Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH2:3][NH:4][CH2:5][CH2:6][NH2:7].[C:14](=S)=[S:15]>C(O)CCC>[OH:1][CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH2:3][N:4]1[CH2:5][CH2:6][NH:7][C:14]1=[S:15]
Reactant: S=C=S
Reactant: NCCNCC(O)c1ccccn1
Solvent: CCCCO
Product: OC(CN1CCNC1=S)c1ccccn1
Reaction time: 0.25 h
Yield: 76.4 %

Procedure:
N-[2-hydroxy-2-(2-pyridyl)ethyl]ethylene-diamine (17 g.) is dissolved in n-butanol (170 cc.) and carbon disulphide (21.4 g.) is added to the solution. During the addition, the temperature rises from 20° to 34° C. The mixture is stirred for 15 minutes and is then heated under reflux for 30 minutes. After concentration under reduced pressure (20 mm.Hg), the residue is taken up in ethyl acetate (100 cc.). The product which crystallises is filtered off and then dried. 1-[2-Hydroxy-2-(2-pyridyl)ethyl]imidazolidine-2-thione (16 g.), which melts at 120° C., is thus obtained.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:6]([N:8]1[CH2:24][CH2:23][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][NH:13][C:12]2=[O:22])[CH2:10][CH2:9]1)=[O:7].Cl.Cl[CH2:36][CH2:37][N:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:14][N:13]([CH2:36][CH2:37][N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)[C:12]2=[O:22])[CH2:23][CH2:24]1)=[O:7]
Reactant: ClCCN1CCCC1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Agent: Cl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)N(CCN1CCCC1)CN2c1ccccc1

Procedure:
The title compound, MS: m/e=569.2 (M+H+), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one and 1-(2-chloroethyl)pyrrolidine hydrochloride.
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([O:10][CH3:11])=[O:9].[NH3:12].CO>>[NH2:12][CH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: N
Reactant: COC(=O)c1sccc1CBr
Solvent: CO
Product: COC(=O)c1sccc1CN
Temperature: 25 °C
Reaction time: 14 h
Yield: 57 %

Procedure:
A 2-L single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was purged with nitrogen and charged with 116c (7.50 g, 32.0 mmol) and a 7 M solution of ammonia in methanol (915 mL, 6.40 mol). The solution was stirred at room temperature for 14 h. After that time, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in water (150 mL) and extracted with methyl tert-butyl ether (2×25 mL). The aqueous layer was basified with sodium hydroxide (5.00 g) and extracted with methyl tert-butyl ether (3×150 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford a 57% yield (3.14 g) of 116d as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.45 (d, 1H, J=5.1 Hz), 7.14 (d, 1H, J=5.1 Hz), 4.11 (s, 2H), 3.88 (s, 3H), 1.72 (br s, 2H); MS (ESI+) m/z 172.0 (M+H). The material was used without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:37])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:27](S(C3C=CC=CC=3)(=O)=O)[C:13]3=[N:14][CH:15]=[CH:16][C:17](B4OC(C)(C)C(C)(C)O4)=[C:12]3[CH:11]=2)=[CH:6][CH:5]=1.Br[C:39]1[C:40]([C:45]2[CH:50]=[CH:49][C:48]([N+:51]([O-:53])=[O:52])=[CH:47][CH:46]=2)=[N:41][N:42]([CH3:44])[CH:43]=1>>[CH3:1][N:2]([CH3:37])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:27][C:13]3=[N:14][CH:15]=[CH:16][C:17]([C:39]4[C:40]([C:45]5[CH:50]=[CH:49][C:48]([N+:51]([O-:53])=[O:52])=[CH:47][CH:46]=5)=[N:41][N:42]([CH3:44])[CH:43]=4)=[C:12]3[CH:11]=2)=[CH:6][CH:5]=1
Reactant: Cn1cc(Br)c(-c2ccc([N+](=O)[O-])cc2)n1
Reactant: CN(C)Cc1ccc(-c2cc3c(B4OC(C)(C)C(C)(C)O4)ccnc3n2S(=O)(=O)c2ccccc2)cc1
Product: CN(C)Cc1ccc(-c2cc3c(-c4cn(C)nc4-c4ccc([N+](=O)[O-])cc4)ccnc3[nH]2)cc1

