Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[CH:11][C:10]=1[F:28])=O)(C)(C)C.CS(C1[N:38]=[C:37]([CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[CH2:47][C:48]([O:50][CH3:51])=[O:49])[C:36]([C:52]([F:55])([F:54])[F:53])=[CH:35][N:34]=1)(=O)=O.C(O)(C(F)(F)F)=O>FC(F)(F)CO>[F:28][C:10]1[CH:11]=[C:12]([CH:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)[CH:13]=[CH:14][C:9]=1[NH:8][C:6]1[N:38]=[C:37]([CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[CH2:47][C:48]([O:50][CH3:51])=[O:49])[C:36]([C:52]([F:53])([F:54])[F:55])=[CH:35][N:34]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1F
Reactant: COC(=O)Cc1ccccc1CCc1nc(S(C)(=O)=O)ncc1C(F)(F)F
Solvent: OCC(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCNCC3)cc2F)ncc1C(F)(F)F
Temperature: 100 °C

Procedure:
To a mixture of tert-butyl 4-(4-((tert-butoxycarbonyl)amino)-3-fluorophenyl)piperidine-1-carboxylate (I57) (0.376 g, 0.954 mmol) and methyl 2-(2-(2-(2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate (I15) (0.268 g, 0.667 mmol) in 2,2,2-trifluoroethanol (15 mL) was added TFA (0.8 mL). The resulting mixture was heated under microwave irradiation at 100° C. for 20 minutes then 15 minutes then concentrated under reduced pressure to give a crude sample of the title compound (I58) (0.344 g) which was used without purification.
Reaction SMILES: [N:1]1([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:7][CH2:6][CH:5]=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.ClC(OCC1C=CC=CC=1)=O>C1COCC1.ClCCl.[Pd]>[N:1]1([C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3][CH2:2]1
Reactant: CCOC(=O)C1=CCCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Agent: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.2 %

Procedure:
A solution of 1-benzyl 4-ethyl 2,3,6,7-tetrahydro-1H-azepine-1,4-dicarboxylate (890 mg, 2.93 mmol) and 5% Pd/C (90 mg) in THF (70 ml) were stirred under a hydrogen atmosphere for 12 hours. The mixture was then filtered over celite and concentrated giving colourless oil. This was dissolved in dichloromethane (10 ml), cooled to 0° C. and DIPEA (1.02 ml, 5.86 mmol) followed by benzyl chloroformate (0.45 ml, 3.22 mmol) were added. On complete addition the reaction was raised to room temperature and stirred for a further 1 hour. The mixture was then diluted with dichloromethane (40 ml) and washed with water (2×20 ml), dried (MgSO4), filtered and concentrated. The residue was purified by silica FCC (using a gradient of eluents; 99:1 to 90:10 dichloromethane/MeOH) to give the title product as colourless oil (521 mg, 59%).
Reaction SMILES: [CH3:1][N:2]1[CH2:19][C:18](=O)[N:5]2[C:6]3[CH:17]=[CH:16][CH:15]=[CH:14][C:7]=3[CH2:8][N:9]3[CH:13]=[CH:12][CH:11]=[C:10]3[CH:4]2[C:3]1=O.C(O)(=O)C>O1CCCC1.B#B>[CH3:1][N:2]1[CH2:19][CH2:18][N:5]2[C:6]3[CH:17]=[CH:16][CH:15]=[CH:14][C:7]=3[CH2:8][N:9]3[CH:13]=[CH:12][CH:11]=[C:10]3[CH:4]2[CH2:3]1
Reactant: CN1CC(=O)N2c3ccccc3Cn3cccc3C2C1=O
Agent: B#B
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN1CCN2c3ccccc3Cn3cccc3C2C1
Temperature: 25 °C

