Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:63])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:33]=[CH:32][C:31]3[C:30]4[C:25](=[CH:26][C:27]([C:34]5[CH:60]=[CH:59][C:37]6[N:38]=[C:39]([CH:41]7[CH:46]8[CH2:47][CH:43]([CH2:44][CH2:45]8)[N:42]7[C:48](=[O:58])[CH:49]([NH:53][C:54]([O:56][CH3:57])=[O:55])[CH:50]([CH3:52])[CH3:51])[NH:40][C:36]=6[CH:35]=5)=[CH:28][CH:29]=4)[C:24]([F:62])([F:61])[C:23]=3[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[NH:64]1CCC[C@H:65]1C(O)=O.C(C1CN[C@H](C(O)=O)C1)#N>>[CH3:57][O:56][C:54](=[O:55])[NH:53][CH:49]([C:48]([N:42]1[CH:41]([C:39]2[NH:40][C:36]3[CH:35]=[C:34]([C:27]4[CH:28]=[CH:29][C:30]5[C:31]6[C:23](=[CH:22][C:21]([C:18]7[NH:17][C:16]([CH:12]8[CH2:13][CH:14]([C:65]#[N:64])[CH2:15][N:11]8[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:63])[CH:6]([CH3:7])[CH3:8])=[N:20][CH:19]=7)=[CH:33][CH:32]=6)[C:24]([F:62])([F:61])[C:25]=5[CH:26]=4)[CH:60]=[CH:59][C:37]=3[N:38]=2)[CH:46]2[CH2:47][CH:43]1[CH2:44][CH2:45]2)=[O:58])[CH:50]([CH3:52])[CH3:51]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3c(c2)C(F)(F)c2cc(-c4ccc5nc(C6C7CCC(C7)N6C(=O)C(NC(=O)OC)C(C)C)[nH]c5c4)ccc2-3)[nH]1)C(C)C
Agent: N#CC1CN[C@H](C(=O)O)C1
Product: COC(=O)NC(C(=O)N1CC(C#N)CC1c1ncc(-c2ccc3c(c2)C(F)(F)c2cc(-c4ccc5nc(C6C7CCC(C7)N6C(=O)C(NC(=O)OC)C(C)C)[nH]c5c4)ccc2-3)[nH]1)C(C)C

Procedure:
was prepared in a similar fashion to (1-{2-[5-(9,9-Difluoro-7-{2-[2-(2-methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-benzoimidazol-5-yl}-9H-fluoren-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (Example DK), replacing the proline derivative with the corresponding 4-cyano-proline derivative.
Reaction SMILES: [F:1][C:2]([F:15])([C:7]1[CH:14]=[CH:13][C:10]([CH2:11][NH2:12])=[CH:9][CH:8]=1)[C:3]([F:6])([F:5])[F:4].[F:16][C:17]([F:29])([F:28])[C:18]1[CH:19]=[C:20]([CH2:24][C:25](O)=[O:26])[CH:21]=[CH:22][CH:23]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]([F:15])([C:7]1[CH:14]=[CH:13][C:10]([CH2:11][NH:12][C:25](=[O:26])[CH2:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:28])([F:16])[F:29])[CH:19]=2)=[CH:9][CH:8]=1)[C:3]([F:5])([F:4])[F:6]
Reactant: NCc1ccc(C(F)(F)C(F)(F)F)cc1
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(Cc1cccc(C(F)(F)F)c1)NCc1ccc(C(F)(F)C(F)(F)F)cc1
Yield: 77.9 %

Procedure:
A solution of 4-pentafluoroethyl-benzylamine (485 mg, 2.16 mmol), 3-(trifluoromethyl)-phenylacetic acid (484 mg, 2.37 mmol), 4-methylmorpholine (654 mg, 6.46 mmol), and HBTU (1.23 g, 3.23 mmol) in DMF (30 mL) was stirred at RT for 16 h, then the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) afforded the title compound (692 mg, 78%). Light yellow solid, MS (ISP) 412.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][CH2:9][C:10](Cl)=[O:11]>N1C=CC=CC=1.C(Cl)Cl>[Cl:8][CH2:9][C:10]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:11]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CCl)Nc1ccccc1
Yield: 91.1 %

