Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1([F:22])[CH2:12][CH2:11][CH:10]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH2:9]1.[CH3:23][O:24][C:25](=[O:36])[C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>O1CCOCC1>[CH3:23][O:24][C:25](=[O:36])[C:26]1[CH:27]=[CH:28][C:29]([S:32]([N:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:13]([CH:10]3[CH2:11][CH2:12][C:8]([F:7])([F:22])[CH2:9]3)=[CH:14]2)(=[O:33])=[O:34])=[CH:30][CH:31]=1
Reactant: FC1(F)CCC(c2c[nH]c3ccccc23)C1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(S(=O)(=O)n2cc(C3CCC(F)(F)C3)c3ccccc32)cc1
Reaction time: 0.08 h
Yield: 223.5 %

Procedure:
Add potassium tertbutoxide (368 mg, 3.28 mmol, 1.1 eq) to a 3 ml dioxane solution of 3-(3,3-difluoro-cyclopentyl)-1H-indole (660 mg, 2.98 mmol, 1.0 eq) under N2. Stir solution for 5 minutes. Add 4-Chlorosulfonyl-benzoic acid methyl ester 117 mg, 0.497 mmol, 1.1 eq). Stir reaction for 4 hours at room temperature. Strip reaction of solvent and purify by silica gel chromatography to give 4-[3-(3,3-Difluoro-cyclopentyl)-indole-1-sulfonyl]-benzoic acid methyl ester (466 mg, 37% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:15][S:16]([C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([F:29])[CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[CH3:31]I>>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([S:16]([C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([F:29])[CH:20]=3)(=[O:18])=[O:17])[CH3:31])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ncc2c1CCC[C@H]2NS(=O)(=O)c1cc(F)cc(C(F)(F)F)c1
Reactant: CI
Product: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1cc(F)cc(C(F)(F)F)c1

Procedure:
Starting with [(R)-4-(3-fluoro-5-trifluoromethyl-benzene-sulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (prepared by a method described above for example 1-1) and methyl iodide, using the method analogous to the one described for example 2-1, {(R)-4-[(3-fluoro-5-trifluoro-methyl-benzenesulfonyl)-methyl-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester (500 mg, 94%) was prepared as a white solid. LC-MS cald. for C19H21F4N3O4S 463, obsd. (ESI+) [(M+H)+] 464.
Reaction SMILES: Br.[N:2]1([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[S:15][CH:16]=[C:17]([C:19]4[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=4)[N:18]=3)[CH2:10][CH2:9]2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH3:28][O:29][C:30]([C:32]1([NH2:38])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:31]>>[CH3:28][O:29][C:30]([C:32]1([NH:38][C:23]([C:22]2[CH:26]=[CH:27][C:19]([C:17]3[N:18]=[C:14]([N:11]4[CH2:10][CH2:9][N:8]([N:2]5[CH2:3][CH2:4][O:5][CH2:6][CH2:7]5)[CH2:13][CH2:12]4)[S:15][CH:16]=3)=[CH:20][CH:21]=2)=[O:24])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1)=[O:31]
Reactant: COC(=O)C1(N)CCCCC1
Reactant: O=C(O)c1ccc(-c2csc(N3CCN(N4CCOCC4)CC3)n2)cc1
Agent: Br
Product: COC(=O)C1(NC(=O)c2ccc(-c3csc(N4CCN(N5CCOCC5)CC4)n3)cc2)CCCCC1

Procedure:
4.50 g (9.90 mmol) of 4-[2-[4-(4-morpholinyl)-1-piperazinyl]-4-thiazolyl]benzoic acid hydrobromide was used instead of 4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]benzoic acid hydrobromide and 1.57 g (9.90 mmol) of 1-aminocyclohexanecarboxylic acid methyl ester was used instead of 1-aminocyclohexanecarboxylic acid phenylmethyl ester in the process according to Reference example 201 to obtain 5.08 g (quantitative) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([NH2:13])=[CH:11][C:10]([CH:14]([CH3:16])[CH3:15])=[N:9]2)[CH:5]=[N:6][CH:7]=1.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([NH:13][C:18](=[O:19])[O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:11][C:10]([CH:14]([CH3:16])[CH3:15])=[N:9]2)[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)c1cc(N)n(-c2cncc(F)c2)n1
Reactant: O=C(Cl)Oc1ccccc1
Product: CC(C)c1cc(NC(=O)Oc2ccccc2)n(-c2cncc(F)c2)n1
Yield: 35 %

