Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[OH:20][C:21]1[CH:26]=[CH:25][C:24]([SH:27])=[CH:23][CH:22]=1>>[OH:20][C:21]1[CH:26]=[CH:25][C:24]([S:27][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=3[CH:19]=2)=[CH:23][CH:22]=1
Reactant: Oc1ccc(S)cc1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCl)cc21
Product: CC1(C)OC(=O)Nc2ccc(OCCCCSc3ccc(O)cc3)cc21

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-hydroxy-thiophenol.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:21]([C:23]3[O:24][C:25]4[C:30]([C:31](=[O:40])[C:32]=3[C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=3)=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH3:22])[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([F:17])[C:14]([O:18]C)=[C:13]([F:20])[CH:12]=3)[C:3]=12>ClCCl.B(Br)(Br)Br>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:21]([C:23]3[O:24][C:25]4[C:30]([C:31](=[O:40])[C:32]=3[C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=3)=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH3:22])[N:9]=[C:10]([C:11]3[CH:12]=[C:13]([F:20])[C:14]([OH:18])=[C:15]([F:17])[CH:16]=3)[C:3]=12
Reactant: COc1c(F)cc(-c2nn(C(C)c3oc4ccccc4c(=O)c3-c3cccc(F)c3)c3ncnc(N)c23)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(-c2cc(F)c(O)c(F)c2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.5 %

Procedure:
To a solution of example 126 (0.122 g, 0.224 mmoles) in dichloromethane (10 ml), BBr3 (1M in dichloromethane, 1.2 ml) was added at 0° C. and the reaction mixture was warmed to RT and then stirred for 12 h. The reaction mixture was quenched with 1.5N HCl solution and extracted with dichloromethane. The organic layer was dried over sodium sulphate and concentrated to afford the title compound as brown solid (0.086 g, 72% yield). MP: 253-257° C. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 9.64(s,1H), 8.05(s,1H), 8.04(dd, J=8.0,1.4 Hz, 1H), 7.83(m,1H), 7.68(d, J=8.4 Hz, 1H), 7.52(t, J=5.3 Hz, 1H), 7.30(m,1H), 7.20(d, J=8.7 Hz, 2H), 7.06(dt, J=8.7,2.2 Hz, 1H), 6.98(br s, 2H), 6.00(q, J=7.0 Hz, 1H), 1.88(d, J=7.0 Hz, 3H). Mass: 5530.14(M++1).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:21])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1.[O:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[N:28]1[C:32]([CH:33]=[O:34])=[CH:31][CH:30]=[N:29]1>>[Br:1][C:2]1[C:3]([F:21])=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([CH:33]([OH:34])[C:32]4[N:28]([CH:23]5[CH2:24][CH2:25][CH2:26][CH2:27][O:22]5)[N:29]=[CH:30][CH:31]=4)=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1
Reactant: O=Cc1ccnn1C1CCCCO1
Reactant: COC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1C1CC2C1
Product: COC(=O)c1nc2n(c1C(O)c1ccnn1C1CCCCO1)C1CC(C1)c1cc(F)c(Br)cc1-2
Yield: 43 %

Procedure:
Methyl 10-bromo-9-fluoro-3-(hydroxy(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was prepared similarly according to the procedure in Example 9. Methyl 10-bromo-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was reacted with 2-tetrahydropyran-2-ylpyrazole-3-carbaldehyde to afford 329 mg (43% yield) of the title compound.
Reaction SMILES: [CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[O:2]1.[C:11]1([C:17]([CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)O)=O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(C)C(C)=CC=CC=1>C(Cl)(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:11]1([C:17]2[NH:6][C:5]3[CH:4]=[C:3]4[O:2][CH2:1][O:10][C:9]4=[CH:8][C:7]=3[C:19]=2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Reactant: Nc1ccc2c(c1)OCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1C
Product: c1ccc(-c2[nH]c3cc4c(cc3c2-c2ccccc2)OCO4)cc1
Temperature: 25 °C
Yield: 91.6 %

