Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[Na+].C[O:4][C:5]([C:7]1[CH:31]=[CH:30][C:10]([CH2:11][C:12]23[CH2:19][CH2:18][CH2:17][N:16]2[C:15](=[O:20])[N:14]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)[C:13]3=[O:29])=[CH:9][CH:8]=1)=[O:6]>CO.O.O>[Cl:28][C:23]1[CH:22]=[C:21]([NH:14][C:15]([N:16]2[CH2:17][CH2:18][CH2:19][C@@:12]2([CH2:11][C:10]2[CH:9]=[CH:8][C:7]([C:5]([OH:4])=[O:6])=[CH:31][CH:30]=2)[C:13]([OH:1])=[O:29])=[O:20])[CH:26]=[C:25]([Cl:27])[CH:24]=1
Reactant: COC(=O)c1ccc(CC23CCCN2C(=O)N(c2cc(Cl)cc(Cl)c2)C3=O)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(C[C@@]2(C(=O)O)CCCN2C(=O)Nc2cc(Cl)cc(Cl)c2)cc1
Temperature: 45 °C
Yield: 87.2 %

Procedure:
NaOH (0.406 g) was added to a solution of 5-(4-methoxycarbonylbenzyl)-3-(3,5-dichlorophenyl)-1,3-diazabicyclo[3.3.0]octane-2,4-dione (0.601 g) in MeOH/H2O (20 mL/4 mL) and the mixture was heated at 45° C. for 18 hours. The reaction mixture was cooled, acidified, diluted with water and extracted with EtOAc. The extract was washed with water, brine, dried (MgSO4), filtered, and concentrated. The residue was recrystallized from EtOAc/hexane (1:1) to give N-[N-(3,5-dichlorophenyl)carbamoyl]-2-(4-carboxybenzyl)proline (0.529 g). mp. 144.6° C.; MS (m/z) 459 (M++Na).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[N:15]=[C:14]([NH2:16])[N:13]=[C:12]2[NH:17][N:18]=[CH:19][C:11]=12>ClC(Cl)C>[Br:1][C:19]1[C:11]2[C:12](=[N:13][C:14]([NH2:16])=[N:15][C:10]=2[Cl:9])[NH:17][N:18]=1
Reactant: Nc1nc(Cl)c2cn[nH]c2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(Cl)Cl
Product: Nc1nc(Cl)c2c(Br)n[nH]c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-bromosuccinimide (673 mg, 3.8 mmol) is added to a suspension of 4-Chloro-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (500 mg, 2.96 mmol) in dichloroethane (30 ml) and heated to reflux overnight. The reaction mixture is cooled to room temperature and the solvent is removed in vacuo. The resulting solid is diluted with water, stirred for 30 minutes at room temperature, then collected by filtration to afford the title compound.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH:7]([CH:8]=[C:9]2SCCCS2)[CH2:6][CH:5]([O:15][CH3:16])[O:4]1.C[OH:18].C1[CH2:23][O:22]CC1.O>>[CH3:1][O:2][CH:3]1[CH:7]([CH2:8][C:9]([O:22][CH3:23])=[O:18])[CH2:6][CH:5]([O:15][CH3:16])[O:4]1
Reactant: C1CCOC1
Reactant: COC1CC(C=C2SCCCS2)C(OC)O1
Reactant: CO
Solvent: O
Product: COC(=O)CC1CC(OC)OC1OC
Temperature: 80 °C
Reaction time: 5 h
Yield: 77 %

Procedure:
Also according to a procedure from Boger, D. L.; Brotherton, C. E. J. Org. Chem. 1984, 49, 4050-4055, to a solution of 2-(2,5-dimethoxy-tetrahydrofuran-3-yl-methylidene)-1,3-dithiane (200 mg, 0.76 mmol) in a mixture of MeOH:THF:H2O (8:1:1; 10 mL) was added mercuric chloride (450 mg, 1.66 mmol). Upon heating at 80° C., a white precipitate formed, and after 5 hours at 80° C., the mixture was filtered through Celite. The collected solid was washed with EtOAc followed by aqueous. NH4Cl. The filtrates were combined, and the biphasic mixture separated. The aqueousueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to yield 120 mg (77%) of methyl 2-(2,5-dimethoxy-tetrahydrofuran-3-yl)-acetate as an oil, which was a mixture of diastereomers as evident by NMR, and which was used without further purification. An analytical sample was obtained by flash column chromatography with 0-20% EtOAc/hex as gradient eluant. 1H NMR: δ 3.68 (s, 3H), 3.67 (s, 3H). Anal. Calculated for C9H16O5: C, 53.27; H, 7.90. Found: C, 53.11; H, 7.96.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:18](Cl)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]>ClCCl>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:5][CH:4]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 97.3 %