Procedure:
To the solution of 140 mg of 2-methyl-1,4-dioxo-1,3,4,14b-tetrahydro-10H-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine in 5 ml of tetrahydrofuran, 2 ml of 1-molar diborane in tetrahydrofuran are added while stirring and cooling in ice. The mixture is allowed to stir at room temperature overnight and is then refluxed for 4 hours. After cooling to room temperature it is combined with 0.5 ml of glacial acetic acid, evaporated and the residue basified with 3 N aqueous sodium hydroxide. The mixture is extracted with methylene chloride, the extract dried, evaporated and the residue dissolved in diethyl ether. The solution is filtered and the filtrate evaporated to yield the 2-methyl-1,3,4,14b-tetrahydro-10H-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine, which is identical with that obtained according to Example 1; its monomaleate melts at 176°-178°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@@H:9]([C:42]2[CH:56]=[CH:55][C:45]([O:46][CH2:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[CH:44][CH:43]=2)[C@@H:10]([S:25][CH2:26][C:27]2([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)[O:32][CH2:31][C:30]([CH3:34])([CH3:33])[CH2:29][O:28]2)[C:11](=[O:24])N2[C@@H](C3C=CC=CC=3)COC2=O)=[CH:4][CH:3]=1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:11](=[O:24])[C@H:10]([S:25][CH2:26][C:27]3([C:35]4[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=4)[O:28][CH2:29][C:30]([CH3:33])([CH3:34])[CH2:31][O:32]3)[C@H:9]2[C:42]2[CH:43]=[CH:44][C:45]([O:46][CH2:47][C:48]([O:50][C:51]([CH3:53])([CH3:54])[CH3:52])=[O:49])=[CH:55][CH:56]=2)=[CH:6][CH:7]=1
Reactant: CC1(C)COC(CS[C@@H](C(=O)N2C(=O)OC[C@@H]2c2ccccc2)[C@@H](Nc2ccc(Cl)cc2)c2ccc(OCC(=O)OC(C)(C)C)cc2)(c2ccc(Cl)cc2)OC1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: Cc1ccccc1
Product: CC1(C)COC(CS[C@H]2C(=O)N(c3ccc(Cl)cc3)[C@@H]2c2ccc(OCC(=O)OC(C)(C)C)cc2)(c2ccc(Cl)cc2)OC1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
tert-Butyl (4-{(1S,2R)-1-[(4-chlorophenyl)amino]-2-({[2-(4-chlorophenyl)-5,5-dimethyl-1,3-dioxan-2-yl]methyl}thio)-3-oxo-3-[(4S)-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]propyl}phenoxy)acetate (1.69 g, 2.06 mmol) was dissolved in dry toluene (140 ml) and heated to 90° C. under inert atmosphere. N,O-Bis(trimethylsilyl)acetamide (BSA, 1.48 ml, 6.05 mmol) was added and the mixture was stirred at 90° C. for one hour. The mixture was cooled to 45° C. and tetrabutylammonium fluoride (TBAF, 0.1 g) was added and the mixture was stirred at 45° C. for one hour and at room temperature overnight. The mixture was concentrated under reduced pressure and purified by flash-chromatography (10%-20% EtOAc in hexane). This afforded 0.84 g (61%) of the title compound as a white solid. 1H-NMR (CDCl3, 200 MHz): δ 0.6 (s, 3H), 1.2 (s, 3H), 1.5 (s, 9H), 2.9-3.1 (t, broad, 2H), 3.4 (s, 4H), 4.0 (s, 1H), 4.5 (s, 2H), 4.8 (s, 1H), 6.9 (d, 2H), 7.2-7.4 (m, 10H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][CH2:12][CH2:13][NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.Br[CH:23]([CH2:27]Br)[C:24]([NH2:26])=[O:25]>>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([N:11]2[CH2:12][CH2:13][N:14]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:23]([C:24]([NH2:26])=[O:25])[CH2:27]2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(NCCNCc2ccccc2)cc(OC)c1
Reactant: NC(=O)C(Br)CBr
Product: COc1cc(OC)cc(N2CCN(Cc3ccccc3)C(C(N)=O)C2)c1

