Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C=O.Cl.NO.O.O.O.C([O-])(=O)C.[Na+].S([O-])([O-])=O.[Na+].[Na+].N[C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][C:22]=1[CH2:29][CH3:30].Cl.N([O-])=O.[Na+].[CH2:36]=[N:37][OH:38]>O.[Cl-].[Na+].O.S([O-])([O-])(=O)=O.[Cu+2]>[C:25]([C:24]1[CH:27]=[CH:28][C:21]([CH:36]=[N:37][OH:38])=[C:22]([CH2:29][CH3:30])[CH:23]=1)#[N:26]
Reactant: CCc1cc(C#N)ccc1N
Reactant: C=NO
Agent: [Cu+2]
Agent: C=O
Agent: CC(=O)[O-]
Solvent: O
Product: CCc1cc(C#N)ccc1C=NO
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
4-Cyano-2-ethylbenzaldehyde oxime was prepared by the procedure of Jolad et al., Org. Syntheses, Coll. Vol. V, 139 (1973). A mixture of paraformaldehyde (2.8 g, 93 mmol) and hydroxylamine hydrochloride (6 g, 86 mmol) in water (39 mL) was heated in a 500 mL 3-necked flask. When a clear, colorless solution was obtained, sodium acetate trihydrate (11.8 g, 87 mmol) was added. The solution was heated for 15 minutes, then cooled in an ice-salt bath to approximately 5°-10° C. To this solution was added copper sulfate (0.97 g, 6.08 mmol), sodium sulfite (0.23 g, 1.82 mmol) and sodium acetate trihydrate (37 g, 272 mmol) in water (42 mL). The resulting green solution was cooled to an internal temperature of approximately 5°-10° C. A diazonium salt solution of 4-amino-3-ethylbenzonitrile was previously prepared as follows: A mixture of 4-amino-3-ethylbenzonitrile (8.32 g, 57 mmol), concentrated hydrochloric acid (13.2 mL), ice (23 g), and water (11.6 mL) was cooled in an ice-salt bath. While maintaining the internal temperature below 10° C., a solution of sodium nitrite (4.2 g, 61 mmol) in water (5.8 mL) was added dropwise. The resulting slurry was stirred at 5°-10° C. for an additional 15 minutes. Then a solution of sodium acetate trihydrate (5.1 g, 37 mmol) in water (8.1 mL) was added. This solution of the diazonium salt was siphoned under the surface of the 10% formaldoxime solution. The reaction mixture was stirred vigorously and allowed to slowly warm to room temperature as the ice-salt bath melted. After 2 hours the reaction mixture was diluted with brine (100 mL), extracted with dichloromethane (2×400 mL), and dried (Na2 SO4). Purification by chromatography (silica gel, hexane:ethyl acetate (7:1)) gave 2.97 g (30%) of a solid: 1H NMR (DMSO-d6) δ11.80 (s, 1H), 8.45 (s, 1H), 8.00-7.60 (m, 3H), 2.90 (m, 2H), 1.20 (m, 3H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:20])[N:7]([CH2:16][C:17]([OH:19])=[O:18])[C:8](=[O:15])[C:9]3[C:14]=2[C:13]=1[CH:12]=[CH:11][CH:10]=3.[CH2:21]([SH:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[O:15]=[C:8]1[C:9]2[C:14]3[C:13](=[C:2]([S:31][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:3]=[CH:4][C:5]=3[C:6](=[O:20])[N:7]1[CH2:16][C:17]([OH:19])=[O:18])[CH:12]=[CH:11][CH:10]=2
Reactant: CCCCCCCCCCS
Reactant: O=C(O)CN1C(=O)c2cccc3c(Cl)ccc(c23)C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCSc1ccc2c3c(cccc13)C(=O)N(CC(=O)O)C2=O
Yield: 60.8 %

Procedure:
