Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[C@H:12]1[CH2:18][N:17]2[C:19]([CH2:22][CH:23]=[O:24])=[CH:20][N:21]=[C:16]2[C@H:15]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:14][CH2:13]1>O1CCCC1>[F:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[C@H:12]1[CH2:18][N:17]2[C:19]([CH2:22][CH:23]([OH:24])[CH3:1])=[CH:20][N:21]=[C:16]2[C@H:15]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:31])[CH3:30])[CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC=O)cnc21
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)Cc1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 82.5 %

Procedure:
Methylmagnesium bromide (3.0 M in ether; 0.70 mL, 2.10 mmol) was added to a solution of tert-butyl (6S,9R)-6-(2,3-difluorophenyl)-3-(2-oxoethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-ylcarbamate (85 mg, 0.210 mmol) in tetrahydrofuran (5 mL). After 2 h, the reaction was quenched with saturated aqueous ammonium chloride. Saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography (100% dichloromethane→95% dichloromethane/methanol) gave the title compound (73 mg). MS 422.2 (M+1).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[NH2:42][CH:43]1[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:42][CH:43]5[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CN1CCC(N)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.7 %

Procedure:
To a mixture of 0.10 g (0.22 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.16 mL (0.90 mmole) of ethyldiisopropyl amine and 0.028 g (0.25 mmole) of 4-amino-1-methyl-piperidine in 3.0 mL of dimethylformamide was added 0.11 g (0.25 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The resulting solid was collected by filtration, washed with saturated sodium carbonate and water, and dried under vacuum. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-90:10) gave 0.057 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-59) as a white solid.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][NH:6][C:7]([N:9]1[CH2:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[O:12][C:11]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:10]1=2)=[O:8])=[O:4].[CH2:25]([O:27][P:28]([O:32]CC)[O:29][CH2:30][CH3:31])[CH3:26].[Na+].[I-]>O1CCCC1.[Na+].[I-]>[CH2:25]([O:27][P:28]([CH2:2][C:3]([NH:5][NH:6][C:7]([N:9]1[CH2:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[O:12][C:11]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:10]1=2)=[O:8])=[O:4])([O:29][CH2:30][CH3:31])=[O:32])[CH3:26]
Reactant: O=C(CBr)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: CCOP(OCC)OCC
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOP(=O)(CC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21)OCC
Yield: 83.5 %

Procedure:
To a stirring solution of 2.57 g (6.3 mmol) of 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-(bromoacetyl) hydrazide (19), prepared as described in Example 19 above, in 75 mL of tetrahydrofuran (THF) was added 1.25 g (7.5 mmol) of triethylphosphite and 0.15 g (1 mmol) of NaI. After 22 hours of refluxing, an additional 0.62 g (3.75 mmol) of triethylphosphite and 0.05 g (0.33 mmol) of NaI were added to the reaction, which was refluxed an additional 24 hours. The solvent was then removed under aspirator vacuum, and the reaction mixture was chromatographed to yield 2.46 g (83%) of 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[(diethoxyphosphinyl)acetyl]hydrazide (20), which was a beige foam.
Reaction SMILES: Cl.Cl.[O:3]=[C:4]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]3[CH:20]=[N:21][CH:22]=[C:23]([CH:27]=3)[C:24]([OH:26])=[O:25])[CH:17]=2)[O:12][C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5]1.[CH:28]1([C:31]2[CH:32]=[CH:33][CH:34]=[C:35]3[C:40]=2[N:39]=[C:38]([C:41](N2C=CN=C2)=[O:42])[CH:37]=[C:36]3[O:48][CH3:49])[CH2:30][CH2:29]1.Cl>CN(C=O)C.O>[CH:28]1([C:31]2[CH:32]=[CH:33][CH:34]=[C:35]3[C:40]=2[N:39]=[C:38]([C:41]([N:9]2[CH2:10][CH2:11][C:6]4([CH2:5][C:4](=[O:3])[C:18]5[C:13](=[CH:14][CH:15]=[C:16]([C:19]6[CH:20]=[N:21][CH:22]=[C:23]([CH:27]=6)[C:24]([OH:26])=[O:25])[CH:17]=5)[O:12]4)[CH2:7][CH2:8]2)=[O:42])[CH:37]=[C:36]3[O:48][CH3:49])[CH2:29][CH2:30]1
Reactant: COc1cc(C(=O)n2ccnc2)nc2c(C3CC3)cccc12
Reactant: O=C(O)c1cncc(-c2ccc3c(c2)C(=O)CC2(CCNCC2)O3)c1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4cncc(C(=O)O)c4)ccc2O3)nc2c(C3CC3)cccc12
Temperature: 70 °C
Reaction time: 19 h