Procedure:
Following the procedure described in Intermediate 100 and Intermediate 21 using N,N-dimethyl-1-{4-[1-(phenylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl]phenyl}methanamine and 4-bromo-1-methyl-3-(4-nitrophenyl)-1H-pyrazole provided the title compound. ESMS [M+H]+: 453.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]=[CH:6][C:7]1[C:8](Cl)=[N:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=1)[CH3:2].[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)C>[CH2:1]([O:3][C:4](=[O:18])[CH:5]=[CH:6][C:7]1[C:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc(C(F)(F)F)nc1Cl
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: COCCOC
Product: CCOC(=O)C=Cc1ccc(C(F)(F)F)nc1-c1ccccc1
Yield: 80 %

Procedure:
Microwave vial was charged with 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid ethyl ester (100 mg, 0.376 mmol), phenylboronic acid (2 eq), Cs2CO3 (3 eq), Pd(PPh3)2Cl2 (0.08 eq), DME (1 ml), and ethanol (0.25 ml). The vial was irradiated in microwave synthesizer at 140° C. for 20 min. The contents of the vial were filtered through a celite pad, which was washed out thoroughly with methanol. The filtrate was evaporated, and the residue was purified by column chromatography to give 3-(2-phenyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid ethyl ester (96 mg, 80%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:22])=[C:11]([N:15]4[CH2:20][CH2:19][NH:18][CH:17]([CH3:21])[CH2:16]4)[C:12]=3[CH3:14])[C:7](=[O:23])[C:6]([C:24]([OH:26])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1.[C:27](OC(=O)C)(=[O:29])[CH3:28].Cl>[OH-].[Na+]>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:22])=[C:11]([N:15]4[CH2:20][CH2:19][N:18]([C:27](=[O:29])[CH3:28])[CH:17]([CH3:21])[CH2:16]4)[C:12]=3[CH3:14])[C:7](=[O:23])[C:6]([C:24]([OH:26])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(N2CCNC(C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)N1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2C)CC1C
Reaction time: 0.5 h

Procedure:
1-Cyclopropyl-7-(3-methyl-1-piperazinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.3 g) is dissolved in 10% aqueous sodium hydroxide (5 ml), and thereto is added acetic anhydride (0.3 ml) at room temperature, and the mixture is stirred at the same temperature for 30 minutes. The reaction mixture is acidified with conc. hydrochloric acid and is extracted with dichloromethane. After removing the solvent by concentration, the resulting residue is purified by silica gel column chromatography (solvent, dichoromethane) and then recrystallized from methanol to give 1-cyclopropyl-7-(4-acetyl-3-methyl-1-piperazinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.1 g), as white powder, m.p. 219°-221° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30]C(=O)C)[C@@H:22]([O:23]C(=O)C)[C@H:17]([O:18]C(=O)C)[C@H:12]1[O:13]C(=O)C.[I:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=O)=[CH:37][CH:36]=1>>[I:34][C:35]1[CH:43]=[CH:42][C:38]([CH2:39][C:4]2[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[CH3:1])[N:6]([C@@H:11]3[O:28][C@H:27]([CH2:29][OH:30])[C@@H:22]([OH:23])[C@H:17]([OH:18])[C@H:12]3[OH:13])[CH:5]=2)=[CH:37][CH:36]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: Cc1cccc2c1c(Cc1ccc(I)cc1)cn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
4-Methyl-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole obtained in Example 23-(1) and 4-iodobenzoyl chloride were treated in a manner similar to Example 27 to give the titled compound as a colorless powder. APCI-Mass m/Z 510 (M+H). 1H-NMR (DMSO-d6) δ 2.38 (s, 3H), 3.24 (m, 1H), 3.30-3.47 (m, 4H), 3.68 (m, 1H), 4.16 (s, 2H), 4.52 (t, J=5.6 Hz, 1H), 5.08 (d, J=5.3 Hz, 1H), 5.14 (d, J=5.0 Hz, 1H), 5.16 (d, J=5.9 Hz, 1H), 5.34 (d, J=9.0 Hz, 1H), 6.71 (d, J=7.1 Hz, 1H), 6.98 (dd, J=8.3, 6.9 Hz, 1H), 6.99 (d, J=8.2 Hz, 2H), 7.15 (s, 1H), 7.35 (d, J=8.3 Hz, 1H), 7.46 (d, J=8.2 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:27])[N:7]([CH2:25][CH3:26])[CH2:8][CH2:9][NH:10][C:11]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][C:18]([N+:22]([O-:24])=[O:23])=[CH:17][CH:16]=2)=[O:12])([CH3:4])[CH3:3].[CH2:28](NCCNC(C1NC2C(C=1)=CC([N+]([O-])=O)=CC=2)=O)CC>>[CH3:4][C:2]([O:5][C:6](=[O:27])[N:7]([CH2:8][CH2:9][NH:10][C:11]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][C:18]([N+:22]([O-:24])=[O:23])=[CH:17][CH:16]=2)=[O:12])[CH2:25][CH2:26][CH3:28])([CH3:1])[CH3:3]
Reactant: CCCNCCNC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: CCN(CCNC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1)C(=O)OC(C)(C)C
Product: CCCN(CCNC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1)C(=O)OC(C)(C)C
Yield: 88 %