In a nitrogen atmosphere, a suspension of 6-chloro-1,3-dioxo-1H-benz[de]-isoquinoline-2(3H)-acetic acid (5.0 g, 17.3 mmoles, described in Example 2), 1-decanethiol (3.3 g, 3.9 ml, 19 mmoles) and anhydrous sodium carbonate (2.4 g, 17.3 mmoles) in dimethylformamide (150 ml) was stirred and heated at reflux for 15 minutes. After cooling the precipitate was collected by filtration and then dissolved in water. The solution was acidified with 2 N hydrochloric acid and extracted with ethyl acetate. The extract was dried (MgSO4) and evaporated to dryness the oily residue was triturated with hexane. The solid was recrystallized from benzene-hexane to give 4.50 g of the title product; mp 137°-140° C.; UV (MeOH) 257, 329, 343 and 382, ε=16,375, 2,849, 4,929 and 15,820, respectively; IR (CHCl3) δ2900, 1725 (inflection), 1698, 1662 cm-1 ; NMR (CDCl3) 0.85 (t, 3H, J=5), 1.25 (m, 16H), 3.1 (t, 2H, J=6.5), 4.92 (s, 2H), 8.45 (m, 3H), 9.75 (broad, 1H); Anal. Calc'd: C, 67.42%; H, 6.84%; N, 3.28%; Found: C, 67.17%; H, 6.84%; N, 3.21%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11](=O)[CH3:12])=[CH:4][CH:3]=1.[C:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])#[N:15].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.C(O)(=O)C.C1C=CC=CC=1>[CH2:20]([O:19][C:17](=[O:18])[C:16]([C:14]#[N:15])=[C:10]([CH2:11][CH3:12])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[CH3:21]
Reactant: CCOC(=O)CC#N
Reactant: CC(=O)CCCc1ccc(Br)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)=C(CC)CCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 5-(4-bromophenyl)pentanone (50 mmole), ethyl cyanoacetate (50 mmole), acetic acid (1.14 mL) ammonium acetate (400 mg), and benzene (50 mL) is heated to reflux in a Dean-Stark apparatus. After approximately 10 hours, additional ethyl cyanoacetate (50 mmole), acetic acid (1.14 mL), and ammonium acetate (400 mg) are added. After an additional 10 hours, the reaction is cooled to room temperature, diluted with ethyl acetate (30 mL), washed with water (240 mL), brine (40 mL), and dried (Na2SO4). After filtering, the extract is concentrated in vacuo and the desired product, as a mixture of E- and Z-isomers, is isolated by column chromatography on silica gel, eluting with 5% ethyl acetate/petroleum ether.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:15][CH2:14][O:13][CH2:12]2)=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[N:6]=1)=[O:4].O.[OH-].[Li+]>CO.C(OCC)(=O)C>[Cl:22][C:18]1[CH:17]=[C:16]([C:7]2[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=[CH:9][C:8]=2[CH:11]2[CH2:15][CH2:14][O:13][CH2:12]2)[CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc(C2CCOC2)c(-c2cccc(Cl)c2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(C2CCOC2)c(-c2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
A mixture of 6-(3-chlorophenyl)-5-(tetrahydrofuran-3-yl)-pyridine-2-carboxylic acid methyl ester (0.15 g, 0.5 mmol) and lithium hydroxide monohydrate (CAN 1310-66-3, 88 mg, 2.1 mmol) in THF/H2O 1/1 (20 mL)) was stirred at room temperature for 1 h. After removal of the organic solvent under reduced pressure, the aqueous phase was washed with ethyl acetate (10 mL) and acidified with 1 N HCl to pH=3. The resulting solution was extracted with ethyl acetate (2×20 mL). The combined organic layer was concentrated under reduced pressure to provide the title compound (0.12 g, 81%) as black oil which was used in the next step without further purification; MS (EI): m/e=304.1 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[NH:29]1[CH2:34][CH2:33][S:32][CH2:31][CH2:30]1.C(=O)([O-])O.