Procedure:
In a manner similar to Preparation 1, react N-(3,5-dimethoxyphenyl)-N'-(phenylmethyl)-1,2-ethanediamine with 2,3-dibromopropanamide to obtain the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[N:18]=1>>[N:20]1[CH:21]=[CH:22][N:23]=[CH:24][C:19]=1[C:17]1[N:18]=[C:13]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:14]2[CH:27]=[C:26]([C:28]([F:30])([F:31])[F:29])[S:25][C:15]=2[N:16]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3cnccn3)nc2s1
Product: O=[N+]([O-])c1cccc(CNc2nc(-c3cnccn3)nc3sc(C(F)(F)F)cc23)c1

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyrazin-2-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3-nitrobenzylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[C:17]([O:19]C)=[O:18])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O>[CH2:1]([N:8]1[CH2:16][C:15]2[C:14]([C:17]([OH:19])=[O:18])=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc2c1CN(Cc1ccccc1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cccc2c1CN(Cc1ccccc1)C2

Procedure:
48 1 g of 2-benzyl-4-methoxycarbonylisoindoline prepared in Reference Example 14-(3) was added to a solution of 16 g of sodium hydroxide in 160 ml of water and the mixture was heated under reflux for 3 hours. After removing insoluble materials by filtration, the filtrate was adjusted to pH 5 with 6 N hydrochloric acid. The resulting crystals were collected by filtration, and was washed with water, cold ethanol, ether, and then chloroform to give 35.0 g of 2-benzylisoindoline-4-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:51]=[CH:52][CH:53]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([N:28]5[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]5)=[N:24][C:25]=4[O:26][CH3:27])[CH:18]=3)[N:13]([S:41]([C:44]3[CH:50]=[CH:49][C:47]([CH3:48])=[CH:46][CH:45]=3)(=[O:43])=[O:42])[CH:12]=2)[CH:8]=[N:7]1>CO.Cl.O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:51]=[CH:52][CH:53]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:25]([O:26][CH3:27])=[N:24][C:23]([N:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)=[CH:22][CH:21]=4)[CH:18]=3)[N:13]([S:41]([C:44]3[CH:50]=[CH:49][C:47]([CH3:48])=[CH:46][CH:45]=3)(=[O:43])=[O:42])[CH:12]=2)[CH:8]=[N:7]1
Reactant: COc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1-c1cnc2c(c1)c(-c1cnn(Cc3cccc(F)c3)c1)cn2S(=O)(=O)c1ccc(C)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COc1nc(N2CCNCC2)ccc1-c1cnc2c(c1)c(-c1cnn(Cc3cccc(F)c3)c1)cn2S(=O)(=O)c1ccc(C)cc1
Yield: 90.6 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(5-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-6-methoxypyridin-2-yl)piperazine-1-carboxylate (67 mg, 0.090 mmol) was deprotected in methanol/HCl in dioxane (2/5 ml) to afford 52 mg (89% yield) of the titled compound. MS: m/z=638.2 (M+1).
Reaction SMILES: C([O:4][C:5]([C:7]1([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[O:26][N:25]=[C:24]([CH3:27])[C:23]=4[NH:28][C:29]([O:31][C@@H:32]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH3:33])=[O:30])=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:9][CH2:8]1)=[O:6])(C)C.[OH-].[Na+]>C1COCC1.CO.O>[CH3:27][C:24]1[C:23]([NH:28][C:29]([O:31][C@@H:32]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH3:33])=[O:30])=[C:22]([C:19]2[CH:20]=[CH:21][C:16]([C:13]3[CH:12]=[CH:11][C:10]([C:7]4([C:5]([OH:6])=[O:4])[CH2:9][CH2:8]4)=[CH:15][CH:14]=3)=[CH:17][CH:18]=2)[O:26][N:25]=1
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)OC(C)C)CC4)cc3)cc2)c1NC(=O)O[C@H](C)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1NC(=O)O[C@H](C)c1ccccc1
Temperature: 65 °C
Yield: 72.5 %

