Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[OH:13])([CH3:3])[CH3:2].[OH-].[Na+].Br[CH2:17][Cl:18]>C1COCC1>[Cl:18][CH2:17][O:13][C:5]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=[CH:7][C:6]=1[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)c1cccc(C(C)C)c1O
Reactant: ClCBr
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)c1cccc(C(C)C)c1OCCl
Temperature: 64 °C
Yield: 74 %

Procedure:
A four-necked 500 mL round bottom flask was equipped with a mechanical stirrer, nitrogen inlet, condenser and thermometer. It was charged with 17.8 grams (0.10 moles) of 2,6-diisopropylphenol, 200 mL of THF, 8.0 grams (0.20 mole) of sodium hydroxide pellets, and 387 grams (3.0 moles, 194 mL) of bromochloromethane. The reaction mixture was heated to 64° C. and held for 2-3 hours until no more 2,6-diisopropylphenol was present as measured by GC. After cooling to 25° C., the suspension was filtered and the filter cake was washed with THF. The THF was removed by rotary evaporation and the resultant oil was distilled under vacuum (0-1 torr, b.p.=80° C.) to give 16.9 grams (0.074 moles, 75% yield) of O-chloromethyl 2,6-diisopropyl phenol.
Reaction SMILES: [O:1]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([C:21]([O:23][CH3:24])=[O:22])([CH3:20])[CH3:19])=[CH:13][CH:12]=1)[Si](C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH3:24][O:23][C:21]([C:18]([CH3:20])([CH3:19])[CH2:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][OH:1])=[CH:16][CH:15]=1)=[O:22]
Reactant: COC(=O)C(C)(C)Cc1ccc(CCO[Si](C)(C)C(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)Cc1ccc(CCO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
To a solution of lithium diisopropylamide (0.1 mol/l solution in tetrahydrofuran, 15 ml) was added a solution of 1-(2-t-butyldimethylsiloxyethyl)-4-(2-methoxycarbonylpropyl)benzene (0.62 g) in tetrahydrofuran (2 ml) at -78° C., and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added a solution of iodomethane (0.20 g) in tetrahydrofuran (2 ml), and the mixture was stirred at room temperature for 4 hours. To the reaction mixture was added water, and the mixture was extracted with diethyl ether. The extract was washed with water, and dried over anhydrous MgSO4. The solvent was removed under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on a silica gel column using a mixture of n-hexane and methylene chloride (3:1) as eluent to give 1-(2-t-butyldimethylsiloxyethyl)-4-(2-methoxycarbonyl-2-methylpropyl)benzene (0.49 g) as an oily liquid. To a solution of 1-(2-t-butyldimethylsiloxyethyl)-4-(2-methoxycarbonyl-2-methylpropyl)benzene (0.49 g) in tetrahydrofuran (1.5 ml) was added tetra-n-butylammonium fluoride (1 mol/l solution in tetrahydrofuran, 1.34 ml), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added water, and the mixture was extracted with diethyl ether. The extract was washed with water, and dried over anhydrous MgSO4. The solvent was removed under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on a silica gel column using a mixture of methylene chloride and diethyl ether (7:1) as eluent to give 2-[4-(2-methoxycarbonyl-2-methylpropyl)phenyl]ethyl alcohol (0.300 g) as an oily liquid. To a solution of 2-[4-(2-methoxycarbonyl-2-methylpropyl)phenyl]ethyl alcohol (0.300 g) in methylene chloride (3 ml) were added carbon tetrabromide (0.48 g) and triphenylphosphine (0.38 g), and the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on a silica gel column using a mixture of n-hexane and methylene chloride (3:1) as eluent to give 2-[4-(2-methoxycarbonyl-2-methylpropyl)phenyl]ethyl bromide (0.323 g) as an oily liquid.
Reaction SMILES: [CH:1](/[C:4]1[C:14]2[O:13][CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)=[CH:2]\[CH3:3]>[Pd].CO>[CH2:1]([C:4]1[C:14]2[O:13][CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: C/C=C/c1cccc2c1OCCN(C(=O)OC(C)(C)C)C2
Agent: [Pd]
Solvent: CO
Product: CCCc1cccc2c1OCCN(C(=O)OC(C)(C)C)C2
Reaction time: 12 h
Yield: 81.9 %

Procedure:
A mixture of tert-butyl 9-[(1E)-propa-1-ene-1-yl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (170 mg, 0.587 mmol) and 10% palladium on carbon (100 mg) in methanol (5 ml) was stirred under a hydrogen atmosphere for 12 hr. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (140 mg, 81.9%) as an oil.
