Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-:1].[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N+:8]([CH2:11][CH2:12][NH:13][C:14]([C:16]1[C:21]([NH2:22])=[N:20][C:19]([NH2:23])=[C:18]([Cl:24])[N:17]=1)=[O:15])([CH3:10])[CH3:9].[CH2:25]([O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40](O)=[O:41])=[CH:35][CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CN1CCOCC1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[Br-:1].[CH2:25]([O:32][C:33]1[CH:34]=[CH:35][C:36]([CH2:39][C:40]([NH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N+:8]([CH2:11][CH2:12][NH:13][C:14]([C:16]2[C:21]([NH2:22])=[N:20][C:19]([NH2:23])=[C:18]([Cl:24])[N:17]=2)=[O:15])([CH3:9])[CH3:10])=[O:41])=[CH:37][CH:38]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Reactant: C[N+](C)(CCCCCN)CCNC(=O)c1nc(Cl)c(N)nc1N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C[N+](C)(CCCCCNC(=O)Cc1ccc(OCc2ccccc2)cc1)CCNC(=O)c1nc(Cl)c(N)nc1N

Procedure:
A solution of (5-amino-pentyl)-{2-[(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-amino]-ethyl}-dimethyl-ammonium bromide (Intermediate O) (1.0 g, 2.35 mmol), 4-benzyloxy phenyl acetic acid (0.57 g, 2.35 mmol), N-methylmorpholine (1.0 mL, 9.09 mmol), DCC (0.49 g, 2.35 mmol) and HOBt (0.32 g, 2.36 mmol) in DMF (20 mL) is stirred at RT for 1 h. The reaction mixture is concentrated in vacuo, and the residue is purified by column chromatography (basic alumina, 0-4% methanol in DCM) to afford a brown solid which is crystallised from methanol and EtOAc to afford the title compound. M+ 568.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:14]=1)[C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CCN(CC)CC.[F:34][C:35]([F:42])([F:41])[C:36](OCC)=[O:37]>CO>[CH:22]1([O:21][C:15]2[CH:14]=[C:13]([CH:4]([C:5]#[C:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:3][NH:2][C:36](=[O:37])[C:35]([F:42])([F:41])[F:34])[CH:18]=[CH:17][C:16]=2[O:19][CH3:20])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CCOC(=O)C(F)(F)F
Reactant: COc1ccc(C(C#Cc2ccccc2)CN)cc1OC1CCCC1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc(C(C#Cc2ccccc2)CNC(=O)C(F)(F)F)cc1OC1CCCC1

Procedure:
A solution of (+/-)-4-amino-3-(3-cyclopentyloxy-4-methoxyphenyl)-1-phenyl-1-butyne hydrochloride (50 mg, 0.14 mmol) and Et3N (40 mg) in a mixture of MeOH (1 ml) and ethyl trifluoroacetate (0.5 ml) was refluxed overnight. The solvents were evaporated, the residue taken up in Et2O, washed with H2O, 0.01N HCl, dried, and the solvent evaporated. The residue was crystallized from a mixture of cyclohexane and Et2O, and gave the titled compound, 32 mg (55%). mp 143-145°. 1H NMR (400 MHz, CDCl3) δ 7.42 (m, 2 H), 7.32 (m, 3 H), 6.94 (m, 2 H), 6.84 (d, 1 H), 6.54 (broad s, 1 H), 4.78 (m, 1 H), 4.08 (t, 1 H), 3.82 (s, 3 H), 3.78 (m, 1 H), 3.58 (m, 1 H), 1.76-1.92 (m, 6 H), 1.60 (m, 2 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([NH2:13])=[N:10][N:9]=2)=[CH:4][CH:3]=1.[Cl:14][CH2:15][CH2:16][CH2:17][C:18](Cl)=[O:19].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([NH:13][C:18](=[O:19])[CH2:17][CH2:16][CH2:15][Cl:14])=[N:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Nc1nnc(-c2ccc(Br)cc2)s1
Reactant: O=C(Cl)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(CCCCl)Nc1nnc(-c2ccc(Br)cc2)s1
Yield: 86.6 %

