Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](Cl)[C:5]2[C:6](=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:9]([CH3:11])[N:10]=2)[N:7]=1.[C:21]1([CH3:31])[CH:26]=CC(S(O)(=O)=O)=CC=1>C(NCCC)CC>[CH3:1][C:2]1[CH:3]=[C:4]([N:7]([CH2:26][CH2:21][CH3:31])[CH2:2][CH2:3][CH3:4])[C:5]2[C:6](=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:9]([CH3:11])[N:10]=2)[N:7]=1
Reactant: Cc1cc(Cl)c2nn(C)c(-c3ccc(Cl)cc3Cl)c2n1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCNCCC
Product: CCCN(CCC)c1cc(C)nc2c(-c3ccc(Cl)cc3Cl)n(C)nc12

Procedure:
Intermediate (5) was suspended in dipropylamine (1 ml) and p-toluenesulfonic acid (30 mg) and heated to 200° C. for 2 hours in a sealed tube. The reaction mixture was cooled and partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was separated, dried and concentrated. The residue was purified over silica gel (eluens: ethyl acetate/hexanes), yielding 5-methyl-7-(dipropylamino)-2-methyl-3-(2,4-dichlorophenyl)pyrazolo[4,3-b]pyridine (compound 1).
Reaction SMILES: [Si]([O:8][C:9]1[C:17]([CH2:18]/[CH:19]=[C:20](\[CH3:28])/[CH2:21][CH:22]([CH3:27])[C:23]([O:25][CH3:26])=[O:24])=[C:16]([O:29][CH3:30])[C:15]([CH3:31])=[C:14]2[C:10]=1[C:11](=[O:32])[O:12][CH2:13]2)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C:9]1[C:17]([CH2:18]/[CH:19]=[C:20](\[CH3:28])/[CH2:21][CH:22]([CH3:27])[C:23]([O:25][CH3:26])=[O:24])=[C:16]([O:29][CH3:30])[C:15]([CH3:31])=[C:14]2[C:10]=1[C:11](=[O:32])[O:12][CH2:13]2
Reactant: COC(=O)C(C)C/C(C)=C/Cc1c(OC)c(C)c2c(c1O[Si](C)(C)C(C)(C)C)C(=O)OC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)C(C)C/C(C)=C/Cc1c(O)c2c(c(C)c1OC)COC2=O
Temperature: 0 °C

Procedure:
To methyl (E)-6-(4-tert-butyldimethylsilyloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2,4-dimethyl-4-hexenoate (0.8 g) in tetrahydrofuran (5 ml) was added 1N tetra-n-butylammonium fluoride in tetrahydrofuran (4 ml). After 10 minutes the solution was diluted with ice water and extracted with ethyl acetate. The extract was dried and evaporated to give methyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2,4-dimethyl-4-hexenoate as an oil.
Reaction SMILES: O=[C:2]([CH:8]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=1)[CH2:9][C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].O.[NH2:28][NH2:29]>C(O)C>[N+:24]([C:20]1[CH:19]=[C:18]([CH:8]2[CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:29][N:28]=[C:2]2[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:23]=[CH:22][CH:21]=1)([O-:26])=[O:25]
Reactant: NN
Reactant: CCOC(=O)C(=O)C(CC(=O)c1ccccc1)c1cccc([N+](=O)[O-])c1
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1=NNC(c2ccccc2)=CC1c1cccc([N+](=O)[O-])c1
Yield: 35.1 %

