Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18](O)=[O:19])[NH:11][C:12](=[O:14])[N:13]=2)=[CH:4][C:3]=1[CH3:24].[CH3:25][O:26][CH2:27][CH2:28][NH2:29].ON1C2C=CC=CC=2N=N1.CCN=C=NCCC[N+](C)(C)C.[I-]>ClC(Cl)C.CN(C)C=O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18]([NH:29][CH2:28][CH2:27][O:26][CH3:25])=[O:19])[NH:11][C:12](=[O:14])[N:13]=2)=[CH:4][C:3]=1[CH3:24]
Reactant: COCCN
Reactant: Cc1cc(-c2cc(-c3cccc(C(=O)O)c3)[nH]c(=O)n2)ccc1O
Agent: CCN=C=NCCC[N+](C)(C)C
Agent: On1nnc2ccccc21
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Product: COCCNC(=O)c1cccc(-c2cc(-c3ccc(O)c(C)c3)nc(=O)[nH]2)c1
Yield: 35.6 %

Procedure:
To a solution of 3-(6-(4-hydroxy-3-methylphenyl)-2-oxo-2,3-dihydropyrimidin-4-yl)benzoic acid (16.9 mg, 48 umol) and 2-methoxyethanamine (3.0 mg, 40 umol) in dichloroethane (1.25 mL) and N,N-dimethylformamide (0.79 mL) was added 1-hydroxybenzotriazole (6.8 mg, 50 umol) followed by 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide methiodide (17.8 mg, 60 umol). The resultant mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated in vacuo. Purification of the residue by HPLC (reverse-phase, acetonitrile/water with 0.1% formic acid) followed by concentration in vacuo gave the title compound 3-[6-(4-hydroxy-3-methylphenyl)-2-oxo-2,3-dihydropyrimidin-4-yl]-N-[2-(methyloxy)ethyl]benzamide (5.4 mg, 36%).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][NH:12][CH2:13][CH2:14][OH:15]>O1CCCC1>[CH3:11][N:12]([CH2:13][CH2:14][OH:15])[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CNCCO
Reactant: Clc1nc2ccccc2o1
Solvent: C1CCOC1
Product: CN(CCO)c1nc2ccccc2o1
Temperature: 25 °C

Procedure:
A solution of 2-chlorobenzoxazole (15.4 g ) in dry tetrahydrofuran (50 ml) was added dropwise to an ice cooled solution of 2-methylaminoethanol (15.0 g) in dry tetrahydrofuran (100 ml) with stirring and protection from atmospheric moisture. The mixture was stirred at 0° C. for 1 hour, allowed to warm to room temperature and stirred for a further 2 hours. The solvent was removed under reduced pressure, the product was dissolved in ethyl acetate (200 ml) and washed with brine (2×150 ml). The organic layer was dried (MgSO4), filtered and the solvent evaporated. Chromatography of the residue on silica-gel in dichloromethane gave the title compound (mp 62°-3° C.) which was used in Preparation 3 without further purification.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([OH:15])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1.[CH3:16][O:17][C:18]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=O.C(N(CC)CC)C.B.[Na]>CO>[CH3:16][O:17][C:18]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][NH:2][CH2:3][CH:4]([OH:15])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1
Reactant: COc1ccc(C(O)CN)cc1OC
Reactant: COc1cccc(C=O)c1OC
Agent: B
Agent: Cl
Agent: [Na]
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc(C(O)CNCc2cccc(OC)c2OC)cc1OC
Temperature: 25 °C
Yield: 72 %

Procedure:
1.0 g of α-(aminomethyl)-3,4-dimethoxybenzyl alcohol hydrochloride was suspended in 5 ml of methanol, and after adding thereto 0.85 g of 2,3-dimethoxybenzaldehyde, 0.63 ml of triethylamine was added dropwise to the mixture while stirring at room temperature. The mixture was heated under reflux for 30 minutes, and 0.24 g of sodium boron hydride was added slowly to the mixture while stirring under ice cooling. After the foaming stopped, the mixture was concentrated. The residue was subjected to a separating procedure with chloroform and water, the chloroform layer was collected, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was recrystallized from ethyl acetate-n-hexane, giving 1.07 g of α-[[(2,3-dimethoxybenzyl)amino]methyl]-3,4-dimethoxybenzyl alcohol, m.p. 96°-97° C.
Reaction SMILES: C[N:2]([CH3:19])/[CH:3]=[C:4](/[C:10](=[O:18])[C:11]1[C:16](Cl)=[CH:15][CH:14]=[CH:13][N:12]=1)\[C:5]([O:7][CH2:8][CH3:9])=[O:6].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Br:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1CN.O>CC(N(C)C)=O>[Br:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:19][N:2]1[C:16]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:18])[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3]1
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)c1ncccc1Cl
Reactant: NCc1ccccc1Br
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)c1cn(Cc2ccccc2Br)c2cccnc2c1=O
Temperature: 74 °C
Reaction time: 15 h
Yield: 49.2 %

