Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[C:12]3[CH2:13][CH2:14][CH:15]([CH2:17][O:18][CH2:19][C:20]4[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=4)[C:23]#[N:24])[CH2:16][C:11]=3[N:10]=[CH:9]2)C=CC=CC=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)N2C3CC(COCC4C=C(C=CC=4)C#N)CCC=3N=C2)C=CC=CC=1>C(O)(=O)C.O>[NH:8]1[C:12]2[CH2:13][CH2:14][CH:15]([CH2:17][O:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=3)[C:23]#[N:24])[CH2:16][C:11]=2[N:10]=[CH:9]1
Reactant: N#Cc1cccc(COCC2CCc3c(ncn3C(c3ccccc3)(c3ccccc3)c3ccccc3)C2)c1
Agent: N#Cc1cccc(COCC2CCc3ncn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c3C2)c1
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1cccc(COCC2CCc3[nH]cnc3C2)c1
Temperature: 90 °C

Procedure:
A solution of a mixture of 3-(((1-triphenylmethyl-4,5,6,7-tetrahydro-1H-benzimidazol-5-yl)methoxy)methyl)benzonitrile and 3-(((3-triphenylmethyl-4,5,6,7-tetrahydro-3H-benzimidazol-5-yl)methoxy)methyl)benzonitrile (0.18 g, 0.34 mmol) in acetic acid (5 ml) and water (0.6 ml) was heated to 90° C. for 2 hours. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (40 g), using DCM/methanol/−25% aqueous ammonia (100:10:1) as eluent, to give 71 mg of the title compound.
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([N:6]1[CH2:10][CH2:9][N:8]=[C:7]1SC)=[O:5].[NH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>O>[N:18]1([N:17]2[C:2]3[C:3](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:4](=[O:5])[N:6]3[CH2:10][CH2:9][N:8]=[C:7]23)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: NN1CCOCC1
Reactant: CSC1=NCCN1C(=O)c1ccccc1F
Solvent: O
Product: O=C1c2ccccc2N(N2CCOCC2)C2=NCCN12
Yield: 74 %

