Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]1[S:15][CH:14]=[C:13]([CH:16]=O)[CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:18]([C:21]1[S:22][CH:23]=[C:24]([C:26]([N:28]2[CH2:33][C:32]3([CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[O:31][CH2:30][CH2:29]2)=[O:27])[N:25]=1)([CH3:20])[CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>CN1CCCC1=O.C(O)(=O)C.O>[Si:1]([O:8][CH2:9][CH2:10][C:11]1[S:15][CH:14]=[C:13]([CH2:16][N:36]2[CH2:37][CH2:38][C:32]3([O:31][CH2:30][CH2:29][N:28]([C:26]([C:24]4[N:25]=[C:21]([CH:18]([CH3:19])[CH3:20])[S:22][CH:23]=4)=[O:27])[CH2:33]3)[CH2:34][CH2:35]2)[CH:12]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Reactant: CC(C)(C)[Si](C)(C)OCCc1cc(C=O)cs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4csc(CCO[Si](C)(C)C(C)(C)C)c4)CC3)C2)cs1
Reaction time: 0.5 h

Procedure:
5-(2-(tert-butyldimethylsilyloxy)ethyl)thiophene-3-carbaldehyde (0.6 g) (example 278, step c) was added to (2-isopropylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone (0.94 g) (example 22, step b) in a mixture of N-methyl-2-pyrrolidinone (5 mL) and acetic acid (0.13 mL) and stirred for 30 min. Sodium triacetoxyborohydride (0.71 g) was then added and the mixture stirred overnight. The reaction was poured into water (100 mL), the pH was adjusted to 8 using saturated sodium bicarbonate solution and the resulting aqueous solution extracted with ethyl acetate (3×100 mL). The combined organic solutions were washed with water (3×100 mL), brine (100 mL), dried over sodium sulphate, filtered and evaporated. The residue was purified by silica gel chromatography eluting with 77.5:17.5:5 i-hexane:ethyl acetate:triethylamine to 47.5:47.5:5 i-hexane:ethyl acetate:triethylamine gradient. The fractions containing product were combined and evaporated in vacuo to give the subtitled compound as a clear oil. Yield 0.8 g.
Reaction SMILES: [C:1]([C:5]1[CH:25]=[CH:24][CH:23]=[CH:22][C:6]=1[C:7]([NH:9][N:10]([CH3:21])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)=[S:12])=[O:8])(OC)=[O:2].[BH4-].[Na+].O.Cl>C(O)C>[OH:2][CH2:1][C:5]1[CH:25]=[CH:24][CH:23]=[CH:22][C:6]=1[C:7]([NH:9][N:10]([CH3:21])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)=[S:12])=[O:8]
Reactant: COC(=O)c1ccccc1C(=O)NN(C)C(=S)Nc1cccc(F)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CN(NC(=O)c1ccccc1CO)C(=S)Nc1cccc(F)c1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
1-(2-Carbomethoxybenzoyl)-2-methyl-4-(3-fluorophenyl)-3-thiosemicarbazide (7.2 g) was dissolved in ethanol (100 ml). The solution was cooled to below 10° and sodium borohydride (1.1 g) added. The mixture was then stirred at room temperature for 60 hours. Water was then added with production of an amorphous precipitate. Dilute hydrochloric acid was then added to the filtrate to bring it to pH 7 and further precipitate removed by filtration. The filtrate was thereupon acidified to yield the title product as a solid, m.p. 136°-137°, yield 3.4 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][O:10][CH3:11])[CH:6]=[CH:5][C:4]=1[N+:12]([O-])=O>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][O:10][CH3:11])[CH:6]=[CH:5][C:4]=1[NH2:12]
Reactant: COCc1ccc([N+](=O)[O-])c(OC)c1
Agent: [Pd]
Solvent: CCO
Product: COCc1ccc(N)c(OC)c1
Yield: 90.8 %