Procedure:
A mixture of 5-(4-bromophenyl)-1,3,4-thiadiazol-2-amine (10.2 g, 0.04 mol), 4-chlorobutyryl chloride (11.3 g, 9.0 ml, 0.08 mol) and potassium carbonate (5.5 g, 0.04 mole) in toluene (100 ml) was heated under reflux for 4 hr. The toluene was then evaporated under reduced pressure. The residue was then quenched with water, stirred, and filtered. The solid obtained was washed, dried and recrystallized from toluene to give the required product (12.5 g, 87% yield), mp 187-9° C., m/e 360, 15.7% (consistent with molecular formula C12H11BrClN3OS, calcd. 360.66). 1H NMR (DMSO-d6): δ 1.96-2.22 (m, 2H, —CH2), 2.69-2.81 (m, 2H, —CH2), 3.71-3.72 (m, 2H, —CH2), 7.49-7.88 (dd, 4H, ArH), 12.76 (br s, 1H, NH). 13C NMR: δ 27.3, 32.1, 44.6, 123.8, 128.7, 129.4, 132.3, 158.5, 160.7, 170.7.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]#[C:6][C:7]([O:9][CH3:10])=[O:8])=[O:4].[NH2:11][NH2:12]>C(OCC)C.C1COCC1>[CH3:1][O:2][C:3](=[O:4])/[C:5](/[NH:11][NH2:12])=[CH:6]\[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)C#CC(=O)OC
Reactant: NN
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)/C=C(/NN)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
To a solution of dimethylacetylene dicarboxylate (1.4 g, 9.9 mmol) in diethylether (40 mL) under argon was added a solution of hydrazine in THF (1 M, 10 mL) and the resulting mixture stirred at room temperature overnight. The precipitate was filtered off and dried to afford the title compound (597 mg, 35%) as a white solid. MS: m/e=175.2 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:16]=[C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:14]([Br:22])=[CH:13][C:7]=2[C:8]=1[C:9]([NH:11][CH3:12])=[O:10])(=[O:3])[CH3:2].[C:23]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[C:1]([C:4]1[O:5][C:6]2[CH:16]=[C:15]([N:17]([CH3:23])[S:18]([CH3:21])(=[O:19])=[O:20])[C:14]([Br:22])=[CH:13][C:7]=2[C:8]=1[C:9]([NH:11][CH3:12])=[O:10])(=[O:3])[CH3:2]
Reactant: CNC(=O)c1c(C(C)=O)oc2cc(NS(C)(=O)=O)c(Br)cc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CNC(=O)c1c(C(C)=O)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Temperature: 60 °C
Yield: 45.7 %

Procedure:
To a solution of 2-acetyl-5-bromo-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (150 mg, 0.38 mmol) in DMF (3 mL) was added K2CO3 (160 mg, 1.16 mmol) and MeI (164 mg, 1.16 mmol). The mixture was heated at 60° C. for 1 hour, concentrated in vacuo to remove DMF and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give crude product. The crude product was purified by column chromatography to give 2-acetyl-5-bromo-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (70 mg, yield: 45%). 1H-NMR (CDCl3, 400 MHz) δ 9.73 (s, 1H), 9.01 (s, 1H), 7.78 (s, 1H), 3.35 (s, 3H), 3.09 (s, 3H), 3.02 (d, J=4.8 Hz, 3H), 2.77 (s, 3H). MS (M+H)+: 403/405.
Reaction SMILES: [CH3:1][C:2]1([CH3:46])[CH2:7][CH2:6][CH2:5][N:4]([C:8]([CH:10]2[CH:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]([C:21](=[O:38])[CH2:22][NH:23][C:24]([NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([O:35]CC)=[O:34])[CH:28]=3)=[O:25])[CH:12]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:11]2)=[O:9])[CH2:3]1.[OH-].[K+]>O.CO>[C:42]([O:41][C:39]([CH:12]1[CH2:11][CH:10]([C:8]([N:4]2[CH2:5][CH2:6][CH2:7][C:2]([CH3:46])([CH3:1])[CH2:3]2)=[O:9])[CH:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:13]1[C:21](=[O:38])[CH2:22][NH:23][C:24](=[O:25])[NH:26][C:27]1[CH:28]=[C:29]([CH:30]=[CH:31][CH:32]=1)[C:33]([OH:35])=[O:34])=[O:40])([CH3:43])([CH3:44])[CH3:45]
Reactant: CCOC(=O)c1cccc(NC(=O)NCC(=O)N2C(C(=O)OC(C)(C)C)CC(C(=O)N3CCCC(C)(C)C3)C2c2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)CCCN(C(=O)C2CC(C(=O)OC(C)(C)C)N(C(=O)CNC(=O)Nc3cccc(C(=O)O)c3)C2c2ccccc2)C1
Yield: 52.8 %

