Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[F:42][C:43]1[CH:44]=[C:45]([S:50](Cl)(=[O:52])=[O:51])[CH:46]=[CH:47][C:48]=1[CH3:49]>C(#N)C>[F:42][C:43]1[CH:44]=[C:45]([S:50]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:52])=[O:51])[CH:46]=[CH:47][C:48]=1[CH3:49]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1F
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Oc2ccc(-c3cc4cc(CN5CCCCC5)ccc4n3C(=O)OC(C)(C)C)c3c2CNC3=O)cc1F
Yield: 46.4 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0300 g, 0.0650 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 3-fluoro-4-methylbenzenesulfonyl chloride (0.0410 g, 0.195 mmol) to obtain 4-(3-fluoro-4-methylbenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0191 g, yield 46%).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Cl:23])[C:9]=1[S:10][C:11]1[S:15][C:14]([C:16]([O:18]C)=[O:17])=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21]>O1CCCC1.O>[Cl:23][C:8]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:3])[C:9]=1[S:10][C:11]1[S:15][C:14]([C:16]([OH:18])=[O:17])=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 46.7 %

Procedure:
An aqueous solution of sodium hydroxide (1N, 1.5 mL, 1.5 mmol) was added to a solution of Methyl 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylate (0.275 g, 0.75 mmol) in tetrahydrofuran (5 mL), and the resulting mixture was stirred at ambient temperature for 4 hours. After this time the mixture was diluted with water (4.5 mL) and washed the ethyl ether (2×5 mL). The aqueous phase was then acidified to pH 5 by the addition of hydrochloric acid solution (1 M), then the product was extracted into ethyl acetate (5×5 mL), dried (Na2SO4) and the solvent removed under reduced pressure to afford the title product as a white solid (123 mg, 47% yield). 1H NMR (300 MHz, d6-DMSO) δ: 9.0 (2H, s), 8.1 (1H, s). MS m/z: 350.85, 352.90 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19]C)[N:10]=[N:9]1.Br>C(O)(=O)C>[OH:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:11]1[N:10]=[N:9][N:8]([CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:21])=[O:2])[CH:12]=1
Reactant: COC(=O)CCCCn1cc(-c2ccccc2OC)nn1
Agent: Br
Solvent: CC(=O)O
Product: O=C(O)CCCCn1cc(-c2ccccc2O)nn1
Temperature: 25 °C
Yield: 66.9 %

Procedure:
Combine 5-[4-(2-methoxy-phenyl)-[1,2,3]triazol-1-yl]-pentanoic acid methyl ester (2.40 g, 8.29 mmol), hydrobromic acid (50 mL, 48% in water), and acetic acid (25 mL, glacial) and heat to reflux under N2 for 4 hours. Add hydrobromic acid (25 mL, 48% in water) and acetic acid (25 mL, glacial) and continue heating at reflux under N2 overnight Cool to room temperature, filter out solids and dry in a 50° C. vacuum oven overnight to yield the title compound (1.45 g, 67%). MS (IS) 260 (M−1)−.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@@H:9]1[C:14]([OH:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC.Cl>C1COCC1>[CH2:1]([N:8]1[C:12](=[O:13])[C@@H:11]([CH3:17])[CH2:10][C@@H:9]1[C:14]([OH:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: O=C(O)[C@H]1CCC(=O)N1Cc1ccccc1
Agent: Cl
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: C[C@H]1C[C@H](C(=O)O)N(Cc2ccccc2)C1=O
Reaction time: 1 h
Yield: 84 %