Procedure:
A mixture of ethyl 2,5-dioxo-3-(3-nitrophenyl)-5-phenylpentanoate (1.5 g) and hydrazine monohydrate (0.24 g) in ethanol (30 ml) was refluxed for 5.5 hours. After evaporating the solvent in vacuo, the residue was subjected to a column chromatography on silica gel (100 ml) eluting with a mixture of benzene and ethyl acetate (50:1 V/V). The fractions containing the object compound were combined and concentrated under reduced pressure to give ethyl 1,4-dihydro-4-(3-nitrophenyl)-6-phenyl-3-pyridazinecarboxylate (0.52 g).
Reaction SMILES: Br[C:2]12[CH2:11][C:6]3([CH3:12])[CH2:7][CH:8]([CH2:10][C:4]([CH3:13])([CH2:5]3)[CH2:3]1)[CH2:9]2.[NH2:14]C(N)=O.Cl>C(O)=O>[NH2:14][C:2]12[CH2:11][C:6]3([CH3:12])[CH2:7][CH:8]([CH2:10][C:4]([CH3:13])([CH2:5]3)[CH2:3]1)[CH2:9]2
Reactant: NC(N)=O
Reactant: CC12CC3CC(C)(C1)CC(Br)(C3)C2
Agent: Cl
Solvent: O=CO
Product: CC12CC3CC(C)(C1)CC(N)(C3)C2
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To 100 g of 1-bromo-3,5-dimethyl adamantane and 86 g of urea, adding 72 ml of 94 wt % formic acid, heating to 120° C. and holding for 2 hours. Cooling to the room temperature and adding 385 ml of 10% hydrochloric acid to hydrolyze at 100° C. for about 1 hour. Adjusting with 30% sodium hydroxide solution to a pH of 12, extracting with butyl acetate twice, combining the organic layers and washing with water. Concentrating under reduced pressure to yield a limpid yellow solution as 1-amino-3,5-dimethyl adamantane crude. To the crude, adding 150 ml of ethanol and concentrated hydrochloric acid, heating to dissolve and crystallizing to yield white solid. Drying the solid and re-crystallizing with water to yield 60.4 g of pure Memantine Hydrochloride. The yield is 68.1% (GC 99.1%).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]=[C:2]1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1Br)=[O:9].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C1C=CC=CC=1>[N:1]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:8](=[O:9])[C:2]=12
Reactant: O=C(C1=NCCCCN1)c1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: O=C1C2=NCCCCN2c2ccccc21

Procedure:
A solution of o-bromophenyl 4,5,6,7-tetrahydro-1H-1,3-diazepin-2-yl ketone (0.7 g.) in dry dimethylformamide (5 ml.) was stirred with potassium carbonate (0.35 g.) and cupric oxide (0.030 g.) at 90°C for 2 hr. under nitrogen. The mixture was diluted with benzene (100 ml.), filtered, washed with water (3 × 50 ml.) and dried over magnesium sulphate. After removal of the solvent under reduced pressure the residue was extracted with hot cyclohexane (ca.150 ml). The extracts slowly crystallised to give the 2,3,4,5-tetrahydro-1,3-diazepino[1,2-a]-indol-11-one as reddish-brown needles (0.179 g.) m.p. 137° - 139°C(dec.). An analytical sample was recrystallised from toluene, m.p. 140° - 141°C(dec.)
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-])=O>CO.[Pd]>[NH2:11][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[OH:1])[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1ccc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: Nc1cc(C(=O)O)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
A mixture of 4-hydroxy-3-nitrobenzoic acid (10 g, 1.0 eq) and 2 g Pd/C in 100 mL MeOH was stirred at rt under H2 (1 atm) overnight, and then filtered. The filtrate was concentrated under reduced pressure to afford the desired product (8.0 g, 95%). 1H NMR (400 MHz, DMSO-d6) δ 10.00 (brs, 1H), 7.19 (s, 1H), 7.07 (d, J=8.4 Hz, 1H), 6.67 (d, J=8.4 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:9][O:8][C:7]2[CH:10]=[C:11]([N+:17]([O-])=O)[C:12]([C:14]([OH:16])=[O:15])=[CH:13][C:6]=2[O:5]1>CO.[Pd]>[NH2:17][C:11]1[C:12]([C:14]([OH:16])=[O:15])=[CH:13][C:6]2[O:5][CH:4]([CH2:3][O:2][CH3:1])[CH2:9][O:8][C:7]=2[CH:10]=1
Reactant: COCC1COc2cc([N+](=O)[O-])c(C(=O)O)cc2O1
Agent: [Pd]
Solvent: CO
Product: COCC1COc2cc(N)c(C(=O)O)cc2O1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The titled compound of Example 4 (1.22 g, 4.53 mmol) was dissolved in 10 ml of methanol, and added 10% (w/v) Pd/C as a catalyst, followed by stirring for 24 hours at 25° C. Then, the reaction mixture was filtered to give a filtrate, which was then dried under vacuum to obtain a solid compound. The solid compound was recrystallized with ethanol to prepare the titled compound (0.702 g, 65%, m.p. 161-167° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([NH:20][CH:21]1[CH2:27][S:26][CH:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24][N:23]([CH2:34][C:35]([O:37]C(C)(C)C)=[O:36])[C:22]1=[O:42])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[CH2:1]([O:8][C:9]([CH:11]([NH:20][CH:21]1[CH2:27][S:26][CH:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24][N:23]([CH2:34][C:35]([OH:37])=[O:36])[C:22]1=[O:42])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CN1CC(c2ccccc2)SCC(NC(CCc2ccccc2)C(=O)OCc2ccccc2)C1=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CN1CC(c2ccccc2)SCC(NC(CCc2ccccc2)C(=O)OCc2ccccc2)C1=O

