Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][C:26]1[N:30]=[C:29]([NH2:31])[S:28][N:27]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:13]=[N:12]2)[C:8]([NH:31][C:29]2[S:28][N:27]=[C:26]([CH3:25])[N:30]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2ccccc2)cc1=O
Reactant: Cc1nsc(N)n1
Product: Cc1nsc(NC(=O)C(CC2CCCC2)n2ncc(Oc3ccccc3)cc2=O)n1
Yield: 12.1 %

Procedure:
Using the method described in Example 1, 3-cyclopentyl-2-(6-oxo-4-phenoxy-6H-pyridazin-1-yl)-propionic acid (Intermediate 19) and 3-methyl-[1,2,4]thiadiazol-5-ylamine afforded 3-cyclopentyl-N-(3-methyl-[1,2,4]thiadiazol-5-yl)-2-(6-oxo-4-phenoxy-6H-pyridazin-1-yl)-propionamide as a white solid (23.8 mg, 12.1%); ES+-HRMS m/e calcd for C21H23N5O3S [M+H+] 426.1595, found 426.1594. 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.01-1.77 (m, 9H), 2.03 (m, 1H), 2.27 (m, 1H), 2.44 (s, 3H), 5.57 (dd, J=4.5, J=10.6 Hz, 1H), 5.76 (d, J=2.8 Hz, 1H), 7.30 (d, J=7.5 Hz, 2H), 7.37 (t, J=7.5 Hz, 1H), 7.54 (t, J=7.5 Hz, 2H), 8.17 (d, J=2.8 Hz, 1H), 13.26 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:10](=[O:23])[CH:11]([CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH2:12][C:13]=2[O:14]C)=[C:4]([CH3:24])[CH:3]=1>Cl.CC(C)=O>[OH:1][C:2]1[CH:3]=[C:4]([CH3:24])[C:5]([CH:9]2[C:10](=[O:23])[CH:11]([CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH2:12][C:13]2=[O:14])=[C:6]([CH3:8])[CH:7]=1
Reactant: COC1=C(c2c(C)cc(O)cc2C)C(=O)C(CC2CCOCC2)C1
Agent: Cl
Solvent: CC(C)=O
Product: Cc1cc(O)cc(C)c1C1C(=O)CC(CC2CCOCC2)C1=O
Temperature: 120 °C

Procedure:
A solution of 2-(4-hydroxy-2,6-dimethylphenyl)-3-methoxy-5-(tetrahydropyran-4-ylmethyl)cyclopent-2-enone (0.375 g, 0.0014 mol) in a mixture of 2M hydrochloric acid (3 ml) and acetone (5 ml) is heated at 120° C. for 30 minutes under microwave irradiation. The reaction mixture is concentrated in vacuo then azeotroped with toluene to afford 2-(4-hydroxy-2,6-dimethylphenyl)-4-(tetrahydropyran-4-ylmethyl)cyclopentane-1,3-dione as a cream solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:3]=1[C:4]#[N:5].[OH-].[Na+]>C(O)C>[C:4]([C:3]1[CH:6]=[C:7]([CH:8]=[CH:9][C:2]=1[Cl:1])[NH2:10])#[N:5]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1cc(N)ccc1Cl
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
2-Chloro-5-nitrobenzonitrile (25 g, 137 mmol) was dissolved in ethanol (275 mL). Stannous chloride dihydrate (154.5 g, 0.685 M) was added and the mixture stirred at 70° C. for 30 min. The mixture was then cooled to room temperature and poured into crushed ice. The mixture was made basic with solid sodium hydroxide. This mixture was extracted with ethyl acetate (3×100 mL). The extracts were combined, washed with brine, dried (MgSO4), concentrated and the residue dried under vacuum and recrystallized from ethanol to yield light brown needles (10.6 g, 51%).
Reaction SMILES: [OH:1][N:2]=[C:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C([Li])CCC.I[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=1.Cl>O1CCCC1.CCCCCC>[OH:1][N:2]=[C:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][CH:21]=1
Reactant: CCOC(=O)C(C)c1ccc(CI)cc1
Reactant: ON=C1CCCCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C(C)c1ccc(CC2CCCCC2=NO)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 11.2 %