Procedure:
To a solution of aniline (1 mL, 11 mmol) and CH2Cl2 (150 mL), pyridine (886 mL, 1 mmol) was added. Then 2-chloroacetyl chloride (872 mL, 11 mmol) was added dropwise over 10 min. After the addition was complete, the mixture was reacted at room temperature for 2 hours. The reaction was then quenched with water (100 mL), the layers were separated and the aqueous layer was extracted with CH2Cl2 (2×50 mL). The combined organic layer was washed water, brine, and dried over Na2SO4. The solvent was evaporated to give a colorless solid (1.7 g, 91% yield). The crude product was directly used for next step. 1H NMR (CDCl3, 400 MHz) δ 8.25 (br s., 1H), 7.57 (d, J=7.6 Hz, 2H), 7.39 (t, J=7.6 Hz, 2H), 7.20 (t, J=7.4 Hz, 1H), 4.22 (s, 2H).
Reaction SMILES: N1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC.[C:19]([OH:23])(=O)[CH:20]=[CH2:21].[NH2:24][CH2:25][CH2:26][C:27]([NH:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[N:36]=[CH:35][N:34]=[C:33]2[NH:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][C:49]2[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=2)=[C:43]([Cl:55])[CH:42]=1)=[O:28]>C1COCC1>[Cl:55][C:43]1[CH:42]=[C:41]([NH:40][C:33]2[C:32]3[C:37](=[CH:38][CH:39]=[C:30]([NH:29][C:27]([CH2:26][CH2:25][NH:24][C:19](=[O:23])[CH:20]=[CH2:21])=[O:28])[CH:31]=3)[N:36]=[CH:35][N:34]=2)[CH:46]=[CH:45][C:44]=1[O:47][CH2:48][C:49]1[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=1
Reactant: NCCC(=O)Nc1ccc2ncnc(Nc3ccc(OCc4cccnc4)c(Cl)c3)c2c1
Reactant: C=CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C=CC(=O)NCCC(=O)Nc1ccc2ncnc(Nc3ccc(OCc4cccnc4)c(Cl)c3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 18 %

Procedure:
46 μl of pyridine and 85 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added to 31 μl of acrylic acid dissolved in 3 ml of THF at 0° C., reacted with 100 mg of the compound (132-1) of Example 132 for 30 mins, and stirred for 2 hours while heating to room temperature. The reacted solution was extracted with 6 ml of ethylacetate 3 times after adding 4 ml of water, dried over anhydrous magnesium sulfate, filtered and distilled under a reduced pressure, and the resulting residue was subjected to column chromatography (eluent-chloroform:methanol=15:1) to obtain the title compound (20 mg, 18%).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]1([S:15]([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[CH:20]=[CH:19]2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28].O>C1COCC1.ClCCl>[C:9]1([S:15]([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[CH:20]=[C:19]2[C:27](=[O:29])[CH3:28])(=[O:17])=[O:16])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cccnc21
Reactant: CC(=O)OC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1cc2cccnc2n1S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 41.1 %

Procedure:
Lithium diisopropylamide (19.4 mL, 35.0 mmol, 1.8M in heptane/THF/ethylbenzene) was added to a solution of 1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (4.50 g, 17.4 mmol) in THF (100 mL) at −78° C. The reaction mixture was stirred at −78° C. for 30 minutes, and then acetic anhydride (6.6 mL, 69.7 mmol) was added. The reaction mixture was warmed up to room temperature and stirred for 40 minutes. The reaction mixture was treated with water and dichloromethane, and the layers were separated. The aqueous layer was extracted once with dichloromethane. The organic layers were dried with sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography to afford 1-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)ethanone (2.15 g, 41%).
Reaction SMILES: Br[CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:3]1.CC(C)=[O:19].O>[B-](F)(F)(F)F.[Ag+].CO>[C:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:4]1[C:5](=[O:7])[CH2:6][CH:2]([OH:19])[CH:3]=1)([OH:16])=[O:15]
Reactant: O=C(O)CCCCCCC1=CC(Br)CC1=O
Reactant: CC(C)=O
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: O
Product: O=C(O)CCCCCCC1=CC(O)CC1=O
Reaction time: 1.5 h