Procedure:
To a brown solution of (Z)-ethyl 2-(3-chloropicolinoyl)-3-(dimethylamino)acrylate (35) (850 mg, 3.01 mmol) in DMA (dimethylacetamide) (50 mL) were added a solid powder of tribasic potassium phosphate (1.4 g, 6.61 mmol) and then (2-bromophenyl)methanamine (615 mg, 3.31 mmol) at room temperature under a nitrogen atmosphere. The resulting brown suspension was heated to 74° C. and stirred for 15 h at which time LCMS analysis indicated the absence of starting material. Then, it was cooled to room temperature and poured slowly into water (100 mL). Then, the organic compound was extracted into dichloromethane (2×200 mL). The combined extracts were washed with water, brine solution, and dried over anhydrous MgSO4. Filtration and concentration gave a crude brown oil which was purified using an ISCO (120 g) column, eluting with ethyl acetate in hexanes (0 to 100%) and then 5 to 10% methanol in dichloromethane. The pure fractions were combined and the solvent was removed under vacuum to obtain ethyl 1-(2-bromobenzyl)-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate (36) (574 mg, 46.8% yield) as a light brown solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:7]2[CH:8]=[C:9]([C:12]3[CH:13]=[C:14]([CH:17]=[C:18]([F:20])[CH:19]=3)[C:15]#[N:16])[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:21])[O:3]1.C([O-])(=O)C.[Na+].[Br:28]Br>C(O)(=O)C>[Br:28][C:11]1[C:6]2[NH:5][C:4](=[O:21])[O:3][C:2]([CH3:22])([CH3:1])[C:7]=2[CH:8]=[C:9]([C:12]2[CH:13]=[C:14]([CH:17]=[C:18]([F:20])[CH:19]=2)[C:15]#[N:16])[CH:10]=1
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cc(F)cc(C#N)c3)cc21
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC1(C)OC(=O)Nc2c(Br)cc(-c3cc(F)cc(C#N)c3)cc21
Temperature: 0 °C
Reaction time: 20 h
Yield: 75.3 %

Procedure:
To a mixture of 3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-5-fluorobenzonitrile (0.5 g, 1.7 mmol) and sodium acetate (0.2 g, 2.4 mmol) in acetic acid (5 mL) was added, at room temperature under nitrogen, bromine (0.12 mL, 2.34 mmol). The reaction mixture was stirred for 20 hours and then poured into ice water (30 mL). The precipitate was collected on a filter and washed with water (3×5 mL) to yield 3-(8-bromo-4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-5-fluorobenzonitrile as an off-white solid (0.48 g, 75%): mp 216-217° C.; 1H-NMR (DMSO-d6) δ 9.78 (s, 1H), 8.18 (t, 1H, J=1.6 Hz), 8.02-8.08 (m, 2H), 7.81 (m, 1H), 7.75 (d, 1H, J=1.8 Hz), 1.66 (s, 6H). MS (ESI) m/z 373, 375 [M−H]−.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[C:20]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:14]=1>>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[O:4][CH2:3][CH2:2][N:28]1[CH2:29][CH2:30][N:25]([C:20]2[C:19]([C:15]3[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=3)=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:26][CH2:27]1
Reactant: COc1cccc(OCCCl)c1
Reactant: c1cncc(-c2cccnc2N2CCNCC2)c1
Product: COc1cccc(OCCN2CCN(c3ncccc3-c3cccnc3)CC2)c1

