Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=O)[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:12](=[O:14])[C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[CH:9]=[CH:8][C:4]=2[CH:3]=1
Reactant: O=C(O)c1ccccc1C=Cc1cccc(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: O
Product: O=c1c2ccccc2ccc2cc(Cl)ccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To 500 g (1.933 mol) of (E/Z)-2-[2-(3-chlorophenylethenyl]benzoic acid (in a ratio of about 23:77) in 500 ml of methylene chloride were added dropwise with stirring at the reflux temperature 241.6 g (2.031 mol) of thionyl chloride in the course of 1 hour and stirred in for 1 hour. Thereafter a suspension of 333 g (2.497 mol) of anhydrous aluminum chloride in 100 ml of methylene chloride was added at room temperature in the course of 45 min and stirred in at room temperature for 30 min, and the reaction mixture was then poured with stirring onto a mixture of 3 kg of ice and 1 l of water. The hydrolysis mixture was stirred for about 30 min. 1 l of petroleum ether (boiling range from 40° to 60° C.) was then added with stirring. The mixture was stirred for a further 30 min and then filtered with suction. The filter residue was washed first with 5 l of water and then with 1 l of petroleum ether (boiling range from 40° to 60° C.) and dried. 270 g were isolated of 2-chloro-5H-dibenzo-[a,d]cyclohepten-5-one in 58% yield; melting point 160°-161° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[O:9][C:10]=1[CH2:11]Br)=[O:5])[CH3:2].CN(C)C=[O:24]>[Cl-].[Na+].O.FC(F)(F)C([O-])=O.[Ag+]>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[O:9][C:10]=1[CH2:11][OH:24])=[O:5])[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1nc(-c2ccc(OC)cc2)oc1CBr
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Agent: [Cl-]
Solvent: O
Product: CCOC(=O)c1nc(-c2ccc(OC)cc2)oc1CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
8.0 g 5-Bromomethyl-2-(4-methoxy-phenyl)-oxazole-4-carboxylic acid ethyl ester were dissolved in 50 ml dry dimethylformamide. 7.8 g Silver trifluoroacetate were added and the mixture was stirred at room temperature for two hours. 30 ml brine were added and the mixture was stirred for two hours. The reaction mixture was filtered through a pad of celite, the solvent removed in vacuo and the resulting residue dissolved in 200 ml ethanol. The mixture was heated to reflux for three hours. Then the solvent was removed in vacuo and the residue dissolved in water and extracted five times with ethyl acetate. The combined organic layers were dried over MgSO4, the solvent removed in vacuo and the residue purified by flash chromatography on silica gel (eluting with n-heptane:ethyl acetate=2:3=>ethylacetate) to obtain 4.8 g 5-hydroxymethyl-2-(4-methoxy-phenyl)-oxazole-4-carboxylic acid ethyl ester as a solid.
Reaction SMILES: [CH2:1]1[C:7]([OH:12])([CH2:8][C:9]([OH:11])=[O:10])[C:5](=[O:6])[O:4][C:2]1=[O:3].[OH2:13]>>[C:2]([OH:13])(=[O:3])[CH2:1][C:7]([CH2:8][C:9]([OH:11])=[O:10])([C:5]([OH:4])=[O:6])[OH:12]
Reactant: O
Reactant: O=C(O)CC1(O)CC(=O)OC1=O
Product: O=C(O)CC(O)(CC(=O)O)C(=O)O