Reaction SMILES: [CH3:1][N:2]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.Br[CH:20]([CH3:25])[C:21]([O:23][CH3:24])=[O:22].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][N:2]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH:20]([CH3:25])[C:21]([O:23][CH3:24])=[O:22])=[CH:14][CH:13]=1)[C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[N:4]=1
Reactant: COC(=O)C(C)Br
Reactant: CN(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1ccc(N(C)c2nc3ccccc3[nH]2)cc1
Temperature: 100 °C
Yield: 64.5 %

Procedure:
A mixture of 4-[N-methyl-N-(2-benzimidazolyl)amino]phenol (1.14 g), methyl 2-bromopropionate (0.80 g), anhydrous potassium carbonate (0.72 g) and dimethylformamide (25 ml) was heated for 4 hours at a temperature of 100° C. with vigorous stirring. After cooling, the mixture was poured into water and the aqueous solution was extracted with dichloromethane. The organic extract was washed with water, dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue was purified by chromatography over silica gel with dichloromethane elution to give methyl 2-{4-[N-methyl-N-(2-benzimidazolyl)amino]phenoxy}propionate (1.0 g) as a colourless oil. The pmr spectrum of the compound was consistent with the assigned structure (CDCl3 ; chemical shift δppm): 1.50, d, 3H; 3.35, s, 3H; 3.70, s, 3H; 4.60, q, 1H; 6.50-7.60, m, 9H.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][C:4]2[CH:7]([NH2:11])[CH2:8][CH2:9][CH2:10][C:3]1=2.C(N(CC)CC)C.[CH3:19][N:20]=[C:21]=[O:22]>C1C=CC=CC=1>[CH3:19][NH:20][C:21]([NH:11][CH:7]1[C:4]2[CH:5]=[CH:6][S:2][C:3]=2[CH2:10][CH2:9][CH2:8]1)=[O:22]
Reactant: NC1CCCc2sccc21
Reactant: CN=C=O
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CNC(=O)NC1CCCc2sccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1.89 grams (0.01 mole) of 4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine hydrochloride in 20 ml. of dry benzene is stirred while 1.05 grams (0.01 mole) of triethylamine and 01.7 ml. (excess) of methyl isocyanate are added successively. Addition of the latter gives rise to an exotherm, and the mixture becomes very pasty. The mixture is kept at 45° C. for 1 hour, and after cooling to room temperature, the solid is collected, washed thoroughly with benzene and then with water. On drying, this gives 1.7 grams (81%) of product, melting point 183° C. to 186° C. Recrystallization from acetone gives 1.23 grams, melting point 187.5° C. to 189° C.
Reaction SMILES: [CH3:1][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[C:31]([O:34][CH2:35][CH2:36][CH2:37][C:38]([C:40]1[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][CH:41]=1)=O)(=[O:33])[CH3:32]>O1CCCC1>[C:31]([O:34][CH2:35][CH2:36][CH2:37][C:38]([C:40]1[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][CH:41]=1)=[CH2:1])(=[O:33])[CH3:32]
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(C(=O)CCCOC(C)=O)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C(CCCOC(C)=O)c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl triphenylphosphonium (1.5 g, 1.1 eq) was suspended in 50 ml of anhydrous tetrahydrofuran and 4.0 ml of 1.0M solution of sodium hexamethyldisilazide (1.05 eq) in tetrahydrofuran were added via syringe. The mixture was stirred at room temperature for one hour and a solution of 1.0 g (1.0 eq) of methyl 4-(4-acetoxy-1-oxobutyl)benzoate in anhydrous tetrahydrofuran, was added dropwise. The resulting reaction mixture was stirred for 2 hours at room temperature. Sodium bromide/triphenylphosphineoxide precipitate was removed by filtration, and the filtrate washed with water. After extraction of the aqueous layer with diethyl ether, the organic layers were dried over magnesium sulfate and evaporated to dryness to yield the product which was further purified by flash chromatography eluting with 1:5 ethyl acetate:hexanes. M.S.:m/z=262 (M+,CI), 231.1020 (M+ --CH3O, calc. for C14H15O3 : 231.1021), 202 (M+ - AcOH), 176, 143 (100%). 1H-N.M.R. (CDCl3, 300 MHz): δ=1.80(quin, 2H, CH2 --CH2 --CH2, J=7.5 Hz); 2:04(s, 3H, CH3 --CO); 2.62 (t, 2H, CH2 --C=, J=7.5 Hz); 3.94(s, 3H, CH3O); 4.10(t, 2H, CH2O, J=7.5 Hz); 5.20 (s, 1Holef.); 5.41(s, 1Holef.); 7.48(d, 2Harom., J=9 Hz); 8.01(d, 2Harom., J=9 Hz).
