Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([OH:9])=[N:5][CH:6]=[N:7][CH:8]=1.C(N(CC)CC)C.[CH3:17][O:18][C:19]1[C:20](=O)[C:21](=[O:25])[C:22]=1[O:23]C>CO>[OH:9][C:4]1[C:3]([NH:2][C:20]2[C:21](=[O:25])[C:22](=[O:23])[C:19]=2[O:18][CH3:17])=[CH:8][N:7]=[CH:6][N:5]=1
Reactant: COc1c(OC)c(=O)c1=O
Reactant: Nc1cncnc1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1c(Nc2cncnc2O)c(=O)c1=O
Temperature: 50 °C
Yield: 79.4 %

Procedure:
1.00 g (6.78 mmol, 1 eq) of 5-aminopyrimidin 4-ol hydrochloride and 0.95 ml (6.78 mmol, 1 eq) of triethylamine were added to a suspension of 3.86 g (27.16 mmol, 4 eq) of 3,4-dimethoxycyclobut-3-ene-1,2-dione in 20 ml of methanol. The reaction medium was heated at 50° C. for 18 hours. The reaction medium was left at ambient temperature. The precipitate was filtered off and washed with methanol. 1.19 g of product were obtained in the form of a yellow solid. Yield=79%.
Reaction SMILES: [CH:1]([S:4]([C:7]1[N:11]=[CH:10][NH:9][N:8]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].[CH2:12]([N:15]([CH2:19][CH2:20][CH3:21])[C:16](Cl)=[O:17])[CH2:13][CH3:14]>>[CH2:12]([N:15]([CH2:19][CH2:20][CH3:21])[C:16]([N:9]1[CH:10]=[N:11][C:7]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])=[N:8]1)=[O:17])[CH2:13][CH3:14]
Reactant: CCCN(CCC)C(=O)Cl
Reactant: CC(C)S(=O)(=O)c1nc[nH]n1
Product: CCCN(CCC)C(=O)n1cnc(S(=O)(=O)C(C)C)n1

Procedure:
In an analogous manner to that described in Example 20, 3-isopropylsulphonyl-1,2,4-triazole was reacted with dipropylcarbamoyl chloride (4 hours reflux) to give 1-dipropylcarbamoyl-3-isopropylsulphonyl-1,2,4-triazole, m.p. 61° .varies. 63°C. Elemental analysis satisfactory.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[CH:9]=[CH:10][NH:11][C:6]2=[CH:5][CH:4]=1.[H-].[Na+].[CH3:14][CH:15]([Si:17](Cl)([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])[CH3:16]>C1COCC1>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[CH:9]=[CH:10][N:11]([Si:17]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:16])[CH3:14])[C:6]2=[CH:5][CH:4]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: COc1ccc2[nH]ccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)n1
Reaction time: 1 h
Yield: 100.3 %

