Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:8][CH2:9][CH3:10])(OCC)OCC.C(O[C@@H:15]1[C@H:21]2[C@H:22]3[C@H:31]([CH2:32][CH2:33][C@:18]2([CH2:19][CH3:20])[C:17](=[O:35])[CH2:16]1)[C@@H:30]1[C:25](=[CH:26]C(=O)[CH2:28][CH2:29]1)[CH2:24][CH2:23]3)(=O)C.C(NC(C)C)(C)C.O>CCO.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:9]([O:8][C:1]1[CH2:28][CH2:29][C@H:30]2[C:25](=[CH:24][CH2:23][C@@H:22]3[C@@H:31]2[CH2:32][CH2:33][C@@:18]2([CH2:19][CH3:20])[C@H:21]3[CH:15]=[CH:16][C:17]2=[O:35])[CH:26]=1)[CH3:10]
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](OC(C)=O)CC2=O
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Solvent: CC(C)NC(C)C
Product: CCOC1=CC2=CC[C@@H]3[C@H](CC[C@]4(CC)C(=O)C=C[C@@H]34)[C@H]2CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
Triethyl orthoformate (5 ml, 30 mmol) and p-Toluenesulfonic acid (50 mg, 0.26 mmol) were added to a suspension of 15α-acetoxy-18-methyl-estr-4-en-3,17-dione (5 g, 14.5 mmol) in EtOH (30 ml). The mixture was stirred at room temperature for 1 h. Diisopropylamine (6.3 ml, 36 mmol) was added, and the mixture was heated under reflux for 2 h, cooled to 10° C. and water (15 ml) was then added. The precipitate was filtered, washed with water and dried. The crude product was purified by flash chromatography, eluting with heptane and ethyl acetate (7:3), crystallized from heptane, and dried under vacuum to afford 3-ethoxy-18-methyl-estra-3,5,15-trien-17-one (3.18 g, yield: 71%).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:24])([F:23])[C:10]([N:12]1[CH2:17][C:16]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[O:15][CH2:14][CH2:13]1)=[O:11].[CH:25]1([N:31]([CH2:47][CH2:48][N:49]([CH2:57][CH2:58][C:59]2[C:64]3[O:65][CH2:66][C:67](=[O:69])[NH:68][C:63]=3[C:62]([OH:70])=[CH:61][CH:60]=2)[C:50](=[O:56])[O:51][C:52]([CH3:55])([CH3:54])[CH3:53])[C:32](=[O:46])[CH2:33][CH2:34][O:35][CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([CH:44]=O)[CH:39]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[BH4-].[Na+].C(=O)(O)[O-].[Na+]>CN1C(=O)CCC1.C(O)(=O)C>[CH:25]1([N:31]([CH2:47][CH2:48][N:49]([CH2:57][CH2:58][C:59]2[C:64]3[O:65][CH2:66][C:67](=[O:69])[NH:68][C:63]=3[C:62]([OH:70])=[CH:61][CH:60]=2)[C:50](=[O:56])[O:51][C:52]([CH3:54])([CH3:53])[CH3:55])[C:32](=[O:46])[CH2:33][CH2:34][O:35][CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][N:20]3[CH2:21][CH2:22][C:16]4([O:15][CH2:14][CH2:13][N:12]([C:10](=[O:11])[C:9]([F:8])([F:23])[F:24])[CH2:17]4)[CH2:18][CH2:19]3)[CH:39]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(O)c2c1OCC(=O)N2)CCN(C(=O)CCOCCc1cccc(C=O)c1)C1CCCCC1
Reactant: O=C(N1CCOC2(CCNCC2)C1)C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N(CCc1ccc(O)c2c1OCC(=O)N2)CCN(C(=O)CCOCCc1cccc(CN2CCC3(CC2)CN(C(=O)C(F)(F)F)CCO3)c1)C1CCCCC1
Reaction time: 0.08 h

Procedure:
A solution of 2,2,2-trifluoro-1-(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)ethanone trifluoroacetate [Example 9, step a] (4.5 g) in NMP (30 mL) was treated with acetic acid (0.6 mL), stirred for 5 minutes, and then added in one portion to tert-butyl 2-(N-cyclohexyl-3-(3-formylphenethoxy)propanamido)ethyl(2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)ethyl)carbamate [Examples 81-175, step f] (6.6 g), completing the transfer with more NMP (30 mL). The resulting solution was stirred at room temperature for 4 hours and then cooled in an ice-water bath and treated with sodium triacetoxyborohydride (3.3 g) in one portion. The resulting suspension was stirred at room temperature overnight, then more sodium borohydride (2.2 g) was added and the mixture was stirred for a further 5 hours. The mixture was cautiously poured into saturated sodium bicarbonate solution and extracted twice with ethyl acetate. The combined organic phases were washed three times with water, once with brine, then dried (MgSO4), filtered and concentrated onto flash silica (100 mL) in-vacuo. The resulting powder was purified by flash chromatography on silica eluted with acetic acid:methanol:dichloromethane (1:5:94) to elute off the benzyl alcohol corresponding to reduced starting material, 100% dichloromethane to wash the column free from acetic acid, then triethylamine:methanol:dichloromethane (1:5:94) to elute off the product. Fractions containing the desired product were combined and concentrated in-vacuo to afford the subtitled compound as an off-white foam. Yield 4.6 g.