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[CH3:14][C:15]1[N:20]=[C:19]([SH:21])[N:18]=[C:17]([OH:22])[CH:16]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[ClH:2].[CH3:14][C:15]1[N:20]=[C:19]([S:21][CH2:3][C:4]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[N:18]=[C:17]([OH:22])[CH:16]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: Cc1cc(O)nc(S)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(O)nc(SCc2ccc3ccccc3n2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
A mixture of 2-(chloromethyl)quinoline hydrochloride (1.0 g, 4.67 mmol) and 6-methyl-2-sulfanylpyrimidin-4-ol (0.46 g, 3.26 mmol) and K2CO3 (1.28 g, 9.34 mmol) in DMF (25 mL) was stirred overnight at room temperature. The solvent was filtered and evaporated to provide the crude product. Water was added to the crude reaction mixture to precipitate the product, which was then filtered and washed with water and ether to provide the titled product as a beige solid (0.68 g, 52% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.09 (s, 3H), 2.31 (s, 3H), 4.95 (s, 2H), 6.04 (bs, 1H), 7.87 (t, J=7.8, 15.0 Hz, 1H), 8.08 (m, 2H), 8.26 (d, J=8.1 Hz, 1H), 8.48 (d, J=8.2 Hz, 1H), 9.00 (d, J=8.2 Hz, 1H); M+283.3.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:37]2[CH:42]=[CH:41][C:40]([S:43]([NH2:46])(=[O:45])=[O:44])=[CH:39][CH:38]=2)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][O:16][C:12]1[C:11]2[C:7]([C:37]3[CH:42]=[CH:41][C:40]([S:43]([NH2:46])(=[O:45])=[O:44])=[CH:39][CH:38]=3)=[N:8][N:9]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[C:10]=2[CH:15]=[CH:14][N:13]=1
Reactant: COc1ccc(Cn2nc(OS(=O)(=O)C(F)(F)F)c3c(OC)nccc32)cc1
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2nc(-c3ccc(S(N)(=O)=O)cc3)c3c(OC)nccc32)cc1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
To a solution of 4-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (100 mg) in DMF (4 mL)/water (0.30 mL) were added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (102 mg), tetrakis(triphenylphosphine)palladium(0) (27.7 mg) and potassium carbonate (66.2 mg). The reaction mixture was stirred under microwave irradiation at 130° C. for 30 min. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (45.0 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([F:27])[CH:26]=1)[CH2:5][C@H:6]1[CH2:11][C@H:10]([C:12](=[O:19])[CH2:13][C:14](OCC)=[O:15])[CH2:9][CH2:8][N:7]1[C:20]([O:22][CH3:23])=[O:21].[OH-].[Na+].[NH2:30]O.Cl>CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([F:27])[CH:26]=1)[CH2:5][C@H:6]1[CH2:11][C@H:10]([C:12]2[O:19][NH:30][C:14](=[O:15])[CH:13]=2)[CH2:9][CH2:8][N:7]1[C:20]([O:22][CH3:23])=[O:21]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](Cc2cc(F)cc(F)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1cc(F)cc(F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 76 %

Procedure:
Trans-methyl 2-(3,5-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (0.927 g, 2.42 mmol) (from example 130, step 1) was dissolved in MeOH (8 mL) and cooled to −40° C. under nitrogen atmosphere. Sodium hydroxide (0.097 g, 2.42 mmol) dissolved in water (0.800 mL) was added over 7 min. After 20 min with stirring, hydroxylamine (50% by weight in water, 0.148 mL, 2.42 mmol) was added over 4.5 minutes and the solution was stirred for 3.5 hours at −40° C. The reaction mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (12.45 mL, 74.71 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and the crude mixture redissolved in DCM and washed with water. The organic phase was dried and concentrated. The compound was purified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-25% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Trans-methyl 2-(3,5-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.648 g, 76%) was isolated as a white solid. 1H NMR (400 MHz, cd3od) δ 1.45-2.12 (m, 4H), 2.80-3.35 (m, 4H), 3.35-3.70 (m, 3H), 4.12 (s, br., 1H), 4.62 (s, br., 1H), 5.71 (s, 1H), 6.77 (t, 1H), 6.87 (s, br., 2H). MS m/z 353 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:20])[N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:21]=O.[CH3:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][C:27](=[O:33])[NH:28]2>>[CH3:1][C:2]1[C:6]2[C:7](=[O:20])[N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1/[CH:21]=[C:26]1\[C:27](=[O:33])[NH:28][C:29]2[C:25]\1=[C:24]([CH3:23])[CH:32]=[CH:31][CH:30]=2