Procedure:
To a solution of 5-methoxy-1H-pyrrolo[3,2-b]pyridine (4.0 g, 27.0 mmol) in THF (50 mL) was added NaH (60%, 1.30 g, 32.4 mmol) in small portions at 0° C. over 10 min. The resulting mixture was stirred under N2 for 1 hr, followed by dropwise addition of TIPS-Cl (6.86 mL, 32.4 mmol) in neat through an syringe at 0° C. over 2 min, and stirred for additional 1 hr. The reaction was quenched with sat. NH4Cl (50 mL), extracted with Et2O (500 mL). The extract was washed with brine (50 mL), dried (MgSO4), concentrated on rotary vacuo, and the residue was purified on Biotage Flash Collector eluting with 20-75% EtOAc/Hexanes (1600 mL) to afford the expected product, 5-methoxy-1-(triisopropylsilyl)-1H-pyrrolo[3,2-b]pyridine (8.25 g, 100%). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.11 (d, J=7.55 Hz, 19 H) 1.57-1.67 (m, J=7.55, 7.55, 7.55, 7.55 Hz, 3 H) 3.98 (s, 3 H) 6.54 (d, J=9.06 Hz, 1 H) 6.67 (d, J=3.02 Hz, 1 H) 7.35 (d, J=3.27 Hz, 1 H) 7.65 (d, J=9.06 Hz, 1 H); Mass spec 305.1 (MH+) calc. for C17H28N2O Si 304.2.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](O)=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.Cl.[F:62][C@@H:63]1[CH2:67][CH2:66][NH:65][CH2:64]1>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:26])([F:28])[F:27])=[N:20][C:21]([C:22]([N:65]3[CH2:66][CH2:67][C@@H:63]([F:62])[CH2:64]3)=[O:23])=[C:15]2[CH2:14]1)=[O:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Reactant: F[C@@H]1CCNC1
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CC[C@@H](F)C3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 96.5 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (0.15 g, 0.27 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.140 g, 0.54 mmol), triethylamine (0.4 mL, 2.6 mmol) and (R)-3-fluoropyrrolidine hydrochloride (68 mg, 0.54 mmol) were dissolved in 10 mL of dichloromethane under stirring. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-[1-((R)-3-fluoro-pyrrolidine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 25a (0.162 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:7][CH:6]=[CH:5][N:4]=1.[F:21][C:22]([F:37])([F:36])[C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:26](Cl)=[O:27]>CCCCCCC.CCOC(C)=O>[CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]([CH2:16][C:17]([F:18])([F:20])[F:19])[C:26](=[O:27])[C:25]2[CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=[C:23]([C:22]([F:21])([F:36])[F:37])[CH:24]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COc1ncccc1-c1ccncc1NCC(F)(F)F
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COc1ncccc1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from (2-methoxy-[3,4]bipyridinyl-3′-yl)-(2,2,2-trifluoro-ethyl)-amine and 3,5-bis(trifluoromethyl)benzoyl chloride (CAS RN 1271-19-8) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Light yellow foam (21%). MS (ESI): m/z=524.100 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].[CH3:21][C@@H:22](O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].[N+](C1C=CC=CC=1O)([O-])=O>>[CH3:21][C@H:22]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCC[C@@H](C)O
Reactant: COC(=O)c1ccc(-c2ccc(O)c([N+](=O)[O-])c2)cc1
Agent: O=[N+]([O-])c1ccccc1O
Product: CCCCCC[C@H](C)Oc1ccc(-c2ccc(C(=O)OC)cc2)cc1[N+](=O)[O-]

Procedure:
Methyl 4'-hydroxy-3'-nitro-4-biphenylcarboxylate was coupled with (R)-2-octanol using the same procedure as that given for alkylation of phenol 9, Scheme I, to give (S)-methyl 4'-(1-methylheptyloxy)-3'-nitro-4-biphenylcarboxylate (Compound 30, Scheme V, R1 =(S)--OCH(CH3)C6H13) as a slightly yellow solid after flash chromatography with hexanes/ethyl acetate [93/7]. Recrystallization from hexanes gave material with mp 69° C.; Rf [hexanes/ethyl acetate 90/10]: 0.23; 1H-NMR (300 MHz, CDCl3): δ 0.85(t, 3H, J=6.8 Mz), 1.20-1.52(m, 8H), 1.36(d, 3H, J=6.1 Hz), 1.62(m, 1H), 1.80(m, 1H), 3.92(s, 3H), 4.53(m, 1H), 7.12(d, 1H, J=8.7 Hz), 7.59(d, 2H, J=8.4 Hz), 7.72(dd, 1H, J=2.4 Hz, J=8.7 Hz), 8.02(d, 1H, J=2.4 Hz), 8.08(d, 2H, J=8.4 Hz); 13C NMR (300 Mz, CDCl3): δ 13.99, 19.46, 22.50, 25.19, 29.09, 31.65, 36.13, 52.17, 76.58, 116.07, 124.04, 126.53, 129.31, 130.35, 131.90, 132.06, 141.11, 142.81, 151.49, 166.75; IR (CHCl3): 3020, 2920, 2850, 1725, 1625, 1620, 1540, 1490, 1360, 1280, 1180, 1120, 1020, 820 cm-1 ; Mass spectrum m/z(rel.intensity): 385(M+ 47), 354(27), 273(100), 242(34), 139(17), 71(10) 57(20), 43(45), 41(38).
Reaction SMILES: C(OC1([CH2:23][C:24]2[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=2)C2C(=CC=C(C)C=2)N(CC)C1=O)(=O)C1C=CC=CC=1.[C:36]([O:44][CH:45]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[N:47]([CH2:54][CH:55]([CH3:57])[CH3:56])[C:46]1=[O:58])(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[C:36]([O:44][C:45]1([CH2:23][C:24]2[CH:25]=[C:26]([O:34][CH3:35])[C:27]([O:32][CH3:33])=[C:28]([O:30][CH3:31])[CH:29]=2)[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[N:47]([CH2:54][CH:55]([CH3:56])[CH3:57])[C:46]1=[O:58])(=[O:43])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CC(C)CN1C(=O)C(OC(=O)c2ccccc2)c2ccccc21
Reactant: CCN1C(=O)C(Cc2cc(OC)c(OC)c(OC)c2)(OC(=O)c2ccccc2)c2cc(C)ccc21
Product: COc1cc(CC2(OC(=O)c3ccccc3)C(=O)N(CC(C)C)c3ccccc32)cc(OC)c1OC

