Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:15]1[CH:26]=[CH:25][C:18]([O:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:27](Cl)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CCOCC>N1C=CC=CC=1>[CH2:1]([C:15]1[CH:26]=[CH:25][C:18]([O:19][CH2:20][CH:21]([OH:24])[CH2:22][O:23][C:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCc1ccc(OCC(O)CO)cc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCc1ccc(OCC(O)COC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 72 h

Procedure:
An about 364 mg portion of 3-(4-tetradecylphenoxy)-1,2-propanediol was dissolved in about 1.5 ml of dry pyridine and about 501 mg of tritylchloride was added. The mixture was stirred under argon for about 72 hours, ether was added and the mixture was washed with ice-cold dilute (about 1N) hydrochloric acid, sodium bicarbonate solution, brine, then dried and the solvent evaporated. The residue was recrystallized from ethanol, giving about 700 mg of the desired title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[C:17]3[C:16]([NH:18][C@H:19]([C:21]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:25](=[O:33])[C:24]5=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]5[N:22]=4)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=3[N:11]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>>[CH3:37][C:34]1[CH:35]=[CH:36][N:23]2[C:24]=1[C:25](=[O:33])[N:26]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]([C@@H:19]([NH:18][C:16]1[C:17]3[C:9]([S:8][C:4]4[CH:3]=[C:2]([NH:1][S:47]([CH3:46])(=[O:49])=[O:48])[CH:7]=[CH:6][CH:5]=4)=[CH:10][N:11]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:43])([CH3:45])[CH3:44])[C:12]=3[N:13]=[CH:14][N:15]=1)[CH3:20])=[N:22]2
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Sc3cccc(N)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Sc3cccc(NS(C)(=O)=O)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 21.5 %

Procedure:
(S)-2-(1-((5-((3-Aminophenyl)thio)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.13 mmol) was treated with methanesulfonyl chloride (10 μl, 0.14 mmol) according to the method described in Preparation 15b. The residue was purified by reverse phase using SP1® Purification System to give 20 mg (23% yield) of the title compound. Purity 98%.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:25]3=[N:26][CH:27]=[N:28][C:29]([O:30][C:31]4[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=4)=[C:24]3[CH:23]=[N:22]2)[CH2:17][CH2:16]1)=[O:14])(C)([CH3:10])[CH3:9].ClC(OC(C)C)=O.C1(C)C=CC=CC=1.C(N(CC)CC)C>ClCCl.O>[CH:8]([O:12][C:13]([N:15]1[CH2:16][CH2:17][CH:18]([N:21]2[C:25]3=[N:26][CH:27]=[N:28][C:29]([O:30][C:31]4[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=4)=[C:24]3[CH:23]=[N:22]2)[CH2:19][CH2:20]1)=[O:14])([CH3:10])[CH3:9]
Reactant: Cc1ncccc1Oc1ncnc2c1cnn2C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)OC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ncccc1Oc1ncnc2c1cnn2C1CCN(C(=O)OC(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104.9 %

Procedure:
Trifluoroacetic acid (3 mL) was added to a solution of 4-[4-(2-methyl-pyridin-3-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 92; 300 mg, 0.7 mmol) in dichloromethane (12 mL). The solution was stirred at room temperature for 30 min and then the solvents were evaporated, first using house vacuum and then high vacuum. Dichloromethane (10 mL) was added to the residue, and then a solution of isopropyl chloroformate in toluene (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 1 M; 1.1 mL, 1.1 mmol) was added at room temperature, followed by triethylamine (480 mg, 4.7 mmol). The mixture was stirred for 2 h at room temperature and then water was added. The layers were separated and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were evaporated, and purified by silica gel column chromatography, eluting with 0-80% ethyl acetate/hexanes) to give 4-[4-(2-methyl-pyridin-3-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid isopropyl ester (291 mg, 100%) as a viscous oil. 1H NMR (300 MHz, CDCl3) δ 1.28 (d, 6H, J=6.4 Hz), 2.00-2.03 (m, 1H), 2.24-2.30 (m, 2H), 2.46 (s, 3H), 2.95-3.04 (m, 2H), 4.27-4.39 (m, 2H), 4.93-5.00 (m, 2H), 7.28-7.32 (m, 1H), 7.52-7.55 (m, 1H), 8.07 (s, 1H), 8.48-8.52 (m, 2H). Mass spectrum MH+=397. HRMS Calcd. For C20H25N6O3 (MH+): 397.1983. Found: 397.1982.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[N+:10]([O-])=O.[H][H]>[Ni].O1CCCC1>[NH2:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[NH2:1])[CH2:6][OH:7]
Reactant: [H][H]
Reactant: Nc1ccc(CO)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1ccc(CO)cc1N
Yield: 82 %