Procedure:
A The reaction is carried out in a way analogous to that described in Example 3, but from 2.3 g of tert-butyl (2RS,4SR,5SR)-4-(3,3-dimethylpiperidinocarbonyl)-1-{2-[3-(3-(ethoxycarbonyl)phenyl]ureido]acetyl}-5-phenylpyrrolidine-2-carboxylate and 0.2 g of potassium hydroxide in a mixture of 20 cm3 of distilled water and 50 cm3 of methanol. After treatment, there are obtained 1.16 g of (2RS,4SR,5SR)-3-{3-[2-(2-tert-butoxycarbonyl-4-(3,3-dimethylpiperidinocarbonyl)-5-phenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}benzoic acid [Rf =0.2; eluent=methylene chloride/methanol (97.5/2.5)].
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([C:47]([F:50])([F:49])[F:48])(=[O:46])=[O:45])=[CH:40][CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:51][C:52]1[S:53][CH:54]=[C:55]([CH2:57][C:58]([O:60][CH2:61][CH3:62])=[O:59])[N:56]=1>C(Cl)Cl>[CH2:61]([O:60][C:58](=[O:59])[CH2:57][C:55]1[N:56]=[C:52]([NH:51][C:35](=[O:37])[CH:34]([C:38]2[CH:39]=[CH:40][C:41]([S:44]([C:47]([F:49])([F:48])[F:50])(=[O:45])=[O:46])=[CH:42][CH:43]=2)[CH2:33][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32]2)[S:53][CH:54]=1)[CH3:62]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(S(=O)(=O)C(F)(F)F)cc1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)Cc1csc(NC(=O)C(CC2CCCC2)c2ccc(S(=O)(=O)C(F)(F)F)cc2)n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 72.4 %

Procedure:
A solution of triphenylphosphine (97 mg, 0.371 mmol) in methylene chloride (1.5 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (66 mg, 0.371 mmol). The reaction mixture was stirred at 0° C. for 20 min and then treated with 3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)propionic acid (100 mg, 0.285 mmol). The resulting reaction mixture was stirred at 0° C. for 10 min, allowed to warm to 25° C., and then treated with ethyl 2-amino-4-thiazoleacetate (123 mg, 0.657 mmol). The resulting reaction mixture was stirred at 25° C. for 3 d. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate) afforded {2-[3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)-propionyl-amino]-thiazol-4-yl}-acetic acid ethyl ester (107 mg, 72%) as a yellow foam: mp 48-51° C.; EI-HRMS m/e calcd for C22H25F3N2O5S2 (M+) 518.1157, found 518.1157.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:21][CH3:22])[CH:8]=[C:9]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[CH:10]=1)=[O:5])C.[Li+].[OH-]>O1CCOCC1>[CH2:21]([N:7]1[CH:8]=[C:9]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[CH:10]=[C:6]1[C:4]([OH:5])=[O:3])[CH3:22]
Reactant: CCOC(=O)c1cc(C#Cc2cccc(OC)c2)cn1CC
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCn1cc(C#Cc2cccc(OC)c2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 80.5 %

Procedure:
To a solution of 1-ethyl-4-(3-methoxy-phenylethynyl)-1H-pyrrole-2-carboxylic acid ethyl ester (3.5 g, 11.76 mmol) in dioxane (70 mL) was added LiOH (2M, 35 mL). The reaction mixture was stirred at room temperature for 3 days, and then concentrated in vacuo. The residue was dissolved in H2O (30 ml) and extracted with ether. Under cooling the aqueous was acidified with HCl (3N) and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and recrystallzation from ether and hexane gave the 1-ethyl-4-(3-methoxy-phenylethynyl)-1H-pyrrole-2-carboxylic acid intermediate as light yellow solid (2.55 g, 79% yield), mp 129° C., 1H NMR (400 MHZ, CDCl3) δ 1.26 (t, 3H), 3.73 (s, 3H), 4.26-4.28 (q, 2H), 6.96-6.97 (m, 2H), 6.99-7.0 (m, 2H), 7.23-7.24 (m, 1H), 7.46 (s, 1H), 12.46 (bs, 1H), MS m/e (M−H)− 268.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH:17]([CH:20]2[CH2:23][CH2:22][CH2:21]2)[CH2:18][CH3:19])[C:11]=1[N+:24]([O-])=O.[O-]S(S([O-])=O)=O.[Na+].[Na+]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH:17]([CH:20]2[CH2:21][CH2:22][CH2:23]2)[CH2:18][CH3:19])[C:11]=1[NH2:24]
Reactant: CCC(Nc1nccc(-c2ccc(OC)cc2Cl)c1[N+](=O)[O-])C1CCC1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: CCC(Nc1nccc(-c2ccc(OC)cc2Cl)c1N)C1CCC1
Yield: 151.1 %

