Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7](Br)=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[Cl-].[Li+].C([Mg]Cl)(C)C.CN([CH:20]=[O:21])C>C1COCC1>[Br:1][C:2]1[C:7]([CH2:20][OH:21])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: CN(C)C=O
Reactant: Clc1cnc(Br)c(Br)c1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc(Cl)cnc1Br
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a solution of 2,3-dibromo-5-chloropyridine (60 g, 221 mmol) in THF (500 mL) was added a solution of isopropylmagnesium chloride lithium chloride solution in THF (1.3M, 185 mL) at −40° C. over about 30 min. The solution was stirred for 30 min at −40° C. and DMF (50 mL) was added. The resulting solution was warmed up to room temperature and stirred for 30 min. The reaction was quenched with 1 N HCl (400 mL) and MTBE (200 mL) was added. Organic layer was separated and washed twice with 5% aqueous NaHCO3 (200 mL). The solvent was removed under vacuum at 50° C. The resulting solids (aldehyde intermediate) were dissolved in methanol (400 mL). The solution was cooled to 5° C. under an ice bath. NaBH4 (3.6 g) was added slowly over 30 min while maintaining the reaction temperature below room temperature. The reaction mixture was stirred for another 30 min followed by addition of water (125 mL). The resulting mixture was concentrated under vacuum to approximately 150 ml. Solids precipitated during the concentration. The suspension was stirred vigorously at room temperature for 1 h and solids were collected by filtration. The wet cake was dried in a vacuum oven over night at 60° C. to give 1 (45.6 g, 93%) as a solid. 1H NMR (CDCl3, 400 MHz): δ 8.26 (d, J=2.5 Hz, 1H), 7.88 (d, J=2.5 Hz, 1H), 4.73 (d, J=5.8 Hz, 2H), 2.33 (t, J=11.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz): δ 147.12, 138.48, 138.39, 136.14, 132.06, 62.76.
Reaction SMILES: [OH:1][C:2]1[C:7]2[N:8]([CH3:17])[C:9]3[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][C:14]=3[C:6]=2[S:5](=[O:19])(=[O:18])[NH:4][C:3]=1[C:20]([O:22][CH3:23])=[O:21].[OH-].[Na+].[CH3:26]I>CO>[CH3:26][N:4]1[C:3]([C:20]([O:22][CH3:23])=[O:21])=[C:2]([OH:1])[C:7]2[N:8]([CH3:17])[C:9]3[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][C:14]=3[C:6]=2[S:5]1(=[O:19])=[O:18]
Reactant: COC(=O)C1=C(O)c2c(c3cc(OC)ccc3n2C)S(=O)(=O)N1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C1=C(O)c2c(c3cc(OC)ccc3n2C)S(=O)(=O)N1C
Yield: 85 %

Procedure:
20.4 gm (60 millimols) of methyl 2,5-dihydro-4-hydroxy-8-methoxy-5-methyl-1,2-thiazino[5,6-b]indole-3-carboxylate 1,1-dioxide were reacted analogous to Example 18 (f) wtih a sodium hydroxide solution and methyl iodide in methanol to yield 17.9 gm (85% of theory) of methyl 2,5-dihydro-2,5-dimethyl-4-hydroxy-8-methoxy-1,2-thiazino[5,6-b]indole-3-carboxylate 1,1-dioxide; M.p.: 200°-201° C.
Reaction SMILES: Cl.[CH3:2][C:3]1[NH:7][CH:6]=[N:5][C:4]=1[C:8]([OH:10])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C[Si](C)(C)NC(=O)C.[OH:40][CH2:41][CH2:42][NH:43][CH:44]1[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH2:45]1>C(#N)C.C(N(CC)CC)C>[OH:40][CH2:41][CH2:42][N:43]([C:8]([C:4]1[N:5]=[CH:6][NH:7][C:3]=1[CH3:2])=[O:10])[CH:44]1[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH2:45]1
Reactant: Cc1[nH]cnc1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(NCCO)CC1
Agent: CC(=O)N[Si](C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1[nH]cnc1C(=O)N(CCO)C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 57.7 %