Procedure:
A similar procedure as described for preparation of 78 from compound 81 (0.12 g, 0.413 mmol) gave brown powder (0.142 g, 88%). ESI MS: 391.17 (M+H+), 413.15 (M+Na+).
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][C:8]([O:14]C(=O)C)=[CH:7][C:6]=1[C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:3])[CH3:2].Cl>CO>[C:1]([O:4][C:5]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][C:8]([OH:14])=[CH:7][C:6]=1[C:18]([CH3:19])([CH3:20])[CH3:21])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(C(C)C)c(OC(C)=O)c(C(C)(C)C)c1
Agent: Cl
Solvent: CO
Product: CC(=O)Oc1c(C(C)C)cc(O)cc1C(C)(C)C
Temperature: 25 °C
Yield: 70.1 %

Procedure:
1.10 g of 1,4-diacetoxy-2-t-butyl-6-isopropylbenzene was dissolved in 22 ml of methanol, 2.5 ml of 3N hydrochloric acid was added, and the solution was heated under reflux for 2.5 hours. After cooling to room temperature, methanol was distilled off on a rotary evaporator. The concentrate was combined with water and extracted with ethyl acetate. The organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated. The concentrate was purified by silica gel column chromatography (in n-hexane containing 5%-10% ethyl acetate) to give 0.66 g of 4-acetoxy-3-t-butyl-5-isopropylphenol as a pale yellow solid (yield 70%).
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][N:4]1[CH2:32][CH2:31][C:7]2[N:8]([CH2:16][CH:17]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:18][C:19]([O:21]CC)=O)[C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=3[C:6]=2[CH2:5]1>O>[CH3:3][N:4]1[CH2:32][CH2:31][C:7]2[N:8]([CH2:16][CH:17]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:18][C:19]([NH:2][CH3:1])=[O:21])[C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=3[C:6]=2[CH2:5]1
Reactant: CCOC(=O)CC(Cn1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccc(F)cc1
Reactant: CN
Solvent: O
Product: CNC(=O)CC(Cn1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccc(F)cc1
Temperature: 100 °C

Procedure:
Methylamine (1 mL) was added to ethyl 4-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(4-fluorophenyl)butanoate (50 mg, 0.122 mmol) and the reaction mixture was heated at 100° C. overnight. The reaction mixture was cooled to RT, diluted with water (5 mL) and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product was purified by silica gel chromatography (100-200 mesh) eluting with 0-7% MeOH-DCM as eluent.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:24])[CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.O=[CH:26][CH2:27][CH2:28][NH:29][C:30](=[O:39])[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[CH2:32]([O:31][C:30]([NH:29][CH2:28][CH2:27][CH2:26][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:24])[CH2:9][CH2:10][CH:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:15][CH2:16]1)=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=CCCNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)c2ccccc2N)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CCC(=O)c2ccccc2NCCCNC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.8 %