Procedure:
To a stirred solution of 4-trifluoromethylaniline (25 g, 0.155 mol) and pyridine (62 ml, 0.775 mol) in dichloromethane (300 ml) cooled to 0° C. under nitrogen was added dropwise pivaloyl chloride (19 ml, 0.155 mol). The reaction mixture was stirred at room temperature for 3.5 hr, then diluted with dichloromethane (300 ml). The resulting solution was washed sequentially with 1N aqueous hydrochloric acid solution (2×), saturated aqueous sodium bicarbonate solution, water and brine, dried (anhydrous sodium sulfate)and concentrated in vacuo to yield the title compound as a white solid (37 g, 97% yield).
Reaction SMILES: [I-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:22]([Li])[CH2:23][CH2:24][CH3:25].[CH:27]([C:29]1[CH:30]=[C:31](C=CC=1)[C:32]([O:34][CH3:35])=[O:33])=O>O1CCCC1.CCCCCC>[CH:24]([C:23]1[CH:22]=[C:31]([CH:30]=[CH:29][CH:27]=1)[C:32]([O:34][CH3:35])=[O:33])=[CH2:25]
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=Cc1cccc(C(=O)OC)c1
Temperature: -50 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 590 mg of methyl triphenylphosphonium iodide in 50 ml of dry tetrahydrofuran cooled to -50° C. was added dropwise 5.3 ml of 2.5M n-butyl lithium in hexane. The resulting mixture was allowed to warm to 0° C. over a period of one hour. The mixture was then cooled to -70° C. and 2.0 g of methyl 3-formylbenzoate in 20 ml of dry tetrahydrofuran was added dropwise over a period of 20 minutes. The reaction mixture was allowed to warm to room temperature and stir overnight. The reaction mixture was concentrated in vacuo and the residue treated with water (200 ml) and extracted with diethyl ether (2×200 ml). The extracts were combined, washed with water and a brine solution and dried over magnesium sulfate. Removal of the solvent gave 2 g of an oil which was flash chromatographed on silica gel (30% ethyl acetate--hexane; v:v) , 2.0 g. Distillation in vacuo gave 1.36 g.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:3]=1[C:4](=NN)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11].[OH-].[K+]>C(O)COCCO>[Cl:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:4][C:3]1[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:2]=1[NH2:1]
Reactant: NN=C(c1cc([N+](=O)[O-])ccc1N)c1ccccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Product: Nc1ccc([N+](=O)[O-])cc1Cc1ccccc1Cl

Procedure:
In the manner given in Preparation 11, 2-amino-2'-chloro-5-nitrobenzophenone hydrazone is refluxed with potassiumhydroxide in diethylene glycol to give 2-(o-chlorobenzyl)-4-nitroaniline.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:13])[O:10][CH2:11]C)=[N:6][CH:7]=1.[CH3:14][O-:15].[Na+]>CO>[CH3:14][O:15][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:13])[O:10][CH3:11])=[N:6][CH:7]=1
Reactant: CCOC(=O)Nc1cnc(Cl)cn1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)Nc1cnc(OC)cn1
Temperature: 100 °C
Yield: 22.01 %

Procedure:
A 20 mL microwave vial was charged with ethyl (5-chloropyrazin-2-yl)carbamate (500 mg, 2.480 mmol) and 22% sodium methoxide in MeOH (10 mL). The tube was sealed and heated to 100° C. for 6 h. The reaction mixture was then concentrated, diluted between DCM and 2N HCl. The layers were separated and the aqueous layer was extracted with DCM (2×). The combined organic layers were washed with 2N HCl, brine, eluted through a phase separator and concentrated to afford methyl (5-methoxypyrazin-2-yl)carbamate as a brown oil (100 mg, 22.01% yield). MS (m/z) 184 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=O)[CH3:21])=[CH:15][CH:14]=1>>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:2]3[CH:7]=[CH:6][N:5]=[CH:4][C:3]=3[N:8]=[C:20]2[CH3:21])=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: COc1ccc(NC(C)=O)cc1
Product: COc1ccc(-n2c(C)nc3cnccc32)cc1
Yield: 70.2 %

