Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:24])(C)=C.O.Cl.C(Cl)Cl>CO>[C:14]1([CH2:13][N:6]2[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:4][C:5]2=[O:24])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: C=C(C)n1c(=O)n(Cc2cccc3ccccc23)c2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: O=c1[nH]c2ccccc2n1Cc1cccc2ccccc12
Temperature: 60 °C
Yield: 92.9 %

Procedure:
1-Isopropenyl-3-naphthalen-1-ylmethyl-1,3-dihydro-benzimidazol-2-one (1.6 g, 5.1 mmol) is dissolved in MeOH (5.0 mL) and water (5.0 mL) is added into the solution. To this heterogeneous reaction mixture is added 37% hydrochloric acid (4.0 mL). The reaction mixture is heated to 60° C. for 30 min and then water (50 mL) and CH2Cl2 (50 mL) are added. The organic layer is separated and the aqueous layer is extracted with CH2Cl2 (3×50 mL). The organic layers are combined, washed with Sat. NaHCO3 (100 mL), Sat. NH4Cl (100 mL) and water (3×100 mL), dried over MgSO4 and concentrated to give 1.3 g (93%) of crude product which is pure enough for the next step.
Reaction SMILES: C(OC([NH:8][CH:9]([CH:39]([CH3:41])[CH3:40])[C:10]([O:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[C:18]2[C:23](=[C:24]([F:26])[CH:25]=1)[N:22]=[CH:21][C:20]([C:27]([NH:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)=[O:28])=[C:19]2[OH:38])=[O:11])=O)(C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[NH2:8][CH:9]([CH:39]([CH3:41])[CH3:40])[C:10]([O:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[C:18]2[C:23](=[C:24]([F:26])[CH:25]=1)[N:22]=[CH:21][C:20]([C:27]([NH:29][CH2:30][C:31]1[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=1)=[O:28])=[C:19]2[OH:38])=[O:11]
Reactant: CC(C)C(NC(=O)OC(C)(C)C)C(=O)OCCCc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(N)C(=O)OCCCc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1

Procedure:
3-(3-{[(4-Chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)propyl 2-[(tert-butoxycarbonyl)amino]-3-methylbutanoate from Example No. 146 (0.13 g) is stirred in a mixture of 4 mL trifluoroacetic acid and 7 mL CH2Cl2 at 0° C. for approximately 1.5 h. Once the reaction is complete, the mixture is partitioned between CH2Cl2 and saturated NaHCO3. After the TFA is neutralized, any undissolved material is filtered off. The organic layer is washed once with water. The combined aqueous layers are back-extracted with CH2Cl2 and EtOAc. The organics are combined, dried over Na2SO4, filtered, and concentrated in vacuo to give a white solid. The solid is recrystallized from a minimal amount of EtOH. (0.040 g, 0.082 mmol, 35%).
Reaction SMILES: B(Br)(Br)Br.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=2)[CH2:13][NH:14][CH3:15])=[CH:8][CH:7]=1>ClCCl.C([O-])(O)=O.[Na+]>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:16]2[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=2)[CH2:13][NH:14][CH3:15])=[CH:8][CH:7]=1
Reactant: CNCC(c1ccc(Br)cc1)c1ccc(OC)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CNCC(c1ccc(O)cc1)c1ccc(Br)cc1
Temperature: 25 °C

Procedure:
Boron tribromide (7.8 ml, 1.0M in dichloromethane) was added slowly to a solution of [2-(4-Bromo-phenyl)-2-(4-methoxy-phenyl)-ethyl]-methyl-amine (500 mg, 1.56 mmol) in dichloromethane (8 ml) at 0° C., under an atmosphere of nitrogen. The reaction mixture was allowed to warm to room temperature and then stirred for a further hour. The mixture was poured on to ice and then diluted with dichloromethane and saturated NaHCO3 solution. The organic layer was dried (MgSO4), filtered and concentrated to afford the desired product. LC/MS: (PS-B3) Rt 2.76 [M+H]+ 306.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([NH:21][C:22]1[C:27]([CH:28]([CH3:30])[CH3:29])=[CH:26][C:25]([OH:31])=[CH:24][C:23]=1[CH:32]([CH3:34])[CH3:33])=[O:20].[Cl-].[NH4+]>C(#N)C>[OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:18][C:19]([NH:21][C:22]2[C:27]([CH:28]([CH3:30])[CH3:29])=[CH:26][C:25]([OH:31])=[CH:24][C:23]=2[CH:32]([CH3:34])[CH3:33])=[O:20])[CH2:7][CH2:6]1
Reactant: CC(C)c1cc(O)cc(C(C)C)c1NC(=O)CBr
Reactant: OCCCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)c1cc(O)cc(C(C)C)c1NC(=O)CN1CCN(CCCO)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.3 %