Procedure:
To a solution of (R)-1-benzyl-5-oxopyrrolidine-2-carboxylic acid (1000 mg, 4.56 mmol) in 55 ml of THF 10.03 ml of a 1M lithium bis(trimethylsilyl)amide solution in THF (10.03 mmol) were added slowly at −10° C., and stirring was continued at this temperature for 1 h. Subsequently iodomethane (0.284 ml, 647 mg, 4.56 mmol) in 9 ml of THF were added (slight exothermic reaction), and the reaction was completed by stirring overnight at room temperature. The brown reaction mixture was acidified using 2M HCl, extracted three times with ethyl acetate. The combined organic layers were then washed with brine, dried over Na2SO4 and the solvent evaporated under reduced pressure. The title compound was obtained as a brown oil, which was reacted in the next step without further purification (890 mg of raw material, yield: 84%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:20])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([F:19])[CH:13]=3)[O:11][C:6]=2[C:5]([F:21])=[CH:4][C:3]=1[F:22].[C:23](Cl)(=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25].O>N1C=CC=CC=1>[NH2:1][C:2]1[C:7]2[C:8](=[O:20])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[C:14]([F:19])[CH:13]=3)[O:11][C:6]=2[C:5]([F:21])=[CH:4][C:3]=1[F:22]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
5.00 g (16.3 mmol) of Compound 26 obtained in Example 26 was dissolved in 50 ml of pyridine, 2.2 ml of pivaloyl chloride was added under ice-cooling and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction solution and the precipitated crystals were collected by filtration to give 6.35 g (100%) of 5-amino-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:12]I.[H-].[Na+].Cl>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:11][CH3:12])([CH3:9])[CH3:10])=[CH:6][CH:7]=1
Reactant: CC(C)(O)c1ccc(Br)cc1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(C)(C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 26.6 %

Procedure:
2-(4-Bromo-phenyl)-propan-2-ol (Preparation 39, 1.77g, 8.2 mmol) and methyl iodide (0.5 mL, 8.2 mmol) in tetrahydrofuran (100 mL) were treated with sodium hydride (60% dispersion in mineral oil, 328 mg, 8.2 mmol). The mixture was stirred for 24 hours at room temperature, was poured into 0.5 M aqueous hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, was dried over magnesium sulfate, was filtered, and the solvent was removed in vacuo. The residue was purified by silica gel chromatography (200:1 hexanes-ethyl acetate) to afford 500 mg (27% yield) of the title compound. 13C NMR (100 MHz, CDCl3) d 145.4, 131.5, 127.9, 121.0, 76.7, 50.9, 28.1; MS (AP/Cl) 197.0, 199.0 (M+H—OMe)+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([C:19]([CH2:22][C:23]5[CH:24]=[C:25]6[C:30](=[CH:31][CH:32]=5)[N:29]=[CH:28][CH:27]=[CH:26]6)=[CH:20][N:21]=4)[N:18]=3)[CH:10]=[N:9]2)CCC[CH2:2]1.CN>CO>[CH3:2][NH:1][CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19]([CH2:22][C:23]4[CH:24]=[C:25]5[C:30](=[CH:31][CH:32]=4)[N:29]=[CH:28][CH:27]=[CH:26]5)=[CH:20][N:21]=3)[N:18]=2)[CH:10]=[N:9]1
Reactant: c1cnc2ccc(Cc3cnc4ccc(-c5cnn(CCN6CCCC6)c5)nn34)cc2c1
Agent: CN
Solvent: CO
Product: CNCCn1cc(-c2ccc3ncc(Cc4ccc5ncccc5c4)n3n2)cn1

Procedure:
The title compound was prepared in analogy to the compound of Example 236 using a 2 M solution of methylamine in MeOH instead of pyrrolidine (tR 2.61 min (conditions 3), MH+=384.3, 1H-NMR in DMSO-d6: 8.82 (m, 1H); 8.56 (s, 1H); 8.32 (m, 1H); 8.19 (s, 2H); 8.11 (d, 1H); 7.94 (m, 2H); 7.78 (m, 1H); 7.66 (s, 1H); 7.54 (d, 1H); 7.48 (dd, 1H); 4.53 (m, 4H); 3.40 (t, 2H); 2.55 (s, 3H)).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]#[N:15])=[CH:4]1)[CH3:2].[Li+].CC([N-]C(C)C)C.B(OC(C)C)(OC(C)C)OC(C)C.I[C:38]1[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C=O)C>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]#[N:15])=[C:4]1[C:38]1[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=1)[CH3:2]
Reactant: CCn1cc(C#N)c2ccc(OC)cc21
Reactant: Oc1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)OB(OC(C)C)OC(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCn1c(-c2ccc(O)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 73 %