Procedure:
Following the procedure for Example 282A Step 2, 1-(5-fluoropyridin-3-yl)-3-isopropyl-1H-pyrazol-5-amine was treated with phenyl chloroformate. Purification using silica gel chromatography eluting with MeOH/DCM (0-10%) afforded phenyl 1-(5-fluoropyridin-3-yl)-3-isopropyl-1H-pyrazol-5-ylcarbamate (235 mg, 35% yield) for steps B and C. 1H NMR (300 MHz, DMSO d6) δ 1.25 (s, 6H), 2.93 (m, 1H), 6.40 (s, 1H), 7.15 (bs, 2H), 7.29 (m, 2H), 7.42 (m, 3H), 8.00 (m, 1H), 8.65 (s, 1H), 8.72 (s, 1H), 10.32 (s, 1H); LC-MS (ESI) m/z 341 (M+H)+
Reaction SMILES: [H-].[Na+].[Si:3]([O:20][CH2:21][C@H:22]1[CH2:26][O:25][C:24](=[O:27])[NH:23]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:28][C:29]1[N:34]=[C:33](F)[CH:32]=[CH:31][N:30]=1>CN(C=O)C>[Si:3]([O:20][CH2:21][C@H:22]1[CH2:26][O:25][C:24](=[O:27])[N:23]1[C:31]1[CH:32]=[CH:33][N:34]=[C:29]([F:28])[N:30]=1)([C:16]([CH3:17])([CH3:18])[CH3:19])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)[Si](OC[C@H]1COC(=O)N1)(c1ccccc1)c1ccccc1
Reactant: Fc1ccnc(F)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OC[C@H]1COC(=O)N1c1ccnc(F)n1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 72.8 %

Procedure:
Sodium hydride (34 mg, 0.84 mmol, 1.5 equiv) was carefully added to a solution of (R)-4-(((tert-butyldiphenylsilyl)oxy)methyl)oxazolidin-2-one (200 mg, 0.563 mmol) in DMF (2.8 mL). The mixture was stirred at room temperature for 20 minutes and then 2,4-difluoropyrimidine (0.072 mL, 0.84 mmol, 1.5 equiv) was added (bubbling). The yellow suspension was stirred for minutes and the reaction was then carefully quenched with saturated aqueous ammonium chloride (5 mL). Water (20 mL) was added and the mixture was extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (20 mL), dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 30%) provided (R)-4-(((tert-butyldiphenylsilyl)oxy)methyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (0.185 g, sticky colorless oil) in 73% yield. 1H NMR (400 MHz, CDCl3) δ 8.44 (dd, J=5.8, 2.2 Hz, 1H), 8.12 (dd, J=5.8, 3.4 Hz, 1H), 7.58 (m, 2H), 7.48-7.32 (m, 6H), 7.23 (m, 2H), 4.80 (m, 1H), 4.65 (dd, J=8.6, 3.0 Hz, 1H), 4.55 (m, 1H), 4.18 (dd, J=11.1, 3.5 Hz, 1H), 3.83 (dd, J=11.1, 2.1 Hz, 1H), 1.04 (s, 9H). MS m/z 452.3 (M+H)+; Rt-1.15 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]2[S:13][C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)=[N:11][C:10]2=[O:21])=[CH:4][C:3]=1[O:22][CH3:23].CC#N.[CH2:27](Cl)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O>[CH2:27]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]2[S:13][C:12]([N:14]3[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]3)=[N:11][C:10]2=[O:21])=[CH:4][C:3]=1[O:22][CH3:23])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COc1cc(C=C2SC(N3CCN(C)CC3)=NC2=O)ccc1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc(C=C2SC(N3CCN(C)CC3)=NC2=O)ccc1OCc1ccccc1
Temperature: 70 °C
Reaction time: 6 h
Yield: 28 %