Procedure:
Following a procedure resembling that of Example 11, a beverage is prepared by first preparing a mixture of about 43 grams of citric anhydride and 957 grams of water to prepare 100 grams of water to provide 1000 grams of 0.25 molar solution of citric acid. Using power mixing, about 90 grams of Corn Starch Solids marketed as C-STAR-DRY GLO 1920 from Cerestar, Cargill Foods, Cedar Rapids, Iowa, 52406-1467. Such dispersion was aged for 15 minutes, and then a mixture consisting of orange flavor, an artificial sweetener, and sodium citrate bugger were added. Using power mixing. A glass electrode pH meter is employed during the terminal stages of adding mixing. A glass electrode pH meter was employed during the terminal stages of adding about 3,000 g. of tap water to prepared about 4000 g of beverage having a pH between 3.2 and 3.5 of liquid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([CH2:14][O:15][C:16]3[C:21]([F:22])=[CH:20][C:19]([CH2:23][CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])=[CH:18][C:17]=3[F:32])=[C:12]([C:33]([F:36])([F:35])[F:34])[S:11][N:10]=2)=[CH:5][CH:4]=1)[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]([CH2:14][O:15][C:16]3[C:21]([F:22])=[CH:20][C:19]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:18][C:17]=3[F:32])=[C:12]([C:33]([F:34])([F:35])[F:36])[S:11][N:10]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(-c2nsc(C(F)(F)F)c2COc2c(F)cc(CCC(=O)OC(C)(C)C)cc2F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1ccc(-c2nsc(C(F)(F)F)c2COc2c(F)cc(CCC(=O)O)cc2F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed tert-butyl 3-(4-[[3-(4-ethylphenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methoxy]-3,5-difluorophenyl)propanoate (520 mg, 0.99 mmol, 1.00 equiv), CF3COOH (2.0 mL), dichloromethane (8.0 mL). The resulting solution was stirred overnight at 25° C. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The solid was washed by EtOAc and hexane. The mixture was filtered and the solid was dried under vacuum. This resulted in 0.37 g (80%) of 3-(4-[[3-(4-ethylphenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methoxy]-3,5-difluorophenyl) propanoic acid as a white solid. 1H-NMR (300 Hz, CD3OD): δ 7.67 (d, J=8.4 Hz, 2H), 7.34 (d, J=8.4 Hz, 2H), 6.86 (d, J=9.6 Hz, 2H), 5.21 (s, 2H), 2.87 (t, J=7.5 Hz, 2H), 2.74 (q, J1=7.5 Hz, J2=15.2 Hz, 2H), 2.61 (t, J=7.8 Hz, 2H), 1.30 (t, J=7.5 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C22H18F5NO3S, 472.1 (M+H). found 472.1.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[C:5](OC)=[O:6].C[O-].[Na+].Cl.[CH:21]([NH2:23])=[NH:22]>CO>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:4]2[C:5]([OH:6])=[N:22][CH:21]=[N:23][C:3]=2[OH:2])=[CH:10][CH:11]=1
Reactant: N=CN
Reactant: COC(=O)C(C(=O)OC)c1ccc(Cl)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Oc1ncnc(O)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 94.8 %

Procedure:
A solution of 18.90 g of 2-(4-chloro-phenyl)-malonic acid dimethyl ester in 200 ml of methanol was added dropwise at 0° C. to a solution of 14.60 g sodium methylate in 150 ml of methanol. The mixture was stirred for 1 h at 0° C. before 7.66 g of formamidine hydrochloride was added. The suspension was stirred at rt for 20 h. The solvent was removed and the residue was suspended in 200 ml 2 N aq. HCl. The pH of the suspension was carfully adjusted to 4-5 by adding 20 ml of 10 M NaOH, stirring was continued for 30 min. The white precipitate was collected, washed with water and diethyl ether and dried to give 16.44 g of 5-(4-chlorophenyl)-pyrimidine-4,6-diol as a white powder. LC-MS: tR=2.75 min, [M+H]+=222.96 (ES+), [M−H]−=220.92 (ES−).
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:12][CH3:13])=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:23]([O:22][C:20]([N:14]1[CH2:19][CH2:18][N:17]([C:2]2[S:3][C:4]([NH:12][CH3:13])=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=2)[CH2:16][CH2:15]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CCOC(=O)c1nc(Br)sc1NC
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1nc(N2CCN(C(=O)OC(C)(C)C)CC2)sc1NC
Temperature: 100 °C
Yield: 35.2 %

Procedure:
To a solution of ethyl 2-bromo-5-methylamino-thiazole-4-carboxylate (401 mg, 1.512 mmol) and tert-butyl piperazine-1-carboxylate (1.06 g, 5.69 mmol) in anhydrous dioxane (15 ml) was added DIPEA (2 ml, 11.5 mmol) and the reaction was heated at 100° C. in a sealed flask for 23 hours. The mixture was cooled to room temperature, partitioned between DCM and sat. sodium bicarbonate solution and the phases were separated. The aqueous layer was extracted twice with DCM and the combined organic layers were dried (sodium sulfate) and concentrated under reduced pressure. The residue was purified by column chromatography (silica, gradient from 10 to 70% ethyl acetate in n-heptane) to yield 197 mg of a white solid (0.532 mmol, yield 35%) MS (multi-mode) m/z=371.2 [M+1]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.[S:18]([NH2:28])(=[O:27])([C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)=[O:19]>CN1C(=O)CCC1>[S:18]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:2]2[N:7]=[C:6]([O:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)[C:5]([Cl:17])=[CH:4][N:3]=2)=[CH:22][CH:21]=1)(=[O:19])(=[O:27])[NH2:28]
Reactant: COc1ccc(Oc2nc(Cl)ncc2Cl)cc1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Solvent: CN1CCCC1=O
Product: COc1ccc(Oc2nc(Nc3ccc(S(N)(=O)=O)cc3)ncc2Cl)cc1
Yield: 19 %

