Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11](=[O:50])[O:12][C:13]([OH:49])([C:41]4[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=4)[C:14]=3[CH2:15][C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][N:38]=[N+]=[N-])[CH:17]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11](=[O:50])[O:12][C:13]([OH:49])([C:41]4[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=4)[C:14]=3[CH2:15][C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][NH2:38])[CH:17]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1ccc(C2(O)OC(=O)C(c3ccc4c(c3)OCO4)=C2Cc2cc(OC)c(OC)c(OCCOCCOCCOCCN=[N+]=[N-])c2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C2(O)OC(=O)C(c3ccc4c(c3)OCO4)=C2Cc2cc(OC)c(OC)c(OCCOCCOCCOCCN)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.2 %

Procedure:
A mixture of 1.49 g (2.15 mmol) of 3-Benzo[1,3]dioxol-5-yl-4-(3-(2-{2-[2-(2-azidoethoxy)ethoxy]ethoxy}ethoxy)-4,5-dimethoxybenzyl)-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one 9 and 1.00 g (3.00 mmol) of polymer bound PPh3 (polystyrene, 2% DVB, FLUKA) was suspended in 10 ml of THF and stirred at room temperature overnight. Water is added (200 μl, ≈10 mmol) and stirring was continued for 3 d. The polymer was removed by filtration and the filtrate was evaporated in vacuo. The remaining oil was purified by silica gel column chromatography (EtOAc/MeOH/NEt3 5/1/0.3), yielding 246 mg of the product (0.37 mmol, 17%). 1H-NMR (CDCl3) δ=7.32 (d, 2H, J=8.1 Hz), 6.83, (m, 2H), 6.75 (d, 2H, J=8.1 Hz), 6.68 (d, 1H, J=7.7 Hz), 6.14 (s, 1H), 5.91 (s, 1H), 5.85 (s, 2H), 3.88 (m, 2H), 3.70 (s, 4H), 3.64 (s, 3H), 3.59 (m, 4H), 3.54 (s, 3H), 3.48 (m, 4H) 3.37 (m, 2H), 3.15 (m, 2H) ppm. The protons of the butenolide hydroxy group and the amino function were not detected. 13C-NMR δ=171.2, 160.8, 160.1, 152.8, 151.9, 147.9, 147.5, 137.2, 131.8, 129.2, 127.8, 127.4, 123.2, 123.1, 113.7, 109.4, 108.5, 108.2, 106.6, 106.0, 101.2, 70.6, 70.4, 70.3, 70.2, 69.8, 69.7, 68.6, 60.6, 55.8, 55.2, 40.0, 32.0 ppm. MS: m/z=690 [M+Na]+, 668 [M+H]+. Elemental or HRMS analysis could not be obtained from this product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10](=[O:23])[CH2:11][C:12](=[O:22])/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[C:4]([O:24][CH3:25])[CH:3]=1.CN(C)C1C=CC(/C=C/C(=O)CC(=O)/C=C/C2C=CC(O)=C(OC)C=2)=CC=1>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=[O:23])[CH2:11][C:12](=[O:22])[CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=2)=[C:4]([O:24][CH3:25])[CH:3]=1
Reactant: COc1cc(O)ccc1/C=C/C(=O)CC(=O)/C=C/c1ccc(O)cc1
Agent: COc1cc(/C=C/C(=O)CC(=O)/C=C/c2ccc(N(C)C)cc2)ccc1O
Product: COc1cc(O)ccc1CCC(=O)CC(=O)CCc1ccc(O)cc1