Procedure:
The title compound was prepared starting from 1-(2-chloroethoxy)-3-methoxybenzene and 1-[3-(3-pyridyl)-2-pyridyl]piperazine following the procedure outlined for Example 15. 1H NMR (CDCl3): δ 2.48 (br s, 4H), 2.77 (t, 2H, J=6.0 Hz), 2.88 (app t, 4H), 3.78 (s, 3H), 4.06 (t, 2H, J=6.0 Hz), 6.45-6.52 (m, 3H), 7.04-7.10 (m, 2H) 7.33-7.37 (m, 1H), 7.46 (dd, 1H, J=1.9, 7.4 Hz), 7.97 (dt, 1H, J=1.9, 7.7 Hz), 8.28 (dd, 1H, J=1.9, 4.9 Hz), 8.56 (dd, 1H, J=1.7, 4.9 Hz), 8.82 (d, 1H, J=1.7 Hz). GC-MS m/z 391 (M+1, 3), 390 (M+, 3), 267 (35), 253 (100), 198 (29), 184 (63).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:22](=[O:24])[CH3:23])[C:14]4[C:19]([C:20]=3[CH:21]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)O1.[Br:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29](Br)[CH:28]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:26][C:27]1[CH:28]=[C:29]([C:9]2[CH:21]=[CH:20][C:12]3[N:13]([C:22](=[O:24])[CH3:23])[C:14]4[C:19]([C:11]=3[CH:10]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:30]=[CH:31][CH:32]=1
Reactant: CC(=O)n1c2ccccc2c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: Brc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)n1c2ccccc2c2cc(-c3cccc(Br)c3)ccc21
Temperature: 25 °C
Yield: 23 %

Procedure:
A mixture solution of 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-carbazol-9-yl)ethanone (10.00 g, 29.8 mmol), 1,3-dibromobenzene (17.59 g, 74.6 mmol), Pd(PPh3)4 (0.689 g, 0.597 mmol) and K2CO3 (12.37 g, 89 mmol) in toluene (100 mL) and water (20 mL) was refluxed under N2 overnight. After cooling to room temperature, the organic phase was isolated and the solvent was evaporated. The residue was purified by column chromatography on silica gel with hexane/DCM (1/1, v/v) as eluent to yield 1-(3-(3-bromophenyl)-9H-carbazol-9-yl)ethanone (2.5 g, 23%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[CH:13]=1)[C:5]([O:7][CH3:8])=[O:6].CCN(C(C)C)C(C)C.[CH2:33]([O:36][CH2:37][CH2:38]Br)[CH2:34]Br>C1(C)C=CC=CC=1>[CH3:23][O:22][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[N:1]1[CH2:38][CH2:37][O:36][CH2:33][CH2:34]1)[CH:21]=[CH:20]2
Reactant: BrCCOCCBr
Reactant: COC(=O)c1ccc(-c2ccc3cc(OC)ccc3c2)c(N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccc3cc(OC)ccc3c2)c(N2CCOCC2)c1
Temperature: 110 °C
Yield: 80.3 %

Procedure:
To a solution of methyl 3-amino-4-(6-methoxynaphthalen-2-yl)benzoate (1.00 g, 3.30 mmol) (see Step 1 of Example 5) and DIPEA (1.70 g, 13.2 mmol) in anhydrous toluene (20 mL) containing catalytic amount of KI (100 mg, 0.660 mmol) was added 2,2′-dibromodiethyl ether (1.50 g, 6.60 mmol). The mixture was heated to 110° C. for 3 days. The mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (PE/EtOAc=10/1) to give the product (1.00 g, yield 81%).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:8]1([NH2:11])[CH2:10][CH2:9]1>C(OCC)C>[CH:8]1([NH:11][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:10][CH2:9]1
Reactant: NC1CC1
Reactant: CCOC(=O)CBr
Solvent: CCOCC
Product: CCOC(=O)CNC1CC1
Reaction time: 3 h

Procedure:
Ethyl bromoacetate in diethyl ether was added dropwise to a solution cooled to +5° C. of cyclopropylamine in diethyl ether. A white solid formed. The mixture was stirred for 3 hours while maintaining the cooling. The precipitate was filtered off and extracted with ether and the filtrate was evaporated. The residue was triturated with benzene/cyclohexane and the solid was filtered off. The filtrate was evaporated and the residue was distilled and fractionated to give ethyl cyclopropylaminoacetate of boiling point 32°-33° C./0.7 mmHg: nD19 =1.4384.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:10][CH2:11][NH:12][CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[CH:14]=1.ClCCl.[C:26](OC(=O)C)(=[O:28])[CH3:27]>O>[C:26]([N:12]1[CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[CH:14]=[C:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[CH2:10][CH2:11]1)(=[O:28])[CH3:27]
Reactant: COc1cccc(C2C=C(c3cc(F)ccc3F)CCN2)c1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: ClCCl
Product: COc1cccc(C2C=C(c3cc(F)ccc3F)CCN2C(C)=O)c1
Reaction time: 0.17 h

