Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:11]2[C:12]3[C:8]([CH2:9][CH2:10]2)=[CH:7][CH:6]=[CH:5][C:4]=3[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([OH:21])C.S(=O)(=O)(O)O.[OH-].[Na+]>O>[C:2]([CH:3]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH2:10][CH2:9]2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:21])[CH3:1]
Reactant: Cc1c(-c2ccccc2)c2cccc3c2n1CC3
Reactant: CCO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C(c1ccccc1)c1cccc2c1NCC2

Procedure:
A mixture of 6.0 g. (0.0258 mole) of 1,2-dihydro-4-methyl-5-phenylpyrrolo[3,2,1-hi]indole in 60 ml. of ethanol, 30 ml. of water and 30 ml. of conc. sulfuric acid was refluxed for one hour. The hot solution was poured into a cold concentrated sodium hydroxide solution and the basic solution was extracted several times with ether. The combined ether extracts were washed with water, dried over sodium sulfate and concentrated at reduced pressure. The residual oil solidified and was recrystallized from petroleum ether to give 7-(α-acetylbenzyl) indoline which melted at 55°-56°C.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[CH:44]=[CH:43][C:14]([CH2:15][O:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[C:23]4[N:28]=[C:27]([N:29]5[C:33]([C:34]([F:37])([F:36])[F:35])=[C:32]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:31]=[N:30]5)[CH:26]=[CH:25][CH:24]=4)=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4]CC1>C(O)(=O)C.O>[O:4]=[C:5]1[CH2:6][CH2:7][CH:8]([C:11]2[CH:12]=[CH:13][C:14]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:28]=[C:27]([N:29]4[C:33]([C:34]([F:36])([F:37])[F:35])=[C:32]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:31]=[N:30]4)[CH:26]=[CH:25][CH:24]=3)=[CH:43][CH:44]=2)[CH2:9][CH2:10]1
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3OCc3ccc(C4CCC5(CC4)OCCO5)cc3)n2)c1C(F)(F)F
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3OCc3ccc(C4CCC(=O)CC4)cc3)n2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of the title compound from Example 10 Step D (300 mg, 0.49 mmol) in acetic acid (1.8 mL) and water (0.6 mL) was stirred at 80° C. After 2 h, the mixture was allowed to cool to ambient temperature, then was concentrated in vacuo. The resulting oil was diluted with ether, then was washed successively with water, saturated aqueous sodium bicarbonate, water, and brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 20% EtOAc in hexanes, then 20 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 564.2 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.14 (d, J=8.0 Hz, 1H), 8.12 (s, 1H), 7.96 (dd, J=8.0, 1.5 Hz, 1H), 7.87 (t, J=8.0 Hz, 1H), 7.54 (d, J=7.5 Hz, 1H), 7.40-7.36 (m, 1H), 7.32 (d, J=8.0 Hz, 2H), 7.23 (d, J=8.0 Hz, 2H), 7.12 (t, J=7.5 Hz, 1H), 7.07 (d, J=7.5 Hz, 1H), 5.14 (s, 2H), 4.38 (q, J=7.0 Hz, 2H), 3.04 (dddd, J=12.0, 12.0, 3.5, 3.5 Hz, 1H), 2.54-2.50 (m, 4H), 2.25-2.21 (m, 2H), 1.99-1.91 (m, 2H), 1.39 (t, J=7.0 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.[CH2:18]([O:25][C:26]([NH:28][C@H:29]([C:33](O)=[O:34])[CH:30]([CH3:32])[CH3:31])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(Cl)(Cl)Cl.CO>N1C=CC=CC=1>[CH2:18]([O:25][C:26]([NH:28][C@H:29]([C:33]([O:13][CH2:12][C@H:11]1[O:14][C@@H:7]([N:6]2[CH:15]=[C:2]([F:1])[C:3](=[O:17])[NH:4][C:5]2=[O:16])[CH2:8][C@@H:9]1[OH:10])=[O:34])[CH:30]([CH3:32])[CH3:31])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1F
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: c1ccncc1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1O
Temperature: -10 °C
Reaction time: 48 h
Yield: 43.6 %