Procedure:
To a solution of 1-ethyl-6-methoxy-1H-indole-3-carbonitrile (2.5 g, 12.5 mmol) in 21 mL of THF is added LDA (23 mL, 22.5 mmol) at −78° C. After warming to 0° C. and stirring for 10 min, the mixture is re-cooled to −78° C. and B(O—iPr)3 (4.35 mL, 18.8 mmol) is added. After the addition, the reaction is allowed to warm to room temperature and stirred for about 1 h. 4-iodophenol (2.89 g, 13.1 mmol), PdCl2(dppf) (510 mg, 0.625 mmol), aqueous K2CO3 (25 mL, 50 mmol) and DMF (42 mL) is added and the reaction mixture is stirred at room temperature overnight. The organic solvent is evaporated under reduced pressure. The residue is washed with water and the mixture is filtered. The filtrate is concentrated to afford crude solid which is purified via column chromatography on silica gel using EtOAc/petroleum ether (1/5 to 2/1) as eluant to yield 73% of 1-ethyl-2-(4-hydroxyphenyl)-6-methoxy-1H-indole-3-carbonitrile.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH2:6][NH2:7].[F:12][C:13]1[CH:18]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:16]=[CH:15][C:14]=1[C:28]1[CH:29]=[N:30][C:31]([NH2:34])=[N:32][CH:33]=1>>[NH2:7][CH2:6][CH2:5][O:4][C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=1[C:17]1[CH:16]=[CH:15][C:14]([C:28]2[CH:33]=[N:32][C:31]([NH2:34])=[N:30][CH:29]=2)=[C:13]([F:12])[CH:18]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: NCCOc1ccccc1Br
Product: NCCOc1ccccc1-c1ccc(-c2cnc(N)nc2)c(F)c1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 2-(2-bromophenoxy)ethanamine and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C18H17FN4O, 324.14; m/z found, 325.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J=0.9, 2H), 8.29 (s, 1H), 7.58-7.54 (m, 1H), 7.53-7.49 (m, 1H), 7.45 (dd, J=8.0, 1.4, 1H), 7.39-7.34 (m, 2H), 7.15 (d, J=8.1, 1H), 7.09-7.05 (m, 1H), 6.86 (s, 2H), 4.13 (t, J=5.4, 2H), 3.05 (t, J=5.4, 2H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[C:15](=[O:22])[NH:14][C:13]3[CH:23]=[CH:24][CH:25]=[N:26][C:12]2=3)=[O:10])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(O)C>[CH2:33]([N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][C:9]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[C:15](=[O:22])[NH:14][C:13]3[CH:23]=[CH:24][CH:25]=[N:26][C:12]2=3)=[O:10])[CH2:2][CH2:3]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C1Nc2cccnc2N(C(=O)CCN2CCNCC2)c2ccccc21
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C1Nc2cccnc2N(C(=O)CCN2CCN(Cc3ccccc3)CC2)c2ccccc21
Yield: 42 %

Procedure:
A mixture of 3.51 g of 5,11-dihydro-11-[3-(1-piperazinyl)-propionyl]-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one and 1.6 g of sodium carbonate were added to the mixture of 2.14 g of benzylbromide in 100 ml of absolute ethanol and the mixture was refluxed for 6 hours. Then, the hot mixture was vacuum filtered and the filtrate was evaporated to dryness in vacuo and purified by a silica gel column. The residue of the eluent was then crystallized from xylene to obtain a 42% yield of 11-[3-(4-benzyl-1-piperazinyl)-propionyl]-5,11-dihydro-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one melting at 205°-207° C.
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=1.[B:31](OC)([O:34]C)[O:32]C.Cl>O1CCCC1>[C:29]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([B:31]([OH:34])[OH:32])[C:17]=1[F:16])#[N:30]
Reactant: COB(OC)OC
Reactant: N#Cc1ccccc1-c1ccccc1F
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#Cc1ccccc1-c1cccc(B(O)O)c1F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 67 %