Procedure:
5-{4-oxospiro[chroman-2,4′-piperidin]-6-yl}nicotinic acid di-hydrochloride (4.93 g, 12.0 mmol), TEA (5.14 mL, 36.9 mmol) were suspended in DMF (49 mL) and (8-cyclopropyl-4-methoxy-quinolin-2-yl)-imidazol-1-yl-methanone (2.70 g, 9.22 mmol) was added thereto at room temperature, and the reaction mixture was stirred at 70° C. for 19 h. After cooled to room temperature, the mixture was poured into 1N HCl aq. (27.7 mL, 27.7 mmol) in H2O (367 mL) solution and the suspension was stirred for 2 h. The resulting precipitate was filtered, washed with H2O to give crude intended compound as a pale brown solid. This solid was washed with EtOAc-MeOH (1:1), then EtOH, and dried to afford the intended compound as a colorless solid. 1H-NMR (400 MHz, DMSO-d6) δ: 9.08 (1.0H, d, J=2.4 Hz), 9.03 (1.0H, d, J=2.0 Hz), 8.41 (1.0H, dd, J=2.0, 2.4 Hz), 8.07-8.03 (2.0H, m), 7.94 (1.0H, dd, J=8.3, 1.5 Hz), 7.49 (1.0H, dd, J=8.3, 7.6 Hz), 7.30-7.23 (2.0H, m), 7.20 (1.0H, s), 4.40-4.33 (1.0H, m), 4.07 (3.0H, s), 3.94-3.87 (1.0H, m), 3.57-3.48 (1.0H, m), 3.39-3.24 (1.0H, m), 3.11-3.04 (1.0H, m), 2.98 (2.0H, s), 2.15-2.07 (1.0H, m), 2.03-1.79 (3.0H, m), 1.10-1.04 (2.0H, m), 0.87-0.72 (2.0H, m). MS [M+H]+=564.
Reaction SMILES: CO.N.[C:4]([CH:6]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:7]1([OH:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)#[N:5]>[Ni].C(O)(=O)C>[NH2:5][CH2:4][CH:6]([C:7]1([OH:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1
Reactant: COc1ccc(C(C#N)C2(O)CCCCC2)cc1
Agent: [Ni]
Agent: N
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(C(CN)C2(O)CCCCC2)cc1
Yield: 70 %

Procedure:
The reactor was charged with 25.0 g of Raney-Ni (Kawaken, Grace 2400, 2724, Degussa B111W, 112W), and 250 ml of MeOH and 25 ml of an ammonia solution (25% NH3) were added. To the mixture was added 50g of 1-[cyano(4-methoxyphenyl)methyl]cyclohexanol, followed by 250 ml of MeOH. The reactor was settled and purged with N2 gas two or three times. After fully purged with N2, the reactor was purged with H2 gas two or three times. Internal pressure of the reactor was adjusted to 60 psi and the reaction mixture was stirred. After 20 to 30 hours of reaction at room temperature (about 10 to 20° C.), in-process analysis of a sample of mixture was made. After the reaction was completed, Ra—Ni was removed by filtration with a celite pad. The filtrate was distilled under reduced pressure until all of the solvent was evaporated, and 200 ml of isopropyl alcohol and 400 ml of ethyl acetate were added to the residue oil to dissolve the resulting product to give a clear or a little hazy solution. To the solution was added 10 ml of acetic acid dropwise, and an exothermic reaction began with some fumes given off. After about 10 to 20 minutes of adding all of the acetic acid, a solid began to form. The solution was stirred for about one hour, filtered and washed with ethyl acetate to give the desired product, 1-[2-amino-1-(4-methoxyphenyl)ethyl]-cyclohexanol, 44.2 g (yield 70%, purity 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.[C:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)#[N:10].C(=O)([O-])[O-].[K+].[K+]>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.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:14]2[CH:15]=[CH:16][C:11]([C:9]#[N:10])=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Clc1cc(I)ccn1
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: C1COCCO1
Product: N#Cc1ccc(-c2ccnc(Cl)c2)cc1
Temperature: 150 °C
Yield: 72.8 %