Procedure:
In pyridine (20 ml) was dissolved 2.00 g (8.12 m-mol) of 2'-deoxy-5-fluorouridine, and the solution was cooled to -10° C. To this solution was added a solution of 2.05 g (8.16 m-mol) of N-benzyloxycarbonylvaline and 2.45 g (8.11 m-mol) of TPS in pyridine (20 ml), and the mixture was allowed to stand for 2 days under cooling (about 5° C.). The solvent was distilled off under reduced pressure from the reaction mixture and the residue was subjected twice to silica gel column chromatography [column size: 3.0×10 cm; developing solvent: CHCl3 -CH3OH (98:2)] under the same operation conditions whereby 1.70 g (yield: 43.7%) of 5'-O-(N-benzyloxycarbonylvalyl)-2'-deoxy-5-fluorouridine was obtained as amorphous powders.
Reaction SMILES: [OH:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].S(Cl)([Cl:18])=O>O1CCOCC1>[OH:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6]([Cl:18])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(C(=O)O)cc([N+](=O)[O-])c1O
Solvent: C1COCCO1
Product: COc1cc(C(=O)Cl)cc([N+](=O)[O-])c1O
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A suspension of compound of Example 1a (1.0 eq) in dioxane (approx 4.5 vol) was treated with thionyl chloride (1.5 eq) and heated to 80° C. A clear solution formed at approximately 75° C. The mixture was stirred for 3 hours at 80° C. Unreacted thionyl chloride was distilled off and after distillation the residue was cooled to 10° C.
Reaction SMILES: CCN=C=NCCCN(C)C.CN(C=O)C.[C:17]1([N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[C:24]2[C:32](O)=[O:33])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[NH2:35][C@H:36]([C:40]([NH:42][CH:43]([CH:52]([OH:55])[CH2:53][F:54])[CH2:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[O:41])[CH:37]([CH3:39])[CH3:38]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:17]1([N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[C:24]2[C:32]([NH:35][C@H:36]([C:40]([NH:42][CH:43]([CH:52]([OH:55])[CH2:53][F:54])[CH2:44][C:45]([O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:46])=[O:41])[CH:37]([CH3:38])[CH3:39])=[O:33])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)[C@H](N)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF
Reactant: O=C(O)c1cc2ccccc2n1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)c1cc2ccccc2n1-c1ccccc1)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 76.1 %

Procedure:
DMAP (122 mg, 1.0 mmol) and EDAC (249 mg, 1.3 mmol) were added as solids to a DMF solution of 1-phenylindole-2-carboxylic acid (237 mg, 1.0 mmol in 2 ml, DMF), and the resultant reaction mixture was stirred for 10 minutes under a nitrogen atmosphere at 0° C. A methylene chloride solution of N-(valinyl)-3-amino-4-hydroxy-5-fluoropentanoic acid, t-butyl ester (306 mg, 1.0 mmol in 2 mL of methylene chloride) was added to the reaction mixture and the mixture was stirred for 1 hour under a nitrogen atmosphere at 0° C. and 4 hours at room temperature. The yellow reaction mixture was partitioned between ethyl acetate and 5% KHSO4 solution and the aqueous solution was back-extracted with ethyl acetate. The combined ethyl acetate solutions were washed with 5% KHSO4 solution, saturated sodium bicarbonate solution (2×) and brine, dried over sodium sulfate, and concentrated to give a colorless film (0.827 g). The film was subjected to flash chromatography on silica gel with ethyl acetate/hexanes (1:2) to yield the title product as a white foam (400 mg, 78%). TLC: (ethyl acetate/hexanes 1: 1): Rf=0.27.
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[C:5]([C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1)=O.O.O.[NH2:25]N>CO>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:4]2[C:5]([C:7]3[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=3)=[N:25][NH:2][CH:3]=2)=[CH:16][CH:17]=1
Reactant: CSc1ccc(C(=O)C(=CN(C)C)c2ccc(F)cc2)cc1
Reactant: NN
Solvent: CO
Solvent: O
Product: CSc1ccc(-c2n[nH]cc2-c2ccc(F)cc2)cc1
Yield: 90.1 %