Procedure:
A solution of 2,5 dichloro-4-(4-methoxyphenoxy)pyrimidine (Method 25; 0.65 g, 2.4 mmol) and sulphanilamide (0.38 g, 2.2 mmol) in NMP(1.5 ml) was heated to 100° C. for 4 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic solution was evaporated and the residue purified by column chromatography eluting with 0.1% formic acid, 4% methanol in dichloromethane to afford a solid product (0.17 g, 19%). NMR: 3.81 (s, 3H), 7.05 (d, 2H), 7.10 (s, 2H), 7.22 (d, 2H), 7.50 (d, 4H), 8.50 (s, 1H), 10.6 (br s, 1H); MS [M−H]−: 405, 407.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.CC[N:45](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N>CO.C(Cl)Cl>[C:35]([C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:42])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10]2)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=1)(=[O:36])[NH2:45]
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CO
Solvent: ClCCl
Product: COc1cc(C(N)=O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reaction time: 0.03 h

Procedure:
In a 10 mL round-bottomed flask, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (200 mg, 324 μmol, Eq: 1.00) was combined with CH2Cl2 (5.43 ml) to give a suspension. DIPEA (50.3 mg, 68.0 μl, 389 μmol, Eq: 1.2) and HATU (136 mg, 357 μmol, Eq: 1.1) were added. The reaction was stirred for 2 minutes and 2M ammonia (811 μl, 1.62 mmol, Eq: 5) in methanol was added. The reaction mixture was stirred for 4 h.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[C:14]([C:23]([O:25][CH2:26][CH2:27][CH3:28])=[O:24])=[CH:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:29][CH3:30].Br[CH2:32][CH2:33][Cl:34].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:34][CH2:33][CH2:32][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[C:14]([C:23]([O:25][CH2:26][CH2:27][CH3:28])=[O:24])=[CH:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:29][CH3:30]
Reactant: CCCOC(=O)c1cc2ccccc2cc1Oc1ccnc2cc(O)c(OC)cc12
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOC(=O)c1cc2ccccc2cc1Oc1ccnc2cc(OCCCl)c(OC)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
Propyl 3-(7-hydroxy-6-methoxy-quinolin-4-yloxy)-naphthalene-2-carboxylate (80 mg) and 1-bromo-2-chloroethane (0.082 ml) were dissolved in N,N-dimethylformamide (2 ml) to prepare a solution. Potassium carbonate (274 mg) was added to the solution, and the mixture was stirred at room temperature overnight. Water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (85 mg, yield 91%).
Reaction SMILES: C[O-].[Na+].CO.C(O[C:9](=[O:17])[CH2:10][CH2:11][C:12](=[O:16])[CH2:13][CH2:14][CH3:15])C>C1(C)C(C)=CC=CC=1>[CH2:14]([CH:13]1[C:9](=[O:17])[CH2:10][CH2:11][C:12]1=[O:16])[CH3:15]
Reactant: CCCC(=O)CCC(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1C
Product: CCC1C(=O)CCC1=O
Temperature: 25 °C
Yield: 46 %