Reaction SMILES: [CH3:1][C:2]1[C:3](=O)[NH:4][N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.P(Cl)(Cl)([Cl:17])=O.Cl.OP(O)(O)=O>C(#N)C>[Cl:17][C:3]1[N:4]=[N:5][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1cc(-c2ccccc2)n[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Agent: O=P(O)(O)O
Solvent: CC#N
Product: Cc1cc(-c2ccccc2)nnc1Cl
Temperature: 25 °C
Yield: 96 %

Procedure:
6.0 g (32 mmol) of 14 was placed in a 250 nit single neck round bottom flask and 30 ml acetonitrile was added to create a pale yellow slurry. 6.0 ml (64 mmol, 2 equiv) of phosphorus oxychloride was added and the reaction mixture was heated at reflux for 2.5 h. After the reaction was completed, the Mixture was cooled to ambient temperature and placed in an ice water bath. Ice water (150 mL) was slowly poured into the reaction mixture with stirring to decompose the phosphorus oxychloride into HCl and H3PO4. The solid was then collected by filtration and washed with Milli-Q water (3×50 mL). The solid was suspended in 100 mL of water and 1N NaOH was added until the aqueous suspension was at pH=8. The mixture was stirred for 5 minutes to remove all trace starting material contaminants. The solid was filtered and washed with Milli-Q water (3×100 mL). The product was dried over a medium frit sintered glass funnel in vacuo to provide 15 as a light pink powder in 96% yield. 1H NMR (DMSO-d6): δ 829 (s, 1H), 8.10 (at, 2H), 7.53 (m, 3H), 2.41 (s, 3H), HPLC (tr/purity): 2888.98 min, >94%. ESI m/z (MeOH) 205.49 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:25][NH:26][O:27][CH3:28].CCN(CC)CC>C(Cl)Cl>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:26]([O:27][CH3:28])[CH3:25])=[O:5]
Reactant: O=C(O)c1cccc(F)c1Cl
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cccc(F)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
To a solution of 2-chloro-3-fluorobenzoic acid (30 g, 172 mmol) in 300 mL of DCM was added carbonyldiimidazole (CDI) (32.0 g, 198 mmol) in portions. After addition and then stirring at RT for 1 h, N,O-dimethylhydroxylamine HCl salt (18.5 g, 189 mmol) was added into the mixture followed by Et3N (20 mL). The mixture was stirred at RT overnight. After the reaction was quenched with water, the aqueous layer was extracted with DCM (2×). The organic layers were washed with 2N HCl (aq), water, sat. NaHCO3 (aq) and brine. The solution was dried (MgSO4) and concentrated. The product 2-chloro-3-fluoro-N-methoxy-N-methylbenzamide (32.0 g) was obtained by silica gel chromatography (elution with 0-30% EtOAc/Hex).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:17]([O-])=O)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:6]=2.[NH4+].[Cl-]>CCO.O.[Fe]>[NH2:17][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])[CH:6]=2)[CH:11]=[C:2]([Br:1])[CH:3]=1
Reactant: CC(C)(C)Oc1ccc2cc(Br)cc([N+](=O)[O-])c2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)Oc1ccc2cc(Br)cc(N)c2c1

Procedure:
A mixture of 3-bromo-7-tert-butoxy-1-nitronaphthalene, as described above in Step G, (1.08 g, 3.33 mmol), NH4Cl (89 mg, 1.67 mmol), and iron powder (930 mg, 16.7 mmol) in EtOH (70 mL) and H2O (30 mL) was heated to reflux for 7 hours, then cooled and filtered through a pad of celite, washing with EtOH. The filtrate was concentrated under reduced pressure and the residue was partitioned between dilute aqueous NaHCO3 (50 mL) and CH2Cl2 (150 mL). The aqueous layer was extracted further with CH2Cl2 (50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with a gradient of hexane—5% to 20% EtOAc to afford the titled compound.