Procedure:
The crude ketone from step 1 (23.9 g) was stirred in 500 mL methanol and 100 mL water with 8 mL hydrazine hydrate at reflux under nitrogen for 24 hour. The mixture was cooled, concentrated, diluted with ethyl acetate, washed successively with 1N HCl and brine, dried over MgSO4 and concentrated in vacuo. Recrystallization from ethyl acetate-hexane gave 4-(4-fluorophenyl)-3-[4-(methylthio)phenyl]-1H-pyrazole as a pale yellow solid (16.9 g, 90.1%). Elemental analysis Calc'd for C16H13 N2FS: C, 67.58, H, 4.61, N, 9.85, S, 11.28. Found: C, 67.44, H, 4.76, N, 9.69, S, 11.27.
Reaction SMILES: [CH2:1]([CH:5]([C:7]1[N:8]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:19]=1)[OH:6])[CH2:2][CH2:3][CH3:4].[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[C:24]([O:6][CH:5]([C:7]1[N:8]([CH2:20][CH:21]([CH3:22])[CH3:23])[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:19]=1)[CH2:1][CH2:2][CH2:3][CH3:4])(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCC(O)c1nc2cnc3ccccc3c2n1CC(C)C
Product: CCCCC(OC(C)=O)c1nc2cnc3ccccc3c2n1CC(C)C

Procedure:
Using the general method of Example 46, α-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-methanol (11.6 g; 37 mmol, Example 56) was reacted with acetic anhydride to provide the desired product.
Reaction SMILES: CCO.[C:4]([O:8][C:9]([NH:11][CH2:12][CH:13]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][OH:29])=[CH:22][CH:21]=1)[C:14]([O:16]CC)=[O:15])=[O:10])([CH3:7])([CH3:6])[CH3:5].[Li+].[OH-]>C1COCC1>[C:4]([O:8][C:9]([NH:11][CH2:12][CH:13]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][OH:29])=[CH:22][CH:21]=1)[C:14]([OH:16])=[O:15])=[O:10])([CH3:5])([CH3:7])[CH3:6]
Reactant: CCOC(=O)C(CNC(=O)OC(C)(C)C)Cc1ccc(OCCO)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)NCC(Cc1ccc(OCCO)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a 5:3 (v/v) solution of EtOH and THF (0.2 M) of ethyl 3-[(tert-butoxycarbonyl)amino]-2-[4-(2-hydroxyethoxy)benzyl]propanoate from the previous step (1 eq.) was added LiOH (1 M aqueous solution, 2 eq.). The resulting mixture was stirred at RT for 48 h. Following the removal of the volatiles in vacuo, the resulting residue was partitioned between ether and 1 N aq. NaOH. The aqueous layer was separated and washed further with ether. The aqueous layer was then acidified to pH ˜2 with conc. HCl and the resulting suspension extracted with dichloromethane. The combined dichloromethane extracts was concentrated in vacuo. The crude product thus obtained was recrystallized from EtOAc-hexane to afford the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[C:9]([C:11]2[C:12]([CH2:17][CH3:18])=[N:13][O:14][C:15]=2[CH3:16])=[O:10])[CH:5]=[CH:6][CH:7]=1>[Pd].C(O)C>[C:15]([C:11](=[C:12]([NH2:13])[CH2:17][CH3:18])[C:9]([N:8]([CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)=[O:10])(=[O:14])[CH3:16]
Reactant: CCc1noc(C)c1C(=O)N(CCN(C)C)c1cccc(F)c1
Agent: [Pd]
Solvent: CCO
Product: CCC(N)=C(C(C)=O)C(=O)N(CCN(C)C)c1cccc(F)c1

