Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)=[O:4].[Br:19]Br>C(O)(=O)C>[CH2:12]([O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH:2]([Br:19])[CH3:1])=[CH:6][CH:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrBr
Reactant: CCC(=O)c1ccc(OCc2ccccc2)cc1
Solvent: CC(=O)O
Product: CC(Br)C(=O)c1ccc(OCc2ccccc2)cc1

Procedure:
Scheme X depicts the bromination of 4-benzyloxypropiophenone in acetic acid with bromine to yield 4′-(benzyloxy)-2-bromopropiophenone. When this reaction is complete, the mixture can be quenched with water. The resulting precipitate can be collected, washed with dilute acetic acid, water and heptane, and dried.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][O-].[K+].S(=O)(=O)(O)O.C(O)C>C(OCC)(=O)C>[Br:1][C:2]1[C:3]2[N:4]([C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][N:12]=2)[CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: Nc1ncc(C(F)(F)F)cc1Br
Reactant: CCOC(=O)C(Cl)=C[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2c(Br)cc(C(F)(F)F)cn12
Temperature: 90 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
A mixture of 3-bromo-5-(trifluoromethyl)pyridin-2-amine (3.0 g), potassium 2-chloro-3-ethoxy-3-oxoprop-1-en-1-olate (5.4 g), sulfuric acid (0.80 mL) and ethanol (60 mL) was stirred overnight at 90° C. The reaction mixture was diluted with ethyl acetate, and washed with water. The aqueous layer was neutralized with 1N sodium hydroxide, and extracted with ethyl acetate. The organic layers were combined, washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was suspended in a mixed solvent of IPE and hexane, and the obtained solid was collected by filtration to give the title compound (2.6 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[CH2:5][S:6][CH2:7][CH2:8][NH2:9].CS[C:16]1[NH:21][C:20](=[O:22])[C:19]([CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:18][N:17]=1>O>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[CH2:5][S:6][CH2:7][CH2:8][NH:9][C:16]1[NH:21][C:20](=[O:22])[C:19]([CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:18][N:17]=1
Reactant: CSc1ncc(Cc2cccnc2)c(=O)[nH]1
Reactant: COc1ccccc1CSCCN
Solvent: O
Product: COc1ccccc1CSCCNc1ncc(Cc2cccnc2)c(=O)[nH]1

Procedure:
2-(2-Methoxybenzylthio)ethylamine (1.18 g) and 2-methylthio-5-(3-pyridylmethyl)-4-pyrimidone (1.0 g) were fused together at 170° for 50 minutes and allowed to cool. Water was added and the mixture was extracted at pH 13 with chloroform (discarded), adjusted to pH 7 and extracted a second time with chloroform. The second extract was evaporated to give 2-[2-(2-methoxybenzylthio)-ethylamino]-5-(3-pyridylmethyl)-4-pyrimidone as an oil which was treated with hydrogen chloride in ethanol and recrystallised from ethanol-ether to give the dihydrochloride m.p. 180°-183°.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:29])[CH2:4][CH:5]([OH:28])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24]COC)[CH:19]=1>O1CCOCC1.C(Cl)Cl>[ClH:1].[CH3:29][N:3]([CH3:2])[CH2:4][CH:5]([OH:28])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=1
Reactant: COCOc1cccc(CCCCc2ccccc2OCC(O)CN(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CN(C)CC(O)COc1ccccc1CCCCc1cccc(O)c1
Reaction time: 0.25 h
Yield: 89 %

Procedure:
5 ml of a 4N solution of hydrogen chloride in dioxane were added to a solution of 1.00 g of 3-dimethylamino-1-{2-[4-(3-methoxymethoxyphenyl)butyl]phenoxy}-2-propanol [prepared as described in step (b) above] in 10 ml of methylene chloride, and the resulting mixture was allowed to stand at room temperature for 15 minutes. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the resulting residue was dissolved in ethyl acetate and then allowed to stand. The crystals which precipitated were collected by filtration and dried in vacuo, to give 0.87 g (yield 89%) of the title compound as colorless crystals, melting at 124°-125° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.Cl[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][N:1]2[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]2)=[CH:16][CH:17]=1
Reactant: COc1ccc(CCCl)cc1
Reactant: CCOC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(CCc2ccc(OC)cc2)CC1
Temperature: 70 °C
Yield: 25.7 %

