Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])#[N:2].[N-:13]=[N+:14]=[N-:15].[Na+].[Cl-].[NH4+]>>[N:2]1[NH:13][N:14]=[N:15][C:1]=1[C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccccc1C#N
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: COC(=O)c1ccccc1-c1nn[nH]n1
Reaction time: 20 h

Procedure:
Methyl 2-cyanobenzoate (54 g, 0.33 mole) in D.M.F. (165 ml) was treated with sodium azide (23.4 g, 0.36 mole) and ammonium chloride (19.3 g, 0.36 mole). After the reaction mixture had been stirred on the steam bath for 20 hrs., the D.M.F. was removed under reduced pressure and the residue dissolved in water (200 ml). The solution was filtered, cooled in ice and acidified to give a white precipitate which was filtered, washed with water and dried. This gave methyl 2-(5-2H-tetrazolyl)benzoate, M.P. 132°-5°, 19 g (28%). (Found: C, 53.79, 52.59, 52.33; H, 4.25, 4.17, 4.07; N, 26.79, 26.84, 27.25. C9H8N4O2 requires C, 52.94; H, 3.95; N, 27.44.)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].[CH:13](=O)[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.[BH3-]C#N.[Na+]>C(O)(=O)C>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH:1][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1
Reactant: COc1ccc(C=O)cc1
Reactant: COc1cc([N+](=O)[O-])ccc1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(CNc2ccc([N+](=O)[O-])cc2OC)cc1
Yield: 72.9 %

Procedure:
This compound was prepared according to General Method 3 (EXAMPLE 1) from 2-amino-5-nitroanisole (1.00 g, 5.95 mmol), p-anisaldehyde (1.62 g, 11.9 mmol), NaBH3CN (0.373 g, 5.95 mmol) in 100 mL acetic acid to afford 1.25 g (75%) of (2-methoxy-4-nitrophenyl)-(4-methoxybenzyl)amine, an orange solid, after washing the crude product with 4:1 hexanes:EtOAc. Data for (2-methoxy-4-nitrophenyl)-(4-methoxybenzyl)amine: Rf 0.80 (3:2 EtOAc:hexanes); 1NMR (500 MHz, CDCl3) δ 7.88 (dd, 1H, J=8.8, 2.4), 7.64 (d, 1H, J=2.4), 7.22-7.28 (m, 2H), 6.85-6.90 (m, 2H), 6.51 (d, 1H, J=9.0), 5.31 (broad s, 1H), 4.38 (d, 2H, J=5.4), 3.93 (s, 3H), 3.82 (s, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)=O.[C:12](#[N:15])[CH:13]=C.C(N1CCOCC1)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(OC)C=CC=CC=1>[CH:7]([C:6]1[CH:10]=[CH:11][C:3]([CH:1]=[CH:13][C:12]#[N:15])=[CH:4][CH:5]=1)=[O:8]
Reactant: O=Cc1ccc(C(=O)Cl)cc1
Reactant: C=CC#N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCN1CCOCC1
Solvent: COc1ccccc1
Product: N#CC=Cc1ccc(C=O)cc1
Temperature: 120 °C
Reaction time: 12 h
Yield: 50.9 %

Procedure:
0.0018 g (0.008 millimol) of palladium acetate, 6.74 g (40 millimols) of 4-formylbenzoyl chloride, 3.29 g (50 millimols) of acrylonitrile and 5.12 ml (40 millimols) of N-ethylmorpholine are added to 80 ml of anisole. The mixture is stirred for 12 hours at 120° C., under argon. The crude product is distilled in vacuo and is then recrystallised from isopropanol. 3.2 g (52% of theory) of 4-formylcinnamonitrile are obtained in the form of white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O=[C:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: N#Cc1ccccc1N
Reactant: CCOC(=O)CC(=O)c1ccccc1
Product: CCOC(=O)c1c(-c2ccccc2)nc2ccccc2c1N

