Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][C@H:5]1[CH2:10][CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[C@@H:6]1[C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:26][C:24]([F:25])([F:27])[C:21]1[CH:20]=[CH:19][C:18]([C@@H:6]2[C@@H:5]([CH2:4][C:3]([O:2][CH3:1])=[O:28])[CH2:10][CH2:9][CH2:8][NH:7]2)=[CH:23][CH:22]=1
Reactant: COC(=O)C[C@H]1CCCN(C(=O)OC(C)(C)C)[C@@H]1c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C[C@H]1CCCN[C@@H]1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of the resulting tert-butyl (2S,3R)-3-(2-methoxy-2-oxoethyl)-2-[4-(trifluoromethyl)phenyl]piperidine-1-carboxylate (2.8 g, 7.0 mmol) in DCM (50 mL) was treated with TFA (2.7 mL, 35 mmol) and stirred at ambient temperature for 16 hours. The reaction mixture was evaporated in vacuo and partitioned between saturated sodium bicarbonate solution and ethyl acetate. The organics were dried over sodium sulfate, filtered and evaporated in vacuo to give methyl {(2S,3R)-2-[4-(trifluoromethyl)phenyl]piperidin-3-yl}acetate. LC/MS (EIMS, M+H)=302.1.
Reaction SMILES: [Cl:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[C:16]([Cl:23])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([CH:12]=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.[Br:24]N1C(=O)CCC1=O>C(O)C.O1CCOCC1>[Br:24][C:12]1[N:8]2[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][C:3]3[C:16]([Cl:23])=[CH:17][CH:18]=[C:19]([N+:20]([O-:22])=[O:21])[C:2]=3[Cl:1])[C:7]2=[N:14][C:13]=1[CH3:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cn2cccc(OCc3c(Cl)ccc([N+](=O)[O-])c3Cl)c2n1
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1nc2c(OCc3c(Cl)ccc([N+](=O)[O-])c3Cl)cccn2c1Br
Reaction time: 1 h
Yield: 81.7 %

Procedure:
To a solution of 8-(2,6-dichloro-3-nitrobenzyloxy)-2-methylimidazo[1,2-a]pyridine (85 mg) in a mixture of ethanol (1 ml) and 1,4-dioxane (1 ml) was added in one portion N-bromosuccinimide (43 mg) at ambient temperature. After stirring for one hour at the same temperature, the mixture was filtered to give 3-bromo-8-(2,6-dichloro-3-nitrobenzyloxy)-2-methylimidazo[1,2-a]pyridine (85 mg) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(=O)O[C:11](=[O:12])[CH2:10][CH2:9]1>>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([CH2:8][CH2:9][CH2:10][C:11]2=[O:12])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)O1
Reactant: Brc1ccccc1
Product: O=C1CCCc2ccc(Br)cc21

Procedure:
7-Bromo-3,4-dihydronaphthalen-1-one was prepared from bromobenzene and succinic anhydride as described in Example 64 (Steps A to C).
Reaction SMILES: [CH2:1]([CH:3]([CH2:9][CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[Br:11][CH2:12][CH2:13][CH2:14]Br>>[Br:11][CH2:12][CH2:13][CH2:14][C:3]([CH2:9][CH3:10])([CH2:1][CH3:2])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(CC)CC
Reactant: BrCCCBr
Product: CCOC(=O)C(CC)(CC)CCCBr

Procedure:
Using ethyl 2-ethylbutyrate and 1,3-dibromopropane, the title compound was produced in the same manner as in Reference Example 6.
Reaction SMILES: [OH:1][CH:2]1[CH:6]([CH:7]2[O:16][CH:10]3[O:11][C:12]([CH3:15])([CH3:14])[O:13][CH:9]3[CH:8]2[OH:17])[NH:5][C:4](=O)[CH2:3]1.[Li]>>[OH:17][CH:8]1[CH:9]2[CH:10]([O:11][C:12]([CH3:15])([CH3:14])[O:13]2)[O:16][CH:7]1[CH:6]1[CH:2]([OH:1])[CH2:3][CH2:4][NH:5]1
Reactant: CC1(C)OC2OC(C3NC(=O)CC3O)C(O)C2O1
Agent: [Li]
Product: CC1(C)OC2OC(C3NCCC3O)C(O)C2O1

