Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[CH:33]=[C:32]([CH3:34])[NH:31][C:30]=2[CH:35]=O)=[O:28])[CH2:23][CH2:22][CH2:21][CH2:20]1>C(O)C.N1CCCCC1>[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[CH:33]=[C:32]([CH3:34])[NH:31][C:30]=2[CH:35]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[NH:13][C:12]2=[O:18])=[O:28])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Cc1cc(C(=O)NCCN2CCCC2)c(C=O)[nH]1
Reactant: COc1cccc(-c2cccc3c2CC(=O)N3)c1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cccc(-c2cccc3c2C(=Cc2[nH]c(C)cc2C(=O)NCCN2CCCC2)C(=O)N3)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 34 %

Procedure:
To a solution of 4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 2-Formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (64.8 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2-[4-(3-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellow solid (40 mg, 34%).
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][CH2:13][C:14]#[N:15])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:16][N:17]([CH3:34])[C:18]([C:20]1[CH:21]=[N:22][N:23]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:24]=1[CH2:25][CH2:26][CH3:27])=[O:19])=[CH:7]2.[N-:35]=[N+:36]=[N-:37].[Na+].[Cl-].[NH4+].[OH-].[Na+]>CN(C=O)C.O>[Br:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[NH:37][N:36]=[N:35][N:15]=2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:16][N:17]([CH3:34])[C:18]([C:20]1[CH:21]=[N:22][N:23]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:24]=1[CH2:25][CH2:26][CH3:27])=[O:19])=[CH:7]2
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1c(C(=O)N(C)Cc2ccc3c(Br)c(OCC#N)ccc3c2)cnn1-c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1c(C(=O)N(C)Cc2ccc3c(Br)c(OCc4nnn[nH]4)ccc3c2)cnn1-c1ccccc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 33.2 %

Procedure:
A mixture of 1-phenyl-5-propyl-1H-pyrazole-4-carboxylic acid (5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-methyl-amide (0.30 g, 0.58 mmol), prepared in the previous step, sodium azide (0.113 g, 1.74 mmol) and ammonium chloride (0.093 g, 1.74 mmol) in 10 mL of DMF was stirred under nitrogen at 100° C. for 6 h. By TLC the reaction was not complete. Sodium azide (0.113 g, 1.74 mmol) and ammonium chloride (0.093 g, 1.74 mmol) were added and the reaction was stirred under nitrogen at 100° C. for 6.5 h. The reaction was diluted with water, made basic by the addition of 1N NaOH and extracted five times with ethyl acetate. The combined organic extracts were acidified with 1N HCl and the solvent removed under reduced pressure. The residue was diluted with water and the solid that formed was collected by filtration and dried under reduced pressure to give the title compound (0.108 g, 33%) as a tan solid, mp 75-85° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)[C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:4].CCN(CC)CC.S([N:37]=[N+:38]=[N-])(C(F)(F)F)(=O)=O>CO.O.C(Cl)Cl.[O-]S([O-])(=O)=O.[Cu+2]>[N:1]([C@@H:2]([CH2:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)[C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:4])=[N+:37]=[N-:38]
Reactant: [N-]=[N+]=NS(=O)(=O)C(F)(F)F
Reactant: N[C@@H](CC1CCNCC1)C(=O)Nc1cnc2ccccc2c1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: [N-]=[N+]=N[C@@H](CC1CCNCC1)C(=O)Nc1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (2S)-2-amino-3-(piperidin-4-yl)-N-(quinolin-3-yl) propanamide LXXVI in a mixture of methanol (15 mL) and water (5 mL) was added Et3N (0.60 mL, 4.24 mmol) and CuSO4 (20 mg). The mixture was treated at 0° C. with freshly prepared solution of triflic azide (5.9 mmol) in DCM (10 mL). The mixture was stirred at r.t. for 48 h. The solvent was evaporated under reduced pressure and dissolved in EtOAc, washed with satd. aq. NaHCO3, water and dried over Na2SO4. The solvent was removed under vacuum to give crude (2S)-2-azido-3-(piperidin-4-yl)-N-(quinolin-3-yl) propanamide LXXVII (320 mg). ESIMS found for C17H20N6O m/z 325 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:13](=[O:14])[C:12]3[CH:15]([CH3:19])[CH2:16][CH2:17][CH2:18][C:11]=3[C:10]2=[O:20])=[C:4]([F:21])[CH:3]=1.[C:22](=O)([O-])[O-].[K+].[K+].CI>C(C(C)=O)CC>[Cl:1][C:2]1[C:7]([O:8][CH3:22])=[CH:6][C:5]([N:9]2[C:13](=[O:14])[C:12]3[CH:15]([CH3:19])[CH2:16][CH2:17][CH2:18][C:11]=3[C:10]2=[O:20])=[C:4]([F:21])[CH:3]=1
Reactant: CC1CCCC2=C1C(=O)N(c1cc(O)c(Cl)cc1F)C2=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCCC(C)=O
Product: COc1cc(N2C(=O)C3=C(C2=O)C(C)CCC3)c(F)cc1Cl
Temperature: 45 °C
Reaction time: 2 h
Yield: 72.6 %