Reaction SMILES: [NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:13]/[C:14]1[NH:18][CH:17]=[N:16][C:15]=1[CH3:19])/[C:5](=[O:12])[NH:6]2.Cl.[CH:21](N)=N>C(O)C>[CH3:19][C:15]1[N:16]=[CH:17][NH:18][C:14]=1/[CH:13]=[C:4]1\[C:5](=[O:12])[NH:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:11][CH:21]=[N:1][C:2]=3[C:3]\1=2
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(N)c(N)c21
Reactant: N=CN
Agent: Cl
Solvent: CCO
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc3[nH]cnc3c21
Temperature: 25 °C

Procedure:
A mixture of (Z)-4,5-diamino-1,3-dihydro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (30 mg, 0.1175 mmol) (from Example 45 above) and formamidine hydrochloride (95 mg, 1.18 mmol) (Aldrich) in ethanol (1.5 mL) was heated at reflux for 1 h. The mixture was cooled to r.t., and the reaction was quenched with water. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous Mg2SO4 and concentrated under reduced pressure. The crude oily residue was triturated with ether and the resulting yellow precipitate was collected by suction filtration. (First crop; yield 5 mg, 16%).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[NH:8][C:9](=[O:11])[O:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].[CH3:14][CH:15](O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[N:8]([CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:14])[C:9](=[O:11])[O:10][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: CC(O)c1ccccc1
Reactant: O=c1[nH]c2ccc([N+](=O)[O-])cc2o1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(c1ccccc1)n1c(=O)oc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Into a solution of 6-nitrobenzo[d]oxazol-2(3H)-one (40-1, 5 g, 27.8 mmol) in THF (139 ml) was added α-methylbenzylalcohol (3.7 g, 30.5 mmol), polymer-bound triphenylphosphine (27.7 g, 83 mmol), and DIAD (11.2 g, 55.5 mmol). The reaction was shaken for 1 h at rt, filtered, and concentrated to yield 6-nitro-3-(1-phenylethyl)benzo[d]oxazol-2(3H)-one (7.89 g, 27.8 mmol) which was taken on to the next step without further purification. LRMS C15H14N202 [M−79] calc 205.1, obs 205.4.