Procedure:
A process according to claim 1 for converting 5-(t-BOC)amino -5-deoxy-l,2-0-isopropylidene-α-D-glucuronolactone to castanospermine which comprises (a) reacting 5-(t? -0 BOC)amino-5-deoxy-l,2-O-isopropylidene-α-D-glucuronolactone (I) with ethyl acetate and lithium diisopropylamine in an inert solvent at low temperature whereby the ethyl acetate adds across the carbonyl group of the lactone to give the corresponding cyclic hemiketal of an β-keto ester (II); (b) hydrogenating the hemiketal catalytically under pressure over a platinum oxide catalyst in ethyl acetate to reduce the β-keto function and give β-hydroxy ester (III); (c) treating the β-hydroxy ester with formic acid in an inert solvent with cooling to remove the protecting group from the amine followed by basification of the resulting amine salt using a basic ion exchange resin to provide internal cyclization of the amine to give lactam (IV); (d) reducing the lactam with lithium aluminumhydride to give the corresponding pyrrolidine (V); and (e) treating the pyrrolidine first with trifluoroacetic acid with cooling and then hydrogenating over platinum or carbon catalyst under pressure to give castanospermine (VI).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([O:14]C)=[O:13])=[N:10][CH:11]=1>[OH-].[Na+].C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([OH:14])=[O:13])=[N:10][CH:11]=1
Reactant: COC(=O)c1ccc(Cc2cccc(F)c2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(Cc2cccc(F)c2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 5-(3-fluorobenzyl)picolinate (0.149 g; 0.607 mmol) in NaOH 2M (2 mL) and ethanol (2 mL) was stirred at room temperature for 2 hours and then evaporated to dryness. The residue was dissolved in water and acidified to pH 2 with a 6N solution of hydrochloric acid in water. The mixture was extracted with ethyl acetate and the combined organic layers were dried and concentrated under reduced pressure. The crude material was used in the next step without any further purification.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:7]=3[C:6]=2[CH:5]=1)([CH3:3])[CH3:2].[F:18][C:19]([F:29])([F:28])[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[CH:26]=[CH2:27].[OH-].[K+]>CN1C(=O)CCC1>[F:29][C:19]([F:18])([F:28])[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[CH2:26][CH2:27][N:9]1[C:10]2[CH:11]=[CH:12][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][C:6]=2[C:7]2[CH2:16][N:15]([CH3:17])[CH2:14][CH2:13][C:8]1=2
Reactant: CC(C)c1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1cnccc1C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CC(C)c1ccc2c(c1)c1c(n2CCc2cnccc2C(F)(F)F)CCN(C)C1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-8-isopropyl-2-methyl-1H-pyrido[4,3-b]indole, 4-(trifluoromethyl)-3-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH2:10][C:11]([OH:13])=O)[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.Cl.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([OH:30])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][C:19]=1[O:31][CH3:32].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH2:10][C:11]([N:27]3[CH2:28][CH2:29][C:24]([C:21]4[CH:22]=[CH:23][C:18]([Cl:17])=[C:19]([O:31][CH3:32])[CH:20]=4)([OH:30])[CH2:25][CH2:26]3)=[O:13])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1
Reactant: COc1cc(C2(O)CCNCC2)ccc1Cl
Reactant: O=C(O)Cn1c(=O)oc2cc(Cl)ccc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C2(O)CCN(C(=O)Cn3c(=O)oc4cc(Cl)ccc43)CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(6-chloro-2-oxobenzo[d]oxazol-3(2H)-yl)acetic acid (22.7 mg, 0.1 mmol, 1 equiv), 4-(4-chloro-3-methoxy-phenyl)-piperidin-4-ol hydrochloride (69) (27.7 mg, 1 equiv), BOP (58 mg, 1.3 equiv), triethylamine (56 μL, 4 equiv) in 1 ml of DMF was stirred at room temperature for overnight. The solution was then diluted with EtOAc (50 mL) and washed with water. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude residue was purified by flash chromatography to provide 6-chloro-3-{2-[4-(4-chloro-3-methoxy-phenyl)-4-hydroxy-piperidin-1-yl]-2-oxo-ethyl}-3H-benzooxazol-2-one (70): MS (ES) [M+H]+ expected 451.1, found 451.1.
Reaction SMILES: [CH3:1][C:2]([C:12]1[CH:16]=[C:15]([NH:17][C:18]([C@@H:20]2[CH2:24][CH2:23][CH2:22][N:21]2[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[O:19])[O:14][N:13]=1)([CH3:11])[CH2:3][O:4]C1CCCCO1.CO.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(#N)C>O>[OH:4][CH2:3][C:2]([C:12]1[CH:16]=[C:15]([NH:17][C:18]([C@@H:20]2[CH2:24][CH2:23][CH2:22][N:21]2[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[O:19])[O:14][N:13]=1)([CH3:11])[CH3:1]
Reactant: CC(C)(COC1CCCCO1)c1cc(NC(=O)[C@@H]2CCCN2c2ccc(Cl)cc2)on1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Solvent: CO
Product: CC(C)(CO)c1cc(NC(=O)[C@@H]2CCCN2c2ccc(Cl)cc2)on1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of (S)-1-(4-Chloro-phenyl)-pyrrolidine-2-carboxylic acid {3-[1,1-dimethyl-2-(tetrahydro-pyran-2-yloxy)-ethyl]-isoxazol-5-yl}-amide (130 mg, 0.29 mmol) in the mixture of methanol in water (10:1, 3 mL) is added p-toluenesulfonic acid monohydrate (10 mg, 0.053 mmol) and acetonitrile (1 mL). The reaction mixture is stirred at room temperature for 18 hours. After this time, the reaction mixture is concentrated in vacuo. Purification by flash chromatography on silica gel using ethyl acetate/hexanes provides the title compound, ESI m/z 364 [M+H+].
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][C:21]([OH:23])=O)[CH2:15][CH2:14]1)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:24][O:25][C:26]([N:28]1[CH2:34][CH2:33][C:32]2[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=2[CH2:30][CH2:29]1)=[O:27].[Cl-].[Al+3].[Cl-].[Cl-]>>[CH3:24][O:25][C:26]([N:28]1[CH2:34][CH2:33][C:32]2[CH:35]=[CH:36][C:37]([C:21](=[O:23])[CH2:20][CH2:19][CH:16]3[CH2:15][CH2:14][N:13]([C:5](=[O:12])[C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH2:18][CH2:17]3)=[CH:38][C:31]=2[CH2:30][CH2:29]1)=[O:27]
Reactant: COC(=O)N1CCc2ccccc2CC1
Reactant: O=C(O)CCC1CCN(C(=O)c2ccccc2)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Product: COC(=O)N1CCc2ccc(C(=O)CCC3CCN(C(=O)c4ccccc4)CC3)cc2CC1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 83.5 %