Procedure:
To a stir bar equipped flask containing 4-(2,5-difluorophenyl)-6-(3-methoxyphenyl)-1,2,3,6-tetrahydropyridne (1-5, 0.6 g, 0.19 mmol) was added dichloromethane (15 mL) followed successively by TEA (0.14 mL, 0.19 mmol), and acetic anhydride (0.06 mL, 0.59 mmol). The resulting solution stirred for 10 min. Water was added (2 mL), and then the reaction was washed with dichloromethane (2×30 mL). The organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude reside was purified by reverse phase liquid chromatography (0.1% TFA) to give 1-acetyl-4-(2,5-difluorophenyl)-6-(3-methoxyphenyl)-1,2,3,6-tetrahydropyridine (1-6). 1H NMR (300 MHz, CDCl3) δ 7.26 (m, 1H), 6.96 (m, 4H), 6.82 (m, 1H); 6.36 (m, 1H), 6.20 (m, 1H), 3.82 (s, 3H), 3.80 (m, 2H); 3.40 (dt, J=11.9, 4.2 Hz, 1H); 2.74 (m, 1H); 2.42 (dd, J=16.0, 1.0 Hz, 1H), 2.20 (s, 3H); MS 344.1 found, 343.3 (M+H+) required.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH3:13])[CH:6]=[CH:5]2.[CH3:14]B(O)O.C([O-])([O-])=O.[K+].[K+]>O.O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:13][N:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH3:14])[CH:3]=2)[C:8]1=[O:12]
Reactant: CB(O)O
Reactant: Cn1ccc2cc(Br)ccc2c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc2c(=O)n(C)ccc2c1
Yield: 82.5 %

Procedure:
A mixture of 6-bromo-2-methylisoquinolin-1-one (200.0 mg, 0.84 mmol), methylboronic acid (251.0 mg, 4.2 mmol), Pd(PPh3)4 (93.0 mg, 0.08 mmol), K2CO3 (232.0 mg, 1.68 mmol) and H2O (2 drops) in dioxane (10.0 mL) was microwaved at 120° C. for 1 h. Purification by silica gel chromatography (PE:EA=5:1) gave the title compound (120.0 mg, 82.8%) as a light yellow solid. LCMS: 174.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[C:5]([NH:7][C@@H:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([N+:18]([O-])=O)[CH:16]=2)[CH2:11][CH2:10][C@H:9]1[O:21][C:22](=[O:24])[CH3:23])=[O:6]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[C:5]([NH:7][C@@H:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([NH2:18])[CH:16]=2)[CH2:11][CH2:10][C@H:9]1[O:21][C:22](=[O:24])[CH3:23])=[O:6]
Reactant: CC(=O)O[C@@H]1CCc2ccc([N+](=O)[O-])cc2[C@H]1NC(=O)c1ccc(Cl)c(Cl)c1
Solvent: CN(C)C=O
Product: CC(=O)O[C@@H]1CCc2ccc(N)cc2[C@H]1NC(=O)c1ccc(Cl)c(Cl)c1
Reaction time: 4 h
Yield: 107.6 %

Procedure:
A solution of 114 (1.9 g) in DMF (100 mL) was treated with SnCl2-2H2O (4 g). After 4 h, additional SnC2-2H2O (1 g) was added three times over three days. The solvent was then evaporated, the residue suspended in H2O-EtOAc, the mixture neutralized with 5N NaOH, and the mixture filtered. The organics were separated, washed with brine, dried, and the solvent evaporated to give a brown foam (1.9 g).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1([NH:17][C:18]([C:20]2[C:29]3[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=3[CH:23]=[CH:22][CH:21]=2)=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])[CH3:4].[CH3:30]I>C1COCC1>[CH2:3]([O:5][C:6]([C:8]1([N:17]([CH3:30])[C:18]([C:20]2[C:29]3[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=3[CH:23]=[CH:22][CH:21]=2)=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])[CH3:4]
Reactant: CCOC(=O)C1(NC(=O)c2cccc3c2CCCC3)Cc2ccccc2C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(N(C)C(=O)c2cccc3c2CCCC3)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86 %