Procedure:
5-Methylimidazole-4-carboxylic acid hydrochloride (G. Wellman et al., Synthesis, 356 (1984); 1.6 g) was suspended in acetonitrile (100 ml). HOBt (2.8 g) and WSC (3.5 g) were sequentially added thereto, and mixed at room temperature for 20 minutes (the reaction solution A). In a separate flask were dissolved tert-butyl 4-(2-hydroxyethyl)amino-1-piperidinecarboxylate (3.0 g) obtained in Example 91a), N-trimethylsilylacetamide (8.1 g) and triethylamine (5.0 ml) in acetonitrile (50 ml), and mixed at room temperature for 20 minutes (the reaction solution B). The reaction solution B was added to the reaction solution A, and mixed at room temperature for 15 hours. Acetonitrile was distilled off under reduced pressure, and then to the residue were added chloroform and water. The organic layer was collected by separation and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with basic silica gel column (ethyl acetate:ethanol=5:1) to obtain the title compound as a colorless oil (2.0 g, 59%).
Reaction SMILES: [S:1]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)([O:4][CH2:5][C@@:6]1([CH3:16])[CH2:10][O:9]C2(CCCCC2)[O:7]1)(=[O:3])=[O:2].CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[S:1]([C:17]1[CH:18]=[CH:19][C:20]([CH3:21])=[CH:22][CH:23]=1)([O:4][CH2:5][C@@:6]([OH:7])([CH3:16])[CH2:10][OH:9])(=[O:2])=[O:3]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@]2(C)COC3(CCCCC3)O2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)OC[C@](C)(O)CO)cc1

Procedure:
2.22 g (6.52 mmol) of {(R)-2-methyl-1,4-dioxaspiro[4,5]dec-2-yl}methyl tosylate are repeatedly evaporated from methanol in the presence of a catalytic amount of p-toluenesulfonic acid and the residue is finally purified by chromatography over silica gel 60 (0.040-0.063 mm, 55 g) using diethyl ether/methylene chloride (1:2) as the eluent. There are obtained 829 mg (3.18 mmol, 49% of the theoretical yield) of (R)-2,3-dihydroxy-2-methylpropyl tosylate, 98% pure by gas chromatography, [α]365 =-19.9° (1% in CHCl3).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([C:10]2[CH:19]=[C:18]([CH3:20])[C:13]3[NH:14][C:15](=[O:17])[O:16][C:12]=3[CH:11]=2)=[O:9])[CH:3]=1.[NH2:21][C:22]1[CH:23]=[C:24]2[C:37](=[CH:38][CH:39]=1)[CH2:36][C:26]1([C:34]3[C:29](=[N:30][CH:31]=[CH:32][CH:33]=3)[NH:28][C:27]1=[O:35])[CH2:25]2.C1(S(O)(=O)=O)C=CC=CC=1>CC(O)CCC>[CH3:20][C:18]1[C:13]2[NH:14][C:15](=[O:17])[O:16][C:12]=2[CH:11]=[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:21][C:22]3[CH:23]=[C:24]4[C:37](=[CH:38][CH:39]=3)[CH2:36][C:26]3([C:34]5[C:29](=[N:30][CH:31]=[CH:32][CH:33]=5)[NH:28][C:27]3=[O:35])[CH2:25]4)[N:7]=[CH:6][N:5]=2)=[O:9])[CH:19]=1
Reactant: Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)[nH]c12
Agent: O=S(=O)(O)c1ccccc1
Solvent: CCCC(C)O
Product: Cc1cc(C(=O)c2cc(Nc3ccc4c(c3)CC3(C4)C(=O)Nc4ncccc43)ncn2)cc2oc(=O)[nH]c12

Procedure:
144 mg (0.500 mmol) 6-(6-chloropyrimidine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one, 126 mg (0.500 mmol) 5-amino-1,3-dihydrospiro[inden-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one and 16.1 mg (0.100 mmol) benzenesulphonic acid were combined in 5.0 mL 2-pentanol and refluxed for 4 h. The reaction mixture was evaporated down, the residue was triturated with PE, suction filtered and washed with PE. The residue was purified by preparative HPLC, the fractions containing the product were combined and the organic solvent was eliminated i.vac. The aqueous phase was neutralised by the addition of 1N aqueous NaOH solution. The product precipitated as a solid was filtered off, washed with water and dried.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][CH:16]=3)[CH:13]=[N:12][CH:11]=2)[OH:9])=[C:6]([Cl:23])[N:5]=[CH:4][N:3]=1.ClC1C(C(C2C=NN(C)C=2C2C=CC(C)=CC=2)=O)=C(Cl)N=CN=1>C(OCC)(=O)C>[Cl:23][C:6]1[C:7]([C:8]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][CH:16]=3)[CH:13]=[N:12][CH:11]=2)=[O:9])=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1
Reactant: CCc1ccc(-n2cncc2C(O)c2c(Cl)ncnc2Cl)cc1
Agent: Cc1ccc(-c2c(C(=O)c3c(Cl)ncnc3Cl)cnn2C)cc1
Solvent: CCOC(C)=O
Product: CCc1ccc(-n2cncc2C(=O)c2c(Cl)ncnc2Cl)cc1

