Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=CC2C=CC=CC=2)=[CH:5][N:4]=[C:3]1[N+:15]([O-:17])=[O:16].C[OH:19]>O=[Os](=O)(=O)=O.O>[CH3:1][N:2]1[C:6]([CH:7]=[O:19])=[CH:5][N:4]=[C:3]1[N+:15]([O-:17])=[O:16]
Reactant: CO
Reactant: Cn1c(C=Cc2ccccc2)cnc1[N+](=O)[O-]
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: Cn1c(C=O)cnc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 60 %

Procedure:
To a solution of 0.8 g. of 1-methyl-2-nitro-5-styrylimidazole in 300 ml. of methanol, a solution of 1.6 g. of NaIO4 in 40 ml. of water, and 0.02 g. of OsO4 are added. The mixture is stirred at room temperature for ten hours, then an additional 0.01 g. of OsO4 is added and stirring is carried on for eight hours. The reaction mixture is filtered and evaporated to dryness under vacuum at room temperature. The residue is extracted with ethyl acetate. After concentration of the resulting solution, 0.325 g. of the product are obtained. Yield 60%.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][C@H:5]([NH:15]C(=O)OCC(C)C)[CH2:6][NH:7]C(=O)OCC(C)C.[ClH:24]>>[CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][C@H:5]([NH2:15])[CH2:6][NH2:7].[ClH:24]
Reactant: CC(C)COC(=O)NC[C@H](CCN(C)C)NC(=O)OCC(C)C
Agent: Cl
Product: CN(C)CC[C@H](N)CN

Procedure:
A round bottom flask was charged with (S)-diisobutyl (4-(dimethylamino)butane-1,2-diyl)dicarbamate (0.9 g, 2.7 mmol) and 6 M HCl (50 mL). The reaction mixture was refluxed for 50 h. The acidic solvent was evaporated in vacuum and the hydrochloride salt (S)—N4,N4-dimethylbutane-1,2,4-triamine was obtained as sticky solid (0.607 g). The compound was highly hygroscopic.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:7][CH2:6][NH:5][C:4]1=[O:8].Cl[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:20])=[C:15]([C:17](=[O:19])[CH3:18])[CH:16]=1>CN(C)C=O>[C:17]([C:15]1[CH:16]=[C:11]([CH2:10][N:3]2[CH2:7][CH2:6][NH:5][C:4]2=[O:8])[CH:12]=[CH:13][C:14]=1[OH:20])(=[O:19])[CH3:18]
Reactant: O=C1NCCN1
Reactant: CC(=O)c1cc(CCl)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1cc(CN2CCNC2=O)ccc1O
Reaction time: 0.5 h
Yield: 43.1 %

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 0.80 g, 20.0 mmol) in 15 mL dry dimethylformamide under argon, cooled in an ice-bath was added dropwise a solution of 2-imidazolidone (1.72 g, 20.0 mmol) in 5 mL dimethylformamide. The ice bath was removed, the mixture was stirred 30 minutes and a solution of 5'-chloromethyl-2'-hydroxyacetophenone (1.85 g, 10.0 mmol) in 5 mL dimethylformamide was added dropwise. The mixture was stirred four hours and the product was isolated in the same manner as in the previous example to give a solid. The solid was stirred under 20 mL n-butylchloride, filtered off, and dried in vacuo to give 1.01 g (43%) product as a white solid, mp 131°-133° C.
Reaction SMILES: [CH3:1][C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH2:21][C:22]([OH:24])=[O:23].[OH-].[Na+]>C1COCC1.CO>[NH2:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:10]2[C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:4]3[C:3]([CH2:21][C:22]([OH:24])=[O:23])=[C:2]2[CH3:1])=[CH:17][CH:16]=1
Reactant: Cc1c(CC(=O)O)c2cccnc2n1Cc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)c2cccnc2n1Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
[2-Methyl-1-(4-nitro-benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid: 1M Aqueous NaOH (1.18 ml) is added to a stirring suspension of [2-methyl-1-(4-nitro-benzyl)-1-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester (0.2 g, 0.54 mmol) in 4:1 THF/MeOH (5 ml). The reaction mixture is allowed to stir at room temperature for 4 hours and then the solvent is removed in vacuo. The crude residue is dissolved in 1:1 THF/water and acidified to pH 3-4 using 6M HCl. After stirring for 30 minutes the resulting suspension is filtered and dried in vacuo at 110° C. to yield the titled product as a yellow solid. (MH+ 326)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[O:9]1[CH2:13][CH2:12][C@H:11](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:10]1>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]([C@@H:11]2[CH2:12][CH2:13][O:9][CH2:10]2)[C:4](=[O:8])[CH:3]=1
Reactant: O=c1cc(Br)cc[nH]1
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CCOC2)cc1
Product: O=c1cc(Br)ccn1[C@@H]1CCOC1
Yield: 18 %