Procedure:
The title compound was synthesized using the same procedure employed for Example 372, but with (1E,6E)-1-(4-hydroxy-2-methoxyphenyl)-7-(4-hydroxyphenyl)hepta-1,6-diene-3,5-dione (20 mg, 59 μmol, synthesized in Example 63) as the starting material instead of (1E,6E)-1-(4-dimethylaminophenyl)-7-(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione, and was purified by silica gel column chromatography eluting with hexane/ethyl acetate=65/35 to 55/45. The product was obtained as a gum (14.4 mg, 72%) having the following characteristics.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[CH3:11][C:12]1[CH:26]=[CH:25][C:15]([O:16][C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[CH:20]=O)=[CH:14][CH:13]=1>>[CH3:8][C:6]1([CH3:9])[CH2:7][C:2]2[NH:1][C:2]3[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]=3[CH:20]([C:19]3[CH:22]=[CH:23][CH:24]=[C:17]([O:16][C:15]4[CH:25]=[CH:26][C:12]([CH3:11])=[CH:13][CH:14]=4)[CH:18]=3)[C:3]=2[C:4](=[O:10])[CH2:5]1
Reactant: CC1(C)CC(=O)C=C(N)C1
Reactant: Cc1ccc(Oc2cccc(C=O)c2)cc1
Product: Cc1ccc(Oc2cccc(C3C4=C(CC(C)(C)CC4=O)NC4=C3C(=O)CC(C)(C)C4)c2)cc1

Procedure:
3-Amino-5,5-dimethyl-2-cyclohexen-1-one was reacted with 3-(4-methylphenoxy)benzaldehyde in an analogous manner to that described in Example 1 to give 3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-9-[3-(4-methylphenoxy)-phenyl]-1,8(2H,5H)-acridinedione. Crystallization from ethanol gave a pale yellow crystalline solid of melting point 202-203° C.
Reaction SMILES: [N:1]1[C:10]2[N:9]3[CH2:11][CH2:12][O:13][CH2:14][CH:8]3[CH2:7][NH:6][C:5]=2[CH:4]=[N:3][C:2]=1[C:15]1[C:23]2[C:18](=[C:19]([O:24][CH3:25])[CH:20]=[CH:21][CH:22]=2)[N:17](C(OC(C)(C)C)=O)[CH:16]=1.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C(Cl)Cl>[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34].[CH3:25][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:18]=1[NH:17][CH:16]=[C:15]2[C:2]1[N:3]=[CH:4][C:5]2[NH:6][CH2:7][CH:8]3[CH2:14][O:13][CH2:12][CH2:11][N:9]3[C:10]=2[N:1]=1
Reactant: COc1cccc2c(-c3ncc4c(n3)N3CCOCC3CN4)cn(C(=O)OC(C)(C)C)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc2c(-c3ncc4c(n3)N3CCOCC3CN4)c[nH]c12