Procedure:
A stirred mixture of 5.0 grams (0.032 mole) of ethyl piperidin-4-ylcarboxylate, 5.4 grams (0.032 mole) of 1-(2-chloroethyl)-4-methoxybenzene and 4.4 grams (0.032 mole) of potassium carbonate in 50 mL of dried N,N-dimethylformamide was heated at 70° C. for about 16 hours. After this time the reaction mixture was cooled and partitioned between diethyl ether and water. The organic layer was separated and washed with water and then with an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue, which was subjected to column chromatography on silica gel, with diethyl ether/hexane mixtures as eluants. The product-containing fractions were combined and concentrated under reduced pressure, yielding 2.4 grams of ethyl N-[2-(4-methoxyphenyl)ethyl]piperidin-4-ylcarboxylate. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Mg].[CH2:2](Br)[C:3]#[CH:4].BrCCBr.[CH2:10]=[C:11]([CH2:14][CH2:15][CH3:16])[CH:12]=[O:13].[Cl-].[NH4+]>CCOCC>[OH:13][CH:12]([C:11](=[CH2:10])[CH2:14][CH2:15][CH3:16])[CH2:4][C:3]#[CH:2]
Reactant: C=C(C=O)CCC
Reactant: C#CCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: BrCCBr
Solvent: CCOCC
Product: C#CCC(O)C(=C)CCC
Temperature: 0 °C

Procedure:
To a stirred mixture of 12.16 g. of magnesium in 120 ml. of ether containing 200 mg. of mercuric chloride is added 2 ml. of propargyl bromide and 0.5 ml. of 1,2-dibromoethane. This mixture is stirred under argon until the reaction begins. To this is added with stirring a solution of 41.57 g. of 2-methylene valeraldehyde and 64.95 g. of propargyl bromide in 90 ml. of ether, dropwise, at a rate to maintain reflux. After addition is complete the mixture is refluxed 15 minutes, stirred at room temperature one hour, cooled to 0° C. and saturated ammonium chloride solution is added dropwise until reflux stops. The mixture is filtered through Celite, dried over magnesium sulfate and the ether is removed giving the product as a light orange oil.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13](=[O:15])[NH:12][N:11]=2)=[CH:6][CH:5]=1.[Cl:18][C:19]1[N:20]([CH2:27][C@:28]2([CH3:31])[CH2:30][O:29]2)[CH:21]=[C:22]([N+:24]([O-:26])=[O:25])[N:23]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:18][C:19]1[N:20]([CH2:27][C@:28]([OH:29])([CH3:30])[CH2:31][N:12]2[N:11]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:16])[F:17])=[CH:9][CH:8]=3)[O:14][C:13]2=[O:15])[CH:21]=[C:22]([N+:24]([O-:26])=[O:25])[N:23]=1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: O=c1[nH]nc(-c2ccc(OC(F)(F)F)cc2)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@](O)(Cn1cc([N+](=O)[O-])nc1Cl)Cn1nc(-c2ccc(OC(F)(F)F)cc2)oc1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.4 %

Procedure:
To a solution of 5-(4-trifluoromethoxy-phenyl)-3H-[1,3,4]oxadiazol-2-one (0.68 g, 2.76 mmol) and (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (0.50 g, 2.30 mmol) in DMF (5 ml), potassium carbonate (0.38 g, 2.76 mmol) was added followed by stirring at room temperature for 16 hours, and then water was added. The solution was extracted with ethyl acetate, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=4/1) to afford (R)-3-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]-5-(4-trifluoromethoxyphenyl)-3H-[1,3,4]oxadiazol-2-one (1.06 g, quantitative yield) as a white amorphous form.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=3)[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:25])[C:6]=2[CH:26]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH3:25][C:7]1[C:6]2[CH:26]=[C:2]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:3]=[CH:4][C:5]=2[S:9][C:8]=1[S:10]([NH:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:12])=[O:11]
Reactant: C1CCNC1
Reactant: CCOC(=O)c1cccc(NS(=O)(=O)c2sc3ccc(Br)cc3c2C)c1
Product: CCOC(=O)c1cccc(NS(=O)(=O)c2sc3ccc(N4CCCC4)cc3c2C)c1