Procedure:
This compound was made in an analogous fashion to 1-ethyl-5-methyl-2-oxo-3-(3,4,5-trimethoxybenzyl)indolin-3-yl benzoate using 1-isobutyl-2-oxoindolin-3-yl benzoate. 1H-NMR δ 8.05 (d, 2H), 7.57 (dd, 1H), 7.43 (dd, 2H), 7.27 (m, 1H), 7.17 (d, 1H), 7.01 (dd, 1H), 6.73 (d, 1H), 6.17 (2H), 3.78 (s, 3H), 3.66 (s, 6H), 3.51 (m, 2H), 3.25 (m, 2H), 1.97 (m, 1H), 0.82 (dd, 6H). Calculated mass for C29H31NO6, 489.22. Observed 512.3 (M+Na).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:21])[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[CH:18][NH:17][C:16](=[O:20])[N:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.OC1(C2C=CC=CC=2)CCN(C2N=CNC(=O)N=2)CC1.CC1C=CC(S(O[CH2:53][C:54]2[S:55][C:56]([C:59]([F:62])([F:61])[F:60])=[CH:57][CH:58]=2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:21])[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[CH:18][N:17]([CH2:53][C:54]4[S:55][C:56]([C:59]([F:62])([F:61])[F:60])=[CH:57][CH:58]=4)[C:16](=[O:20])[N:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=c1nc(N2CCC(O)(c3ccc(Cl)cc3)CC2)nc[nH]1
Reactant: Cc1ccc(S(=O)(=O)OCc2ccc(C(F)(F)F)s2)cc1
Agent: O=C([O-])[O-]
Agent: O=c1nc(N2CCC(O)(c3ccccc3)CC2)nc[nH]1
Agent: [K+]
Product: O=c1nc(N2CCC(O)(c3ccc(Cl)cc3)CC2)ncn1Cc1ccc(C(F)(F)F)s1

Procedure:
A mixture (100 mg) of 4-[4-(4-Chlorophenyl)-4-hydroxypiperidin-1-yl]-1,3,5-triazin-2(1H)-one synthesized in Reference Synthesis Example 22a and 4-(4-hydroxy-4-phenylpiperidin-1-yl)-1,3,5-triazin-2(1H)-one, [5-(trifluoromethyl)thiophen-2-yl]methyl 4-methylbenzenesulfonate (558 mg, 0.65 mmol) synthesized in Reference Synthesis Example 51, and potassium carbonate (180 mg, 1.30 mmol) were used to obtain a mixture of compounds in Reference Synthesis Examples 92a and 92b being the title compounds (21 mg) by synthesis in a similar manner to Reference Synthesis Example 91.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:19]=[CH:18][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=O)=[CH:5][CH:4]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1.C1(C)C=CC=CC=1>O>[F:1][C:2]([F:21])([F:20])[C:3]1[CH:19]=[CH:18][C:6]([C:7](=[S:31])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[CH:5][CH:4]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccccc1NC(=O)c1ccc(C(F)(F)F)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccccc1NC(=S)c1ccc(C(F)(F)F)cc1
Temperature: 100 °C
Yield: 145.1 %