Procedure:
A TFA salt of the title compound was prepared in a manner similar to EXAMPLE 8 using tert-butyl 3-(5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)-7-methoxy-1H-indole-1-carboxylate (60 mg, 0.137 mmol) in CH2Cl2 and TFA. 1H NMR (400 MHz, DMSO-d6) δ 2.92-3.05 (m, 1 H), 3.27-3.30 (m, 1 H), 3.53-3.66 (m, 1 H), 3.76-3.90 (m, 1 H), 3.91-3.98 (m, 5 H), 3.97-4.06 (m, 1 H), 4.08-4.18 (m, 1 H), 4.68-4.84 (m, 1 H), 6.33-6.45 (br s, 1 H), 6.79-6.87 (m, 1 H), 7.09-7.20 (m, 1 H), 7.38-7.46 (m, 1 H), 7.80-7.89 (m, 1 H), 8.15-8.23 (m, 1 H), 12.18-12.29 (m, 1 H). ESI-MS m/z [M+H]+ calc'd for C18H19N5O2S, 338.15; found 338.4.
Reaction SMILES: C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2([NH:44][C:45]3[N:50]=[C:49]([O:51][CH2:52][C:53]([F:56])([F:55])[F:54])[N:48]=[C:47]([NH:57][C:58]4[CH:66]=[CH:65][C:61]([C:62](O)=[O:63])=[CH:60][CH:59]=4)[N:46]=3)[CH2:43][CH2:42]2)=[CH:37][CH:36]=1.[NH2:67][CH2:68][CH2:69][C@@H:70]([NH:74][C:75]([O:77][C:78]([CH3:81])([CH3:80])[CH3:79])=[O:76])[C:71]([OH:73])=[O:72]>CN(C=O)C>[C:78]([O:77][C:75]([NH:74][C@H:70]([CH2:69][CH2:68][NH:67][C:62](=[O:63])[C:61]1[CH:60]=[CH:59][C:58]([NH:57][C:47]2[N:46]=[C:45]([NH:44][C:41]3([C:38]4[CH:39]=[CH:40][C:35]([Cl:34])=[CH:36][CH:37]=4)[CH2:43][CH2:42]3)[N:50]=[C:49]([O:51][CH2:52][C:53]([F:56])([F:54])[F:55])[N:48]=2)=[CH:66][CH:65]=1)[C:71]([OH:73])=[O:72])=[O:76])([CH3:81])([CH3:80])[CH3:79]
Reactant: CC(C)(C)OC(=O)N[C@H](CCN)C(=O)O
Reactant: O=C(O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](CCNC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N,N-Di-iso-propylethylamine (0.054 g) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.079 g) were added into a solution of 4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzoic acid (0.1 g) and (R)-4-amino-2-((tert-butoxycarbonyl)amino)butanoic acid (0.045 g) in DMF (1 mL). The reaction was stirred at room temperature for 16 hours and (R)-2-((tert-butoxycarbonyl)amino)-4-(4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)butanoic acid was isolated by using preparative HPLC system.
Reaction SMILES: [CH2:1]([C:5]1([CH2:40][CH3:41])[CH2:11][S:10](=[O:13])(=[O:12])[C:9]2[CH:14]=[CH:15][C:16]([N:18]([CH3:20])[CH3:19])=[CH:17][C:8]=2[CH:7]([C:21]2[CH:22]=[C:23]([NH:27][C:28]([CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][C:36](O)=[O:37])=[O:29])[CH:24]=[CH:25][CH:26]=2)[CH:6]1[OH:39])[CH2:2][CH2:3][CH3:4].[NH2:42][CH2:43][C:44]1[CH:49]=[CH:48][C:47]([N:50]2[CH:53]([C:54]3[CH:59]=[CH:58][C:57]([O:60][CH3:61])=[CH:56][CH:55]=3)[CH:52]([CH2:62][CH2:63][CH:64]([C:66]3[CH:71]=[CH:70][C:69]([F:72])=[CH:68][CH:67]=3)[OH:65])[C:51]2=[O:73])=[CH:46][CH:45]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH2:1]([C:5]1([CH2:40][CH3:41])[CH2:11][S:10](=[O:13])(=[O:12])[C:9]2[CH:14]=[CH:15][C:16]([N:18]([CH3:20])[CH3:19])=[CH:17][C:8]=2[CH:7]([C:21]2[CH:22]=[C:23]([NH:27][C:28]([CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][C:36]([NH:42][CH2:43][C:44]3[CH:49]=[CH:48][C:47]([N:50]4[C:51](=[O:73])[CH:52]([CH2:62][CH2:63][CH:64]([C:66]5[CH:67]=[CH:68][C:69]([F:72])=[CH:70][CH:71]=5)[OH:65])[CH:53]4[C:54]4[CH:59]=[CH:58][C:57]([O:60][CH3:61])=[CH:56][CH:55]=4)=[CH:46][CH:45]=3)=[O:37])=[O:29])[CH:24]=[CH:25][CH:26]=2)[CH:6]1[OH:39])[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(CN)cc2)cc1
Reactant: CCCCC1(CC)CS(=O)(=O)c2ccc(N(C)C)cc2C(c2cccc(NC(=O)COCCOCC(=O)O)c2)C1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCCC1(CC)CS(=O)(=O)c2ccc(N(C)C)cc2C(c2cccc(NC(=O)COCCOCC(=O)NCc3ccc(N4C(=O)C(CCC(O)c5ccc(F)cc5)C4c4ccc(OC)cc4)cc3)c2)C1O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
At room temperature, 140 mg of (2-{[3-(3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-5-yl)-phenylcarbamoyl]methoxy}-ethoxy)acetic acid (17) and 100 mg of 1-(4-aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-methoxyphenyl)azetidin-2-one are dissolved in 5 ml of dimethylformamide, 35 mg of 1-hydroxybenzotriazole and 45 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride are added and the mixture is stirred at room temperature for 6 h. The reaction mixture is concentrated under reduced pressure. Dichloromethane is added to the residue, the mixture is extracted twice with water and once with sat. sodium chloride solution and the organic extract is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product is purified chromatographically (RP18; dichloromethane/methanol 92/8, changed over 25 min to dichloromethane/methanol 96/4). This gives the product of melting point 116-125° C. Molecular weight 1007.24 (C56H67FN4O10S); MS (ESI): 1008.53 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=2)[CH:3]=1.B(Br)(Br)Br>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH:3]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1
Reactant: COc1ccc(Cc2cc(Br)ccc2Cl)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
4-bromo-1-chloro-2-(4-methoxybenzyl)-benzene (10 g, 32 mmol) was dissolved in dichloromethane (32 mL) and cooled to 0° C. under nitrogen. A 1.0 M boron tribromide solution in dichloromethane (35.3 mL, 34.3 mmol) was added dropwise over 10 minutes. Following the addition, the ice bath was removed and the solution was stirred at room temperature for 1 hour. The reaction mixture was cooled to 0° C. and quenched by addition of 1N aqueous hydrochloric acid solution (45 mL). The mixture was stirred for 30 minutes, transferred to a separatory funnel, the organic layer was collected, and the aqueous layer was extracted with dichloromethane (45 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 4-(5-bromo-2-chlorobenzyl)phenol (9.5 g, 99% yield) as a white solid.
Reaction SMILES: Cl[C:2]1[C:10]2[C:6](=[N:7][N:8]([CH2:11][C:12]([NH:16][C:17](=[O:29])[C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)([C:14]#[N:15])[CH3:13])[N:9]=2)[CH:5]=[C:4]([C:30]([F:33])([F:32])[F:31])[CH:3]=1.C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C.C[C:64]([N:66](C)C)=O>[C-]#N.[Zn+2].[C-]#N.[Zn].FC(F)(F)C([O-])=O.[Pd+2].FC(F)(F)C([O-])=O>[C:14]([C:12]([NH:16][C:17](=[O:29])[C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=1)([CH3:13])[CH2:11][N:8]1[N:7]=[C:6]2[CH:5]=[C:4]([C:30]([F:31])([F:32])[F:33])[CH:3]=[C:2]([C:64]#[N:66])[C:10]2=[N:9]1)#[N:15]
Reactant: CC(C#N)(Cn1nc2cc(C(F)(F)F)cc(Cl)c2n1)NC(=O)c1ccc(OC(F)(F)F)cc1
Reactant: CC(=O)N(C)C
Agent: [Pd+2]
Agent: CC(C)(C)P(c1ccc2ccccc2c1-c1cccc2ccccc12)C(C)(C)C
Agent: O=C([O-])C(F)(F)F
Product: CC(C#N)(Cn1nc2cc(C(F)(F)F)cc(C#N)c2n1)NC(=O)c1ccc(OC(F)(F)F)cc1
Yield: 63 %