Procedure:
To a N2-purged flask was added ′5-[1-(4-Hydroxy-3-methoxy-phenyl)-methylidene]-2-(4-methyl-piperazin-1-yl)thiazol-4-one (57 mg, 0.17 mmol), MeCN (5 mL), benzyl chloride (30 μL, 1.5 equiv), and K2CO3 (70 mg, 3 equiv). The reaction mixture was stirred at 70° C. for 6 h. The reaction mixture was diluted with EtOAc (100 mL), and the excess K2CO3 was removed by filtration through a fritted glass funnel. The product solution was washed with aq NH4Cl (50 mL×2) and H2O (50 mL). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was chromatographed (SiO2, DCM/MeOH 100:0 to 92:8) to provide pure title compound (20 mg, 28% yield). 1H NMR (DMSO-d6) δ 7.66 (1H, s), 7.44-7.52 (5H, m), 7.29 (1H, s), 7.23-724 (2H, m), 5.22 (2H, s), 3.96 (2H, t, J=4.6 Hz), 3.89 (3H, s), 3.70 (2H, t, J=4.6 Hz), 2.48-2.52 (4H, m), 2.29 (3H, s); MS (ESI) 424 (MH+).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH:19]=O)[CH:15]=[CH:14]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[I:21][C:22]1[CH:27]=[CH:26][NH:25]/[C:24](=[N:28]\[NH2:29])/[CH:23]=1>C(Cl)Cl>[Si:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16](/[CH:19]=[N:29]/[N:28]=[C:24]1\[NH:25][CH:26]=[CH:27][C:22]([I:21])=[CH:23]\1)[CH:15]=[CH:14]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: N/N=c1/cc(I)cc[nH]1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2ccc(C=O)nc12
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cccc2ccc(/C=N/N=c3/cc(I)cc[nH]3)nc12
Reaction time: 1 h

Procedure:
To 8-(tert-butyldimethylsilyloxy)quinoline-2-carbaldehyde (3.21 g, 11.2 mmol) in DCM (30 mL) was added (Z)-1-(4-iodopyridin-2(1H)-ylidene)hydrazine (3.15 g, 13.4 mmol). The reaction was stirred for 1 hour, affording a yellow precipitate, which was collected by filtration and used without further purification in the next step.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[NH2:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12](=O)[C:13]([O-:15])=[O:14])[N:7]=1.[K+]>CO>[NH2:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12](=[N:4][O:3][CH3:2])[C:13]([OH:15])=[O:14])[N:7]=1
Reactant: Nc1ccnc(C(=O)C(=O)[O-])n1
Reactant: CON
Agent: Cl
Agent: [K+]
Solvent: CO
Product: CON=C(C(=O)O)c1nccc(N)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of O-methylhydroxylamine hydrochloride (0.25 g.) in methanol (6 ml.) was added a mixture of potassium 2-(4-aminopyrimidin-2-yl)glyoxylate and its monohydrate with stirring at ambient temperature, and the mixture was stirred for 4 hours. The reaction mixture was allowed to stand overnight at ambient temperature, filtered, and the filtered precipitates were washed with ethanol. After the filtrate and washings were combined together, the solvents were distilled off. The resultant oily substance was pulverized in acetone (15 ml.) and collected by filtration. Thus obtained powder was washed successively with acetone and diethyl ether and then dried to give a pale brown powder of 2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetic acid (syn isomer) (290 mg.).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1.Cl[CH2:12][C:13]1[C:14]([CH3:19])=[N:15][O:16][C:17]=1[CH3:18].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.Cl>[CH3:19][C:14]1[C:13]([CH2:12][N:1]2[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]2)=[C:17]([CH3:18])[O:16][N:15]=1
Reactant: Cc1noc(C)c1CCl
Reactant: CCOC(=O)c1cn[nH]c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(Cc2c(C)noc2C)c1
Temperature: 25 °C
Yield: 80.2 %