Procedure:
The title compound was prepared from 4-bromo-1H-pyridin-2-one and (S)-toluene-4-sulfonic acid tetrahydrofuran-3-yl ester following a procedure analogous to that described for Intermediate 8. Yield: 18% of theory; LC (method 3): tR=2.18 min; Mass spectrum (ESI+): m/z=244/246 (Br) [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:20]=[C:21]([C:25](O)=[O:26])[N:22]([CH3:24])[CH:23]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1.[CH3:35][NH2:36]>C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:20]=[C:21]([C:25]([NH:36][CH3:35])=[O:26])[N:22]([CH3:24])[CH:23]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1
Reactant: CN
Reactant: CC1Cc2ccc(-c3cc(C(=O)O)n(C)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Solvent: C1CCOC1
Product: CNC(=O)c1cc(-c2ccc3c(c2)CN(c2cc(N4CCN(C)CC4)nc(N)n2)C(C)C3)cn1C

Procedure:
The compound was prepared by using procedures analogous to those described for the synthesis of Example 87A, Step 9 starting from 4-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-1-methyl-1H-pyrrole-2-carboxylic acid (Step 2) and methylamine in THF solution (2.0 M). LCMS (M+H)+: m/z=475.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[CH:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([C@@H:19]4[O:24][CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]4)=[CH:15][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[ClH:32].CCOCC>O1CCOCC1>[ClH:32].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[CH:11][N:10]([C:13]3[CH:14]=[CH:15][C:16]([C@@H:19]4[O:24][CH2:23][CH2:22][NH:21][CH2:20]4)=[CH:17][CH:18]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(-n3cnc(-c4ccc(F)cc4)n3)cc2)C1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Fc1ccc(-c2ncn(-c3ccc([C@H]4CNCCO4)cc3)n2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
(S)-tert-butyl 2-(4-(3-(4-fluorophenyl)-1H-1,2,4-triazol-1-yl)phenyl)morpholine-4-carboxylate (201 mg, 0.47 mmol) was dissolved in dioxane (0.5 ml) and a solution of HCl in dioxane (4M, 1.75 ml, 7.1 mmol) was added. The reaction mixture was stirred for 3 h at 60° C. After cooling ether (2 ml) was added and the solid was filtered off. It was washed with ether and dried in vacuo to afford (S)-2-(4-(3-(4-fluorophenyl)-1H-1,2,4-triazol-1-yl)phenyl)morpholine hydrochloride as a white solid (170 mg, 99%). MS (ISP): 325.2 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([CH3:10])=[CH:5][C:3]=1[NH2:4].Cl[C:12](OC(Cl)(Cl)Cl)=[O:13]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([CH3:10])=[CH:5][C:3]=1[N:4]=[C:12]=[O:13]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(N)c(Cl)cc1Cl
Solvent: Cc1ccccc1
Product: Cc1cc(N=C=O)c(Cl)cc1Cl
Yield: 107.9 %

Procedure:
In a manner similar to Kurita, et al., J. Org. Chem., 41, 2070 (1976), incorporated herein by reference, the reaction of 3.43 g (0.0156 mole) of 2,4-dichloro-5-methylaniline and 3.5 g (0.018 mole) of trichloromethyl chloroformate in 50 mL of toluene produced 3.4 g of 2,4-dichloro-5-methylphenyl isocyanate.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[F:10][C:11]1[C:12]([F:24])=[C:13]([F:23])[C:14]([F:22])=[C:15]2[C:20](=O)[O:19][C:17](=[O:18])[C:16]=12>C(O)(=O)C>[F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[N:4]1[C:17](=[O:18])[C:16]2[C:15](=[C:14]([F:22])[C:13]([F:23])=[C:12]([F:24])[C:11]=2[F:10])[C:20]1=[O:19]
Reactant: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Reactant: Nc1ccc(F)cc1F
Solvent: CC(=O)O
Product: O=C1c2c(F)c(F)c(F)c(F)c2C(=O)N1c1ccc(F)cc1F
Yield: 42.3 %