Procedure:
A flask equipped with a Dean-Stark apparatus was charged with 3,4-(methylenedioxy)aniline (5.0 g, 36.4 mmol), p-toluenesulfonic acid (245 mg, 1.2 mmol), benzoin (5.20 g, 24.4 mmol), and xylene (30 mL). The mixture was heated to reflux for 10 hours, then cooled to room temperature. The reaction mixture was diluted with chloroform, then washed twice with 10% sulfuric acid, once with water, and once with brine. The organic layer was concentrated to a minimum volume and petroleum ether was added. The mixture was stirred well and then the precipitated solid was filtered off and dried to give Intermediate 3A (7.0 g, 92%). HPLC: RT=2.261 min (H2O/MeCN with NH4OAc, PUROSPHER® Star RP-18 3 μM, 4×55 mm, gradient=3 min, wavelength=220 nm); MS(ES, negative ionization): m/z=312 [M−H]−.
Reaction SMILES: [CH2:1]([C:8]1[CH:27]=[CH:26][CH:25]=[CH:24][C:9]=1[CH2:10][N:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([O:22]C)=[O:21])=[CH:16][N:15]=1)[CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.CO>[CH2:1]([C:8]1[CH:27]=[CH:26][CH:25]=[CH:24][C:9]=1[CH2:10][N:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][N:15]=1)[CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(Cc1ccccc1Cc1ccccc1)c1ccc(C(=O)OC)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCN(Cc1ccccc1Cc1ccccc1)c1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.4 %

Procedure:
Methyl 2-[N-(2-(benzyl)benzyl)-N-ethylamino]-5-pyridinecarboxylate (0.9 g, 2.5 mmol) in THF (6 ml) and methanol (6 ml) were treated with 1N aqueous sodium hydroxide (7 ml), and stirred at ambient temperature overnight. The clear solution was evaporated to low bulk, treated with water and glacial acetic acid to pH 4. The resultant white precipitate was stirred for 15 minutes, filtered, washed well with water, then sucked dry to yield the title product as a white solid (0.8 g, 92%). MS: (M+H)+347 (M·)+346
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.[NH:67]1[CH2:72][CH2:71][O:70][CH2:69][CH2:68]1>C(Cl)Cl>[CH3:32][O:31][C:29](=[O:30])[CH2:28][CH2:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:13][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[C:10]([N:67]3[CH2:72][CH2:71][O:70][CH2:69][CH2:68]3)=[O:12])=[CH:15][CH:16]=2)=[CH:22][CH:23]=1
Reactant: C1COCCN1
Reactant: COC(=O)CCc1ccc(Oc2ccc(CC(NC(=O)OC(C)(C)C)C(=O)O)cc2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCc1ccc(Oc2ccc(CC(NC(=O)OC(C)(C)C)C(=O)N3CCOCC3)cc2)cc1
Temperature: 25 °C
Yield: 72.1 %