Procedure:
In a 250 mL Parr apparatus, 2.1 g (10.6 mmol) of 2-methoxy-4-methoxymethyl-1-nitro-benzene, in 40 mL of ethanol was hydrogenated at 2 atm over 300 mg of 10% Pd on carbon for 2.5 h. The catalyst was removed by filtration through a glass fiber filter and the filtrate was concentrated to give 1.61 g (91%) of product as a light yellow oil. 1H NMR (400 MHz, CDCl3): δ6.80 (s, 1H), 6.74 (d, J=7.8 Hz, 1H), 6.67 (d, J=7.8 Hz), 4.35 (s, 2H), 3.86 (s, 3H), 3.78 (br d, 2H), 3.35 (s, 3H). MS ESI-pos, M+1=168.1
Reaction SMILES: C([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[C:20]3[C:26]([C:27]4[C:28]([CH3:41])=[N:29][N:30]([CH2:33][C:34]5[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=5)[C:31]=4[CH3:32])=[CH:25][N:24]([S:42]([C:45]4[CH:51]=[CH:50][C:48]([CH3:49])=[CH:47][CH:46]=4)(=[O:44])=[O:43])[C:21]3=[N:22][CH:23]=2)=[CH:14][C:13]=1[NH:52][S:53]([CH3:56])(=[O:55])=[O:54])C1C=CC=CC=1.C1(C)C=CC=CC=1.C(O)(C(F)(F)F)=O>>[F:40][C:36]1[CH:35]=[C:34]([CH:39]=[CH:38][CH:37]=1)[CH2:33][N:30]1[C:31]([CH3:32])=[C:27]([C:26]2[C:20]3[C:21](=[N:22][CH:23]=[C:18]([C:15]4[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][OH:8])=[C:13]([NH:52][S:53]([CH3:56])(=[O:55])=[O:54])[CH:14]=4)[CH:19]=3)[N:24]([S:42]([C:45]3[CH:46]=[CH:47][C:48]([CH3:49])=[CH:50][CH:51]=3)(=[O:44])=[O:43])[CH:25]=2)[C:28]([CH3:41])=[N:29]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(OCCOCc5ccccc5)c(NS(C)(=O)=O)c4)cnc32)cc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(OCCO)c(NS(C)(=O)=O)c4)cnc32)cc1
Temperature: 25 °C

Procedure:
A stirred solution of N-(2-(2-(benzyloxy)ethoxy)-5-(3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)methane sulfonamide (120 mg, 0.151 mmol), toluene/TFA (5/5 ml) was heated to 70° C. for overnight. TLC showed reaction completion. Reaction mass was cooled to RT and solvents evaporated under reduced pressure. This afforded 152 mg of the crude titled compound. MS: m/z=704.2 (M+1).
Reaction SMILES: [C:1]1([CH:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:8][NH:9][CH2:10][CH2:11][C@@H:12]([CH3:24])[O:13][C:14]2[CH:15]=[C:16]([CH2:20][C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[F:41])[CH:36]=O.COC(=O)C.[Cl:49]C1C(C(F)(F)F)=CC=CC=1C=O.Cl.CCOCC>CCOCC>[ClH:49].[F:42][C:32]([F:31])([F:43])[C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[F:41])[CH2:36][N:9]([CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:10][CH2:11][C@@H:12]([CH3:24])[O:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=1
Reactant: C[C@H](CCNCC(c1ccccc1)c1ccccc1)Oc1cccc(CC(=O)O)c1
Reactant: O=Cc1cccc(C(F)(F)F)c1Cl
Reactant: O=Cc1ccc(F)c(C(F)(F)F)c1
Agent: Cl
Solvent: COC(C)=O
Solvent: CCOCC
Product: C[C@H](CCN(Cc1ccc(F)c(C(F)(F)F)c1)CC(c1ccccc1)c1ccccc1)Oc1cccc(CC(=O)O)c1