Procedure:
A mixture of 102.4 g of 4-trifluoromethyl-2'-methoxybenzanilide prepared by the same manner as described in (1), 77.2 g of Lawesson's reagent, and 400 ml of toluene was refluxed for 1 hour. The reaction mixture was cooled to about 100° C. and then 300 ml of water was added. The resulting mixture was refluxed for 1 hour. The organic layer was separated, dried over magnesium sulfate, and concentrated to about 200 ml of volume. The precipitate was collected by filtration, washed with toluene, and dried to give 86.2 g of 4-trifluoromethyl-2'-methoxybenzothioanilide.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][NH:11]2)=O)(C)(C)C.C[Si]([N:19]=C=O)(C)C.[ClH:22]>C(Cl)Cl>[ClH:22].[C@H:9]12[CH2:14][C@H:12]([NH:11][CH2:10]1)[CH2:13][N:8]2[C:6]([NH2:19])=[O:5]
Reactant: C[Si](C)(C)N=C=O
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Agent: Cl
Solvent: ClCCl
Product: NC(=O)N1C[C@@H]2C[C@H]1CN2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl-(S,S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (35.6 g, 179 mmol) in CH2Cl2 (600 mL) was added trimethylsilylisocyanate (82.5 g, 716 mmol, 4 equiv.). The reaction was stirred at rt for 2 h. After concentration, the resulting white solid was dissolved in CH2Cl2 (500 mL) and treated with a solution of HCl (4 M in dioxane, 135 mL, 3 equiv.). The solution quickly became heterogeneous. The suspension was then stirred at rt overnight. Upon concentration, the desired product was isolated as a white solid (33 g, 104%), which was used directly in the next step. [Note: the mass balance was found to be 104%, which arises from additional HCl that could not be removed by standard evaporation under vacuum]. 1H NMR (500 MHz, CD3OD): 4.77 (s, 1H), 4.55 (s, 1H), 3.69 and 3.64 (AB, JAB=12.1, 2H), 3.47 and 3.40 (AB, JAB=11.3, 2H), 2.22 and 2.15 (AB, JAB=11.5, 2H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH2:6][N:7]([S:28]([C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:40]=1[N:39]=[CH:38][CH:37]=[CH:36]2)(=[O:30])=[O:29])[C:8]1[CH:27]=[CH:26][C:11]2[N:12]([CH3:25])[C:13]([CH2:15][C:16]3[CH:24]=[CH:23][C:19]([C:20]([NH2:22])=[NH:21])=[CH:18][CH:17]=3)=[N:14][C:10]=2[CH:9]=1)=[O:5].C(=O)([O-])[O-].[K+].[K+].CC(C)=O.[CH3:51][O:52][C:53](Cl)=[O:54]>O>[CH3:2][O:3][C:4]([CH2:6][N:7]([S:28]([C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:40]=1[N:39]=[CH:38][CH:37]=[CH:36]2)(=[O:29])=[O:30])[C:8]1[CH:27]=[CH:26][C:11]2[N:12]([CH3:25])[C:13]([CH2:15][C:16]3[CH:24]=[CH:23][C:19]([C:20]([NH2:22])=[N:21][C:53]([O:52][CH3:51])=[O:54])=[CH:18][CH:17]=3)=[N:14][C:10]=2[CH:9]=1)=[O:5]
Reactant: COC(=O)Cl
Reactant: COC(=O)CN(c1ccc2c(c1)nc(Cc1ccc(C(=N)N)cc1)n2C)S(=O)(=O)c1cccc2cccnc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)CN(c1ccc2c(c1)nc(Cc1ccc(C(N)=NC(=O)OC)cc1)n2C)S(=O)(=O)c1cccc2cccnc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.7 g (1.2 mmol) of 4-[(5-(N-methoxycarbonylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride and 0.66 g (4.8 mmol) of potassium carbonate are dissolved in 5 ml water and 20 ml acetone and after the addition of 0.12 9 (1.3 mmol) of methylchloroformate the mixture is stirred for 30 minutes at ambient temperature. The solvent is evaporated off, the residue chromatographed on silica gel and eluted with methylene chloride/methanol 40:1. The desired fractions are concentrated by evaporation, the residue is triturated with ether and suction filtered.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22](O)[CH2:21][CH2:20][CH2:19]2>>[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]([O:1][C:2]1[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=1)[CH2:21][CH2:20][CH2:19]2
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OC1CCCc2cc(Cl)ccc21
Product: N#Cc1ccnc(-n2nccc2OC2CCCc3cc(Cl)ccc32)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and 6-chloro-1,2,3,4-tetrahydronaphthalen-1-ol according to the procedure for the preparation of Example 39, part C. [M+H] Calc'd for C19H15ClN4O, 351; Found, 351.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]2[N:13]=[C:14]([CH2:17][N:18]3[CH:22]=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:20]=[N:19]3)[S:15][CH:16]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34]O)[CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.O>[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][O:1][C:2]2[CH:3]=[C:4]([C:12]3[N:13]=[C:14]([CH2:17][N:18]4[CH:22]=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:20]=[N:19]4)[S:15][CH:16]=3)[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=2)[CH:29]=1
Reactant: OCc1cccnc1
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3cc(O)cc(C(F)(F)F)c3)cs2)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(Cc2nc(-c3cc(OCc4cccnc4)cc(C(F)(F)F)c3)cs2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101 %