Procedure:
The compound prepared in Example 302 (0.455 g) was suspended in 1,2-dichloroethane (10 mL). Benzyl 3-oxopropylcarbamate (0.425 g) and beaded molecular sieves were added and the reaction mixture stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.870 g) was added and the reaction mixture stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and brine. The organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography (eluant: 20-30% ethyl acetate/hexane) to furnish the title compound (0.629 g) with the following physical properties.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:24])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]#[N:14])[CH:11]=2)[NH:6][CH:5]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[CH:16]=2)[CH2:4]1>C(O)C.O.[Fe]>[NH2:21][C:17]1[CH:16]=[C:15]([CH:5]2[CH2:4][C:3]([CH3:2])([CH3:24])[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([C:13]#[N:14])[CH:11]=3)[NH:6]2)[CH:20]=[CH:19][CH:18]=1
Reactant: CC1(C)CC(c2cccc([N+](=O)[O-])c2)Nc2ccc(C#N)cc21
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC1(C)CC(c2cccc(N)c2)Nc2ccc(C#N)cc21
Yield: 92.9 %

Procedure:
To a round bottom flask, iron powder (9.13 g, 162.7 mmol) and concentrated hydrochloric acid (0.16 mL) were added to a mixture of 4,4-dimethyl-2-(3-nitro-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (5 g, 16.3 mmol) in ethanol (50 mL) and water (12 mL). The resultant mixture was allowed to stir at reflux for 1.5 h. The mixture was filtrated and the filtered cake was washed by ethanol several times. The ethanol was removed under vacuum. The residue was dissolved in ethyl acetate (100 mL) and water (50 mL), separated the organic layer. The organic layer was washed by brine twice and dried over anhydrous sodium sulfate. Filtered and concentrated to provide 2-(3-amino-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonitrile as yellow solid (4.2 g, yield: 85%). MS (ESI+APCI) 278.2.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH:10]([C:12]2[N:17]=[N:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:14][CH:13]=2)[CH3:11])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>ClCCCl>[Br:1][C:2]1[S:6][C:5]([C:7]2[N:17]3[C:12]([CH:13]=[N:14][C:15]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)=[N:16]3)=[C:10]([CH3:11])[N:9]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)c3ccc(Br)s3)nn2)cc1
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(Nc2ncc3c(C)nc(-c4ccc(Br)s4)n3n2)cc1
Yield: 24 %

Procedure:
Applying the Cyclization Procedure 1, using 5-bromo-N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]-2-thiophenecarboxamide (Intermediate 48) (106 mg, 0.24 mmol), 1,2-dichloroethane (5 mL) and phosphorus oxychloride (0.182 mL, 1.95 mmol), to afford 7-(5-bromo-2-thienyl)-5-methyl-N-[4-(methyloxy)phenyl]imidazo[5,1-f][1,2,4]triazin-2-amine (24 mg) as a yellow solid. MS m/z 416/418 (M+1).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.[C:19]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[F:1][C:2]1[C:3]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[N:4][C:5](=[O:8])[N:6]([CH3:19])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(C(=O)Nc2nc(O)ncc2F)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1ccc(C(=O)Nc2nc(=O)n(C)cc2F)cc1
Temperature: 60 °C
Yield: 8 %

Procedure:
To N-(5-fluoro-2-hydroxypyrimidin-4-yl)-4-methylbenzamide (200 mg, 0.81 mmol) in DMF (5 mL) was added K2CO3 (224 mg, 1.6 mmol), and iodomethane (230 mg, 1.6 mmol). The mixture was stirred and heated to 60° C. for 30 min and then stirred for 16 h at room temperature. The mixture was partitioned between ethyl acetate (EtOAc) and water (H2O). The organic phase was dried over magnesium sulfate (MgSO4), filtered and evaporated. The crude material was purified by reverse phase chromatography to yield the title compound as a white solid (17 mg, 8%): mp 229-230° C.; 1H NMR (300 MHz, CDCl3) δ13.2 (br s, 1H), 8.23-8.15 (br m, 2H), 7.42-7.37 (br m, 1H), 7.30-7.25 (br m, 2H), 3.45 (s, 3H), 2.44 (s, 3H); ESIMS m/z 262 ([M+H]+), m/z 260 ([M−H]−).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[NH2:14].[N:16]1[CH:21]=[CH:20][CH:19]=[C:18](B(O)O)[CH:17]=1>COCCOC.C(=O)([O-])O.[Na+]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([C:18]2[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=2)[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[NH2:14]
Reactant: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1N
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1cc(-c2cccnc2)cc([N+](=O)[O-])c1N
Temperature: 25 °C