Procedure:
To a stirred solution of 10.6 g. (ca. 34 moles) of crude 4-bromo-2-(6-carboxyhexyl)cyclopent-2-en-1 -one (Example 93) in 100 ml. of acetone and 65 ml. of water is added 8.80 g. (45.2 mmoles) of silver fluoborate during 2 minutes. The temperature is maintained at 25°-30° C. by external cooling. The mixture is stirred for 90 minutes, filtered, saturated with sodium chloride, and extracted with ether. The extract is extracted with half saturated sodium bicarbonate solutions. The basic solutions is reacidified with dilute hydrochloric acid, saturated with sodium chloride, and extracted with ether. The extract is washed with water and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The crude product is purified by partition chromatography on Celite to give an oil; λmax.MeOH =233 mμ. (7360); νmax.=3380 (hydroxyl groups), 1710 (carbonyl groups), and 1632 cm-1 (olefin group).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]([OH:22])[C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C@@H:13]2[CH2:12][O:22]2)=[CH:15][N:16]=1
Reactant: COc1ccc([C@@H](O)COS(=O)(=O)c2ccc(C)cc2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1ccc([C@@H]2CO2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
To a stirred solution of (R)-2-hydroxy-2-(6-methoxypyridin-3-yl)ethyl 4-methylbenzenesulfonate in MeOH (150 mL) at 0° C. was added potassium carbonate (4.4 g, 0.032 mol) and the mixture was stirred at rt overnight. The mixture was filtered through Celite and the filter cake was washed with MeOH. The filtrate was concentrated and the residue was treated with EtOAc (150 mL) and aq. Na2CO3. The organic layer was separated and washed with brine, dried (Na2SO4), and concentrated. The residue was purified by silica gel column to yield the desired expoxide as a colorless oil (1.02 g, 42%).
Reaction SMILES: [OH-].[Na+].[O:3]=[C:4]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:8][CH:7]=[CH:6][C:5]1=2.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCCl>[C:13]1([S:19]([N:8]2[C:9]3[CH2:10][CH2:11][CH2:12][C:4](=[O:3])[C:5]=3[CH:6]=[CH:7]2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C1CCCc2[nH]ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: O=C1CCCc2c1ccn2S(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NaOH (4.44 g) in 1,2-dichloroethane (250 mL) was added 4-oxo-4,5,6,7-tetrahydroindole (5.0 g). The mixture was then cooled to 0° C. and stirred for 30 min, following which a solution of phenylsulfonyl chloride (5.7 mL) in 1,2-dichloroethane (50 mL) was added dropwise over a period of 30 min. After 30 min of stirring, the reaction mixture was allowed to come to room temperature and stirred overnight. The reaction was quenched by pouring onto distilled water (100 mL). The organic layer was separated, and the aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic extract was washed with distilled water to neutrality, dried over MgSO4, and concentrated in vacuo to afford 7.0 g of the title compound.
Reaction SMILES: Cl.[F:2][C:3]1([F:7])[CH2:6][NH:5][CH2:4]1.[Cl:8][C:9]1[C:10]([CH2:15][NH:16][C:17]([CH:19]2[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]2)=[O:18])=[N:11][CH:12]=[CH:13][N:14]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>ClCCl.CO>[Cl:8][C:9]1[C:10]([CH2:15][NH:16][C:17]([C@H:19]2[CH2:24][CH2:23][C@H:22]([N:5]3[CH2:6][C:3]([F:7])([F:2])[CH2:4]3)[CH2:21][CH2:20]2)=[O:18])=[N:11][CH:12]=[CH:13][N:14]=1.[Cl:8][C:9]1[C:10]([CH2:15][NH:16][C:17]([C@H:19]2[CH2:24][CH2:23][C@@H:22]([N:5]3[CH2:6][C:3]([F:7])([F:2])[CH2:4]3)[CH2:21][CH2:20]2)=[O:18])=[N:11][CH:12]=[CH:13][N:14]=1
Reactant: FC1(F)CNC1
Reactant: O=C1CCC(C(=O)NCc2nccnc2Cl)CC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(NCc1nccnc1Cl)[C@H]1CC[C@@H](N2CC(F)(F)C2)CC1
Product: O=C(NCc1nccnc1Cl)[C@H]1CC[C@H](N2CC(F)(F)C2)CC1
Temperature: 25 °C