Procedure:
A solution of 10.0 g (42.0 mmoles) of the product of Example 1 in 50 ml of N-aminomorpholine was heated to reflux for 10 minutes. The clear solution deposited crystals on cooling. This mixture was diluted with water (100 ml) and a white, crystalline solid was collected, washed with water, and air-dried to give 8.47 g of 2,10-dihydro-10-(4-morpholinyl)imidazo[2,1-b]quinazolin-5(3H)-one. Melting point 250°-251° C. Total yield 74%. This compound exhibits the following formula ##STR5##
Reaction SMILES: [F:1][C:2]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:3]=1[O:4][C:5]1[C:13]2[NH:12][C:11](=[O:14])[N:10]([CH3:15])[C:9]=2[CH:8]=[CH:7][C:6]=1[C:16]1[C:17]2[CH:26]=[CH:25][N:24](S(C3C=CC(C)=CC=3)(=O)=O)[C:18]=2[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1.[OH-].[Na+].O>C(O)C>[F:1][C:2]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:3]=1[O:4][C:5]1[C:13]2[NH:12][C:11](=[O:14])[N:10]([CH3:15])[C:9]=2[CH:8]=[CH:7][C:6]=1[C:16]1[C:17]2[CH:26]=[CH:25][NH:24][C:18]=2[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4ccc5c([nH]c(=O)n5C)c4Oc4ccc(F)cc4F)cn(C)c(=O)c32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1cc(-c2ccc3c([nH]c(=O)n3C)c2Oc2ccc(F)cc2F)c2cc[nH]c2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
A solution of 4-(2,4-difluorophenoxy)-1-methyl-5-{6-methyl-1-[(4-methylphenyl)sulfonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one (20.0 mg, 0.0347 mmol) in ethanol (2.0 mL) was treated with 3.0 M Sodium hydroxide in water (116 μL, 0.347 mmol) and stirred at RT overnight. The reaction mixture was purified via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% trifluoroacetic acid, at flow rate of 60 mL/min) to give the desired product (14.5 mg, 99%). 1H NMR (400 MHz, DMSO-d6) δ 11.94 (s, 1H), 11.25 (s, 1H), 7.25-7.06 (m, 5H), 6.74-6.62 (m, 1H), 6.51-6.38 (m, 1H), 6.14-6.05 (m, 1H), 3.44 (s, 3H), 3.34 (s, 3H); LCMS calculated for C22H17F2N4O3 (M+H)+: m/z=423.1. found: 423.1.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([OH:17])[C@H:12]2[O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]1[CH:20]=[CH:21][C:22]([N+:26]([O-:28])=[O:27])=[C:23](O)[CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH2:1]([O:8][C@@H:9]1[CH2:10][O:11][C@@H:12]2[C@@H:16]([O:17][C:21]3[CH:20]=[C:19]([F:18])[CH:24]=[CH:23][C:22]=3[N+:26]([O-:28])=[O:27])[CH2:15][O:14][C@H:13]12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1O[C@H]1CO[C@H]2[C@@H]1OC[C@H]2OCc1ccccc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To 6.0 g (25.2 mmol) (3R,3aR,6R,6aR)-6-benzyloxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol, 3.3 g (21 mmol) 5-fluoro-2-nitro-phenol and 8.3 g (31.5 mmol) triphenyl phosphine in 150 ml THF 7.3 g (31.5 mml) di-tert-butyl azodicarboxylate in 30 ml THF are added dropwise and the reaction mixture is stirred at 40° C. for 2 h. The reaction mixture is evaporated and the residue is purified by FC.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][S:11]2(=[O:17])=[O:16])[CH:7]=[C:6]([C:18](=[O:20])[CH3:19])[CH:5]=1.CO.O.[Li+].[OH-]>C1COCC1>[C:18]([C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][S:11]2(=[O:16])=[O:17])[CH:7]=1)[C:3]([OH:21])=[O:2])(=[O:20])[CH3:19]
Reactant: COC(=O)c1cc(C(C)=O)cc(N2CCCCS2(=O)=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(=O)c1cc(C(=O)O)cc(N2CCCCS2(=O)=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
To a solution of 3-acetyl-5-(1,1-dioxo-1λ6-[1,2]thiazinan-2-yl)-benzoic acid methyl ester (100 mg, 0.32 mmol) in a mixture of THF (0.3 mL), MeOH (0.6 mL) and H2O (1.5 mL) was added LiOH (23.1 mg, 0.96 mmol) and the mixture was stirred at room temperature for 1 h. The mixture was concentrated and partitioned between ethyl acetate and H2O. The aqueous layer was washed with ethyl acetate twice and acidified with 1N HCl solution to pH around 2˜3. The aqueous layer was extracted with ethyl acetate 3 times and the combined organic layers were dried over sodium sulfate and concentrated under vacuum to give the title compound (93 mg): 1H NMR (CD3OD, 500 MHz) δ ppm 1.93-1.99 (2H, m), 2.31-2.37 (2H, m), 2.67 (3H, s), 3.27-3.30 (2H, m), 3.83 (2H, t, J=5 Hz), 8.13 (1H, m), 8.20 (1H, m), 8.52 (1H, m). HPLC retention time: 1.292 min (method A). MS (ESI) (M+Na)+ 320.14.
Reaction SMILES: Cl[C:2]1[N:3]([C@@H:15]2[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@H:16]2[OH:17])[C:4]2[C:9]([C:10]=1[CH:11]=O)=[CH:8][C:7]([Cl:13])=[C:6]([Cl:14])[CH:5]=2.[CH3:24][NH:25][NH2:26].CO.O>CO>[Cl:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[Cl:14])[N:3]([C@@H:15]1[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@H:16]1[OH:17])[C:2]1[N:25]([CH3:24])[N:26]=[CH:11][C:10]2=1
Reactant: O=Cc1c(Cl)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2cc(Cl)c(Cl)cc12
Reactant: CNN
Solvent: O
Solvent: CO
Product: Cn1ncc2c3cc(Cl)c(Cl)cc3n([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 33 %