Procedure:
N-[2-(4-Chloro-6-trifluoromethyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide (100 mg, described in Example 19), zinc cyanide (50 mg), zinc powder (10 mg), 2-di-t-butylphosphino-1,1′-binaphthyl (40 mg) and palladium trifluoroacetate (34 mg) were heated under nitrogen in degassed dimethylacetamide (1 mL) at 100° C. overnight. The mixture was concentrated under reduced pressure to give a residue that was purified by chromatography (SiO2, heptane/EA) to afford the title compound as a white solid (62 mg, 63%). Rf=0.6 (1:1 EA/heptane). MS (ES): M/Z [M+H]=483. NMR: (400 MHz, DMSO-d6): 1.77 (s, 3H), 5.56 (d, J=13.3 Hz, 1H), 5.66 (d, J=13.3 Hz, 1H), 7.49 (d, J=8.2 Hz, 2H), 7.92 (d, J=8.6 Hz, 2H), 8.59 (s, 1H), 8.90 (s, 1H) and 9.02 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −61.0 (s, 3F) and −57.1 (s, 3F).
Reaction SMILES: [CH2:1]([C:4]1([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.C1(C)C(S(O)(=O)=O)=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CCOCC.C1(C)C(S(O)(=O)=O)=CC=CC=1.C(Cl)(Cl)Cl>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:10][C:4]1([CH2:1][C:2]#[CH:3])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: C#CCC1(O)CCCCC1
Reactant: C1=COCCC1
Agent: Cc1ccccc1S(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: C#CCC1(OC2CCCCO2)CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
A solution of 2.9 g (21 mmol) of (prop-2-ynyl)cyclohexanol in 10 ml of dry ether was stirred under argon as 0.24 ml (26 mmol) of dihydropyran was added followed by about 5 mg of toluenesulfonic acid. After one hour, tlc (CHCl3, silica gel) analysis indicated that significant starting material remained. Another 0.2 ml of dihydropyran and about 5 mg of toluenesulfonic acid were added. Twice more at one hour intervals, 0.2 ml portions of dihydropyran along with a small amount of toluenesulfonic acid were added to the reaction mixture. It was left to stir under argon at room temperature for 15 hours. Potassium carbonate was then added to the mixture and it was stirred for several minutes before it was washed with water. The wash solution was back extracted with ether and the combined extracts were then washed with brine, dried (Na2SO4) and evaporated in vacuo to yield 4.6 g of 1-(tetrahydropyran-2-yloxy)-1-(prop-2-ynyl)cyclohexane) having the following spectral characteristics: nmr (CDCl3) δ 1.0-2.5 (19H, m), 3.6 (2H, broad m) and 4.65 ppm (1H, broad s); ir (CHCl3) 980, 1030, 1050, 1070, 1120, 1150, 1270, 1450, 2120, (weak) 2760, 2930 and 3300 cm-1.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4]1.C(N(CC)CC)C.[Br:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.O>C(Cl)Cl>[Br:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([O:1][CH2:2][C@H:3]2[O:8][C:7]([CH3:9])([CH3:10])[O:6][C@@H:5]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4]2)(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](COS(=O)(=O)c2ccc(Br)cc2)OC(C)(C)O1
Reaction time: 20 h
Yield: 144.4 %