Procedure:
2-Chloro-4-iodopyridine (1.6 mmol), 4-cyanophenyl boronic acid (2.5 mmol), 2 M potassium carbonate (3.3 mmol), tetrakis(triphenylphosphine)palladium(0) (0.01 mmol) and dioxane (8 mL) were combined in a vial and heated by microwave for 10 min at 150° C. The crystallized product was filtered and subsequently dried in vacuo to yield 250 mg of 4-(2-chloropyridin-4-yl)-benzonitrile as yellow needles. 1H NMR (400 MHz, CDCl3) δ 8.52 (d, J=5.1 Hz, 1H), 7.81 (d, J=8.4 Hz, 2H), 7.72 (d, J=8.2 Hz, 2H), 7.55 (m, 1H), 7.43 (dd, J=5.2, 1.4 Hz, 1H); EIMS 214 m/z (M+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH2:12])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].Br[CH:14]([CH3:18])[C:15](=O)[CH3:16]>C(#N)C>[NH2:1][C:2]1[C:3]2[N:4]([C:14]([CH3:18])=[C:15]([CH3:16])[N:12]=2)[CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=1
Reactant: CC(=O)C(C)Br
Reactant: COC(=O)c1cnc(N)c(N)c1
Solvent: CC#N
Product: COC(=O)c1cc(N)c2nc(C)c(C)n2c1
Yield: 59.1 %

Procedure:
Methyl 5,6-diaminonicotinate (0.9 g, 5.4 mmol) and 3-bromo-2-butanon (0.9 g, 6.0 mmol) were added to acetonitril (30 ml) and refluxed for 24 h. Upon cooling some of the product was filtered off as hydrobromide salt. 20 ml of the filtrate was evaporated under reduced pressure and diethyl ether was added. More product was filtrated off as hydrobromide salt. The salt was dissolved in methylene chloride and washed with a bicarbonate solution. The organic layer was separated, dried over Na2SO4 and evaporated under reduced pressure to give 0.7 g (59%) of the desired compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]([NH2:17])=[O:16])=[CH:10]3)[C:6]=2[CH:18]=1.C1C(=O)N([I:27])C(=O)C1>CS(C)=O>[Br:1][C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]([NH2:17])=[O:16])=[C:10]3[I:27])[C:6]=2[CH:18]=1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Reactant: O=C1CCC(=O)N1I
Solvent: CS(C)=O
Product: NC(=O)c1nc2n(c1I)CCOc1cc(F)c(Br)cc1-2
Temperature: 80 °C
Reaction time: 8 h
Yield: 47.1 %

Procedure:
Into a 3000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of 9-Bromo-8-fluoro-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid amide (150 g, 459.95 mmol, 1.00 equiv) in DMSO (1500 mL), and NIS (206.1 g, 916.08 mmol, 2.00 equiv). The resulting solution was stirred overnight at 80° C., cooled to room temperature, quenched by the addition of 6 L of water, and diluted with 600 mL of saturated aqueous Na2SO3 and 600 mL saturated aqueous Na2CO3. The solids were collected by filtration and washed with 5×300 mL of water. The crude product was purified by Flash-Prep-HPLC to afford 98 g (47%) of 9-Bromo-8-fluoro-3-iodo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid amide as a light brown solid. LC-MS: 452 [M+H]+: 1H-NMR (DMSO, 300 MHz, ppm): δ 8.80 (d, J=8.1 Hz, 1H), 7.76 (s, 1H), 7.20 (s, 1H), 7.14 (d, J=9.6 Hz, 1H), 4.57-4.54 (m, 2H), 4.39-4.36 (m, 2H).
Reaction SMILES: [CH:1]([B-](F)(F)F)=[CH2:2].[K+].C(N(CC)CC)C.Br[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[N:17]=1.C(=O)([O-])O.[Na+]>C(O)CC>[F:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH:1]=[CH2:2])[N:17]=1
Reactant: Fc1cccc(Br)n1
Reactant: C=C[B-](F)(F)F
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCCO
Product: C=Cc1cccc(F)n1
Temperature: 100 °C
Reaction time: 11 h
Yield: 35.7 %