Procedure:
0.10 g of isomer B of t-butyl α-[6-(1-benzyloxycarbonyl-3-phenylpropylamino)-5-oxo-2-phenylperhydro-1,4-thiazepin-4-yl]acetate (prepared as described in Example 21) was treated with trifluoroacetic acid to remove its t-butyl group by the process described in Example 3. 70 mg of the title compound were obtained as amorphous solid.
Reaction SMILES: [C:1]([C:5]1[N:6]([CH2:31][C:32](=[O:36])[C:33]([OH:35])=[O:34])[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([NH:14][C:15]([C:17]1([C:20]3[CH:30]=[CH:29][C:23]4[O:24][C:25]([F:28])([F:27])[O:26][C:22]=4[CH:21]=3)[CH2:19][CH2:18]1)=[O:16])=[CH:9][CH:8]=2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([C:5]1[N:6]([CH2:31][CH:32]([OH:36])[C:33]([OH:35])=[O:34])[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([NH:14][C:15]([C:17]1([C:20]3[CH:30]=[CH:29][C:23]4[O:24][C:25]([F:28])([F:27])[O:26][C:22]=4[CH:21]=3)[CH2:19][CH2:18]1)=[O:16])=[CH:9][CH:8]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2n1CC(=O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2n1CC(O)C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-(2-tert-butyl-5-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-1H-indol-1-yl)-2-oxopropanoic acid (50 mg, 0.10 mmol) in MeOH (1 mL) was added NaBH4(19 mg, 0.50 mmol) at 0° C. The mixture was stirred at room temperature for 15 min. The resulting mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc twice and the combined organic layers were washed with brine and dried over anhydrous MgSO4. After the removal of the solvent, the residue was taken up in DMSO and purified by preparative LC/MS to give 3-(2-tert-butyl-5-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-1H-indol-1-yl)-2-hydroxypropanoic acid. 1 H NMR (400 MHz, CDCl3) δ 7.36(s), 7.27-7.23(m, 2H), 7.15-7.11 (m, 2H), 6.94(d, J=8.5 Hz, 1H), 6.23(s, 1H), 4.71(s, 3H), 4.59(q, J=10.3 Hz, 1H), 4.40-4.33 (m, 2H), 1.70(d, J=1.9 Hz, 2H), 1.15(q, J=4.0 Hz, 2H). 13C NMR (400 MHz, CDCl3) δ 173.6, 173.1, 150.7, 144.1, 143.6, 136.2, 135.4, 134.3, 131.7, 129.2, 129.0, 127.6, 126.7, 116.6, 114.2, 112.4, 110.4, 110.1, 99.7, 70.3, 48.5, 32.6, 30.9, 30.7, 16.8. MS (ESI) m/e (M+H+) 501.2.
Reaction SMILES: NC1C=CC=C2C=1C=CN=C2.C(N(CC)CC)C.C(=S)=[S:20].[CH:22]1([N:28]=[C:29]=[N:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>N1C=CC=CC=1>[CH:31]1([NH:30][C:29]([NH:28][CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)=[S:20])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: S=C=S
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Nc1cccc2cnccc12
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: S=C(NC1CCCCC1)NC1CCCCC1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of 5-aminoisoquinoline (14.4 g.) in pyridine (40 cc.) is added dropwise to a solution of triethylamine (10.1 g.) and carbon disulphide (40 cc.) in pyridine (20 cc.), whilst stirring at a temperature of about -10° C. After 1 hour at this temperature, a solution of N,N'-dicyclohexylcarbodiimide (20.6 g.) in pyridine (20 cc.) is added dropwise. Stirring is continued for 3 hours at a temperature changing from -10° to 20° C . and then for 20 hours at a temperature of about 20° C. The N,N'-dicyclohexylthiourea formed is filtered off and washed with methylene chloride (50 cc.); the filtrate is evaporated to dryness under reduced pressure (20 mm. Hg) at 40° C. The solid residue is taken up in methylene chloride (100 cc.); the new insoluble material is filtered off and washed with methylene chloride (30 cc.); the filtrate is evaporated to dryness under reduced pressure (20 mm. Hg) at 40° C. The residue is dissolved in boiling acetonitrile (100 cc.); after cooling, the crystals formed are filtered off and then suspended in diisopropyl ether (180 cc.). After 30 minutes'stirring at a temperature of about 20° C, the insoluble material is filtered off. The filtrate is evaporated to dryness under reduced pressure (20 mm. Hg) at 50° C. The residue is crystalline beige solid (5.9 g.) consisting of 5-isothiocyanatoisoquinoline, melting at 99° C. after recrystallisation from acetonitrile (40 cc.) and at 102° C. after sublimation at 70° C under reduced pressure (1 mm. Hg).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([O:10][CH2:11][C@@H:12]([NH:14][C:15](=[O:17])[CH3:16])[CH3:13])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Br[C:19]1[CH:20]=[C:21]([Cl:30])[C:22]([O:25][CH2:26][CH:27]2[CH2:29][CH2:28]2)=[N:23][CH:24]=1>>[Cl:30][C:21]1[CH:20]=[C:19]([C:2]2[O:1][C:5]3[CH:6]=[C:7]([O:10][CH2:11][C@@H:12]([NH:14][C:15](=[O:17])[CH3:16])[CH3:13])[CH:8]=[CH:9][C:4]=3[N:3]=2)[CH:24]=[N:23][C:22]=1[O:25][CH2:26][CH:27]1[CH2:28][CH2:29]1
Reactant: Clc1cc(Br)cnc1OCC1CC1
Reactant: CC(=O)N[C@@H](C)COc1ccc2ncoc2c1
Product: CC(=O)N[C@@H](C)COc1ccc2nc(-c3cnc(OCC4CC4)c(Cl)c3)oc2c1