Procedure:
Under ice-cooling, 1.5 ml of thionyl chloride was added dropwise to 1.08 g (4.1 mmol.) of 3-(1-benzoylpiperidin-4-yl)propionic acid obtained in Reference Example 9. The mixture was stirred for 40 minutes at 0° C., then thionyl chloride was distilled off. The residue was dissolved in 20 ml of 1,2-dichloroethane, to which was added 0.81 g (3.9 mmol.) of 3- methoxycarbonyl-2,3,4,5-tetrahydro-1H-3-benzazepine obtained in Reference Example 10. To the mixture was added 1.75 g (13.1 mmol.) of aluminum chloride in small portions. The mixture was stirred for one hour at room temperature, then the reaction mixture was poured into ice-water and extracted with dichloromethane. The organic layers were combined and washed with water once, then dried over anhydrous sodium sulfate, followed by distilling off the solvent. Purification by means of a silica gel column chromatography gave 1.46 g (83%) of 3-methoxycarbonyl-7-[3-(1- benzoylpiperidin-4-yl)-1-oxopropyl]-2,3,4,5-tetrahydro-1H-3-benzazepine. Recrystallization from ethyl acetate --n-hexane gave colorless needles, m.p. 120°-123° C.
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([O:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:3][CH:2]=1.[CH3:15][C@@H:16]1[CH2:20][O:19][C:18](=[O:21])[N:17]1[C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1>>[CH3:15][C@@H:16]1[CH2:20][O:19][C:18](=[O:21])[N:17]1[C:22]1[CH:30]=[CH:29][C:25]([C:26]([N:11]2[CH2:12][CH2:13][CH:8]([O:7][C:4]3[CH:3]=[CH:2][C:1]([CH3:14])=[CH:6][CH:5]=3)[CH2:9][CH2:10]2)=[O:27])=[CH:24][CH:23]=1
Reactant: C[C@@H]1COC(=O)N1c1ccc(C(=O)O)cc1
Reactant: Cc1ccc(OC2CCNCC2)cc1
Product: Cc1ccc(OC2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C)cc3)CC2)cc1
Yield: 77.6 %