Procedure:
The intermediate ethyl 3-{[(3-methyl-5-pyrrolidin-1-yl-1-benzothiophen-2-yl)sulfonyl]amino}benzoate was prepared from ethyl 3-{[(5-bromo-3-methyl-1-benzothien-2-yl)sulfonyl]amino}benzoate (Intermediate 18) (45 mg, 0.1 mmol) and pyrrolidine (8 mg, 0.12 mmol) according to General Procedure 4, described in Example 45.
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:8][CH2:7][NH:6][CH:5]([C:9]([OH:11])=[O:10])[CH2:4]1.[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27]([OH:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1.O>C1C=CC=CC=1>[C:21]1([CH3:31])[CH:22]=[CH:23][C:24]([S:27]([OH:30])(=[O:28])=[O:29])=[CH:25][CH:26]=1.[CH2:12]([N:6]1[CH2:7][CH2:8][CH:3]([CH3:2])[CH2:4][CH:5]1[C:9]([OH:11])=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC1CCNC(C(=O)O)C1
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: c1ccccc1
Product: CC1CCN(Cc2ccccc2)C(C(=O)O)C1
Yield: 22 %

Procedure:
A solution of 20 g (0.112 mole) of 4-methyl-2-piperidinecarboxylic acid hydrochloride, 24 g (0.224 mole) of benzyl alcohol and 25.6 g (0.134 mole) of p-toluenesulfonic acid monohydrate in 100 ml of benzene was refluxed for 5 hours with the continuous removal of water through a Dean-Stark water trap. At the end of this period, the solvent was distilled off, and the residue was washed with ether-n-hexane and recrystallized to give 10 g (22%) of benzyl 4-methyl-2-piperidinecarboxylic p-toluenesulfonate, M.P. 160°-163° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH3:25])=[N:8][C:9]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:10][C:11]=1[C:12](OCC)=[O:13])=O)C.O.[NH2:27][NH2:28]>>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:9]2[N:8]=[C:7]([CH3:25])[C:6]3[C:4](=[O:3])[NH:27][NH:28][C:12](=[O:13])[C:11]=3[CH:10]=2)=[CH:18][CH:19]=1
Reactant: NN
Reactant: CCOC(=O)c1cc(-c2ccc(OC)cc2)nc(C)c1C(=O)OCC
Solvent: O
Product: COc1ccc(-c2cc3c(=O)[nH][nH]c(=O)c3c(C)n2)cc1

Procedure:
10 parts by weight of 3,4-diethoxycarbonyl-6-(p-methoxyphenyl)-2-methylpyridine is incorporated into 40 parts by volume of hydrazine hydrate, and the resulting mixture is refluxed for three hours. The precipitated crystals are collected by filtration, washed with ethanol and suspended in 100 parts by volume of water. The mixture is acidified by the addition of acetic acid to obtain 1,2,3,4-tetrahydro-7-(p-methoxyphenyl)-5-methyl-1, 4-dioxopyrido-(3,4-d)pyridazine as colorless fine crystals. A mixture is made of 3.0 parts by weight of the fine crystals, 45 parts by volume of phosphorus oxychloride and 4.5 parts by volume of N,N-dimethylaniline. The mixture is heated at temperatures ranging from 90° to 100° C for three hours. Then, the reaction mixture is left standing at room temperature overnight. The precipitated crystals are collected by filtration, washed with ether, recrystallized from chloroform to obtain the desired compounds melting at 214° to 219° C (decomposition) as pale yellow needles.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[N:15][CH:14]=[C:13](Cl)[N:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[NH2:23]>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([NH:23][C:13]2[CH:14]=[N:15][CH:16]=[C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=3)[N:12]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: COc1ccc(N)cc1OC
Reactant: CC(=O)Nc1cccc(-c2cncc(Cl)n2)c1
Product: COc1ccc(Nc2cncc(-c3cccc(NC(C)=O)c3)n2)cc1OC
Yield: 27.1 %