Procedure:
Prepared as in Example 2a from 2-aminobenzonitrile and ethyl 3-oxo-3-phenylpropanoate as a yellow solid (45%). 1H NR (400 MHz, DMSO-d6) δ 0.72 (t, J=8.0 Hz, 3H), 3.92 (q, J=8.0 Hz, 2H), 7.44 (m, 5H), 7.50 (m, 1H), 7.61 (bs, 2H), 7.73 (m, 1H), 7.83 (d, J=8.0 Hz, 1H), 8.37 (d, J=8.0 Hz, 1H). MS 293 (MH+).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:11]=1
Reactant: C1CNCCN1
Reactant: Cc1cc(Cl)nc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(N2CCNCC2)nc2ccccc12
Temperature: 140 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of 2-chloro-4-methylquinoline (2 g, 11 mmol) in N,N-dimethylformamide (40 ml) was added piperazine (4.86 g, 56.4 mmol, 5 eq) and potassium carbonate (2.34 g, 16.8 mmol, 1.5 eq). The mixture was stirred overnight at 140° C., quenched by the addition of water (200 ml), and extracted with ethyl acetate (3×100 ml). The organic layers were combined and washed with saturated aqueous sodium chloride (200 ml). The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude material was purified by silica gel chromatography using 1-10% methanol in dichloromethane to elute. The product-containing fractions were combined and concentrated to afford 4-methyl-2-(piperazin-1-yl)quinoline as colorless oil (2.2 g, 86%); (ES, m/z) [M+H]+ 228; 1H NMR (300 MHz, CDCl3): δ 7.70-7.78 (m, 2H), 7.50-7.55 (t, J=7.5 Hz, 1H), 7.22-7.27 (t, J=6.9 Hz, 1H), 6.83 (s, 2H), 3.70-3.73 (t, J=4.8 Hz, 1H), 3.00-3.03 (t, J=5.1 Hz, 1H), 2.59 (s, 3H).
Reaction SMILES: [I:1]I.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:14][C@H:13]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:12]2)=[CH:7][CH:6]=1>CO.S([O-])([O-])(=O)=O.[Ag+2]>[I:1][C:10]1[CH:9]=[C:8]([C@H:11]2[CH2:12][C@H:13]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:14]2)[CH:7]=[CH:6][C:5]=1[O:4][CH3:3]
Reactant: II
Reactant: COC(=O)C[C@H]1C[C@H](c2ccc(OC)cc2)C1
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: COC(=O)C[C@H]1C[C@H](c2ccc(OC)c(I)c2)C1
Reaction time: 4 h

Procedure:
Silver sulfate (0.149 g, 0.478 mmol) and iodine (0.025 mL, 0.478 mmol) were added successively to a solution of methyl [trans-3-(4-methoxyphenyl)cyclobutyl]acetate (0.1119 g, 0.478 mmol) in MeOH (2.4 mL) at 25° C. and the reaction was stirred vigorously for 4 h. After this time the reaction mixture was filtered through a plug of Celite®. The filtrate was diluted with EtOAc (50 mL), washed with water (2×10 mL), aq. Na2SO3 (2×10 mL), and brine (10 mL), dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Biotage Horizon, 25M, Si, ˜20 mL/min, 100% hexanes for 144 mL, gradient to 20% EtOAc in hexanes over 2394 mL) to afford methyl [trans-3-(3-iodo-4-methoxyphenyl)cyclobutyl]acetate, as a colorless oil. Rf=0.45 (20% EtOAc/hexanes), LCMS calc.=383.01. found=382.92 (M+Na). 1H NMR (500 MHz, CDCl3): δ 7.64 (d, J=2.2 Hz, 1H); 7.16 (dd, J=8.4, 2.2 Hz, 1H); 6.76 (d, J=8.4 Hz, 1H); 3.85 (s, 3H); 3.68 (s, 3H); 3.56-3.46 (m, 1H); 2.74-2.66 (m, 1H); 2.60 (d, J=7.9 Hz, 2H); 2.35-2.27 (m, 2H); 2.17-2.10 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:8].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:9]([O:8][N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]1=[O:1])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCc1ccccc1
Reactant: [O-][n+]1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1ccccn1OCc1ccccc1
Temperature: 25 °C
Yield: 84 %