Procedure:
6.1 g (0.02 mol) of N-(4-chloro-2-fluoro-5-hydroxyphenyl)-3-methyl-3,4,5,6-tetrahydrophthalic acid imide are heated at 80° C. together with 3.0 g (0.022 mol) of potassium carbonate in 50 ml of methyl propyl ketone. After 30 minutes thick salt is precipitated. 1.5 ml (0.024 mol) of methyl iodide are added at 35° C. and the reaction mixture, which is now thinly liquid again, is stirred for 2 hours at 45° C. in order to complete the reaction. The salts are filtered off and the filtrate is concentrated by evaporation and the residue is chromatographed over a small column of silica gel with hexane/ethyl acetate 9:1. After concentration of the main fractions by evaporation there are obtained 4.7 g (73.4%) of the title compound (Compound No. 1.113) of the formula ##STR10## in the form of a clear colourless oil, nD21 =1.412.
Reaction SMILES: [C:1]([NH2:4])(=[S:3])[CH3:2].Br[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)=O.N>C(O)C>[F:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]2[N:4]=[C:1]([CH3:2])[S:3][CH:6]=2)=[CH:10][CH:11]=1
Reactant: CC(N)=S
Reactant: O=C(CBr)c1ccc(F)cc1
Agent: N
Solvent: CCO
Product: Cc1nc(-c2ccc(F)cc2)cs1
Temperature: 70 °C
Yield: 89.9 %

Procedure:
Thioacetamide (1.73 g, 23.03 mmol) was added to a solution of 2-bromo-1-(4-fluorophenyl)ethanone (5.0 g, 23.03 mmol) in ethanol (50 mL) and the reaction was refluxed at 70° C. for 4 h. The reaction mixture was then cooled to room temperature, neutralized to pH 7 with aqueous ammonia solution (20 ml), and extracted with ethyl acetate (200 mL). The combined extracts were washed with water (100 mL), dried over Na2SO4, and concentrated to provide 4-(4-fluorophenyl)-2-methylthiazole (4.0 g, 90%). 1H NMR (400 MHz, DMSO) δ 7.95-8.00 (m, 2H), 7.91 (s, 1H), 7.23-7.29 (m, 2H), 2.71 (s, 3H). MS (ESI) m/z: Calculated for C10H8FNS: 193.04. found: 194.0 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([CH2:13][C:14]2[C:15]([NH2:21])=[N:16][C:17]([NH2:20])=[N:18][CH:19]=2)=[C:7]([O:22][CH3:23])[CH:6]=1)=[O:4].[Na].[CH2:25](O)C>>[CH2:1]([O:2][C:3]([C:5]1[CH:6]=[C:7]([O:22][CH3:23])[C:8]([CH2:13][C:14]2[C:15]([NH2:21])=[N:16][C:17]([NH2:20])=[N:18][CH:19]=2)=[C:9]([O:11][CH3:12])[CH:10]=1)=[O:4])[CH3:25]
Reactant: COC(=O)c1cc(OC)c(Cc2cnc(N)nc2N)c(OC)c1
Reactant: CCO
Agent: [Na]
Product: CCOC(=O)c1cc(OC)c(Cc2cnc(N)nc2N)c(OC)c1