Procedure:
By reaction and treatment in the same manner as in Example 52 and using 4-(p-tolyloxy)piperidine (1 g) and (R)-4-(4-methyl-2-oxooxazolidin-3-yl)benzoic acid (1.2 g) described in Preparation Example 37, the title compound (1.6 g) was obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:29])[CH2:18][S:19][C:20]2[N:24]([CH3:25])[N:23]=[C:22]([CH3:26])[C:21]=2[CH:27]=[O:28])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].P([O-])(O)(O)=[O:31].[Na+].CC(=CC)C.Cl([O-])=O.[Na+].S([O-])(O)=O.[Na+]>O.C(O)(C)(C)C.O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17](=[O:29])[CH2:18][S:19][C:20]2[N:24]([CH3:25])[N:23]=[C:22]([CH3:26])[C:21]=2[C:27]([OH:31])=[O:28])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nn(C)c(SCC(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)c1C=O
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: Cc1nn(C)c(SCC(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)c1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.8 %

Procedure:
To a mixture of 5-({2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxoethyl}sulfanyl)-1,3-dimethyl-1H-pyrazole-4-carbaldehyde (900 mg), sodium dihydrogen phosphate (1.19 g), 2-methyl-2-butene (1.17 mL), tetrahydrofuran (10 mL), tert-butanol (3 mL), and water (1.5 mL) was added sodium chlorite (393 mg) at 0° C. and stirred at room temperature for 1 h. Aqueous sodium hydrogen sulfite was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to provide the title compound (550 mg, 59%) as a colorless solid.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:9][C:8]2[CH:10]=[C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:12]=[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[O:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[C:20]1([C:11]2[CH:12]=[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]3[O:6][CH:5]([CH2:4][NH2:1])[CH2:9][C:8]=3[CH:10]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: [N-]=[N+]=NCC1Cc2cc(-c3ccccc3)cc(-c3ccccc3)c2O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: NCC1Cc2cc(-c3ccccc3)cc(-c3ccccc3)c2O1
Yield: 99 %

Procedure:
Treatment of 3-bromo-4-hydroxybiphenyl (15.7 g, 63.0 mmol) with potassium carbonate (34.84 g, 252.0 mmol) and allyl bromide (9.15 g, 75.63 mmol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 3-allyl-5-bromobiphenyl-4-ol. Treatment of 3-allyl-5-bromobiphenyl-4-ol (17.8 g, 61.5 mmol) with 3-chloroperoxybenzoic acid (31.87 g, 184.67 mmol, 77%) followed by potassium carbonate (21.27 g, 153.89 mmol) generally according to the procedure described for Intermediate 9 afforded 15.8 g (84%) of (±)-(7-bromo-5-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanol. Treatment of (±)-(7-bromo-5-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanol (15.8 g, 51.77 mmol) with p-toluenesulfonyl chloride (14.79 g, 77.65 mmol) generally according to the procedure described for Intermediate 10 gave 18.8 g (79%) of (±)-(7-bromo-5-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. Treatment of (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.5 g, 3.26 mmol) and phenylboronic acid (0.59 g, 4.89 mmol) generally according to the procedure described for Intermediate 35 afforded 1.17 g, (78%) of (±)-(5,7-diphenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (0.342 g, 5.26 mmol) generally according to the procedure described for Intermediate 98 afforded 0.39 g (91%) of (±)-2-(azidomethyl)-5,7-diphenyl-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-5,7-diphenyl-2,3-dihydro-1-benzofuran with polymer-supported triphenylphosphine (0.314 g, 1.21 mmol) according to the procedure described in Example 154 afforded 0.34 g (99%) of (±)-(5,7-diphenyl-2,3-dihydro-1-benzofuran-2-yl)methylamine as a white solid, hydrochloride salt. mp >250° C.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9](O)(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].Cl.[F:15][C:16]([F:29])([F:28])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:24](=[O:27])[NH:25][NH2:26]>>[F:15][C:16]([F:28])([F:29])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:24](=[O:27])[NH:25][N:26]=[C:9]1[C:10](=[O:11])[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:7]1=[O:8]
Reactant: NNC(=O)Nc1ccccc1C(F)(F)F
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Agent: Cl
Product: O=C(NN=c1c(=O)c2ccccc2c1=O)Nc1ccccc1C(F)(F)F