Procedure:
To a stirring, 20°-25° C. solution of the (4R-cis)-1,1-dimethylethyl 6-hydroxymethyl-2,2 dimethyl-1,3- dioxane-4-acetate (European Patent Application 0319,847) (10 g, 38 mmol) in methylene chloride) (250 mL) containing triethylamine (10 mL, 72 mmol) is added 4-bromobenzenesulfonyl chloride (15 g, 57.5 mmol). Stirring is continued at 20°-25° C. for 20 hours, the solution is poured onto 250 mL of water and the layers separated. The upper aqueous layer is extracted with 250 mL of methylene chloride and the combined organic layers are washed with 200 mL each of saturated sodium bicarbonate solution, to ensure complete removal of 4-bromobenzenesulfonyl chloride and then saturates sodium chloride solution. Drying the solution with magnesium sulfate and concentration in vacuo gives 26.3 g of the product as a light orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:45]=[CH:44][C:6]([CH2:7][N:8]([CH:41]([CH3:43])[CH3:42])[CH2:9][CH2:10][C@H:11]([NH:16][C:17]([C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[N:24][N:25]3[CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:21][C:20]=2[O:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=2[F:40])=[O:18])[C:12](OC)=[O:13])=[CH:5][CH:4]=1.[BH4-].[Na+]>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:45]=[CH:44][C:6]([CH2:7][N:8]([CH:41]([CH3:43])[CH3:42])[CH2:9][CH2:10][C@H:11]([NH:16][C:17]([C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[N:24][N:25]3[CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:21][C:20]=2[O:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=2[F:40])=[O:18])[CH2:12][OH:13])=[CH:5][CH:4]=1
Reactant: COC(=O)[C@H](CCN(Cc1ccc(OC)cc1)C(C)C)NC(=O)c1cc2c(cnn2CC(C)C)cc1Oc1ccc(F)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CN(CC[C@@H](CO)NC(=O)c2cc3c(cnn3CC(C)C)cc2Oc2ccc(F)cc2F)C(C)C)cc1
Temperature: 50 °C
Yield: 59 %