Procedure:
2.0 G. of α-(2,4-diamino-5-pyrimidinyl)-2,6-dimethoxy-p-toluic acid methyl ester were added to a solution of about 100 mg. of sodium metal in 200 ml. of absolute ethanol. The solution was heated at reflux for 48 hours and filtered. The filtrate was concentrated to 1/4 and cooled. The precipitated α-(2,4-diamino-5-pyrimidinyl)-2,6-dimethoxy-p-toluic acid ethyl ester was removed by filtration under vacuum and recrystallized from ethanol, m.p. 201°-202°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:41][CH2:42][CH2:43][F:44]>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:41][CH2:42][CH2:43][F:44])=[CH:22][CH:21]=1)[C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: FCCCI
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(O)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(OCCCF)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To 93 mg (0.20 mmol) of di-tert-butyl (4S)—N-(tert-butoxycarbonyl)-4-(4-hydroxybenzyl)-L-glutamate (Example 1b) in 9 mL N,N-dimethylformamide were added 60.7 mg (0.44 mmol) of powdered potassium carbonate and 45 mg (0.24 mmol) of 1-iodo-3-fluoropropane (ABCR GmbH, Germany) and the resulting suspension was stirred for 5 h at 60° C. and overnight at room temperature. The reaction mixture was than filtered, the solvent evaporated and the residue was taken up in ethyl acetate and water. The organic phase was separated off, washed with water until neutral, dried over sodium sulfate and filtered, and the filtrate was concentrated in vacuo. The crude product obtained in this manner was chromatographed on silica gel using a dichloromethane/methanol gradient, and the appropriate fractions were combined and concentrated.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[F:21][C:22]1[CH:23]=[C:24]([CH:34]=[C:35]([F:37])[CH:36]=1)[CH2:25][NH:26][C:27](=[O:33])[CH:28]([F:32])[C:29](O)=[O:30]>>[F:21][C:22]1[CH:23]=[C:24]([CH:34]=[C:35]([F:37])[CH:36]=1)[CH2:25][NH:26][C:27](=[O:33])[CH:28]([F:32])[C:29]([NH:1][CH:2]1[C:3](=[O:20])[N:4]([CH3:19])[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8]1)=[O:30]
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reactant: O=C(O)C(F)C(=O)NCc1cc(F)cc(F)c1
Product: CN1C(=O)C(NC(=O)C(F)C(=O)NCc2cc(F)cc(F)c2)N=C(c2ccccc2)c2ccccc21

Procedure:
The title compound, MS: m/e=495.3 (M+H+), was prepared in analogy to example 16 from 3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and N-(3,5-difluoro-benzyl)-2-fluoro-malonamic acid.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[CH2:21][NH:22][CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)C.[C:26](Cl)(=[O:28])[CH3:27].C(OC(=O)CC1C=C(C2C=CC(F)=CC=2CN(C(OCC2C=CC=CC=2)=O)CC)C(OC)=CC=1)C.[Li+].[OH-]>C1COCC1>[C:26]([N:22]([CH2:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[C:8]1[C:9]([O:12][CH3:13])=[CH:10][CH:11]=[C:6]([CH2:5][C:4]([OH:25])=[O:3])[CH:7]=1)[CH2:23][CH3:24])(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: CCNCc1cc(F)ccc1-c1cc(CC(=O)OCC)ccc1OC
Agent: CCOC(=O)Cc1ccc(OC)c(-c2ccc(F)cc2CN(CC)C(=O)OCc2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCN(Cc1cc(F)ccc1-c1cc(CC(=O)O)ccc1OC)C(C)=O

Procedure:
{2′-[(Acetyl-ethyl-amino)-methyl]-4′-fluoro-6-methoxy-biphenyl-3-yl}-acetic acid (Compound 1-184) was prepared by reacting (2′-ethylaminomethyl-4′-fluoro-6-methoxy-biphenyl-3-yl)-acetic acid ethyl ester and acetyl chloride according to the procedure described in Example 1, Step 6 and then hydrolyzing the ester with aqueous LiOH in THF at room temperature.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][C:8]=2[CH:16]=1)([O-:3])=[O:2].[Cl:17][S:18](O)(=[O:20])=[O:19]>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:11]3[CH:12]=[C:13]([S:18]([Cl:17])(=[O:20])=[O:19])[CH:14]=[CH:15][C:10]=3[O:9][C:8]=2[CH:16]=1)([O-:3])=[O:2]
Reactant: O=S(=O)(O)Cl
Reactant: O=[N+]([O-])c1ccc2c(c1)oc1ccccc12
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2c(c1)oc1ccc(S(=O)(=O)Cl)cc12
Temperature: 25 °C
Reaction time: 66 h