Procedure:
A cooled (−78° C.) solution of n-butyllithium (11.7 ml of a 2.5M solution in hexanes, 29.1 mmol) in tetrahydrofuran (100 ml) was treated with 2,2,6,6-tetramethylpiperidine (5.16 ml) and stirring at −78° C. was continued for 15 min. The reaction was then treated with a cooled (0° C.) solution of 2′-fluorobiphenyl-2-carbonitrile (5.50 g) in tetrahydrofuran (15 ml) added dropwise over 10 min. This mixture was stirred at −78° C. for 2 h and then treated with trimethyl borate (6.30 ml) added dropwise over 5 min. The reaction was stirred at −78° C. for 10 min then allowed to warm to ambient temperature. 2N Hydrochloric acid (5 ml) was added and the mixture evaporated to dryness. The residue was stirred with 2N hydrochloric acid (95 ml) for 30 min and then extracted with diethyl ether (2×100 ml). The organics were combined, extracted with 2N sodium hydroxide (100 ml) and the organics discarded. The aqueous was cooled to 0° C. and made just acidic (pH 6) with 36% hydrochloric acid. After stirring at 0° C. for 1 h the resulting solid was collected by filtration and dried. Crystallisation from diethyl ether/isohexane afforded 2′-cyano-2-fluorobiphenyl-3-boronic acid as a yellow solid (4.50 g, 67%): δH (360 MHz, CDCl3) 5.23 (1H, s), 5.25 (1H, s), 7.33 (1H, m), 7.42-7.56 (3H, m), 7.65 (1H, m), 7.77 (1H, m), 7.93 (1H, m).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:20])=[C:4]([F:19])[C:5]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[Si](C=[N+]=[N-])(C)(C)[CH3:22]>C1COCC1.CO>[CH3:22][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[C:3]([F:20])=[C:4]([F:19])[C:5]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18]
Reactant: O=C(O)c1cc(Br)c(F)c(F)c1Nc1ccccc1Cl
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(Br)c(F)c(F)c1Nc1ccccc1Cl
Reaction time: 2 h
Yield: 99.4 %

Procedure:
To a solution of 5-bromo-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid (17.4 g, 48.1 mmol) in THF-MeOH (100 mL-30 mL) was added TMSCHN2 (31.0 mL, 62.0 mmol, 2M solution in hexanes) at room temperature. The resulting mixture was stirred for 2 hours, quenched with AcOH, and diluted with EtOAc. The organic layer was washed with water, saturated NaHCO3 (2×), and brine. The organic layer was dried over MgSO4, filtered, and concentrated to give the crude product (18.0 g, 99%) that was used directly without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:20]([O:27][C:28](=[O:32])[CH2:29][CH2:30][NH2:31])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.P(C#N)(=O)(OCC)OCC.C(N(CC)CC)C>CN(C=O)C>[NH:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:31][CH2:30][CH2:29][C:28]([O:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:32])=[O:8])=[CH:2]1
Reactant: O=C(O)c1cc[nH]c1
Reactant: NCCC(=O)OCc1ccccc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CCNC(=O)c1cc[nH]c1)OCc1ccccc1
Yield: 88.6 %

