Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:8]=2[CH:9]=[C:10]2[C:16]4[CH:17]=[C:18]([C:21]([O:23]C)=[O:22])[CH:19]=[CH:20][C:15]=4[N:14]4[CH2:25][CH:26]=[N:27][C:13]4=[CH:12][N:11]23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([C:7]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:8]=2[CH:9]=[C:10]2[C:16]4[CH:17]=[C:18]([C:21]([OH:23])=[O:22])[CH:19]=[CH:20][C:15]=4[N:14]4[CH2:25][CH:26]=[N:27][C:13]4=[CH:12][N:11]23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(c1)-c1cc3c(C4CCCCC4)cccc3n1C=C1N=CCN12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)-c1cc3c(C4CCCCC4)cccc3n1C=C1N=CCN12
Temperature: 70 °C
Yield: 144.6 %

Procedure:
To a solution of methyl 10-cyclohexyl-4H-imidazo[1,2-a]indolo[1,2-d][1,4]benzodiazepine-7-carboxylate (34 mg, 0.083 mmol) in THF (1.5 mL) and MeOH (1 mL), was added aq NaOH (1.0N, 0.4 mL, 0.4 mmol). The reaction mixture was heated at 70° C. for 2 h, cooled to rt, neutralized with aq HCl (1.0N, 0.4 mL) and concentrated to dryness. The solid residue was dissolved into MeOH, filtered, concentrated and dried under N2 to yield 10-cyclohexyl-4H-imidazo[1,2-a]indolo[1,2-d][1,4]benzodiazepine-7-carboxylic acid (47 mg, 0.12 mmol) as an off-white solid which was used without further purification. 1H NMR (500 MHz, d6-DMSO) δ 1.04-1.22 (m, 1H), 1.32-1.50 (m, 3H), 1.61-1.77 (m, 2H), 1.84-2.15 (m, 4H), 2.74-2.90 (m, 1H), 5.05 (d, J=15.7 Hz, 1H), 6.00 (d, J=15.7 Hz, 1H), 7.31 (s, 1H), 7.63-7.85 (m, 5H), 7.91-7.99 (m, 2H), 8.37 (s, 1H). LCMS: m/e 398 (M+H)+, ret time 1.87 min.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:12][CH:13]([Cl:17])[C:14](Cl)=[O:15]>C1C=CC=CC=1>[CH:1]1([NH:4][C:14](=[O:15])[CH:13]([Cl:17])[Cl:12])[CH2:3][CH2:2]1
Reactant: O=C(Cl)C(Cl)Cl
Reactant: NC1CC1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(NC1CC1)C(Cl)Cl
Yield: 81.3 %

Procedure:
To a solution of cyclopropylamine (28.6 g, 0.5 mol) and 50 ml of triethylamine in 200 ml of anhydrous benzene was added dropwise with stirring and ice-bath cooling dichloroacetyl chloride (73.7 g, 0.5 mol). The solution was stirred 2 hr at room temperature. The benzene solution was washed successively with 10% HCl, H2O and saturated NaCl solution and dried over anhydrous MgSO4. The solvent was distilled affording 68.3 g (82%) of white crystalline product, m.p. 125-71/4. Recrystallization from ethanol-benzene yielded purified product; m.p. 130°-2°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=3)[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[C:6]([NH:24]C(=O)C(F)(F)F)[C:5]2=1.C([O-])([O-])=O.[K+].[K+]>CO>[NH2:24][C:6]1[C:5]2[C:4]3[C:12](=[C:13]([NH:15][C:16](=[O:23])[C:17]4[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=4)[CH:14]=[C:2]([Cl:1])[CH:3]=3)[NH:11][C:10]=2[CH:9]=[N:8][CH:7]=1
Reactant: O=C(Nc1cc(Cl)cc2c1[nH]c1cncc(NC(=O)C(F)(F)F)c12)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Nc1cncc2[nH]c3c(NC(=O)c4cccnc4)cc(Cl)cc3c12
Temperature: 60 °C
Yield: 9.4 %