Procedure:
Potassium vinyltrifluoroborate (2.28 g), triethylamine (2.38 mL) and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane complex (928 mg) were added in that order to an n-propanol solution (12 mL) of 2-bromo-6-fluoropyridine (2.0 g), and stirred at 100° C. for 11 hours, and then at room temperature for 2 days. Saturated sodium hydrogencarbonate solution was added to the reaction liquid, and extracted with ethyl acetate. The organic layer was washed with saturated saline water, dried, concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (hexane/ethyl acetate=9/1) to obtain the entitled compound (500 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8]C2([Si](C)(C)C)C#N.Cl[Sn]Cl.O.Cl.[CH3:23][C:24]([OH:26])=[O:25]>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][CH:23]2[C:24]([OH:26])=[O:25]
Reactant: C[Si](C)(C)C1(C#N)CCOc2c(Br)cccc21
Reactant: CC(=O)O
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Product: O=C(O)C1CCOc2c(Br)cccc21

Procedure:
A solution of 8-bromo-4-(trimethylsilyl)-3,4-dihydro-2H-chromene-4-carbonitrile (9.6 g, 29.45 mmol) in a mixture of conc. HCl/HOAc (50 mL/40 mL) was added SnCl2.H2O (26.57 g, 117.8 mmol) and the miture was refluxed for 48 hours. The reaction solution was concentrated and the residue was partitioned between water and EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated to afford 8-bromo-3,4-dihydro-2H-chromene-4-carboxylic acid. 1H-NMR (300 MHz, CDCl3) δ ppm 7.15˜7.46 (m, 2H), 6.75˜6.92 (m, 1H), 4.24˜4.4 (m, 2H), 3.78˜3.84 (m, 1H), 2.1˜2.39 (m, 2H).
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH3:6])=[O:4].[C:7]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])[C:11]=1Cl)(=O)[CH3:8].C([O-])([O-])=O.[K+].[K+].O>CO>[CH3:24][O:23][CH2:22][CH2:21][O:20][CH2:19][N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]2[C:7]([CH3:8])=[C:2]([C:3]([O:5][CH3:6])=[O:4])[S:1][C:11]1=2
Reactant: COC(=O)CS
Reactant: COCCOCn1c(Cl)c(C(C)=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COCCOCn1c2ccccc2c2c(C)c(C(=O)OC)sc21
Reaction time: 48 h

Procedure:
400 μl of methyl 2-mercaptoacetate was added to a slurry of 1050 mg of (80) and 1.1 g of K2CO3 in 10 ml of MeOH, and left with stirring for 48 hours. 20 ml of water was added, and the precipitate filtered off and dried. This material was thoroughly washed with pentane, filtered, dried, and recrystallized from EtOH giving 230 mg of (81) as a white powder. M.p. 85.4°-86° C.
Reaction SMILES: [N:1]1([CH2:6]/[CH:7]=[CH:8]/[CH2:9][NH2:10])[CH:5]=[CH:4][N:3]=[CH:2]1.[IH:11].CS[C:14]1[C:22]2[CH:23]=[CH:24][CH:25]=[C:20]3[C:21]=2[C:16](=[CH:17][CH:18]=[CH:19]3)[N:15]=1>C(O)C>[IH:11].[N:1]1([CH2:6]/[CH:7]=[CH:8]/[CH2:9][NH:10][C:14]2[C:22]3[CH:23]=[CH:24][CH:25]=[C:20]4[C:21]=3[C:16](=[CH:17][CH:18]=[CH:19]4)[N:15]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: NC/C=C/Cn1ccnc1
Reactant: CSC1=Nc2cccc3cccc1c23
Agent: I
Solvent: CCO
Product: C(=C/Cn1ccnc1)\CNC1=Nc2cccc3cccc1c23
Temperature: -10 °C
Yield: 63.6 %