Procedure:
Six grams (0.035 mole) of 4-amino-3-nitrobenzyl alcohol, 95 ml. of tetrahydrofuran and 0.5 g. of Raney Nickel were hydrogenated at 40 psi at room temperature until 3 moles of hydrogen were absorbed. The catalyst was filtered and the filtrate was evaporated in vacuo to yield 4.83 g. (82 percent yield) of 3,4-diaminobenzyl alcohol, mp. 74°-75° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH2:21]OS(C)(=O)=O)=[N:19][N:18]=[C:17]1[CH2:27][N:28]([CH3:30])[CH3:29].[NH3:32]>CO>[Cl:15][C:13]1[CH:12]=[CH:11][C:10]2[N:16]3[C:17]([CH2:27][N:28]([CH3:30])[CH3:29])=[N:18][N:19]=[C:20]3[CH2:21][N:32]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:9]=2[CH:14]=1
Reactant: CN(C)Cc1nnc(COS(C)(=O)=O)n1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl
Reactant: N
Solvent: CO
Product: CN(C)Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
Derwent Abstract 48681A briefs a Japanese Patent Publication No. 59696/78, published May 29, 1978, disclosing the ring closure of 2',5-dichloro-2-[3-(dimethylaminomethyl)-5-mesyloxymethyl-4H-1,2,4-triazol-4-yl]benzophenone in a sealed tube with ammonia containing methanol to obtain 8-chloro-6-(2-chlorophenyl)-1-[(dimethylamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine. However, sealed tube procedures are not practical for commercial scale chemical process operations, and the abstract does not disclose how the (3-hydroxymethyl-triazol-4-yl)-compounds are obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]=[C:6]=[S:7])[CH3:4].[NH2:8]/[C:9](/[C:16]([F:19])([F:18])[F:17])=[CH:10]\[C:11](OCC)=[O:12]>CN(C=O)C>[CH2:3]([N:5]1[C:11](=[O:12])[CH:10]=[C:9]([C:16]([F:19])([F:18])[F:17])[N:8]=[C:6]1[SH:7])[CH3:4]
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: CCN=C=S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(S)nc(C(F)(F)F)cc1=O
Yield: 99 %

Procedure:
With stirring under ice-cooling, sodium hydride (60% in oil, 3.73 g, 56.0 mmol) and ethyl isothiocyanate (4.38 ml, 56.0 mmol) were added in that order to DMF (35 ml) solution of ethyl 3-amino-4,4,4-trifluorocrotonate, Followed by stirring overnight while gradually returning to room temperature. After completion of the reaction, the reaction solution was concentrated under a reduced pressure, water (20 ml) was added to the thus obtained residue, and then concentrated hydrochloric acid (15 ml) was added. The thus precipitated solid was isolated by filtration, washed with water (100 ml) and then thoroughly dried to obtain 3-ethyl-2-mercapto-6-trifluoromethyl-4-(3H)-pyrimidinone (11.0 g, 99%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1([N:17]([CH3:19])[CH3:18])[CH2:16][CH2:15][C:10]2(OCC[O:11]2)[CH2:9][CH2:8]1.Cl>O>[CH3:19][N:17]([CH3:18])[C:7]1([CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[CH2:8][CH2:9][C:10](=[O:11])[CH2:15][CH2:16]1
Reactant: COCCCCC1(N(C)C)CCC2(CC1)OCCO2
Agent: Cl
Solvent: O
Product: COCCCCC1(N(C)C)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
[8-(4-Methoxy-butyl)-1,4-dioxa-spiro[4.5]dec-8-yl]-dimethyl-amine (C-3) (6.44 g, 23.7 mmol) was dissolved in water (9.3 ml); conc. HCl (14.6 ml) was added, and the mixture was stirred for 4 d at room temperature. The reaction mixture was washed with ether (2×50 ml). Then the solution was rendered alkaline with 5N NaOH and extracted with dichloromethane (3×50 ml). The combined organic phases were washed with water (50 ml), dried over Na2SO4 and filtered, and the solvent was removed in vacuo.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5]1.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C1COCC1>[CH3:18][S:19]([O:1][CH2:2][CH2:3][CH:4]1[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5]1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)OCC(CCO)O1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)OCC(CCOS(C)(=O)=O)O1