Procedure:
A mixture of about 1 g (about 7.75 mmol) of 2,4-difluoroaniline, about 1.54 g (about 7 mmol) of tetrafluorophthalic anhydride and about 50 mL of glacial acetic acid was refluxed for about 3.5 hours. The solvent was evaporated to dryness under reduced pressure of from about 200 to about 15 mbar. The residue was dissolved in about 75 mL of CH2C12. The solution was washed three times with about 25 mL of about 0.1 M HCl and twice with about 25 mL of water. The residue was then dried with Na2SO4. After removal of the solvent, the residue was recrystallized from ethyl alcohol to yield about 980 mg (about 42%) of 2-(2,4-difluorophenyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3(2H)-dione with a melting point of about 145° to about 146° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[F:13][C:14]1[CH:15]=[C:16]([CH:26]([NH:28][C:29]([C:31]2[N:32]=[C:33](Cl)[O:34][CH:35]=2)=[O:30])[CH3:27])[CH:17]=[C:18]([F:25])[C:19]=1[NH:20][S:21]([CH3:24])(=[O:23])=[O:22].C([O-])([O-])=O.[Cs+].[Cs+]>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>[F:25][C:18]1[CH:17]=[C:16]([CH:26]([NH:28][C:29]([C:31]2[N:32]=[C:33]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=3)[O:34][CH:35]=2)=[O:30])[CH3:27])[CH:15]=[C:14]([F:13])[C:19]=1[NH:20][S:21]([CH3:24])(=[O:23])=[O:22]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: CC(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(=O)c1cccc(-c2nc(C(=O)NC(C)c3cc(F)c(NS(C)(=O)=O)c(F)c3)co2)c1
Yield: 38.2 %

Procedure:
3-Acetylphenylboronic acid (42.6 mg, 0.26 mmol) and 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted using Pd(PPh3)2Cl2 (7 mg, 0.01 mmol), Cs2CO3 (127 mg, 0.39 mmol) as described above to give the title compound (23 mg, 38%) after purification by flash chromatography on silica gel (hexane: EtOAc=1:1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:21]2[S:25][C:24]([C:26]3([O:30]COC)[CH2:29][CH2:28][CH2:27]3)=[N:23][CH:22]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:20]=[CH:19][C:14]4[O:15][CH2:16][CH2:17][O:18][C:13]=4[CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.ClC1C(C2SC(C3(OCOC)CCC3)=NC=2)=C2C=C(C3N=C(C4CCCN(C(OC(C)(C)C)=O)C4)ON=3)NC2=NC=1>>[Cl:1][C:2]1[C:3]([C:21]2[S:25][C:24]([C:26]3([OH:30])[CH2:29][CH2:28][CH2:27]3)=[N:23][CH:22]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:20]=[CH:19][C:14]4[O:15][CH2:16][CH2:17][O:18][C:13]=4[CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4[nH]c(-c5ccc6c(c5)OCCO6)cc34)s2)CCC1
Agent: COCOC1(c2ncc(-c3c(Cl)cnc4[nH]c(-c5noc(C6CCCN(C(=O)OC(C)(C)C)C6)n5)cc34)s2)CCC1
Product: OC1(c2ncc(-c3c(Cl)cnc4[nH]c(-c5ccc6c(c5)OCCO6)cc34)s2)CCC1

Procedure:
The title compound was prepared as described in Example 22E, substituting 1-(5-(5-chloro-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)cyclobutanol (Example 75B) for 1 tert-butyl 3-(3-(5-chloro-4-(2-(1-(methoxymethoxy)cyclobutyl)thiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate (Example 22D). 1H NMR (500 MHz, DMSO-d6) ppm 12.42 (s, 1H) 8.29 (s, 1H) 8.25 (s, 1H) 7.56 (d, 1H) 7.49 (dd, 1H) 6.94 (m, 2H) 6.66 (s, 1H) 4.29 (s, 4H) 2.63 (m, 2H) 2.41 (m, 2H) 1.97 (m, 2H); MS ESI(+) m/z 440.0 [M+H]+.
Reaction SMILES: C1C2NC3C(=CC=CC=3)SC=2C=CC=1.[CH3:15][O:16][CH:17]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=[CH:18]1>>[CH3:15][O:16][C:17]1[CH2:23][CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC1C=CC=CC=C1
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: COC1=CC=CC=CC1