Procedure:
Ethyl 1H-pyrazole-4-carboxylate (4.2 g, 30 mmol), 4-(chloromethyl)-3,5-dimethylisoxazole (5.1 g, 35 mmol), and cesium carbonate (9.8 g, 30 mmol), in DMF (50 mL), were stirred at 80° C. for 12 hours. The reaction was cooled to ambient temperature, diluted with 0.1 N HCl (150 mL) and extracted with ethyl acetate (3×, 75 mL). The combined organic extracts were dried over sodium sulfate and concentrated on the rotovap. The solid product was triturated with ethyl acetate/hexanes (1/9) and collected by filtration to afford ethyl 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazole-4-carboxylate (6 g, 80%) as a white solid. 1H NMR (CDCl3, 400 MHz): δ1.34 (t, J=7.2 Hz, 3H), 2.19 (s, 3H), 2.43 (s, 3H), 4.29 (q, J=7.2 Hz, 2H), 5.06 (s, 2H), 7.77 (s, 1H), 7.91 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[N:4][CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.Cl>C(O)C.O.[Fe]>[Cl:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:15])([F:16])[F:14])=[N:4][CH:5]=[C:6]([NH2:8])[CH:7]=1
Reactant: O=[N+]([O-])c1cnc(OCC(F)(F)F)c(Cl)c1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1cnc(OCC(F)(F)F)c(Cl)c1
Yield: 65.1 %

Procedure:
3-Chloro-5-nitro-2-(2,2,2-trifluoroethoxy)-pyridine (5.39 g) obtained in Step A was reduced with iron (13.6 g) and concentrated hydrochloric acid (0.73 ml) in ethanol (6.5 ml) and water (1 ml) at 80° C. for 1 hour. Filtration over Celite® and evaporation of the solvent followed by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 9:1) afforded 3-chloro-5-amino-2-(2,2,2-trifluoro-ethoxy)-pyridine (3.1 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].BrN1C(=O)CCC1=O.[N:21]#[C:22][NH2:23].[Na]>CN(C)C=O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11](=[N:23][C:22]#[N:21])[O-:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(N=O)cc1
Reactant: N#CN
Agent: O=C1CCC(=O)N1Br
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc([N+]([O-])=NC#N)cc1
Reaction time: 0.75 h
Yield: 89.9 %

Procedure:
4-(N-acetylamino)nitrosobenzene (15.0 g, 91.5 mmol) and N-bromosuccinimide (16.3, 91.6 mmol) were dissolved in dimethylformamide (150 ml). At ambient temperature, the solution was treated with monosodium cyanamide (9.14 g, 142.8 mmol). After 45 minutes, the brown solution was treated with N-bromosuccinimide (6.4 g, 36 mmol) and stirred for an additional 11/2 hours. The mixture was poured on ice-water (500 ml) and left overnight. The yellow crystallised precipitate was collected and dried to give 16.8 g 4-(N-acetylamino)phenyl-ONN-azoxycyanide as a yellow powder, m.pt. 240°-242° C. (Yield: 90% of theoretical).
Reaction SMILES: [CH3:1][Mg]I.[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[N:13][C:14]([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[O:27])[CH:24]=3)[C:19]([CH:34]=[O:35])=[CH:18]2)=[N:15][CH:16]=1>C1COCC1>[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[N:15][C:14]([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[O:27])[CH:24]=3)[C:19]([CH:34]([OH:35])[CH3:1])=[CH:18]2)=[N:13][CH:12]=1
Reactant: O=Cc1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Reactant: C[Mg]I
Solvent: C1CCOC1
Product: CC(O)c1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Reaction time: 2 h