Procedure:
Following the procedure of Example 7(d) except (R)-2-(3-{3-[(2,2-diphenylethyl)amino]-1-methyl-propoxy}-phenyl)acetic acid and 3-(trifluoromethyl)-4-fluoro-benzaldehyde were used instead of (R)-2-(3-{3-(2,2-diphenylethyl)amino]-3-methyl-propoxy}phenyl)acetic acid methyl ester and 2-chloro-3-trifluoromethylbenzaldehyde in step (d) the corresponding carboxylic acid was obtained. The crude product was purified by preparative HPLC (TMC CombiPrep PDS, 75×30 mm, 25 mL/min, acetonitrile: H2O, UV detection at 254 nm) to afford the free base. The resulting amine/carboxylic acid was dissolved in Et2O (diethylether) and acidified with 1.0 M HCl/Et2O. The reaction mixture was concentrated in vacuo and dried under reduced pressure to give the title compound as a white solid, 95 mg (88%). MS (ESI) 580.6 (M+H+).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4](S(O)(=O)=O)=[CH:3][CH:2]=1.N1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:18][OH:19]>>[CH2:18]([OH:19])[CH:13]=[CH:14][CH:15]=[CH:16][CH2:17][CH2:6][CH2:1][CH2:2][CH2:3][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:1][CH3:11]
Reactant: CO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: c1ccncc1
Product: CCCCCCCCCCCCC=CC=CCO
Temperature: 25 °C

Procedure:
The mixture of compounds from Example 16(a) (0.24 mole) was dissolved in 3 liters of methanol and pyridine p-toluenesulfonic acid (0.012 mole) was added to the mixture, with stirring under argon at room temperature. The progress of the reaction was monitored by thin layer chromatography. When the reaction was complete the solvent was evaporated and the residue flash chromatographed on silica gel eluted with 90:10 hexane:ethyl acetate to give a 3:1 mixture of the resulting trans:cis isomers. Separation was accomplished by careful chromatography on silica gel.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=[O:15])[CH2:9][CH2:8]2)[C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[NH:3]1.O=C1N(C2CCNCC2)[C:25]2C=CC=C[C:24]=2N1.BrCC(OCC)=O>C(#N)C>[O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([O:16][CH2:24][CH3:25])=[O:15])[CH2:9][CH2:8]2)[C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[NH:3]1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: O=C(O)CN1CCC(n2c(=O)[nH]c3ccccc32)CC1
Agent: CCOC(=O)CBr
Solvent: CC#N
Product: CCOC(=O)CN1CCC(n2c(=O)[nH]c3ccccc32)CC1

Procedure:
Compounds of formula A in which Z=2,3-dihydro-2-oxo-1H-benzimidazol-1-yl and L=(N-methylene)piperidin-4-yl are prepared from β-aminotetralins (VII) or phenethylamines (XI) and [4-(2-keto-1-benzimidazolinyl)piperidin-1-yl]acetic acid (Schemes 6–7). For example, 4-(2-keto-1-benzimidazolinyl)piperidine is reacted with a bromoacetic acid ester, such as ethyl bromoacetate, in the presence of an amine base, such as diusopropylethylamine, in an inert solvent such as acetonitrile, at a temperature ranging from ambient temperature to reflux, to afford ethyl [4-(2-keto-1-benzimidazolinyl)piperidin-1-yl]acetate. This ester is subjected to hydrolysis under basic conditions, for example, by treatment with sodium hydroxide in an alcoholic solution such as aqueous methanol, to yield, upon acidification with an inorganic or organic acid such as hydrochloric or acetic acid for example, [4-(2-keto-1-benzimidazolinyl)piperidin-1-yl]acetic acid. This carboxylic acid is reacted directly with βaminotetralins (VII) or phenethylamines (XI), in the presence of an amine base, under peptide coupling conditions described above, to afford benzimidazolinones (XVII) and (XVIII) of formula A in which Y=carbonyl and L=(N-methylene)piperidin-4-yl (Schemes 6–7).
Reaction SMILES: [CH:1]([O:4][C:5]([NH:7][C@H:8]([C:12]([OH:14])=O)[CH:9]([CH3:11])[CH3:10])=[O:6])([CH3:3])[CH3:2].CN1CCOCC1.C(Cl)(=O)OCC(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:41][C:42]1[CH:53]=[CH:52][C:45]2[N:46]=[C:47]([C@@H:49]([NH2:51])[CH3:50])[S:48][C:44]=2[CH:43]=1>C1(C)C=CC=CC=1>[F:41][C:42]1[CH:53]=[CH:52][C:45]2[N:46]=[C:47]([C@@H:49]([NH:51][C:12]([C@@H:8]([NH:7][C:5](=[O:6])[O:4][CH:1]([CH3:2])[CH3:3])[CH:9]([CH3:10])[CH3:11])=[O:14])[CH3:50])[S:48][C:44]=2[CH:43]=1
Reactant: CC(C)OC(=O)N[C@H](C(=O)O)C(C)C
Reactant: C[C@H](N)c1nc2ccc(F)cc2s1
Agent: CC(C)COC(=O)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN1CCOCC1
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)N[C@H](C(=O)N[C@@H](C)c1nc2ccc(F)cc2s1)C(C)C
Yield: 80.8 %