Procedure:
To a solution of 3.95 g of hydroxyiminocyclohexane in 40 ml of tetrahydrofuran was added 45 ml of 15% n-hexane solution of n-butyllithium at room temperature. After the mixture was stirred for 30 minutes at the same temperature, a solution of 9.4 g of ethyl 2-(4-iodomethylphenyl)propionate in 30 ml of tetrahydrofuran was added and stirring was continued for further 1 hour at room temperature. The reaction mixture was poured into a mixture of 100 ml of ice-water and 20 ml of concentrated hydrochloric acid, and extracted with ether. The product thus obtained was purified through a chromatography on a column of silica gel [eluent: ethyl acetate -- methylene chloride (1:3)] to afford 1.0 g of the starting compound recovered and 4.5 g of the desired compound, which by recrystallization from a mixture of ether and n-hexane yielded colorless crystals, m.p. 102°-104° C.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]1[C:13]([CH:16]=C)=[CH:14][N:15]=[C:8]1[C:7]([NH:18][CH2:19][CH2:20][CH2:21][OH:22])=[N:6]2.C[N+]1([O-])CC[O:29]CC1.I([O-])(=O)(=O)=O.[Na+]>CC(C)=O.O.O.[Os](=O)(=O)(=O)=O>[OH:22][CH2:21][CH2:20][CH2:19][NH:18][C:7]1[C:8]2[N:9]([C:13]([CH:16]=[O:29])=[CH:14][N:15]=2)[C:10]2[C:5]([N:6]=1)=[CH:4][C:3]([C:2]([F:23])([F:1])[F:24])=[CH:12][CH:11]=2
Reactant: C=Cc1cnc2c(NCCCO)nc3cc(C(F)(F)F)ccc3n12
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(C)=O
Solvent: O
Product: O=Cc1cnc2c(NCCCO)nc3cc(C(F)(F)F)ccc3n12
Temperature: 30 °C
Reaction time: 96 h

Procedure:
To a suspension of 3-{[7-(trifluoromethyl)-1-vinylimidazo[1,2-a]quinoxalin-4-yl]amino}propan-1-ol (33 mg, 0.099 mmol) in acetone-water (9:1, 1 mL), was added osmium tetroxide (2.5% wt. in t-BuOH, 53 mg, 0.05 mmol) and 4-methylmorpholine 4-oxide (25 mg, 0.20 mmol). The reaction mixture was stirred for 4 days at 30° C. under argon, and then a suspension of sodium periodate (85 mg, 0.40 mmol) in water (500 μL) was added. The mixture was stirred for one day at 30° C. under argon. Then it was filtered, washed with an aqueous saturated solution of Na2SO3 and extracted with ethyl acetate. The combined organic phases were dried over Na2SO4, concentrated in vacuo, filtered, concentrated to give, after purification by preparative TLC (dichloromethane/methanol 9/1), the title compound (24 mg, 70%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[N:12]=[C:11]2[S:13][C:14]3[CH2:15][NH:16][CH2:17][CH2:18][C:19]=3[C:10]2=[C:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:8]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:4][CH3:5])[CH3:2].[CH3:35][N:36]=[C:37]=[O:38]>O1CCCC1>[CH2:4]([N:3]([CH2:6][C:7]1[N:12]=[C:11]2[S:13][C:14]3[CH2:15][N:16]([C:37](=[O:38])[NH:36][CH3:35])[CH2:17][CH2:18][C:19]=3[C:10]2=[C:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:8]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:1][CH3:2])[CH3:5]
Reactant: CCOC(=O)c1c(CN(CC)CC)nc2sc3c(c2c1-c1ccc(OC)c(OC)c1)CCNC3
Reactant: CN=C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(CN(CC)CC)nc2sc3c(c2c1-c1ccc(OC)c(OC)c1)CCN(C(=O)NC)C3
Temperature: 25 °C
Reaction time: 5 h
Yield: 22 %