Procedure:
2,5,6-Trichloro-3-formyl-1-(β-D-ribofuranosyl)indole (4.3, 82 mg, 0.22 mmol) was dissolved in methanol (4 mL) to which was added methylhydrazine (0.5 mL). The solution was stirred at room temperature for 16 h, then the solvent was removed under vacuum. The residue was suspended in 20 mL of brine and extracted with EtOAc (2×20 mL). The combined organic extracts were dried over MgSO4, filtered and evaporated to yield a yellow oil. The oil was subjected to column chromatography (40×350 mm) on C18-reverse phase silica gel with 75% MeOH/water. Fractions containing product were pooled and evaporated to yield 29 mg (33%) of 4.36 as a pale yellow solid: mp 135-138° C.; Rf 0.6 (20% MeOH/CHCl3); 1H-NMR (500 MHz, DMSO-d6): δ 8.25 (s, 1H), 7.94 (s, 1H), 7.73 (s, 1H), 5.95 (d, 1H), 5.38 (d, 1H, D2O exch.), 5.25 (m, 2H, D2O exch.), 4.21 (q, 1H), 4.13 (m, 1H), 4.05 (s, 3H), 3.97 (m, 1H), 3.74 (m, 2H). 13C-NMR (125 MHz, DMSO-d6): δ 146.23, 139.94, 128.98, 123.94, 122.80, 120.16, 119.24, 115.28, 109.15, 88.91, 85.71, 71.94, 68.75, 60.89, 37.81. HRMS (ES) m/z calcd. for C15H15Cl2N3O4.Na.MeOH 426.0599. found 426.0593. Anal calcd for C15H15Cl2N3O4: C, 48.40; H, 4.06; N, 11.29. Found: C, 48.13; H, 4.16; N, 11.12.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[F:23][C:24]([F:51])([F:50])[C:25]1[CH:26]=[C:27]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[CH2:28][N:29]1[CH2:36][CH2:35][CH2:34][O:33][C:32]2[N:37]=[CH:38][CH:39]=[C:40](I)[C:31]=2[C:30]1=[O:42]>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[F:23][C:24]([F:51])([F:50])[C:25]1[CH:26]=[C:27]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[CH2:28][N:29]1[CH2:36][CH2:35][CH2:34][O:33][C:32]2[N:37]=[CH:38][CH:39]=[C:40]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:31]=2[C:30]1=[O:42]
Reactant: OB(O)c1ccccc1
Reactant: O=C1c2c(I)ccnc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C1c2c(-c3ccccc3)ccnc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 7 h
Yield: 80.5 %

Procedure:
Phenylboronic acid (417 mg), tetrakis(triphenylphosphine)palladium (132 mg), toluene (10 mL), 1,4-dioxane (5 mL), and a 2 mol/L aqueous solution of sodium carbonate (10 mL) were added to 5-[3,5-bis(trifluoromethyl)benzyl]-7-iodo-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (1.00 g). While heated, the mixture was stirred for 7 hours under a stream of argon gas. The mixture was then diluted with ethyl acetate, was washed with a 2 mol/L aqueous solution of sodium carbonate, and was dried on anhydrous sodium sulfate. The solvent was removed and the resulting residue was recrystallized from isopropanol to obtain 5-[3,5-bis(trifluoromethyl)benzyl]-6-oxo-7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (729 mg, 80%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O)(=O)=[O:15].O.C1C=C(Cl)C=C(C(OO)=O)C=1>CC(C)=O>[CH2:1]([N:8]1[CH2:12][CH:11]2[O:15][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)O
Reactant: C1=CCN(Cc2ccccc2)C1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: CC(C)=O
Product: c1ccc(CN2CC3OC3C2)cc1
Yield: 94.7 %

