Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=O)[CH3:20])[N:14]=1)[CH3:12].[CH3:22][O:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=[N:28][C:27]2[CH:29]=[CH:30][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)[CH3:20])[N:14]=1)[CH3:12]
Reactant: COc1ccc(N)cc1
Reactant: CC(=O)c1cccc(C(C)=Nc2c(C)cc(C)cc2C)n1
Solvent: Cc1ccccc1
Product: COc1ccc(N=C(C)c2cccc(C(C)=Nc3c(C)cc(C)cc3C)n2)cc1
Reaction time: 144 h

Procedure:
Monoimine (1, 280 mg, 1 mmol) and 4-methoxyaniline (123 mg, 1 mmol) were dissolved in 20 ml of toluene. To this solution 4 Å molecular sieves were added. After standing for 6 days at room temperature the reaction mixture was filtered and the solvent was removed in vacuo. The residue was recrystallised from ethanol. Yield 148 mg (38%) of mixed diimine (6). 1H-NMR (CDCl3) δ 8.42 (dd, 1H), 8.34 (dd, 1H), 7.86 (t, 1H), 6.93 (d, 2H), 6.88 (s, 2H), 6.81 (d, 2H), 3.82 (s, 3H), 2.43 (s, 3H), 2.29 (s, 3H), 2.22 (s, 3H), 2.00 (s, 6H).
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:9]([CH2:10][N:11]=[N+:12]=[N-:13])=[C:8]([CH3:14])[N:7]=[CH:6]1)([OH:3])=O.[C:15]([NH2:19])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([NH:19][C:1]([CH2:4][N:5]1[C:9]([CH2:10][N:11]=[N+:12]=[N-:13])=[C:8]([CH3:14])[N:7]=[CH:6]1)=[O:3])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)N
Reactant: Cc1ncn(CC(=O)O)c1CN=[N+]=[N-]
Product: Cc1ncn(CC(=O)NC(C)(C)C)c1CN=[N+]=[N-]

Procedure:
The title compound was prepared from 1-carboxymethyl-4-methyl-5-azidomethylimidazole and tert-butylamine using the procedure described in EXAMPLE I, Step A. 1H NMR (CDCl3) d 1.32 (s, 9 H), 2.29 (s, 3 H), 4.31 (s, 2 H), 4.48 (s, 2 H), 5.25 (br s, 1 H), 7.47 (s, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[C:20](O)=[O:21])=[C:8]2[CH3:27])=[CH:4][CH:3]=1.S(C)C.Cl.C(OCC)(=O)C>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[CH2:20][OH:21])=[C:8]2[CH3:27])=[CH:28][CH:29]=1
Reactant: COc1ccc2c(c1)c(-c1ccccc1C(=O)O)c(C)n2Cc1ccc(Br)cc1
Agent: Cl
Solvent: CSC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(-c1ccccc1CO)c(C)n2Cc1ccc(Br)cc1
Yield: 99 %

Procedure:
A solution of the acid from Step 1 (300 mg, 0.66 mmol) and BH3 Σ SMe2 (0.1 mL, 1 mmol) in THF (3 mL) was gently refluxed for 2 h. The cooled mixture was poured over icy dilute HCl and ethyl acetate. The organic layer was washed with brine and dried with MgSO4. Removal of the solvents yielded essentially pure product (285 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@:5]1([NH:10]C(OC(C)(C)C)=O)[CH2:7][C@H:6]1[CH:8]=[CH2:9])=[O:4].[ClH:18]>O1CCOCC1>[ClH:18].[CH3:1][O:2][C:3]([C@@:5]1([NH2:10])[CH2:7][C@H:6]1[CH:8]=[CH2:9])=[O:4]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)OC
Agent: Cl
Solvent: C1COCCO1
Product: C=C[C@@H]1C[C@]1(N)C(=O)OC
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 76 %