Procedure:
A mixture of 5.0 g of (E)-4-(1H-imidazol-1-yl)-2-butenamine, 11.5 g of 2-(methylthio)benz[cd]indole hydroiodide and 400 ml of ethanol was stirred and heated at reflux for 16 hours, then clarified while hot. The filtrate was concentrated to 250 ml, cooled to -10° C. and the resulting solid collected, washed with ethanol, ether and dried at 60° C. in vacuo, giving 9.3 g of the desired product, mp 152°-155° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[CH3:14][NH2:15]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([S:8]([NH:15][CH3:14])(=[O:10])=[O:9])[CH:7]=1
Reactant: CN
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1cc(Cl)ccc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 5-Chloro-2-methoxy-benzenesulfonyl chloride (1.0 g, 4.15 mmol) in tetrahydrofuran(8 ml) was bubbled methylamine gas until saturated. The reaction mixture was sealed with a septa and stirred overnight at ambient temperature. The reaction mixture was then concentrated, triterated in dichloromethane and ether, filtered and dried yielding the above titled compound 1.05 g (>100%) white solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C([O:11][C:12](=[O:30])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1/[CH:22]=[C:23]1/[C:24](=[O:29])[NH:25][C:26](=[O:28])[S:27]/1)C>>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][C:12]([OH:30])=[O:11])=[C:16]([CH2:22][CH:23]2[S:27][C:26](=[O:28])[N:25]([CH2:2][C:3]3[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=3)[C:24]2=[O:29])[CH:17]=1
Reactant: BrCc1ccncc1
Reactant: CCOC(=O)COc1ccc(Br)cc1/C=C1\SC(=O)NC1=O
Product: O=C(O)COc1ccc(Br)cc1CC1SC(=O)N(Cc2ccncc2)C1=O

Procedure:
Prepared from 4-bromomethylpyridine and 4-bromo-2-[2,4-dioxothiazolidin-(5Z)-ylidenemethyl]phenoxyacetic acid ethyl ester according to GP13, GP14 and GP16: LC/MS (an10p8): Rt 2.1 min, m/z 451 [M+H]+.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH2:20]([O:22][C:23]([C:25]12[CH2:42][CH:41]1[CH:40]=[CH:39][CH2:38][CH2:37][CH2:36][CH2:35][N:34]([CH3:43])[C:33](=[O:44])[N:32]1[CH:28]([CH2:29][CH:30]([OH:45])[CH2:31]1)[C:27](=[O:46])[NH:26]2)=[O:24])[CH3:21].[F:47][C:48]1[CH:49]=[C:50]([C:54]2[N:63]=[C:62](O)[C:61]3[C:56](=[C:57]([CH3:67])[C:58]([O:65][CH3:66])=[CH:59][CH:60]=3)[N:55]=2)[CH:51]=[CH:52][CH:53]=1.N#N.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CN(C=O)C>[CH2:20]([O:22][C:23]([C:25]12[CH2:42][CH:41]1[CH:40]=[CH:39][CH2:38][CH2:37][CH2:36][CH2:35][N:34]([CH3:43])[C:33](=[O:44])[N:32]1[CH:28]([CH2:29][CH:30]([O:45][C:62]3[C:61]4[C:56](=[C:57]([CH3:67])[C:58]([O:65][CH3:66])=[CH:59][CH:60]=4)[N:55]=[C:54]([C:50]4[CH:51]=[CH:52][CH:53]=[C:48]([F:47])[CH:49]=4)[N:63]=3)[CH2:31]1)[C:27](=[O:46])[NH:26]2)=[O:24])[CH3:21]
Reactant: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)N1CC(O)CC1C(=O)N2
Reactant: COc1ccc2c(O)nc(-c3cccc(F)c3)nc2c1C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)N1CC(Oc3nc(-c4cccc(F)c4)nc4c(C)c(OC)ccc34)CC1C(=O)N2
Reaction time: 18 h
Yield: 74.7 %