Procedure:
[4-(2-Chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclobutyl-propyl)-amine (0.33 g, 0.88 mmol) and Na2S2O4 (1.33 g, 7.6 mmol) were treated substantially as described in Part E of Example 9 to give 0.46 g (100%) 4-(2-chloro-4-methoxy-phenyl)-N2-(1-cyclobutyl-propyl)-pyridine-2,3-diamine: MS (AP) m/z 345.9 [(M+H)+, 100].
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][C@@H:16](OS(C(F)(F)F)(=O)=O)[C@@H:15]2[C@H:12]1[C:13](=[O:37])[N:14]2[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.O.[F-:41].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:17][C@H:16]([F:41])[C@@H:15]2[C@H:12]1[C:13](=[O:37])[N:14]2[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [F-]
Reactant: COc1ccc(CN2C(=O)[C@@H]3[C@H]2[C@H](OS(=O)(=O)C(F)(F)F)CN3C(=O)OCc2ccccc2)cc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)[C@@H]3[C@H]2[C@@H](F)CN3C(=O)OCc2ccccc2)cc1OC

Procedure:
(1S,4R ,5S)-6-(3,4-Di methoxy-benzyl)-7-oxo-4-trifluoromethanesulphonyloxy-2,6-diazabicyclo[3.2.0]heptane-2-carboxylic acid benzyl ester (1.1 g, 2.02 mmol) and tetrabutylammonium fluoride trihydrate (704 mg, 2.23 mmol) were stirred together in 10 ml of tetrahydrofuran at room temperature for 10 min. Thereafter, the solvent was removed in a vacuum, the oily residue was taken up in ethyl acetate and extracted three times with water and once with saturated aqueous sodium chloride solution. The organic phase was dried over magnesium sulphate and concentrated. The residual brown oil was chromatographed over silica gel with ethyl acetate and a pale yellow oil was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:15][CH:16]=1
Reactant: CCOC(=O)COc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)COc1ccc(N)cc1
Yield: 76.9 %