Procedure:
(4,6-Dichloropyrimidin-5-yl)[1-(4-ethylphenyl)-1H-imidazol-5-yl]methanol (C20) was converted to the product using a procedure analogous to that described for the synthesis of (4,6-dichloropyrimidin-5-yl)[1-methyl-5-(4-methylphenyl)-1H-pyrazol-4-yl]methanone (C5) in Example 1, step 5, except that the ethyl acetate layer was washed with aqueous sodium bicarbonate solution rather than aqueous sodium hydroxide solution. Recrystallization was not carried out in this case; the product was obtained as a solid. Yield: 701 mg, 2.02 mmol, 94%. LCMS m/z 346.9 (M+1). 1H NMR (500 MHz, CDCl3) δ 1.31 (t, J=7.6 Hz, 3H), 2.75 (q, J=7.6 Hz, 2H), 7.30-7.36 (m, 4H), 7.61 (br s, 1H), 7.85 (d, J=0.8 Hz, 1H), 8.85 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[N:6](O)[C:7]([C:17]2[CH:22]=[CH:21][NH:20][C:19](=[O:23])[CH:18]=2)=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]>CO>[C:1]([C:5]1[NH:6][C:7]([C:17]2[CH:22]=[CH:21][NH:20][C:19](=[O:23])[CH:18]=2)=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(-c2ccc(F)cc2)c(-c2cc[nH]c(=O)c2)n1O
Solvent: CO
Product: CC(C)(C)c1nc(-c2ccc(F)cc2)c(-c2cc[nH]c(=O)c2)[nH]1
Temperature: 10 °C
Reaction time: 8 h

Procedure:
To a solution of 4-[2-tert-butyl-4-(4-fluorophenyl)-1-hydroxy-1H-imidazol-5-yl]pyridin-2(1H)-one (28 g, 0.086 mol) in methanol (1 L) at 0° C. under nitrogen was added TiCl3 (10% w/w in 20% w/w HCl, 450 ml) over 45 minutes while maintaining the reaction temperature under 10° C. The solution was warmed to RT and stirred overnight. The methanol was removed under reduced pressure and the solution was made basic with saturated NaHCO3 and 5 N NaOH. Ethyl acetate was added and it was stirred for 4 hours. The solution was filtered through a Solka floc pad to remove the solids. The filtrate was extracted with EtOAc and the organic layer was then washed twice with brine, dried over Na2SO4 and concentrated to dryness to yield crude product. It was purified by flash chromatography using CH2Cl2/2%-10% methanol as an eluant to yield the title compound as a mixture of imidazole tautomers.
Reaction SMILES: [C:1]([O:5][C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([OH:16])([CH2:9]3)[CH2:7]1)[CH2:13]2)(=[O:4])[CH:2]=[CH2:3].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26].S([O-])([O-])(=O)=O.[Mg+2]>O.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([O:16][S:25]([CH3:24])(=[O:27])=[O:26])([CH2:9]3)[CH2:7]1)[CH2:13]2)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OC12CC3CC(CC(O)(C3)C1)C2
Reactant: CS(=O)(=O)Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=CC(=O)OC12CC3CC(C1)CC(OS(C)(=O)=O)(C3)C2
Temperature: 0 °C