Procedure:
The compound 4 (2.0 g, 4.6 mmol) was dissolved in CH2Cl2 (25 mL) and stirred at room temperature under an atmosphere of argon. Triethylamine (0.94 mL, 6.76 mmol) and BOP reagent (2.19 g, 4.96 mmol) were added and the reaction mixture was stirred for 15 min. Morpholine (0.79 mL, 9.02 mmol) was added and the resulting solution was stirred at room temperature for about 1 h. The solvent was removed under reduced pressure and the resulting oil was taken up in EtOAc (60 mL). The organic layer was extracted with 1.0 N NaOH (1×10 mL), water (2×20 mL) and brine (1×20 mL). Drying and concentration of the organic layer gave the desired amide 13 (1.7 g, ˜74%). 1H NMR (400 MHz, DMSO-d6): 7.24 (d, J=8.8 Hz, 2H), 7.20 (d, J=8.4 Hz, 2H), 7.17 (d, J=8.4 Hz, 2H), 6.90 (d, J=8.4 Hz, 2H), 6.86 (d, J=8.4 Hz, 2H), 4.56 (m, 1H), 3.58 (s, 3H), 3.24-3.54 (m, 8H), 2.74-2.87 (m, 4H), 2.62 (t, J=6.0 Hz, 2H), 1.32 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:6]=[CH:7][CH:8]=1.[Cl-].[NH4+].C(OCC)(=O)C.[CH2:25]1[CH2:29]OC[CH2:26]1>>[CH:26]1([C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[OH:10])[CH2:25][CH2:29]1
Reactant: COc1cccc(C(=O)c2cccnc2)c1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: COc1cccc(C(O)(c2cccnc2)C2CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (3-methoxyphenyl)-(3-pyridinyl)methanone (500 mg) in THF (10 ml) was added 1.1M cyclopropylmagnesium bromide THF solution (2 ml) at 0° C. The reaction mixture was warmed to room temperature, and stirred for 30 minutes. Aqueous ammonium chloride and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was filtered and washed with ethyl acetate-hexane (1:2) to give cyclopropyl-(3-methoxyphenyl)-(3-pyridinyl)methanol (470 mg).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:5]2[S:10][C:9]([N:11]([CH3:19])[CH:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[N:8][C:6]=2[N:7]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1.C([O-])(=O)C.[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C>[NH2:26][C:27]1[N:28]=[CH:29][C:30]([C:2]2[N:3]=[C:4]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[C:5]3[S:10][C:9]([N:11]([CH3:19])[CH:12]4[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]4)=[N:8][C:6]=3[N:7]=2)=[CH:31][CH:32]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: CN1CCC(N(C)c2nc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC#N
Product: CN1CCC(N(C)c2nc3nc(-c4ccc(N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
5-Chloro-N-methyl-N-(1-methylpiperidin-4-yl)-7-morpholinothiazolo[4,5-d]pyrimidin-2-amine, 2-aminopyridine-5-boronic acid pinacol ester (2 eq), and trans-dichlorobis(triphenylphosphine)palladium(II) (0.1 eq) were slurried with equal parts 1M potassium acetate (3 eq) and acetonitrile. The solution was microwaved at 140° C. for 10 minutes. The solvent was removed in vacuo and the resulting precipitate was purified by reverse phase silica gel chromatography to give the product 144.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][N:30]=[C:29](S(C)(=O)=O)[N:28]=3)=[CH:23][C:22]2=[O:37])[C@@H:9]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)=[CH:4][C:3]=1[F:38].[O:39]1[CH2:44][CH2:43][CH:42]([NH2:45])[CH2:41][CH2:40]1>CC(N(C)C)=O.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C@@H:9]2[CH2:13][CH2:12][NH:11][CH2:10]2)[N:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][N:30]=[C:29]([NH:45][CH:42]4[CH2:43][CH2:44][O:39][CH2:40][CH2:41]4)[N:28]=3)=[CH:23][C:22]2=[O:37])=[CH:4][C:3]=1[F:38]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]([C@H](c2ccc(Cl)c(F)c2)n2ccc(-c3ccnc(S(C)(=O)=O)n3)cc2=O)C1
Reactant: NC1CCOCC1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=c1cc(-c2ccnc(NC3CCOCC3)n2)ccn1[C@@H](c1ccc(Cl)c(F)c1)[C@@H]1CCNC1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