Procedure:
2-hydroxypyridine-1-oxide (0.50 g, 4.5 mmol) was reacted with benzyl bromide (0.64 mL, 5.4 mmol) in DMF (10 mL) in the presence of K2CO3 (1.8 g, 13.5 mmol) at 80° C. for 16 h. After cooling to room temperature, the solvent was removed by rotary evaporation. The crude product was redissolved in DCM and washed twice with water. The organic layer was then dried over MgSO4, filtered, and concentrated resulting in 7 as a white solid in 84% yield (0.78 g, 3.8 mmol) without the need for further purification. 1H NMR (400 MHz, CDCl3) δ=7.41-7.36 (m, 5H), 7.25 (td, J1=6.8 Hz, J2=2.0 Hz, 1H), 7.10 (dd, J1=7.2 Hz, J2=2.0 Hz, 1H), 6.68 (dd, J1=9.2 Hz, J2=1.6 Hz, 1H), 5.91 (td, J1=6.8 Hz, J2=1.6 Hz, 1H), 5.28 (s, 2H). 13C NMR (100 MHz, CDCl3) δ=159.2, 138.9, 136.9, 133.9, 130.3, 129.6, 128.9, 122.9, 104.7, 78.6. ESI-MS(+): m/z 202.19 [M+H]+, 224.29 [M+Na]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)=[O:7].[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1>>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:22]=[C:23]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH:24]=[CH:25][CH:26]=3)[CH2:17][CH2:16]2)=[CH:9][CH:10]=1
Reactant: O=C(CCCCCl)c1ccc(F)cc1
Reactant: CCC(=O)Nc1cccc(C2CCNCC2)c1
Product: CCC(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 using 5-chloro-1-(4-fluorophenyl)-1-pentanone and N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 411.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:54])[CH2:7][CH2:6][CH2:5][N:4]([C:8]([CH:10]2[CH2:14][CH:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:12]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[N:11]2[C:31](=[O:53])[CH2:32][NH:33][C:34](=[O:52])[NH:35][C:36]2[CH:37]=[C:38]([CH:49]=[CH:50][CH:51]=2)[C:39]([O:41]CC2C=CC=CC=2)=[O:40])=[O:9])[CH2:3]1>C(O)C.[Pd]>[CH3:1][C:2]1([CH3:54])[CH2:7][CH2:6][CH2:5][N:4]([C:8]([CH:10]2[CH2:14][CH:13]([S:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)(=[O:16])=[O:17])[CH:12]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[N:11]2[C:31](=[O:53])[CH2:32][NH:33][C:34](=[O:52])[NH:35][C:36]2[CH:37]=[C:38]([CH:49]=[CH:50][CH:51]=2)[C:39]([OH:41])=[O:40])=[O:9])[CH2:3]1
Reactant: CC1(C)CCCN(C(=O)C2CC(S(=O)(=O)c3ccccc3)C(c3ccccc3F)N2C(=O)CNC(=O)Nc2cccc(C(=O)OCc3ccccc3)c2)C1
Agent: [Pd]
Solvent: CCO
Product: CC1(C)CCCN(C(=O)C2CC(S(=O)(=O)c3ccccc3)C(c3ccccc3F)N2C(=O)CNC(=O)Nc2cccc(C(=O)O)c2)C1
Yield: 24.8 %

Procedure:
A The reaction is carried out in a way analogous to that described in Example 2A, but from 1.6 g of benzyl (2RS,4RS,5RS)-3-{3-[2-(2-(3,3-dimethylpiperidino)carbonyl-5-(2-fluorophenyl)-4-phenylsulphonyl-1-pyrrolidinyl)-2-oxoethyl]ureido}benzoate and 0.15 g of 10% palladium-on-charcoal in 100 cm3 of ethanol. After treatment, there is obtained 0.35 g of (2RS,4RS,5RS)-3-{3-[2-(2-(3,3-dimethylpiperidino)carbonyl-5-(2-fluorophenyl)-4-phenylsulphonyl-1-pyrrolidinyl)-2-oxoethyl}ureido}benzoic acid, melting at 258° C.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)#[C:11][CH3:12].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:1]([N:16]1[CH2:17][CH2:18][N:13]([C:10]#[C:11][CH3:12])[CH2:14][CH2:15]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC#CN1CCNCC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC#CN1CCN(C(=O)c2ccccc2)CC1
Reaction time: 4 h