Procedure:
A stirred solution of 2-Amino-5-bromo-3-nitro-benzoic acid methyl ester (2 g, 7.27 mmol) in 1,2-dimethoxyethane (53 ml) was purged with nitrogen for 15 min and treated with aqueous sodium hydrogen carbonate solution (1M, 14.5 ml) followed by pyridine 3-boronic acid (1.33 g, 10.9 mmol) and 1,1-bis-(diphenylphosphino)ferrocene palladium (II) chloride complex (0.6 g, 0.733 mmol). The resultant mixture was boiled under reflux in a nitrogen atmosphere for 18 h. After cooling to ambient temperature, the dark mixture was diluted with saturated aqueous sodium hydrogen carbonate solution (300 ml) and extracted with ethyl acetate (3×250 ml). This was washed with brine (200 ml), dried (MgSO4) and the solvent removed in vacuo to give a residue which was purified by flash chromatography (silica) eluting with 30% to 100% ethyl acetate in 40-60 petroleum ether. The 2-Amino-3-nitro-5-pyridin-3-yl-benzoic acid methyl ester was obtained as a yellow solid (1.1 g, 56%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[NH:10][C@H:11]([C:15](=[O:21])[NH:16][CH2:17][CH2:18][CH:19]=O)[C@@H:12]([OH:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][C@@H:24]([C@H:32]([C@@H:34]1[C@@H:38]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[C@@H:37]([O:47][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])[C@H:36]([N:55]2[CH:60]=[CH:59][C:58](=[O:61])[N:57]([CH2:62][C:63]3[CH:68]=[CH:67][C:66]([O:69][CH3:70])=[CH:65][CH:64]=3)[C:56]2=[O:71])[O:35]1)[OH:33])[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.O1CCCC1>[Si:40]([O:39][C@H:38]1[C@@H:37]([O:47][Si:48]([C:51]([CH3:53])([CH3:54])[CH3:52])([CH3:49])[CH3:50])[C@H:36]([N:55]2[CH:60]=[CH:59][C:58](=[O:61])[N:57]([CH2:62][C:63]3[CH:68]=[CH:67][C:66]([O:69][CH3:70])=[CH:65][CH:64]=3)[C:56]2=[O:71])[O:35][CH:34]1[C@H:32]([OH:33])[C@@H:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[NH:23][CH2:19][CH2:18][CH2:17][NH:16][C:15](=[O:21])[C@H:11]([C@@H:12]([OH:14])[CH3:13])[NH:10][C:9](=[O:22])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([C:43]([CH3:44])([CH3:45])[CH3:46])([CH3:42])[CH3:41]
Reactant: C[C@H](O)[C@H](NC(=O)OCc1ccccc1)C(=O)NCCC=O
Reactant: COc1ccc(Cn2c(=O)ccn([C@@H]3O[C@H]([C@H](O)[C@H](N)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NCCCNC(=O)[C@@H](NC(=O)OCc4ccccc4)[C@H](C)O)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Yield: 53.8 %