Reactant: Cc1cccc2c1CC(=O)N2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Product: Cc1cccc2c1/C(=C/c1[nH]c3c(c1C)C(=O)N(CCN1CCCCC1)CCC3)C(=O)N2
Yield: 70.9 %

Procedure:
The title compound was prepared under the same conditions as described in step 5 of Example 32 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 32d obtained from step 4 of Example 32 and 4-methyl-1,3-dihydro-indol-2-one as starting materials to obtain (Z)-3-methyl-2-(4-methyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-piperidin-1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 58 (46 mg, yield 70.9%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH2:7][CH3:8])[N:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:3]=1[C:13]([OH:15])=O.S(Cl)(Cl)=O.[OH-].[NH4+:21]>ClCCl>[Cl:1][C:2]1[N:6]([CH2:7][CH3:8])[N:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:3]=1[C:13]([NH2:21])=[O:15]
Reactant: [NH4+]
Reactant: CCn1nc(C(F)(F)F)c(C(=O)O)c1Cl
Agent: [OH-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCn1nc(C(F)(F)F)c(C(N)=O)c1Cl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A mixture of 22.5 g (91.6 mmol) of 5-chloro-1-ethyl-3-(trifluoromethyl)pyrazole-4-carboxylic acid and 45 mL of thionyl chloride was prepared and heated to reflux with stirring for 3 hours. The slurry became a dark orange solution. The excess thionyl chloride and other volatiles were removed by evaporation under reduced pressure to obtain a dark brown oil. This was taken up in 250 mL of dichloromethane and the resulting solution was cooled to about 0° C. and treated with 100 mL of concentrated ammonium hydroxide, which was added dropwise with stirring and cooling. When the addition was complete, the mixture was allowed to warm to ambient temperature and stir over a 2-hour period. The solids were collected by filtration and washed with water (3×50 mL). The solids that formed in the filtrate due to evaporation of the dichloromethane were collected in the same way. The combined solids were washed with water (2×100 mL) and were then suspended in water for 2 hours, recollected by filtration, and dried in an oven under reduced pressure. The white solid obtained was 18.4 g of the title compound melting at 15°-152° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[O:40]([C:47]1[CH:48]=[C:49]([CH:53]=[CH:54][CH:55]=1)[C:50](Cl)=[O:51])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[O:40]([C:47]1[CH:48]=[C:49]([CH:53]=[CH:54][CH:55]=1)[C:50]([O:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:29][CH2:30]4)(=[O:26])=[O:27])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1)=[O:51])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: O=C(Cl)c1cccc(Oc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)NC1COCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Product: CC(C)(C)OC(=O)NC1COCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(OC(=O)c3cccc(Oc4ccccc4)c3)CN2C1=O
Yield: 15.6 %

Procedure:
Prepared by way of method I using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-12-oxatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.175 mmol) and 3-phenoxybenzoyl chloride (122 μL, 0.53 mmol). The final trituration (diethyl ether/hexane) and filtration gave 21 mg (16%) of 18-(3-phenoxybenzoyloxy)-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-12-oxatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 98.0% pure (HPLC), MS m/z 765 (M−H)−, HRMS: calcd. 767.2962 and found 767.2971 (M+H)+, mp 123-125° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(C(C)C)C(C)C)C.C1(C)C=CC(S(O[CH2:31][CH2:32][CH:33]2[CH2:42][CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[O:34]2)(=O)=O)=CC=1>CN(C)C=O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:31][CH2:32][CH:33]2[CH2:42][CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[O:34]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OCCC2CCc3ccccc3O2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(CCC2CCc3ccccc3O2)CC1