Procedure:
A stirrer and a dropping funnel were equipped with a 3 L-glass reactor. Then, 222.3 g (1.0 mol) of Adamantate HA (manufactured by Idemitsu Kosan Co., Ltd.: 3-hydroxy-1-adamantyl acrylate), 151.8 g (1.5 mol) of dried triethylamine, and 2,000 mL of dried toluene were added into the glass reactor, and were stirred at 0° C. in an ice bath. Subsequently, 137.5 g (1.2 mol) of methanesulfonyl chloride was added thereto, and was stirred for 5 minutes. As a result of conducting gas chromatography-mass spectrography analysis, it was confirmed that the peak of the adamantate HA was completely disappeared. Subsequently, 100 mL of water was added into it, thereby unreacted methanesulfonyl chloride was deactivated. The reaction solution thus obtained was transferred to a 4 L-separating funnel, 800 mL of water was further added, and then the reaction solution was sufficiently stirred. After leaving at rest, the aqueous layer was removed. To remove the triethylamine, 500 mL of 0.5 N hydrochloric acid was added, and stirred. After leaving at rest, the aqueous layer was removed. Furthermore, an organic layer was washed using an aqueous saturated sodium hydrogen carbonate and an aqueous saturated sodium chloride. This organic layer was transferred to a conical flask, and 12.0 g (0.1 mol) of anhydrous magnesium sulfate was added. The magnesium sulfate was removed by filtration after being dried. Then, the toluene was distilled away from the filtrate by evaporation. As a result of conducting GC analysis, it was confirmed that compound 1 (chemical formula shown below) having purity of 95.4% was obtained (yield 301.6 g).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].Br[C:9]1[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)[C:3]1=[O:7]
Reactant: O=C1NCC[C@@H]1O
Reactant: Cc1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: Cc1cccc(N2CC[C@H](O)C2=O)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
(S)-3-Hydroxypyrrolidin-2-one (1.52 g, 15.0 mmol), 3-bromotoluene (2.57 g, 15.0 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.26 g, 0.45 mmol), palladium(II) acetate (0.067 g, 0.30 mmol) and cesium carbonate (7.33 g, 22.5 mmol) were mixed together in dioxane (50 mL) and stirred overnight at 80° C. overnight. The reaction mixture was washed with water (150 mL), and the aqueous layer was extracted with dichloromethane (3×150 mL). The combined organic layers were dried (sodium sulfate) and concentrated in vacuo. Chromatography over silica gel, eluting with hexanes/ethyl acetate, afforded the title compound as a white solid. 1H NMR (500 MHz, CDCl3) δ 7.47 (s, 1H), 7.42 (d, J=8.3 Hz, 1H), 7.26 (t, J=7.9 Hz, 1H), 7.00 (d, J=7.6 Hz, 1H), 4.81 (d, J=3.1 Hz, 1H), 4.56-4.49 (m, 1H), 3.80-3.70 (m, 2H), 2.60-2.53 (m, 1H), 2.37 (s, 3H), 2.16-2.06 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[S:18](Cl)(=[O:20])=[O:19]>>[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[S:18]([NH:9][C:3]1[C:2]([Br:1])=[N:7][C:6]([Br:8])=[CH:5][N:4]=1)(=[O:20])=[O:19]
Reactant: Nc1ncc(Br)nc1Br
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Product: O=S(=O)(Nc1ncc(Br)nc1Br)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 3,5-dibromo-2-pyrazinamine (2.9 g) and 2,3-dichloro benzenesulphonyl chloride (2.8 g). Yield 4.4 g.
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:5]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:6][C:7]2[C:12]([C:13]=1[C:14]([NH:16][C@H:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:18][CH3:19])=[O:15])=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:2].C[OH:33]>O.CCOC(C)=O>[CH2:1]([S:3]([C:4]1[C:5]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:6][C:7]2[C:12]([C:13]=1[C:14]([NH:16][C@H:17]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:18][CH3:19])=[O:15])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:33])[CH3:2]
Reactant: CCSc1c(-c2ccccc2)nc2ccccc2c1C(=O)N[C@@H](CC)c1ccccc1
Reactant: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CC[C@H](NC(=O)c1c(S(=O)CC)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 28.4 %

Procedure:
To a solution of 3-(ethylthio)-2-phenyl-N-[(1S)-1-phenylpropyl]quinolin-4-carboxamide (5) (300 mg, 0.70 mmol) in MeOH (25 mL) was added a solution of NaIO4 (300 mg, 1.4 mmol) in water (15 mL) while it was cooled to 0° C. The cooling bath was removed, and reaction allowed stir for 12 h. LCMS indicated no reaction take place. Added another 2 eq of NaIO4 and the reaction mixture was heated to reflux for 8 h. It was then diluted with EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10-35% EtOAc/CH2Cl2) to give the desired product (two diastereomers) as a solid (88 mg, 28.4%). 1H NMR (300 MHz, CDCl3) δ 0.97 (t, 3H), 1.21 (t, 3H), 2.01 (m, 2H), 2.71 (m, 2H), 5.21 (q, 1H), 7.21 (d, 2H), 7.34 (d, 2H), 7.39 (m, 2H), 7.78 (m, 2H), 7.84 (m, 2H), 8.00 (m, 1H), 8.11 (m, 2H), 8.14 (m, 1H), 8.16 (m, 1H). MS APCI, m/z=443 (M+1). LCMS: 2.15 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=[CH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[C:27]([F:30])([F:29])[F:28])[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:40])[C:18](=[O:39])[N:19]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[N:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[C:27]([F:28])([F:30])[F:29])[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:40])[C:18](=[O:39])[N:19]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:37])([CH3:36])[CH3:38])[N:20]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3cc(C(F)(F)F)c(C=C4CN(C(=O)OC(C)(C)C)C4)cc3N21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3cc(C(F)(F)F)c(CC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Reaction time: 14 h
Yield: 70 %