Procedure:
Using N-((2S)-1-(1,3-benzoxazol-6-yloxy)propan-2-yl)acetamide and 5-bromo-3-chloro-2-(cyclopropylmethoxy)pyridine, and in the same manner as in Step B of Example 22, the title compound was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:29](=[O:33])[N:30]([CH3:32])[CH3:31])[CH2:10][C:11]1[CH:28]=[CH:27][C:14]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][CH2:23][C:24]([OH:26])=O)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.Cl.[CH2:64]([O:71][NH2:72])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1>CN(C=O)C.CCCCCC.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:29](=[O:33])[N:30]([CH3:32])[CH3:31])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][CH2:23][C:24](=[O:26])[NH:72][O:71][CH2:64][C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)=[CH:27][CH:28]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CN(C)C(=O)C(Cc1ccc(Oc2ccccc2CCC(=O)O)cc1)NC(=O)OC(C)(C)C
Reactant: NOCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)C(Cc1ccc(Oc2ccccc2CCC(=O)NOCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 92.9 %

Procedure:
The acid compound 62 (0.7 g, 1.533 mmol) was dissolved in dry DMF and cooled to 0-5° C. 1-Hydroxybenzotriazole (0.227 g, 1.686 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 0.293 g, 1.533 mmol), and triethylamine (0.641 mL, 4.59 mmol) were added to the above mixture followed by stirring for 15 min. O-Benzylhydroxylamine hydrochloride (0.269 g, 1.686 mmol) was added and the mixture was allowed to come to room temperature and stirred for 18 h. The solvent was evaporated under reduced pressure and the residual oil was taken up in EtOAc (100 mL). The organic layer was extracted with 2.0 M HCl (1×20 mL), saturated NaHCO3 (1×20 mL), and brine (1×50 mL). The resulting EtOAc layer was dried and concentrated to yield the crude product. Flash chromatography (30-50% ethyl acetate in hexane containing 1% acetic acid) yielded the desired benzyl hydroxamate 63 (0.8 g, 98%). 1H NMR (400 MHz, DMSO-d6) 10.9 (s, 1H), 7.37-7.2 (m, 9H), 7.07 (t, J=7.2 Hz, 2H), 6.85 (d, J=8.4 Hz, 2H), 6.76 (d, J=7.6 Hz, 1H), 4.71 (s, 2H), 4.54 (m, 1H), 2.89 (s, 3H), 2.81-2.72 (m, 7H), 2.49 (t, J=1.6 Hz, 2H), 1.30 (s, 9H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]2[CH:22]=[CH:21][N:20]3[N:23]=[CH:24][C:25]([C:26]([O:28]CC)=[O:27])=[C:19]3[N:18]=2)[C:6]1=[O:31].C1COCC1.CO.[Li+].[OH-].Cl>CO>[NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]2[CH:22]=[CH:21][N:20]3[N:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[C:19]3[N:18]=2)[C:6]1=[O:31]
Reactant: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cn(CCCN)c3=O)nc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: NCCCn1cc(F)cc([C@H]2CCCN2c2ccn3ncc(C(=O)O)c3n2)c1=O
Temperature: 70 °C
Yield: 96.1 %