Procedure:
To a solution of 15.9 g (0.1 mol) of 1-benzyl-3-pyrroline, 13.1 g (0.24 mol) of methanesulfonic acid (produced by Tokyo Chemical Industry Co., Ltd), 15.0 g of water, and 60.0 g of acetone in a round flask reactor, 31.1 g (0.13 mol) of 70% m-CPBA (m-chloroperbenzoic acid produced by Tokyo Chemical Industry Co., Ltd.) was added with stirring and allowed to react for 10 hours at room temperature without irradiation by lamps. After completion, acetone was evaporated under reduced pressure, neutralized by NaOH (aq), and extracted with toluene and water. After the solvent was evaporated under reduced pressure, 16.6 g of 1-benzyl-3,4-epoxypyrrolidine (yield 94.7%) was obtained.
Reaction SMILES: NC1C=CC(C)=C(C(C2C=CC(NC3C=CC(C(F)(F)F)=CC=3)=CC=2Cl)=O)C=1.[Cl:29][C:30]1[CH:35]=[C:34]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:38]=2[CH3:44])[CH:33]=[CH:32][C:31]=1[C:45]([C:47]1[CH:52]=[C:51]([N+:53]([O-])=O)[CH:50]=[CH:49][C:48]=1[CH3:56])=[O:46]>>[NH2:53][C:51]1[CH:50]=[CH:49][C:48]([CH3:56])=[C:47]([C:45]([C:31]2[CH:32]=[CH:33][C:34]([NH:36][C:37]3[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:38]=3[CH3:44])=[CH:35][C:30]=2[Cl:29])=[O:46])[CH:52]=1
Reactant: Cc1cc(Cl)ccc1Nc1ccc(C(=O)c2cc([N+](=O)[O-])ccc2C)c(Cl)c1
Agent: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(C(F)(F)F)cc2)cc1Cl
Product: Cc1cc(Cl)ccc1Nc1ccc(C(=O)c2cc(N)ccc2C)c(Cl)c1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 415, using compound 443 (0.24 mmol). The crude product was used without any further purification.
Reaction SMILES: COC(=O)CCCN1CCC[C@H]1COC1C=CC(CC2C=CC=CC=2)=CC=1.[CH2:28]([C:35]1[CH:56]=[CH:55][C:38]([O:39][CH2:40][C@H:41]2[CH2:45][CH2:44][CH2:43][N:42]2[CH2:46][CH2:47][CH2:48][C:49]2[O:53][NH:52][N:51]([CH3:54])[CH:50]=2)=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([C:35]1[CH:56]=[CH:55][C:38]([O:39][CH2:40][C@@H:41]2[CH2:45][CH2:44][CH2:43][N:42]2[CH2:46][CH2:47][CH2:48][C:49]2[O:53][NH:52][N:51]([CH3:54])[CH:50]=2)=[CH:37][CH:36]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CN1C=C(CCCN2CCC[C@@H]2COc2ccc(Cc3ccccc3)cc2)ON1
Agent: COC(=O)CCCN1CCC[C@H]1COc1ccc(Cc2ccccc2)cc1
Product: CN1C=C(CCCN2CCC[C@H]2COc2ccc(Cc3ccccc3)cc2)ON1
Yield: 40 %