Procedure:
A 1 l. three-necked flask, equipped with a dropping funnel, mechanical stirrer and a distillation head with thermometer and Liebig condenser was charged with 515 ml of xylene (b.p. 138°-140°), stirred and heated to boiling. 65.9 g of a 24% (wt/wt) sodium methoxide solution (prepared as in Example 1) in methyl alcohol (15.8 g = 0.293 moles) was added over 10 min., distilling off continuously the methyl alcohol. 300 ml of additional xylene were added and distillation was continued until the vapor temperature reached 135°. After the addition of 6.6 ml of dimethylsulfoxide, a solution of 40 g (0.232 moles) of 4-oxoheptanoic acid ethyl ester in 80 ml of xylene was added over 25 min. to the vigorously stirred sodium methoxide suspension while keeping the vapor temperature at ca. 135°C by continuous distillation of xylene. The orange-colored mixture was stirred and heated for an additional 5 min. and then allowed to cool to room temperature. Water was added, the mixture was acidified and the product filtered, washed, dried and recrystallized from water to afford 13.45 g (46%) of 2-ethyl-cyclopentan-1,3-dione, m.p. (uncorr.): 171°-172°C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([CH3:10])=[O:9])[C:5](Br)=[CH:4][C:3]=1[S:12]([CH3:14])=[O:13].[CH2:15]([C:21]1[S:25][C:24]([Sn](C)(C)C)=[CH:23][CH:22]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:14][S:12]([C:3]1[CH:4]=[C:5]([C:24]2[S:25][C:21]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:22][CH:23]=2)[C:6]([S:8]([CH3:10])=[O:9])=[CH:7][C:2]=1[C:24]1[S:25][C:21]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:22][CH:23]=1)=[O:13]
Reactant: CCCCCCc1ccc([Sn](C)(C)C)s1
Reactant: CS(=O)c1cc(Br)c(S(C)=O)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCCCCCc1ccc(-c2cc(S(C)=O)c(-c3ccc(CCCCCC)s3)cc2S(C)=O)s1
Temperature: 80 °C
Yield: 74.8 %

Procedure:
1,4-dibromo-2,5-bis(methylsulfinyl)benzene 3 (0.900 g, 2.5 mmol) was added to a solution of 4b (1.82 g, 5.5 mmol) in anhydrous DMF (30 mL), and the resulting mixture was purged with Ar for 30 min. Pd(PPh3)4 (87 mg, 0.075 mmol) was then added, and the reaction mixture was heated to 80° C. overnight. Excess DMF was removed under high vacuum, and the residue was dissolved in ethyl acetate and treated with 10% aqueous KF. The mixture was filtered through a pad of Celite. The filtrate was dried over Mg2SO4, filtered, and the solvent removed in vacuo. The crude product was purified by flash chromatography (silica gel, eluent:hexane/THF) 1:1) to afford 1 g (75%) of 2b.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]3[NH:15][CH:16]=[C:17]([CH2:18][CH2:19][OH:20])[C:11]=3[CH:10]=2)=[CH:3][CH:2]=1.[CH2:21]([C:23]([CH2:25][CH3:26])=O)[CH3:22].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:21]([C:23]1([CH2:25][CH3:26])[C:16]2[NH:15][C:12]3[C:11]([C:17]=2[CH2:18][CH2:19][O:20]1)=[CH:10][C:9]([O:8][CH2:7][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)=[CH:14][CH:13]=3)[CH3:22]
Reactant: CCC(=O)CC
Reactant: OCCc1c[nH]c2ccc(OCc3ccccc3)cc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCC1(CC)OCCc2c1[nH]c1ccc(OCc3ccccc3)cc21
Temperature: 25 °C

Procedure:
A mixture consisting of 5-benzyloxytryptophol (7.0 g, 0.0262 mol), diethyl ketone (10 mL), benzene (400 mL) and p-toluene sulfonic acid is refluxed for 3.5 hours using a Dean-Stark tap to remove the water. The reaction mixture is cooled to room temperature, washed with 5% sodium bicarbonate, water (200 mL), brine (200 mL), dried (MgSO4), filtered and concentrated to give 9.9 g of crude product. The crude product is flash chromatographed on silica gel using 15% ethyl acetate/hexane as an eluent to afford 6.5 g of pure title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:35])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[C:21]([C:23]([NH:25][CH:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29]C)=[O:28])=[O:24])[O:20][N:19]=2)=[CH:14][C:13]=1[CH3:34].FC1C=CC=C(F)C=1NC(=O)NC1C=CC(C2C=C(C(NC(C(C)C)C(O)=O)=O)ON=2)=CC=1C>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:35])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[C:21]([C:23]([NH:25][CH:26]([CH:31]([CH3:32])[CH3:33])[C:27]([OH:29])=[O:28])=[O:24])[O:20][N:19]=2)=[CH:14][C:13]=1[CH3:34]
Reactant: COC(=O)C(NC(=O)c1cc(-c2ccc(NC(=O)Nc3ccc(F)cc3F)c(C)c2)no1)C(C)C
Agent: Cc1cc(-c2cc(C(=O)NC(C(=O)O)C(C)C)on2)ccc1NC(=O)Nc1c(F)cccc1F
Product: Cc1cc(-c2cc(C(=O)NC(C(=O)O)C(C)C)on2)ccc1NC(=O)Nc1ccc(F)cc1F