Procedure:
N-[6-chloro-4-(2,2,2-trifluoro-acetylamino)-9H-β-carbolin-8-yl]-nicotinamide (38 mg, 0.088 mmol, 1 equiv.) was suspended in 5 ml of MeOH and a 2 ml aqueous solution of K2CO3 (121 mg, 0.92 mmol, 10 equiv.) was added thereto. The resulting clear solution was heated at 60° C. for 11 hr. After cooling to RT, fine solids precipitated that were captured by filtration and washed with 10 ml of water to give 2.78 mg (10%) of N-(4-amino-6-chloro-9H-β-carbolin-8-yl)-nicotinamide. 1H-NMR (300 MHz, DMSO-d6): δ 11.32 (s, 1H), 10.56 (s, 1H), 9.26 (s, 1H), 8.82 (d, 1), 8.42 (d, 1), 8.36 (s, 1H), 8.18 (s, 1H), 7.79 (s, 1H), 7.70 (s, 1H), 7.64 (m, 1H), 5.91 (br, 2H). Formic acid standard conditions. DAD RT=1.55 min. M+H=338.
Reaction SMILES: COC1C=CC([C:9]2[N:14]([CH3:15])[C:13](=[O:16])[N:12]([CH3:17])[C:11](=[N:18][C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])[CH:10]=2)=CC=1SC.ClC1C=CC=C(C(OO)=O)C=1.O>CN(C)C=O>[CH3:15][N:14]1[CH:9]=[CH:10][C:11](=[N:18][C:19]2[C:20]([CH3:27])=[CH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])[N:12]([CH3:17])[C:13]1=[O:16]
Reactant: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(=O)n2C)cc1SC
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)c(N=c2ccn(C)c(=O)n2C)c(C)c1
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
To a solution of 3,4-dihydro-6-(4-methoxy-3-methylthiophenyl)-1,3-dimethyl-4-(2,4,6-trimethylphenylimino)-2(1H)-pyrimidinone (1.5 g) in N,N-dimethylformamide (15 ml) was added m-chloroperbenzoic acid (1.58 g), and stirred at 5°-10° C. for 30 minutes, and at ambient temperature for 5 hours. To the reaction mixture was added water (50 ml), and extracted with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate solution, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel, eluting with chloroform. The fractions containing a sulfonyl compound were collected, dissolved in 1-N-hydrochloric acid and neutralized by aqueous sodium bicarbonate solution to give powdery 3,4-dihydro-6-(4- ro methoxy-3-methylsulfonylphenyl)-1,3-dimethyl-4-(2,4,6-trimethylphenylimino)-2(1H)-pyrimidinone (0.78 g).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[O:8][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:10][N:11]=2)[N:3]=1.CN(C=O)C.[Na+].[I-].[Cl:25][C:26]1[CH:31]=[C:30]([CH2:32]Cl)[CH:29]=[CH:28][N:27]=1>O>[Cl:25][C:26]1[CH:31]=[C:30]([CH2:32][N:6]2[C:2]([CH3:1])=[N:3][C:4]([C:7]3[O:8][C:9]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[N:10][N:11]=3)=[N:5]2)[CH:29]=[CH:28][N:27]=1
Reactant: ClCc1ccnc(Cl)c1
Reactant: Cc1nc(-c2nnc(-c3ccccc3)o2)n[nH]1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(-c2nnc(-c3ccccc3)o2)nn1Cc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.7 %