Procedure:
A mixture of the compound obtained in Example 5A (1.22 g), methyl isocyanate (0.17 g) and tetrahydrofuran (20 ml) was stirred at room temperature for 5 hours, after which it was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane-methanol (20:20:1, v/v) to yield ethyl 2-(N,N-diethylaminomethyl)-4-(3,4-dimethoxyphenyl)-7-methylcarbamoyl-5,6,7,8-tetrahydrothieno[2,3-b:5,4-c']dipyridine-3-carboxylate (for structural formula, see below), (0.30 g, 22%), which was then recrystallized from ethyl acetate-hexane to yield colorless prismatic crystals having a melting point of 153 to 155° C. ##STR53##
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:13][C:14]2[C:20]([F:21])=[CH:19][C:18]([F:22])=[CH:17][C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[F:22][C:18]1[CH:19]=[C:20]([F:21])[C:14]2[O:13][C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[N:16][C:15]=2[CH:17]=1
Reactant: Brc1ccccn1
Reactant: C#CCCc1nc2cc(F)cc(F)c2o1
Product: Fc1cc(F)c2oc(CCC#Cc3ccccn3)nc2c1
Yield: 20.1 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (236 mg, 1.49 mmol) and 2-(but-3-ynyl)-5,7-difluoro benzo[d]oxazole (309 mg, 1.49 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 86 mg (0.3 mmol, 20%) of 5,7-difluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a brown solid (M.P.: 93.5-94° C.).
Reaction SMILES: N12CCCC1=NCCC2.[CH2:10]1[CH2:15][CH:14]2[O:16][CH:13]2[CH2:12][CH2:11]1.[CH2:17]([SH:19])[CH3:18]>CO>[CH2:17]([S:19][CH:14]1[CH2:15][CH2:10][CH2:11][CH2:12][CH:13]1[OH:16])[CH3:18]
Reactant: C1CCC2OC2C1
Reactant: CCS
Agent: C1CN=C2CCCN2C1
Solvent: CO
Product: CCSC1CCCCC1O

Procedure:
Following the addition of 4 ml of DBN (1,5-diazabicyclo-[4,3,0]-non-5-ene), 98.1 g (1 mole) of cyclohexane oxide (Aldrich) were added dropwise to 65 g of ethane thiol (1.05 moles) in 300 ml of methanol. The mixture was kept under reflux overnight in a steam bath, the reflux temperature rising from 325° K. to 338° K. After adjustment to pH~8 with carbon dioxide, the methanol was distilled off and the residue was fractionated in vacuo.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:25])[CH2:12][CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([C:13]3[N:14]=[C:15]([N:18]4[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]4)[S:16][CH:17]=3)[CH:6]=[CH:5][C:4]1=2.CC1(C)[O:31][C@@H:30]([CH:32]=O)[CH2:29][O:28]1.Cl.CO.Cl>>[CH3:2][C:3]1([CH3:25])[CH2:12][CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([C:13]3[N:14]=[C:15]([N:18]4[CH2:23][CH2:22][CH:21]([NH:24][CH2:32][C@H:30]([OH:31])[CH2:29][OH:28])[CH2:20][CH2:19]4)[S:16][CH:17]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CC1(C)CCCc2cc(-c3csc(N4CCC(N)CC4)n3)ccc21
Reactant: CC1(C)OC[C@H](C=O)O1
Agent: Cl
Solvent: CO
Product: CC1(C)CCCc2cc(-c3csc(N4CCC(NC[C@H](O)CO)CC4)n3)ccc21

Procedure:
The preparation was carried out as already described above starting from 100 mg (0.27 mmol) of 1-[4-(5,5-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-4-ylamine hydrochloride and 34 mg (0.27 mmol) of (R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde. The protecting group was cleaved off as described by means of a 1.25 N HCl/methanol solution. The product was converted into the hydrochloride.
Reaction SMILES: C.CC.[CH3:4]CC.[CH3:7][CH2:8]CC.[CH2:11]([S:19]([OH:22])(=[O:21])=[O:20])[CH2:12][CH2:13][CH2:14]CCCC>CCCCCC>[CH4:4].[CH3:7][CH3:8].[CH3:11][CH2:12][CH3:13].[CH2:11]([S:19]([OH:22])(=[O:21])=[O:20])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCS(=O)(=O)O
Reactant: CCCC
Agent: C
Agent: CC
Solvent: CCCCCC
Solvent: CCC
Product: CCCCS(=O)(=O)O

Procedure:
In a Gotte foam beater (DIN 53 902, Part 1), methane, ethane, propane, butane, n-hexane and n-octane sulfonic acid were tested for their foaming behavior in 0.5% aqueous solution (0° Gh) at 40° C. The solutions of methane, ethane, propane and butane sulfonic acid did not produce any foam.
Reaction SMILES: C([C:10]1[NH:11][C:12]2[C:17]([C:18]=1[CH2:19][N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)=[CH:16][CH:15]=[CH:14][CH:13]=2)C1C=CC(OC)=CC=1.N1(CC2[C:39]3[C:34](=[CH:35][CH:36]=[C:37]([O:40]C)[CH:38]=3)NC=2)C=CN=C1>>[OH:40][C:37]1[CH:38]=[CH:39][C:34]([C:10]2[NH:11][C:12]3[C:17]([C:18]=2[CH2:19][N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:35][CH:36]=1
Reactant: COc1ccc(Cc2[nH]c3ccccc3c2Cn2ccnc2)cc1
Reactant: COc1ccc2[nH]cc(Cn3ccnc3)c2c1
Product: Oc1ccc(-c2[nH]c3ccccc3c2Cn2ccnc2)cc1