[Na+]>C1COCC1>[CH3:28][C:25]1[CH:24]=[CH:23][C:22]([C:16]2[CH:15]=[C:14]3[C:19]([CH2:20][CH2:21][C:12]([C:10]([NH:9][C:6]4[CH:5]=[CH:4][C:3]([CH2:2][N:29]5[CH2:34][CH2:33][S:32][CH2:31][CH2:30]5)=[CH:8][CH:7]=4)=[O:11])=[CH:13]3)=[CH:18][CH:17]=2)=[CH:27][CH:26]=1
Reactant: C1CSCCN1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CC3)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN4CCSCC4)cc2)CC3)cc1
Temperature: 25 °C

Procedure:
In THF (10ml) was dissolved N-[4-(chloromethyl)-phenyl]-7-(4-methylphenyl)-3,4-dihydro-naphthalene-2-carboxamide (300mg), and to the mixture was added thiomorpholine (233 μl). The mixture was refluxed for 20 hours. The reaction mixture was cooled to room temperature, and to the mixture was added 5% sodium hydrogen carbonate solution (50ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give 7-(4methylphenyl)-N-[4-(thiomorpholinomethyl)-phenyl]-3,4-dihydro-naphthalene-2-carboxamide (Compound 50) (309mg) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[C:18]1([N:24]=[C:25]=[S:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[C:18]1([NH:24][C:25]([NH:1][C:2]2[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([NH:15][C:25](=[S:26])[NH:24][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:11][CH:10]=3)=[O:7])=[CH:4][CH:3]=2)=[S:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccc(NC(=O)c2ccc(N)cc2)cc1
Reactant: S=C=Nc1ccccc1
Solvent: CC(C)=O
Product: O=C(Nc1ccc(NC(=S)Nc2ccccc2)cc1)c1ccc(NC(=S)Nc2ccccc2)cc1
Temperature: 55 °C
Reaction time: 0.17 h
Yield: 72.3 %

Procedure:
4,4'-Diaminobenzanilide (0.658 g, 2.5 mM) was dissolved in 20 ml of acetone, and 2 equivalents of phenylisothiocyanate (0.676 g, 5 mM) was added. The mixture was stirred at 55° C. for 10 minutes. After cooling, the reaction mixture was filtered, and washed with acetone/n-hexane to obtain 0.90 g (72.3% yield) of a colorless crystal of compound A-15.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[C:10]([F:18])[CH:9]=2)=[CH:6][C:5]([Br:19])=[CH:4][N:3]=1.[Li+].[OH-].Cl.CCOC(C)=O>C1COCC1.CO>[NH2:1][C:2]1[C:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[C:10]([F:18])[CH:9]=2)=[CH:6][C:5]([Br:19])=[CH:4][N:3]=1
Reactant: COC(=O)c1ccc(-c2cc(Br)cnc2N)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ncc(Br)cc1-c1ccc(C(=O)O)c(F)c1
Reaction time: 5 h

Procedure:
To a solution of methyl 4-(2-amino-5-bromopyridin-3-yl)-2-fluorobenzoate (1.9 g, 5.84 mmol) in THF (19.48 mL) and MeOH (9.74 mL, Ratio: 1.000) was added LiOH (1 M aqueous solutionueous solution) (10.52 mL, 10.52 mmol). The reaction mixture was stirred for 5 h. After 1N HCl (1.9 mL) was added up to pH 5, the reaction mixture was worked up with EtOAc, the organic layer was dried over Na2SO4, filtered off and concentrated in vacuo. The crude 4-(2-amino-5-bromopyridin-3-yl)-2-fluorobenzoic acid was used for the next step without further purification. LCMS (m/z): 311.1/313.1 (MH+), 0.5 min.