Procedure:
The title compound was prepared from methyl 2-(3-(4-(3-(2,4-difluorophenyl)ureido)-3-methylphenyl)isoxazole-5-carboxamido)-3-methylbutanoate using the same procedure as described for preparation of the compound of step 9 of Example 98. The compound was obtained as an off-white solid after drying in vacuo. 1H NMR (300 MHz, DMSO-d6) δ: 0.86-0.88 (d, J=6.6 Hz, 6H), 2.12-2.18 (m, 1H), 2.33 (s, 3H), 3.95-3.99 (m, 1H), 7.00-7.05 (m, 1H), 7.25-7.33 (m, 1H), 7.62 (S, 1H), 7.68-7.71 (d, J=8.4 Hz, 1H), 7.76 (s, 1H), 7.99-8.11 (m, 3H), 8.89 (s, 1H), 9.45 (s, 1H); ms (ESI) m/z 473.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16].[CH3:21][N:22]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[CH:24][C:23]1=[O:37]>O1CCOCC1.C(=O)(O)[O-].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:16][C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[O:8][C:7]1[CH:6]=[CH:5][C:4]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:3][C:2]=1[C:26]1[CH:25]=[CH:24][C:23](=[O:37])[N:22]([CH3:21])[CH:27]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)ccc1=O
Reactant: NS(=O)(=O)c1ccc(Oc2ccc(F)cc2F)c(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: Cn1cc(-c2cc(S(N)(=O)=O)ccc2Oc2ccc(F)cc2F)ccc1=O
Yield: 18 %

Procedure:
3-Bromo-4-(2,4-difluorophenoxyl)benzenesulfonamide (1 eq., 62 mg), the title compound of Example 98, step 1 (40 mg, 0.17 mmol), Pd(dppf)Cl2 (10 mg, 8%) in 1,4-dioxane (880 μL) and saturated bicarbonate solution (aq) (220 μL) were reacted at 105° C. for 30 min in a manner similar to Example 117. Work up and preparative HPLC, also in a similar manner, gave the title compound (12 mg, 18%) as a white solid. 1H NMR (DMSO, 400 MHz): δ3.51 (s, 3H), 6.49 (d, J=9.4, 1H), 4.15 (q, J=6.9, 2H), 6.45 (d, J=9.4 Hz, 1H), 7.20-7.23 (m, 3H), 7.64 (dd, J=2.6, 9.4 Hz, 1H), 7.72-7.74 (m, 2H), 7.89 (d, J=2.6 Hz, 1H). LCMS (M+H)+=393.
Reaction SMILES: [I-].[C:2]1(C([PH3+])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[H-].[Na+].[OH:24][C:25]1[CH:42]=[CH:41][C:40]2[C@:39]3([CH:43]=O)[C@H:30]([C@H:31]4[C@@:35]([CH2:37][CH2:38]3)([CH3:36])[CH2:34][C@H:33]([OH:45])[CH2:32]4)[CH2:29][CH2:28][C:27]=2[CH:26]=1.O>CS(C)=O>[CH:43]([C@:39]12[CH2:38][CH2:37][C@@:35]3([CH3:36])[C@@H:31]([CH2:32][C@@H:33]([OH:45])[CH2:34]3)[C@@H:30]1[CH2:29][CH2:28][C:27]1[CH:26]=[C:25]([OH:24])[CH:42]=[CH:41][C:40]2=1)=[CH2:2]
Reactant: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[C@]12CC[C@]3(C=O)c4ccc(O)cc4CC[C@H]3[C@@H]1C[C@@H](O)C2
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C=C[C@]12CC[C@]3(C)C[C@H](O)C[C@H]3[C@@H]1CCc1cc(O)ccc12
Reaction time: 0.17 h