Procedure:
The 4-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolane (Aldrich, 0.19 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]=2)[O:4][CH:3]=1.[CH3:16][S:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[CH3:16][S:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]=3)[O:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1cnc2occ(Br)c2c1
Product: CCOC(=O)c1cnc2occ(-c3ccc(SC)cc3)c2c1
Yield: 95 %

Procedure:
In the same manner as in Reference Example 19 and using ethyl 3-bromofuro[2,3-b]pyridine-5-carboxylate instead of methyl 3-iodoimidazo[1,2-a]pyridine-6-carboxylate and [4-(methylthio)phenyl]boronic acid instead of (4-methoxyphenyl)boronic acid, the title compound (yield 95%) was obtained as colorless crystals.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1/[C:18](=[N:22]/[OH:23])/[C:19]([OH:21])=[O:20].C(Br)(Br)Br>CS(C)=O>[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1/[C:18](=[N:22]/[O:23][CH2:2][C:3](=[O:4])[NH:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)/[C:19]([OH:21])=[O:20]
Reactant: O=C(CCl)NOc1ccccc1
Reactant: O=C(O)/C(=N\O)c1ccco1
Solvent: BrC(Br)Br
Solvent: CS(C)=O
Product: O=C(CO/N=C(\C(=O)O)c1ccco1)NOc1ccccc1
Yield: 50 %

Procedure:
This compound was prepared as described in Preparation 4 from phenyl chloroacetohydroxamate and Z-2-(fur-2-yl)-2-hydroxyiminoacetic acid. νmax (CHBr3) 3350 (NH), 3700-2100 (bonded OH), 1754, 1725 (--CO2H), 1705, 1680 cm-1 (--CONH--), τ(DMSO d6) 2.05, 3.11, 3.29 (furyl), 5.3 (--OCH2CO--), 2.4-3.1 (phenyl). Yield 50%.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][S:15]([C:12]2[CH:13]=[CH:14][C:9]([CH3:19])=[CH:10][CH:11]=2)(=[O:17])=[O:16])[CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CCOCC2)cc1
Reaction time: 8 h
Yield: 75.1 %

Procedure:
At room temperature, a mixture of (tetrahydro-pyran-4-yl)-methanol (2.4 g, 20.7 mmol), p-toluenesulfonyl chloride (6.73 g, 35.4 mmol), triethylamine (6.6 mL, 47.6 mmol) and DMAP (0.288 g, 2.36 mmol) in DCM (50 mL) was stirred overnight. The solution was washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography to give the title compound as an oil (4.2 g).
Reaction SMILES: [Cl:1][CH2:2][S:3](Cl)(=[O:5])=[O:4].[NH2:7][C:8]1[S:9][C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:12]=1>N1C=CC=CC=1>[Cl:1][CH2:2][S:3]([NH:7][C:8]1[S:9][C:10]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:12]=1)(=[O:5])=[O:4]
Reactant: Nc1nc(-c2ccccc2)c(-c2ccccc2)s1
Reactant: O=S(=O)(Cl)CCl
Solvent: c1ccncc1
Product: O=S(=O)(CCl)Nc1nc(-c2ccccc2)c(-c2ccccc2)s1
Temperature: 25 °C
Yield: 44.2 %