Procedure:
The title compound (0.210 mg, 40%) was prepared from 4-[(S)-2-(4-benzyl-penoxymethyl)-pyrrolidin-1-yl]-butyric acid methyl ester (337 mg, 1 mmol) by a similar procedure as that described for the synthesis of 5-{3-[(R)-2-(4-benzyl-phenoxymethyl)-pyrrolidin-1-yl]-propyl}-3-methyl-[1,2,3]oxadiazole: MS; m/z 392 (M+1); 1H NMR (400 HMz, CDCl3) δ 1.62-1.79 (m, 3H), 1.92-2.03 (m, 3H), 2.23 (m, 1H), 2.33 (s, 3H), 2.49 (m, 1H), 2.81-2.99 (m, 4H), 3.14 (m, 1H), 3.73 (dd, J1=6.4 Hz, J2=9.2 Hz, 1H), 3.86 (dd, J1=4.8 Hz, J2=9.6 Hz, 1H), 3.92 (s, 2H), 6.81 (dd, J1=2.0 Hz, J2=6.8 Hz, 2H), 7.08 (d, J=8.0 Hz, 2H), 7.16-7.29 (m, 5H).
Reaction SMILES: Cl.[CH3:2][S:3][C:4]1[NH:5][CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[N:8]=1.[Sn]>O>[CH3:2][S:3][C:4]1[NH:5][CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[N:8]=1
Reactant: CSc1nc(-c2ccc([N+](=O)[O-])cc2)c[nH]1
Agent: Cl
Agent: [Sn]
Solvent: O
Product: CSc1nc(-c2ccc(N)cc2)c[nH]1
Temperature: 100 °C
Reaction time: 3 h
Yield: 58.5 %

Procedure:
Concentrated hydrochloric acid (60 ml) was added dropwise to a stirred suspension of 2-methylthio-4-(4-nitro-phenyl)-1H-imidazole (5.88 g) and granulated tin (8.9 g) in water (25 ml). After an additional 3 hours of stirring at 100° C., the mixture was cooled to room temperature and filtered. The filter cake was dissolved in water, and the solution was filtered and evaporated to dryness. The residual solid was washed with ethanol, filtered off and treated with an ethanolic solution of sodium ethoxyde to give the free base (3 g).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:20]#[N:21])=[C:18]([OH:19])[C:13]=3[C:12]3[CH:22]=[C:23]([Br:26])[CH:24]=[N:25][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:27][O:28][CH2:29][CH2:30]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>CN(C=O)C.C(OCC)(=O)C>[C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:20]#[N:21])=[C:18]([O:19][CH2:30][CH2:29][O:28][CH3:27])[C:13]=3[C:12]3[CH:22]=[C:23]([Br:26])[CH:24]=[N:25][C:11]2=3)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1ncc2c(c1O)c1cc(Br)cnc1n2S(=O)(=O)c1ccccc1
Reactant: COCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOc1c(C#N)ncc2c1c1cc(Br)cnc1n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.9 %

Procedure:
A solution of 9-benzenesulfonyl-3-bromo-5-hydroxy-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (145 mg, 0.3 mmol), 2-methoxyethanol (158 μL, 2.0 mmol) and triphenylphosphine (525 mg, 2.0 mmol) in anhydrous DMF (1.25 mL) was treated with diethyl azodicarboxylate (0.315 mL, 2.0 mmol) and the mixture stirred at ambient temperature for 30 min then left to stand for 4 days. The mixture was diluted with ethyl acetate (20 mL) and washed with brine (3×10 mL) then the aqueous phase was extracted with ethyl acetate (10 mL). The combined organic phase was dried over magnesium sulfate and concentrated in vacuo. The resultant residue was purified by flash chromatography (silica, 5 g column, Si-SPE, 0-100% ethyl acetate in DCM) to afford the title compound (35 mg, 23%). 1H NMR (CDCl3, 300 MHz): 9.58 (s, 1H), 8.97 (d, J=2.3 Hz, 1H), 8.76 (d, J=2.3 Hz, 1H), 8.26-8.18 (m, 2H), 7.68-7.60 (m, 1H), 7.57-7.47 (m, 2H), 4.74-4.69 (m, 2H), 3.89-3.80 (m, 2H), 3.49 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:21]([NH2:31])[C:22]1[CH:30]=[CH:29][C:28]2[O:27][CH2:26][O:25][C:24]=2[CH:23]=1>C(#N)C.C(N(CC)C(C)C)(C)C>[O:27]1[C:28]2[CH:29]=[CH:30][C:22]([CH2:21][NH:31][C:2]3[C:3]4[CH2:11][N:10]([C:12]5[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=5[C:14]#[N:15])[CH2:9][CH2:8][C:4]=4[N:5]=[CH:6][N:7]=3)=[CH:23][C:24]=2[O:25][CH2:26]1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCc3ncnc(NCc4ccc5c(c4)OCO5)c3C2)c(C#N)c1