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C:13]2=[O:18])(=[O:11])=[O:10])=[C:5]([N+:19]([O-:21])=[O:20])[CH:4]=1.[CH:22]([O:35][C:36]([NH:38][C:39]1[CH:44]=[CH:43][N:42]([CH2:45][C:46](O)=[O:47])[C:41](=[O:49])[N:40]=1)=[O:37])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH:22]([O:35][C:36]([NH:38][C:39]1[CH:44]=[CH:43][N:42]([CH2:45][C:46]([N:15]2[CH2:16][CH2:17][N:12]([S:9]([C:6]3[CH:7]=[CH:8][C:3]([F:2])=[CH:4][C:5]=3[N+:19]([O-:21])=[O:20])(=[O:11])=[O:10])[C:13](=[O:18])[CH2:14]2)=[O:47])[C:41](=[O:49])[N:40]=1)=[O:37])([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C1CNCCN1S(=O)(=O)c1ccc(F)cc1[N+](=O)[O-]
Reactant: O=C(O)Cn1ccc(NC(=O)OC(c2ccccc2)c2ccccc2)nc1=O
Agent: Cl
Product: O=C(Nc1ccn(CC(=O)N2CCN(S(=O)(=O)c3ccc(F)cc3[N+](=O)[O-])C(=O)C2)c(=O)n1)OC(c1ccccc1)c1ccccc1
Yield: 59.7 %

Procedure:
The title compound (1.19 g, 60%) was synthesized by reaction of 1-(4-fluoro-2-nitro-benzenesulfonyl)-piperazin-2-one HCl salt (1.02 g, 3.0 mmol) with [4-N-(benzhydryloxycarbonyl)-cytosin-1-yl]-acetic acid (1.14 g, 3.0 mmol), as per the procedure of example 77. 1H NMR (DMSO-d6) δ 10.98 (s, 1H), 8.41 (m, 1H), 8.24 (dd, 1H), 7.87 (m, 2H), 7.50˜7.25 (m, 10H), 6.96 (m, 1H), 6.79 (s, 1H), 4.81 (s, 1.2H), 4.73 (s, 0.8H), 4.45 (s, 0.8H), 4.27 (s, 1.2H), 4.06˜3.95 (m, 2.4H), 3.90˜3.80 (m, 1.6H).
Reaction SMILES: [N:1]([C@H:4]1[C@H:12]2[O:13][C@H:6]([C@@H:7]3[C@H:11]2[S:10](=[O:15])(=[O:14])[N:9]([C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:17]=2)[CH2:8]3)[CH2:5]1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.O>[NH2:1][C@H:4]1[C@H:12]2[O:13][C@H:6]([C@@H:7]3[C@H:11]2[S:10](=[O:15])(=[O:14])[N:9]([C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([C:24]([F:25])([F:26])[F:27])[CH:17]=2)[CH2:8]3)[CH2:5]1
Reactant: N#Cc1ccc(N2C[C@H]3[C@H]([C@@H]4O[C@H]3C[C@H]4N=[N+]=[N-])S2(=O)=O)cc1C(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(N2C[C@H]3[C@H]([C@@H]4O[C@H]3C[C@H]4N)S2(=O)=O)cc1C(F)(F)F
Temperature: 70 °C
Reaction time: 2 h

Procedure:
The mixture of Examples 24i and 24ii was dissolved in a mixed solvent of THF (3 mL) and H2O (0.25 mL). To the mixture, PPh3 (147 mg, 0.56 mmol) was added. The mixture was stirred at 70° C. for 2 h, and then cooled down. The reaction mixture was purified by SCX cartridge to give a mixture of Examples 25i and 25ii.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)[CH:12]=[N:11][CH:10]=1.[OH-].[Na+]>ClCCl>[Cl:8][C:9]1[N:14]=[C:13]([N:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)[CH:12]=[N:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cncc(Cl)n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1cncc(N2CCNCC2)n1
Reaction time: 1 h

Procedure:
A solution of trifluoroacetic acid (TFA; 6 mL) in dichloromethane (24 mL) was added to a stirred solution of the product of step 1 above (5.79 g, 19.4 mmol) in dichloromethane (20 mL) at 0° C. After 1 h and 1.5 h of stirring, additional portions (10 mL and 5 mL) of TFA were added. Crushed ice and 5 M aqueous NaOH were added and the mixture was extracted with dichloromethnae (12×200 mL). The combined organic layers were dried (K2CO3), filtered and concentrated in vacuo. This furnished 3.48 g (90%) of the title compound as a light yellow solid. *Previously described in a) J. Med. Chem. 1978, 21, 536-542; b) U.S. Pat. No. 4,082,844