Procedure:
Method B applied to 4-chloro-3-nitropyridine (79 mg, 0.5 mmol) and N-(4-methoxyphenyl)acetamide (99 mg, 0.6 mmol) afforded the title compound as viscous oil (84 mg, 70%). 1H NMR (DMSO) δ 2.55 (s, 3H), 3.88 (s, 3H), 7.21 (d, J=8.8Hz, 2H), 7.57 (d, J=8.8Hz, 2H), 7.69 (d, J=5.4Hz, 1H), 8.57 (d, J=5.4Hz, 1H), 9.44 (s, 1H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]23[CH2:24][CH:16]([C:17]4[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][C:22]=42)[C:15]2[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:3]1.Cl[C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1.C(N(CC)CC)C.CO>CN1CCCC1=O>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]2[CH:16]3[CH2:24][C:9]([CH2:8][N:5]4[CH2:6][CH2:7][CH:2]([NH:1][C:26]5[N:31]=[CH:30][CH:29]=[CH:28][N:27]=5)[CH2:3][CH2:4]4)([C:10]4[C:15]3=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:22]=2[CH:21]=1
Reactant: Clc1ncccn1
Reactant: NC1CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Solvent: CO
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Clc1ccc2c(c1)C1(CN3CCC(Nc4ncccn4)CC3)CC2c2ccccc21

Procedure:
4-amino-1-(2-chloro-9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)piperidine (0.500 g, 1.48 mmol, prepared as described in Example 7b) was heated to 100° C. for 5 hours in 1.5 mL N-methylpyrrolidinone with 2-chloropyrimidine (0.212 g, 1.85 mmol, commercial grade purified by extraction into petroleum ether) and triethylamine (0.300 g, 2.96 mmol) under a nitrogen atmosphere. Aqueous methanol (3 mL, 50% v/v) was added to the warm (50° C.) reaction mixture to give a white precipitate. The solid was collected by filtration and washed with fresh aqueous methanol (5 mL, 50% v/v) to give the title compound as a white solid. The solid was dissolved in methanolic hydrogen chloride, evaporated to dryness on a rotary evaporator, redissolved in a minimum volume of fresh methanol (2 mL) and added at a slow dropwise rate to rapidly stirring ethyl ether (80 mL) to precipitate the hydrochloride salt as a white solid (0.414 g, 0.99 mmol, 67%), mp 212°-214° C.; MS(CI) 417 (M+H); NMR (250 MHz, DMSO-d6): 10.17(br s, 1H), 8.38-8.33(m, 2H), 7.67(br m, 1H), 7.52`7.49(m, 1H), 7.38-7.31(m, 3H), 7.05-6.96(m, 3H), 6.70-6.63(m, 1H), 4.47(s, 1H), 4.35-4.29(m, 2H), 4.16(br m, 1H), 3.57-3.36(m, 4H), 2.76(m, 2H), 2.12-1.90(m, 4H).
Reaction SMILES: CCOCC.[CH3:6][N:7]([CH2:9][CH2:10][CH2:11]Cl)[CH3:8].[CH3:13][C:14]1([C:19]2[C:29]3[CH2:28][CH2:27][C:26]4[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=4[C:24](=[O:34])[C:23]=3[CH:22]=[CH:21][CH:20]=2)[O:18][CH2:17][CH2:16][O:15]1>O1CCCC1>[CH3:13][C:14]1([C:19]2[C:29]3[CH2:28][CH2:27][C:26]4[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=4[C:24]([CH2:11][CH2:10][CH2:9][N:7]([CH3:8])[CH3:6])([OH:34])[C:23]=3[CH:22]=[CH:21][CH:20]=2)[O:15][CH2:16][CH2:17][O:18]1
Reactant: CC1(c2cccc3c2CCc2ccccc2C3=O)OCCO1
Reactant: CN(C)CCCCl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C)CCCC1(O)c2ccccc2CCc2c(C3(C)OCCO3)cccc21
Temperature: 0 °C