Procedure:
A mixture of 15.3 grams (0.048 mole) of N-(m-fluorophenyl)-N-(2-dimethylaminoethyl)-3-ethyl-5-methyl-4-isoxazole carboxamide and 1.5 grams of 10% palladium on carbon in 120 ml. of ethanol is hydrogenated at 50 psi at room temperature overnight. The catalyst is then removed by filtration and the solvent evaporated in vacuo. The residue is crystallized from ether; petroleum ether (1:1) to give 2-acetyl-3-amino-N-(2-dimethylaminoethyl)-N-(m-fluorophenyl)-2-pentenamide (m.p. 96°-97° C.).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[C:22]1([C:28]2([C:33]([OH:35])=O)[CH2:32][CH2:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[CH2:36]([N:43]1[CH2:47][C@H:46]2[CH:48]([NH2:51])[CH2:49][CH2:50][C@H:45]2[CH2:44]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>ClCCl>[CH2:36]([N:43]1[CH2:47][C@H:46]2[C@H:48]([NH:51][C:33]([C:28]3([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:29][CH2:30][CH2:31][CH2:32]3)=[O:35])[CH2:49][CH2:50][C@H:45]2[CH2:44]1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: O=C(O)C1(c2ccccc2)CCCC1
Reactant: NC1CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21)C1(c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-Hydroxybenzotriazole (33 mg, 0.24 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (43 μL, 0.24 mmol) were added to a solution of 1-phenylcyclopentanecarboxylic acid (46 mg, 0.24 mmol) in dichloromethane (2 mL). The reaction was stirred at room temperature for 10 minutes, then (3aS*,6aR*)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine (52 mg, 0.24 mmol) was added and the reaction stirred at room temperature overnight. The reaction mixture was quenched with water, and extracted with dichloromethane, then purified by silica gel chromatography using 1-10% methanol (2 N ammonia)/chloroform as eluent to give the title compounds.
Reaction SMILES: [N-]=C=O.[N-]=C=O.C1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)C=CC=CC=1.[N+:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([O-])=O.NC1C=CC=CC=1.C=O>C1C=CC=CC=1>[CH2:13]=[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]1[NH:20][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: c1ccc(Cc2ccccc2)cc1
Reactant: O=[N+]([O-])c1ccccc1
Agent: C=O
Agent: [N-]=C=O
Solvent: c1ccccc1
Solvent: Nc1ccccc1
Product: C=C1C=CC=CC1Nc1ccccc1

Procedure:
The invention relates to a process for preparation and distillative workup of diphenylmethane diisocyanate, referred to hereinafter as MDI for short, proceeding from a benzene-comprising feed stream, in which benzene is nitrated to nitrobenzene which is hydrogenated to aniline, aniline is reacted with formaldehyde to give methylenediphenylamine (MDA) and MDA is phosgenated to MDI. In this process, not the pure products but at first product mixtures are obtained in each process step, which are purified before further processing.
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[CH:6][C:5]=1[C:27]([F:30])([F:29])[F:28])([O-])=O.C([O-])=O.[NH4+].C1(C)C=CC=CC=1>[Fe].O>[NH2:1][C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[CH2:14][CH2:13]2)=[CH:6][C:5]=1[C:27]([F:29])([F:30])[F:28]
Reactant: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Agent: [Fe]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc(N)c(C(F)(F)F)c2)CC1

Procedure:
A flask was charged with tert-butyl 4-(3-(4-nitro-3-(trifluoromethyl)phenoxy)propyl)piperazine-1-carboxylate (0.78 g, 1.8 mmol), ammonium formate (0.45 g, 7.2 mmol), and iron powder (0.40 g, 7.2 mmol). Toluene (15 mL) and water (15 mL) were added to the flask and the mixture was heated to reflux for 2 hours, after which time, the hot mixture was filtered through a plug of Celite. The solvent was removed on a rotary evaporator under reduced pressure to yield tert-butyl 4-(3-(4-amino-3-(trifluoromethyl)phenoxy) propyl)piperazine-1-carboxylate. The material was used without further purification. MS (EI): 404 (MH+).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][O:4][CH2:5][CH2:6]O.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([C:23]([C:25]2[NH:29][C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[N:26]=2)=[O:24])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([O:14][C:15]([N:17]1[CH2:18][CH2:19][CH:20]([C:23]([C:25]2[N:26]([CH2:6][CH2:5][O:4][CH2:3][C:2]([F:1])([F:8])[F:9])[C:27]3[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=3[N:29]=2)=[O:24])[CH2:21][CH2:22]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: OCCOCC(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2nc3ccccc3[nH]2)CC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2nc3ccccc3n2CCOCC(F)(F)F)CC1