Procedure:
To the isopropyl ester from Step 7 (5.2 g, 10 mmol) in THF (30 mL), MeOH (10 mL) was added NaOH (2 g, 50 mmol) in water (10 mL). The solution is heated to 65° C. for 5 hours. The solution was cooled to room temperature, extracted with methylene chloride and dilute hydrochloric acid. The organic was dried and evaporated and the product was purified by column chromatography (0 to 60% EtOAc/hexanes) to yield ˜3.5 grams of product.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:9][C@@H:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.[CH3:16][O:17][CH2:18][CH2:19][NH2:20]>>[CH3:16][O:17][CH2:18][CH2:19][NH:20][CH:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[CH:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:9]
Reactant: COCCN
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Product: COCCNC(c1ccccc1)C(O)c1ccccc1
Temperature: 125 °C

Procedure:
A mixture of trans-stilbene oxide (3.93 g, 0.020 mole) and 2-methoxyethylamine (4.51 g, 0.060 mole) was heated at 125° C. for 2 hours with an oil bath. A mass spectra analysis showed no title compound was present. The mixture was heated for another 2 hours at 150° C. The mixture was poured into water (using methanol rinse) to obtain an off-white solid. NMR analysis showed the solid contained approximately 60% unreacted stilbene oxide. The mixture was added to another 4.51 g (0.060 mole) of 2-methoxy ethylamine and the mixture heated at 135° C. for 4 hours in a stainless-steel bomb. After cooling, the reaction mixture was shown by NMR analysis to contain 20% stilbene oxide and 80% of the title compound. The solid was recrystallized from toluene to give 2.92 g (54%) of a white solid, m.p. 137°-139° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C:4](=[O:7])[N:3]1[C:8]1[N:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16]([N:18]([CH3:30])[CH2:19][C:20]2[S:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[C:21]=2[CH3:29])=[O:17])=[CH:10][CH:9]=1.O=C1CCC(=O)N1C1N=CC(/C=C/C([N:48]([CH3:60])[CH2:49][C:50]2[N:51]([CH3:59])[C:52]3C(C=2)=CC=CC=3)=O)=CC=1.CN1CCNCC1.N>>[CH3:30][N:18]([CH2:19][C:20]1[S:24][C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[C:21]=1[CH3:29])[C:16](/[CH:15]=[CH:14]/[C:11]1[CH:10]=[CH:9][C:8]([NH:3][C:4](=[O:7])[CH2:5][CH2:6][C:2]([N:48]2[CH2:49][CH2:50][N:51]([CH3:59])[CH2:52][CH2:60]2)=[O:1])=[N:13][CH:12]=1)=[O:17]
Reactant: Cc1c(CN(C)C(=O)C=Cc2ccc(N3C(=O)CCC3=O)nc2)sc2ccccc12
Reactant: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1ccc(N2C(=O)CCC2=O)nc1
Agent: CN1CCNCC1
Agent: N
Product: Cc1c(CN(C)C(=O)/C=C/c2ccc(NC(=O)CCC(=O)N3CCN(C)CC3)nc2)sc2ccccc12
Yield: 51 %