Procedure:
ninhydrin, 4-(2-trifluoromethyl phenyl)-semicarbazide hydrochloride
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:21][O:22][C:23]([C:25]3[S:26][C:27]([CH3:30])=[CH:28][CH:29]=3)=[O:24])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]3[CH3:20])=[C:4]([O:31][CH3:32])[CH:3]=1.[CH3:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][N:35]=1.C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>CN(C)C=O>[CH3:32][O:31][C:4]1[CH:3]=[C:2]([O:1][C:38]([C:37]2[CH:36]=[N:35][C:34]([CH3:33])=[CH:42][CH:41]=2)=[O:39])[CH:7]=[CH:6][C:5]=1[C:8]1[C:9]([CH2:21][O:22][C:23]([C:25]2[S:26][C:27]([CH3:30])=[CH:28][CH:29]=2)=[O:24])=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH3:18])([CH3:19])[CH:12]=[C:11]2[CH3:20]
Reactant: COc1cc(O)ccc1-c1ccc2c(c1COC(=O)c1ccc(C)s1)C(C)=CC(C)(C)N2
Reactant: Cc1ccc(C(=O)O)cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OC(=O)c2ccc(C)nc2)ccc1-c1ccc2c(c1COC(=O)c1ccc(C)s1)C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.3 %

Procedure:
6-(4-Hydroxy-2-methoxyphenyl)-5-(5-methylthiophen-2-ylcarbonyloxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 3-2, 32.5 mg, 0.0723 mmol) and 6-methylnicotinic acid (15.7 mg, 0.114 mmol) were dissolved in N,N-dimethylformamide (1 mL), N,N-diisopropylethylamine (35 μL, 0.201 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (38.3 mg, 0.101 mmol) were added thereto, and then the mixture was stirred at room temperature overnight. Ethyl acetate (20 mL) was added to the reaction mixture, and then the mixture was washed with water (20 mL) and saturated brine (20 mL) successively. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (21.5 mg) as a gray amorphous product. (Yield 57%)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:24][C:14]3=[N:15][C:16](O)=[C:17]([N+:20]([O-:22])=[O:21])[C:18](=[O:19])[N:13]3[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)([Cl:27])=O.CCN(C1C=CC=CC=1)CC>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:24][C:14]3=[N:15][C:16]([Cl:27])=[C:17]([N+:20]([O-:22])=[O:21])[C:18](=[O:19])[N:13]3[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)c1ccc(-c2nn3c(=O)c([N+](=O)[O-])c(O)nc3s2)cc1
Solvent: CCN(CC)c1ccccc1
Product: CC(C)(C)c1ccc(-c2nn3c(=O)c([N+](=O)[O-])c(Cl)nc3s2)cc1