Procedure:
(S)-methyl 4-((4-methoxybenzyl)(isopropyl)amino)-2-(5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxamido)butanoate (0.035 g, 0.057 mmol) and NaBH4 (0.022 g, 0.57 mmol) were dissolved in THF/MeOH (5 mL, 3:2) and heated to 50° C. for 3 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was chromatographed eluting with 5% MeOH in dichloromethane with 1% triethylamine to provide 0.020 g of gel (59% yield).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].Cl.[CH3:9][CH:10]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][C:11]1=[O:17].N1C=CC=CC=1>C(Cl)Cl>[C:1]([N:14]1[CH2:15][CH2:16][CH:10]([CH3:9])[C:11](=[O:17])[CH2:12][CH2:13]1)(=[O:3])[CH3:2]
Reactant: CC1CCNCCC1=O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1CCC(=O)C(C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.2 %

Procedure:
Acetic anhydride (0.437 mL, 4.62 mmol) was added at 0° C. to a solution of 5-methyl-azepan-4-one hydrochloride (0.740 g, 3.08 mmol) in DCM (20 mL) and pyridine (0.25 mL, 3.08 mmol). The reaction mixture was stirred at RT for 8 hours before being partitioned between DCM and H2O. The organic layer was dried (Na2SO4), filtered, and evaporated. The crude residue was purified by SiO2 chromatography (100% EtOAc) to give 0.220 g of 1-acetyl-5-methyl-azepan-4-one (42% yield).
Reaction SMILES: [CH3:1][NH:2][CH:3]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11]C(=O)C(C)(C)C.C1(C)C=CC=CC=1.[ClH:31]>>[ClH:31].[ClH:31].[CH3:1][NH:2][CH:3]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11]
Reactant: CNC(Cc1ccccc1NC(=O)C(C)(C)C)c1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CNC(Cc1ccccc1N)c1ccccc1
Temperature: 100 °C
Reaction time: 28 h
Yield: 92.9 %

Procedure:
N-[2-(2-methylamino-2-phenylethyl)phenyl]-2,2-dimethylpropanamide (155 g, 0.5 mol) was dissolved in 6N HCl (310 g) and stirred under a nitrogen atmosphere at 100° C. for 28 hours. The reaction mixture was cooled to 23° C. and toluene (200 ml) was added. Stirring was continued until the product had crystallized from the aqueous phase. The product was collected by filtration, washed with toluene (2×50 ml) and dried in vacuo (30 mm) at 60° C. for 60 hours to give N-methyl-2-amino-α-phenylphenethyl-amine dihydrochloride (139 g, 93% yield). The melting point of the product was 252°-254° C. The organic phase of the filtrate was concentrated in vacuo to give a 58% recovery of trimethylacetic acid. The aqueous phase of the filtrate afforded a second crop of N-methyl-2-amino-α-phenylphenethylamine dihydrochloride (9.3 g, 6%). The total yield of product was 99%.
Reaction SMILES: [NH2:1][C:2]([CH3:9])=[C:3]([Cl:8])[C:4](OC)=[O:5].[CH:10]([NH2:12])=O.C[O-].[Na+]>CO>[Cl:8][C:3]1[C:4]([OH:5])=[N:12][CH:10]=[N:1][C:2]=1[CH3:9]
Reactant: COC(=O)C(Cl)=C(C)N
Reactant: NC=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1ncnc(O)c1Cl