(R)-tert-Butyl 3-((R)-(4-chloro-3-fluorophenyl)(4-(2-(methylsulfonyl)pyrimidin-4-yl)-2-oxopyridin-1(2H)-yl)methyl)pyrrolidine-1-carboxylate (45.1 mg, 0.0801 mmol) was dissolved in DMA (1.0 mL, 0.1M) at room temperature under nitrogen and treated with tetrahydro-2H-pyran-4-amine (40.5 mg, 0.401 mmol). The solution was heated to 120° C. for 1 hour in the microwave. The reaction was then diluted with EtOAc (15 mL) and washed with water (3×15 mL) and brine (15 mL). The organics were isolated, dried over sodium sulfate, filtered and concentrated. The crude product was loaded onto an SP1 samplet and purified by silica gel chromatography using a 10% to 80% gradient of acetone in hexanes. Product containing fractions were pooled, concentrated and then redissolved in dichloromethane (2 mL) and treated with 1:1 TFA/DCM (1.0 mL) and stirred at room temperature for 1 hour. The reaction was diluted to 15 mL with additional DCM and washed with NaHCO3 (2×15 mL). The organics were isolated, dried over sodium sulfate, filtered and concentrated to afford 1-((R)-(4-chloro-3-fluorophenyl)((R)-pyrrolidin-3-yl)methyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one as an oil. 1H NMR (400 MHz, ((CD3)2SO) δ 8.40 (d, 1H), 8.04 (d, 1H), 7.62 (m, 2H), 7.37 (d, 1H), 7.34 (br s, 1H), 7.13 (d, 1H), 7.08 (s, 1H), 6.86 (d, 1H), 5.84 (br s, 1H), 3.97 (m, 1H), 3.87 (m, 2H), 3.38 (m, 2H), 2.86 (m, 1H), 2.79 (m, 2H), 2.34 (m, 1H), 1.84 (br d, 2H), 1.74 (m, 1H), 1.52 (m, 3H), 1.27 (m, 2H); LCMS (ESI) m/z 484.1 [M+H+].
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH:22]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)[C:21](=O)[C:20]3[C:19]([C:31](OCC)=[O:32])=[CH:18][CH:17]=[CH:16][C:15]=3[NH:14]2)=[CH:9][CH:8]=1)[CH2:4][CH3:5])[CH3:2].O.[NH2:37][NH2:38]>CO>[CH2:4]([N:3]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[NH:14][C:15]3[C:20]4[C:21](=[N:37][NH:38][C:31](=[O:32])[C:19]=4[CH:18]=[CH:17][CH:16]=3)[CH:22]2[C:23]2[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=2)=[CH:9][CH:8]=1)[CH2:1][CH3:2])[CH3:5]
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(C)cc1)C(c1ccc(CN(CC)CC)cc1)N2
Reactant: NN
Solvent: O
Solvent: CO
Product: CCN(CC)Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(C)cc2)cc1
Temperature: 30 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
A mixture of ethyl 2-(4-((diethylamino)methyl)phenyl)-4-oxo-3-p-tolyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (320 mg) in hydrazine monohydrate (2 mL, 85%) and methanol (10 mL) was stirred at 30° C. for overnight. Methanol was removed under reduced pressure. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate=1:1) to give the title compound (85 mg, yield 29%). LC-MS (ESI) m/z: 439 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 0.93 (t, 6H), 2.20 (s, 3H), 2.39 (q, 4H), 3.42 (d, 2H), 4.27 (d, J=8.0 Hz, 1H), 4.73 (d, J=8.0 Hz, 1H), 6.98-7.00 (m, 4H), 7.15-7.17 (m, 3H), 7.22-7.24 (m, 2H), 7.35-7.38 (m, 2H), 7.54-7.56 (m, 1H), 12.12 (s, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:6]=[N:5][C:4]=1[C:15]([N:17]([CH2:39][CH:40]([CH3:42])[CH3:41])[C@H:18]1[CH2:23][C@@H:22]([C:24]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:25])[CH2:21][N:20]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:19]1)=[O:16].[P:43](OCC)([O:48][CH2:49][CH3:50])([O:45][CH2:46][CH3:47])=[O:44]>CN(C=O)C.C(OCC)(=O)C>[CH2:46]([O:45][P:43]([CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:6]=[N:5][C:4]=1[C:15]([N:17]([CH2:39][CH:40]([CH3:42])[CH3:41])[C@H:18]1[CH2:23][C@@H:22]([C:24]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:25])[CH2:21][N:20]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:19]1)=[O:16])([O:48][CH2:49][CH3:50])=[O:44])[CH3:47]
Reactant: CC(C)CN(C(=O)c1nnn(-c2ccccc2F)c1CBr)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Reactant: CCOP(=O)(OCC)OCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOP(=O)(Cc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1F)OCC
Temperature: 110 °C
Reaction time: 12 h