Procedure:
To a solution of 1-(3-hydroxypropyl)piperazine (700 mg, 4.88 mmol) in acetonitrile (15 ml) were added potassium carbonate (805 mg, 5.82 mmol) and 2-bromo-N-(2,6-diisopropyl-4-hydroxyphenyl)acetamide (1.53 g, 4.88 mmol), and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added a saturated ammonium chloride solution and the mixture was extracted with chloroform-methanol mixture solvent. The organic layer was washed with water and a saturated sodium chloride successively and dried over anhydrous sodium sulfate, and the solvent was evaporated therefrom. The resulting residue was recrystallized from chloroform-methanol-hexane to provide 1.13 g (yield 62%) of 2-[4-(3-hydroxypropyl)piperazin-1-yl]-N-[2,6-diisopropyl-4-hydroxyphenyl]acetamide as colorless powdery crystals.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[CH3:19][N:20]([CH3:24])[C:21](=[O:23])[CH3:22].[C:25](OCC)(=[O:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27]>C1COCC1>[CH3:19][N:20]([CH3:24])[C:21](=[O:23])[CH2:22][C:25](=[O:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)N(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)CC(=O)N(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.4 %

Procedure:
10.2 g of diisopropylamine (0.1 mol) were dissolved in 100 ml of dry THF under nitrogen and cooled in a freezing mixture. 40 ml n-butyllithium in hexane (2.5 M, 0.1 mol) were slowly added dropwise. When the addition was completed it was allowed to stir for 60 minutes and then 8.7 g N,N-dimethylacetamide (0.1 mol) were added dropwise. The reaction mixture was stirred for another 20 min in the freezing mixture. In a second flask, 43.7 g of diethyl oxalate (0.3 mol) in 50 ml of dry THF were cooled in a freezing mixture and the cooled reaction mixture was cannulated with stirring in small portions to it. It was left overnight under stirring to warm to room temperature. The THF was removed on a rotary evaporator and the residue was taken up in 80 ml half concentrated hydrochloric acid. The aqueous phase was extracted five times with 150 ml ethyl acetate, the combined organic phases dried over sodium sulfate and concentrated on a rotary evaporator to dryness. The excess diethyl oxalate was removed by distillation (2-3 mbar, 80° C.) and 17 g of crude product were obtained. 5.5 g product was obtained as white crystals with a melting point of 28° C. after crystallization from n-hexane.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+]>CCOC(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>[C:17]([O:16][C:14]([NH:13][C@H:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:21])[CH:27]=2)=[CH:3][CH:4]=1)[C:10]([OH:12])=[O:11])=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Br)cc1)C(=O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)O
Temperature: 25 °C

Procedure:
(R)-3-(4-Bromo-phenyl)-2-tert-butoxycarbonylamino-propionic acid (4.0 g, 11.6 mmol), 3-chlorophenylboronic acid (2.36 g, 15.11 mmol), Pd(PPh3)4 (0.067 g, 0.058 mmol) and 2M Na2CO3 aqueous solution (8.0 mL) are refluxed in 1,2-dimethmethane (70 mL) for 2.5 h under N2 atomosphere. After cooling to room temperature, the reaction mixture is diluted with EtOAc and washed with 1M HCl and brine. The organic layer is dried over Na2SO4 and concentrated. The residue is purified by flash column chromatography (silica gel, DCM/10% MeOH in DCM=100:0 to 0:100) to give (R)-2-tert-butoxycarbonylamino-3-(3′-chloro-biphenyl-4-yl)-propionic acid (containing impurities). HPLC retention time=1.56 minutes (condition A): MS (m+1)=376.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:23])[N:7]=1)=[O:5])[CH3:2].Br[C:25]1[CH:26]=[N:27][N:28]([CH2:30][CH2:31][CH3:32])[CH:29]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:25]3[CH:26]=[N:27][N:28]([CH2:30][CH2:31][CH3:32])[CH:29]=3)[C:14]=2[CH3:23])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCCn1cc(Br)cn1
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)n1
Product: CCCn1cc(-n2c(C)c(Sc3cccc(C(=O)OCC)n3)c3ccc(Cl)cc32)cn1