Procedure:
3,3-Difluoroazetidine hydrochloride (5.60 mmol, 0.726 g) was dissolved in dichloromethane/methanol (20 mL; 1/1) and 15 g Si-Carbonate (Silicycle, Loading 0.7 mmol/g) was added. After 20 minutes this slurry was put on a column with 7 g of Si-Carbonate (Silicycle, Loading 0.7 mmol/g) and eluated with dichloromethane/methanol (40 mL; 1/1). The solution was concentrated (900 mbar, bath 45 deg) to a volume of 30 mL. To this solution N-((3-chloropyrazin-2-yl)methyl)-4-oxocyclohexanecarboxamide (3.74 mmol, 1 g), acetic acid (0.1 mL) and sodium cyanoborohydride (7.47 mmol, 0.469 g) were added and the reaction mixture stirred at room temperature. After 3 days the reaction mixture was concentrated, dichloromethane added and washed with aqueous sodium hydrogencarbonate and water. Both aqueous layers were extracted four times with dichloromethane. The combined organic extracts were dried (sodium sulfate) and concentrated in vacuo. Purification by column chromatography (silica gel, gradient heptanes/ethyl acetate 2/1 to ethyl acetate) yielded (trans)-N-((3-chloropyrazin-2-yl)methyl)-4-(3,3-difluoroazetidin-1-yl)cyclohexanecarboxamide (0.47 g) and (cis)-N-((3-chloropyrazin-2-yl)methyl)-4-(3,3-difluoroazetidin-1-yl)cyclohexanecarboxamide (0.49 g).
Reaction SMILES: Cl[C:2]1[NH:7][C:6](=[O:8])[N:5]([CH:9]([CH3:11])[CH3:10])[C:4](=[O:12])[CH:3]=1.CN([C:16]1[C:21]2[C:22]([N:26](C)C)=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[CH:18][CH:17]=1)C.CN1[C:34](=[O:35])CCC1>>[CH:23]1([C@H:22]([NH:26][C:2]2[NH:7][C:6](=[O:8])[N:5]([CH:9]([CH3:11])[CH3:10])[C:4](=[O:12])[CH:3]=2)[C:21]2[CH:16]=[CH:17][CH:18]=[C:19]([O:35][CH3:34])[CH:20]=2)[CH2:24][CH2:25]1
Reactant: CC(C)n1c(=O)cc(Cl)[nH]c1=O
Reactant: CN1CCCC1=O
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Product: COc1cccc([C@@H](Nc2cc(=O)n(C(C)C)c(=O)[nH]2)C2CC2)c1
Temperature: 25 °C
Yield: 11 %