Procedure:
2.70 g of chloromethanesulfonyl chloride was dropped into a solution of 2.27 g of 2-amino-4,5-diphenylthiazole in pyridine under stirring at room temperature, and the resulting mixture was stirred as such for 2 hours. Then the reaction mixture was poured into ice-water and the crystals thus precipitated were recovered by filtration and separated with a silica gel column by using isopropyl ether and ethyl acetate as a developer. The crystals thus obtained were recrystallized from isopropyl ether/ethyl acetate to give 1.45 g of 2-chloromethanesulfonylamino-4,5-diphenylthiazole. The melting point of this product was from 201° to 203° C.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[C:34]([N:38]=[C:39]=[O:40])([CH3:37])([CH3:36])[CH3:35]>C(#N)C>[C:34]([NH:38][C:39]([NH:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24])=[O:40])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)N=C=O
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)NC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 49 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.28 g, 1.9 mmol) was added to stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.9 mmol) in acetonitrile (50 ml). After stirring for 1 hour, t-butylisocyanate (0.21 g, 2 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in dichloromethane (70 ml) and washed with 0.1 N HCl (20 ml), water (20 ml), brine (20 ml) and dried. The solvent was removed in vacuo and the resulting solid was recrystallized from ethanol/isopropyl ether to give 0.36 g (51%) of the product: mp 186-188° C.; 1H NMR (DMSO-d6) δ 11.04 (s, 1H), 7.77-7.59 (m, 3H), 6.17 (t, J=6.2 Hz, 1H), 5.86 (s, 1H), 5.08-5.01 (dd, J=5.4 and 12.4 Hz, 1H), 4.49 (d, J=6.0 Hz, 2H), 2.82-2.73 (m, 1H), 2.54-2.40 (m, 2H), 1.98-1.94 (m, 1H), 1.12 (s, 9H); 13C NMR (DMSO-d6) δ 172.33, 169.39, 167.11, 166.59, 156.85, 140.72, 134.20, 132.99, 131.06, 126.54, 121.20, 48.69, 48.37, 37.89, 30.46, 28.88, 21.53; Anal. Calcd. For C19H22N4O5+0.2 water: C, 58.51; H, 5.79; N, 14.37. Found: C, 58.86; H, 6.15; N, 14.24.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[Cl:15])[NH:11][CH:10]([C:16]1[CH:17]=[C:18]([CH:47]=[CH:48][CH:49]=1)[O:19][C@@H:20]1[CH2:24][N:23]([C:25]([N:27]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:28][CH3:29])=[O:26])[C@H:22]([C:37]([O:39]CC3C=CC=CC=3)=[O:38])[CH2:21]1)[NH:9][C:8]2=[O:50])(=[O:4])=[O:3]>[Pd].C(O)C>[NH2:1][S:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[Cl:15])[NH:11][CH:10]([C:16]1[CH:17]=[C:18]([CH:47]=[CH:48][CH:49]=1)[O:19][C@@H:20]1[CH2:24][N:23]([C:25]([N:27]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:28][CH3:29])=[O:26])[C@H:22]([C:37]([OH:39])=[O:38])[CH2:21]1)[NH:9][C:8]2=[O:50])(=[O:4])=[O:3]
Reactant: CCOC(=O)CCN(CC)C(=O)N1C[C@@H](Oc2cccc(C3NC(=O)c4cc(S(N)(=O)=O)c(Cl)cc4N3)c2)C[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCN(CC)C(=O)N1C[C@@H](Oc2cccc(C3NC(=O)c4cc(S(N)(=O)=O)c(Cl)cc4N3)c2)C[C@H]1C(=O)O
Reaction time: 2.5 h