Procedure:
Compound 20a (39.96 g, 165.7 mmol) was dissolved in dioxane (25 mL) and the solution added dropwise with stirring to 4 N HCl in dioxane (Aldrich, 250 mL). After 45 min, TLC analysis indicated complete deprotection. Volatiles were removed under reduced pressure, and the residue co-evaporated twice with MeOH (2×100 mL). Ether (300 mL) and MeOH (10 mL) were added to the brown, oily residue and the mixture stirred overnight at room temperature resulting in the precipitation of a semi-solid. Additional MDeOH (15 mL) was added and stirring continued for 6 h, at which point a yellowish solid was collected by filtration. The product was washed with 5% MeOH in ether (50 mL) and ether (2×50 mL), and dried in vacuo to give compound 20b as a yellowish solid (22.60 g, 76% yield). Filtrates (including washings) were evaporated in vacuum to give additional 20b as a brown oil (7.82 g, 26% yield). Both fractions-were pure enough for use in the synthesis of HCV protease inhibitors: [α]D25+38.2° C. (c 1.0, MeOH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH:10]2[CH2:14][CH2:13][NH:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[C:15](O)(=O)C.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH:10]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11]2)=[O:9])=[N:6][CH:7]=1
Reactant: CC(=O)O
Reactant: O=C(c1ccc(Br)cn1)C1CCNC1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CN1CCC(C(=O)c2ccc(Br)cn2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46.8 %

Procedure:
To a solution of (5-bromo-pyridin-2-yl)-pyrrolidin-3-yl-methanone (0.35 g, 1.35 mmol) in methanol (68 mL), add acetic acid (0.15 mL, 2.7 mmol), and formaldehyde (0.33 g, 4.1 mmol, 37% aqueous solution). After 15 min, add sodium triacetoxyborohydride (0.86 g, 4.1 mmol) and allow the mixture to stir at RT for 1 h. Concentrate the reaction mixture, dissolve in CH2Cl2, and wash with saturated NaHCO3. Back-extract the aqueous with CH2Cl2. Wash the combined organic layer with water, dry over Na2SO4, filter, and concentrate. Purify the crude material by flash chromatography, eluting with 5-10% MeOH (2N NH3)/CH2Cl2 to give 0.17 g (47%) of the title compound. LC-MS/ES m/z (79Br) 270 [M+H]+.
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C:11]=2[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(#N)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(O)(=O)C>[C:1]1([C@H:7]([NH:9][C@@H:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:12][C@@H:11]2[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C1=C(N[C@H](C)c2ccccc2)CCN(C(=O)OC(C)(C)C)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCOC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N[C@H](C)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 40.9 %

Procedure:
A 1L 3-neck round bottom flask equipped with a mechanical stirrer and addition funnel was charged with 252B (14.7 g, 39 mmol) and acetonitrile (200 mL) and acetic acid (100 mL). The solution was cooled to 0° C. and Na(OAc)3BH (33.3 g, 157 mmol) was added in three portions over 2 hours. The reaction was stirred for two hours at this temperature after the final addition. The mixture was then cooled to −10° C. and slowly quenched by addition of 1 N NaOH (100 mL), 4 N NaOH (100 mL), 6 N NaOH (100 mL) followed by 50% NaOH (50 mL). The reaction was warmed to room temperature and the layers were separated. The aqueous layer was extracted with CH2Cl22 (2×250 mL) and the combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash chromatography (10% to 30% EtOAc/hexane gradient) on silica gel afforded 6.0 g (yield: 41%) of Compound 252C.
Reaction SMILES: [ClH:1].O1CCOCC1.C(OC([N:15]1[CH2:20][C@H:19]([O:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:18][CH2:17][C@@H:16]1[C@H:27]1[O:31]C(C)(C)[N:29]([C:34](=[O:36])[CH3:35])[C@H:28]1[CH2:37][C:38]1[CH:43]=[C:42]([F:44])[CH:41]=[C:40]([F:45])[CH:39]=1)=O)(C)(C)C>>[ClH:1].[F:44][C:42]1[CH:43]=[C:38]([CH:39]=[C:40]([F:45])[CH:41]=1)[CH2:37][C@H:28]([NH:29][C:34](=[O:36])[CH3:35])[C@H:27]([OH:31])[C@H:16]1[CH2:17][CH2:18][C@@H:19]([O:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:20][NH:15]1
Reactant: CC(=O)N1[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2CC[C@@H](OCCC(C)C)CN2C(=O)OC(C)(C)C)OC1(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1CC[C@@H](OCCC(C)C)CN1
Yield: 92 %