Procedure:
tert-Butyl(3S,5R)-3-[{[5-(bromomethyl)-1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (440 mg) was dissolved in DMF (4 ml), triethyl phosphate (295 μl) was added and the mixture was stirred at 110° C. for 12 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object product (473 mg).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1([NH2:11])[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].[OH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[C:23](O)=[O:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C)C=O>[CH3:2][O:3][C:4]([C:6]1([NH:11][C:23]([C:14]2[CH:15]=[CH:16][C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:13]=2[OH:12])=[O:24])[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5]
Reactant: COC(=O)C1(N)CCCC1
Reactant: O=C(O)c1ccc2ccccc2c1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1(NC(=O)c2ccc3ccccc3c2O)CCCC1
Reaction time: 48 h
Yield: 43 %

Procedure:
1.00 g 1-amino-cyclopentanecarboxylic acid methyl ester hydrochloride, 0.698 g 1-hydroxy-2-naphthoic acid, 2.12 g HATU and 1.94 ml N,N′diisopropyl-ethylamine in 40 ml of dimethylformamide were stirred at 65° C. for 1 hour, followed by room temperature for 2 days. Water was added and the mixture was extracted with diethyl ether three times. The combined organic layers were dried with magnesium sulfate and concentrated in vacuo. Purification by flash chromatography on silica with heptane/ethyl acetate afforded 0.5 g of 1-[(1-Hydroxy-naphthalene-2-carbonyl)-amino]-cyclopentanecarboxylic acid methyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][C:16]([C:17](=[O:19])[NH2:18])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:26]N1C(=O)CCC1=O>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:15]([Cl:26])[C:16]([C:17](=[O:19])[NH2:18])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCn2c(-c3ccccc3)cc(C(N)=O)c2C1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCn2c(c(C(N)=O)c(Cl)c2-c2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49 %

Procedure:
A solution of 8-carbamoyl-6-phenyl-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester (8.0 g, Reference Example 3) in dichloromethane (300 mL) was treated with N-chlorosuccinimide (3.12 g). After stirring at room temperature for a further 16 hours the reaction mixture was washed four times with water (50 mL) and then once with brine (50 mL). The organic phase was then dried over magnesium sulfate and evaporated. The residue was subjected to column chromatography on silica eluting with a mixture of ethyl acetate and pentane (3:7, v/v) to give the title compound (4.3 g) as a white solid, m.p. 183–185° C. 1H NMR [(CD3)2SO]: δ 7.52–7.40 (m, 5H), 7.30 (bs, 1H), 6.80 (bs, 1H), 4.81 (s, 2H), 3.82 (t, 2H), 3.66 (t, 2H), 1.43 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9][CH3:10].[N:11]([O-])=O.[Na+].Cl>O>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][NH2:11])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1cc(N)ccc1C
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1cc(NN)ccc1C
Yield: 52.2 %

Procedure:
The compound was prepared by a method analogous to that of Example 22, Step 1. The reaction of 100 g (0.73 mole) of 4-methyl-3-methoxyaniline and 50.5 g (0.73 mole) of sodium nitrite in the presence of 330 g (1.46 moles) of stannous chloride dihydrate, 1160 mL of concentrated hydrochloric acid and 250 mL of water gave 58.0 g of product as an oil.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15]([Cl:17])=[N:14][C:13](N)=[N:12][C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N(OC(C)(C)C)=O.[Cl:26]CCCl>>[CH2:1]([N:8]1[C:16]2[C:15]([Cl:17])=[N:14][C:13]([Cl:26])=[N:12][C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCCl
Reactant: Nc1nc(Cl)c2c(ccn2Cc2ccccc2)n1
Agent: CC(C)(C)ON=O
Product: Clc1nc(Cl)c2c(ccn2Cc2ccccc2)n1
Temperature: -10 °C
Reaction time: 5 h
Yield: 77 %

