Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([CH3:5])(=[O:4])=[O:3].C([Li])CCC.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1/[CH:18]=[N:19]/[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH2:1][S:2]([CH3:5])(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)/N=C/c1ccccc1Cl
Reactant: CS(C)(=O)=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(CS(C)(=O)=O)c1ccccc1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
A solution of 1 g (10.6 mmol) of (methylsulphonyl)methane in 30 ml of THF was cooled to −78° C. and admixed slowly with 6.65 ml of n-butyllithium solution (1.6M in hexane, 10.6 mmol). After 30 min at −78° C., the suspension obtained was added to a solution, cooled to −78° C. beforehand, of 850 mg (3.55 mmol) of the compound from Example 111A in 20 ml of THF. The reaction mixture was stirred at −78° C. for a further 30 min and then slowly warmed to RT. After 30 min, it was cooled to −20° C. again and the reaction was halted by addition of 20 ml of 10% strength aqueous ammonium chloride solution. The mixture was diluted with ethyl acetate. The organic phase was separated and washed twice with water and once with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulphate, filtered and freed from the solvent on a rotary evaporator. The residue was stirred with 10 ml of methanol/water 10:1 and the solid was filtered off with suction. The slightly yellowish solid was stirred with 20 ml of pentane/isopropanol 5:1, then filtered off with suction again. Drying in an HV gave 800 mg (55% of theory) of the title compound (82% purity according to LC/MS).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:9][CH2:8][NH:7][C:5](=[O:6])[CH2:4]1.[C:10]([S:13][CH2:14][C@@H:15]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26])[C:16](O)=[O:17])(=[O:12])[CH3:11].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:10]([S:13][CH2:14][C@@H:15]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26])[C:16]([NH:2][C@H:3]1[CH2:9][CH2:8][NH:7][C:5](=[O:6])[CH2:4]1)=[O:17])(=[O:12])[CH3:11]
Reactant: CC(=O)SC[C@@H](Cc1ccccc1C)C(=O)O
Reactant: N[C@H]1CCNC(=O)C1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)SC[C@@H](Cc1ccccc1C)C(=O)N[C@H]1CCNC(=O)C1
Reaction time: 18 h

Procedure:
Prepare 3(S)-amino-δ-valerolactam hydrochloride according to the procedure of J. Chem. Soc. Dalton Trans., 1987, p. 1127. Combine this lactam (0.29 g,2.0 mmol), 2(S)-acetylthiomethyl-3-(2-methylphenyl)propionic acid (0.50 g,2.0 mmol), triethylamine (0.03 g,3.0 mmol), and HOBT (0.30 g,2.0 mmol) in DMF (20 ml). Add DEC (0.38 g,2.0 mmol). Stir 18 hr, partition between EtOAc and H2O, dry and concentrate. Chromatograph on silica, eluting with 3% MeOH/CH2Cl2 to obtain the title compound as a foam, [α]D26 =-28.6° (EtOH)
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:12]=3[C:13]=2[CH3:14])O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:22])=O.C(=O)([O-])O.[Na+]>N1C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:22][CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[O:10][C:11]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:12]=2[C:13]=1[CH3:14]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc2oc(C(O)C3CCCCC3)c(C)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1ccc2oc(C(Cl)C3CCCCC3)c(C)c2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 93 %