Reaction SMILES: C[O:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:5][CH:4]=1.[ClH:12].COC1CCCC1.[C:20]([O:24][CH2:25][CH3:26])(=[O:23])[CH:21]=O.C1(C)C=CC=CC=1>CCO>[ClH:12].[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:21]([C:20]([O:24][CH2:25][CH3:26])=[O:23])[NH:11][CH2:10][CH2:9][C:7]=2[N:8]=1
Reactant: COc1cccc(CCN)n1
Reactant: CCOC(=O)C=O
Agent: Cl
Solvent: COC1CCCC1
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C1NCCc2nc(O)ccc21
Yield: 81.2 %

Procedure:
A solution of 2-(6-methoxypyridin-2-yl)ethanamine (14.43 g, 94.81 mmol), 4N hydrogen chloride/CPME (26.1 mL, 104.29 mmol) and 47% ethyl glyoxylate/toluene solution (polymer form) (30.0 mL, 142.22 mmol) in EtOH (175 mL) was heated under reflux for 8 hr. To the reaction mixture were added 4N hydrogen chloride/CPME (26.1 mL, 104.29 mmol) and 47% ethyl glyoxylate/toluene solution (polymer form) (30.0 mL, 142.22 mmol), and the mixture was heated again under reflux for 16 hr. The reaction mixture was concentrated under reduced pressure to half volume, and to the residue was added diethyl ether (ca. 150 mL). The precipitate was collected by filtration, and washed with EtOH/diethyl ether to give crude ethyl 2-hydroxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxylate hydrochloride (20.01 g, 77 mmol, 82%) as an off-white powder.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([N:20]3[CH2:29][C:28]4[C:23](=[N:24][C:25](SC)=[N:26][CH:27]=4)[N:22]([CH3:32])[C:21]3=[O:33])[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[N:7]([C:36]2[CH:37]=[C:38]3[C:43](=[CH:44][CH:45]=2)[N:42]=[CH:41][CH:40]=[CH:39]3)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:57][NH2:58]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([N:20]3[CH2:29][C:28]4[C:23](=[N:24][C:25]([NH:58][CH3:57])=[N:26][CH:27]=4)[N:22]([CH3:32])[C:21]3=[O:33])[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[N:7]([C:36]2[CH:37]=[C:38]3[C:43](=[CH:44][CH:45]=2)[N:42]=[CH:41][CH:40]=[CH:39]3)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CSc1ncc2c(n1)N(C)C(=O)N(c1cc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc4ncccc4c3)c(F)cc1C)C2
Agent: O=C(OO)c1cccc(Cl)c1
Product: CNc1ncc2c(n1)N(C)C(=O)N(c1cc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc4ncccc4c3)c(F)cc1C)C2

Procedure:
Using a procedure analogous to Example A2, the sulfide was oxidized with mCPBA to the sulfone and then treated with methylamine to provide 1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea. 1H NMR (400 MHz, DMSO-d6): δ 8.95 (m, 2H), 8.48 (m, 1H); 8.15 (m, 1H), 8.04 (d, J=8 Hz, 1H), 7.92 (m, 2H), 7.60 (dd, J=8, Hz, 1H), 7.17 (d, J=12 Hz, 1H), 7.02 (m, 1H), 6.46 (s, 1H), 4.53 (d, J=14 Hz, 1H), 4.33 (d, J=14 Hz, 1H), 3.25 brs, 3H), 2.78 (d, J=5 Hz, 3H), 2.04 (s, 3H), 1.28 (s, 9H); MS (ESI) m/z 609.2 (M+H+).