Procedure:
According to the procedure of Example 110 except substituting 3-[6-(2,5-dioxo-pyrrolidin-1-yl)pyridin-3-yl]-N-methyl-N-(3-methyl-benzo[b]thiophen-2-ylmethyl)acrylamide for the (E)-3-[6-(2,5-dioxo-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-N-(1-methyl-1H-indol-2-ylmethyl)acrylamide, and substituting 1-methylpiperazine for the ammonia, the title compound (0.53 g, 51%) was prepared as a light yellow solid: 1H NMR 300 MHz, DMSO-d6) δ 10.71 (br s, 1H), 8.74-8.61 (m, 1H), 8.22-8.15 (m, 1H), 8.13-8.05 (m, 1H), 7.91-7.85 (m, 1H), 7.78-7.71 (m, 1H), 7.60-7.50 (m, 1H), 7.39-7.33 (m, 3H), 5.15-4.88 (m, 2H), 3.75-3.61 (m, 2H), 3.38-3.28 (m, 3H), 3.19-3.10 (m, 2H), 3.05-2.75 (m, 4H), 2.71-2.51 (m, 7H), 2.41 (s, 3H); MS (ESI) m/e 520 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[C:4]([F:11])[CH:3]=1.Cl.[Cl:13][C:14]1[CH:31]=[CH:30][C:17]([CH2:18][N:19]2[C:23]([C@H:24]3[CH2:28][CH2:27][CH2:26][NH:25]3)=[N:22][N:21]=[C:20]2[CH3:29])=[CH:16][CH:15]=1.C(N(CC)C(C)C)(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.[Cl-].[Na+].O>[Cl:13][C:14]1[CH:31]=[CH:30][C:17]([CH2:18][N:19]2[C:20]([CH3:29])=[N:21][N:22]=[C:23]2[C@H:24]2[CH2:28][CH2:27][CH2:26][N:25]2[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[F:11])=[O:10])=[CH:16][CH:15]=1
Reactant: O=C=Nc1ccc(Cl)cc1F
Reactant: Cc1nnc([C@H]2CCCN2)n1Cc1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1nnc([C@H]2CCCN2C(=O)Nc2ccc(Cl)cc2F)n1Cc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
To a stirring solution of 4-chloro-2-fluoro-1-isocyanatobenzene (102.92 mg, 0.6 mmol) in 20 mL of CH2Cl2 at 0° C. was slowly added a solution of the (R)-4-(4-chlorobenzyl)-3-methyl-5-(pyrrolidin-2-yl)-4H-1,2,4-triazole HCl salt (209.8 mg, 0.6 mmol) and N,N-diisopropylethylamine (0.2091 mL, 1.2 mmol) in dichloromethane (20 mL). The resulting mixture was stirred 0° C. for 30 minutes, then at room temperature overnight. The reaction mixture was treated with sat. aqueous NaHCO3 (10 mL) and brine, dried over Na2SO4, and concentrated in vacuo. Flash chromatography purification (Hex/EtOAc gradient, 10-100% EtOAc with 10% of MeOH) afforded the desired product as white foamy powder (215 mg, 79.9%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:17])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[Cl:12])[CH:8]([C:14]([OH:16])=[O:15])[CH2:7][CH2:6][CH2:5]2.S(=O)(=O)(O)O.[CH3:23]O>C1C=CC=CC=1>[NH2:1][C:2]1[C:3]([Cl:17])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[Cl:12])[CH:8]([C:14]([O:16][CH3:23])=[O:15])[CH2:7][CH2:6][CH2:5]2
Reactant: CO
Reactant: Cc1c(Cl)c(N)c(Cl)c2c1C(C(=O)O)CCC2
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: COC(=O)C1CCCc2c(Cl)c(N)c(Cl)c(C)c21
Yield: 89 %

Procedure:
The product from Example 135 (0.5 g) was dissolved in methanol (50 ml) and concentrated sulfuric acid (3 ml) was added. The reaction was refluxed for 4 hours and solvent was evaporated to one-half the volume. The concentrated reaction mixture was diluted with benzene (50 ml) and washed with brine, and aqueous sodium bicarbonate. The organic layer was separated, dried and evaporated affording the desired ester in 89% yield.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][PH:11](=[O:15])[O:12][CH2:13][CH3:14].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([P:11]([CH3:10])(=[O:15])[O:12][CH2:13][CH3:14])=[CH:3][CH:4]=1)=[O:7]
Reactant: CCO[PH](C)=O
Reactant: O=Cc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOP(C)(=O)c1ccc(C=O)cc1
Temperature: 110 °C
Reaction time: 10 h