Procedure:
Utilizing 1.13 g. of Gilman alloy, 5 ml. of absolute ether, 5.2 g. of dimethylaminoproyl chloride and 5 ml. of absolute tetrahydrofuran, in a similar manner, is obtained the corresponding Grignard compound. After cooling to 0°C., there is added dropwise a solution containing 7.2 g. of 1-(2-methyl-1,3-dioxolan-2-yl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one in 40 ml. of absolute tetrahydrofuran. Subsequently, the mixture is heated for 3 hours at reflux, cooled to about 0°C., hydrolyzed with 4 ml. of water, filtered, and then washed with ether. The ethereal solution is dried over sodium sulfate, filtered and concentrated under reduced pressure, whereby 1-(2-methyl-1,3-dioxolan-2-yl)-10,11-dihydro-5-(3-dimethylaminopropyl)-5-hydroxy-5H-dibenzo[a,d]cycloheptene is obtained as a yellow oil which is crystallized from 50 ml. of high-boiling petroleum ether and has a melting point of 122°-124°C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[CH3:35][Si:36]([C:39]#[CH:40])([CH3:38])[CH3:37]>C1COCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(Cl)Cl>[CH3:35][Si:36]([C:39]#[C:40][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1)([CH3:38])[CH3:37]
Reactant: C#C[Si](C)(C)C
Reactant: Nc1cncc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si](C)(C)C#Cc1cncc(N)c1
Temperature: 75 °C

Procedure:
To a stirred solution of 7.23 g (41.8 mmol) 5-bromo-3-amino-pyridine in 70 mL dry THF under argon atmosphere is added 238.8 mg (1.3 mmol) CuI, 880 mg (1.3 mmol) bis(triphenylphosphine)palladium(II) chloride, 1.1 g (4.2 mmol) triphenylphosphine and 70 mL (501 mmol) triethylamin. Then 8.3 mL (58.5 mmol) trimethylsilylethyne are added and the reaction is heated at 75° C. over night. After cooling to RT, 100 mL DCM is added and the reaction mixture is extracted twice with 100 water. The organic layer is dried over MgSO4 and the product is purified by chromatography on silica gel. Yield: 5.26 g (66%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]([CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[C:25]([O:27]CC)=[O:26])[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].O.[OH-].[Li+]>CO.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]([CH:30]2[CH2:31][CH2:32][CH2:33][CH2:34]2)[C:25]([OH:27])=[O:26])[CH:5]=[C:6]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=2)[C:7]=1[O:8][CH2:9][C:10]([F:12])([F:13])[F:11]
Reactant: CCOC(=O)C(c1cc(Cl)c(OCC(F)(F)F)c(-c2ccc(C(F)(F)F)cc2)c1)C1CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(c1cc(Cl)c(OCC(F)(F)F)c(-c2ccc(C(F)(F)F)cc2)c1)C1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 21.3 %

Procedure:
A mixture of ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-2-cyclopentylacetate (400 mg, 0.78 mmol) and lithium hydroxide monohydrate (0.330 g, 7.87 mmol) in a MeOH/THF/Water solvent mixture (10 ml/10 ml/10 ml) was stirred for 3 h at room temperature. After completion of reaction volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by Flash Column Chromatography to give 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-2-cyclopentylacetic acid (0.08 g). 1H-NMR (CDCl3, 400 MHz): 12.5 (s, 1H), 7.84 (d, 2H); 7.70 (d, 2H), 7.55 (s, 1H); 7.35 (s, 1H); 4.22 (q, 2H); 3.3.35 (d, 1H); 1.82 (m, 1H); 1.18-1.68 (m, 7H); 1.08 (m, 1H).
Reaction SMILES: [C:1]([S:4][C:5]([S:28]C(=O)C)=[C:6]([N:18]1[CH:21]([S:22](CC=C)=O)[CH2:20][C:19]1=[O:27])[C:7]([O:9][CH2:10][O:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[O:8])(=[O:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[C:1]([S:4][C:5]1[S:28][S:22][CH:21]2[N:18]([C:19](=[O:27])[CH2:20]2)[C:6]=1[C:7]([O:9][CH2:10][O:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[O:8])(=[O:3])[CH3:2]
Reactant: C=CCS(=O)C1CC(=O)N1C(C(=O)OCOC(=O)C(C)(C)C)=C(SC(C)=O)SC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)SC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)CC2SS1
Yield: 53.6 %