Procedure:
To a stirred solution of 100 mg of 3-nitrodibenzofuran in 1.7 mL of dichloromethane at −20° C. under a nitrogen atmosphere was added 0.44 mL chlorosulfonic acid in small portions. The reaction mixture was allowed to slowly warm to room temperature and stirred for 66 hours at room temperature. The reaction mixture was poured into ice-cold water, extracted four times with dichloromethane, dried (magnesium sulfate) and concentrated. Purification on silica gel (dichloromethane) yielded 129 mg of 50a: rf=0.73.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]1[S:9][C:10]2[C:16]3[N:17]([C:26]4[CH:36]=[CH:35][C:29]([C:30]([N:32]([CH3:34])[CH3:33])=O)=[CH:28][C:27]=4[Cl:37])[N:18]=[C:19]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:15]=3[CH2:14][CH2:13][C:11]=2[N:12]=1>C1COCC1>[Cl:37][C:27]1[CH:28]=[C:29]([CH2:30][N:32]([CH3:34])[CH3:33])[CH:35]=[CH:36][C:26]=1[N:17]1[C:16]2[C:10]3[S:9][C:8]([NH2:7])=[N:12][C:11]=3[CH2:13][CH2:14][C:15]=2[C:19]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[N:18]1
Reactant: CN(C)C(=O)c1ccc(-n2nc(-c3cccnc3)c3c2-c2sc(N)nc2CC3)c(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)Cc1ccc(-n2nc(-c3cccnc3)c3c2-c2sc(N)nc2CC3)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under an argon atmosphere at −78° C. a solution of lithium aluminium hydride (1 M in THF, 3 mL) is added to a solution of 4-(7-amino-3-pyridin-3-yl-4,5-dihydro-pyrazolo[4,3-g]benzothiazol-1-yl)-3-chloro-N,N-dimethylbenzamide (PCT/EP05055021) (0.46 g, 1 mmol) in 25 mL dry THF. After 5 min the cooling bath is removed and the reaction mixture is heated to RT. Then while cooling, 1 mL of water is added dropwise and the mixture is stirred for 30 min. The precipitate is filtered and the filtrate evaporated down.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH3:12])=[CH:5][C:4]=1[NH:13][C:14]([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[O:15].[OH:21]O>>[CH3:1][S:2]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH3:12])=[CH:5][C:4]=1[NH:13][C:14]([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[O:15])=[O:21]
Reactant: CCN(CC)C(=O)Nc1cc(OC)c(OC)cc1SC
Reactant: OO
Product: CCN(CC)C(=O)Nc1cc(OC)c(OC)cc1S(C)=O

Procedure:
The resulting product, N-[2-methylthio-4,5-dimethoxyphenyl]-N',N'-diethylurea was oxidized with hydrogen peroxide to yield N-[2-methylsulfinyl-4,5-dimethoxyphenyl]-N',N'-diethylurea. Reaction of this compound with O-mesitylenesulfonylhydroxylamine yielded S-methyl-S-[2-diethylaminocarbonylamino-4,5-dimethoxyphenyl]sulfoximine. Heating the sulfoximine yielded 6,7-dimethoxy-1-methyl-1H-1,2,4-benzothiadiazine-3(4H)-one-1-oxide melting at 333°-335° C. Total yield was 59 percent based on 2-methylthiol-4,5-dimethoxyaniline.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][CH2:14][C:15]3=[O:20])=[N:8][CH:9]=1)([O-:3])=[O:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:32](OC(C)=C)(=[O:34])[CH3:33]>>[C:32]([O:20][C:15]1[C:16]2[C:12](=[C:11]([O:10][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=3)[CH:19]=[CH:18][CH:17]=2)[CH2:13][CH:14]=1)(=[O:34])[CH3:33]
Reactant: O=C1CCc2c(Oc3ccc([N+](=O)[O-])cn3)cccc21
Reactant: C=C(C)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(=O)OC1=CCc2c(Oc3ccc([N+](=O)[O-])cn3)cccc21
Temperature: 80 °C
Reaction time: 7.5 h