Procedure:
A solution of 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione (1.3, 50 mg, 0.265 mmol), (S)-cyclopropyl-(3-methoxyphenyl)methylamine (Sigma-Aldrich, 104 mg, 0.587 mmol), and proton sponge (85 mg, 0.397 mmol) in NMP (0.5 mL) was stirred at 130° C. for 2 h. After cooling to room temperature, the mixture was purified by preparative RP-HPLC (Shimadzu, Prominence LC-20AP system equipped with a Phenomenex Gemini-NX C18 column), eluting with 20-90% CH3CN in H2O (both containing 0.1% TFA). The fractions containing pure compound were combined and lyophilized to give 10 mg (11%) of the title compound as a white solid. LC/MS: m/z (ES+) 330 (M+H)+. 1H-NMR (400 MHz, CD3OD): δ ppm 7.26 (t, J=7.8 Hz, 6H), 6.92-6.79 (m, 3H), 5.00 (m, 1H), 3.79 (s, 3H), 3.74 (d, J=8.6 Hz, 1H), 1.36 (d, J=7.0 Hz, 6H), 1.23-1.13 (m, 1H), 0.68-0.60 (m, 1H), 0.58-0.50 (m, 1H), 0.50-0.42 (m, 1H), 0.41-0.34 (m, 1H).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([C:25]4[O:26][C:27]([CH:30]5OCC[O:31]5)=[CH:28][CH:29]=4)=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>Cl.O1CCCC1>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([C:25]4[O:26][C:27]([CH:30]=[O:31])=[CH:28][CH:29]=4)=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Oc2ccc(Nc3ccnc4cc(-c5ccc(C6OCCO6)o5)ccc34)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2ccc3c(Nc4ccc(Oc5ccccc5)cc4)ccnc3c2)o1
Yield: 95 %

Procedure:
(4-Phenoxyphenyl)-(7-(5-(1,3-dioxolan-2-yl)furan-2-yl)-quinolin-4-yl)amine (1.4 g) was treated with 1M aqueous hydrochloric acid-tetrahydrofuran (60 ml, 1:1) in accordance with procedure C. Addition of 1M aqueous sodium hydroxide solution to pH 10 followed by extraction with ethyl acetate, drying (magnesium sulfate) and concentration to dryness afforded a yellow solid (1.2 g); δ H [2H6]DMSO 9.70 (1H, s), 9.10 (1H, s), 8.51 (2H, m), 8.35 (1H, s), 8.02 (1H, d), 7.73 (1H, d), 7.57 (1H, d), 7.42 (4H, m), 7.22-7.04 (5H, m), 6.88 (1H, d); m/z 407 (M+1)+.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([F:25])([F:24])[F:23])=[CH:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14].[N+:28]([C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1)([O-:30])=[O:29].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:28]([C:31]1[CH:36]=[CH:35][C:34]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:24])([F:23])[F:25])[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:26])([F:27])[F:1])=[CH:33][CH:32]=1)([O-:30])=[O:29]
Reactant: O=C(O)/C=C/C=C(c1ccccc1C(F)(F)F)c1ccccc1C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(/C=C/C=C(c1ccccc1C(F)(F)F)c1ccccc1C(F)(F)F)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 97.3 %

Procedure:
As in Example 115, (E)-5,5-bis[2-(trifluoromethyl) phenyl]-2,4-pentadienoic acid (1.135 g) and 4-nitrophenol (0.450 g) in dichloromethane (15 mL) was treated with 1,3-dicyclohexylcarbodiimide (0.607 g). The mixture was stirred at 0°-5° C. for 1 hour, then at room temperature for 30 minutes. The usual work up furnished 1.45 g of (E)-5,5-bis[-2-(trifluoromethyl)phenyl]-2,4-pentadienoic acid 4-nitrophenyl ester as an oil essentially homogeneous by tlc. This material was used without further purification in subsequent reactions.
Reaction SMILES: Br[CH2:2][C:3]1[CH:15]=[CH:14][C:6]2[O:7][C:8]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:9][C:5]=2[CH:4]=1.[CH3:16][NH:17][CH3:18]>CO>[CH3:16][N:17]([CH2:2][C:3]1[CH:15]=[CH:14][C:6]2[O:7][C:8]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:9][C:5]=2[CH:4]=1)[CH3:18]
Reactant: NS(=O)(=O)c1cc2cc(CBr)ccc2o1
Reactant: CNC
Solvent: CO
Product: CN(C)Cc1ccc2oc(S(N)(=O)=O)cc2c1
Temperature: 0 °C