Procedure:
To a suspension of Pd/C (0.5 g) in methanol (10 mL), ethyl 2-(4-nitrophenoxy)acetate (1.5 g) was added under nitrogen atmosphere into the 50 mL 3-neck RBF at room temperature. Hydrogen gas was bubbled through the reaction for 2 hr at room temperature. The reaction was monitored on TLC using CHCl3:methanol (9.5:0.5) as mobile phase. After completion of the reaction, the mixture was filtered using Celite and the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure at 40° C. to give 1.0 g of ethyl 2-(4-aminophenoxy)acetate as a brown solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:27]C)[N:12]2[CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:17]2)=[C:8]([NH2:29])[N:7]=1)[CH2:2][CH2:3][CH3:4].[ClH:30]>CO.O1CCOCC1>[ClH:30].[NH2:29][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:27])[N:12]2[CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26]2)[CH2:17]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCCN(C4CCCC4)C3)c2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CC3CCCN(C4CCCC4)C3)c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(butyloxy)-9-[(1-cyclopentyl-3-piperidinyl)methyl]-8-(methyloxy)-9H-purin-6-amine (37.2 mg, 0.092 mmol) in methanol (3 ml) at room temperature was added 4.0 M HCl in 1,4-dioxane (0.578 ml). The reaction mixture was stirred at ambient temperature overnight. The reaction solution was evaporated under N2 in a Radleys blow down unit to give the title compound as an off-white solid (39 mg). LCMS (System B): tRET=1.39 min; MH+ 389
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10](=[O:18])OC2C=CC=CC=2)=[C:4]([O:19][CH3:20])[CH:3]=1.[C:21]1([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10]([N:30]2[CH2:31][CH2:32][N:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:28][CH2:29]2)=[O:18])=[C:4]([O:19][CH3:20])[CH:3]=1
Reactant: COc1cc(C)c(C)cc1NC(=O)Oc1ccccc1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(C)c(C)cc1NC(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
Phenyl N-(4,5-dimethyl-2-methoxyphenyl)carbamate(5.422 g, 0.02 mol) and 1-phenylpiperazine(3.44 g, 0.02 mol) were dissolved in tetrahydrofuran(10 ml). After DBU(3.04 g, 0.02 mol) was added, the resulting solution was stirred at room temperature for 2 hrs, concentrated and purified by column chromatography to obtain the titled compound.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[NH:22][C@@:16]2([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17][CH2:18]3)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Cl:31][C:32]#[C:33][CH2:34][CH2:35]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[N:22]([CH2:35][C:34]#[C:33][CH2:32][Cl:31])[C@@:16]2([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:17][CH2:18]3)[CH:4]=[C:3]([C:2]([F:29])([F:1])[F:30])[CH:8]=1
Reactant: FC(F)(F)c1cc(CO[C@@H]2CC[C@H]3CC[C@]2(c2ccccc2)N3)cc(C(F)(F)F)c1
Reactant: ClC#CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1cc(CO[C@@H]2CC[C@H]3CC[C@]2(c2ccccc2)N3CC#CCCl)cc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A solution of (1R*,2R*,5R*)-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octane (Example 60; 400 mg, 0.93 mmol) in dimethylformamide (4 ml) was added to 1,4-dichlorobutyne (0.23 ml, 2.33 mmol) and potassium carbonate (386 mg, 2.79 mmol) in dimethylformamide (2 ml) at 60° C. The reaction mixture was stirred under N2 at 60° C. overnight. The mixture was diluted with water and extracted with ethyl acetate (×3), dried (MgSO4) and concentrated in vacuo to give a brown oil. This was purified by flash column chromatography [2.5%-7.5% methanol in dichloromethane] to give the title compound as a brown oil.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:18])[CH:8]=2)[N:3]=1.[CH2:19]([NH2:25])[C:20]1[O:24][CH:23]=[CH:22][CH:21]=1>O>[Cl:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:25][CH2:19][C:20]1[O:24][CH:23]=[CH:22][CH:21]=1)[N:11]=[C:10]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Clc1ccc2nc(Cl)nc(-c3ccccc3)c2c1
Reactant: NCc1ccco1
Solvent: O
Product: Clc1ccc2nc(NCc3ccco3)nc(-c3ccccc3)c2c1
Yield: 83.4 %