Procedure:
Prepare by the method of Preparation 9 using 2-hydroxyethyl 2,2,2-trifluorethyl ether and 1-(t-butoxycarbonyl)-4-(1H-benzimidazole-2-carbonyl)piperidine (2.0 g, 6.1 mmol) to give 1-(t-butoxycarbonyl)-4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazole-2-carbonyl)piperidine.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[N:8]1.Br[C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][CH2:27][N:28]2[C:31](=[O:48])[C@@H:32]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.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]>[O:48]=[C:31]([N:28]1[C:29]2[C:25](=[CH:24][CH:23]=[C:22]([C:11]3[N:7]([CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[N:8]=[CH:9][CH:10]=3)[CH:30]=2)[CH2:26][CH2:27]1)[C@@H:32]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:44])[CH3:45])[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCc2ccc(Br)cc21
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCc2ccc(-c3ccnn3C3CCCCO3)cc21
Temperature: 85 °C
Reaction time: 3 h
Yield: 28.6 %

Procedure:
To DMF (1.1 ml) in a sealed tube flushed with nitrogen was added 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (62 mg, 230 μmol), (S)-tert-butyl 1-(6-bromoindolin-1-yl)-1-oxo-3-phenylpropan-2-ylcarbamate (100 mg, 230 μmol), 1M sodium carbonate solution (630 μl, 630 μmol), and 1,1′-dis(diphenylphosphino)ferrocene-palladium (II) dichloride dichloromethane complex (Pd(dppf)Cl2) (9.2 mg, 11 μmol). The slurry was heated to 85° C. and stirred for three hours. A significant amount of starting material remained. Another portion of (Pd(dppf)Cl2) (9.2 mg, 11 μmol) was added and the reaction was stirred for eight hours. The reaction was then allowed to cool to room temperature. The reaction was diluted with water and extracted with ethyl acetate (2×40 mL). The combined organic layers were washed with 1M lithium chloride solution (1×30 mL) and brine (1×30 mL) and dried over magnesium sulfate. The crude product was purified by medium pressure chromatography (silica, 0 to 60% ethyl acetate:hexanes) to give tert-butyl (S)-1-oxo-3-phenyl-1-(6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)indolin-1-yl)propan-2-ylcarbamate (34 mg, 29% yield). MS ESI (pos.) m/e: 433.1 (M+H-THP).
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([Cl:9])[S:6][C:5]=1[Cl:10])(=[O:3])[CH3:2].CO[CH2:13][Cl:14]>[Ti](Cl)(Cl)(Cl)Cl.ClCCl>[C:1]([C:4]1[C:8]([CH2:13][Cl:14])=[C:7]([Cl:9])[S:6][C:5]=1[Cl:10])(=[O:3])[CH3:2]
Reactant: COCCl
Reactant: CC(=O)c1cc(Cl)sc1Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(=O)c1c(Cl)sc(Cl)c1CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 33 %

Procedure:
33 ml of titanium tetrachloride (a 2 moles/liter dichloromethane solution, 66.0 mmoles) was dropwise added, at 10° C. with ice-cooling, to a solution of 5.0 g (32.4 mmoles) of 3-acetyl-2,5-dichlorothiophene dissolved in 26 ml (323.0 mmoles) of chloromethyl methyl ether. The mixture was stirred at room temperature for 2 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into ice water, followed by extraction with chloroform. The resulting organic layer was washed with sodium bicarbonate, water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=9/1) to obtain 2.6 g (yield: 39.7%) of 3-acetyl-4-chloromethyl-2,5-dichlorothiophene as yellow crystals.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:22][C@H:21]([CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[N:8]2[C:9]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N+:12]([O-])=[CH:11][C:10]=3[N:20]=[C:7]2[CH2:6]1)(=[O:4])=[O:3].[NH4+:34].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>C(Cl)Cl>[NH2:34][C:11]1[C:10]2[N:20]=[C:7]3[CH2:6][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:22][C@H:21]([CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[N:8]3[C:9]=2[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)NCCC[C@H]1CN(S(C)(=O)=O)Cc2nc3c[n+]([O-])c4ccccc4c3n21
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NCCC[C@H]1CN(S(C)(=O)=O)Cc2nc3c(N)nc4ccccc4c3n21
Reaction time: 3 h