Procedure:
A solution of 82 mg of pivaloyloxymethyl 3,3-di(acetylthio)-2-(4-allylsulphinylazetidin-2-on-1-yl)propenoate and 32 mg of 4-toluenesulphonic acid hydrate in 10 ml of dioxan was heated rapidly to reflux and maintained under reflux for 1 hour. The solvent was removed by evaporation and the residue chromatographed on silica gel using ethyl acetate/hexane mixtures as eluant. The product (35 mg, 54%) was obtained as a yellow oil.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:8]([NH:10][CH2:11][C:12]([NH:14][C@H:15]([C:23]([CH:25]1[C:32]2([NH2:34])[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:35][C:26]1([C:36]([O:38][CH3:39])=[O:37])[CH2:27]3)[CH2:31]2)=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13])=[O:9])[CH2:4][CH2:5][S:6][CH3:7].ClC1C([O:47][C:48](=O)[C@H:49]([CH2:58][C:59]2[CH:64]=[CH:63][C:62]([OH:65])=[CH:61][CH:60]=2)[NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])=C(Cl)C(Cl)=C(Cl)C=1Cl.CN1CCOCC1>O1CCCC1.C(OCC)(=O)C>[C:51]([NH:50][C@H:49]([C:48]([NH:2][C@@H:3]([C:8]([NH:10][CH2:11][C:12]([NH:14][C@H:15]([C:23]([CH:25]1[C:32]2([NH2:34])[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:35][C:26]1([C:36]([O:38][CH3:39])=[O:37])[CH2:27]3)[CH2:31]2)=[O:24])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:13])=[O:9])[CH2:4][CH2:5][S:6][CH3:7])=[O:47])[CH2:58][C:59]1[CH:64]=[CH:63][C:62]([OH:65])=[CH:61][CH:60]=1)([O:53][C:54]([CH3:56])([CH3:55])[CH3:57])=[O:52]
Reactant: COC(=O)C12CC3CC(CC(N)(C3)C1C(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@H](N)CCSC)C2
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C12CC3CC(CC(N)(C3)C1C(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H](CCSC)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C2
Reaction time: 4 h

Procedure:
To a solution of 3.513 g of methyl D-methionylglycyl-L-phenylalanyl-3-amino-1-adamantanecarboxylate hydrochloride in 30 ml of tetrahydrofuran is added 3.17 g of Boc-L-tyrosine pentachlorophenyl ester followed by 1.12 ml of N-methylmorpholine. The reaction mixture is allowed to stand for 4 hours at room temperature then diluted with 200 ml ethyl acetate. The ethyl acetate layer is separated and washed three times with a 0.5 M solution of potassium bisulfate then dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue is purified by low pressure chromatography on silica gel to give methyl Boc-L-tyrosyl-D-methionyl-glycyl-L-phenylalanyl-3-amino-1-adamantanecarboxylate which is represented by the following formula ##STR19##
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[CH:5]1.C([Li])CCC.CN([CH:26]=[O:27])C>O1CCCC1>[CH3:1][CH:2]([CH3:17])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[C:5]1[CH:26]=[O:27]
Reactant: CN(C)C=O
Reactant: CC(C)Cn1cnc2cnc3ccccc3c21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)Cn1c(C=O)nc2cnc3ccccc3c21
Temperature: 25 °C

Procedure:
A solution of 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (U.S. Pat. No. 5,175,296 Example 1 Part C, 25.64 g, 113.8 mmol) in tetrahydrofuran (THF) (450 mL) was cooled to −78° C. Butyllithium (45.5 mL of a 2.5 M solution in hexanes) was added dropwise over a period of ten minutes, and the resulting solution was stirred for ten minutes. DMF (20.1 mL, 274.4 mmol) was added, and the reaction was allowed to warm to room temperature and stirred for one hour. The THF was then removed under reduced pressure, and the residue was dissolved in ethyl acetate (400 mL). The resulting solution was washed with brine (400 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting sequentially with 0.5% and 1% methanol in dichloromethane) to provide 10.5 g of 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-carbaldehyde as a light brown solid.
Reaction SMILES: [CH2:1]1C2[C:7]3[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9][C:8]=3[C:21]3[CH:22]=[CH:23][CH:24]=[C:4]([C:5]=32)[O:3][CH2:2]1.[BH3-]C#[N:27].[Na+].Cl.[OH-].[Na+]>C(O)(C(F)(F)F)=O>[CH2:1]1[N:27]2[C:5]3[C:21]([CH:8]4[CH2:9][CH2:10][NH:11][CH2:12][CH2:13][CH:7]42)=[CH:22][CH:23]=[CH:24][C:4]=3[O:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC2=C(CC1)C1CCOc3cccc2c31
Reactant: [BH3-]C#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: c1cc2c3c(c1)C1CCNCCC1N3CCO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 112.4 %