Procedure:
To a solution (20 mL) of cyclohexyl(3,5-dimethyl-1-benzofuran-2-yl)methanol (1.13 g) synthesized above in toluene pyridine (424 μL) and thionyl chloride (382 μL) were added, and the mixture was stirred at room temperature for 5 hr. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title object compound (1.12 g, 93%) as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][CH2:8][C:9]1[N:10]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:11](=[O:35])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:16][C:15]([O:27]CC1C=CC=CC=1)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.C(O)C.[C].[Pd]>[C:1]([O:5][C:6](=[O:40])[NH:7][CH2:8][C:9]1[N:10]([CH2:36][CH:37]([CH3:38])[CH3:39])[C:11](=[O:35])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][C:23]([F:26])([F:24])[F:25])=[CH:16][C:15]([OH:27])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(OCCCC(F)(F)F)c2cc(OCc3ccccc3)ccc2c1=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(OCCCC(F)(F)F)c2cc(O)ccc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
A suspension of tert-butyl[6-benzyloxy-2-isobutyl-1-oxo-4-(4,4,4-trifluorobutoxy)-1,2-dihydro-3-isoquinolinyl]methylcarbamate (3.09 g, 5.5 mmol) and 5% palladium carbon (1.0 g) in tetrahydrofuran (20 mL) and ethanol (20 mL) was stirred under a hydrogen atmosphere at room temperature for 2 h. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl[6-hydroxy-2-isobutyl-1-oxo-4-(4,4,4-trifluorobutoxy)-1,2-dihydro-3-isoquinolinyl]methylcarbamate (2.48 g, 95.4%) as crystals.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:16][OH:17])[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2.C(N(CC)CC)C.[CH3:25][Si:26](Cl)([CH3:28])[CH3:27]>ClCCl>[CH3:25][Si:26]([CH3:28])([CH3:27])[O:1][CH2:2][C:3]1([CH2:16][O:17][Si:26]([CH3:28])([CH3:27])[CH3:25])[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: C[Si](C)(C)Cl
Reactant: OCC1(CO)c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[Si](C)(C)OCC1(CO[Si](C)(C)C)c2ccccc2-c2ccccc21
Temperature: 0 °C
Yield: 88 %

Procedure:
1 g of 9,9-bis(hydroxymethyl)fluorene (4.4 mmol) was admixed with 20 ml of dichloromethane. The mixture was cooled in ice-water bath, and 1.9 ml of triethyl amine (13.2 mmol) was added thereto. Then 1.4 ml of trimethylsilyl chloride (11 mmol) was added drop-wise, and the mixture was stirred in ice-water bath for further 2 hours. The reaction mixture was washed with water, and the organic layer separated was dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated to give 1.14 g of concentrate (yield 88%). MS (EI) m/e: 370(M+).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:12]=O)=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:14]([NH2:16])[CH3:15].C(O)(=O)C.C([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>CO>[Br:1][C:2]1[C:3]([CH2:12][NH:16][CH2:14][CH3:15])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CCN
Reactant: O=Cc1nc2ccccc2cc1Br
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCNCc1nc2ccccc2cc1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-Bromo-quinoline-2-carbaldehyde (3.34 g, 16.3 mmol), ethylamine (2M in MeOH; 9.78 mL, 19.6 mmol), and acetic acid (1.02 mL, 17.8 mmol) were combined in MeOH (25 mL) and stirred at 0° C. for 30 minutes. Sodium cyanoborohydride (1.53 g, 24.5 mmol) was added, and the reaction was monitored by analytical LCMS. The mixture was worked-up with saturated aqueous NaHCO3 and extracted with CH2Cl2, and the residue was purified by silica gel chromatography (0-5% MeOH in CH2Cl2) to give the title compound.
Reaction SMILES: [OH:1]N1C(=O)CCC1=O.[CH2:9]1[CH2:14][CH2:13][CH:12]([N:15]=[C:16]=[N:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:11][CH2:10]1>CN(C1C=CN=CC=1)C.C(#N)C>[C:16]([NH:15][CH:12]1[CH2:11][CH2:10][CH2:9][CH2:14][CH2:13]1)([NH:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:1]
Reactant: O=C1CCC(=O)N1O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 5 h

Procedure:
To a cooled (0 to 5° C.) solution of DPGS-ω-carboxy-PEG (200 mg) from Step B, N-hydroxysuccinimide (6 mg), DMAP (2 mg) and acetonitrile (40 mL) in a 250 mL round bottom flask was added dropwise a solution of DCC (12 mg) in acetonitrile (10 mL). The resulting mixture was stirred for 5 hours and the white solid which formed (dicyclohexylurea) was removed by filtration. The filtrate was concentrated in vacuo to afford 200 mg of DPGS-ω-carboxy-PEG-succinimide as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[N+:15]([C:18]1[CH:27]=[CH:26][C:21]([O:22][CH2:23][CH2:24]Br)=[CH:20][CH:19]=1)([O-:17])=[O:16].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([CH2:24][CH2:23][O:22][C:21]3[CH:20]=[CH:19][C:18]([N+:15]([O-:17])=[O:16])=[CH:27][CH:26]=3)[CH2:9][CH2:8]2)=[CH:13][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(OCCBr)cc1
Reactant: Cc1ccc(CC2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1ccc(CC2CCN(CCOc3ccc([N+](=O)[O-])cc3)CC2)cc1
Yield: 95 %