Procedure:
To a solution of the phenylmethyl ester product of part (i) (505 mg., 0.69 mmole) in 40 ml. of absolute ethanol is added approximately 70 mg. of 10% palladium on charcoal. The resulting mixture is stirred under hydrogen for approximately 2.5 hours at which time Tlc analysis shows no starting material remaining. The mixture is filtered and concentrated at reduced pressure to give a pale gray foam which is dried under vacuum overnight to give 430 mg. of material. In order to remove additional palladium/charcoal, this material is dissolved in ethanol, millipore filtered, and concentrated at reduced pressure. The residue is dissolved in tetrahydrofuran, precipitated with ether to give a white solid, and dried overnight under vacuum to give (cis)-4-[3-[6-(aminosulfonyl)-7-chloro-1,2,3,4-tetrahydro-4-oxo-2-quinazolinyl]phenoxy]-1-[[(3-ethoxy-3-oxopropyl)ethylamino]carbonyl]-L-proline.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:19][C:20]3[C:25]([F:26])=[CH:24][C:23]([Cl:27])=[CH:22][C:21]=3[F:28])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:29][CH3:30])C1C=CC=CC=1>C(O)(C(F)(F)F)=O>[Cl:27][C:23]1[CH:22]=[C:21]([F:28])[C:20]([NH:19][C:13]2[C:12]3[C:17](=[CH:18][C:9]([OH:8])=[C:10]([O:29][CH3:30])[CH:11]=3)[N:16]=[CH:15][N:14]=2)=[C:25]([F:26])[CH:24]=1
Reactant: COc1cc2c(Nc3c(F)cc(Cl)cc3F)ncnc2cc1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Nc3c(F)cc(Cl)cc3F)ncnc2cc1O
Yield: 79.4 %

Procedure:
A solution of 7-benzyloxy-4-(4-chloro-2,6-difluoroanilino)-6-methoxyquinazoline (200 mg, 0.47 mmol) in TFA (3 ml) was stirred at 80° C. for 3 hours. After cooling, the volatiles were removed under vacuum and the residue was dissolved in water containing 5% methanol. The pH was adjusted to 8 with sodium hydrogen carbonate and the solid was collected by filtration and washed with water. The solid was solubilised in a mixture of ethyl acetate/methanol/methylene chloride (47/6/47). The volatiles were removed under vacuum to give 4-(4-chloro-2,6-difluoroanilino)-7-hydroxy-6-methoxyquinazoline (126 mg, 80%).
Reaction SMILES: [O:1]=[CH:2][C:3]([Cl:6])([Cl:5])[Cl:4].[C:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8].[Cl-].[Al+3].[Cl-].[Cl-].Cl>O>[C:7]([C:11]1[CH:16]=[CH:15][C:14]([CH:2]([OH:1])[C:3]([Cl:6])([Cl:5])[Cl:4])=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: CC(C)(C)c1ccc(C(O)C(Cl)(Cl)Cl)cc1
Temperature: 5 °C

Procedure:
A solution of 22 g (0.15 mole) of chloral and 15g of tert-butylbenzene was added in ten portions alternatively with 4.4g (0.03 mole) of aluminum chloride to a 120g portion of tert-butylbenzene with vigorous stirring at 5°C. The mixture was stirred at 20°C. for 0.5 hr. and again cooled to 5°C. before 40 ml of 6N HCl was added dropwise. The mixture was diluted with 20 ml of water and the organic products were extracted into ethyl ether (2 × 100 ml). The etheral solution was washed with 5% HCl, water, aqueous sodium carbonate and brine, dried over magnesium sulfate and concentrated. A 27g portion of the 33g residue was distilled via short path to provide 18.4g of a colorless, viscous product: Bp 144°C (0.2mm); ir (film) 2.85 (s), 3.4 (s), 9.4 (s), 12.1 (s), 12.8 (s) microns; nmr (CDCl3) 7.40 (4H, m), 5.06 (1H,s), 3.56 (1H, s), 1.28 (9H, s) ppm.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][C:6]=1[N+:19]([O-:21])=[O:20])(=O)C.[OH-].[Na+]>CO.O>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][C:6]=1[N+:19]([O-:21])=[O:20]
Reactant: CC(=O)Nc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]