Procedure:
The procedure described in Example XLVII was repeated except that 2-(p-anisyl)-3-(imidazol-1-ylmethyl)indole was the starting material employed in place of 3-(imidazol-1-ylmethyl)-5-methoxyindole, using the same molar proportions as before. In this particular case, the solid product obtained was chromatographed on silica gel and then finally eluted with chloroform/methanol (20:1 by volume). Evaporation of the product-containing eluate then gave a solid material which was crystallized from ethanol to afford pure 2-(p-hydroxyphenyl)-3-(imidazol-1-ylmethyl)indole, m.p. 245°-247° C.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)=[O:16])=O)(C)(C)C.FC(F)(F)C(O)=O>>[NH2:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)=[O:16]
Reactant: CC(C)(C)OC(=O)Nc1cnccc1C(=O)Nc1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1cnccc1C(=O)Nc1ccc(Cl)cc1
Reaction time: 0.17 h
Yield: 93.2 %

Procedure:
To 3-(N-tert-butoxycarbonylamino)-N-(4-chlorophenyl)-pyridine-4-carboxamide (552 mg, 1.59 mmol) was added trifluoroacetic acid (3 mL, 38.95 mmol). After stirring for 10 min, the reaction mixture was concentrated, diluted with CH2Cl2, washed with satd Na2CO3, dried (Na2SO4) and concentrated to give the title compound (367 mg, 93%) as a pale yellow solid.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8])(=[O:3])[CH3:2].[CH2:13](O)[CH2:14][OH:15].O>C1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]1[O:15][CH2:14][CH2:13][O:8]1)(=[O:3])[CH3:2]
Reactant: OCCO
Reactant: CC(=O)Oc1ccccc1C=O
Solvent: c1ccccc1
Solvent: O
Product: CC(=O)Oc1ccccc1C1OCCO1

Procedure:
2-Hydroxygenzaldehyde (10 g) was dissolved in acetic anhydride (30 ml) and pyridine (30 ml) followed by stirring at room temperature for 3 hours. The reaction mixture was poured into ice-water and the resulting precipitate was recovered by filtration. The precipitate was dissolved in chloroform (100 ml), washed with water, dried and evaporated to give 2-acetoxybenzaldehyde. To a solution of 2-acetoxy-benzaldehyde (13 g) and ethyleneglycol (10 ml) in benzene (80 ml) was added Amberlist 15 (Rohm and Haas Co.) (3 g) and followed by refluxing for 5 hours. Water generated during refluxing was removed as an azeotropic mixture. The reaction mixture was washed with an aqueous solution of sodium bicarbonate, and then with water, and dried and evaporated. The residue was distilled under reduced pressure to collect a fraction distilled out at 115°-125° C./4 mmHg to give 10 g of 2-(2-acetoxyphenyl)-1,3-dioxolan. To a solution of 2-(2-acetoxy-phenyl)-1,3-dioxolan (19.6 g) in dichloromethane (50 ml), bis(trimethylsilyl)-5-fluorouracil prepared as in Example 1 from 5-fluorouracil (10 g) was added and treated as in Example 10 to give 4.2 g of crystalline 1-[α-(2-hydroxyethoxy)-2-acetoxybenzyl]-5-fluorouracil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.[NH2:14][C@H:15]1[CH2:20][C:19]2[C:21]([N:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)=[CH:22][CH:23]=[CH:24][C:18]=2[O:17][CH2:16]1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:31][N:28]1[CH2:29][CH2:30][N:25]([C:21]2[C:19]3[CH2:20][C@H:15]([NH:14][C:5](=[O:7])[C:4]4[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:3]=4[O:2][CH3:1])[CH2:16][O:17][C:18]=3[CH:24]=[CH:23][CH:22]=2)[CH2:26][CH2:27]1
Reactant: COc1ccc(C(=O)O)c(OC)c1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CO3)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COc1ccc(C(=O)N[C@@H]2COc3cccc(N4CCN(C)CC4)c3C2)c(OC)c1
Yield: 70.8 %