Procedure:
From a mixture of 4-(4-methylbenzyl)piperidine (2.27 g, 12.0 mmol), 2-(4-nitrophenoxy)ethyl bromide (1.42 g, 6.0 mmol), K2CO3 (130 mg) and KI (120 mg) in toluene (25 mL) was obtained 2.02 g (100%) of the title compound as a viscous oil. 1H NMR (CDCl3): 1.25-1.38 (m, 2H), 1.46-1.56 (m, 1H), 1.63-1.67 (m, 2H), 2.01-2.09 (m, 2H), 2.314 (s, 3H), 2.498 (d, 2H), J=7), 2.797 (t, 2H), J=6), 2.94-2.98 (m, 2H), 4.171 (t, 21, J=6), 6.950 (d, 26, J=9), 7.059 (AB, 4H, J=8), 8.191 (d, 2H, J=9). The hydrochloride, mp. 180-1° C.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[NH2:14].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[Br:1][C:8]1[CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[C:5]([NH2:14])=[C:4]([CH3:3])[CH:9]=1
Reactant: Cc1cccc(C(F)(F)F)c1N
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1cc(Br)cc(C(F)(F)F)c1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under a nitrogen atmosphere a solution of 11.0 mL (214 mmol) bromine in 100 mL chloroform was added dropwise to a solution of 35.8 g (204 mmol) 2-methyl-6-trifluoromethyl-phenylamine in 350 mL chloroform and after the end of the addition the reaction mixture was stirred for 3 h at RT. Saturated NaHCO3 solution was added with stirring, the mixture was stirred for a further 20 min at RT, the organic phase was separated off and dried over Na2SO4. After the desiccant and solvent had been eliminated the product was obtained as an oil, which was further reacted without purification.
Reaction SMILES: [CH:1]1[C:6]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[O:9])=[CH:5][CH:4]=[C:3]([Cl:18])[CH:2]=1.[OH-].[Na+].Cl[O-].[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.CO.O>[Cl:18][C:3]1[CH:2]=[CH:1][C:6]2[NH:7][C:8](=[O:9])[N:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[C:5]=2[CH:4]=1
Reactant: O=C(Nc1ccc(Cl)cc1)Nc1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: O=c1[nH]c2ccc(Cl)cc2n1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4,4'-Dichlorocarbanilide (14.1 g, 0.05 mole) and tetra-n-butyl ammonium chloride (0.7 g) were dissolved in a mixture of methylene chloride (150 ml) and methanol (150 ml). To this solution was added a solution (20 ml) of sodium hydroxide (4 g) in water and the resulting biphasic mixture was stirred vigorously before the dropwise addition of a solution of sodium hypochlorite (100 ml, 1 N in 0.1 molar sodium hydroxide) over 15 minutes. A small exotherm produced a final temperature of 33° C. The reaction mixture was then vigorously stirred for 4 hours at room temperature. Solids were removed by filtration and the biphasic system was then evaporated to a volume of about 100 ml, acidified with hydrochloric acid, and then diluted with water (500 ml). The tilted product was then recovered by filtration, dried at 80° C., and identified by infrared spectra. The product was recovered in a yield of better than 99 percent of theoretical and melted at 239° C. (recrystallized from toluene).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[CH3:11][O:12][C:13]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[CH2:20][CH2:19][C@H:18]2[NH2:24])=[O:14].[F:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>ClCCl>[F:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:24][C@H:18]2[C:17]3[C:21](=[CH:22][CH:23]=[C:15]([C:13]([O:12][CH3:11])=[O:14])[CH:16]=3)[CH2:20][CH2:19]2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: COC(=O)c1ccc2c(c1)[C@H](N)CC2
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)[C@H](NS(=O)(=O)c1ccc(F)cc1)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