Reaction time: 16 h
Yield: 74.8 %

Procedure:
First 1.57 g (10 mmol) of piperidine-4-carboxylic acid ethyl ester and then 2.07 g (16 mmol) of N-ethyl-N,N-diisopropylamine are added to a solution of 2.66 g (8 mmol) of 2-[2-(p-toluenesulphonyloxy)ethyl]chroman in 35 ml of absolute dimethylformamide. The mixture is stirred for 16 hours at 60° and then, after cooling, is concentrated by evaporation under a high vacuum. Water is added to the oily residue and extraction is carried out with diethyl ether. The combined organic phases are washed with water and extracted with 2N hydrochloric acid. The combined hydrochloric acid extracts are rendered alkaline, while cold, with sodium hydroxide solution (30% strength) and extracted with dichloromethane. The combined dichloromethane phases are dried over sodium sulphate and concentrated by evaporation in vacuo. 2.17 g (85.7%) of crude product are obtained and are chromatographed on 110 g of silica gel (0.040-0.063 mm) using ethyl acetate as the eluant. 1.90 g (75.1%) of 1-[2 -(chroman-2-yl)ethyl]-piperidine-4-carboxylic acid ethyl ester are thus obtained in the form of a yellow oil. The 1-[2-(chroman-2-yl)ethyl]-piperidine-4-carboxylic acid ethyl ester hydrochloride produced therefrom using hydrochloric acid in diethyl ether crystallises from ethanol/diethyl ether and melts at 190°-192°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:23][C:22](=[O:24])[C:9]3([CH2:14][CH2:13][N:12]([CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:11][CH2:10]3)[N:8]=[C:7]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:6]=2[CH:31]=1.[H-].[Na+].[CH3:34]I>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:23]([CH3:34])[C:22](=[O:24])[C:9]3([CH2:10][CH2:11][N:12]([CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:13][CH2:14]3)[N:8]=[C:7]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:6]=2[CH:31]=1
Reactant: O=C1Nc2ccc(Cl)cc2C(c2ccccc2)=NC12CCN(Cc1ccccc1)CC2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)C2(CCN(Cc3ccccc3)CC2)N=C(c2ccccc2)c2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
3.0 g (0.0069 mole) of 7-chloro-5-phenyl-1'-benzyl-spiro[1H-1,4-benzodiazepine-3,4'-piperidin]-2(3H)-one are dissolved in 25 ml of absolute dimethylformamide, and 0.3 g (0.007 mole) of sodium hydride (55-60% strength dispersion) is added at 20° C. After the mixture has been stirred for 20 minutes, it is cooled to 0° C., a solution of 1.0 g (0.0065 mole) of methyl iodide in 5 ml of absolute dimethylformamide is added dropwise and the mixture is stirred at 25° C. for 3 hours. The solvent is distilled off and the residue is purified by column chromatography over silica gel 60 (Merck). After the column has been eluted with methylene chloride/methanol (9:1), the oily base is obtained, which slowly crystallizes completely. Colorless crystals of melting point 169°-170° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=1.[NH4+:12].[OH-]>>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:12])[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=1
Reactant: [NH4+]
Reactant: Clc1cc(Cl)n2nccc2n1
Agent: [OH-]
Product: Nc1cc(Cl)nc2ccnn12
Temperature: 85 °C
Yield: 100 %

Procedure:
To 5,7-dichloropyrazolo[1,5-a]pyrimidine (7.6 g, 40.4 mmol) in a sealed vessel was added NH4OH (100 mL). The vessel was then sealed and heated at 85° C. for 2.5 hours, at which time the consistency of the white solid had changed (from foamy white solid to free-flowing white solid). The vessel was removed from the heat source and allowed to cool to room temperature overnight. On cooling, the contents of the vessel were collected and dried by vacuum filtration giving 5-chloropyrazolo[1,5-a]pyrimidin-7-amine as a yellow-tinged white solid (6.8 g, 40.3 mmol, 100%).