Procedure:
To a solution of 2-(5-methyl-1H-1,2,4-triazol-3-yl)-5-phenyl-1,3,4-oxadiazole (1.00 mg, 0.44 mmol) in DMF (3 mL) Cs2CO3 (430 mg, 1.32 mmol), NaI (78 mg, 0.52 mmol) and 2-chloro-4-(chloromethyl)pyridine (78 mg, 0.48 mmol) were added. The reaction was allowed to stir overnight at RT and then diluted with H2O (10 mL), extracted with EtOAc (3×10 mL), 4:1 CHCl3:i-PrOH (5×10 mL), dried with MgSO4 and concentrated. The crude product was purified on a Biotage pre-packed silica gel column (EtOAc:Hexane 12% to 100% EtOAc) to afford 2-(1-((2-chloropyridin-4-yl)methyl)-5-methyl-1H-1,2,4-triazol-3-yl)-5-phenyl-1,3,4-oxadiazole (88 mg, 57%) as an off-white powder. MS (ES+) C17H13ClN6O requires: 352 found: 353 [M+H]+.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:15]=[CH:14][C:9]2[NH:10][C:11](=S)[O:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2].Cl.Cl.[NH:18]1[CH2:22][CH2:21][C@@H:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:19]1>C1(C)C=CC=CC=1.ClCCl>[CH2:1]([NH:3][C:4]([C:6]1[CH:15]=[CH:14][C:9]2[N:10]=[C:11]([N:18]3[CH2:22][CH2:21][C@@H:20]([N:23]4[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]4)[CH2:19]3)[O:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)c1ccc2[nH]c(=S)oc2c1
Reactant: C1CCN([C@@H]2CCNC2)CC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCNC(=O)c1ccc2nc(N3CC[C@@H](N4CCCCC4)C3)oc2c1
Temperature: 130 °C

Procedure:
N-Ethyl-2-thioxo-2,3-dihydrobenzo[d]oxazole-6-carboxamide (Example 93A, 56 mg, 0.253 mmol) and (R)-1-(pyrrolidin-3-yl)piperidine (Reference Example 5c, 39 mg, 253 mmol) were combined in toluene (1 mL) and heated to 130° C. for one hour. The reaction mixture was diluted with dichloromethane, washed with a 1 N aqueous solution of sodium hydroxide, and the organic layer was absorbed on silica gel. The crude mixture was purified using silica gel chromatography (12 g column) eluting with a gradient of methanol/dichloromethane (1-18%) to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.26 (t, J=7.34 Hz, 3 H) 1.40-1.53 (m, 2 H) 1.59-1.69 (m, 4 H) 1.89-2.07 (m, 1 H) 2.22-2.35 (m, 1 H) 2.36-2.60 (m, 4 H) 2.89-3.03 (m, 1 H) 3.42-3.58 (m, 3 H) 3.59-3.68 (m, 1 H) 3.82-3.92 (m, 1 H) 3.97 (dd, J=10.11, 7.34 Hz, 1 H) 5.98-6.11 (m, 1 H) 7.31 (d, J=8.33 Hz, 1 H) 7.53 (dd, J=8.33, 1.59 Hz, 1 H) 7.78 (d, J=1.59 Hz, 1 H); MS (ESI+) m/z 343.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]2[C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=[CH:10][C:4]=2[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:18][O:19]C(Cl)Cl.Cl>ClCCl>[CH:18]([C:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:5]=2[O:6][C:2]=1[CH3:1])=[O:19]
Reactant: Cc1cc2cccc([N+](=O)[O-])c2o1
Reactant: COC(Cl)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1oc2c([N+](=O)[O-])cccc2c1C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-methyl-7-nitrobenzo[b]furan (1.77 g) and aluminum chloride (2.66 g) in dichloromethane (40 ml) was added dropwise a solution of dichloromethyl methyl ether (3.6 ml) in dichloromethane (10 ml). The mixture was stirred at ambient temperature for 30 minutes and the reaction mixture was poured into a mixture of ice and 1N-hydrochloric acid. The separated oil was extracted with dichloromethane and the extract was washed with brine, aqueous saturated sodium bicarbonate and brine. Then, the solution was dried over sodium sulfate and evaporated in vacuo. The obtained oil was crystallized from diethyl ether to give 3-formyl-2-methyl-7-nitrobenzo[b]furan (1.83 g).
Reaction SMILES: [N:1]([CH2:8][CH2:9][OH:10])([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[C:11](OC)(=[O:15])[C:12]([CH3:14])=[CH2:13].C[O-].[Na+]>>[C:11]([O:4][CH2:3][CH2:2][N:1]([CH2:8][CH2:9][OH:10])[CH2:5][CH2:6][OH:7])(=[O:15])[C:12]([CH3:14])=[CH2:13]
Reactant: OCCN(CCO)CCO
Reactant: C=C(C)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Product: C=C(C)C(=O)OCCN(CCO)CCO