Procedure:
To 5.00 g of 4-[(5-nitro-2-piridinyl)oxy]-1-indanone, 10 ml of isopropenyl acetate and 70 mg of p-toluenesulfonic acid were added and the mixture was stirred at 80° C. After 7.5 hours, the reaction solution was concentrated under reduced pressure. To the resulting residue, ethyl acetate was added and the solution was washed in turn with a saturated sodium hydrogencarbonate solution and a saturated sodium chloride solution. The solution extracted with ethyl acetate was dried over anhydrous magnesium sulfate and the solvent was distilled off. The resulting residue was washed with isopropyl ether in a hot state to obtain 4.70 g of the titled compound.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C[Si](Cl)(C)C.[CH2:16]([C:19]1[CH:40]=[C:39]([O:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:38]=[CH:37][C:20]=1[O:21][CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:28][CH:27]=1)[CH2:17][CH3:18].[Br:48]N1C(=O)CCC1=O>C1COCC1>[Br:48][CH:32]([C:29]1[CH:30]=[CH:31][C:26]([O:25][CH2:24][CH2:23][CH2:22][O:21][C:20]2[CH:37]=[CH:38][C:39]([O:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:40][C:19]=2[CH2:16][CH2:17][CH3:18])=[CH:27][CH:28]=1)[C:33]([O:35][CH3:36])=[O:34]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCc1cc(Oc2ccccc2)ccc1OCCCOc1ccc(CC(=O)OC)cc1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCc1cc(Oc2ccccc2)ccc1OCCCOc1ccc(C(Br)C(=O)OC)cc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of lithium bis(trimethylsilyl)amide (27.36 mL, 27.36 mmol) in dry THF (80 mL) was treated with trimethylsilyl chloride (5.94 mL, 46.76 mmol) at -78° C. To this mixture was added dropwise a solution of the product of Step B (10.80 g, 24.87 mmol) in THF (15 mL). The reaction mixture was stirred at -78° C. for 2 h. N-bromosuccinimide (4.65 g, 26.12 mmol) was added, and the mixture was allowed to warm to room temperature overnight. THF was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was washed once with water, then dried over sodium sulfate. The organic layer was filtered and evaporated to provide methyl α-bromo-4-(3-(2-propyl-4-phenoxy-phenoxy)propoxy)phenylacetate as an oil.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[CH:4]([C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)=O>>[CH2:1]([NH:3][CH2:4][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)[CH3:2]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CCN
Product: CCNCc1ccc(C#N)cc1

Procedure:
prepared by reaction of ethylamine with 4-formyl-benzonitrile
Reaction SMILES: [C:1]([Si:5]([CH3:38])([CH3:37])[O:6][C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:36]=[CH:35][C:19]2[NH:20][C:21]([CH2:23][O:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[N:22][C:18]=2[CH:17]=1)=[CH:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:44]>C(Cl)Cl>[C:1]([Si:5]([CH3:38])([CH3:37])[O:6][C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[CH:36]=[CH:35][C:19]3[NH:20][C:21]([CH2:23][O:24][C:25]4[CH:26]=[CH:27][C:28]([C:31]([F:32])([F:34])[F:33])=[CH:29][CH:30]=4)=[N:22][C:18]=3[CH:17]=2)[CH:8]([CH3:9])[O:44]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC=C(O[Si](C)(C)C(C)(C)C)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Solvent: ClCCl
Product: CC1OC1(O[Si](C)(C)C(C)(C)C)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Reaction time: 2 h
Yield: 93.4 %

Procedure:
A solution of 5-{2-[1-(tert-butyl-dimethyl-silanyloxy)-propenyl]-phenyl}-2-(4-trifluoromethyl-phenoxymethyl)-1H-benzoimidazole (0.052 g, 0.0965 mmol) in CH2Cl2 (4 mL) at rt was added m-chloroperoxybenzoic acid (77% max, 0.035 g, 0.154 mmol). After stirring for 2 hours, the reaction mixture was concentrated, and the residue was purified by chromatography (silica, hexanes: EtOAc, 2:1) to afford the title compound as a yellow oil (0.050 g, 94%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C:4]([N:19]=C(C1C=CC=CC=1)C1C=CC=CC=1)([CH2:12][C:13]1[N:14]([CH3:18])[CH:15]=[N:16][CH:17]=1)[CH2:5][C:6]1[N:7]([CH3:11])[CH:8]=[N:9][CH:10]=1.Cl>C1COCC1>[CH3:1][O:2][C:3](=[O:33])[C:4]([NH2:19])([CH2:12][C:13]1[N:14]([CH3:18])[CH:15]=[N:16][CH:17]=1)[CH2:5][C:6]1[N:7]([CH3:11])[CH:8]=[N:9][CH:10]=1
Reactant: COC(=O)C(Cc1cncn1C)(Cc1cncn1C)N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)C(N)(Cc1cncn1C)Cc1cncn1C