Procedure:
The 1-acetamido-4-benzyloxy-2-nitrobenzene so produced is treated with sodium hydroxide in methanol, warmed briefly on a steam bath for about 15 minutes until the reaction is complete, diluted with water and extracted with dichloromethane to give 1-amino-4-benzyloxy-2-nitrobenzene.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[O:7]([C@@H:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][C@H:15]1[NH:23][C:24](OCC)=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(OCC)C>[O:7]([C@@H:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][C@H:15]1[NH:23][CH3:24])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)N[C@@H]1Cc2ccccc2[C@H]1Oc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CN[C@@H]1Cc2ccccc2[C@H]1Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
To a stirred suspension of LiAlH4 (0.22 g, 5.7 mmol) in dry diethyl ether (5 ml) under nitrogen was added a solution of (±) trans 1-(phenoxy)-2-ethoxycarbonylaminoindane (0.34 g, 1.14 mmol) in diethyl ether (10 ml). After stirring overnight at room temperature the reaction was worked up as described in Preparation 4 to give the title compound as a brown oil (0.25 g) which was used in the next stage without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:11]1([C:14]2[CH:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:23][CH:24]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CCOC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1ccc(N2CCNCC2)cc1
Reaction time: 3 h
Yield: 99.9 %

Procedure:
To a stirred solution of ethyl 4-[4-(tert-butyloxycarbonyl)-1-piperazinyl]benzoate (240 mg, 0.718 mmol) in CH2Cl2 (5 mL) was added TFA (5 mL), and the resulting mixture was stirred for 3 hr. The mixture was concentrated in vacuo and the residue was made basic by the addition of sat. NaHCO3, followed by extraction with CHCl3 (2×100 mL). The combined extracts were dried over Na2CO3 and evaporated to give 168 mg ethyl 4-(1-piperazinyl)benzoate (100%) as a yellow oil. 1H-NMR (CDCl3) δ 1.37 (3 H, t, J=7.3 Hz), 3.03 (4 H, t, J=4.9 Hz), 3.29 (4 H, t, J=4.9 Hz), 4.33 (2 H, q, J=7.3 Hz), 6.87 (2 H, dt, J=8.8, 2.4 Hz), 7.91–7.94 (2 H, m).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][OH:15])[O:7][C@H:6]1[N:16]1[CH:24]=[N:23][C:22]2[C:17]1=[N:18][CH:19]=[N:20][C:21]=2[NH:25][C@@H:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27]1)(=[O:3])[CH3:2].C(N(CC)CC)C.Cl[S:43]([NH2:46])(=[O:45])=[O:44]>C(Cl)Cl.C(#N)C>[C:11]([O:10][C@H:9]1[C@H:5]([O:4][C:1](=[O:3])[CH3:2])[C@H:6]([N:16]2[CH:24]=[N:23][C:22]3[C:17]2=[N:18][CH:19]=[N:20][C:21]=3[NH:25][C@@H:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28][CH2:27]2)[O:7][C@@H:8]1[CH2:14][O:15][S:43]([NH2:46])(=[O:45])=[O:44])(=[O:13])[CH3:12]
Reactant: NS(=O)(=O)Cl
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@@H](CO)O[C@H]1n1cnc2c(N[C@H]3CCc4ccccc43)ncnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@@H](COS(N)(=O)=O)O[C@H]1n1cnc2c(N[C@H]3CCc4ccccc43)ncnc21
Temperature: 0 °C
Yield: 48 %

Procedure:
(2R,3S,4R,5R)-2-{6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-5-(hydroxymethyl)tetrahydrofuran-3,4-diyl diacetate (0.188 g, 0.40 mmol) was stirred in anhydrous methylene chloride (0.6 mL) cooled to 0° C. Triethylamine (0.081 mL, 0.80 mmol) was added followed by the dropwise addition of a 2 N solution of chlorosulfonamide in acetonitrile (0.6 mL). The yellow solution was concentrated after one hour. The residue was purified by column chromatography using 0-5% methanol/methylene chloride concentrated to give the title compound as a yellow solid (0.104 g, 48%).