Procedure:
Triethanolamine is reacted with methyl methacrylate and sodium methoxide at ambient temperature until the unreacted mono-, di- and trimethacryloxy substituted products reached the desired distribution as determined by gas chromatography. The resulting solution is stripped of excess reagent under reduced pressure. Next, N-(2-methacryloxyethyl)diethanolamine is separated from the solution by chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:9][C@@H:8]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH:6]=1)=[O:4]>CO.ClCCl>[CH3:1][O:2][C:3]([C@H:5]1[CH2:6][CH2:7][C@H:8]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9]1)=[O:4]
Reactant: COC(=O)C1=CC[C@H](NC(=O)OC(C)(C)C)C1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)C1
Reaction time: 62 h

Procedure:
((1,2-Bis(2R,5R)-2,5-dimethylphospholano)ethane)(cyclooctadiene)rhodium(I) trifluoromethanesulfonate (179 mg, 0.1 mol %) was added to a degassed solution of (4S)-4-tert-butoxycarbonylaminocyclopent-1-enecarboxylic acid methyl ester (70 g, 0.29 mol) in methanol (350 ml). The reaction mixture was transferred to a bomb and after purging with nitrogen and then hydrogen, a hydrogen pressure of 5 bar was applied and the reaction stirred for 62 h. The pressure was released and the bomb purged with nitrogen. Concentration of the reaction mixture gave a residue which was redissolved in dichloromethane (300 ml). Addition of silica (20 g) with stirring removed the catalyst from the reaction and filtration and concentration of the organic solution gave crude product as a yellow oil that solidified on standing (92% d.e.; measured by gc analysis). Crystallisation from tert-butylmethylether and heptane gave the title compound as colourless needles of 97% d.e. (63 g, 89%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:15]O>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([O:7][CH3:15])=[O:6]
Reactant: CO
Reactant: Cc1cc(C(=O)O)ccn1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccnc(C)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 61 %

Procedure:
To an ice-cooled suspension of 1.32 g (9.62 mmol) of 2-methylisonicotinic acid in 20 mL of MeOH was added 1.47 mL (20.2 mmol) of thionyl chloride. The ice-bath was removed and the reaction was stirred at rt. After 22 h, the MeOH was evaporated and the residue was taken up in H2O. The aqueous mixture was neutralized with saturated NaHCO3, then extracted with Et2O. The organic extracts were washed with saturated NaCl, dried over MgSO4, then filtered through a bed of celite. Eva-poration of solvent in vacuo afforded the title compound as a yellow liquid (0.89 g, 61%): 1H NMR (CDCl3): d 8.66 (d, 1H); 7.72 (s, 1H); 7.64 (d, 1H); 3.98 (s, 3H); 2.64 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.Cl[CH2:26][CH2:27][NH2:28]>CCCCC.CN(C=O)C>[CH2:3]([N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:26][CH2:27][NH2:28])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: NCCCl
Reactant: Oc1cccc2c1c1ccccc1n2Cc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCC
Product: NCCOc1cccc2c1c1ccccc1n2Cc1ccccc1
Reaction time: 0.08 h
Yield: 71.6 %