Procedure:
6.0 g of 2-(4-tert-butylphenyl)-7-hydroxy-6-nitro-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one was added to a mixture of 25 ml of phosphorus oxychloride and 4 ml of diethylaniline, and the resulting mixture was heated at a temperature of 70° to 80° C. for 2 hours. After cooling, the precipitate formed was filtered, washed successively with water, isopropanol and diethyl ether to obtain 4.3 g of 2-(4-tert-butylphenyl)-7-chloro-6-nitro-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one as crystals having a melting point of 245° to 248° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH:10]([OH:21])[CH:9]1[CH2:22][CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][Si:14]([C:17]([CH3:18])([CH3:20])[CH3:19])([CH3:16])[CH3:15])[CH:10]([O:21][S:45]([CH3:44])(=[O:47])=[O:46])[CH:9]1[CH2:22][CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC(O[Si](C)(C)C(C)(C)C)C(O)C1CCNC(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(O[Si](C)(C)C(C)(C)C)C(OS(C)(=O)=O)C1CCNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution containing crude 8 (500 mg, 1.01 mmol) in DCM (15 mL) was cooled to 0° C. DIPEA (261 mg, 2.02 mmol) was added followed by the addition of MsCl (117 mg, 1.02 mmol) and DMAP (13 mg, 0.1 mmol). After 2 h, the reaction mixture was warmed to ambient temperature, diluted with DCM, washed successively with 1M HCl and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 578 mg (quant.) of crude 9 as a tan-colored foam which was used without further purification. 1H NMR (CDCl3, 300 MHz), mixture of rotomers: δ7.35 (m, 5H), 5.90 (m, 1H), 5.10 (m, 2H), 4.67 (m, 1H), 4.40 (m, 1H), 4.11 (m, 2H), 3.94 (m, 0.5H), 3.80 (m, 0.5H), 3.74 (app dd, J=12.2, 5.0 Hz, 1H), 3.51 (m, 0.5H), 3.31 (m, 0.5H), 3.02 (s, 3H), 1.96 (m, 0.5H), 1.85 (m, 0.5H), 1.46 (s, 9H), 0.88 (s, 9H), 0.05 (s, 6H) ppm. Mass spectrum, m/z [595.2] (M+Na)+.
Reaction SMILES: Cl.C([C:4]1[CH:8]=[C:7]([CH2:9][CH3:10])[N:6]([CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([NH2:18])[CH2:14][CH2:13]2)[N:5]=1)C.N1N[CH:21]=C2CCCC=12>>[N:6]1([CH2:11][C@H:12]2[CH2:13][CH2:14][C@H:15]([NH2:18])[CH2:16][CH2:17]2)[C:7]2[CH2:9][CH2:10][CH2:21][C:8]=2[CH:4]=[N:5]1
Reactant: c1[nH]nc2c1CCC2
Reactant: CCc1cc(CC)n(C[C@H]2CC[C@H](N)CC2)n1
Agent: Cl
Product: N[C@H]1CC[C@H](Cn2ncc3c2CCC3)CC1

Procedure:
This compound was prepared analogously to Intermediate B by replacing 3,5-diethyl-1H-pyrazole with 2,4,5,6-tetrahydrocyclopenta[c]pyrazole; LCMS Rt=1.39 min, [M+H]+ 234.29; Method LowpH_v002.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[C@@H:13]([OH:21])[C@H:12]2[OH:22])=[C:4]([NH:23][CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[N:3]=1.C(OC(=O)N([C@H]1C[C@@H](N2C=NC3C2=NC(Cl)=NC=3Cl)C=C1)C(=O)CC)(C)(C)C.[NH2:57][C@H:58]1[CH2:63][CH2:62][C@H:61]([NH2:64])[CH2:60][CH2:59]1>>[NH2:57][CH:58]1[CH2:63][CH2:62][CH:61]([NH:64][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[C@@H:11]3[CH2:15][C@H:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[C@@H:13]([OH:21])[C@H:12]3[OH:22])=[C:4]([NH:23][CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[N:3]=2)[CH2:60][CH2:59]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NC(CC)CC)nc(Cl)nc32)[C@H](O)[C@@H]1O
Agent: CCC(=O)N(C(=O)OC(C)(C)C)[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NC(CC)CC)nc(NC4CCC(N)CC4)nc32)[C@H](O)[C@@H]1O

Procedure:
N-{(1S,2R,3S,4R)-4-[2-Chloro-6-(1-ethyl-propylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide (the compound of Example 14) is reacted with trans-1,4-diaminocyclohexane to give the title compound using a procedure analogous to that of Example 9. MS (ES+) m/e 489 (MH+).