Procedure:
To a solution of 3-[4-methyl-3-oxo-7-trifluoromethyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylmethylene]-azetidine-1-carboxylic acid tert-butyl ester (0.072 g, 0.127 mmol) in CH3OH (10 mL) was added Pd(OH)2/C (0.02 g) and the mixture was stirred under an atmosphere of H2 (50 psi) for 14 hr. The reaction mixture was filtered and the filtrate was concentrated to give 3-[4-methyl-3-oxo-7-trifluoromethyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylmethyl]-azetidine-1-carboxylic acid tert-butyl ester (0.052 g, 70%) as a pale yellow powder. LC/MS (Table 1, Method 2) Rt=1.502 min.; MS m/z: 607 [M+23]+.
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=1)(=[O:3])C.[CH:18]([O:25][CH2:26][CH3:27])([O:22][CH2:23][CH3:24])OCC>C(O)C>[CH2:26]([O:25][CH:18]([O:22][CH2:23][CH3:24])[C:1]([C:4]1[CH:17]=[CH:16][C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=1)=[O:3])[CH3:27]
Reactant: CC(=O)c1ccc(C(=O)c2ccccc2)cc1
Reactant: CCOC(OCC)OCC
Solvent: CCO
Product: CCOC(OCC)C(=O)c1ccc(C(=O)c2ccccc2)cc1

Procedure:
78 g of 4-acetyl-benzophenone is boiled together with 500 ml of ethanol and 200 ml of triethyl orthoformate for 5 hours. The solvent is then distilled off under reduced pressure and the residue is subjected to fractional distillation. 4-(Diethoxyacetyl)-benzophenone is obtained; b.p. 200°/67 P.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)[C:5]1=[O:29])[CH3:3].Cl>CCOC(C)=O.C1COCC1.CCOC(C)=O>[NH:18]1[C:19]2[C:15](=[CH:14][C:13]([N:6]3[C:7]4=[N:8][CH:9]=[CH:10][CH:11]=[C:12]4[N:4]([CH:2]([CH3:1])[CH3:3])[C:5]3=[O:29])=[CH:21][CH:20]=2)[CH2:16][CH2:17]1
Reactant: CC(C)n1c(=O)n(-c2ccc3c(c2)CCN3C(=O)OC(C)(C)C)c2ncccc21
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)n1c(=O)n(-c2ccc3c(c2)CCN3)c2ncccc21
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of tert-butyl 5-[1-(1-methylethyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-indole-1-carboxylate in AcOEt/EtOH (1/1, 10 mL) was added 4N HCl in AcOEt (4 mL). The mixture was stirred at 80° C. for 2 h, evaporated, treated with saturated NaHCO3, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was suspended in IPE and the suspension was collected by filtration to give the title compound as white crystals (313 mg).
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].C1COCC1.[CH2:10]([N:12]([CH2:24][CH3:25])[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][C:14]=1[CH:21]([CH3:23])[CH3:22])[CH3:11]>>[CH2:24]([N:12]([CH2:10][CH3:11])[C:13]1[CH:20]=[CH:19][C:16]([CH:17]([OH:18])[C:1]#[CH:2])=[CH:15][C:14]=1[CH:21]([CH3:23])[CH3:22])[CH3:25]
Reactant: C#C[Mg]Br
Reactant: CCN(CC)c1ccc(C=O)cc1C(C)C
Solvent: C1CCOC1
Product: C#CC(O)c1ccc(N(CC)CC)c(C(C)C)c1
Yield: 83.8 %