Procedure:
A solution of 2,4-dimethoxybenzoic acid (185 mg, 1.01 mmol) in thionyl chloride (5 mL) was heated at 55° C. for 15 min. The excess of thionyl chloride was removed in vacuo, and the residue was evaporated with two portions of toluene. The acid chloride was then dissolved in anhydrous methylene chloride (5 mL) and added to an ice-cooled solution of (S)-3-amino-5-(4-methylpiperazin-1-yl)-1,4-dihydro-2H-1-benzopyran (228 mg, 0.920 mmol) in anhydrous methylene chloride (20 mL) with stirring. The precipitated product was dissolved by the addition of triethylamine (193 μL, 1.38 mmol) to give a clear light yellow solution. The ice-bath was removed, and the reaction mixture was stirred at room temperature for 1 h. The mixture was washed with a saturated NaHCO3 solution, dried (MgSO4), and the solvent was removed in vacuo. The residue was purified by column chromatography on silica (eluent: chloroform/ethanol; 92.8+0.5% conc. NH3) affording 268 mg (71% yield) of the title compound as an oil: [α]21D−91° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 411 (4, M30 ). The base (238 mg, 0.578 mmol) was dissolved in anhydrous diethyl ether (10 mL) under nitrogen and was cooled on an ice-bath. A solution of HCl in diethyl ether (3 M, 0.5 mL), diluted with diethyl ether (5 mL), was added dropwise with stirring. The HCl salt was filtered, washed with diethyl ether, and dried in vacuo affording 187 mg (69% yield) of the product as a white powder: mp sinters>44° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:11][Si:12]([CH2:15][CH2:16][O:17][CH2:18]Cl)([CH3:14])[CH3:13].[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH2:18][O:17][CH2:16][CH2:15][Si:12]([CH3:14])([CH3:13])[CH3:11])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Clc1ncnc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2c(Cl)ncnc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (3.00 g, 19.5 mmol) in DMF (45 mL) was added SEM-Cl (5.20 mL, 29.3 mmol). The resulting mixture was placed under nitrogen and cooled to 0° C. in an ice bath. NaH (0.938 g of a 60% dispersion in mineral oil, 23.4 mmol) was added, the resulting yellow suspension was stirred at 0° C. for approximately 1 hour. The reaction was quenched with 10% aqueous NaCl (180 mL), and the resulting mixture was extracted with EtOAc (180 mL). The organic washings were washed with additional 10% aqueous NaCl (180 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to a crude oil. The oil was purified by column chromatography on silica gel eluting with EtOAc/hexane (2-20%) to afford the title compound as an oil. LRMS calc'd for C12H19ClN3OSi [M+H]+, 284; found 284. 1H NMR (500 MHz, CDCl3) δ 8.67 (s, 1H), 7.39 (d, 1H), 6.67 (d, 1H), 5.65 (s, 2H), 3.52 (t, 2H), 0.91 (t, 2H), 0.06 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16](F)=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)=[C:4]([F:24])[CH:3]=1.C([Si](C)(C)[O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][OH:36])(C)(C)C.C([Si](C)(C)OCCOC(O)C)(C)(C)C.C[Si](C)(C)[O-].[K+]>CS(C)=O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][OH:36])=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)=[C:4]([F:24])[CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCCOCCO
Reactant: O=[N+]([O-])c1cc2c(Nc3cc(Cl)c(Cl)cc3F)ncnc2cc1F
Agent: CC(O)OCCO[Si](C)(C)C(C)(C)C
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc2c(Nc3cc(Cl)c(Cl)cc3F)ncnc2cc1OCCOCCO
Temperature: 25 °C
Reaction time: 5 h
Yield: 24 %