Procedure:
To a solution of (R)-ethyl 5-(2-(1-(3-aminopropyl)-5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (0.11 g, 0.26 mmol) in 3:1 THF/MeOH (8 mL) was added LiOH (1 N, 1.5 mL, 1.5 mmol), and the reaction mixture was heated at 70° C. for 20 hours. After cooling, the reaction mixture was treated with MeOH, acidified with 1N HCl (1.5 mL), and concentrated to afford the desired product (0.1 g, 100% yield). MS (apci) m/z=401.1 (M+H).
Reaction SMILES: C([S:4][CH2:5][C@@H:6]([C:19]([F:22])([F:21])[F:20])[C:7]([NH:9][C@@H:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C:12]([OH:14])=[O:13])=[O:8])(=O)C.[OH-].[NH4+].CCCCCC.C(OCC)(=O)C>O.CO.C(O)(=O)C>[F:20][C:19]([F:21])([F:22])[C@H:6]([CH2:5][SH:4])[C:7]([NH:9][C@@H:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C:12]([OH:14])=[O:13])=[O:8]
Reactant: CC(=O)SC[C@H](C(=O)N[C@H](CC(=O)O)CC(C)C)C(F)(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)C[C@@H](CC(=O)O)NC(=O)[C@@H](CS)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A suspension of the (S,R) isomer product of Example 35 (1.0 g., 2.9 mmol.) in water maintained at 0° C. under argon was treated with ammonium hydroxide (5M solution, 10 mL, 50 mmol.) and stirred for 5 minutes. The reaction was quenched at 0° C. with 140 mL of 10% potassium bisulfate and then extracted with ethyl acetate (4×). The organic extracts were combined, dried (MgSO4), filtered, and concentrated in vacuo to yield 1.0 g. of yellow solid. The crude reaction product was flash chromatographed on 200 mL of silica gel eluting with hexane:ethyl acetate (2:1) to isolate 0.61 g. of the title (S,R) isomer product as a white solid, m.p. 155 °-156° C., TLC Rf =0.19 (hexane:ethyl acetate:acetic acid, 100:100:1). [α]D =-55.5° (c=0.89, methanol).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH:12]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:11][CH2:10]2>ClCCl>[OH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH:12]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:11][CH2:10]2
Reactant: COC(=O)CC1CCc2cc(OC)ccc21
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)CC1CCc2cc(O)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
A 1.0 M solution of boron tribromide in dichloromethane (22.7 mL, 22.7 mmol) was added to an ice-cold solution of methyl (R/S)-(5-methoxy-indan-1-yl)acetate (2.00 g, 9.08 mmol, from Step B) in dichloromethane (15 mL). The cooling bath was removed and the reaction mixture stirred at ambient temperature. After 1 hr, the reaction mixture was slowly transferred to an ice-cold solution of methanol (50 mL). Methanol was removed in vacuo, and the residue was partitioned between EtOAc and sat. NaH2PO4. The organic layer was washed with H2O, brine, and dried over MgSO4. The mixture was filtered, concentrated in vacuo and purified by flash chromatography (15, 20% EtOAc/hexanes) on SiO2 to afford 1.74 g of the title compound: 1H NMR (CDCl3) δ 1.72-1.79 (m, 1H), 2.35-2.42 (m, 1H), 2.46 (dd, 1H, J=8.5, 15.3 Hz), 2.76 (dd, 1H, J=5.9, 15.3 Hz), 2.80-2.92 (m, 2H), 3.50-3.55 (m, 1H), 3.75 (s, 3H), 5.63-5.86 (brs, 1H), 6.67 (dd, 1H, J=2.4, 8.1 Hz), 6.74 (d, 1H, J=2.0 Hz), 7.01 (d, 1H, J=8.3 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C@@H:12]2[C@@H:10]([O:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[OH:23].[OH-].[Na+].[Cl-].[NH4+]>O1CCOCC1.CCCCCCC.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C@@H:12]([O:23][C:17]2[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=2[Cl:15])[C@H:10]([OH:11])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2O[C@H]2C1
Reactant: Oc1ccc(F)cc1Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCCCCCC
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ccc(F)cc2Cl)[C@H](O)C1