Procedure:
Methyl magnesium iodide (3M solution in diethyl ether, 0.17 mL, 0.522 mmol, 1.5 eq) was added at −70° C. to a stirred solution of 28a) (150 mg, 0.348 mmol, 1.0 eq) in dry THF (10 mL) and stirring was continued for 2 h at −50° C. The reaction mixture was quenched with ammonium chloride solution, diluted with water (20 mL), and extracted with ethyl acetate (2×20 mL). The organic layers were washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by preparative TLC using 70% ethyl acetate in petrolether as eluent. White solid. Yield: 70 mg (45% of theory). Melting range: 209-213° C. HPLC (method 1): Rt=10.09 min. Mass spectroscopy: m/z: [M+H]+=447.0.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][N:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C(CC)CNC1N=CC=CC=1C(OCC)=[O:27])C>>[CH2:1]([N:8]1[C:9]2[CH:10]=[CH:11][N:12]=[CH:13][C:14]=2[C:15](=[O:16])[O:17][C:18]1=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cnccc1NCc1ccccc1
Reactant: CCOC(=O)c1cccnc1NCC(CC)CC
Product: O=c1oc(=O)n(Cc2ccccc2)c2ccncc12

Procedure:
The title compound is prepared according to the procedure of Example 3B substituting the product of Example 180A for the product of Example 3A.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1CCC(O)=O)([O-:3])=[O:2].[Na:18].C(=O)([O-])O.[Na+].NC1C=C(N)C=CC=1[O:27][CH:28]([CH3:32])[C:29]([OH:31])=[O:30]>>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:27][CH:28]([CH3:32])[C:29]([OH:31])=[O:30])([O-:3])=[O:2].[Na:18]
Reactant: CC(Oc1ccc(N)cc1N)C(=O)O
Reactant: O=C(O)CCc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Product: CC(Oc1ccc([N+](=O)[O-])cc1[N+](=O)[O-])C(=O)O

Procedure:
The 2-(2,4-dinitrophenoxy)-propionic acid from step (a) was converted into the sodium salt with sodium hydrogen carbonate and reduced in aqueous solution, using procedures analogous to those set forth in A, and the sodium salt was then isolated. Five grams of 2-(2,4-dinitrophenoxy)-propionic acid yielded 2.4 gm of sodium salt of 2-(2,4-diaminophenoxy)-propionic acid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:19]([CH2:20][O:21][C:22]3[C:27]([F:28])=[CH:26][C:25]([CH2:29][CH2:30][C:31](OCC)=[O:32])=[C:24]([F:36])[C:23]=3[F:37])=[C:18]([C:38]([F:41])([F:40])[F:39])[S:17][N:16]=2)=[CH:11][CH:10]=1)[CH3:8]>>[CH2:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:19]([CH2:20][O:21][C:22]3[C:27]([F:28])=[CH:26][C:25]([CH2:29][CH2:30][CH2:31][OH:32])=[C:24]([F:36])[C:23]=3[F:37])=[C:18]([C:38]([F:39])([F:40])[F:41])[S:17][N:16]=2)=[CH:11][CH:10]=1)[CH3:8]
Reactant: CCOC(=O)CCc1cc(F)c(OCc2c(-c3ccc(CC)cc3)nsc2C(F)(F)F)c(F)c1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCc1ccc(-c2nsc(C(F)(F)F)c2COc2c(F)cc(CCCO)c(F)c2F)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 111 by LAH reduction of ethyl 3-(4-((3-(4-ethylphenyl)-5-(trifluoromethyl)isothiazol-4-yl)methoxy)-2,3,5-trifluorophenyl)propanoate to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J=7.5 Hz, 2H), 7.84 (d, J=7.8 Hz, 2H), 6.76 (m, 1H), 3.70 (t, J=8.5 Hz, 2H), 2.74 (m, 4H), 1.85 (m, 2H), 1.52 (br, s, 1H), 1.27 (t, J=9.5 Hz, 3H).
Reaction SMILES: CC([N:5]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([C:16]#[C:17]C(O)(C)C)[C:10]=1[CH3:22])[C:6](=[O:8])[O-:7])(C)C.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.[C:47]1([CH3:53])[CH:52]=CC=C[CH:48]=1>>[Cl:15][C:13]1[CH:12]=[C:11]([C:16]#[CH:17])[C:10]([CH3:22])=[C:9]([NH:5][C:6](=[O:8])[O:7][C:47]([CH3:53])([CH3:52])[CH3:48])[CH:14]=1
Reactant: Cc1ccccc1
Reactant: Cc1c(C#CC(C)(C)O)cc(Cl)cc1N(C(=O)[O-])C(C)(C)C
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C#Cc1cc(Cl)cc(NC(=O)OC(C)(C)C)c1C
Temperature: 25 °C
Yield: 58 %