Procedure:
Using 1.67 g (15 mmol) of 3-pyrrolecarboxylic acid, 6.33 g (18 mmol) of β-alanine benzyl ester p-toluenesulfonate, 2.94 g (18 mmol) of diethyl phosphorocyanidate, 3.64 g (36 mmol) of triethylamine and 50 ml of DMF, 3.62 g of the title compound were obtained in a similar manner as in Example 1 (yield: 89%).
Reaction SMILES: O.[OH-].[Li+].[NH2:4][C:5]1[C:37]([C:38]([F:41])([F:40])[F:39])=[CH:36][C:8]([CH2:9][C@@H:10]([CH2:15][C:16](=[O:35])[N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[CH2:29][CH2:28][C:27]4[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=4[NH:25][C:24]3=[O:34])[CH2:19][CH2:18]2)[C:11]([O:13]C)=[O:12])=[CH:7][C:6]=1[C:42]([F:45])([F:44])[F:43].Cl>O.C1COCC1>[NH2:4][C:5]1[C:6]([C:42]([F:43])([F:44])[F:45])=[CH:7][C:8]([CH2:9][C@@H:10]([CH2:15][C:16](=[O:35])[N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[CH2:29][CH2:28][C:27]4[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=4[NH:25][C:24]3=[O:34])[CH2:19][CH2:18]2)[C:11]([OH:13])=[O:12])=[CH:36][C:37]=1[C:38]([F:41])([F:40])[F:39]
Reactant: COC(=O)[C@H](CC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1)Cc1cc(C(F)(F)F)c(N)c(C(F)(F)F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1c(C(F)(F)F)cc(C[C@@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 0.72 g (16.75 mmol) lithium hydroxide hydrate in 30 mL water was added to a solution of 6.7 g (11.16 mmol) methyl (S)-2-(4-amino-3,5-bis-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-butanoate in 50 mL THF at RT and the reaction mixture was stirred for 5 h at RT. The THF was eliminated i. vac., the aqueous solution cooled to 10° C. and adjusted to pH 1 with conc. HCl, during which time the product was precipitated. This was suction filtered and dried at 65° C. The dried substance was combined with 300 mL diisopropylether, stirred overnight, suction filtered, washed with diisopropylether and dried.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[CH:16]1[C:28]2[CH:27]([CH2:29][O:30][C:31](C3CC(=O)N(O)C3=O)=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1.O>C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>[CH:16]1[C:28]2[CH:27]([CH2:29][O:30][C:31]([NH:1][CH:2]([C:7]3[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=3)[CH2:3][C:4]([OH:6])=[O:5])=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: NC(CC(=O)O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)C1CC(=O)N(O)C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CC(NC(=O)OCC1c2ccccc2-c2ccccc21)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 43.6 %

Procedure:
A cold (0°) solution of 3-amino-3-(4-nitrophenyl)propanoic acid (3.2 g, 15 mmol) in 10% aqueous sodium carbonate (60 ml) and 1,4-dioxan (30 ml) was treated portion-wise with 9-fluorenylmethoxycarbonyl-N-hydroxysuccinimide (5.6 g, 17 mmol) in 1,4-dioxan (15 ml) and the mixture stirred at room temperature for 12 h. The mixture was poured into water (300 ml) and the aqueous phase washed 3 times with ether. The aqueous layer was then acidified with solid citric acid and extracted into ether. The combined organic layers were dried (MgSO4) and evaporated to a yellow oil then triturated from hexane and EtOAc to afford the title compound as a yellow solid (2.83 g); m/z (ES+, 70V) 432 (MH+).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[S:5][CH:4]([C:12]([OH:14])=O)[CH2:3]1.S(Cl)(Cl)=O.[CH2:19]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(N(CC)CC)C>C1C=CC=CC=1.ClCCl>[CH2:26]([N:25]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:12]([CH:4]1[CH2:3][C:2](=[O:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[S:5]1)=[O:14])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCNCCCCCC
Reactant: O=C1CC(C(=O)O)Sc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: c1ccccc1
Product: CCCCCCN(CCCCCC)C(=O)C1CC(=O)c2ccccc2S1

Procedure:
To a solution of 20.00 g of (4-oxo-thiochroman-2-yl)-carboxylic acid in 200 ml of benzene was added 14.0 ml of thionyl chloride, followed by reflux under heating for 3 hours. The reaction solution was concentrated under reduced pressure to give a residue, a solution of which in 100 ml of dichloromethane was added dropwise to a solution of 24.6 ml of dihexylamine and 20.0 ml of triethylamine in 200 ml of dichloromethane under ice-cooling with stirring. After stirring at room temperature overnight, the reaction solution was concentrated under reduced pressure, and to the residue was added ethyl acetate, and the mixture was washed with water, 1 N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (silica gel; Wakogel C200 (manufactured by Wako Pure Chemicals), developing solvent; hexane-ethyl acetate=5:1-3:1) and recrystallized from hexane to give 29.22 g of N,N-dihexyl-(4-oxo-thiochroman-2-yl)-carboxamide.
Reaction SMILES: [Cl: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]([O-])=O)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1>[Pt]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(/C=C/c2ccc(Cl)cc2)cc1
Agent: [Pt]
Product: Nc1ccc(CCc2ccc(Cl)cc2)cc1