Procedure:
Add 4.0 M hydrogen chloride in dioxane (0.46 mL, 1.86 mmoles) to (2R, 5R)-2-{(4S, 5S)-3-Acetyl-4-[3,5-difluoro-benzyl]-2,2-dimethyl-oxazolidin-5-yl}-5-(3-methyl-butoxy)-piperidine-1-carboxylic acid tert-butyl ester (0.05 g, 0.09 mmol) and stir until all starting material is consumed. Concentrate to afford the title product as a white solid (0.04 g, 92%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][N:11]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=2)[C:12]([CH:14]2[CH2:19][CH2:18][N:17]([S:20]([CH3:23])(=[O:22])=[O:21])[CH2:16][CH2:15]2)=[O:13])[CH2:4][CH2:3]1.[F:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1>>[Cl:31][C:26]1[CH:25]=[C:24]([N:11]([CH2:10][CH2:9][CH2:8][N:5]2[CH2:6][CH2:7][CH:2]([NH:1][C:37](=[O:38])[C:36]3[CH:40]=[CH:41][C:33]([F:32])=[CH:34][CH:35]=3)[CH2:3][CH2:4]2)[C:12]([CH:14]2[CH2:19][CH2:18][N:17]([S:20]([CH3:23])(=[O:21])=[O:22])[CH2:16][CH2:15]2)=[O:13])[CH:29]=[CH:28][C:27]=1[Cl:30]
Reactant: CS(=O)(=O)N1CCC(C(=O)N(CCCN2CCC(N)CC2)c2ccc(Cl)c(Cl)c2)CC1
Reactant: O=C(Cl)c1ccc(F)cc1
Product: CS(=O)(=O)N1CCC(C(=O)N(CCCN2CCC(NC(=O)c3ccc(F)cc3)CC2)c2ccc(Cl)c(Cl)c2)CC1
Yield: 34 %

Procedure:
The title compound was prepared using a similar procedure to that described in example 195 from the title compound of example 199 and 4-fluorobenzoyl chloride. Yield 34%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[C:5]#[N:6].C1COCC1.B.Cl>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][NH2:6])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C#N)cc1Br
Agent: B
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(CN)cc1Br
Temperature: 50 °C

Procedure:
3-Bromo-4-(methyloxy)benzonitrile (2.12 g, 10 mmol), THF (30 mL), and 1.5 M borane in THF (30 mL, 45 mmols) were combined and stirred under argon at reflux, Then additional 1.5 M borane in THF (30 mL, 45 mmols) was added and refluxing was continued. THF (30 mL), and 1.5 M borane in THF (30 mL, 45 mmols) was again added and the mixture refluxed for a total of ten days to drive the reaction to completion. Reaction worked up by the cautious addition of ethanol followed by 1N HCl until the pH was 2. The mixture was then heated to 50° C. for 4 h. The solvents were pumped off and the residue partitioned between EtOAc and water. The aqueous phase was washed 3× with EtOAc, and adjusted to pH 10 by the addition of 2.5 N NaOH. The aqueous phase was extracted 3× with EtOAc. The combined organic phases were dried over anhydrous Na2SO4, filtered and evaporated to give the title compound.
Reaction SMILES: [NH2:1][C:2](=[CH:4][C:5](=[O:9])[CH2:6][CH2:7][CH3:8])[CH3:3].[C:10](OC)(=[O:13])[C:11]#[CH:12]>CN(C)C=O>[C:5]([C:4]1[CH:12]=[CH:11][C:10](=[O:13])[NH:1][C:2]=1[CH3:3])(=[O:9])[CH2:6][CH2:7][CH3:8]
Reactant: CCCC(=O)C=C(C)N
Reactant: C#CC(=O)OC
Solvent: CN(C)C=O
Product: CCCC(=O)c1ccc(=O)[nH]c1C
Temperature: 25 °C