Procedure:
To a solution of NaH (sodium hydride, 60% dispersion, 124 mg, 3.08 mmol) in anhydrous THF (20 mL) is added dropwise the solution of 2-[(5,6,7,8-tetrahydro-naphthalene-1-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (37) (280 mg, 0.77 mmol) in THF (5 mL) at 0° C. After stirring for 20 min, methyl iodide (377 μL, 6.05 mmol) is added dropwise and the resulting suspension is warmed up to RT and continued stirring overnight. After being quenched by saturated ammonium chloride aqueous solution (5 mL), the reaction mixture is diluted in EtOAc (50 mL). The organic layer is separated, washed with water (1×5 mL) and brine (2×5 mL), dried over anhydrous Na2SO4 and concentrated in in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 0%-30% EtOAc in heptane) to give a pure product (120) as a colorless semisolid (250 mg, 86%).
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5]2[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[CH:8][C:6]=2[N:7]=1.[NH:18]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[CH3:13][O:12][C:11]1[C:5]2[NH:4][C:3]([CH2:2][N:18]3[CH2:24][CH2:23][CH2:22][N:21]([CH2:2][C:3]4[NH:4][C:5]5[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[CH:8][C:6]=5[N:7]=4)[CH2:20][CH2:19]3)=[N:7][C:6]=2[CH:8]=[C:9]([O:16][CH3:17])[C:10]=1[O:14][CH3:15]
Reactant: COc1cc2nc(CCl)[nH]c2c(OC)c1OC
Reactant: C1CNCCNC1
Product: COc1cc2nc(CN3CCCN(Cc4nc5cc(OC)c(OC)c(OC)c5[nH]4)CC3)[nH]c2c(OC)c1OC

Procedure:
2-Chloromethyl-4,5,6-trimethoxybenzimidazole (200 mg) and homopiperazine (30 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:11]=[CH:10][N:9]2[N:12]=[CH:13][C:14]([CH:15]=O)=[C:8]2[N:7]=1)[CH:2]([CH3:4])[CH3:3].[NH:17]1[CH2:23][C:21](=[O:22])[NH:20][C:18]1=[O:19].N1CCCCC1>C(#N)C>[CH2:1]([NH:5][C:6]1[CH:11]=[CH:10][N:9]2[N:12]=[CH:13][C:14]([CH:15]=[C:23]3[NH:17][C:18](=[O:19])[NH:20][C:21]3=[O:22])=[C:8]2[N:7]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)CNc1ccn2ncc(C=O)c2n1
Reactant: O=C1CNC(=O)N1
Solvent: C1CCNCC1
Solvent: CC#N
Product: CC(C)CNc1ccn2ncc(C=C3NC(=O)NC3=O)c2n1
Temperature: 70 °C

Procedure:
To 5-(isobutylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (24 mg, 0.110 mmol) in acetonitrile was added hydantoin (11 mg, 0.110 mmol) and piperidine (11 μL, 0.110 mmol). The reaction was heated at 70° C. for 48 hr. The reaction was cooled to room temperature and the solid formed was isolated by filtration to yield 5-((5-(isobutylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=301)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:11])[CH3:10].[C:12]([C:20]1[C:21](=[O:31])[N:22]([CH3:30])[C:23](=[O:29])[N:24]([CH3:28])[C:25]=1[CH2:26]Br)(=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C(O)C>[CH3:28][N:24]1[C:25]2=[CH:26][N:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[NH:8][C:9](=[O:11])[CH3:10])[C:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[C:20]2[C:21](=[O:31])[N:22]([CH3:30])[C:23]1=[O:29]
Reactant: Cn1c(CBr)c(C(=O)c2ccccc2)c(=O)n(C)c1=O
Reactant: CC(=O)Nc1ccccc1N
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccccc1-n1cc2c(c1-c1ccccc1)c(=O)n(C)c(=O)n2C
Temperature: 170 °C
Yield: 50.5 %