Procedure:
Under a nitrogen atmosphere at 0° C., to a solution (7 mL) of the compound (300 mg, 0.75 mmol) obtained in Example 86a, 3-pyridinemethanol (0.088 mL, 0.91 mmol) and triphenylphosphine (260 mg, 0.98 mmol) in tetrahydrofuran was added diisopropyl azodicarboxylate (1.9M toluene solution, 0.51 mL, 0.98 mmol), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=50/50) to give the title compound (370 mg, 100%) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[C:11]([CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:18][CH3:19])[CH:8]=2)[C:3]=1[OH:20].[CH3:21][O:22][CH2:23]Cl.C(N(C(C)C)CC)(C)C>C1COCC1>[Br:1][C:2]1[C:11]([CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:18][CH3:19])[CH:8]=2)[C:3]=1[O:20][CH2:21][O:22][CH3:23]
Reactant: COCCl
Reactant: COc1ccc2c(O)c(Br)c(CCC(F)(F)F)cc2c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1c(Br)c(CCC(F)(F)F)cc2cc(OC)ccc12
Yield: 80 %

Procedure:
2-Bromo-6-(methyloxy)-3-(3,3,3-trifluoropropyl)-1-naphthalenol (122) (0.47 g, 1.35 mmol) was treated with chloromethyl methyl ether in the presence of diisopropylethylamine in THF to give 0.42 g (80%) of the title compound (123) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 2.40-2.55 (m, 2H), 3.10-3.20 (m, 2H), 3.72 (s, 3H), 3.91 (s, 3H), 5.23 (s, 2H), 7.04 (d, J=2.6 Hz, 1H), 7.16 (dd, J1=9.3 Hz, J2=2.5 Hz, 1H), 7.43 (s, 1H), 8.03 (d, J=9.3 Hz, 1H).
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:16][C:17](=[O:29])[CH2:18][N:19]1[C:23](=[O:24])[C:22]([CH3:26])([CH3:25])[N:21]([CH3:27])[C:20]1=[O:28].O>CN(C)C=O>[CH2:1]([S:8][CH2:16][C:17](=[O:29])[CH2:18][N:19]1[C:23](=[O:24])[C:22]([CH3:25])([CH3:26])[N:21]([CH3:27])[C:20]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: SCc1ccccc1
Reactant: CN1C(=O)N(CC(=O)CBr)C(=O)C1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)N(CC(=O)CSCc2ccccc2)C(=O)C1(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.1 %