Procedure:
A mixture containing 22.2 g of 3-methyl-5-n-propylisoxazole [Kashima et al., Bull. Chem. Soc. Japan 46, 310-313 (1973)], 500 mg of platinum dioxide and 200 ml of ethanol was hydrogenated under catalytic hydrogenation conditions for ninety minutes, the catalyst was filtered off and the filtrate was concentrated on a rotary evaporator to yield 18.5 g of colorless residue which solidified on cooling. The residue containing 2-amino-2-hepten-4-one was dissolved in 50 ml of dimethylformamide and to the solution was added 14.8 g of methyl 2-propynoate. The resulting reaction solution was allowed to stand at ambient temperature for thirty minutes (exothermic) and then refluxed for three and one half hours. The dimethylformamide was removed on a rotary evaporator. The remaining dark brown liquid was heated in an oil bath at 195°-200° C. for four hours, cooled to room temperature, crystallized from isopropyl alcohol and dried at 80°-85° C. to produce, as pale yellow flakes, 9.4 g of 5-(n-butanoyl)-6-methyl-2(1H)-pyridinone, m.p. 167°-168° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=O)[CH:6]=[CH:7][CH:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CC(=O)Nc2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc(CCNc2ccccc2)c1
Reaction time: 16 h
Yield: 68.9 %

Procedure:
To a solution of 2-(3-methoxyphenyl)-N-phenylacetamide (2.0 g, 8.3 mmol) in anhydrous tetrahydrofuran (30 mL) under nitrogen was added lithium aluminum hydride (1.59 g, 42 mmol) in small portions over a 1 hour period. After 16 hours, the reaction was poured over ice and the crude product extracted with ethyl acetate (2×100 mL). The organic layer was dried over MgSO4, filtered and concentrated to provide the title compound (1.3 g, 69% yield): EI−MS (m/z) 227.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@@H:7]2[N:16]([C:17]([O:19][C@@H:20]3[CH:25]4[CH2:26][CH2:27][N:22]([CH2:23][CH2:24]4)[CH2:21]3)=[O:18])[CH2:15][CH2:14][C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]2=3)=[CH:5][CH:6]=1.[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]\[C:31]([OH:33])=[O:32]>C(OC(C)C)(=O)C>[CH:1]1[CH:6]=[CH:5][C:4]([C@@H:7]2[N:16]([C:17]([O:19][C@@H:20]3[CH:25]4[CH2:24][CH2:23][N:22]([CH2:27][CH2:26]4)[CH2:21]3)=[O:18])[CH2:15][CH2:14][C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]2=3)=[CH:3][CH:2]=1.[C:28]([O-:35])(=[O:34])/[CH:29]=[CH:30]\[C:31]([O-:33])=[O:32]
Reactant: O=C(O)/C=C\C(=O)O
Agent: O=C(O[C@H]1CN2CCC1CC2)N1CCc2ccccc2[C@@H]1c1ccccc1
Solvent: CC(=O)OC(C)C
Product: O=C([O-])/C=C\C(=O)[O-]
Temperature: 45 °C
Reaction time: 8 h

Procedure:
6 g of solifenacin base from example 1 was dissolved in 60 ml of isopropyl acetate; 1.92 g of maleic acid was added and the mixture was heated to 45° C. for 15 minutes. The mixture is kept at room temperature overnight. In these conditions a colorless oil is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:5].Cl[S:22]([OH:25])(=[O:24])=[O:23]>C(O)(C(F)(F)F)=O>[CH3:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]([S:22]([OH:25])(=[O:24])=[O:23])=[CH:9][CH:8]=1)=[O:5]
Reactant: Cc1ccccc1C(=O)Nc1cccc2c1CCCC2
Reactant: O=S(=O)(O)Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccccc1C(=O)Nc1ccc(S(=O)(=O)O)c2c1CCCC2
Temperature: 25 °C
Reaction time: 72 h
Yield: 68 %

Procedure:
To a 0° C. solution of amide (22) in TFA (1 mL per mmol amide), was added chlorosulfonic acid (2 eq) dropwise under nitrogen atmosphere. The temperature was allowed to warm to 25° C. and stirred for 72 hours. The reaction mixture was quenched by pouring into ice water. The desired product was collected via precipitation from either water/methanol, or ethyl acetate/methanol solution, resulting in a white solid (yield 68%). LC/MS (M+H)+ m/z 346, (M−H)− m/z 344. The crude material was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[C:20]3[C:19]4[CH:21]=[C:22]([N+:25]([O-])=O)[CH:23]=[CH:24][C:18]=4[O:17][C:16]=3[C:15]([O:28][CH3:29])=[CH:14][CH:13]=2)=[O:11])=[CH:5][CH:4]=1.O.NN>[Ni].CO.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[C:20]3[C:19]4[CH:21]=[C:22]([NH2:25])[CH:23]=[CH:24][C:18]=4[O:17][C:16]=3[C:15]([O:28][CH3:29])=[CH:14][CH:13]=2)=[O:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(NC(=O)c2ccc(OC)c3oc4ccc([N+](=O)[O-])cc4c23)cc1
Agent: [Ni]
Agent: NN
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: COc1ccc(NC(=O)c2ccc(OC)c3oc4ccc(N)cc4c23)cc1
Yield: 69.6 %