Procedure:
A mixture of 275 mg of 2,6-dichloro-4-phenylquinazoline (compound No. II-2) and 486 mg of furfurylamine was stirred at 85° C. for 40 minutes and then poured into 50 ml of water. The mixture was extracted with ethyl acetate, and the resultant extract was washed with water and then concentrated. The resulting residue was recrystallized from ethanol to obtain 280 mg of the titled compound. Mp.142.0° C. 1H NMR (CDCl3): 4.77 (2H, d, J=5.6 Hz), 5.70 (1H, br. t, J=5.6 Hz), 6.29-6.32 (2H, m), 7.36 (1H, dd, J=1.8, 0.9 Hz), 7.53-7.70 (7H, m), 7.78 (1H, d, J=2.2 Hz).
Reaction SMILES: C[O:2][C:3](=[O:42])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C@@H:13]2[NH:17][C@@H:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@:15]3([C:30]4[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=4)[NH:24][C:23]3=[O:32])[C@H:14]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=2)=[O:12])=[C:6]([O:40][CH3:41])[CH:5]=1.[OH-].[Na+]>CO>[Cl:31][C:27]1[CH:26]=[C:25]2[NH:24][C:23](=[O:32])[C@:15]3([C@@H:14]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=4)[C@H:13]([C:11]([NH:10][C:7]4[CH:8]=[CH:9][C:4]([C:3]([OH:42])=[O:2])=[CH:5][C:6]=4[O:40][CH3:41])=[O:12])[NH:17][C@H:16]3[CH2:18][C:19]([CH3:21])([CH3:20])[CH3:22])[C:30]2=[CH:29][CH:28]=1
Reactant: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
To a stirred solution of rac-4-{[(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-3-methoxy-benzoic acid methyl ester (100 mg, 0.16 mmol) in methanol (10 mL) was added an aqueous solution (2 mL) of NaOH (33 mg, 0.82 mmol). The reaction mixture was stirred at room temperature overnight. The “pH” of the mixture was adjusted to 4.5, and the solvent was reduced to about 3 ml. The mixture was filtered, and the precipitate was collected, dried to give a white solid, which was purified by chromatography (7%-10% methanol/methylene chloride) to give 20 mg desired product. MS (H+), 596.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:36]=[CH:35][C:12]([O:13][CH2:14][C:15]3([CH3:34])[CH2:24][C:23](=[O:25])[C:22]4[C:17](=[C:18]([CH3:33])[C:19]([CH3:32])=[C:20]([O:27][CH2:28][C:29]([OH:31])=[O:30])[C:21]=4[CH3:26])[O:16]3)=[CH:11][CH:10]=2)[S:3]1.O1CCO[CH2:39][CH2:38]1.Cl.C(=O)(O)[O-].[Na+]>O.C(O)C>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([O:13][CH2:14][C:15]3([CH3:34])[CH2:24][C:23](=[O:25])[C:22]4[C:17](=[C:18]([CH3:33])[C:19]([CH3:32])=[C:20]([O:27][CH2:28][C:29]([O:31][CH2:38][CH3:39])=[O:30])[C:21]=4[CH3:26])[O:16]3)=[CH:35][CH:36]=2)[S:3]1
Reactant: Cc1c(C)c2c(c(C)c1OCC(=O)O)C(=O)CC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Reactant: C1COCCO1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)COc1c(C)c(C)c2c(c1C)C(=O)CC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Reaction time: 8 h

Procedure:
A mixture of 0.5 g of α-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-2,5,7,8-tetramethyl-4-oxo-chroman-6-yloxy}acetic acid (obtained as described in Example 59), 0.5 ml of a 4N dioxane solution of hydrogen chloride and 5 ml of ethanol was allowed to stand overnight at room temperature. The reaction mixture was then poured into water and the solution was neutralized with sodium bicarbonate and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was subjected to preparative silica gel thin layer chromatography (developing solvent, benzene:ethyl acetate=7:3 by volume) to obtain the title compound.
Reaction SMILES: [ClH:1].[CH3:2][N:3](C(OC(C)(C)C)=O)[CH:4]([CH3:43])[CH2:5][CH2:6][N:7](C(OC(C)(C)C)=O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16][CH2:17][CH:18]([CH3:28])[N:19](C)[C:20](OC(C)(C)C)=O>CO>[ClH:1].[ClH:1].[ClH:1].[ClH:1].[CH3:20][NH:19][CH:18]([CH3:28])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][CH:4]([NH:3][CH3:2])[CH3:43]
Reactant: CC(CCN(CCCCCCCN(CCC(C)N(C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)N(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CNC(C)CCNCCCCCCCNCCC(C)NC
Reaction time: 8 h

Procedure:
Add 1N HCl in methanol (50 ml) to 1,2,16,17-tetramethyl-1,5,13,17-tetra(t-butoxycarbonyl)-1,5,13,17-tetraazaheptadecane (3.8 g, 0.0054 mol) and stir overnight. Remove the solvent in vacuo and recrystallize the residue two times from methanol/acetonitrile (40/60, v/v) to yield 0.74 g of the title compound as a white solid (mp 238°-9° C.). Rf is 0.31 for TLC on silica gel developed with 40% conc. ammonia in methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([OH:8])[CH:7]=1.[CH3:10]N(C=O)C.C([O-])([O-])=O.[K+].[K+].IC>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([O:8][CH3:10])[CH:7]=1
Reactant: CN(C)C=O
Reactant: Oc1cc(Cl)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: COc1cc(Cl)ccc1F
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a mixture of 5-chloro-2-fluorophenol (4.68 g) and DMF (dry) (50 mL) were added K2CO3 (8.83 g) and iodomethane (3.99 mL) at room temperature. The mixture was stirred at room temperature for 4.5 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed successively with water and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (4.60 g).