Procedure:
Sodium hydride (60% in oil; 0.934 g, 23.36 mmol) is washed three times with pentane. DMF (5 mL) is added, followed by 9-benzyl-9H-Carbazol-4-ol (1.52 g, 5.56 mmol) dissolved in DMF (10 mL) added over 10 min. The mixture is stirred an additional 5 min and then cooled in an ice-water bath. A solution of 2-chloroethylamine hydrochloride (1.29 g, 11.12 mmol) dissolved in DMF (5 mL) is added dropwise over about 5 min. The cooling bath is removed and the mixture is allowed to stir at room temperature over the weekend. Aq. sodium bicarbonate is added and the mixture partitioned between EtOAc, brine, and aq. sodium bicarbonate. The organic layers are dried over MgSO4 and taken to dryness. The residue is chromatographed on silica gel (120 mL) using CH3OH—CH2Cl2 (4/96) to give 1.26 g (72%) of the title compound as a white solid. An aliquot is crystallized from CH2Cl2-EtOAc-hexane; IR (drift) 1597, 1587, 1458, 1441, 1342, 1329, 1269, 1156, 1145, 1110, 1045, 860, 785, 749, 726 cm−1; 1H NMR (CDCl3) δ3.30, 4.29, 5.51, 6.70, 7.00, 7.12, 7.2-7.4, 8.34. Anal. Calcd for C21H20N2O: C, 79.72; H, 6.37; N, 8.85. Found: C, 78.70; H, 6.41; N, 8.70.
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.[NH2:10][CH:11]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([NH:10][CH:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:9])[CH:3]=1
Reactant: O=C(O)c1csc(Br)c1
Reactant: CC(C)(C)OC(=O)NCC(N)c1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC(NC(=O)c1csc(Br)c1)c1ccccc1
Reaction time: 16 h
Yield: 67.9 %

Procedure:
To a solution of 5-bromo-3-thiophenecarboxylic acid (1 g, 4.85 mmol)[prepared according to J. Org. Chem. 1976, 41, 2350.], 1,1-dimethylethyl (2-amino-2-phenylethyl)carbamate (1.1 g, 4.85 mmol)[from Preparation 1] and diisopropylethyl amine (2.5 mL, 14.60 mmol) in DCM (50 mL) at 25° C. was added PyBrOP (2.5 g, 5.30 mmol) in one portion. After 16 h, the solution was partitioned between H2O and washed with DCM. The combined organic fractions were dried (Na2SO4), concentrated and purified via column chromatography (silica, 1% MeOH in DCM) affording the title compound (1.4 g, 68%) as a white solid: LC-MS (ES) m/z=426 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]Cl)=[CH:4][CH:3]=1.[F:10][C:11]1[CH:12]=[C:13]([CH:30]=[C:31]([F:33])[CH:32]=1)[O:14][C:15]1[CH:29]=[CH:28][C:18]([O:19][CH2:20][CH2:21][NH:22][C:23](=[O:27])[O:24][CH2:25][CH3:26])=[CH:17][CH:16]=1.Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][N:22]([CH2:21][CH2:20][O:19][C:18]2[CH:17]=[CH:16][C:15]([O:14][C:13]3[CH:30]=[C:31]([F:33])[CH:32]=[C:11]([F:10])[CH:12]=3)=[CH:29][CH:28]=2)[C:23](=[O:27])[O:24][CH2:25][CH3:26])=[CH:4][CH:3]=1
Reactant: CCOC(=O)NCCOc1ccc(Oc2cc(F)cc(F)c2)cc1
Reactant: ClSc1ccc(Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)N(CCOc1ccc(Oc2cc(F)cc(F)c2)cc1)Sc1ccc(Cl)cc1