Procedure:
An ice cold, stirred solution of 5-bromomethyl-2-sulfamoylbenzo[b]furan in methanol is treated with an excess of anhydrous dimethylamine to give the title compound.
Reaction SMILES: II.C([Si](C)(C)[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2([C:19]([F:22])([F:21])[F:20])[NH:18][NH:17]2)=[CH:12][CH:11]=1)(C)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.Cl.O1CCOCC1>CO.CCN(CC)CC>[F:22][C:19]([F:20])([F:21])[C:16]1([C:13]2[CH:12]=[CH:11][C:10]([CH2:9][OH:8])=[CH:15][CH:14]=2)[N:17]=[N:18]1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C2(C(F)(F)F)NN2)cc1
Agent: Cl
Agent: II
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1COCCO1
Solvent: CO
Solvent: CCN(CC)CC
Product: OCc1ccc(C2(C(F)(F)F)N=N2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.7 %

Procedure:
I2 (1.14 g, 4.5 mmol) was added to a MeOH (4 mL) solution of Et3N (1.2 mL) and 3-(4-((tert.-butyldimethylsilyloxy)methyl)phenyl)-3-(trifluoromethyl)-diaziridine (1.65 g, 5.00 mmol). The solution was stirred at rt (3 h). Aqueous citric acid 10% (50 mL) and NaS2O3 were added. The organic layer was extracted 3 times with ether (3×30 mL). The organic layers were combined, dried and concentrated in vacuum to obtain a yellow oil; 1H NMR (CDCl3): δ 0.09 (s, (CH3)2Si), 0.94 (s, CH3)3C), 4.74 (s, CH2), 7.15 (d, J=8.0 Hz, 2 C6H4), 7.35 (d, J=8.0 Hz, 2 C6H4). HCl in dioxane (4 M, 5 mL, 20 mmol) was added to a MeOH (10 mL) solution of the yellow residue. The solution was stirred at rt (3 h) and the volatiles were evaporated. The residue was purified by silica gel flash chromatography to obtain 840 mg (78%) of a yellow liquid: Rf=0.19 (1/9 EtOAc/hexanes); 1H NMR (CDCl3): δ 1.95-2.05 (br, OH), 4.70 (s, CH2), 7.18 (d, J=8.4 Hz, 2 C6H4), 7.38 (d, J=8.4 Hz, 2 C6H4); 13C NMR (CDCl3): δ 28.3 (q, J=40.4 Hz, C diazirine), 64.4 (CH2O), 122.1 (q, J=273.0 Hz, CF3), 126.7 (C6H2), 127.1 (C6H2), 128.3 (C6H2), 142.5 (C6H2).
Reaction SMILES: [CH3:1][N:2]([CH2:9][CH:10]([OH:13])[CH2:11][NH2:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O=[C:15]([CH3:32])[CH2:16][O:17][C:18]1[CH:31]=[CH:30][C:21]([CH2:22][CH:23]2[S:27][C:26](=[O:28])[NH:25][C:24]2=[O:29])=[CH:20][CH:19]=1.C([BH3-])#N.[Na+]>CO>[CH3:1][N:2]([CH2:9][CH:10]([OH:13])[CH2:11][NH:12][CH:15]([CH3:32])[CH2:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][CH:23]2[S:27][C:26](=[O:28])[NH:25][C:24]2=[O:29])=[CH:30][CH:31]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CN(CC(O)CN)c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(COc1ccc(CC2SC(=O)NC2=O)cc1)NCC(O)CN(C)c1ccccc1
Yield: 54.7 %