Procedure:
(4,5-Dichloro-2-fluoro-phenyl-(7-fluoro-6-nitro-quinazolin-4-yl)-amine (Compound 25, 0.723 grams, 1.94 mmol), 2-[2-(tert-butyl-dimethyl -silanyloxy)-ethoxy]-ethanol (Compound 28a (0.64 grams, 2.9 mmol) and potassium trimethylsilanolate (0.75 gram, 5.83 mmol) were dissolved in dry DMSO (42 ml) and the resulting mixture was stirred under nitrogen atmosphere for 5 hours at 25° C. The obtained deep crimson mixture was thereafter extracted with ethyl acetate (EtOAc) and water, and the organic phase was washed with NaHCO3 (4%) and brine, and dried over Na2SO4. The solvent was then removed under reduced pressure and the residue was purified by silica gel column chromatography, using a mixture of 2% MeOH in CH2Cl2 as eluent, to obtain Compound 29a (0.217 gram, 24% yield).
Reaction SMILES: [C:1]([CH:5]1[CH2:12][CH2:11][CH2:10][C:9](=[CH:13][CH2:14][OH:15])[CH:8]([O:16][SiH:17]([CH3:19])[CH3:18])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]>ClCCl.[O-2].[O-2].[Mn+4]>[C:1]([CH:5]1[CH2:12][CH2:11][CH2:10][C:9](=[CH:13][CH:14]=[O:15])[CH:8]([O:16][SiH:17]([CH3:19])[CH3:18])[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[SiH](C)OC1CCC(C(C)(C)C)CCCC1=CCO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: C[SiH](C)OC1CCC(C(C)(C)C)CCCC1=CC=O
Temperature: 25 °C
Yield: 77.5 %

Procedure:
3.9 g of the above product (b) was dissolved in 150 ml of dichloromethane. To the solution was added 44 g of manganese dioxide while stirring at room temperature. After completion of adding the reagent, the reaction solution was stirred at room temperature for three days. The reaction solution was filtered and the filtrate was concentrated to afford 3.0 g of the titled product (c) as a colorless oily matter.
Reaction SMILES: [CH:1]1([C:6]2[C:7]([O:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[N:8][NH:9][C:10]=2[CH:11]([OH:13])[CH3:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl>[C:11]([C:10]1[NH:9][N:8]=[C:7]([O:14][S:15]([C:18]2[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=2)(=[O:17])=[O:16])[C:6]=1[CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:13])[CH3:12]
Reactant: Cc1ccc(S(=O)(=O)Oc2n[nH]c(C(C)O)c2C2CCCC2)cc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(=O)c1[nH]nc(OS(=O)(=O)c2ccc(C)cc2)c1C1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.4 %

Procedure:
To toluene-4-sulfonic acid 4-cyclopentyl-5-(1-hydroxyethyl)-1H-pyrazol-3-yl ester (3.65 g, 10.43 mmol) in dichloromethane (250 ml) was added pyridinium dichromate (3.92 g, 1 molar eq) and the resulting slurry was stirred at room temperature for 1 h. The mixture was poured directly onto a column of silica gel, and the crude product was eluted off with ethyl acetate. Evaporation and further purification on silica gel using 0 to 20% ethyl acetate in isohexane as eluent yielded toluene-4-sulfonic acid 5-acetyl-4cyclopentyl-1H-pyrazol-3-yl ester as a colourless oil (1.36 g). 1H NMR (400 MHz, CDCl3) δ 1.62-1.91 (8H, m), 2.46 (3H, 8), 2.53 (3H, s), 3.26 (1H, m), 7.37 (2H, d, J=6.8 Hz), 7.90 (2H, d, J=6.8 Hz); MS (ES+) m/e 349 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([NH2:16])=[O:15])[CH:12]=2)[C:7]([CH:17]=[O:18])=[CH:6]1.S(=O)(=O)(O)[OH:24]>CN(C)C=O>[C:14]([C:11]1[CH:12]=[C:13]2[C:8]([C:7]([C:17]([OH:24])=[O:18])=[CH:6][N:5]2[CH2:4][C:3]2[CH:19]=[CH:20][CH:21]=[CH:22][C:2]=2[Cl:1])=[CH:9][CH:10]=1)(=[O:15])[NH2:16]
Reactant: NC(=O)c1ccc2c(C=O)cn(Cc3ccccc3Cl)c2c1
Reactant: O=S(=O)(O)O
Solvent: CN(C)C=O
Product: NC(=O)c1ccc2c(C(=O)O)cn(Cc3ccccc3Cl)c2c1
Temperature: 20 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 1-(2-chlorobenzyl)-3-formylindole-6-carboxamide (47 mg) in dimethylformamide (1.6 ml) was added chromic anhydride (125 mg) and sulfuric acid (0.05 ml), and the mixture was stirred at 20° C. for 5 hours. The resulting mixture was evaporated in vacuo and the residue was chromatographed on silica gel eluting with a mixture of chloroform and methanol (9:1) to give 6-carbamoyl-1-(2-chlorobenzyl)indole-3-carboxylic acid (8.3 mg) as a solid.