Procedure:
To a solution of 1,1-dimethylethyl[5-chloro-3-(3-hydroxy-3-methylbut-1-yn-1-yl)-2-methylphenyl]carbamate (504 mg 1.56 mmol) in toluene (3 mL) was added potassium carbonate (215 mg, 1.56 mmol) and 18-crown-6 (82 mg, 0.31 mmol). The mixture was stirred at reflux for 5 hours, then was cooled to room temperature and partitioned between water and ethyl acetate. The aqueous portion was extracted twice with ethyl acetate. The combined organic portions were washed with brine, dried over sodium sulfate, filtered and concentrated in-vacuo to afford a brown residue which was purified by column chromatography (silica gel, 5% ethyl acetate in hexane). The product was collected to afford 242 mg, 0.91 mmol (58%) of 1,1-dimethylethyl (5-chloro-3-ethynyl-2-methylphenyl)carbamate as a tan solid. 1H NMR (400 MHz, CDCl3): 7.40 (d, 1H), 7.07 (d, 1H), 3.32 (s, 1H), 2.25 (s, 3H), 1.39 (s, 9H); MS (EI) for C14H16ClNO2: 266 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][CH:24]=1)[O:7][C:8]1[C:13]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:12]([N:19]([CH3:21])[CH3:20])[N:11]=[CH:10][N:9]=1)(=O)[CH3:2].Cl.[NH2:26][OH:27].C([O-])(=O)C.[Na+]>CO>[N:26](=[C:1]([C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][CH:24]=1)[O:7][C:8]1[C:13]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:12]([N:19]([CH3:21])[CH3:20])[N:11]=[CH:10][N:9]=1)[CH3:2])[OH:27]
Reactant: COC(=O)Cc1c(Oc2cccc(C(C)=O)c2)ncnc1N(C)C
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1c(Oc2cccc(C(C)=NO)c2)ncnc1N(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The methyl 4-(3-acetylphenoxy)-6-dimethylamino-pyrimidin-5-yl-acetate obtained is dissolved in 500 ml methanol, and hydroxylamine hydrochloride (76 g, 1.1 mol) and sodium acetate (107 g, 1.3 mol) are added at 0° C. After stirring for 2 hours at room temperature the product is crystallized by adding water. Filtering and drying gives methyl 4-[3-(1-hydroximinoethyl)-phenoxy]-6-dimethylamino-pyrimidin-5-yl-acetate in form of yellowish crystals (292 g) having a m.p. of 113°-115° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])[CH2:4][CH2:3]1.[C:19]([N:27]=[C:28]=S)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][CH2:10][N:11]2[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:18]=[C:28]2[NH:27][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:6][CH2:7]1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CN1CCN(CCCNc2ccccc2N)CC1
Solvent: CCO
Product: CN1CCN(CCCn2c(NC(=O)c3ccccc3)nc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.6 %