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[N:9]=[C:8]2[CH2:10][O:11][CH:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][C:7]2=[CH:6][CH:5]=1.[C:20]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:23])([CH3:22])[CH3:21].OC(C1N=CC=CC=1)CN(CC1C=CC=CC=1)C(C)(C)C.NO>CO>[OH:1][CH:2]([C:4]1[N:9]=[C:8]2[CH2:10][O:11][CH:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][C:7]2=[CH:6][CH:5]=1)[CH2:3][N:24]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)NCc1ccccc1
Reactant: c1ccc(C2OCc3nc(C4CO4)ccc3O2)cc1
Agent: CC(C)(C)N(Cc1ccccc1)CC(O)c1ccccn1
Agent: NO
Solvent: CO
Product: CC(C)(C)N(Cc1ccccc1)CC(O)c1ccc2c(n1)COC(c1ccccc1)O2

Procedure:
A solution of 33.0 g. (0.13 mole) 6-(1,2-epoxyethyl)-2-phenyl-4H-1,3-dioxino-[5,4-b]pyridine and 22.0 g. (0.135 mole) of N-tert-butylbenzylamine in 200 ml. of methanol was heated to the reflux temperature overnight. Upon cooling there deposited 6-[1- hydroxy-2-(N-tert-butylbenzylamino)ethyl]pyridine which was recrystallized from isopropanol to give 29.4 g. (54%) of the amino alcohol m.p. 126°-130° C.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)=[CH:7][CH:8]=1)[NH2:2].[C:19](OCC)(=O)[CH2:20][OH:21]>C(O)CCC>[OH:21][CH2:20][C:19]1[N:4]2[N:5]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[CH:7]=[CH:8][C:3]2=[N:1][N:2]=1
Reactant: CCOC(=O)CO
Reactant: NNc1ccc(-c2cccc(C(F)(F)F)c2)nn1
Solvent: CCCCO
Product: OCc1nnc2ccc(-c3cccc(C(F)(F)F)c3)nn12

Procedure:
A mixture of 2.3 g. of 3-hydrazino-6-[3-(trifluoromethyl)phenyl]pyridazine, 188 g. of ethyl glycolate and 40 ml. of n-butyl alcohol is heated at reflux temperature for 18 hours. The mixture is evaporated in vacuo. To the residue is added dichloromethane and hexane. The mixture is filtered to give 2.0 g. of cream colored crystals. Recrystallization from ethyl acetate gives the product of the Example as off-white crystals, m.p. 224°-226° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[O:6][C:7]1[C:14]([O:15][CH2:16][CH2:17][O:18]C2CCCCO2)=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[N+:25]([O-])=O.O.O.[Sn](Cl)Cl>C(O)C.Cl>[NH2:25][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([O:15][CH2:16][CH2:17][OH:18])[C:7]=1[O:6][C:5]1[CH:28]=[CH:29][CH:30]=[C:3]([O:2][CH3:1])[CH:4]=1)[C:11]#[N:12]
Reactant: COc1cccc(Oc2c(OCCOC3CCCCO3)cc(C#N)cc2[N+](=O)[O-])c1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: COc1cccc(Oc2c(N)cc(C#N)cc2OCCO)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2.0 g of 4-(3-methoxy-phenoxy)-3-nitro-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzonitrile were dissolved in ethanol (60 ml), a solution of tin dichloride dihydrate (4.5 g) in 37% HCl (12 ml) was added dropwise thereto at room temperature and the mixture was subsequently stirred at room temperature for 12 hours. The mixture was poured on to ice-water, adjusted to pH 7 and the product was extracted with ethyl acetate. After usual processing of the organic phase there was obtained 3-amino-5-(2-hydroxy-ethoxy)-4-(3-methoxy-phenoxy)-benzonitrile as a white solid.