Procedure:
In 250 ml of toluene, 13.4 g (0.066 mol) of N-isopropoxycarbonyl-L-valine was dissolved. Thereto was added 14.3 g (0.144 mol) of N-methylmorpholine. Then was dropwise added at −10° C., 8.6 g (0.063 mol) of isobutyl chlorocarbonate. Thereto was added 22 g (0.06 mol) of (S)-1-(6-fluoro-2-benzothiazolyl)ethylamine p-toluenesulfonate. A reaction and a post-treatment were conducted in the same manner as in Reference Example 1, and the suspension of a solid in toluene was filtered at 70° C. to collect the solid. The solid was washed with water and toluene and dried to obtain 18.5 g (yield: 81.1%) of isopropyl {(S)-1-[(S)-1-(6-fluorobenzothiazol-2-yl)ethylcarbamoyl]-2-methylpropyl}carbamate. The compound obtained was confirmed for the structure by IR analysis and NMR analysis in comparison with its authentic material and identified.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[CH:8][CH:9]=2)[N:4]([C:19]2[N:24]=[CH:23][N:22]=[C:21]([NH:25][CH3:26])[CH:20]=2)[CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC1(C)C(C)(C)OB([C:43]2[CH:51]=[C:50]3[C:46]([CH:47]=[CH:48][NH:49]3)=[CH:45][CH:44]=2)O1.C(OCC)(=O)C>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:7]2[CH:6]=[C:5]3[C:10]([C:2]([C:43]4[CH:51]=[C:50]5[C:46]([CH:47]=[CH:48][NH:49]5)=[CH:45][CH:44]=4)=[CH:3][N:4]3[C:19]3[N:24]=[CH:23][N:22]=[C:21]([NH:25][CH3:26])[CH:20]=3)=[CH:9][CH:8]=2)=[CH:12][CH:13]=1
Reactant: CC1(C)OB(c2ccc3cc[nH]c3c2)OC1(C)C
Reactant: CNc1cc(-n2cc(Br)c3ccc(-c4ccc(OC)cc4)cc32)ncn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CNc1cc(-n2cc(-c3ccc4cc[nH]c4c3)c3ccc(-c4ccc(OC)cc4)cc32)ncn1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
6-(3-Bromo-6-(4-methoxyphenyl)-1H-indol-1-yl)-N-methylpyrimidin-4-amine (50 mg, 0.074 mmol), K3PO4 (47.1 mg, 0.222 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (27 mg, 0.111 mmol) were dissolved in dimethylformamide (2 mL) and then Pd(PPh3)4 (12.83 mg, 0.011 mmol) was added. After stirring at 120° C. for 3 hours, followed by addition of ethyl acetate and water, the reaction solution was filtered using a diatomite pad. The aqueous layer was extracted with ethyl acetate and the collected organic layer was washed with brine and then concentrated under reduced pressure by drying with magnesium sulfate. The residue was purified by chromatography (silica gel, EtOAc:hexane=1:10→1:4→1:2). The target compound was obtained as brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:15]([OH:17])=[O:16])[N:12]([CH3:14])[CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:18]1[CH:19]=[CH:20][C:21]2[N:26](O)[N:25]=[N:24][C:22]=2[CH:23]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:15]([O:17][N:24]2[C:22]3[CH:23]=[CH:18][CH:19]=[CH:20][C:21]=3[N:26]=[N:25]2)=[O:16])[N:12]([CH3:14])[CH:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: On1nnc2ccccc21
Reactant: Cn1cc(NC(=O)OC(C)(C)C)cc1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: Cn1cc(NC(=O)OC(C)(C)C)cc1C(=O)On1nnc2ccccc21
Reaction time: 24 h
Yield: 84.6 %