Procedure:
A solution of 5.6 g. of benzoyl chloride was added to a stirred solution of 1.96 g. of N-propynyl piperazine, 4.04 g. of triethylamine and 100 ml. of chloroform. The mixture was stirred 4 hours, filtered and the filtrate washed in sequence with 100 ml. of water, 100 ml. of 5% aqueous potassium carbonate and 100 ml. of water. The chloroform solution was then evaporated in vacuo to produce a white solid. Crystallization from cyclohexane produced the expected white crystals of N'-benzoyl-N-propynyl piperazine, m.p. 94°-5° C.
Reaction SMILES: C([N:5]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19](=[O:24])[C:18]([C:25]4[N:29]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[N:28]=[CH:27][CH:26]=4)=[N:17]3)=[C:12]([F:36])[CH:11]=2)[C:6]1=[O:37])(C)(C)C>FC(F)(F)C(O)=O>[F:36][C:12]1[CH:11]=[C:10]([N:7]2[CH2:8][CH2:9][NH:5][C:6]2=[O:37])[CH:15]=[CH:14][C:13]=1[N:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19](=[O:24])[C:18]([C:25]2[N:29]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:28]=[CH:27][CH:26]=2)=[N:17]1
Reactant: COc1cn(-c2ccc(N3CCN(C(C)(C)C)C3=O)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(-c2ccc(N3CCNC3=O)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 74.8 %

Procedure:
A mixture of 1-[4-(3-tert-butyl-2-oxoimidazolidin-1-yl)-2-fluorophenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (503 mg, 1.0 mmol) in trifluoroacetic acid (3.0 mL) was stirred at 80° C. for 1 h. After cooling to room temperature, the reaction mixture was evaporated. The residue was recrystallized from AcOEt/MeOH to give the title compound (334 mg, 75% yield) as a pale yellow solid: mp 259-260° C.; 1H NMR (300 MHz, DMSO-d6): δ ppm 3.40-3.50 (2H, m), 3.77 (3H, s), 3.82-3.93 (2H, m), 6.95 (1H, d, J=2.3 Hz), 7.01 (1H, t, J=9.0 Hz), 7.23-7.49 (7H, m), 7.73 (1H, dd, J=14.1, 2.4 Hz), 7.78 (1H, d, J=1.9 Hz), 8.44 (1H, d, J=1.9 Hz). LC-MS (ESI) m/z 447 [M+H]+. Anal. Calcd for C23H19FN6O3±0.75H2O: C, 60.06; H, 4.49; N, 18.27. Found: C, 60.05; H, 4.26; N, 18.16.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:8]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:4]=2[N:5]=[CH:6][N:7]=1.O.[NH2:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[NH2:25][C:26]1[CH:31]=[C:30]([C:2]2[C:3]3[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:8]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1cn(COCC[Si](C)(C)C)c2ncnc(Cl)c12
Reactant: Nc1cccc(B(O)O)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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cn(COCC[Si](C)(C)C)c2ncnc(-c3cccc(N)c3)c12
Temperature: 95 °C

Procedure:
A mixture of ethyl 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (1.00 g, 2.81 mmol), 3-aminophenylboronic acid monohydrate (577 mg, 4.21 mmol), 2 M aqueous sodium carbonate (893 mg, 8.43 mmol), and tetrakis(triphenylphosphine)palladium(0) (649 mg, 0.562 mmol) in dioxane (10 mL) and water (2 mL) was purged with argon. The reaction vessel was sealed in a microwave vial and the reaction mixture heated at 95° C. for 2 hours. The resulting mixture was filtered through Celite. Water (10 mL) was added and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (×3). The combined organic layers were washed with brine (15 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica eluting with 0-100% ethyl acetatehexane to afford ethyl 4-(3-aminophenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate. LRMS (ESI) calc'd for C21H29N4O3Si [M+H]+: 413, found 413.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:6](Cl)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[K+]>C1COCC1>[CH2:6]([N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: c1c[nH]cn1
Reactant: ClCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: c1ccc(Cn2ccnc2)cc1
Temperature: 25 °C
Yield: 65.2 %