Procedure:
A mixture of N-(2-aminophenyl)acetamide (315 mg, 2.1 mmol), bromo-compound 4 (680 mg, 2 mmol), triethylamine (200 mg, 280 μL, 2 mmol), and ethanol (2 mL) was microwave-heated at 170° C. for 1 h (2-5 mL vial, pressure 13 bar). The shiny white crystalline mass was filtered, washed, and recrystallized from ethanol to give 5 (392 mg, 51% yield): mp>250° C.; 1H NMR (DMSO-d6): δ 9.17 (s, 1H), 7.69 (d, 1H, pyrrole CH, J=8.06 Hz), 7.33-7.14 (m, 6H), 7.10-6.94 (m, 3H), 3.31 (s, 3H), 3.17 (s, 3H), 1.87 (s, 3H). MS (ES+) (m/z): [M+1]+ calculated for C22H21N4O3, 389.43. found 389.19.
Reaction SMILES: C([Mg]Cl)(C)C.[Cl-].[Li+].[S:8]1[CH:12]=[CH:11][N:10]=[CH:9]1.[O:13]=[C:14]1[CH2:19][CH2:18][CH:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1>C1COCC1>[OH:13][C:14]1([C:9]2[S:8][CH:12]=[CH:11][N:10]=2)[CH2:15][CH2:16][CH:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)C1CCC(=O)CC1
Reactant: c1cscn1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1CCC(O)(c2nccs2)CC1
Reaction time: 1 h
Yield: 80.5 %

Procedure:
To a flask containing TI-IF (82 mL) was added isopropylmagnesium chloride/lithium chloride (1.2 M in THF, 37.7 mL, 45 mmol). A solution of thiazole (3.5 g, 41 mmol) in THF (20 mL) was added slowly. The reaction was stirred for one hour. A solution of tert-butyl 4-oxocyclohexanecarboxylate (12.23 g, 62 mmol) in THF (20 mL) was added and the reaction was stirred for 3 hours. The reaction was then quenched slowly with saturated ammonium chloride and diluted with ethyl acetate. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated. Flash chromatography was used for purification to yield tert-butyl 4-hydroxy-4-(1,3-thiazol-2-yl)cyclohexanecarboxylate (9.25 g, 33 mmol, 79% yield). MS ESI: [M+H]+ m/z 284.1.
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[N:8]=1)=[O:5].C([O-])(O)=O.[Na+].[CH:31]([N:34]1[CH:38]=[C:37]([CH2:39][CH2:40]OS(C)(=O)=O)[CH:36]=[N:35]1)([CH3:33])[CH3:32]>CN(C=O)C>[F:25][C:20]1[CH:21]=[C:22]([F:24])[CH:23]=[C:2]([F:1])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH:14]2[CH2:15][CH2:16][N:17]([CH2:40][CH2:39][C:37]3[CH:36]=[N:35][N:34]([CH:31]([CH3:33])[CH3:32])[CH:38]=3)[CH2:18][CH2:19]2)[N:8]=1)=[O:5]
Reactant: CC(C)n1cc(CCOS(C)(=O)=O)cn1
Reactant: O=C(Nc1cccc(OC2CCNCC2)n1)c1c(F)cc(F)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1cc(CCN2CCC(Oc3cccc(NC(=O)c4c(F)cc(F)cc4F)n3)CC2)cn1
Yield: 27.7 %

Procedure:
Combine 2,4,6-trifluoro-N-[6-(piperidin-4-yloxy)pyridin-2-yl]-benzamide (example 84, 250 mg, 0.71 mmol), NaHCO3 (96 mg, 1.14 mmol), KI (24 mg, 0.14 mmol) and DMF (5 mL). Add methanesulfonic acid 2-(isopropyl-1H-pyrazol-4-yl)-ethyl ester (214 mg, 0.92 mmol) dropwise to the above mixture and then beat at 80° C. overnight. Quench the reaction with 0.1N NaOH solution, extract with ether/ethylacetate (8:1) three times. Combine the organic layers, dry over Na2SO4, filter and concentrate to give a residue. Chromatography (silica gel) eluting with 3-4% methanol in methylene dichloride provides 96 mg (28%) of the title compound as a white solid: mass spectrum (ion spray): m/z=488.1 (M+1); 1H NMR (CDCl3, ppm): 8.04 (s, br, 1H), 7.86 (d, br, 1H), 7.65 (t, 1H), 7.37 (s, 1H), 7.27 (s, 1H), 6.81 (m, 2H), 6.55 (d, 1H), 4.98 (m, 1H), 4.45 (hept, 1H), 2.81 (m 2H), 2.68 (m, 2H), 2.59 (m, 2H), 2.04 (m, 2H), 2.04 (m, 2H), 1.88 (m, 2H), 1.49 (d, 6H). Hydrochloride salt: Anal calcd for C25H28F3N5O2.HCl.0.5H2O: C, 56.34; H, 5.67; N, 13.14. Found: C, 56.35; H, 5.58; N, 12.96.