Procedure:
Boc-Py-acid, 4-[(tert-Butoxycarbonyl)amino]-1-methylpyrrole-2-carboxylic acid (31 g, 129 mmol) was dissolved in 500 mL DMF, HOBt (17.4 g, 129 mmol) was added followed by DCC (34 g, 129 mmol). The reaction was stirred for 24 h and then filtered dropwise into a well stirred solution of 5 L of ice water. The precipitate was allowed to sit for 15 min at 0° C. and then collected by filtration. The wet cake was dissolved in 500 mL DCM, and the organic layer added slowly to a stirred solution of cold petroleum ether (4° C.). The mixture was allowed to stand at −20° C. for 4 h and then collected by vacuum filtration and dried in vacuo to provide (39 g, 85% yield) of 1,2,3-Benzotriazol-1-yl 4-[(tert-butoxycarbonyl)-amino]-1-methylpyrrole-2-carboxylate as a finely divided white powder. TLC (7:2 benzene/ethyl acetate v/v) Rf 0.61H NMR (DMSO-d6) δ 9.43 (s, 1H), 8.12 (d, 1H, J=8.4 Hz), 7.80 (d, 1H, J=8.2 Hz), 7.64 (t, 1H, J=7.0 Hz), 7.51 (m, 2H), 7.18 (s, 1H), 3.83 (s, 3H), 1.45 (s, 9H), 13C NMR (DMSO-d6) δ 156.5, 153.3, 143.2, 129.6, 129.2, 125.7, 125.2, 124.6, 120.3, 112.8, 110.3, 109.8, 79.5, 36.8, 28.6.; IR (KBr) 3246, 3095, 2979, 1764, 1711, 1588, 1389, 1365, 1274, 1227, 1160, 1101, 999, 824, 748.; FABMS m/e 358.152 (M+H 358.151 calc. for C17H20N5O4).
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].[Br:5][C:6]#[C:7][C:8]([O:10][CH3:11])=[O:9]>S(=O)(=O)(O)O>[Br:5][C:6]([S:1][C:2]#[N:3])=[CH:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C#CBr
Reactant: N#C[S-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: COC(=O)C=C(Br)SC#N
Reaction time: 0.08 h