Procedure:
The preferred embodiment of the improved process of this invention involves the use of the above mentioned process modifications of the prior art process, particularly the use of the polymerization inhibitor phenothiazine, with the additional process improvement of heating the 7-methoxycycloheptatriene in the second step of the process to an elevated temperature, e.g., 180° C. at reduced pressure to give a final product 1-methoxycycloheptatriene of increased mole percent yield and purity. More specifically, it has been found that when 7-methoxycycloheptatriene is heated at 180° C. under reduced pressure, a substantial quantity of the order of 80 mole % of 7-isomer is isomerized to 1-methoxycycloheptatriene with complete consumption of the 7-isomer whereas heating at 150° C. (atmosphere pressure), as in the prior art process, yields the 3-methoxycycloheptatriene as a major component with only approximately 12-13 mole % 1-methoxycycloheptatriene product. Subsequent acid catalyzed rearrangement (step 3 of the synthesis) of the product in the preferred process yields a final product containing approximately 92 mole % of the 1-methoxy isomer and a purity of methoxy isomers of 99 mole % versus a yield of 90 mole % 1-methoxy isomer (96% purity of methoxy isomer) obtained when the improved process of this invention utilizes the atmospheric heating at 150° C. of the prior art process.
Reaction SMILES: Br[CH:2]1[C:9]2[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=2[O:7][CH2:6][O:5][C:4]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:3]1=2.[Br:20][CH2:21][CH2:22][OH:23].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Br:20][CH2:21][CH2:22][O:23][CH:2]1[C:9]2[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=2[O:7][CH2:6][O:5][C:4]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:3]1=2
Reactant: Clc1ccc2c(c1)C(Br)c1cc(Cl)ccc1OCO2
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Clc1ccc2c(c1)C(OCCBr)c1cc(Cl)ccc1OCO2
Temperature: 120 °C
Yield: 82.4 %

Procedure:
A mixture of 12-bromo-2,10-dichloro-12H-5,7-dioxa-dibenzo[a,d]cyclooctene (900 mg, 2.5 mmol), 2-bromoethanol (3.75 g, 30 mmol) and potassium carbonate (1.0 g, 7.2 mmol) in dichloromethane (10 mL) was heated at 120 ° C. for 4 h. The reaction mixture was concentrated in vacuo, added water (25 mL) and the product extracted with ethyl acetate (3×25 mL). The combined organic phases were dried (MgSO4), filtered and evaporated to give 832 mg (82%) of 12-(2-bromo-ethoxy)-2,10-dichloro-12H-5,7-dioxa-dibenzo[a,d]cyclooctene.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.[CH3:9][O:10][C:11](=[O:36])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:20](=[O:29])[C:21]#[C:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:13]=1>>[CH3:9][O:10][C:11](=[O:36])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]2[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)/[C:21](=[C:22](\[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Br:1])/[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)/[C:20]2=[O:29])[CH:13]=1
Reactant: Brc1ccccc1I
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)c1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(\c3ccccc3)c3ccccc3Br)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 1-bromo-2-iodobenzene (commercially available) and 3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (CDCl3, 300 MHz) δppm 8.01 (s, 1H), 7.93 (d, 1H), 7.71 (d, 1H), 7.30-7.53 (m, 11H), 7.04-7.09 (m, 2H), 6.62-7.04 (m, 3H), 6.42 (d, 1H), 6.02 (d, 1H), 4.88-5.05 (m, 2H), 3.91 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8]([NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9])=[CH:6][C:5]([Br:16])=[CH:4][N:3]=1.Cl[CH2:18][C:19](=O)[CH3:20]>C(O)C>[Br:16][C:5]1[CH:6]=[C:7]([S:8]([NH:11][C:12]([CH3:13])([CH3:15])[CH3:14])(=[O:10])=[O:9])[C:2]2[N:3]([CH:18]=[C:19]([CH3:20])[N:1]=2)[CH:4]=1
Reactant: CC(=O)CCl
Reactant: CC(C)(C)NS(=O)(=O)c1cc(Br)cnc1N
Solvent: CCO
Product: Cc1cn2cc(Br)cc(S(=O)(=O)NC(C)(C)C)c2n1
Temperature: 80 °C
Reaction time: 48 h
Yield: 65.5 %