Reaction SMILES: CC1ON=C(C2[CH:12]=[CH:11][C:10]([CH:13]3[O:19][CH2:18][CH2:17][N:16]([C:20]4[N:25]([CH3:26])[C:24](=[O:27])[CH:23]=[C:22]([C:28]5[CH:33]=[CH:32][N:31]=[CH:30][N:29]=5)[N:21]=4)[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)N=1.Cl.[CH3:35][C:36]1[N:40]=[C:39]([C:41]2C=CC(C3OCCNCC3)=CC=2)[O:38][N:37]=1.Cl.CC1ON=C(C2C=CC(C3OCCNCC3)=CC=2)N=1>>[CH3:35][C:36]1[N:40]=[C:39]([C:41]2[CH:8]=[CH:9][C:10]([CH:13]3[O:19][CH2:18][CH2:17][N:16]([C:20]4[N:25]([CH3:26])[C:24](=[O:27])[CH:23]=[C:22]([C:28]5[CH:33]=[CH:32][N:31]=[CH:30][N:29]=5)[N:21]=4)[CH2:15][CH2:14]3)=[CH:11][CH:12]=2)[O:38][N:37]=1
Reactant: Cc1nc(-c2ccc(C3CCN(c4nc(-c5ccncn5)cc(=O)n4C)CCO3)cc2)no1
Reactant: Cc1noc(-c2ccc(C3CCNCCO3)cc2)n1
Agent: Cc1nc(-c2ccc(C3CCNCCO3)cc2)no1
Agent: Cl
Product: Cc1noc(-c2ccc(C3CCN(c4nc(-c5ccncn5)cc(=O)n4C)CCO3)cc2)n1

Procedure:
(+)-2-{7-[4-(3-Methyl-[1,2,4]-oxadiazole-5-yl)phenyl]-[1,4]-oxazepane-4-yl}-3-methyl-6-pyrimidin-4-yl-3H-pyrimidin-4-one (A121) was prepared by the same procedure as that of 2-{7-[4-(5-methyl-[1,2,4]-oxadiazole-3-yl)phenyl]-[1,4]-oxazepane-4-yl}-3-methyl-6-pyrimidin-4-yl-3H-pyrimidin-4-one (A100) except for utilizing optically active 7-[4-(3-Methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-[1,4]oxazepane hydrochloride instead of optically active 7-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-[1,4]oxazepane hydrochloride. (+)-2-{7-[4-(3-Methyl-[1,2,4]-oxadiazole-5-yl)phenyl]-[1,4]-oxazepane-4-yl}-3-methyl-6-pyrimidin-4-yl-3H-pyrimidin-4-one (A103) was obtained as white solid (0.07 g, 0.16 mmol, 63%).
Reaction SMILES: [C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=[CH:5][C:4]([CH:7]2[CH:26]=[C:25]3[C:10](=[CH:11][C:12]4[CH:13]=[C:14]5[C:22]([C:23]([CH3:28])([CH3:27])[C:24]=43)=[C:21]3[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]3)=[N:15]5)[CH:9]=[CH:8]2)=[CH:3][CH:2]=1.CN(C=O)C.[Br:40]N1C(=O)CCC1=O>O>[C:1]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:6]=[CH:5][C:4]([CH:7]2[CH:26]=[C:25]3[C:10](=[C:11]([Br:40])[C:12]4[CH:13]=[C:14]5[C:22]([C:23]([CH3:27])([CH3:28])[C:24]=43)=[C:21]3[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]3)=[N:15]5)[CH:9]=[CH:8]2)=[CH:3][CH:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)C2=C(C=C3C=CC(c4ccc(-c5ccccc5)cc4)C=C32)C=C2N=c3ccccc3=C21
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)C2=C(C=C3N=c4ccccc4=C31)C(Br)=C1C=CC(c3ccc(-c4ccccc4)cc3)C=C12
Temperature: 70 °C
Reaction time: 7 h
Yield: 69.5 %

Procedure:
The resulting 10-(biphenyl-4-yl)-12,12-dimethyl-10,12-dihydroindeno[2,1-b]carbazole (42.5 g) and DMF (2.5 L) were added to a reaction vessel, and the mixture was heated up to 70° C. and dissolved. After cooled to a room temperature, N-bromo-succinimide (17.4 g) was added, and the mixture was stirred for 7 hours. Water (2.5 L) was added, and filtration was performed to obtain a white powder of 10-(biphenyl-4-yl)-7-bromo-12,12-dimethyl-10,12-dihydroindeno[2,1-b]carbazole (34.9 g; yield 69.5%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1([CH3:28])[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH2:24][C:25]([OH:27])=[O:26])[CH:22]=2)[S:17][CH2:16][CH2:15]1.[CH2:29](I)[CH2:30][CH2:31][CH2:32][CH3:33]>C1COCC1>[CH3:13][C:14]1([CH3:28])[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH:24]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:25]([OH:27])=[O:26])[CH:22]=2)[S:17][CH2:16][CH2:15]1