Procedure:
tert-Butyl 3-[(11S)-9-(methylsulfonyl)-5-oxido-8,9,10,11-tetrahydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinolin-11-yl]propylcarbamate (6.37 g, 13.4 mmol) was dissolved in 120 mL of CH2Cl2 and treated with 12 mL of concentrated NH4OH solution. The mixture was stirred rapidly and then p-toluenesulfonyl chloride (2.81 g, 14.7 mmol) was carefully added. Rapid stirring was continued for 3 hours. The reaction mixture was treated with 100 mL of CH2Cl2 and 25 mL of H2O. The layers were separated and the organic portion was washed successively with 2% Na2CO3 solution (3×50 mL), H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 33% CMA/CHCl3) gave tert-butyl 3-[(11S)-6-amino-9-(methylsulfonyl)-8,9,10,11-tetrahydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinolin-11-yl]propylcarbamate (5.41 g) as light-orange foam.
Reaction SMILES: B([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])=[O:11])(O)O.C(=O)([O-])[O-].[K+].[K+].O.[NH2:25][C:26]1[N:35]=[C:34]([C:36]([N:38]2[CH2:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH2:39]2)=[O:37])[C:33]2[C:28](=[CH:29][CH:30]=[C:31](I)[CH:32]=2)[N:27]=1>C(O)C.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]>[NH2:25][C:26]1[N:35]=[C:34]([C:36]([N:38]2[CH2:39][C:40]3[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:46]2)=[O:37])[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])=[O:11])[CH:32]=2)[N:27]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1B(O)O
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(I)ccc2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 120 °C

Procedure:
1.6 g of 2-borono-N-tert-butylbenzenesulfonamide, 2.66 g of potassium carbonate, 86 μl of water and 196 mg of [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloride are added to a solution of 2 g of 2-amino-6-iodo-4-(1,3-dihydroisoindol-2-ylcarbonyl)quinazoline in 100 ml of ethanol under argon. The mixture is heated at 120° C. for 16 h, giving a clear solution. The hot solution is filtered through kieselguhr and rinsed with ethanol. The filtrate is evaporated to dryness in vacuo. Crystallisation of the residue from 5 ml of acetonitrile/water gives the product.
Reaction SMILES: [CH3:1][Si:2]([CH3:34])([CH3:33])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[CH:32]=[CH:31][C:21]([C:22](=[O:30])[NH:23][CH2:24][C:25]([O:27]CC)=[O:26])=[CH:20][CH:19]=1.[OH-].[Na+]>C(O)C>[CH3:34][Si:2]([CH3:1])([CH3:33])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([NH:23][CH2:24][C:25]([OH:27])=[O:26])=[O:30])=[CH:31][CH:32]=1
Reactant: CCOC(=O)CNC(=O)c1ccc(NCCCCCCCCCCCCCC[Si](C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[Si](C)(C)CCCCCCCCCCCCCCNc1ccc(C(=O)NCC(=O)O)cc1

Procedure:
A mixture of 12.5 g. of ethyl 4-[14-(trimethylsilyl)tetradecylamino]hippurate, 55 ml. of 1N sodium hydroxide solutions and 50 ml. of ethanol is stirred at ambient temperature for 2 hours and then partially evaporated. The aqueous solution is washed with diethyl ether, acidified with 6N hydrochloric acid, and filtered. The solid is dried in vacuo and recrystallized to yield the product as a white solid.