Procedure:
To a suspension of 5-benzyl-4-chloro-5H-pyrrolo[3,2-d]pyrimidin-2-amine (641 mg, 2.5 mmol) in 1,2-dichloroethane (35 mL) was cooled to −10° C. SbCl3 (850 mg, 3.7 mmol) was added. The reaction mixture was stirred for 5 min. t-butyl nitrite (2.1 mL, 17.4 mmol) was added dropwise and the stirred mixture was from −10° C. to room temperature for 5 h. Upon completion of the reaction, the reaction mixture was poured into ice water and washed with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with Hexanes:Ethyl acetate (9:1-1:1), and gave the product as an off-white solid (528 mg, 77%).
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)=O)#[N:2].CC(C)([O-])C.[K+]>C1C=CC=CC=1>[CH3:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]2[C:6]3[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=3[O:4][C:3]=2[C:1]#[N:2])=[CH:10][CH:11]=1
Reactant: Cc1ccc(C(=O)c2ccccc2OCC#N)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: Cc1ccc(-c2c(C#N)oc3ccccc23)cc1
Reaction time: 1 h
Yield: 10.5 %

Procedure:
To a mixture of 2-cyanomethoxy-4'-methylbenzophenone (18.6 g) and molecular sieves (18 g) in benzene [270 ml) was added potassium tert-butoxide (8.31 g) in one portion at ambient temperature. After stirring at the same temperature for one hour, the mixture was filtered off. The filtrate was washed with diluted hydrochloric acid, dried, and concentrated in vacuo. The residue was purified by flash column chromatography to yield 3-(4-methylphenyl)benzo[b]furan-2-carbonitrile (1.82 g) as white crystals.
Reaction SMILES: [Al](C)(C)C.C(O[C:8]([C:10]1[C:15]([NH:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:14][CH:13]=[C:12]([CH:23]2[CH2:25][CH2:24]2)[N:11]=1)=[O:9])C.[NH2:26][C:27]1[S:28][CH:29]=[C:30]([CH3:32])[N:31]=1>>[CH3:32][C:30]1[N:31]=[C:27]([NH:26][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:14][CH:13]=[C:12]([CH:23]3[CH2:24][CH2:25]3)[N:11]=2)=[O:9])[S:28][CH:29]=1
Reactant: CCOC(=O)c1nc(C2CC2)ccc1Nc1cccnc1
Reactant: Cc1csc(N)n1
Agent: C[Al](C)C
Product: Cc1csc(NC(=O)c2nc(C3CC3)ccc2Nc2cccnc2)n1

Procedure:
The Al(Me)3-catalyzed reaction of 6-Cyclopropyl-3-(pyridin-3-ylamino)-pyridine-2-carboxylic acid ethyl ester and 2-Amino-4-methyl-thiazole in accordance with the general method of Example 78, step 2 yielded the title compound as a yellow cristalline solid, MS (ISP): m/e=352.1 (M+H+).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(O)(=O)C.[C:23]([O:31][C@@H:32]1[C@@H:49]([O:50][Si](C(C)(C)C)(C)C)[C@H:48]([O:58][CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[C@@H:47]([CH2:66][O:67][CH2:68][C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[O:46][C@H:33]1[S:34][C:35]1[CH:40]=[C:39]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:38]=[CH:37][C:36]=1[CH3:45])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[C:23]([O:31][C@@H:32]1[C@@H:49]([OH:50])[C@H:48]([O:58][CH2:59][C:60]2[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=2)[C@@H:47]([CH2:66][O:67][CH2:68][C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[O:46][C@H:33]1[S:34][C:35]1[CH:40]=[C:39]([C:41]([CH3:43])([CH3:44])[CH3:42])[CH:38]=[CH:37][C:36]=1[CH3:45])(=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Cc1ccc(C(C)(C)C)cc1S[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1OC(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cc1ccc(C(C)(C)C)cc1S[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](O)[C@H]1OC(=O)c1ccccc1
Temperature: 35 °C
Reaction time: 72 h

Procedure:
A solution of TBAF.3H2O (1.10 g, 3.48 mmol) and acetic acid (266 μl, 4.64 mmol) in DMF (4 ml) was added to a solution of 29 (430 mg, 0.58 mmol) in DMF (4 ml). The mixture was stirred for 3 days at 35° C. After dilution with Et2O the phases were separated and the organic phase washed with a 0.1 M HCl solution, saturated aqueous NaHCO3 solution and brine. The organic phase was then dried over MgSO4, filtered and concentrated. The product 40 was taken directly to the next step.