Procedure:
Using Method F with 180 mg (0.73 mmol) 4a and 134 mg (0.88 mmol)3,4-dimethoxyaniline, 72 mg (27.1%) pure title compound were obtained after preparative HPLC (eluent: AcOEt) purification of the whole batch. Reaction time: 6 hours. 1H-NMR (DMSO), δ (ppm), J (Hz): 2.07 (s, 3H, CH3CO), 3.73 (s, 3H, CH3O(4)), 3.77 (s, 3H, CH3O(3)), 6.95 (d, 1H, Harom 5, J=8.71), 7.26 (q, 1H, Harom 6, Jo=8.63, Jm=2.35), 7.42 (t, 1H, Harom 5′, J=7.90), 7.62 (s, 1H, Harom 2), 7.64 (d, 1H, Harom 4′ or 6′), 7.72 (d, 1H, Harom 6′ or 4′, J=7.63), 8.13 (s, 1H, HP5), 8.30 (s, 1H, Harom 2′), 8.35 (s, 1H, HP3), 9.45 (s, 1H, NHamino), 10.07 (s, 1H, NHamido); MS, (C20H20N4O3), m/z: 365.3 [M++1, 100].
Reaction SMILES: [BrH:1].[C:2]([C:4]([S:10][C:11]([F:14])([F:13])[F:12])=[CH:5][CH:6]=[CH:7]OC)#[N:3].C([O-])([O-])=O.[Na+].[Na+]>CC(O)=O>[Br:1][C:2]1[C:4]([S:10][C:11]([F:14])([F:13])[F:12])=[CH:5][CH:6]=[CH:7][N:3]=1
Reactant: Br
Reactant: COC=CC=C(C#N)SC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: FC(F)(F)Sc1cccnc1Br
Temperature: 55 °C

Procedure:
A solution of 30% HBr, AcOH (70 mL) was added dropwise with stirring at 40° C. to a solution of 4-cyano-4-trifluoromethylthio-3-butenealdehydedimethylacetal and 1-cyano-1-trifluoromethylthio-4-methoxy-1,3-butadiene (8.8 g) in AcOH (40 mL). After the addition, the solution was heated at 55° C. for 2 hours, poured onto ice and neutralized with solid Na2CO3. The solution was extracted with CH2Cl2 (3x) and the CH2Cl2 extracts dried, filtered and concentrated to dryness. The residual oil was distilled at 68°-71° C. at 0.3 mm of yield 4.0 g (16%) of 2-bromo-3-trifluoromethylthiopyridine 1H NMR (CDCL3) δ7.35 (1H, dd, J=4 and 8), 8.05 (1H, dd, J=2 and 8), 8.45 (1H, dd, J=3 and 4); 19F NFR (CDCl3)+40.7 (s).
Reaction SMILES: [OH:1][C:2]1[S:3][C:4]2[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1.[H-].[Na+].Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)=[O:16].O>CN(C=O)C>[O:16]=[C:15]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)[CH2:14][N:6]1[C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[S:3][C:2]1=[O:1]
Reactant: Cc1ccc(C(=O)CBr)cc1
Reactant: Oc1nc2c(s1)CCCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C(=O)Cn2c3c(sc2=O)CCCC3)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65 %

Procedure:
To a solution of 2-hydroxy-4,5,6,7-tetrahydrobenzothiazole (335 mg, 2.16 mmol) in DMF (3 mL) was added NaH (101 mg, 2.52 mmol). After stirring 10 minutes at room temperature, a solution of 2-bromo-4′-methylacetophenone (668 mg, 2.82 mmol) in DMF (5 mL) was added and the mixture was stirred overnight. Water was added and the mixture was extracted with EtOAc, dried over MgSO4 and the solvent was evaporated. The oil recovered was purified by flash chromatography on silicagel (CH2Cl2) to give 29 as a solid in 65% yield: mp 108-110° C.; 1H-NMR (DMSO-d6) 1.73 (s, 4H), 2.19 (s, 2H) 2.40 (m, 5H), 5.23 (s, 2H), 7.39 (d, 2H), 7.95 (d, 2H); Anal. (C16H17NO2S) C, H, N.
Reaction SMILES: C(OC(C1C=C(C2C=CC(C[Br:19])=CC=2)C=CC=1)=O)C.[CH2:20]([O:22][C:23]([C:25]1[C:26]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:37])=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:24])[CH3:21].BrN1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[CH2:20]([O:22][C:23]([C:25]1[C:26]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH2:37][Br:19])=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:24])[CH3:21]
Reactant: CCOC(=O)c1ccccc1-c1ccccc1C
Reactant: CCOC(=O)c1cccc(-c2ccc(CBr)cc2)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccccc1-c1ccccc1CBr