Procedure:
Under inert-gas atmosphere, 3.1 g (7.9 mmol) of triphenylmethyl phosphonium iodide and 0.24 g (8 mmol) of sodium hydride (80% in paraffin oil) in 20 ml of DMSO in an ultrasound bath are brought to reaction at about 55° C. After 10 minutes, 80 mg (0.16 mmol, about 60%) of 3,16α-dihydroxyestra-1,3,5(10)-triene-9 carbaldehyde is added to the solution, and the mixture is allowed to react for 60 more minutes at about 55° C. in an ultrasound bath. After water is added, it is extracted with ethyl acetate. The collected organic phases are washed with water, and the organic phase is concentrated by evaporation in a vacuum.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:11]2[C:6](=[N:7][C:8]([C@@H:18]([NH2:20])[CH3:19])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[CH:10]=2)[CH:5]=[CH:4]1.[NH2:21][C:22]1[N:27]=[C:26](Cl)[C:25]([C:29]#[N:30])=[C:24]([CH3:31])[N:23]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[NH2:21][C:22]1[N:23]=[C:24]([CH3:31])[C:25]([C:29]#[N:30])=[C:26]([NH:20][C@H:18]([C:8]2[N:7]=[C:6]3[CH:5]=[CH:4][N:3]([CH3:2])[C:11]3=[CH:10][C:9]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH3:19])[N:27]=1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1-c1ccccn1
Reactant: Cc1nc(N)nc(Cl)c1C#N
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2-c2ccccn2)c1C#N
Temperature: 120 °C
Yield: 29 %

Procedure:
(S)-1-(1-Methyl-6-(pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine hydrochloride (151 mg, 0.522 mmol), 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile (80 mg, 0.475 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.248 mL, 1.42 mmol) were combined in acetonitrile (6 mL). The reaction mixture was heated in a microwave reactor at 120° C. for 2 hours and then concentrated. The residue was taken up in DMF and purified by preparative HPLC (basic mode) eluting with 20-35% ACN in water. The fractions containing the desired compound were combined and concentrated in vacuo. The residue was taken up in DMF and further purified by preparative HPLC (acid mode) eluting with 1-25% ACN in water. The fractions containing the desired compound were combined, neutralized with NaHCO3, and extracted with EtOAc (200 mL). The organic layers were combined, dried over Na2SO4, and concentrated in vacuo to give the title compound (53 mg, 29%). 1H NMR (500 MHz, CD3OD) δ ppm 1.34-1.41 (m, 3 H), 2.31 (d, J=1.46 Hz, 3 H), 3.88 (d, J=1.46 Hz, 3H), 5.68-5.79 (m, 1 H), 6.67 (d, J=2.44 Hz, 1 H), 7.47 (dd, J=7.32, 4.88 Hz, 1 H), 7.58-7.61 (m, 1 H), 7.67 (d, J=7.81 Hz, 1 H), 7.86 (s, 1 H), 7.99 (t, J=7.81 Hz, 1 H), 8.68-8.73 (m, 1 H); ESI-MS m/z [M+H]+ calc'd for C21H20N8, 385; found 385.
Reaction SMILES: [CH2:1]([N:3](CC)CC)[CH3:2].[Br-].[Li+].C(OP(CC#N)(=O)OCC)C.O=[C:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:38][C@@H:37]([CH2:39][N:40]=[N+:41]=[N-:42])[O:36][C:35]3=[O:43])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1>O1CCCC1>[C:1]([CH:2]=[C:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:38][C@@H:37]([CH2:39][N:40]=[N+:41]=[N-:42])[O:36][C:35]3=[O:43])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)#[N:3]
Reactant: CCN(CC)CC
Reactant: [N-]=[N+]=NC[C@@H]1CN(c2ccc(N3CCC(=O)CC3)cc2)C(=O)O1
Agent: CCOP(=O)(CC#N)OCC
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CC=C1CCN(c2ccc(N3C[C@@H](CN=[N+]=[N-])OC3=O)cc2)CC1
Reaction time: 5 h

Procedure:
The mixure of triethylamine (13.8 mmol), lithium bromide (8.2 mmol) and diethylcyanomethylphosphonate (7.2 mmol) in 25 ml tetrahydrofuran was stirred for 20 minutes at room temperature. To the suspension, (S)-{3-[4-(4-oxo-piperidin-1-yl)-phenyl]-2-oxo-oxazolodin-5-ylmethyl}-azide (6.9 mmol) was added. The reaction mixture stirred for 5 hours.