Procedure:
In an analogous manner to that described in Example 36b), the hydrogenation of (E)-1-chloro-4-[2-(4-nitrophenyl)ethenyl]-benzene using platinum on carbon (5%) as the catalyst but with a reaction time of 18 hours and simultaneous reduction of the double bond yields the 4-[2-(4-chloro-phenyl)-ethyl]-phenylamine as a light yellow solid; MS: m/e=232 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([CH2:9][CH3:10])=[CH:5][C:3]=1[NH2:4].Br[C:12]#[N:13]>O>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([CH2:9][CH3:10])=[CH:5][C:3]=1[NH:4][C:12]#[N:13]
Reactant: CCc1ccc(Cl)c(N)c1
Reactant: N#CBr
Solvent: O
Product: CCc1ccc(Cl)c(NC#N)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100.3 %

Procedure:
To a heterogeneous slurry of 2-chloro-5-ethylaniline (1.6 g, 10 mmol) in 60 mL of water at 4° C. was added solid BrCN (0.848 g, 8 mmol) slowly. After 5 minutes the cooling bath was removed and the heterogeneous reaction mixture was stirred at room temperature for 24 hours to yield the product in water suspension. The precipitates were collected by filtration, washed with water (100 mL), and dried under vacuum to yield the pure title compound (1.45 g, 80% yield).
Reaction SMILES: C([N:4]1[C:13]2[C:12]3=[N:14][C:15]([CH3:18])=[C:16]([Br:17])[N:11]3[CH:10]=[CH:9][C:8]=2[C@@H:7]([O:19]C(=O)C(C)(C)C)[C@H:6]([O:26][CH2:27][CH2:28][O:29][CH3:30])[C@H:5]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=O)C.[OH-].[K+].O.NN>CO>[Br:17][C:16]1[N:11]2[CH:10]=[CH:9][C:8]3[C@@H:7]([OH:19])[C@H:6]([O:26][CH2:27][CH2:28][O:29][CH3:30])[C@@H:5]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[NH:4][C:13]=3[C:12]2=[N:14][C:15]=1[CH3:18]
Reactant: COCCO[C@H]1[C@H](OC(=O)C(C)(C)C)c2ccn3c(Br)c(C)nc3c2N(C(C)=O)[C@@H]1c1ccccc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCCO[C@H]1[C@H](O)c2ccn3c(Br)c(C)nc3c2N[C@@H]1c1ccccc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A suspension of 0.30 g (0.54 mmol) of (7R,8R,9R)-10-acetyl-3-bromo-8-(2-methoxyethoxy)-2-methyl-9-phenyl-7-pivaloyloxy-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine, 0.10 ml (0.60 mmol) aqueous potassium hydroxide (6 N) and 0.20 ml (5.14 mmol) hydrazine hydrate in methanol is stirred al 60° C. for 4 h. The methanol is removed in vacuo and the reaction mixture is diluted with water. Subsequently the mixture is extracted twice with dichloromethane. The combined organic layers are washed with brine, dried over sodium sulphate and evaporated in vacuo. The crude product is purified by column chromatography (toluene/dioxane/acetic acid: 8/1/1) to give 0.12 g (0.28 mmol/52%) of the title compound as an amorphous solid. 1H-NMR (200 MHz, [D6] DMSO): δ=2.30 (s, 1H), 3.09 (s, 1H), 3.10-3.30 (m, 2H), 3.45-3.70 (m, 2H), 4.48 (d, 1H), 4.68 (d, 1H), 6.96 (d, 1H), 7.20-7.51 (m, 5H), 7.58 (d, 1H).