5-dinitrophenol (Step A, 1.34 g, 6.77 mmol) and 4-chloro-pyridine-2-carboxylic acid methylamide (1.16 g, 6.77 mmol) were combined and heated at 160-180° C. (round bottom flask with condenser). The reaction was cooled to RT, the contents of the flask were dissolved in CH2Cl2 and the organic layer washed with 2 N NaOH, then water. The organic layer was dried with Na2SO4, filtered and evaporated. The mixture was purified by column chromatography using EtOAc/hexanes as the eluant. The title compound was obtained as a tan solid.