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (100 mg, 0.35 mmol) and piperonylamine (120 mg, 0.79 mmol) in acetonitrile (1 mL) and N,N-diisopropylethylamine (400 μL) was subjected to microwave irradiation at 185° C. for 3 h. The reaction mixture was concentrated and the residue was purified by preparative HPLC (100×20.2 mm, C18 column; 30-60% acetonitrile-water [10 mM Et2NH]) to afford a light yellow solid.
Reaction SMILES: [CH2:1]([N:6]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:9](=O)[C:7]1=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[CH:19]1([C:25]([NH:27][NH2:28])=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH3:18][O:17][C:14]1[CH:15]=[C:16]2[C:11](/[C:9](=[N:28]/[NH:27][C:25]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:26])/[C:7](=[O:8])[N:6]2[CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:12][CH:13]=1
Reactant: CCCCCN1C(=O)C(=O)c2ccc(OC)cc21
Reactant: NNC(=O)C1CCCCC1
Product: CCCCCN1C(=O)/C(=N\NC(=O)C2CCCCC2)c2ccc(OC)cc21

Procedure:
The title compound was prepared as a yellow solid, using 1-pentyl-6-methoxy-isatin obtained in Example 39(A) and cyclohexanecarbohydrazide according to the synthetic method E. NMR (CDCl3): δ 0.91 (t, 3H), 1.25 to 2.36 (m, 17H), 3.70 (t, 2H), 3.87 (s, 3H), 6.43 (d, 1H), 6.61 (dd, 1H), 7.51 and 7.73 (d for isomers, 1H), 12.28 and 13.078 (br s for isomers, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[C:10]([CH2:11][CH3:12])=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][CH:14]=3)[N:8]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:5]2=[N:6][CH:7]=1.Cl[CH2:31][CH:32]=O>CCO>[CH2:11]([C:10]1[C:4]2[N:3]3[CH:31]=[CH:32][N:1]=[C:2]3[CH:7]=[N:6][C:5]=2[N:8]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:27])[CH3:28])[C:9]=1[C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:21])[CH3:20])=[CH:17][CH:18]=1)[CH3:12]
Reactant: O=CCCl
Reactant: CCc1c(-c2ccc(C(C)=O)cc2)n(COCC[Si](C)(C)C)c2ncc(N)nc12
Solvent: CCO
Product: CCc1c(-c2ccc(C(C)=O)cc2)n(COCC[Si](C)(C)C)c2ncc3nccn3c12
Temperature: 80 °C
Yield: 52.2 %

Procedure:
1-(4-(2-Amino-7-ethyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-6-yl)phenyl)ethanone (0.217 g, 0.529 mmol) in EtOH (5 mL) was treated with 2-chloroacetaldehyde (˜50 wt % solution in water, 0.100 g, 0.634 mmol). The mixture was heated to about 80° C. for about 2 h then cooled to rt and concentrated under reduced pressure. The material was purified by on a 10 gram silica column with EtOAc then 9:1 DCM/MeOH as eluents to give 1-(4-(1-ethyl-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-2-yl)phenyl)ethanone (0.12 g, 52%): LC/MS (Table 2, Method a) Rt=3.06 min; MS m/z 435 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([OH:16])=[C:11]([Cl:17])[CH:10]=2)[C:5]([F:18])=[CH:4][N:3]=1.[OH:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>>[Cl:17][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[C:5]([F:18])=[CH:4][N:3]=[C:2]([NH:23][C:22]3[CH:24]=[CH:25][CH:26]=[C:20]([OH:19])[CH:21]=3)[N:7]=2)[CH:14]=[C:13]([CH3:15])[C:12]=1[OH:16]
Reactant: Cc1cc(Nc2nc(Cl)ncc2F)cc(Cl)c1O
Reactant: Nc1cccc(O)c1
Product: Cc1cc(Nc2nc(Nc3cccc(O)c3)ncc2F)cc(Cl)c1O