Procedure:
Prepared according to the procedure described in Example 9, Step 4, using the following starting materials: 6-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-pyridine-2-carboxylic acid ethyl ester and 4-bromo-1-propyl-1H-pyrazole.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[O:15][CH:16]=[CH:17][CH:18]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pt]=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]1[CH2:18][CH2:17][CH2:16][O:15]1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccco1)C(=O)O
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCO1)C(=O)O
Yield: 91.2 %

Procedure:
In a Parr shaker bottle was placed (S)-2-t-butoxycarbonylamino-3-furan-2-yl-propionic acid (3.88 g, 15.22 mmol), platinum oxide (200 mg) and ethyl acetate (40 mL). The bottle was then placed on the Parr shaker at 50 psi of hydrogen pressure for 5 h. The reaction was then filtered through a pad of celite and washed with ethyl acetate and concentrated in vacuo to afford (S)-2-t-butoxycarbonylamino-3-(tetrahydro-furan-2-yl)-propionic acid (3.60 g, 91%) as a yellow oil: LR-ES-MS m/z calculated for C12H21NO5 [M]+ 259, observed [M+H]+ 260.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15][N:6]3[C:7]=2[C:3]=1[C:4]1[CH2:18][CH2:17][CH2:16][C:5]=13.C([BH3-])#N.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15][N:6]3[C:7]=2[C:3]=1[CH:4]1[CH2:18][CH2:17][CH2:16][CH:5]13
Reactant: Clc1ccc2c3c1c1c(n3CCNCC2)CCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: Clc1ccc2c3c1C1CCCC1N3CCNCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.6 %

Procedure:
To a solution of 8-chloro-2,3,4,5,10,11-hexahydro-1H,9H-cyclopenta[b][1,4]diazocino[7,8,1-hi]indole (0.60 g, 2.30 mmole) in acetic acid (100 mL) was added sodium cyanoborohydride (0.60 g, 9.07 mmole) and the reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was diluted with methylene chloride (200 mL) and washed with aqueous sodium hydroxide (1N, 150 mL), saturated sodium chloride (150 mL), dried (sodium sulfate) and concentrated. Purification by flash column chromatography (silica gel, 1.5% to 5% methanol in methylene chloride) provided 0.30 g of the title compound as a white solid. 60 mg of this compound was further treated with one equivalent of fumaric acid in ethanol to form a fumarate salt, mp 169-170° C. MS (ES) m/z 263.1 ([M+H]+), MS (ES) m/z 304.1 ([M+ACN+H]+).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.Cl[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[I:1][C:2]1[CH:3]=[N:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=2)[CH:6]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Ic1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-n2cc(I)cn2)nc1
Temperature: 80 °C
Yield: 100.1 %