Procedure:
According to the selected experimental protocol, 44 g of imidazole (0.65 mol.), 100 g of benzyl chloride (0.78 mol.), and 60 g of KOH (1.07 mol.) in 700 ml of THF are placed in a 1-liter balloon flask. The reaction mixture is brought to reflux for 120 h, then cooled at ambient temperature. The organic phase is filtered and the solvent is evaporated under reduced pressure. The obtained solid product is dissolved in 500 ml of CH2Cl2, then washed with water (3×100 ml). The organic phase is dried on Na2SO4, filtered, then evaporated under reduced pressure. The collected solid is recrystallized in toluene to yield 67 g of desired product.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C@H:13]2[N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.O1CCOCC1.Br[C:38]1[S:39][C:40]2[C:46]([C:47]([O:49][CH2:50][CH3:51])=[O:48])=[CH:45][CH:44]=[CH:43][C:41]=2[N:42]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:38]3[S:39][C:40]4[C:46]([C:47]([O:49][CH2:50][CH3:51])=[O:48])=[CH:45][CH:44]=[CH:43][C:41]=4[N:42]=3)[CH2:14][C@H:13]2[N:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1cccc2nc(Br)sc12
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2N2CCCC2)nc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cccc2nc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](N4CCCC4)C3)sc12
Yield: 53.8 %

Procedure:
The same operation as in Example (196c) was performed using tert-butyl cis(±)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-pyrrolidin-1-ylpiperidine-1-carboxylate obtained in Example (201d) (21.0 mg, 0.049 mmol), 4 N hydrochloric acid/1,4-dioxane (2 mL), ethyl 2-bromo-1,3-benzothiazole-7-carboxylate obtained in Example (1f) (16 mg, 0.054 mmol) and sodium carbonate (52 mg, 0.493 mmol), to obtain 14 mg of the title compound (54%) as a pale yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[C:9]([OH:17])=[C:10]([CH2:14][CH:15]=O)[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1.C(O)(=O)[CH2:21][C:22]([OH:24])=[O:23]>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[C:9]([OH:17])=[C:10]([CH2:14][CH:15]=[CH:21][C:22]([OH:24])=[O:23])[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=CCc1cccc(C(=O)c2ccc(Cl)cc2)c1O
Reactant: O=C(O)CC(=O)O
Product: O=C(O)C=CCc1cccc(C(=O)c2ccc(Cl)cc2)c1O

Procedure:
Another modification of the process comprises reacting 3-bromo-1-propene with methyl 2-hydroxybenzoate to obtain methyl 2'-(3-oxy-1-propene)-benzoate, hydrolyzing the latter to form the free acid, reacting the latter with a chlorinating agent such as thionyl chloride to form the corresponding acid chloride, condensing the latter with cadmium chlorophenyl to form 3-(2'-p-chlorobenzoyl-phenyl)oxy-1-propene, heating the latter to form 3-(3'-p-chlorobenzoyl-2'-hydroxy-phenyl)-1-propene, reacting the latter with an oxidizing atent to form 2-(3'-p-chlorobenzoyl-2'-hydroxy-phenyl)-1-oxo-ethane, condensing the latter with malonic acid, decarboxylating the resulting dicarboxylic acid to form 4-(3'-p-chlorobenzoyl-2'-hydroxy-phenyl)-2-butenoic acid and hydrogenating the latter in the presence of palladium to obtain 4-(3'-p-chlorobenzoyl-2-'-hydroxyphenyl)-butyric acid and finally with an oxidizing agent to form 4-(3'-p-chlorobenzoyl-2',5'-dihydroxy-phenyl)-butyric acid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)([CH3:3])=[CH2:2]>CO>[CH:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)([CH3:3])[CH3:2]
Reactant: C=C(C)c1ccc2c(c1)CC(=O)N2
Solvent: CO
Product: CC(C)c1ccc2c(c1)CC(=O)N2
Reaction time: 3 h
Yield: 98.8 %