Procedure:
PPh3 (415 mg, 1.58 mmol) was added to a stirred solution of the alcohol 51 (300 mg, 0.79 mmol) and the quinazolinol 127 (247 mg, 0.87 mmol) in dry THF (35 mL) and dry DMF 7 mL. The reaction was placed under an inert atmosphere (N2) at room temperature. DIAD (311 μL, 1.58 mmol) was added. The reaction mixture was stirred for 18 h. A precipitation was formed in the flask and more white solid precipitated after addition of 40 mL diethyl ether. The precipitation was filtered off and washed with diethyl ether and dried under vacuum which gave the pure title compound (381 mg, 75%). LRMS (M+H) 646.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]3[NH:23][C:22](=[O:24])[N:21]=[CH:20][CH:19]=3)=[CH:11][C:10]=2[F:25])=[CH:4][C:3]=1[C:26]([F:29])([F:28])[F:27].Cl.Cl[CH2:32][C:33]1[CH:34]=[N:35][N:36]([CH3:38])[CH:37]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]3[CH:19]=[CH:20][N:21]([CH2:32][C:33]4[CH:34]=[N:35][N:36]([CH3:38])[CH:37]=4)[C:22](=[O:24])[N:23]=3)=[CH:11][C:10]=2[F:25])=[CH:4][C:3]=1[C:26]([F:29])([F:27])[F:28]
Reactant: Cn1cc(CCl)cn1
Reactant: O=c1nccc(OCCc2cnc(Oc3ccc(Cl)c(C(F)(F)F)c3)c(F)c2)[nH]1
Agent: Cl
Product: Cn1cc(Cn2ccc(OCCc3cnc(Oc4ccc(Cl)c(C(F)(F)F)c4)c(F)c3)nc2=O)cn1

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 6-{[2-(6-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-5-fluoro-3-pyridinyl)ethyl]oxy}-2 (1H)-pyrimidinone and 4-(chloromethyl)-1-methyl-1H-pyrazole hydrochloride. LC-MS (ESI): m/z 524 [M+H]+; 3.36 min (ret time).
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[N:4][CH:3]=1.[F:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1>>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:2]2[S:6][CH:5]=[N:4][CH:3]=2)=[CH:10][CH:9]=1
Reactant: Brc1cncs1
Reactant: OB(O)c1ccc(F)cc1
Product: Fc1ccc(-c2cncs2)cc1

Procedure:
Using 5-bromothiazole (1.0 g, 6.09 mmol) and (4-fluorophenyl)boronic acid (1.0 g, 7.31 mmol) and following the procedure described in example 7 step 1, the title compound was obtained after purification by purified by Biotage IsoleraOne® column (10% ethyl acetate in hexane) as yellow viscous liquid (0.4 g, 36% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.05 (s, 1H), 8.25 (s, 1H), 7.73-7.69 (m, 2H), 7.27 (t, 2H); LC-MS m/z calculated for [M+H]+180.02. found 180.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16](O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([C:28]3[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=3)[CH2:24][CH2:23]2)=[CH:12][CH:11]=1.Cl>>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]([O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([C:28]3[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:37])[CH3:38])[CH:31]=[CH:32][CH:33]=3)[CH2:24][CH2:23]2)=[CH:14][CH:15]=1
Reactant: Oc1ccc(F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccc(Cl)cc3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(Oc3ccc(F)cc3)c3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 4-fluorophenol and N-(3-{1-[6-(4-chlorophenyl)-6-hydroxyhexyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 8.22 (s, br, 1H), 7.74–6.68 (m, 12H) 5.04–4.92 (m, 1H), 3.66–3.50 (m, br, 2H), 3.00–2.82 (br, 2H), 2.80–2.58 (m, br, 4H), 2.58–2.40 (m, br, 2H), 2.001.68 (m, br, 6H), 1.66–1.46 (m, br, 1H), 1.46–1.36 (br, 3H), 1.25 (d, 6H, J=7.2 Hz); ESMS m/e: 551.1 (M+H)+.
Reaction SMILES: [C:1]([O:13][CH3:14])(=[O:12])[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(O)[CH2:16][CH2:17][CH2:18][OH:19]>>[C:6]([O:8][CH2:9][CH2:16][CH2:17][CH2:18][OH:19])(=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([C:1]([O:13][CH2:14][CH2:4][CH2:5][CH2:6][OH:7])=[O:12])=[CH:3][CH:4]=1
Reactant: OCCCCO
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Product: O=C(OCCCCO)c1ccc(C(=O)OCCCCO)cc1

Procedure:
This example demonstrates the transesterification reaction of dimethyl terephthalate with 1,4-butanediol using lanthanum tris(acetylacetonate) hydrate as the transesterification catalyst (150 ppm La based on final polymer) to form bis(4-hydroxybutyl) terephthalate.