Procedure:
A mixture of the 4-iodo-1H-pyrazole (4.59 g, 23.7 mmol) and 2-chloro-5-nitropyridine (3.75 g, 23.7 mmol) in N,N-dimethylformamide (11.8 ml) was treated with potassium carbonate (3.76 g, 27.2 mmol). The mixture was heated to 80° C. for 12 hours. The reaction mixture was diluted with excess water resulting in the precipitation of a solid that was collected by filtration. Further drying in vacuo afforded the product (7.5 g, 100%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 9.27 (d, J=2.3 Hz, 1H), 8.70 (s, 1H), 8.62 (dd, J=9.0, 2.5 Hz, 1H), 8.12 (d, J=9.0 Hz, 1H), 7.80 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([CH2:12][CH2:13][CH2:14][N:8]3[CH2:7][C@@H:6]3[CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17][C@@H:5]23)[CH:11]=1.CC(C)([O-])C.[Na+].Br[C:32]1[CH:33]=[C:34]([C:39]([F:42])([F:41])[F:40])[CH:35]=[CH:36][C:37]=1[Cl:38].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.NC1C=CC=CC=1>C1(C)C=CC=CC=1.CCOCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:38][C:37]1[CH:32]=[CH:33][C:34]([C:39]([F:40])([F:41])[F:42])=[CH:35][C:36]=1[NH:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([CH2:12][CH2:13][CH2:14][N:8]3[CH2:7][C@@H:6]3[CH2:15][NH:16][CH2:17][C@@H:5]23)[CH:11]=1
Reactant: FC(F)(F)c1ccc(Cl)c(Br)c1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CN3CCCc4cc(N)cc(c43)[C@@H]2C1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: Nc1ccccc1
Product: FC(F)(F)c1ccc(Cl)c(Nc2cc3c4c(c2)[C@@H]2CNC[C@H]2CN4CCC3)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 16.9 %

Procedure:
A solution of (±)-trans tert-butyl 2-amino-5,6,8a,9,11,11a-hexahydro-4H-pyrido[3,2,1-ij]pyrrolo[3,4-c]quinoline-10(8H)-carboxylate (100 mg, 0.304 mmol), sodium tert-butoxide (58 mg, 0.608 mmol), and 3-bromo-4-chlorobenzotrifluoride (95 mg, 0.365 mmol) in anhydrous toluene (6 mL) were degassed with argon at 85° C. for 15 min. The solution was cooled slightly, and a mixture of solid Pd2(dba)3 (5.6 mg, 6.1 μmol) and solid BINAP (11 mg, μmol) were added to the solution. The flask was capped under a positive pressure of Ar and heating was continued at 85° C. overnight. After the reaction was complete as evidenced by the lack of starting aniline by TLC analysis, the solution was cooled and diluted with ether. The red slurry was filtered through Celite 521® and concentrated under reduced pressure to give crude N-Boc protected biarylamine as a red oil (101 mg). The crude product was purified by silica gel chromatography on the Isco Combi-flash unit using a 10-g RediSep cartridge and a gradient elution of ethyl acetate in hexanes from 5% to 75%. A CH2Cl2 (4 mL) solution of the N-Boc protected product was cooled to 0° C. and treated with trifluoroacetic acid (TFA) (250 μL). The disappearance of N-Boc protected material was followed by TLC analysis (1:1 hexanes:EtOAc) over 8 h. The TFA solution was then basified with 3 N NaOH to pH >12 and extracted with CH2Cl2. Evaporations of the extracts gave 21 mg of the title compound of EXAMPLE 72 as an off-white powder. 1H NMR (500 MHz, CDCl3) δ 1.26 (br s, 1H), 1.95 (m, 1H), 2.0 (m, 1H), 2.15 (m, 1H), 2.74 (m, 4H), 2.90 (t, 1H, J=1.9 Hz), 3.29 (m, 1H), 3.33 (m, 4H), 3.51 (t, 1H, J=1.9 Hz), 5.96 (s, 1H), 6.52 (s, 1H), 6.69 (s, 1H), 6.86 (m, 1H), 7.07 (s, 1H), 7.34 (m, 1H). LRMS (ES)+: 408 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([C:13]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[NH:23][N:24]=[C:25]([C:26](OC)=[O:27])[C:15]=3[N:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O>O1CCCC1>[C:7]1([C:13]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[NH:23][N:24]=[C:25]([CH2:26][OH:27])[C:15]=3[N:14]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)c1n[nH]c2c1nc(-c1ccccc1)c1ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1n[nH]c2c1nc(-c1ccccc1)c1ccccc12
Reaction time: 0.17 h