Procedure:
N1-(4-methoxyphenyl)-4-methoxy-8-nitro-dibenzo[b,d]furan-1-carboxamide (140 mg) (from step 1) was reduced using raney nickel (100 mg) in methanol (40 ml) and DMF (10 ml) in the presence of hydrazine hydrate (1.0 ml) under gentle reflux for 1 h. The reaction mixture was filtered through celite and the filterate was concentrated in vaccuo. The residue was triturated with water, to obtain a solid which was filtered dried to give the product as white solid (90 mg).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Br[CH:16]([CH2:21][CH3:22])[C:17]([O:19][CH3:20])=[O:18]>>[CH3:20][O:19][C:17]([CH:16]([O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[CH2:21][CH3:22])=[O:18]
Reactant: CCC(Br)C(=O)OC
Reactant: COC(=O)c1ccc(O)c([N+](=O)[O-])c1
Product: CCC(Oc1ccc(C(=O)OC)cc1[N+](=O)[O-])C(=O)OC

Procedure:
Using methyl 4-hydroxy-3-nitrobenzoate and methyl 2-bromobutyrate, the title compound was synthesized in a similar manner to Reference Example 1.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[S:8][C:9]3[C:14]([N:15]=2)=[CH:13][CH:12]=[C:11]([O:16][C:17]2[CH:18]=[C:19]([NH:24]C(=O)OC(C)(C)C)[CH:20]=[CH:21][C:22]=2[CH3:23])[N:10]=3)=[O:5])[CH2:3][CH2:2]1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[NH2:24][C:19]1[CH:20]=[CH:21][C:22]([CH3:23])=[C:17]([CH:18]=1)[O:16][C:11]1[N:10]=[C:9]2[S:8][C:7]([NH:6][C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])=[N:15][C:14]2=[CH:13][CH:12]=1
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1Oc1ccc2nc(NC(=O)C3CC3)sc2n1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)sc2n1
Reaction time: 2 h
Yield: 84.7 %

Procedure:
To tert-butyl [3-({2-[(cyclopropylcarbonyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}oxy)-4-methylphenyl]carbamate (0.80 g, 1.82 mmol) produced in Example C46(v) were added anisole (0.5 mL) and trifluoroacetic acid (5.0 mL) at 4° C. to give a solution, and the solution was stirred at the same temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution (80 mL) was added to the obtained oily residue, and the mixture was extracted with ethyl acetate (80 mL)/tetrahydrofuran (8 mL). The organic layer was washed with saturated brine (80 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate), and the obtained solution was concentrated under reduced pressure. The residue was triturated with hexane to give the title compound (525 mg, 85%) as a colorless powder.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][C:10]([S:16][CH3:17])=[C:11]([CH2:13][O:14][CH3:15])[N:12]=1)(C)(C)C.Cl.O1CCOCC1>>[CH3:15][O:14][CH2:13][C:11]1[N:12]=[C:8]([NH2:7])[S:9][C:10]=1[S:16][CH3:17]
Reactant: COCc1nc(NC(=O)OC(C)(C)C)sc1SC
Agent: Cl
Solvent: C1COCCO1
Product: COCc1nc(N)sc1SC
Temperature: 50 °C
Reaction time: 4 h

Procedure:
(4-Methoxymethyl-5-methylsulfanyl-thiazol-2-yl)-carbamic acid tert-butyl ester (380 mg, 1.3 mmol) was dissolved in 4 M HCl/1,4-dioxane (7.2 mL, 28.8 mmol) and stirred at 50° C. for 4 hours. The reaction was concentrated under reduced pressure and the residue was dissolved in ethyl acetate and extracted with a half saturated sodium hydrogen carbonate solution. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound as a yellow solid. (238 mg, 86%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[N:12][C:13]([CH:16]([NH:18][C:19]([CH:21]3[CH2:23][CH2:22]3)=O)[CH3:17])=[CH:14][N:15]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)=O>ClCCCl>[CH:21]1([C:19]2[N:12]3[C:13]([CH:14]=[N:15][C:10]([NH:9][C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)=[N:11]3)=[C:16]([CH3:17])[N:18]=2)[CH2:23][CH2:22]1
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)C3CC3)nn2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COc1ccc(Nc2ncc3c(C)nc(C4CC4)n3n2)cc1
Yield: 54.4 %