Procedure:
7.6 g of freshly distilled 4-chlorophenylsulfenyl chloride is added dropwise at 0° to +5° C. in the course of 30 minutes to a solution of 12 g of ethyl 2-[4-(3,5-difluorophenoxy)phenoxy]ethylcarbamate in 40 ml of pyridine, with stirring. After this, the mixture is stirred for 16 more hours at room temperature. The reaction mixture is poured into 200 ml of 2N hydrochloric acid and ice, and the mixture is extracted twice using diethyl ether. The combined ether extracts are washed to neutrality with water and dried over sodium sulfate. The solvent is distilled off in vacuo, and the residue is purified by chromatography on silica gel (eluent: hexane/diethyl ether, 9:1), which gives pure ethyl N-(4-chlorophenylthio)-2-[4-(3,5-difluorophenoxy)phenoxy]ethylcarbamate, nD20 1.5763.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH2:18]([N:21]=[C:22]=[O:23])[CH:19]=[CH2:20]>>[CH2:18]([NH:21][C:22]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:23])[CH:19]=[CH2:20]
Reactant: C=CCN=C=O
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: C=CCNC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 95.8 %

Procedure:
Beginning with 15.0 mg (0.0655 mMol) 5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 11.1 mg (0.131 mMol) allyl isocyanate, 19.6 mg (96%) of the title compound were recovered.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.N1C=CC=CC=1.Cl.[C:18]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)(=O)[CH3:19]>C(O)C>[Cl:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:18]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[CH:19]2
Reactant: CC(=O)C1CCNCC1
Reactant: NNc1ccc(Cl)cc1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: Clc1ccc2[nH]c(C3CCNCC3)cc2c1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 36 %

Procedure:
A mixture of 0.60 gm (3.4 mMol) 4-chlorophenylhydrazine hydrochloride and 0.54 mL (6.7 mMol) pyridine in 20 mL ethanol were stirred at 60° C. for 15 minutes. To this mixture was then added 4-acetylpiperidine hydrochloride and the reaction mixture was stirred for 2 hours at 70° C. The reaction mixture was concentrated under reduced pressure and the residue was treated with polyphosphoric acid. This mixture was heated at 90-100° C. for 48 hours. The reaction mixture was quenched with a slurry of ice in 5N sodium hydroxide. The aqueous mixture was extracted well with ethyl acetate. The organic phases were combined, washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with a dichloromethane gradient containing 4-20% methanol. Fractions containing product were combined and concentrated under reduced pressure to provide 0.26 gm (36%) of the title compound as a tan solid.
Reaction SMILES: [S:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12].[Cl:20]N1C(=O)CCC1=O.C(OCC)(=O)C>CN(C=O)C>[Cl:20][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:1][C:2]=1[NH:10][S:11]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:12])=[O:13]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=S(=O)(Nc1cc2cccnc2s1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=S(=O)(Nc1sc2ncccc2c1Cl)c1ccccc1
Reaction time: 16 h
Yield: 34.5 %