Procedure:
2′-Bromomethyl-biphenyl-2-carboxylic acid ethyl ester was synthesized as described for 4′-bromomethyl-biphenyl-3-carboxylic acid ethyl ester. 2′-Methyl-biphenyl-2-carboxylic acid ethyl ester (10.35 g, 43.07 mmol, 1 eq.) in carbon tetrachloride was treated with N-bromosuccinimide (9.20 g, 51.68 mmol, 1.2 eq.) and 2,2′-azobisisobutyronitrile (0.35 g, 2.15 mmol, 5 mol %). When complete, the reaction was worked up as described leaving an orange oil.
Reaction SMILES: [C:1]([C:4]1[N:5]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[C:6]2[C:11]([C:12]=1[C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=1)=[O:14])=[CH:10][CH:9]=[C:8]([O:25][CH:26]([CH3:28])[CH3:27])[CH:7]=2)(=O)[CH3:2].[OH:36][NH2:37].Cl.N1C=CC=CC=1>CO>[F:24][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[F:23])[CH2:16][NH:15][C:13]([C:12]1[C:11]2[C:6](=[CH:7][C:8]([O:25][CH:26]([CH3:27])[CH3:28])=[CH:9][CH:10]=2)[N:5]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[C:4]=1/[C:1](=[N:37]/[OH:36])/[CH3:2])=[O:14]
Reactant: NO
Reactant: CC(=O)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(OC(C)C)cc2n1Cc1ccccn1
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: C/C(=N\O)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(OC(C)C)cc2n1Cc1ccccn1
Temperature: 65 °C
Reaction time: 20 h

Procedure:
General Procedure Q. To a solution of 2-acetyl-N-(3,4-difluorobenzyl)-6-isopropoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 109, 18 mg, 0.038 mmol) in MeOH (3 ml) was added HONH2.HCl (8.0 mg, 0.11 mmol) and pyridine (30 μl, 0.38 mmol). The reaction was stirred at 65° C. for 20 h and the solvent was removed in vacuo. The residue was purified by PTLC (75% EtOAc-hexanes) to yield the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]([CH:14]([NH:20][C:21]([C@@H:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:29](=[O:45])[CH2:30][CH2:31][CH:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]3)[CH2:24]2)=[O:22])[CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:11]=[N:12][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:53][CH2:54][F:55]>O1CCCC1.O>[F:55][CH2:54][CH2:53][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]([CH:14]([NH:20][C:21]([C@@H:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:29](=[O:45])[CH2:30][CH2:31][CH:32]3[CH2:33][CH2:34][N:35]([C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])[CH2:36][CH2:37]3)[CH2:24]2)=[O:22])[CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:11]=[N:12][CH:13]=1
Reactant: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(-c2ccccc2O)c1
Reactant: FCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(-c2ccccc2OCCF)c1
Temperature: 25 °C
Reaction time: 90 h
Yield: 59.8 %