Procedure:
In a manner analogous to example 1 e, the process is carried out by a reaction of 9.3 ml (4.7 mmol) of 0.5M ethynylmagnesium bromide/THF with 780 mg (3.5 mmol) of 4-diethylamino-3-isopropylbenzaldehyde. 720 mg of 1-(4-diethylamino-3-isopropylphenyl)prop-2-yn-1-ol are obtained in the form of a yellow oil (yield=83%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17](=O)[CH3:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH:20]([NH2:22])=[O:21].C(O)=O>>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH:17]([NH:22][CH:20]=[O:21])[CH3:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NC=O
Reactant: CC(=O)c1ccc2c(c1)ncn2-c1cccc(Br)c1
Solvent: O=CO
Product: CC(NC=O)c1ccc2c(c1)ncn2-c1cccc(Br)c1
Temperature: 190 °C
Reaction time: 7 h
Yield: 60 %

Procedure:
A mixture of 1-[1-(3-bromo-phenyl)-1H-benzoimidazol-5-yl]-ethanone (7.5 g, 23.8 mmol), formamide (9.5 ml, 23.8 mmol) and formic acid (22.4 ml, 595 mmol) was stirred at 190° C. for 7 hours. The cooled mixture was decanted. The residue was rendered alkaline by addition of saturated, aqueous sodium carbonate and extracted with ethyl acetate. The organic extract was dried over magnesium sulphate and concentrated in vacuo. The concentrate was eluted through silica gel with a mixture of dichloromethane, methanol and aqueous ammonia (9:1:0.1 v/v/v) to afford the desired product (60%).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])[NH:10][N:9]=1)=[O:7])C>CO>[CH3:17][C:16]([CH3:18])=[CH:15][CH2:14][CH2:13][C:11]1[NH:10][N:9]=[C:8]([C:6]([OH:7])=[O:5])[CH:12]=1
Reactant: CCOC(=O)c1cc(CCC=C(C)C)[nH]n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)=CCCc1cc(C(=O)O)n[nH]1
Yield: 87.6 %

Procedure:
Freshly prepared aq. NaOH (10 M in H2O, 11.85 mmol) was added to a stirring, room temperature solution of 50 (0.0.5269 g, 2.37 mmol) in MeOH (5.9 mL, 0.4 M) under N2. The reaction was then heated to reflux until the reaction was judged complete by HPLC (5 min): The reaction was concentrated, redissolved in H2O, and extracted with EtOAc. 10% aq. HCl was added dropwise to the aqueous layer until the pH=2. The white solid that precipitated from the reaction was filtered off and washed with cold H2O. The solid was dried under vacuum overnight to obtain 0.4034 g (87.6%) of 51. 1H (CD3OD, 400 MHz): δ 6.56 (1H, s), 5.14 (1H, t), 2.68 (2H, t, J=7.3 Hz), 2.33 (2H, q, J=7.3 Hz), 1.67 (3H, s), 1.56 (3H, s) ppm. 13C (CD3OD, 100 MHz): δ 164.94, 148.55, 143.23, 123.94, 107.32, 28.89, 27.04, 25.85, 17.69 ppm. DEPT (CD3OD, 100 MHz): CH3 carbons: 25.85, 17.69; CH2 carbons: 28.89, 27.04; CH carbons: 123.94, 107.32 ppm: HPLC: 8.475 min.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].FC(F)(F)C(O)=O.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:31][C:32]2[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:34][CH:33]=2)=[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][N:21]2[C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH:19]=1.C(=O)(O)[O-].[Na+]>>[NH2:13][C:14]1[C:15]([N+:1]([O-:4])=[O:2])=[CH:16][C:17]([O:31][C:32]2[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:39])=[O:40])=[CH:34][CH:33]=2)=[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][N:21]2[C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH:19]=1
Reactant: CS(=O)(=O)c1ccc(Oc2ccc(N)cc2C2CCCN2C(=O)C(F)(F)F)cc1
Reactant: O=[N+]([O-])[O-]
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(Oc2cc([N+](=O)[O-])c(N)cc2C2CCCN2C(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
153 mg of potassium nitrate was added to a trifluoroacetic acid (2 ml) solution of 588 mg of 1-(2-(5-amino-2-(4-methanesulfonyl-phenoxy)-phenyl)-pyrrolidin-1-yl)-2,2,2-trifluoro-ethanone, and the reaction liquid was stirred overnight at room temperature. Aqueous saturated sodium bicarbonate was added to the reaction liquid to neutralize it, and this was then extracted with ethyl acetate. The organic layer was washed with saturated saline, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=1/1) to obtain the entitled compound as a yellow solid.