Procedure:
A mixture of 5-bromoindolin-2-one (106 mg, 0.500 mmol), isopropenylboronic acid pinacol ester (0.14 mL, 0.750 mmol), K3PO4 (212 mg, 1.00 mmol), water (1 mL) and n-BuOH (4 mL) was briefly sonicated in a microwave vial and then purged with argon for 15 min. Tris(dibenzyldeneacetone)dipalladium (9.2 mg, 0.010 mmol) and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (19 mg, 0.040 mmol) were added, the vial sealed and heated in microwave reactor at 110° C. for 1 hour. The solvent was removed and the residue purified by column chromatography (silica gel, 2:1, hexanes/EtOAc) to give 40 mg, 46% of 5-isopropenylindolin-2-one as a beige solid; 5-isopropenylindolin-2-one (15 mg, 0.0866 mmol) was then dissolved into MeOH and the solution purged with N2 (g). 2 mg of 10% Pd/C (Degussa type) was then added and the mixture purged briefly with H2 (g). The mixture was stirred under 1 atm of H2 (g) for 3 hours and then filtered through a pad of celite. The solvent was removed to give 15 mg, 99% of the product as an off-white solid. MS ESI 176.0 [M+H]+, calcd for [C11H13NO+H]+ 176.11.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]2[C:14](=[O:17])[CH2:15][CH2:16][C@H:10]2[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[CH2:9]1[NH:8][CH2:13][CH2:12][N:11]2[C:14](=[O:17])[CH2:15][CH2:16][C@@H:10]12
Reactant: O=C1CC[C@H]2CN(Cc3ccccc3)CCN12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: O=C1CC[C@H]2CNCCN12
Temperature: 25 °C
Yield: 82.1 %

Procedure:
A mixture of (S)-(−)-2-benzylhexahydropyrrolo[1,2-a]pyrazin-6(7H)-one (2 g, 8.69 mmol), ammonium formate (3.83 g, 60.8 mmol) and 10% Pd/C (500 mg) in MeOH (90 ml) was refluxed for 2 hours. After cooling to room temperature, the catalyst was filtered off and the solvent evaporated under vacuum. The residue was purified by flash chromatography (DCM/MeOH/32% NH4OH, 70/30/3 respectively) to afford the title compound as a colourless oil (1 g, 82% yield).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH:30]=[CH:29][N:28]=[CH:27]1.CCN(C(C)C)C(C)C>CN(C=O)C>[N:26]1([CH2:25][CH2:24][CH2:23][CH2:22][N:9]2[CH:8]([C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[CH2:13][CH2:12][CH2:11][CH:10]2[C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:30]=[CH:29][N:28]=[CH:27]1
Reactant: BrCCCCn1ccnc1
Reactant: Cc1cccnc1C1CCCC(c2ncccc2C)N1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1C1CCCC(c2ncccc2C)N1CCCCn1ccnc1
Yield: 34.2 %

Procedure:
To a stirred solution of imidazole (500 mg, 7.35 mmol) and 1,4-dibromobutane (2.6 mL, 22.0) in THF (50 mL) was added 60% NaH (356 mg, 8.81 mmol), and the resultant mixture was refluxed for 2 h and stirred at room temperature overnight. The mixture was quenched with H2O (50 mL) and diluted with CH2Cl2 (75 mL). The aqueous phase was separated and extracted with CH2Cl2 (3×15 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated to dryness. Purification by flash chromatography on silica gel (CH2Cl2/MeOH, 97:3) resulted in partial decomposition of 1-(4-Bromo-butyl)-1H-imidazole. This material was used without any further purification. Using General Procedure A: 3,3″-Dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (94.4 mg, 0.353 mmol), impure 1-(4-Bromo-butyl)-1H-imidazole (145 mg), KI (6.0 mg, 0.035 mmol), DIPEA (0.18 mL, 1.02 mmol), and DMF (3.5 mL) were stirred for 48 h at 60° C. Purification of the crude material by radial chromatography on a 1 mm TLC grade silica gel plate (CH2Cl2/MeOH/NH4OH, 96:2:2) afforded the free base of the title compound (47 mg, 34% over 2 steps) as a colorless oil.