Procedure:
124 mg (0.20 mmol) tert-butyl 4-{3-[(3R)-3-({1-[5-(2-hydroxyphenyl)pyridin-3-yl]-3-methoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate were dissolved in 2.2 ml tetrahydrofurane. 130 mg (0.40 mmol) cesium carbonate and 66 mg (0.38 mmol) 1-iodo-2-fluoroethane were added. The mixture was stirred at room temperature for 90 hours. 66 mg (0.38 mmol) 1-iodo-2-fluoroethane were added and the mixture stirred at room temperature for 20 hours. 66 mg (0.38 mmol) 1-iodo-2-fluoroethane were added and the mixture stirred at room temperature for 60 hours, diluted with water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated in vacuum. Chromatography over 10 g silica gel (dichloromethane/ethanol 100/0-90/10) gave 80 mg (54%) tert-butyl 4-(3-{(3R)-3-[(1-{5-[2-(2-fluoroethoxy)phenyl]pyridin-3-yl}-3-methoxy-3-oxopropyl)carbamoyl]piperidin-1-yl}-3-oxopropyl)piperidine-1-carboxylate.
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]([NH:6][C:7]2[CH:8]=[CH:9][C:10]3[C:11]([CH:15]=2)=[N:12][O:13][N:14]=3)[CH:5]=1.Cl[CH2:17][C:18]1[N:19]=[CH:20][S:21][CH:22]=1>>[S:21]1[CH:22]=[C:18]([CH2:17][N:6]([C:7]2[CH:8]=[CH:9][C:10]3[C:11]([CH:15]=2)=[N:12][O:13][N:14]=3)[N:4]2[CH:5]=[N:1][N:2]=[CH:3]2)[N:19]=[CH:20]1
Reactant: c1cc2nonc2cc1Nn1cnnc1
Reactant: ClCc1cscn1
Product: c1nc(CN(c2ccc3nonc3c2)n2cnnc2)cs1

Procedure:
Starting Compounds: 5-[N-(4H-1,2,4-triazol-4-yl)-amino]benzofurazan and 4-chloromethylthiazole
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[C:14]3[C:20]([OH:22])=[O:21])[CH:8]=[N:7][CH:6]=1)([CH3:3])[CH3:2].[C:23]([O-])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O>CN(C=O)C>[CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[C:14]3[C:20]([O:22][CH3:23])=[O:21])[CH:8]=[N:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cncc(-c2ccc3[nH]cc(C(=O)O)c3c2)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1c[nH]c2ccc(-c3cncc(OC(C)C)n3)cc12
Temperature: 80 °C
Yield: 77.6 %

Procedure:
To a solution of 5-(6-isopropoxy-pyrazin-2-yl)-1H-indole-3-carboxylic acid (8.0 g, 26.9 mmol) in DMF (80 mL) was added K2CO3 (4.50 g, 32.3 mmol) and dimethyl sulfate (2.50 mL, 26.9 mmol) at RT and the reaction was heated to 80° C. for 3 h. The mixture was cooled to RT and partitioned between ice water (80 mL) and EtOAc (80 mL). The organic layer was separated and dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified with silica gel chromatography (eluting with 15% EtOAc in petroleum ether) to give methyl 5-(6-isopropoxypyrazin-2-yl)-1H-indole-3-carboxylate (6.5 g, 79%) as an off white solid. MS (ESI, pos. ion) m/z: 311.9 (M+1); 1H-NMR (DMSO-d6) δ ppm; 8.70 (d, J=1.6 Hz, 2H), 8.18 (s, 1H), 8.14 (s, 1H), 7.9 (dd, J=2.0 Hz, 1H), 7.62 (d, J=8.4, 1.6 Hz, 1H), 5.39-5.43 (m, 1H), 3.85 (s, 3H), 1.40 (d, J=6.0 Hz, 6H).
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C@H:6]1[CH2:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[CH2:9][N:8]([CH2:17][C:18]([OH:20])=[O:19])[C:7]1=[O:21].[CH3:22]O>>[NH2:5][C@H:6]1[CH2:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[CH2:9][N:8]([CH2:17][C:18]([O:20][CH3:22])=[O:19])[C:7]1=[O:21]
Reactant: CO
Reactant: N[C@H]1Cc2ccccc2CN(CC(=O)O)C1=O
Solvent: O=S(Cl)Cl
Product: COC(=O)CN1Cc2ccccc2C[C@H](N)C1=O
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 97 %

Procedure:
MeOH (5 mL) was cooled with an ice-acetone bath, and thionyl chloride (60 μL) was added. This solution was stirred for 1 min, and then the amino acid from Example 7 (163 mg, 0.70 mmol) was added all at once. After removing the cooling bath, the reaction was stirred while warming to ambient temperature over 1 hr, and then heated to 40° C. for another 1.5 hr. When the reaction mixture was concentrated to dryness, HPLC analysis of the residue indicated that the reaction was incomplete, so the above reaction sequence was repeated, this time heating the reaction for 0.5 hr at the end. The reaction mixture was concentrated to dryness, giving the product as a light yellow solid (168 mg, 97%).