Procedure:
To a solution of 4-bromobenzaldehyde, 38-a, (500 mg, 2.7 mmol) and ethyl methylphosphinate, 38-b, (650 mg, 5.4 mmol) in toluene (10 mL) was added triethylamine (1.1 g, 11 mmol). After being allowed to stir for 10 h at 110° C. under nitrogen atmosphere, the mixture was cooled to ambient temperature, concentrated, diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (2×30 mL), dried over Na2SO4, filtrated and concentrated to give a residue, which was purified by chromatography on silica gel (dichloromethane/methanol=70:1) to afford compound 38-c as a colorless oil. (530 mg, 93%). 1H NMR (300 MHz, DMSO-d6) δ 10.08 (s, 1H), 7.93-8.05 (m, 4H), 3.90-3.98 (m, 2H), 1.68-1.73 (d, J=14.4 Hz, 3H), 1.16-1.24 (m, 3H). LC-MS 213 [M+H]+
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[C:20]1([S:26]([CH2:29][CH2:30][CH2:31][C:32]2[N:36]([CH2:37][CH2:38][CH2:39][CH3:40])[N:35]=[C:34]([C:41]#[N:42])[C:33]=2Br)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:33]1[C:34]([C:41]#[N:42])=[N:35][N:36]([CH2:37][CH2:38][CH2:39][CH3:40])[C:32]=1[CH2:31][CH2:30][CH2:29][S:26]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)(=[O:28])=[O:27]
Reactant: Nc1ccccc1B(O)O
Reactant: CCCCn1nc(C#N)c(Br)c1CCCS(=O)(=O)c1ccccc1
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCCn1nc(C#N)c(-c2ccccc2N)c1CCCS(=O)(=O)c1ccccc1
Temperature: 110 °C
Reaction time: 20 h
Yield: 100.1 %

Procedure:
2-Aminophenyl boronic acid hydrochloride (693 mg, 4.00 mmol) and potassium phosphate tribasic (2.12 g, 10.0 mmol) were added sequentially to a solution of 5-(3-benzenesulfonylpropyl)-4-bromo-1-butyl-1H-pyrazole-3-carbonitrile (550 mg, 1.30 mmol) in 15 mL of toluene in a pressure tube. Nitrogen was bubbled through the resultant slurry for 15 minutes. Tris(dibenzylideneacetone)dipalladium(0) (104 mg, 0.10 mmol), bis[(2-diphenylphosphino)phenyl]ether (65 mg, 0.12 mmol), and 4 angstrom molecular sieves were then added to the reaction mixture. The pressure tube was sealed and heated in a 110° C. oil bath. After 20 hours, the reaction mixture was cooled to ambient temperature, diluted with ethyl acetate and filtered through CELITE filter aid. The filtrate was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The aqueous layer was extracted with additional ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated to an orange oil. Purification via flash column chromatography on silica gel (eluting with hexane:ethyl acetate in a gradient from 2:1 to 2:3) afforded 550 mg of 4-(2-aminophenyl)-5-(3-benzenesulfonylpropyl)-1-butyl-1H-pyrazole-3-carbonitrile as a thick pale yellow oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH:17]([CH3:21])[CH2:18][O:19][CH3:20])[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N+:22]([O-])([N+]([O-])=O)=[O:23]>>[Cl:1][CH2:2][CH2:3][N:4]([N:22]=[O:23])[C:5]([N:7]([CH:17]([CH3:21])[CH2:18][O:19][CH3:20])[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: COCC(C)N(C(=O)NCCCl)C1OC[C@H](O)[C@H](O)[C@H]1O
Product: COCC(C)N(C(=O)N(CCCl)N=O)C1OC[C@H](O)[C@H](O)[C@H]1O
Yield: 27.8 %