Procedure:
To a solution of 2-amino-5-bromo-N-tert-butylpyridine-3-sulfonamide (3.0 g, 9.7 mmol) in ethanol (6 mL) was added chloroacetone (3.0 mL, 48 mmol) and the reaction mixture was stirred at 80° C. for 48 h. The solvents were evaporated under reduced pressure and the residue was purified by flash silica gel column chromatography (5% methanol in DCM) to yield 6-bromo-N-tert-butyl-2-methylimidazo[1,2-a]pyridine-8-sulfonamide (2.2 g, 66%), which was used without further purification. LCMS Method T: retention time 1.33 min; [M+1]=346.64.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][CH2:10][C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]1=2)C.[OH-].[Na+].Cl>C(O)C.O>[CH:17]1[C:12]2[CH2:11][CH2:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=3[N:7]([CH2:6][CH2:5][C:4]([OH:22])=[O:3])[C:13]=2[CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)CCN1c2ccccc2CCc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCN1c2ccccc2CCc2ccccc21
Reaction time: 3.5 h
Yield: 92.5 %

Procedure:
3-(10,11-Dihydro-5H-dibenzo[b,f]azepin-5-yl)propionic acid ethyl ester (1.41 g, 4.77 mmol) was dissolved in ethanol (30 mL) and a solution of sodium hydroxide (0.75 g, 18.8 mmol) in water (5 mL) was added. The mixture was stirred for 3.5 h. 1 N Hydrochloric acid (17 mL) was added and the mixture was extracted with DCM (2×25 mL). The combined organic extracts were washed with brine (50 mL), dried (MgSO4) and the solvent was evaporated to give 1.18 g (92%) of 3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)propionic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[CH2:13][C:12]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[N:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:25](OCC)(=[O:27])[CH3:26].O.N>C(OC(=O)C)(=O)C.[Cl-].[Zn+2].[Cl-]>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14](=[O:15])[CH2:13][C:12]([N:16]([C:25](=[O:27])[CH3:26])[C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[N:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COc1ccc(NC2=NN(c3ccc([N+](=O)[O-])cc3)C(=O)C2)cc1
Reactant: CCOC(C)=O
Agent: N
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(N(C(C)=O)C2=NN(c3ccc([N+](=O)[O-])cc3)C(=O)C2)cc1
Temperature: 5 °C

Procedure:
32.6 g of 1-(4-nitrophenyl)-3-(4-methoxyanilino)-5-oxo-2-pyrazoline was dispersed in 110 g of acetic anhydride and 2.7 g of zinc chloride was added thereto and heated (70° to 80° C) on a steam bath with stirring. The mixture became a uniform solution as the reaction proceeded. After the completion of the reaction, 500 ml of ethyl acetate and 500 ml of water were added the reaction mixture and concentrated aqueous ammonia (28%) was added dropwise thereto under cooling to completely decompose the excess acetic anhydride. The crystals deposited in the ethyl acetate were collected by filtration. The filtrate was sufficiently washed with water and the ethyl acetate solution was concentrated to one-third of its original volume and cooled (5° C) to yield a second amount of crystals which was added to the first crystals obtained. Total yield of the product was 31 g. The melting point was 165° to 167° C.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([O:23][NH:24][C@H:25]([C:30]([NH:32][CH:33]([C:37](=[O:48])[NH:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH3:47])[CH:41]=1)[C:34](O)=[O:35])=[O:31])[CH2:26][CH:27]([CH3:29])[CH3:28])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.ON1C(=O)CCC1=O>O1CCOCC1>[CH2:16]([O:23][N:24]1[CH:25]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:30](=[O:31])[NH:32][CH:33]([C:37](=[O:48])[NH:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH3:47])[CH:41]=2)[C:34]1=[O:35])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1cccc(CNC(=O)C(NC(=O)[C@H](CC(C)C)NOCc2ccccc2)C(=O)O)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: C1COCCO1
Product: COc1cccc(CNC(=O)C2NC(=O)C(CC(C)C)N(OCc3ccccc3)C2=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.7 %