Procedure:
7.5 mg of lithium aluminum hydride were initially introduced into 1.5 ml of tetrahydrofuran and the mixture was stirred for 10 min. 6 mg of methyl 5-phenyl-1H-pyrazolo[4,3-c]isoquinoline-3-carboxylate (61) in 1.5 ml of tetrahydrofuran were then added dropwise. The mixture was stirred at 80° C. for 3 h, after which water was added and the whole was extracted with methylene chloride. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure, and the residue was purified by means of HPLC (Merk-Hibar-Lichrospher 100-RP-18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid) 80/20→10/90). The following was obtained: 62.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[N+:40]([O-])=O)=[C:4]([NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH:5]=[C:6]([CH:8]2[C:17]3[C:16](=[O:18])[CH2:15][CH:14]([CH2:19][CH2:20][CH3:21])[CH2:13][C:12]=3[NH:11][C:10]([CH3:22])=[C:9]2[C:23]#[N:24])[CH:7]=1.C(O)(=O)C>C1COCC1.[Zn]>[NH2:40][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[CH2:33][NH:32][C:3]1[C:2]([Br:1])=[CH:7][C:6]([CH:8]2[C:17]3[C:16](=[O:18])[CH2:15][CH:14]([CH2:19][CH2:20][CH3:21])[CH2:13][C:12]=3[NH:11][C:10]([CH3:22])=[C:9]2[C:23]#[N:24])=[CH:5][C:4]=1[NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:27])=[O:28]
Reactant: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(NCc2ccccc2[N+](=O)[O-])c(NS(=O)(=O)CCC)c1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(NCc2ccccc2N)c(NS(=O)(=O)CCC)c1
Reaction time: 3 h

Procedure:
Propane-1-sulfonic acid [3-bromo-5-(3-cyano-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydro-quinolin-4-yl)-2-(2-nitro-benzylamino)-phenyl]-amide (1.21 g) and acetic acid (1.6 ml) were dissolved in THF (150 ml). Zinc dust (2.32 g) was added under vigorous stirring. After 3 h, the mixture was filtered, diluted with ethyl acetate and washed with sat. aq. NaHCO3. The residue was purified by chromatography on silicagel in heptane/ethyl acetate 1/0→0/1 (v/v) as eluent.
Reaction SMILES: C[O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[O:24][C:25]=1[CH3:26]>>[Cl:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:23]1[O:24][C:25]([CH3:26])=[C:21]([CH2:20][N:11]2[C:12]3[C:8](=[CH:7][C:6]([CH2:5][C@H:4]([O:15][CH2:16][CH3:17])[C:3]([OH:2])=[O:18])=[CH:14][CH:13]=3)[CH:9]=[CH:10]2)[N:22]=1
Reactant: Cc1oc(-c2ccccc2Cl)nc1CCl
Reactant: CCO[C@@H](Cc1ccc2[nH]ccc2c1)C(=O)OC
Product: CCO[C@@H](Cc1ccc2c(ccn2Cc2nc(-c3ccccc3Cl)oc2C)c1)C(=O)O
Yield: 56 %

Procedure:
Starting from (S)-2-ethoxy-3-(1H-indol-5-yl)-propionic acid methyl ester and 4-chloromethyl-2-(2-chloro-phenyl)-5-methyl-oxazole, the title compound was obtained in 56% yield as a pale brown amorphous solid. MS: (M−H)− 437.2.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]3[CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:12]=3[NH:13][N:14]=2)=[CH:6][CH:5]=1)([O-])=O.C([O-])=O.[NH4+]>[Pd]>[NH:13]1[C:12]2[C:15]3[C:20]([CH2:21][C:11]=2[C:10]([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)=[N:14]1)=[CH:19][CH:18]=[CH:17][CH:16]=3
Reactant: O=[N+]([O-])c1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Product: Nc1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Temperature: 70 °C