Procedure:
Rac-cis-7-Oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylic acid tert-butyl ester (1 g, 5 mmol) was solvated in dioxane (5 mL), 2-Chloro-4-Fluorophenol was added (1.471 g, 10 mmol) and sodium hydroxide (0.401 g, 10 mmol). After 20 hours refluxing, the mixture was cooled, ammonium chloride was added and the mixture extracted three times with ethyl acetate. The combined organic phases were dried with magnesium sulfate and concentrated under vacuum. After a flash chromatography with heptane/ethyl acetate 1:1 to 1:2 heptane/ethyl acetate a solid the title compound was obtained as solid (0.778 g, 45% yield). MS (m/e): 404.5 (M+AcO−).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([F:16])([F:15])[F:14])[CH:7]=[C:8]([N+:10]([O-])=O)[CH:9]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:13]([F:14])([F:15])[F:16])[CH:7]=[C:8]([NH2:10])[CH:9]=1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(N)cc(C(F)(F)F)c1
Temperature: 75 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
A 24.8 g sample of 3,5-dinitrobenzotrifluoride purchased from Aldrich Chemical Co. was slurried in 200 ml of ethanol and 5 g of 1% palladium on carbon added. This mixture was transferred to an autoclave, pressured to 400 psi with hydrogen, and heated at 75° C. with stirring for 1 hr. A 91% yield of pure 3,5-diaminobenzotrifluoride was recovered.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:14]=[CH:13][C:12]([O:15]C(C)(C)C)=[CH:11][CH:10]=1)=[O:5])[CH3:2].FC(F)(F)C(O)=O>>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1C[C@@H]1c1ccc(OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O)cc1
Reaction time: 0.08 h
Yield: 88.6 %

Procedure:
(1S,2S)-2-(4-tert-Butoxy-phenyl)-cyclopropanecarboxylic acid ethyl ester (10.5 g, 35.62 mmol) is dissolved in trifluoroacetic acid (15 mL, 195.6 mmol) and stirred for 5 minutes. The mixture is concentrated under vacuum, then reevaporated five times from dichloromethane. The residue is dissolved in boiling cyclohexane (20 mL) and then allowed to cool. The cyclohexane layer is decanted off and the operation repeated. The residue is dried under vacuum to give the title compound (yield 6.51 g).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1([CH3:16])[C:13](=[N:14]O)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][S:5]1.N>COCCOC.[Ti](Cl)(Cl)(Cl)Cl>[NH2:14][CH:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][S:5][C:4]1([CH3:16])[CH3:3]
Reactant: CC1(C)SCc2ccccc2C1=NO
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: N
Agent: [BH4-]
Solvent: COCCOC
Product: CC1(C)SCc2ccccc2C1N
Reaction time: 3 h
Yield: 54.3 %

Procedure:
25.3 g of sodium borohydride in 435 ml of 1,2-dimethoxyethane are placed under a nitrogen atmosphere. 36.9 ml of titanium tetrachloride are added dropwise thereto at a temperature of from +15° to +18° C. The mixture is stirred for 3 hours at a temperature below +20° C. and then, at from +14° to +16° C., a solution of 33.0 g of 3,3-dimethylisothiochroman-4-oneoxime in 135 ml of 1,2-dimethoxyethane is added dropwise thereto. After stirring for 16 hours at room temperature, the mixture is poured onto ice-water and rendered basic with 30% aqueous ammonia solution. The mixture is then extracted twice with ether. The ether phases are washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated by evaporation. Distillation of the residue yields 16.7 g of 4-amino-3,3-dimethylisothiochroman in the form of a colourless liquid having a boiling point of +80° C. at 0.06 mbar.