Procedure:
A procedure similar to that described in Example 2 was repeated, except that 1.55 g of 3-(N-methyl-N-phenylamino)-2-hydroxypropylamine (prepared as described in Preparation 90), 1.6 g of 5-[4-(2-oxopropoxy)benzyl]-thiazolidine-2,4-dione, 0.4 g of sodium cyanoborohydride and 50 ml of anhydrous methanol were used, to give 1.39 g of the title compound, melting at 115° C. to 125° C.
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C(O[CH2:20][CH:21]1[CH2:50][CH2:49][N:24]2[C:25]3[C:30]([C:31]([C:32]4[C:33](=O)[O:34][C:35](=[O:47])[C:36]=4[C:37]4[C:45]5[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=5)[N:39]([CH3:46])[CH:38]=4)=[C:23]2[CH2:22]1)=[CH:29][CH:28]=[CH:27][CH:26]=3)(=O)C.[N:51]1C(C)=CC(C)=CC=1C.[CH3:60][NH:61][CH3:62].[ClH:63]>ClCCl.C(O)C.C(OCC)(=O)C>[ClH:63].[CH3:60][N:61]([CH2:20][CH:21]1[CH2:50][CH2:49][N:24]2[C:25]3[C:30]([C:31]([C:32]4[C:33](=[O:34])[NH:51][C:35](=[O:47])[C:36]=4[C:37]4[C:45]5[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=5)[N:39]([CH3:46])[CH:38]=4)=[C:23]2[CH2:22]1)=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH3:62]
Reactant: CNC
Reactant: CC(=O)OCC1CCn2c(c(C3=C(c4cn(C)c5ccccc45)C(=O)OC3=O)c3ccccc32)C1
Reactant: Cc1cc(C)nc(C)c1
Agent: Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(C)CC1CCn2c(c(C3=C(c4cn(C)c5ccccc45)C(=O)NC3=O)c3ccccc32)C1
Reaction time: 1.5 h

Procedure:
185 mg of trifluoromethanesulfonic anhydride in 30 ml of dichloromethane were treated at 0° C. under a nitrogen atmosphere with a suspension of 140 mg of the pyrroledione product of Example 1 and 70 mg of collidine in 25 ml of dichloromethane. After 1.5 hour, 0.8 ml of a 33% solution of dimethylamine in ethanol was added and the mixture was stirred for 2.5 hours. The solvent was removed under reduced pressure and the residue was triturated with methanol to give a solid which was stirred with ethyl acetate saturated with hydrogen chloride. The solid was filtered off and dried to give 70 mg of 3-[6,7,8,9-tetrahydro-8-[(dimethylamino)methyl]pyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione hydrochloride of melting point 335°-336° C.
Reaction SMILES: [CH3:1][N:2]1[CH:11]([CH2:12][OH:13])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.[C:14]1([CH3:25])[CH:19]=[CH:18][C:17]([S:20]([O:23]C)(=[O:22])=[O:21])=[CH:16][CH:15]=1>CC(C)=O>[C:14]1([CH3:25])[CH:15]=[CH:16][C:17]([S:20]([O-:23])(=[O:21])=[O:22])=[CH:18][CH:19]=1.[CH3:1][N+:2]1([CH3:14])[CH:11]([CH2:12][OH:13])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: CN1Cc2ccccc2CC1CO
Solvent: CC(C)=O
Product: C[N+]1(C)Cc2ccccc2CC1CO
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 144 %

Procedure:
In 12 ml of acetone was dissolved 887 mg of 2-methyl-1,2,3,4-tetrahydro-3-isoquinolinemethanol, and 932 mg of methyl p-toluenesulfonate was added dropwise to the resulting solution. The mixture was stirred at room temperature for 3 hours to precipitate crystals. The crystals were collected by filtration, washed with acetone and dried under reduced pressure to give 1.31 g of the desired compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[CH:5]=[CH:6][C:7]=1[NH2:8].C(O[CH2:21][CH3:22])(=O)C>C(O)C.[Cl-].[Na+].O>[CH2:21]([C:22]1[NH:8][C:7]2[CH:6]=[CH:5][C:4]([C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]#[N:12])=[CH:3][C:2]=2[N:1]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: N#Cc1ccccc1-c1ccc(N)c(N)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#Cc1ccccc1-c1ccc2[nH]c(Cc3ccccc3)nc2c1

Procedure:
2-(3,4-Diaminophenyl)benzonitrile (2.4 mmoles, 0.50 g) was dissolved in 3 ml ethanol. Ethyl phenylacetamidate hydrochloride (2.88 mmoles, 0.573 g) (prepared from HCl gas bubbled through benzyl cyanide and ethanol) was added. The reaction was warmed on a steam bath for 10 minutes. Ethyl acetate and brine were added. The organic phase was separated, dried and concentrated. The product was precipitated from ethyl acetate and hexane and filtered to yield 290 mg of 2-benzyl-5-(2-cyanophenyl)-1H-benzimidazole. (MS)