Procedure:
0.41 g of dicyclohexylcarbodiimide was added to 20 ml of a solution of 0.91 g of N-(N-benzyloxyleucyl)-α-[N-(3-methoxybenzyl)]carbamoylglycine and 0.23 g of N-hydroxysuccinimide in anhydrous dioxane. The mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered to remove the insoluble materials. The filtrate was diluted with 50 ml of ethyl acetate. The resulting solution was washed with 1N hydrochloric acid and an aqueous solution saturated with sodium hydrogen carbonate, then dried with anhydrous magnesium sulfate, and subjected to distillation to remove the solvent, to obtain 0.81 g of 1-benzyloxy-6-isobutyl-3-[N-(3-methoxybenzyl)]carbamoylpiperazine-2,5-dione as a mixture of a cis form and a trans form.
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8]O)=[C:6]([F:10])[CH:5]=[CH:4][C:3]=1[OH:11].P(Br)(Br)[Br:13]>C(OCC)C.ClCCl>[Br:13][CH2:8][C:7]1[C:2]([F:1])=[C:3]([OH:11])[CH:4]=[CH:5][C:6]=1[F:10]
Reactant: OCc1c(F)ccc(O)c1F
Reactant: BrP(Br)Br
Solvent: CCOCC
Solvent: ClCCl
Product: Oc1ccc(F)c(CBr)c1F
Reaction time: 0.5 h
Yield: 44 %

Procedure:
To a stirred solution of 2,4-difluoro-3-(hydroxymethyl)phenol (step 1, 410 mg, 256 mmol) in diethyl ether (4 mL) and dichloromethane (1 mL) was added phosphorus tribromide (0.257 mL, 2.71 mmol) at 0° C. The mixture was stirred for 30 min, and then the mixture was poured onto ice-aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (200 mL), and the organic layer washed with water and brine, dried over magnesium sulfate and evaporated to afford 266 mg (47%) of the title compound as a colorless oil, which was used in the next step without purification:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=2)[N:3]=1.[CH3:22][O-:23].[Na+].CO.[Na]>C(OCC)(=O)C.O>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:7]=[C:2]([O:23][CH3:22])[N:3]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=2)[N:5]=1
Reactant: Cc1cccc(-c2nc(Cl)cc(-c3ccccc3F)n2)n1
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: COc1cc(-c2ccccc2F)nc(-c2cccc(C)n2)n1
Reaction time: 1 h

Procedure:
To the mixture of 4-chloro-6-o-fluoro phenyl-2-(6-metyl-2-pyridinyl)pyrimidine (1 g) was added sodium methoxide prepared from methanol (10 ml) and metallic sodium (0.1 g). After the mixture was left to stand at room temperature for 1 hour, water (30 ml) and ethyl acetate (100 ml) were added thereto, and then extracted. After the extract was dried over anhydrous magnesium sulfate, it was concentrated under reduced pressure to obtain 4-o-fluorophenyl-6-methoxy-2-(6-methyl-2-pyridinyl)pyrimidine (0.82 g).
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([C:11]([F:14])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:19])([F:18])[F:17])[S:3]1.[N+:21]([C:24]1[CH:34]=[CH:33][CH:32]=[CH:31][C:25]=1[C:26]([N:28]=[C:29]=[O:30])=[O:27])([O-:23])=[O:22]>C1(C)C=CC=CC=1>[F:14][C:11]([F:12])([F:13])[C:5]1([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:17])([F:18])[F:19])[S:3][C:2]([NH:1][C:29]([NH:28][C:26](=[O:27])[C:25]2[CH:31]=[CH:32][CH:33]=[CH:34][C:24]=2[N+:21]([O-:23])=[O:22])=[O:30])=[N:6]1
Reactant: N=C1NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Reactant: O=C=NC(=O)c1ccccc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1ccccc1[N+](=O)[O-])NC1=NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In toluene (10 ml) was dissolved 2-imino-4,4-bis(trifluoromethyl)-5-(tetrafluoroethylidene)-1,3-thiazolidine (1.0 g), and 2-nitrobenzoylisocyanate (0.4 g) which is a starting compound was added thereto and the mixture was stirred at room temperature for 3 hours.