Procedure:
Applying the Cyclization Procedure 1, using N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]cyclopropanecarboxamide (Intermediate 62) (103 mg, 0.33 mmol), 1,2-dichloroethane (5 mL) and phosphorus oxychloride (0.25 mL, 2.68 mmol), to afford 7-cyclopropyl-5-methyl-N-[4-(methyloxy)phenyl]imidazo[5,1-f][1,2,4]triazin-2-amine (53 mg) as a yellow solid. MS m/z 296 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=[N:12][CH3:13])=[C:3]1[CH3:14].[BH4-].[Na+]>C(O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][NH:12][CH3:13])=[C:3]1[CH3:14]
Reactant: CN=Cc1c(C)n(C)c2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CNCc1c(C)n(C)c2ccccc12
Temperature: 25 °C
Yield: 68 %

Procedure:
1,2-Dimethyl-3-(methyliminomethyl)-1H-indole was taken up in ethanol (200 mL) and NaBH4 (2.6 g, 68.7 mmole) was added portionwise with stirring at RT (vigorous gas evolution). After 16 h the reaction was concentrated under vacuum, and the residue was basified with aqueous 1.0 N NaOH (200 mL). The mixture was extracted with Et2O (250 mL), and the combined Et2O extracts were washed with brine, dried (Na2SO4) and concentrated. Purification by flash chromatography on silica gel (5-10% (5% NH4OH/MeOH)/CHCl3) gave the title compound (8.47 g, 68%) as an oil which solidified in the freezer: 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J=7.7 Hz, 1H), 7.29 (d, J=8.0 Hz, 1H), 7.19 (t, 1H), 7.12 (t, 1H), 3.93 (s, 2H), 3.69 (s, 3H), 2.49 (s, 3H), 2.45 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=[C:4]([CH2:11]Cl)[CH:3]=1.[C-:13]#[N:14].[Na+].O>CS(C)=O>[Cl:1][C:2]1[C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=[C:4]([CH2:11][C:13]#[N:14])[CH:3]=1
Reactant: ClCc1cc(Cl)c2c(c1)OCO2
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1cc(Cl)c2c(c1)OCO2
Temperature: 40 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
A mixture of 4-chloro-6-(chloromethyl)benzo[d][1,3]dioxole (6.0 g, 29 mmol) and NaCN (1.6 g, 32 mmol) in DMSO (20 mL) was stirred at 40° C. for 1 h and was then poured into water. The mixture was extracted with EtOAc (30 mL×3). The combined organic layers were washed with water and brine, dried over Na2SO4 and evaporated under reduced pressure to afford 2-(7-chlorobenzo[d][1,3]dioxol-5-yl)acetonitrile (3.4 g, 58%). 1H NMR δ 6.81 (s, 1H), 6.71 (s, 1H), 6.07 (s, 2H), 3.64 (s, 2H). 13C-NMR δ149.2, 144.3, 124.4, 122.0, 117.4, 114.3, 107.0, 102.3, 23.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([Cl:23])=[CH:18][CH:19]=2)[N:14]=1.CC(O)C>O>[Cl:23][C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:14]2)=[CH:19][CH:18]=1
Reactant: COc1cccc(C(=O)O)c1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Solvent: CC(C)O
Solvent: O
Product: COc1cccc(C(=O)Nc2ccc3ccc(Cl)nc3n2)c1
Temperature: 4 °C
Yield: 72 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 3-methoxybenzoic acid (12.17 g), N,N'-carbonyldiimidazole (12.9 g) and 2-amino-7-chloro-1,8-naphthyridine (8.9 g). The product produced by precipitation in water (15.5 g; m.p. 176° C.) is dissolved in boiling 2-propanol (500 cc). After 2 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with 2-propanol (3×25 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-(7-chloro-1,8-naphthyridin-2-yl)-3-methoxybenzamide (11.2 g) is produced, m.p. 178° C.