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][CH:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:9]1.Br[CH2:24][CH2:25][C:26]1([OH:36])[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27]1>>[OH:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([CH:10]2[CH2:11][CH2:12][N:8]([CH2:24][CH2:25][C:26]3([OH:36])[CH2:35][CH2:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27]3)[CH2:9]2)(=[O:15])=[O:14])=[CH:17][CH:18]=1
Reactant: OC1(CCBr)CCc2ccccc2C1
Reactant: O=S(=O)(c1ccc(O)cc1)C1CCNC1
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccc(O)cc1)C1CCN(CCC2(O)CCc3ccccc3C2)C1

Procedure:
The title compound, MS: m/e=402.4 (M+H+) was prepared from (RS)-4-(pyrrolidine-3-sulfonyl)-phenol trifluoroacetic acid salt and (RS)-2-(2-bromo-ethyl)-1,2,3,4-tetrahydro-naphthalen-2-ol.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:16])[F:15])[N:5]=[C:4]([NH2:18])[N:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:14]([F:17])([F:16])[F:15])[N:5]=[C:4]([NH2:18])[N:3]=2)=[CH:22][CH:21]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Nc1nc(Cl)cc(-c2ccccc2C(F)(F)F)n1
Product: Nc1nc(Nc2ccc(Cl)cc2)cc(-c2ccccc2C(F)(F)F)n1
Yield: 28 %

Procedure:
Following the method described in Example 53, 4-chloro-6-(2-trifluoromethyl-phenyl)-pyrimidin-2-ylamine and 4-chloro-phenylamine provided the title compound (28% yield). 1H NMR (DMSO-d6) δ 6.06 (s, 1H, Ar), 6.45 (s, 2H, NH2), 7.32 (d, 2H, J=8.9 Hz, Ar), 7.49 (d, 1H, J=9.0 Hz, Ar), 7.62-7.75 (m, 2H, Ar), 7.81 (d, 3H, J=8.9 Hz, Ar), 9.37 (s, 1H, NH).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[C:10]1[CH:15]=[C:14]([Cl:16])[N:13]=[N:12][C:11]=1[CH3:17].C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.O>[Cl:16][C:14]1[N:13]=[N:12][C:11]([CH3:17])=[C:10]([O:8][C:7]2[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=2)[CH:15]=1
Reactant: Nc1ncccc1O
Reactant: Cc1nnc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1nnc(Cl)cc1Oc1cccnc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
2-Aminopyridin-3-ol (5.0 g, 45.4 mmol) and 4,6-dichloro-3-methylpyridazine (7.4 g, 45.4 mmol, prepared according to WO 2003/041712) were dissolved in DMSO (100 mL). Cs2CO3 (16.3 g, 49.9 mmol) was added and the reaction stirred at ambient temperature for one hour. The reaction was diluted with water and the material was extracted with CH2Cl2, dried (Na2SO4), filtered and concentrated. Flash chromatography followed by trituration of the concentrated solid with EtOH gave 3-(6-chloro-3-methylpyridazin-4-yloxy)pyridin-2-amine (5.98 g, 25.3 mmol, 55%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)([CH2:12][CH2:13][CH2:14]OS(C)(=O)=O)[C:8]1=[O:28].C(N(CC)CC)C.I.[C:44]([CH2:49][CH2:50][CH2:51][N:52]1[C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][C:55]=2[N:54]=[C:53]1[NH:61][CH:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1)([O:46][CH2:47][CH3:48])=[O:45]>C(#N)C.ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][CH2:14][N:65]2[CH2:66][CH2:67][CH:62]([NH:61][C:53]3[N:52]([CH2:51][CH2:50][CH2:49][C:44]([O:46][CH2:47][CH3:48])=[O:45])[C:56]4[CH:57]=[CH:58][CH:59]=[CH:60][C:55]=4[N:54]=3)[CH2:63][CH2:64]2)([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[C:8]1=[O:28]
Reactant: COc1cc(CN2CCC(CCCOS(C)(=O)=O)(Cc3ccc(F)cc3)C2=O)cc(OC)c1OC
Reactant: CCOC(=O)CCCn1c(NC2CCNCC2)nc2ccccc21
Agent: I
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: ClCCl
Product: CCOC(=O)CCCn1c(NC2CCN(CCCC3(Cc4ccc(F)cc4)CCN(Cc4cc(OC)c(OC)c(OC)c4)C3=O)CC2)nc2ccccc21
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzyl)-3-(4-fluorophenylmethyl)-3-(3-methanesulfonyloxypropyl)-2-oxopyrrolidine (0.37 g, 0.73 mmol), triethylamine (0.45 mL, 3.23 mmol), and (1-(3-carboethoxypropyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine hydriodic acid salt (0.40 g, 0.68 mmol) in acetonitrile (10 mL). Heat at 80° C. After 18 hours, cool, dilute the reaction mixture with dichloromethane and extract with brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with dichloromethane/methanol/concentrate aqueous ammonium hydroxide 95/5/0.05 to give the title compound: Rf=0.65 (silica gel, dichloromethane/methanol/concentrate aqueous ammonium hydroxide 95/5/0.1).