Procedure:
Tert-butyl 1,7,8,10,11,11b-hexahydropyrano[4′,3′,2′:3,4]indeno[1,2-d]azepine-9(2H)-carboxylate (407 mg, 1.24 mmol) was dissolved in TFA (10 mL). This solution was cooled to 0° C., and NaCNBH3 (234 mg, 3.72 mmol) was added in small portions. The reaction was stirred at 0° C. for 1 hr. Conc. HCl (5 mL) was added to the reaction flask, and then the mixture was refluxed at 50° C. for 30 min. The reaction was re-cooled to 0° C., and ice chips were added. The solution was basified with 50% NaOH until a pH=14. The reaction was extracted with CHCl3 (3×20 mL). The combined organic layers were washed with brine, dried, and concentrated to afford the title compound (321 mg, 100%) as an amorphous solid. 1H NMR (CDCl3, 300 MHz) δ6.57-6.67 (3H, m), 4.39-4.43 (2H, m), 3.61-3.69 (1H, m), 3.45 (1H, dt, J=3.3 Hz, 9.2 Hz), 3.00-3.24 (3H, m), 2.69-2.89 (3H, m), 2.02-2.16 (2H, m), 1.83-1.97 (2H, m).
Reaction SMILES: [S:1]([C:5]1[S:14][C:13]2[S:12](=[O:16])(=[O:15])[CH2:11][CH2:10][NH:9][CH2:8][C:7]=2[CH:6]=1)(=[O:4])(=[O:3])[NH2:2].[C:17](OC(=O)C)(=[O:19])[CH3:18].C(N(CC)CC)C>C(#N)C.O1CCCC1>[C:17]([N:9]1[CH2:8][C:7]2[CH:6]=[C:5]([S:1](=[O:4])(=[O:3])[NH2:2])[S:14][C:13]=2[S:12](=[O:15])(=[O:16])[CH2:11][CH2:10]1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: NS(=O)(=O)c1cc2c(s1)S(=O)(=O)CCNC2
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(=O)N1CCS(=O)(=O)c2sc(S(N)(=O)=O)cc2C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.7 %

Procedure:
A solution of 7-sulfamoyl-2,3,4,5-tetrahydrothieno[3,2-f]-1,4-thiazepin-1,1-dioxide (240 mg, 0.85 mmole) in acetonitrile (5 mL) and tetrahydrofuran (5 mL) containing acetic anhydride (100 mg, 0.94 mmol) and triethylamine (0.17 mL, 1.22 mmol) was stirred at ambient temperature for 1.5 hours. The solvents were evaporated and the residue chromatographed on silica gel. Elution with 10% methanol-methylene chloride gave 250 mg (77%) of the title compound. This material was used as is.
Reaction SMILES: CN(C)C=O.[OH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2.C(=O)([O-])[O-].[K+].[K+].[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[N:45]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[C:39]3[N:40]=[CH:41][N:42]=[C:43](Cl)[C:38]=3[CH:37]=2)=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[CH2:22]([O:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]2[N:45]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[C:39]3[N:40]=[CH:41][N:42]=[C:43]([O:6][C:7]4[CH:8]=[C:9]5[C:13](=[CH:14][CH:15]=4)[NH:12][CH:11]=[CH:10]5)[C:38]=3[CH:37]=2)=[CH:34][CH:35]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OCc3ccccc3)cc2)cc2c(Cl)ncnc21
Reactant: Oc1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(-c2ccc(OCc3ccccc3)cc2)cc2c(Oc3ccc4[nH]ccc4c3)ncnc21
Reaction time: 4 h
Yield: 39.2 %

Procedure:
After adding 1.9 ml of dimethylformamide, 180 mg of 5-hydroxyindole and 112 mg of potassium carbonate to 190 mg of 6-(4-benzyloxyphenyl)-4-chloro-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine, the mixture was stirred at 135–140° C. for 4 hours. After returning it to room temperature, water was added, and liquid separation and extraction were performed with an ethyl acetate:tetrahydrofuran (5:1) mixed solvent. The organic layer was concentrated and subjected to NH silica gel column chromatography (hexane-ethyl acetate) to obtain 90 mg of the title compound.