Procedure:
By using an analogous procedure to that described for Example 1, a solution of [(1S,2S)-2-hydroxy-1-(3-oxo-propylcarbamoyl)-propyl]-carbamic acid benzyl ester (108 mg, 0.35 mmol, obtained from Reference Example 18), tert-butyl (2S,3R)-2-amino-3-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl-(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)-tetrahydro-2-furanyl]-3-hydroxypropanoate (230 mg, 0.319 mmol, obtained from Reference Example 6), acetic acid (3 drops), and sodium triacetoxyborohydride (135 mg, 0.64 mmol) in anhydrous tetrahydrofuran (5 ml) was stirred under nitrogen at room temperature for 4 hours. The residue was chromatographed (flash column, silica gel, 5% methanol in methylene chloride) to provide tert-butyl (5S,12S)-12-[(R)-[(3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl](hydroxy)methyl]-5-[(1S)-1-hydroxyethyl]-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oate (174 mg, 54%) as a pale yellow solid.
Reaction SMILES: [CH:1]([C:4]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([CH3:3])[CH3:2].[N+:14]([CH3:17])([O-:16])=[O:15].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH:1]([C:4]1[C:5]([CH:6]=[CH:17][N+:14]([O-:16])=[O:15])=[CH:8][CH:9]=[CH:10][C:11]=1[O:12][CH3:13])([CH3:3])[CH3:2]
Reactant: C[N+](=O)[O-]
Reactant: COc1cccc(C=O)c1C(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: COc1cccc(C=C[N+](=O)[O-])c1C(C)C
Yield: 88.6 %

Procedure:
Using a method similar to Example 659, Step 1, using 2-isopropyl-3-methoxy-benzaldehyde (3.56 g, 20.0 mmol), nitromethane (3.25 ml, 60.0 mmol), ammonium acetate (2.00 g, 26.0 mmol) and acetic acid (25 ml) gave 2-isopropyl-1-methoxy-3-(2-nitro-vinyl)-benzene (3.92 g) as a viscous oil. 1H NMR (CDCl3): 8.48 (d, 1H), 7.38 (d, 1H), 7.20 (t, 1H), 7.02-6.96 (m, 2H), 3.84 (s, 3H), 3.41 (m, 1H), 1.36 (d, 6H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][OH:10].[H-].[Na+].Br.Cl[C:15]1[CH:16]=[C:17]([CH3:25])[C:18]2[N:19]([C:21]([NH2:24])=[N:22][N:23]=2)[N:20]=1.O>CN(C=O)C>[CH3:25][C:17]1[C:18]2[N:19]([C:21]([NH2:24])=[N:22][N:23]=2)[N:20]=[C:15]([O:10][CH2:9][CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH:16]=1
Reactant: Cc1cc(Cl)nn2c(N)nnc12
Reactant: OCCOC1CCCCO1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCCOC2CCCCO2)nn2c(N)nnc12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
2-(Tetrahydropyran-2-yloxy)ethanol (3.85 ml) was initially charged in DMF (25 ml), admixed under argon with sodium hydride (681 mg) and stirred at 40° C. for 0.5 h. Subsequently, 6-chloro-8-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine hydrobromide (W2.002; 1.5 g), dissolved in DMF (25 ml), was added dropwise. After 40 min, the mixture was admixed with water and extracted by shaking four times with dichloromethane. To eliminate the excess alcohol, the mixture was chromatographed first through a short silica gel column with MtB ether and then with 8:2 dichloromethane/methanol. The clean product fractions were combined and dried. 678 mg of the title compound were obtained.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH3:22])=[C:18](/[F:21])\[CH2:19][OH:20])[C:3]=1[O:23][CH:24]([CH3:26])[CH3:25].C([N+](CCC)(CCC)CCC)CC.C[N+]1([O-])CCOCC1.ClCCl>C(#N)C>[Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH3:22])=[C:18](/[F:21])\[CH:19]=[O:20])[C:3]=1[O:23][CH:24]([CH3:26])[CH3:25]
Reactant: C/C(=C(\F)CO)c1cc2c(c(Br)c1OC(C)C)C(C)(C)CC=C2C(C)C
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: CC#N
Product: C/C(=C(\F)C=O)c1cc2c(c(Br)c1OC(C)C)C(C)(C)CC=C2C(C)C

Procedure:
As described in General Procedure H-1, (2E)-3-(4-bromo-3-isopropoxy-8-isopropyl-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-2-fluoro-but-2-en-1-ol (Compound A-139, 220 mg, 0.52 mmol), tetrapropylammonium peruthenate (10 mg, 0.028 mmol) and 4-methylmorpholine N-oxide (151 mg, 1.25 mmol) were reacted in acetonitrile and dichloromethane to give the title compound after purification by flash column chromatography (silica gel, 5% ethyl acetate in hexane).