Procedure:
3.3 g of 1-(2-chloroethyl)-3-(1-methyl-2-methoxy-ethyl)-3-(L-arabinopyranosyl)urea and 5 g of nitrogen tetroxide gas are treated in the same manner as described in Example 10-(2). 1.0 g of 1-(2-chloroethyl)-1-nitroso-3-(1-methyl-2-methoxy-ethyl)-3-(L-arabinopyranosyl)urea are thereby obtained as yellow caramel.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)=O.[C:20](#[N:24])[CH2:21][C:22]#[N:23].N1CCCCC1>C(O)C>[NH:24]=[C:20]1[C:21]([C:22]#[N:23])=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[C:3]2[C:2](=[CH:7][C:6]([O:8][CH3:9])=[CH:5][CH:4]=2)[S:1]1
Reactant: N#CCC#N
Reactant: COc1cccc(C(=O)c2ccc(OC)cc2S)c1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cccc(-c2c(C#N)c(=N)sc3cc(OC)ccc23)c1
Yield: 74 %

Procedure:
2-Imino-3-cyano-7-methoxy-4-(3′-phenyl)-2H-thiochromene: To a mixture of (2-mercapto-4-methoxyphenyl)-(3′-methoxyphenyl)-methanone (35 mg, 0.13 mmol) and malononitrile (8.5 mg, 0.13 mmol) in 200 μL of dry ethanol was added piperidine (7.0 μL, 0.06 mmol) at 0° C. The resultant mixture was stirred at 0° C. for 2.5 h. The solvent was evaporated and the residue was purified by flash chromatography (25% ethyl acetate/hexanes) to yield 31 mg (75%) of 2-imino-3-cyano-7-methoxy-4-(3′-methoxy-phenyl)-2H-thiochromene as an orange waxy oil. 1H NMR (CDCl3): 9.31 (brs, 1H), 7.42–7.46 (m, 1H), 7.03–7.11 (m, 2H), 6.91 (d, J=7.8 Hz, 1H), 6.85–6.86 (m, 1H), 6.80 (brs, 1H), 6.68 (dd, J=9.1 and 2.6 Hz, 1H), 3.85 (s, 3H), 3.84 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([CH3:8])[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5].[CH2:16]([CH:18]1[O:20][CH2:19]1)Cl>>[CH3:8][C:2]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH:18]2[CH2:19][O:20]2)=[CH:11][CH:10]=1)([CH3:1])[CH2:3][C:4]([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)cc1
Reactant: ClCC1CO1
Product: CC(C)(C)CC(C)(C)c1ccc(OCC2CO2)cc1

Procedure:
The title compound was prepared from 4-(1,1,3,3-tetramethyl-butyl)-phenol and epichlorohydrin employing the procedures as set forth in Step 1 of Example 2.
Reaction SMILES: [I-].C[NH2+]C.C[C:6]1(C)O[C:10](=O)[CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8](=[O:19])[O:7]1>CO>[CH3:6][O:7][C:8](=[O:19])[C:9]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[CH2:10]
Reactant: CC1(C)OC(=O)C(c2ccccc2)C(=O)O1
Agent: C[NH2+]C
Agent: [I-]
Solvent: CO
Product: C=C(C(=O)OC)c1ccccc1
Temperature: 25 °C
Yield: 102.7 %

Procedure:
A solution of 25 g (135.1 mmol) N,N-dimethylammonium iodide and 11.91 g (54.1 mmol) 2,2-dimethyl-5-phenyl-[1,3]dioxane-4,6-dione in 585 ml abs. methanol was heated to 65° C. and the reaction was allowed to continue over night at 65° C. The reaction mixture was allowed to cool down to room temperature and the solvent was removed under reduced pressure. The residue was treated with diethyl ether, extracted with a satured NaHCO3 solution and brine and dried over MgSO4. The solvent was removed under reduced pressure and 9.01 g (quant.) of 2-phenyl acrylic acid methyl ester was isolated as a colourless oil. The compound was used without further purification.