Procedure:
The product from Example 12 (3.0 g) was suspended in industrial methylated spirit (200 ml) and 5% palladium on charcoal (250 mg) was added followed by ammonium formate (2.05 g). The mixture was stirred and heated at 70° C. for 3 hours and then cooled to ambient temperature and then filtered. The filtrate was concentrated under reduced pressure and triturated with dichloromethane to give 4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)aniline, m.p. 253-254° C.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([O:20][CH2:21][CH:22]=[C:23]([Cl:25])[Cl:24])[CH:17]=[C:16]([Cl:26])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][C:12](=[N:14][OH:15])[CH3:13].S(=O)(=O)(O)O.[CH2:32]=[C:33]([CH3:35])[CH3:34].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[C:33]([O:15][N:14]=[C:12]([CH2:11][O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][O:4][C:3]1[C:2]([Cl:1])=[CH:19][C:18]([O:20][CH2:21][CH:22]=[C:23]([Cl:25])[Cl:24])=[CH:17][C:16]=1[Cl:26])[CH3:13])([CH3:35])([CH3:34])[CH3:32]
Reactant: CC(COCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)=NO
Reactant: C=C(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(COCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)=NOC(C)(C)C

Procedure:
First, 0.45 g of 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentyloxyacetone oxime, 0.3 ml of concentrated sulfuric acid, and 10 ml of toluene are placed in a reaction vessel, into which isobutene gas is blown with stirring under ice cooling, and the mixture is further stirred at room temperature. After completion of the reaction, the reaction mixture is slowly poured into a saturated aqueous sodium hydrogencarbonate solution, and extracted twice with diethyl ether. The diethyl ether layers are combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product is subjected to silica gel chromatography, which affords 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentyloxyacetone O-tert-butyloxime.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][C@H:8]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([N:21]([CH3:23])[CH3:22])=[CH:17][C:16]=1[O:24][CH2:25][CH2:26][C:27]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:28]=1[CH:29]=[CH:30][CH:31]=[N:32]2)(=[O:14])=[O:13])[CH:9]=[O:10])(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:23][N:21]([CH3:22])[C:18]1[CH:19]=[CH:20][C:15]([S:12]([NH:11][C@H:8]([CH:9]=[O:10])[CH2:7][C:6]([OH:37])=[O:5])(=[O:13])=[O:14])=[C:16]([O:24][CH2:25][CH2:26][C:27]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:28]=2[CH:29]=[CH:30][CH:31]=[N:32]3)[CH:17]=1
Reactant: CN(C)c1ccc(S(=O)(=O)N[C@H](C=O)CC(=O)OC(C)(C)C)c(OCCc2cccc3ncccc23)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1ccc(S(=O)(=O)N[C@H](C=O)CC(=O)O)c(OCCc2cccc3ncccc23)c1
Yield: 91.9 %

Procedure:
A solution of (S)-3-[4-dimethylamino-2-(2-quinolin-5-yl-ethoxy)-benzenesulfonylamino]-4-oxo-butyric acid tert-butyl ester (0.33 g, 0.60 mmol) in TFA (2 mL) and CH2Cl2 (20 mL) was stirred for 3 h. After the solvent was removed under vacuum, the residue was subjected to preparative reverse-phase HPLC (VYDAC, C18) using a linear gradient of (A) water containing 0.1% TFA and (B) acetonitrile containing 0.1% TFA (20-65% B, in 120 min) at a flow rate of 15 mL/min. Fractions containing the major peak were pooled and lyophilized to yield 0.260 g (92%) of (S)-3-[4-dimethylamino-2-(2-quinolin-5-yl-ethoxy)-benzenesulfonylamino]-4-oxo-butyric acid. MS (APCI) m/z 470.1 (M−1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[C:8]([CH:11]1C(=O)OC(C)(C)[O:13][C:12]1=O)(=[O:10])[CH3:9]>C1C=CC=CC=1>[O:10]=[C:8]([CH3:9])[CH2:11][C:12]([O:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[O:13]
Reactant: OC1CCOCC1
Reactant: CC(=O)C1C(=O)OC(C)(C)OC1=O
Solvent: c1ccccc1
Product: CC(=O)CC(=O)OC1CCOCC1

Procedure:
A solution of tetrahydro-4H-pyran-4-ol (1.6 ml, 16.8 mmoles) and 5-acetyl-2,2-dimethyl-1,3-dioxane-4,6-dione (3.0 g, 16.1 mmoles) in dry benzene (50 ml) was heated under reflux for 4 hours. The solvent was removed in vacuo and the residue distilled at 146°-151°/14 mm Hg to afford the title product as a colourless oil, 2.84 g. Nmr (CDCl3)δ5.1 (m,H), 3.5 (s,3H).