DIPEA (447 μl, 2.634 mmol, 3 eq) was added at 0° C. to a solution of (3R)-3-amino-2,3-dihydro-1H-indene-5-carboxylic acid methyl ester hydrochloride (A-01) (0.878 mmol, 1 eq) in dichloromethane (10 ml). A solution of 4-fluorobenzene-1-sulfonyl chloride (170 mg, 0.878 mmol, 1 eq) dissolved in dichloromethane (6 ml) was added dropwise and the mixture was stirred for 16 h at RT. After monitoring by thin-layer chromatography. the reaction solution was concentrated under reduced pressure and the residue was taken up in ethyl acetate, washed with 10% ammonium chloride solution, sodium hydrogen carbonate solution and sat. NaCl solution (in each case 1x), dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (silica gel, ethyl acetate:cyclohexane 1:5). Yield: 88%
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]=[O:30].O>O1CCCC1>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:29]([OH:30])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=2)=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(Br)cc1
Reactant: O=Cc1ccccn1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(O)c2ccccn2)cc1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
500 mg of the compound [1-1] was dissolved in 10 mL of tetrahydrofuran and cooled to −78° C. Thereafter, 2.33 mL of n-butyllithium (1.57M hexane solution) was added thereto. After the 1 hour stirring at the same temperature, 193 μL of picolinaldehyde was added to the resulting white suspension, and the suspension was stirred overnight while heating back to room temperature. 50 mL of water was added to the reaction mixture, and the mixture was extracted with 200 mL of ethyl acetate. The obtained organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Then, the insolubles were filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=100/0-30/70) to obtain 212 mg of tert-butyl((1S)-1-{4-[hydroxy (pyridin-2-yl)methyl]phenyl}ethyl)carbamate [12-1] (hereinafter, referred to as the compound [12-1]) as a light brown oily product.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:7][CH:8]=1>ClCCl.[O-2].[O-2].[Mn+4]>[OH:12][CH2:11][CH2:10][CH2:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH:2]=[O:1]
Reactant: OCCCc1cccc(CO)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1cccc(CCCO)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Manganese dioxide (2.07 g) was added to a solution of 3-(3-(hydroxymethyl)phenyl)propan-1-ol [Aromatic Intermediate 18, step b] (0.40 g) in dichloromethane (20 mL) and the mixture stirred at ambient temperature for 18 hours. The mixture was filtered through Celite and concentrated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 40%, 50% and 60% ethyl acetate in isohexane. Fractions containing the product were evaporated to dryness to afford the titled compound as a colourless oil. Yield 0.21 g.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[S:4][CH:5]=[C:6]([C:8](=[O:11])[CH2:9]Br)[N:7]=1.O[CH2:15][CH2:16][NH:17][CH:18]([CH3:32])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([NH:30][CH3:31])=[O:29])=[CH:22][CH:21]=1.C(=O)([O-])O.[K+].[BH4-].[Na+]>CC(C)=O.FC(F)(F)C(O)=O>[CH3:31][NH:30][C:28]([CH2:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][CH:18]([N:17]2[CH2:16][CH2:15][O:11][CH:8]([C:6]3[N:7]=[C:3]([C:2]([F:13])([F:12])[F:1])[S:4][CH:5]=3)[CH2:9]2)[CH3:32])=[CH:25][CH:24]=1)=[O:29]
Reactant: CNC(=O)COc1ccc(CC(C)NCCO)cc1
Reactant: O=C(CBr)c1csc(C(F)(F)F)n1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)COc1ccc(CC(C)N2CCOC(c3csc(C(F)(F)F)n3)C2)cc1