Procedure:
25.9 g (0.17 mol) of methyl 3-amino-2-chloro-2-butenoate are reacted with 11.7 g (0.26 mol) of formamide and 51 ml of sodium methylate solution in 20 ml of methanol and worked up in analogy to Example 9 (reaction time 20 h). Yield: 16.6 g (67.5%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[O:8][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)Cc1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)Cc1ccc(OCc2ccccc2)c(Br)c1

Procedure:
Compound 10 (12.3 g) was dissolved in 100 mL acetone and 7.6 g of potassium carbonate was added. 8.6 g of benzyl bromide was added with stirring. The solid was removed by suction filtration and the liquid was evaporated to product 11.
Reaction SMILES: [CH2:1]([S:5]([NH:8][CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19]3[CH2:20][CH2:21][C:22](=[O:25])[NH:23][N:24]=3)[CH:15]=2)[CH2:10]1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4]>CS(C)=O>[CH2:1]([S:5]([NH:8][CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19]3[CH:20]=[CH:21][C:22](=[O:25])[NH:23][N:24]=3)[CH:15]=2)[CH2:10]1)(=[O:6])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCS(=O)(=O)NC1CCc2cc(C3=NNC(=O)CC3)ccc2C1
Solvent: CS(C)=O
Product: CCCCS(=O)(=O)NC1CCc2cc(-c3ccc(=O)[nH]n3)ccc2C1

Procedure:
2-n-Butylsulfonylamino-6-[4,5-dihydropyridazin-3(2H)-on-6-yl]-1,2,3,4-tetrahydronaphthalene was treated with dimethylsulfoxide-25% hydrogen bromide-acetic acid in the same manner as in Example 60 to obtain 2-n-butylsulfonylamino-6-[pyridazin-3(2H)-on-6-yl]-1,2,3,4-tetrahydronaphthalene.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][N:13]2[C:17](=[O:18])[CH2:16][CH2:15][CH:14]2[CH2:19][CH2:20][CH:21]([OH:30])[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:6][CH:5]=1.[OH-].[Na+]>CO>[F:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][CH:21]([OH:30])[CH2:20][CH2:19][CH:14]2[CH2:15][CH2:16][C:17](=[O:18])[N:13]2[CH2:12][CH2:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:31])=[O:2])=[CH:5][CH:6]=2)=[CH:28][CH:27]=1
Reactant: COC(=O)c1ccc(CCCN2C(=O)CCC2CCC(O)Cc2ccc(F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(CCCN2C(=O)CCC2CCC(O)Cc2ccc(F)cc2)cc1
Yield: 76.1 %

Procedure:
Analogous to the procedure described for Example 1A, Step F, 4-(3-{2-[4-(4-fluoro-phenyl)-3-hydroxy-butyl]-5-oxo-pyrrolidin-1-yl}-propyl)-benzoic acid methyl ester (61.1 mg, 0.143 mmol) was hydrolyzed with 6N NaOH (1 mL) in MeOH (5 mL) at room temperature over 24 h. Purification by medium pressure chromatography eluting with a solvent gradient (CH2Cl2to 2% MeOH in CH2Cl2 to 4% MeOH in CH2Cl2 to 6% MeOH in CH2Cl2 to 10% MeOH in CH2Cl2) provided the title compound (45 mg). 1H NMR (CDCl3) δ7.97 (d, 2H), 7.25 (m, 2H), 7.14 (m, 2H), 6.99 (m, 2H), 3.75-3.58 (m, 3H), 2.97 (m, 1H), 2.69 (m, 4H), 2.40 (m, 2H), 2.15-1.35 (m, 9H); MS 413.8 (M+).