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N4-(3-chloro-4-hydroxy-5-methylphenyl)-4-pyrimidineamine with 3-hydroxyaniline gave N4-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine. LCMS: retn, time: 18.20 min.; purity: 94%; MS (m/e): 360 (M+); 1 □ □ □ (DMSO-d6): δ 9.26 (1H, s), 9.23 (1H, s), 9.16 (1H, s), 8.89 (1H, s), 8.14 (1H, d, J=4.5 Hz), 7.66 (1H, d, J=2.1 Hz), 7.60 (1H, d, J=2.1 Hz), 7.29 (1H, d, J=8.4 Hz), 7.11 (1H, s), 7.06 (1H, t, J=8.4 Hz), 6.41 (1H, d, J=8.4 Hz), 2.30 (3H, s).
Reaction SMILES: [OH-].[Na+].C(OC([C:8]1([CH2:23][C:24]([O:26]CC)=[O:25])[C:14](=[O:15])[CH2:13][CH2:12][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:9]1)=O)C>O.C1COCC1>[C:19]([O:18][C:16]([N:11]1[CH2:12][CH2:13][C:14](=[O:15])[CH:8]([CH2:23][C:24]([OH:26])=[O:25])[CH2:9][CH2:10]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CCOC(=O)CC1(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CCC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(=O)C(CC(=O)O)CC1
Temperature: 25 °C
Yield: 65.6 %

Procedure:
23.3 g sodium hydroxide in 218 mL water was added to 38 g 4-ethoxycarbonylmethyl-5-oxo-azepane-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester in 155 mL THF. The reaction was stirred over night at RT, THF was removed and the mixture was extracted with dichlormethane. The aqueous part was acidified with 3M HCl to pH 3 at 0° C. The aqueous solution was extracted with dichloromethane, dried over magnesium sulfate, concentrated under reduced pressure to give 18.2 g of the desired product. (M+H)+=272
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][CH2:5][NH:6][C:7](=[O:38])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=3)=[C:24]([CH3:37])[CH:23]=2)[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:10][CH:9]=1.[OH-].[Na+].Cl>C1COCC1>[CH:34]([C:31]1[CH:30]=[CH:29][C:28]([C:25]2[CH:26]=[CH:27][C:22]([CH:15]([O:14][C:11]3[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:39])=[O:2])=[O:38])=[CH:13][CH:12]=3)[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:23][C:24]=2[CH3:37])=[CH:33][CH:32]=1)([CH3:35])[CH3:36]
Reactant: COC(=O)CCNC(=O)c1ccc(OC(CCCC(C)C)c2ccc(-c3ccc(C(C)C)cc3)c(C)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C(CCCC(C)C)Oc2ccc(C(=O)NCCC(=O)O)cc2)ccc1-c1ccc(C(C)C)cc1

Procedure:
3-{4-[1-(4′-Isopropyl-2-methyl-biphenyl-4-yl)-5-methyl-hexyloxy]-benzoylamino}-propionic acid methyl ester (50 mg) was taken into THF (1.0 mL) and treated with NaOH (1.0 mL, 5.0 N), then refluxed under nitrogen. The reaction mixture was neutralized with HCl (1.0 mL, 5.0 N), extracted with ethyl ether, dried over sodium sulfate. Concentration gave the title compound. MS (ES): 516.7 [M+H]+, the structure was also confirmed by proton NMR.