Reactant: CC1(C)CCSc2ccc(CC(=O)O)cc21
Reactant: CCCCCI
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCCCC(C(=O)O)c1ccc2c(c1)C(C)(C)CCS2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1.12 ml of diisopropylamine were dissolved in 24 ml THF and treated dropwise, at 0° C., with 3.2 ml of butyl lithium (2.5M). After 30 min. at 0° C., a solution of 0.6 g of (4,4-dimethyl-thiochroman-6-yl)-acetic acid in 4 ml of THF was dropped in. The reaction mixture was stirred at 0° C. for one hour then at room temperature for 30 min. After cooling back to 0° C., a solution of 0.5 ml of pentyl iodide in 2 ml THF was added dropwise. The mixture was kept at 0° C. for one hour then at room temperature for two hours. The mixture was quenched with the addition of 25 ml of water and the pH was adjusted to 2 with HCl 1N. The mixture was extracted with three portions of 25 ml of ether. The combined organic extracts were washed with two portions of 25 ml of water and one portion of 25 ml of saturated aqueous sodium chloride solution. The organic phase was dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 10% methanol/methylene chloride), yielding 0.65 g of a pale yellow oil. 1H NMR (CDCl3): 7.27 (d, J=1.8 Hz, 1H), 7.04 (d, J=8.1 Hz, 1H), 6.99 (dd, J=8.1, 1.8 Hz, 1H), 3.46 (t, J=7.7 Hz, 1H), 3.05-2.95 (m, 2H), 2.15-1.95 (m, 3H), 1.85-1.60 (m, 1H), 1.32 (s, 3H), 1.31 (s, 3H), 1.35-1.20 (m, 6H), 0.86 (t, J=6.7 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]([CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10]C)=[O:9])=[O:4].O.[OH-].[Li+]>O1CCCC1.O>[CH3:1][N:2]([CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([OH:10])=[O:9])=[O:4]
Reactant: COC(=O)c1cccc(C(=O)N(C)CCN2CCOCC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
To a solution of methyl 3-(methyl(2-morpholinoethyl)carbamoyl)benzoate (4.4 g, 13.66 mmol, 1.00 equiv, 95%) in tetrahydrofuran/water (15/10 mL) was added lithium hydroxide hydrate (1.77 g, 43.17 mmol, 3.00 equiv) and the resulting solution was stirred for 1 h at 25° C. The resulting mixture was concentrated under vacuum, diluted with 10 mL of water and then adjusted to pH 2-3 with hydrochloric acid. The resulting mixture was washed with 2×30 mL of ethyl acetate. The aqueous layers were concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate:methanol (4:1) to give 2.7 g (65%) of 3-(methyl(2-morpholinoethyl)carbamoyl)benzoic acid as a white solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.17 (m, 2H), 7.78 (m, 1H), 7.61 (m, 1H), 3.98 (m, 6H), 3.56 (m, 5H), 3.47 (m, 1H), 3.10 (s, 3H). MS (ES, m/z): 293 [M+H]+.