Procedure:
To compound 147-F (0.26 g, 0.643 mmol) in DMF (1 mL) under argon at ambient temperature was added N-chlorosuccinimide (94.4 mg, 0.707 mmol) and the reaction mixture was stirred for 16 h. Ethyl acetate was added, the mixture washed with H2O (2×), brine, evaporated under reduced pressure and purified by reverse phase pHPLC (C18) to afford 0.072 g of compound 813-A as a tan solid. 1H-NMR (DMSO-d6): δ 7.50 (dd, 1H), 7.56-7.65 (m, 2H), 7.65-7.74 (m, 1H), 7.81-7.89 (m, 2H), 8.00 (dd, 1H), 8.58 (dd, 1H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:8])=[C:5]([CH3:7])[N:6]=1.[F:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13]>C(#N)C>[F:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([O:13][C:12]([C:11]1[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=1[F:9])=[CH:1][C:2]1[N:3]([C:12](=[O:13])[C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[F:9])[C:4]([CH3:8])=[C:5]([CH3:7])[N:6]=1)=[O:13]
Reactant: Cc1nc(C)c(C)[nH]1
Reactant: O=C(Cl)c1ccccc1F
Solvent: CC#N
Product: Cc1nc(C=C(OC(=O)c2ccccc2F)c2ccccc2F)n(C(=O)c2ccccc2F)c1C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3.00 g (27.23 mmol) 2,4,5-trimethyl-1H-imidazol and 9.37 g (92.59 mmol) TEA are dissolved in 50 ml acetonitrile and cooled to 0° C. 14.25 g (89.87 mmol) 2-fluoro-benzoylchloride are added dropwise and the mixture is stirred 2 h at RT and let stand overnight. The solvent is removed under vacuum, the residue is dissolved in toluene and washed twice with water. The organic phase is filtered through Tonsil (K60) and concentrated under vacuum. The product is used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)[C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C([O:36][CH2:37][CH:38]1[O:40][CH2:39]1)(=O)C(C)=C.[OH-].[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[OH:36][CH2:37][CH:38]([OH:40])[CH2:39][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]([C:24]3[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=3)[C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(N(c2ccc(C)cc2)c2ccc(C=Cc3ccc(O)cc3)cc2)cc1
Reactant: C=C(C)C(=O)OCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(N(c2ccc(C)cc2)c2ccc(C=Cc3ccc(OCC(O)CO)cc3)cc2)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
In a reaction vessel equipped with a stirrer, a thermometer, a condenser, and a dropping funnel, 11.75 g of 4-hydroxy-4′-(di-p-tolylamino)stilbene, 4.35 g of glycidyl methacrylate, and 8 ml of toluene are contained, and the mixture is heated to 90° C. Further, 0.16 g of triethylamine is added thereto, and the mixture is agitated for 8 hours at 95° C. Next, 16 ml of toluene and 20 ml of a 10% aqueous solution of sodium hydroxide are added thereto, and the mixture is further agitated for 8 hours at 95° C.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[H-].[Na+].[CH:13]([OH:16])([CH3:15])[CH3:14]>>[CH:13]([O:16][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])([CH3:15])[CH3:14]
Reactant: CC(C)O
Reactant: Cc1ccc(C#N)c(F)c1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(C#N)c(OC(C)C)c1
Temperature: 50 °C

Procedure:
The 2-fluoro-4-methyl-benzonitrile (0.8 g, 3.99 mmol) was added in small portion to a mixture of NaH 60% (4 mol eq, 0.61 g) in isopropanol (30 mL). The reaction mixture was heated at 50° C. overnight. The solvent was distilled and water was added to the residue. The aqueous solution was extracted with EtOAc (3×25 mL) and the organic phases were evaporated at reduced pressure to give 30a as a deliquescent white solid (1.09 g, 6.22 mmol). 1HNMR (DMSO, 200 MHz) δ 1.21 (s, 3H), 1.28 (s, 3H), 2.10 (s, 3H), 4.89 (m, 1H), 7.41 (d, 1H), 7.55 (s, 1H), 7.89 (m, 1H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:12]=O)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:24])[CH3:23])=[CH:18][CH:17]=1>>[C:1]1([C:7]2[CH:8]=[C:9]([CH:12]=[CH:23][C:22]([C:19]3[CH:20]=[CH:21][C:16]([C:15]([F:14])([F:25])[F:26])=[CH:17][CH:18]=3)=[O:24])[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: O=Cc1cc(-c2ccccc2)cs1
Product: O=C(C=Cc1cc(-c2ccccc2)cs1)c1ccc(C(F)(F)F)cc1

Procedure:
By a procedure similar to that of example 1.59.1, starting from 4-phenylthiophene-2-carbaldehyde and p-(trifluoromethyl)acetophenone, 3-(4-phenylthiophen-2-yl)-1-(4-(trifluoromethyl)phenyl)prop-2-en-1-one was obtained as yellow solid.