Procedure:
To a stirred solution of ammonium thiocyanate (3.06 g., 0.04 mole) in 2M aqueous sulfuric acid (20 ml) at 0° C., methyl 3-bromopropiolate (3.26 g., 0.02 mole) was added dropwise, neat, over 5 minutes. After keeping the temperature at 0° C. for 1 hour, the mixture, consisting of a solid precipitate in the aqueous solution, was extracted with ether which was washed with water, dried (MgSO4), and concentrated. The residual solid was suspended in hexane and removed by filtration, yielding 2.4 g. of product. The solid recrystallized from ethanol as yellowish microcrystals; mp 139°-142.5° C.; IR (KBr) 2170, 1680 cm-1.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:24])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[C:17]([O:22][CH3:23])[CH:16]=3)=[CH:9][CH:8]=1)([CH3:3])[CH3:2].[Cl:25]N1C(=O)CCC1=O>CN(C=O)C.O>[CH:1]([O:4][C:5](=[O:24])[NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[NH:14][C:15]3[C:20]([C:21]=2[Cl:25])=[CH:19][CH:18]=[C:17]([O:22][CH3:23])[CH:16]=3)=[CH:11][CH:12]=1)([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc2cc(-c3ccc(NC(=O)OC(C)C)cc3)[nH]c2c1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(Cl)c(-c3ccc(NC(=O)OC(C)C)cc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To [4-(6-Methoxy-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (11.3 g, 34.9 mmol) in DMF (50 mL) was added a solution of N-chlorosuccinimide (5 g, 37.4 mmol) dropwise over 20 minutes and the mixture stirred at room temperature for 1 h. The reaction mixture was diluted with H2O and extracted with EtOAc. The organic layer was washed with H2O and brine and then dried, concentrated and triturated with ether to provide [4-(3-chloro-6-Methoxy-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (10.65 g, 85%) as a tan solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:32]=[C:31]([CH2:33][C:34]4[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=4)[C:30](=[O:40])[C:8]4[CH:9]=[C:10]([O:15][CH2:16][C:17]([N:19]5[CH2:24][CH2:23][CH:22]([C:25]([O:27]CC)=[O:26])[CH2:21][CH2:20]5)=[O:18])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.[OH-].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:32]=[C:31]([CH2:33][C:34]4[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=4)[C:30](=[O:40])[C:8]4[CH:9]=[C:10]([O:15][CH2:16][C:17]([N:19]5[CH2:20][CH2:21][CH:22]([C:25]([OH:27])=[O:26])[CH2:23][CH2:24]5)=[O:18])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: CCOC(=O)C1CCN(C(=O)COc2cc3c(=O)c(Cc4cccnc4)cn4c5ccc(Br)cc5c(c2)c34)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1CCN(C(=O)COc2cc3c(=O)c(Cc4cccnc4)cn4c5ccc(Br)cc5c(c2)c34)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 42 %

Procedure:
10-bromo-2-(4-ethoxycarbonyl-1-piperidinocarbonylmethyloxy)-5-(3-pyridylmethyl)-4H-pyrido[3,2,1-jk]carbazole-4-one (250 mg) obtained in Example 45 was suspended in ethanol (30 ml), and to the suspension was added 1 N aqueous solution of sodium hydroxide (8 ml) and the mixture was stirred for 90 minutes at room temperature. After evaporate the solvent under reduced pressure, water and ethyl acetate were added to extract the mixture. The aqueous layer was adjusted to pH 6 by adding 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: methylene chloride/methanol=5:1). The crude purification product was washed with ether and recovered by filtration to obtain the title compound (100 mg, 42%).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.Cl.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1.C(N(CC)C(C)C)(C)C.[I-].C(C[P+](C)(C)C)#N>C(#N)CC.CO>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][N:28]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]5[CH2:13][CH2:14][CH2:15][C@H:8]5[C:7](=[O:16])[NH:6][C:5]=4[CH:4]=3)[CH2:27][CH2:26]2)=[CH:23][CH:24]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: O=C1Nc2cc(CN3CCN(c4ccc(Cl)cc4)CC3)cnc2N2CCC[C@@H]12
Temperature: 90 °C
Yield: 39.5 %