Procedure:
Prepared by analogy to Example 32 by reaction of 2-trifluoromethyl-4-bromoacetyl-thiazole with N-(2-hydroxyethyl)-2-(4-methylaminocarbonylmethoxyphenyl)-1-methylethylamine and potassium hydrogen carbonate in acetone at room temperature, followed by reduction with sodium borohydride in trifluoroacetic acid. The resulting crude product is purified on a silica gel column using toluene/ethyl acetate=2:8 as eluant.
Reaction SMILES: [O:1]([C:8]1[C:17]2[N:18]=[CH:19][N:20]([CH2:21][CH2:22][O:23][CH2:24][C:25]#[CH:26])[C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[N:30](C)[CH3:31]>>[CH3:31][N:30]1[C:29]2[C:28](=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:26]=[C:25]1[CH2:24][O:23][CH2:22][CH2:21][N:20]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:17]=2[N:18]=[CH:19]1
Reactant: C#CCOCCn1cnc2c(Oc3ccccc3)nc3ccccc3c21
Reactant: CN(C)c1ccccc1I
Product: Cn1c(COCCn2cnc3c(Oc4ccccc4)nc4ccccc4c32)cc2ccccc21
Yield: 24.2 %

Procedure:
Using the general method of Example 30 Part D, 4-phenoxy-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-c]quinoline (3.16 g, 9.20 mmol) was reacted with 2-iodo-N,N-dimethylaniline (2.5 g, 10.1 mmol) to provide a 1.0 g of 1-{2-[(1-methyl-1H-indol-2-yl)methoxy]ethyl }-4-phenoxy-1H-imidazo[4,5-c]quinoline as a pale yellow crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-])=O.C(O)(=O)C.C(N)=N.[H][H]>[Ni].CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH2:9]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Agent: [Ni]
Agent: N=CN
Solvent: CO
Solvent: CC(=O)O
Product: Nc1cc(Cl)ccc1Cl
Reaction time: 1 h

Procedure:
48.0 g of 1,4-dichloro-2-nitrobenzene, 2 g of Raney nickel (60%, aqueous), 1.5 g of formamidine acetate and 120 ml of methanol are introduced in an autoclave equipped with gas introduction stirrer. The air in the autoclave is then displaced by nitrogen and then by hydrogen. The hydrogenation is carried out at a pressure of 12 bar and a temperature of 80° C. The hydrogenation time is 1 hour. 1,4-Dichloro-2-aminobenzene, 99.6% pure (analysed by gas chromatography), is obtained in quantitative yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:11][S:12][C:13]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:14]=2[NH2:15])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[CH3:21][C:22]([CH3:27])([CH3:26])[C:23](Cl)=[O:24].C(O)C(N)(CO)CO.Cl>C(N(C(C)C)CC)(C)C.CN(C1C=CN=CC=1)C.ClCCl>[Cl:1][C:2]1[C:3]([CH2:11][S:12][C:13]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:14]=2[NH:15][C:23](=[O:24])[C:22]([CH3:27])([CH3:26])[CH3:21])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: Cc1ccc(SCc2cc3c(cc2Cl)OCO3)c(N)c1
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: NC(CO)(CO)CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(SCc2cc3c(cc2Cl)OCO3)c(NC(=O)C(C)(C)C)c1
Reaction time: 8 h

Procedure:
The material from step 2 was suspended in a mixture of diisopropyl ethyl amine (0.15 mL), PS-DMAP resin (50 mg), 2,2-dimethylpropanoyl chloride (0.1 mL) and dichloromethane (7 mL). The reaction was agitated overnight and then treated with PS-Trisamine resin and agitated a further 24 h. The reaction was applied to an Extrelut QE column prepped with 1N HCl, the organic was collected and evaporated under a stream of nitrogen. The residue was chromatographed on silica to afford the title product. MS (ESI+) for C20H22ClNO3S m/z 392 (M+H)+.
Reaction SMILES: C(O[CH:5]1[CH2:9][N:8]([C:10]([CH3:18])([CH3:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7](=[O:19])[CH:6]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=O)C.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[CH3:18][C:10]([N:8]1[CH2:9][CH:5]=[C:6]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:7]1=[O:19])([CH3:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)OC1CN(C(C)(C)c2ccccc2)C(=O)C1c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CC(C)(c1ccccc1)N1CC=C(c2ccccc2)C1=O
Yield: 72.1 %

Procedure:
0.7 g (2 mmol) of 4-acetoxy-1-(α,α-dimethylbenzyl)-3-phenyl-2-pyrrolidinone prepared by the method of Reference Example 15, was dissolved in 30 ml of toluene, and 0.36 g (2.4 mmol) of DBU was added thereto. The mixture was refluxed under heating for five minutes. The reaction solution was cooled, and toluene was added. The toluene solution was thoroughly washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The crude product thereby obtained was purified by silica gel column chromatography to obtain 0.4 g (yield: 73%) of the desired compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].CC1(C)C(C)(C)OB([C:29]2[CH:30]=[C:31]3[C:35](=[CH:36][CH:37]=2)[NH:34][N:33]=[C:32]3[NH2:38])O1>>[NH2:38][C:32]1[C:31]2[C:35](=[CH:36][CH:37]=[C:29]([C:2]3[CH:3]=[CH:4][N:5]4[C:10]([C:11]=3[CH3:12])=[C:9]([CH:13]3[CH2:15][CH2:14]3)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]4=[O:20])[CH:30]=2)[NH:34][N:33]=1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: CC1(C)OB(c2ccc3[nH]nc(N)c3c2)OC1(C)C
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc4[nH]nc(N)c4c3)ccn2c1=O
Yield: 24.2 %

Procedure:
Methyl 8-(3-amino-1H-indazol-5-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-amine (106.4 mg, 0.41 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (32 mg, 42%).