Procedure:
To a solution of N-[3-(4-methyl-1-piperazinyl)propyl]-o-phenylenediamine (1.24 g., 0.005 mole) in ethanol (50 ml.) was added 0.82 g. (0.005 mole) benzoyl isothiocyanate in one portion. After stirring overnight at room temperature, the solution was evaporated in vacuo to a red oil, which was chromatographed on a silica gel column yielding on crystallization from ethyl acetate 390 mg. of 1-[3-(4-methyl-1-piperazinyl)propyl]-2-benzamido-benzimidazole (yield 20.6%), m.p. 147°-148° C. The material isolated by this synthesis was identical in all respects to an authentic sample.
Reaction SMILES: Cl[Si:2]1([CH3:7])[CH2:5][CH2:4][CH:3]1[CH3:6].[CH3:8][N:9]([Si](C)(C)C)[C:10](=[O:12])[CH3:11]>>[CH3:7][Si:2]1([N:9]([CH3:8])[C:10](=[O:12])[CH3:11])[CH2:5][CH2:4][CH:3]1[CH3:6]
Reactant: CC1CC[Si]1(C)Cl
Reactant: CC(=O)N(C)[Si](C)(C)C
Product: CC(=O)N(C)[Si]1(C)CCC1C

Procedure:
In accordance with the general procedure of Example 1, when 1-chloro-1,2-dimethylsilacyclobutane and N-methyl-N-(trimethylsilyl)acetamide are reacted it is predicted that the title compound is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH2:14]([N:16]([CH2:28][CH3:29])[C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH2:19][CH2:20][NH:21][CH:22]2[CH3:27])[CH3:15]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:21]3[CH2:20][CH2:19][C:18]4[C:23](=[CH:24][CH:25]=[CH:26][C:17]=4[N:16]([CH2:28][CH3:29])[CH2:14][CH3:15])[CH:22]3[CH3:27])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CCN(CC)c1cccc2c1CCNC2C
Product: CCN(CC)c1cccc2c1CCN(C(=O)c1cc3ncc(Br)cn3n1)C2C

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with Diethyl-(1-methyl-1,2,3,4-tetrahydro-isoquinolin-5-yl)-amine to provide the title compound in moderate yield.
Reaction SMILES: [B-](F)(F)(F)F.[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+]([F:21])(CC2)C1.[CH:22]1([N:25]2[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[C:30]([C:34]4[C:42]5[C:37](=[N:38][C:39]([C:43]6[CH:48]=[C:47]([O:49][CH3:50])[CH:46]=[C:45]([O:51][CH3:52])[CH:44]=6)=[CH:40][CH:41]=5)[N:36]([CH:53]5[CH2:58][CH2:57][CH2:56][CH2:55][O:54]5)[N:35]=4)[CH:31]=3)[C:26]2=[O:59])[CH2:24][CH2:23]1>C(#N)C>[CH:22]1([N:25]2[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[C:30]([C:34]4[C:42]5[C:37](=[N:38][C:39]([C:43]6[CH:48]=[C:47]([O:49][CH3:50])[CH:46]=[C:45]([O:51][CH3:52])[C:44]=6[F:21])=[CH:40][CH:41]=5)[N:36]([CH:53]5[CH2:58][CH2:57][CH2:56][CH2:55][O:54]5)[N:35]=4)[CH:31]=3)[C:26]2=[O:59])[CH2:23][CH2:24]1
Reactant: F[N+]12CC[N+](CCl)(CC1)CC2
Reactant: COc1cc(OC)cc(-c2ccc3c(-c4ccc5c(c4)CN(C4CC4)C5=O)nn(C4CCCCO4)c3n2)c1
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: COc1cc(OC)c(F)c(-c2ccc3c(-c4ccc5c(c4)CN(C4CC4)C5=O)nn(C4CCCCO4)c3n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
1-(Chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane ditetrafluoroborate (0.21 g, 0.59 mmol) was added to a stirring solution of 2-cyclopropyl-5-[6-(3,5-dimethoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl]isoindolin-1-one (0.15 g, 0.29 mmol) in acetonitrile (3 mL). The mixture was stirred at r.t. for 2 h. Then it was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (0.12 g). LCMS (M+H)+=529.2.