Procedure:
(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (200 mg, 0.912 mmol), 1-(4-chlorophenyl)piperazine hydrochloride (200 mg, 0.858 mmol), N,N-diisopropylethylamine (DIPEA; 0.50 mL), and (cyanomethyl)trimethylphosphonium iodide (220 mg, 1.08 mmol) were suspended in propionitrile (2 mL) and heated in a closed vial at 90° C. for 4 h. The reaction mixture was diluted with MeOH (2 mL) and purified using preparative scale HPLC (45-95% acetonitrile in water, buffered with NH4HCO3). The fractions containing product were concentrated in vacuo and diluted with water (5 mL). The resulting precipitate was filtered and dried in vacuum to afford the title compound as an off-white solid (135 mg, 40%). 1H NMR (DMSO-d6) δ (ppm): 10.43 (s, 1H), 7.61 (d, J=1.8 Hz, 1H), 7.21 (d, J=8.8 Hz, 2H), 6.98 (d, J=1.8 Hz, 1H), 6.92 (d, J=9.1 Hz, 2H), 3.91-4.06 (m, 1H), 3.51-3.66 (m, 1H), 3.37-3.47 (m, 1H), 3.10 (br. s., 4H), 2.46 (d, J=4.3 Hz, 4H), 2.09-2.26 (m, 1H), 1.80-2.03 (m, 3H); [M+H] calc'd for C21H24ClN3O, 398; found, 398; melting point 265-268° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([N:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:9]1)[C:5]([OH:7])=O)[CH3:2].Cl.Cl.[CH2:21]([O:28][C:29](=[O:41])[NH:30][C:31]([C:33]1[CH:38]=[CH:37][C:36]([CH2:39][NH2:40])=[CH:35][CH:34]=1)=[NH:32])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([O:28][C:29](=[O:41])[N:30]=[C:31]([NH2:32])[C:33]1[CH:34]=[CH:35][C:36]([CH2:39][NH:40][C:5](=[O:7])[CH:4]([O:3][CH2:1][CH3:2])[N:8]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:9]2)=[CH:37][CH:38]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(C(=O)O)n1ccc(-c2ccncc2)n1
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc(CN)cc1
Agent: Cl
Product: CCOC(C(=O)NCc1ccc(C(N)=NC(=O)OCc2ccccc2)cc1)n1ccc(-c2ccncc2)n1

Procedure:
According to general method C, ethoxy-(3-pyridin-4-yl-pyrazol-1-yl)-acetic acid was reacted with [(4-aminomethyl-phenyl)-imino-methyl]-carbamic acid benzyl ester dihydrochloride (CAS 172348-75-3) to give (RS)-[amino-(4-{[2-ethoxy-2-(3-pyridin-4-yl-pyrazol-1-yl)-acetylamino]-methyl}-phenyl)-methylene]-carbamic acid benzyl ester. White powder. MS 513.3 ([M+H]+)
Reaction SMILES: [F:1][C:2](I)([F:4])[F:3].[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[SH:13].C(N(CC)CC)C>CN(C)C=O.O>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13][C:2]([F:4])([F:3])[F:1]
Reactant: FC(F)(F)I
Reactant: Fc1ccccc1S
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Fc1ccccc1SC(F)(F)F
Reaction time: 24 h

Procedure:
Methyl viologen hydrochloride (1.17 g) in N,N-dimethylformamide (80 mL) at 25° C. was saturated with trifluoromethyl iodide, treated with 2-fluorobenzenethiol (9.7 mL) and triethylamine (20 mL), stirred for 24 hours, diluted with water (240 mL) and extracted with diethyl ether. The extract was washed with 1M NaOH, saturated ammonium chloride and brine and concentrated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[C:15]([N+:19]([O-:21])=[O:20])[C:16]=1[O:17][CH3:18])[C:6]([CH2:8][C:9]([O:11]CC)=O)=O.[C:22]1([NH:28][NH2:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[CH2:8][C:9](=[O:11])[N:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:29]=2)[CH:14]=[C:15]([N+:19]([O-:21])=[O:20])[C:16]=1[O:17][CH3:18]
Reactant: CCOC(=O)CC(=O)c1cc(OC)c(OC)c([N+](=O)[O-])c1
Reactant: NNc1ccccc1
Product: COc1cc(C2=NN(c3ccccc3)C(=O)C2)cc([N+](=O)[O-])c1OC

Procedure:
10.0 g of ethyl (3,4-dimethoxy-5-nitrobenzoyl)acetate are reacted with 4.0 g of phenylhydrazine in analogy to Example 53a. After recrystallization from methylene chloride/ethanol, there is obtained 3-(3,4-dimethoxy-5-nitrophenyl)-l-phenyl-2-pyrazolin-5-one in the form of yellow crystals of m.p. 190°-192°.