Procedure:
Using the same procedure as described in Example 53B, the title compound of 56A (960 mg, 2.17 mmol) was treated with HCl in THF to afford the title compound of 56B, 652 mg (77% yield).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]([C:23]([C@@H:25]1[CH2:29][CH2:28][CH2:27][N:26]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:24])[NH2:22]>>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:22][NH:21][C:23]([C@@H:25]1[CH2:29][CH2:28][CH2:27][N:26]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:24])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NN
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Yield: 80.7 %

Procedure:
Following a procedure analogous to Example 27, from the carboxylic acid (6b, 390 mg, 1.41 mmol) of Example 9 or 16 and (S)-tert-butyl 2-(hydrazinecarbonyl)pyrrolidine-1-carboxylate (573 mg) described in Reference Example 6, 555 mg of the title compound was afforded (yield 80.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:11]C1C2C(=CC=CC=2)NC=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cc1c[nH]c2ccccc12
Reactant: Clc1ccc2cc[nH]c2c1
Product: Cn1ccc2ccc(Cl)cc21
Yield: 100 %

Procedure:
According to the procedure of Preparation 13 (a), except substituting 6-chloroindole for the 3-methylindole, the title compound (2.2 g, 100%) was obtained as a white solid: MS (ES) m/e 166.2.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]3[S:15](=[O:19])(=[O:18])[CH2:16][CH2:17][C:13]=3[N:12](C(O[C@@H]3C[C@H](C)CC[C@H]3C(C)(C3C=CC=CC=3)C)=O)[C:11]3[CH2:39][O:40][CH2:41][C:42](=[O:43])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8].C[O-].[Na+]>CO.C(Cl)Cl.CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]3[S:15](=[O:18])(=[O:19])[CH2:16][CH2:17][C:13]=3[NH:12][C:11]3[CH2:39][O:40][CH2:41][C:42](=[O:43])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C[C@@H]1CC[C@@H](C(C)(C)c2ccccc2)[C@H](OC(=O)N2C3=C(C(=O)COC3)C(c3ccc(F)c(Br)c3)C3=C2CCS3(=O)=O)C1
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C1COCC2=C1C(c1ccc(F)c(Br)c1)C1=C(CCS1(=O)=O)N2
Reaction time: 16 h
Yield: 62.1 %

Procedure:
A solution of Example 12A (0.98 g, 1.4 mmol) in methanol/methylene chloride (40 mL/10 mL) was degassed with nitrogen, treated with of 25% sodium methoxide in methanol (30 drops), stirred for 16 hours, filtered through a 45 mm syringe filter and concentrated to a volume of 5 mL of methanol. The solid which had precipitated was collected by filtration, washed with methanol and dried under vacuum for 16 hours to provide the title compound (0.36 g).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([F:11])[CH:5]=1.Br[CH2:13][CH2:14][CH2:15][CH3:16]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:13][CH2:14][CH2:15][CH3:16])=[C:6]([F:11])[CH:5]=1
Reactant: Oc1ccc(Br)cc1F
Reactant: CCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: CCCCOc1ccc(Br)cc1F
Temperature: 80 °C
Reaction time: 6 h
Yield: 98.6 %

Procedure:
Sodium hydroxide (20.2 g) was added to a water (400 ml) solution of 4-bromo-2-fluorophenol (T-7) (76.4 g), bromobutane (65.8 g) and tetrabutylammonium bromide (TBAB) (6.44 g), and the mixture was heated with stirring at 80° C. for 6 hours under an atmosphere of nitrogen. After the completion of the reaction, the reaction mixture was extracted with heptane, and the organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure to leave a black oil. The oil was purified by distillation to give 4-bromo-1-butoxy-2-fluorobenzene (T-8) as a colorless oil (97.5 g) in 98% yield.