Procedure:
Benzyl mercaptan (256 μl, 2.2 mmol) was stirred with cesium carbonate (712 mg, 2.2 mmol) in dimethyl formamide (5 ml) at room temperature for 1 hour. 3-(3-bromo-2-oxopropyl)-1,5,5-trimethylimidazolidine-2,4-dione (552 mg, 1.99 mmol) prepared as in WO99/06361 was added and the mixture stirred 18 hours at room temperature. The reaction mixture was treated with water, extracted into ethyl acetate (3×25 ml), the organic phases combined, brine washed and dried. The product was purified by silica chromatography, eluting with 50% ethyl acetate/iso-hexane to give 300 mg product.
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH2:38][CH2:39][CH3:40])[CH:32]=4)[CH2:28][CH2:27][C:26]([C:41](O)=[O:42])=[CH:25][C:24]=3[CH:44]=2)=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH3:9].S(Cl)(Cl)=O>O1CCCC1>[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH2:38][CH2:39][CH3:40])[CH:32]=4)[CH2:28][CH2:27][C:26]([C:41]([NH:29][C:23]4[CH:24]=[CH:44][C:20]([CH2:4][N:2]([CH3:1])[CH:3]5[CH2:12][CH2:11][O:10][CH2:6][CH2:7]5)=[CH:21][CH:22]=4)=[O:42])=[CH:25][C:24]=3[CH:44]=2)=[CH:18][CH:19]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CN(C)C=O
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2cccc(OCCC)c2)cc1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2cccc(OCCC)c2)cc1
Reaction time: 1 h

Procedure:
One droplet of DMF was added to a solution of 7-(4-butoxyethoxyphenyl)-1-(3-propoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (200 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (134 mg) was added at 0° C., the temperature was returned to room temperature, and the mixture was stirred under nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were evaporated under reduced pressure, the resulting residue was suspended in tetrahydrofuran (30 ml), and the suspension was added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (100 mg) and triethylamine (455 mg) in tetrahydrofuran (10 ml) at 0° C. The suspension was stirred under nitrogen atmosphere at room temperature for 4.5 hours, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1:8), which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-(3-propoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 64) (207 mg) as yellow crystals.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:13])[C@@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)[OH:4].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:29]3[C:24](=[CH:25][C:26](I)=[CH:27][CH:28]=3)[CH:23]=[N:22]2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)CCC.[Cu]I>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[C:29]3[C:24](=[CH:25][C:26]([O:4][C@H:3]([C:5]4[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=4)[C@@H:2]([NH2:1])[CH3:13])=[CH:27][CH:28]=3)[CH:23]=[N:22]2)=[CH:19][CH:20]=1
Reactant: COc1cccc([C@@H](O)[C@H](C)N)c1
Reactant: Clc1ccc(-n2ncc3cc(I)ccc32)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCC#N
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(Cl)cc3)c2)[C@H](C)N)c1
Reaction time: 16 h

Procedure:
The subtitle compound was prepared analogous to the method described in Example 6 (step 6a). Starting from the hydrochloride salt of (1R,2S)-2-amino-1-(3-methoxyphenyl)propan-1-ol (6b) (0.88 g, 4.04 mmol), 1-(4-chlorophenyl)-5-iodo-1H-indazole (1.720 g, 4.85 mmol), CuI (0.154 g, 0.81 mmol) and cesium carbonate (3.95 g, 12.13 mmol) in butyronitrile (14 mL) stirred at +110° C. for 16 h. Work up and final purification by HPLC was followed by extraction of product into EtOAc from basic water solution, evaporation of solvents gave the subtitle compound as a sticky oil. Yield 490 mg (29%)
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11]C(=O)C)=[CH:10][C:5]=2[O:4][C:3]=1[C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19](C)=[CH:18][CH:17]=1.[ClH:24].C(OC(=O)C)C>CO>[NH2:11][C:9]1[CH:8]=[CH:7][C:6]2[C:2]([CH3:1])=[C:3]([C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:24])=[CH:18][CH:17]=3)=[O:23])[O:4][C:5]=2[CH:10]=1
Reactant: Cl
Reactant: CC(=O)Nc1ccc2c(C)c(C(=O)c3ccc(C)cc3)oc2c1
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1c(C(=O)c2ccc(Cl)cc2)oc2cc(N)ccc12
Temperature: 25 °C

Procedure:
3.1 g (10 mmol) of N-[3-methyl-2-(4-methyl-benzoyl)benzofuran-6-yl]-acetamide were suspended in 40 ml methanol. 20 ml 2.6 N HCl were added with stirring. The reaction mixture was heated to reflux. After 1 hour a clear solution was obtained. After 3 hours reflux the solution was cooled to room temperature and ethylacetate was added. The organic layer was washed once with NaOH-solution, two times with water, dried over Na4SO4 and concentrated in vacuo. The residue was further purified by crystallisation.