Reaction SMILES: [P:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:2]CC.[CH2:11]([O:18][C:19]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH3:35])=[CH:30][CH:29]=2)=[CH:23][C:20]=1[CH2:21]Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:9]([O:8][P:1]([CH2:21][C:20]1[CH:23]=[C:24]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH3:35])=[CH:30][CH:29]=2)[CH:25]=[CH:26][C:19]=1[O:18][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:2])[O:5][CH2:6][CH3:7])[CH3:10]
Reactant: CCOP(OCC)OCC
Reactant: CCc1ccc(Cc2ccc(OCc3ccccc3)c(CCl)c2)cc1
Product: CCOP(=O)(Cc1cc(Cc2ccc(CC)cc2)ccc1OCc1ccccc1)OCC
Temperature: 155 °C
Reaction time: 4 h

Procedure:
Triethyl phosphite (0.6 mL) was added to 2-benzyloxy-5-(4-ethylbenzyl)benzylchloride (1.00 g), and the mixture was stirred for 4 hr at 150-160° C. The mixture was purified by silica gel column chromatography (ethyl acetate/n-hexane=1/2) to give the title compound (1.09 g) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:17])[C:5](=[O:16])[N:6]2[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(N1C2C(=CC=CC=2)C(=O)C1=O)CCCC.O1C2C=CC(O)=CC=2OC1.[Cl:44][C:45]1[CH:46]=[C:47]([OH:52])[CH:48]=[CH:49][C:50]=1[F:51]>>[Cl:44][C:45]1[C:50]([F:51])=[CH:49][C:48]([C:4]2([OH:17])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][CH:2]=3)[N:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:5]2=[O:16])=[C:47]([OH:52])[CH:46]=1
Reactant: CCCCCN1C(=O)C(=O)c2c(Br)cccc21
Reactant: Oc1ccc(F)c(Cl)c1
Agent: CCCCCN1C(=O)C(=O)c2ccccc21
Agent: Oc1ccc2c(c1)OCO2
Product: CCCCCN1C(=O)C(O)(c2cc(F)c(Cl)cc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1C, and making non-critical variations to replace 4-bromo-1-pentyl-1H-indole-2,3-dione with 1-pentyl-1H-indole-2,3-dione, and 1,3-benzodioxol-5-ol with 3-chloro-4-fluorophenol, the title compound was obtained (14%): MS (ES+) m/z 346 (M−17), 386 (M+23).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)=[O:9].O>CN(C)C=O>[N:1]1([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:12][CH:11]=2)=[O:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(CCl)c1ccc(CCc2ccccc2)cc1
Reactant: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cn1ccnc1)c1ccc(CCc2ccccc2)cc1
Yield: 77.4 %

Procedure:
To a solution containing 3.4 g of imidazole in 5 ml of dimethylformamide, stirred at 0/+5° C., 2.58 g of 4-chloroacetyl-bibenzyl were slowly added. The reaction mixture was stirred for few minutes, then allowed to stand and then poured into water. The product thus formed was filtered off, purified by silica gel column chromatography (eluant: benzene/acetone) and then crystallized from ethyl acetate to give 2.24 g of the title compound melting at 134°-6° C. Yield 77%.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:44]([CH2:45][CH2:46][CH3:47])[C:43](=[O:48])[NH:42][N:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:44]([CH2:45][CH2:46][CH3:47])[C:43](=[O:48])[NH:42][N:41]=5)=[O:58])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4n[nH]c(=O)n4CCC)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4n[nH]c(=O)n4CCC)cc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(4-propyl-1H-1,2,4-triazol-5-on-3-yl)methylthio]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.50 g) was dissolved in dichloromethane (30 ml), and the mixture was cooled to −78° C. To the solution, 3-chloroperbenzoic acid (0.22 g) in dichloromethane solution (5 ml) was added dropwise. The mixture was stirred for 1 hour at −78° C., and then, sodium thiosulfate solution was added to the mixture. The mixture was concentrated, and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: triethylamine/methanol/ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(4-propyl-1H-1,2,4-triazol-5-on-3-yl)methylsulfinyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 66) (0.45 g) as yellow amorphous.