Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][NH:15][C:14](=[O:18])[CH2:13]1)=[N:7][N:6]=[CH:5]2.[CH3:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][C:21]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CCO.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>[CH3:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][C:21]=1[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][NH:15][C:14](=[O:18])[CH2:13]1)=[N:7][N:6]=[CH:5]2
Reactant: Cc1ccc(C(N)=O)cc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C1CN(c2nncc3cc(Br)ccc23)CCN1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: COCCOC
Product: Cc1ccc(C(N)=O)cc1-c1ccc2c(N3CCNC(=O)C3)nncc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 55.3 %

Procedure:
A mixture of 4-(6-bromophthalazin-1-yl)piperazin-2-one (0.1 g, 0.3 mmol), 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.09 g, 0.3 mmol), and tetrakis(triphenylphosphine)palladium (0.02 g, 0.02 mmol) in 5 mL DME/EtOH (4:1) was treated with 2M potassium carbonate (0.5 mL, 1.0 mmol). The mixture resulted was warmed up to 90° C. and stirred for 1 h under nitrogen. The mixture was cooled down to room temperature, and the crude product was purified via flash chromatography (silica gel) eluting with a gradient of 4% 2 M ammonia in MeOH/DCM to 6% 2 M ammonia in MeOH/DCM to give the title compound (60 mg) as a pale yellow solid. Found MS (ES+): 362(M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:36])(=[N:27][C:28](=[O:35])[NH:29][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:26])=[CH:21][CH:20]=1>>[CH:30]1([NH:29][C:28]([N:27]=[S:25]([C:22]2[CH:21]=[CH:20][C:19]([NH:18][C:2]3[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]4[S:14][CH:15]=[CH:16][CH:17]=4)=[CH:4][N:3]=3)=[CH:24][CH:23]=2)([CH3:36])=[O:26])=[O:35])[CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: CS(=O)(=NC(=O)NC1CCCC1)c1ccc(N)cc1
Reactant: C[C@H](CO)Nc1nc(Cl)ncc1-c1cccs1
Product: C[C@H](CO)Nc1nc(Nc2ccc(S(C)(=O)=NC(=O)NC3CCCC3)cc2)ncc1-c1cccs1
Yield: 18 %

Procedure:
In the reaction of (R)-2-(2-chloro-5-(2-thienyl)pyrimidine-4-ylamino)propan-1-ol (103.4 mg, 0.38 mmol) with (RS)—S-(4-aminophenyl)-N-(cyclopentylcarbamoyl)-S-methylsulphoximide (98 mg, 0.35 mmol) according to procedure 5c, the desired product is obtained in 18% yield (33 mg) after chromatographic purification (silica gel, dichloromethane/ethanol (0%-20% ethanol)).
Reaction SMILES: [Na].[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[C:5](Cl)[N:4]=1.[Na+].[Cl-].[CH2:13]([OH:17])[CH:14]([CH3:16])[CH3:15]>>[CH3:15][CH:14]([CH3:16])[CH2:13][O:17][C:5]1[N:4]=[C:3]([NH2:2])[N:8]=[C:7]([NH2:9])[CH:6]=1
Reactant: CC(C)CO
Reactant: Nc1cc(Cl)nc(N)n1
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Product: CC(C)COc1cc(N)nc(N)n1
Reaction time: 10 h
Yield: 75 %

Procedure:
To a solution of 6.9 g (0.30 mol) sodium in 185 ml isobutyl alcohol were added 43.4 g (0.30 mol) 2,4-diamino-6-chloropyrimidine. The mixture was heated under reflux with stirring for 10 h. The reaction mixture was then stirred at 80° C. for a further 36 h. After the reaction was ended the precipitated NaCl was separated off and the solution was concentrated to dryness. The residue was repeatedly taken up in ethanol and again concentrated in order to remove residual isobutyl alcohol. After drying, 6-(2-methylpropoxy)-2,4-diaminopyrimidine (41.3 g, 75%) was obtained as a yellow oil.
Reaction SMILES: [F:1][C:2]1([F:44])[CH2:7][CH2:6][CH2:5][C@H:4]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([S:16]([N:19](CC3C=CC(OC)=CC=3OC)[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:18])=[O:17])=[C:11]([F:37])[CH:10]=2)[C@H:3]1[C:38]1[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:44][C:2]1([F:1])[CH2:7][CH2:6][CH2:5][C@H:4]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([S:16]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:17])=[O:18])=[C:11]([F:37])[CH:10]=2)[C@H:3]1[C:38]1[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CCCC(F)(F)[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@@H]1[C@@H](Oc2cc(F)c(S(=O)(=O)Nc3ccncn3)cc2F)CCCC1(F)F
Yield: 114.4 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 4-{[(1S*,2R*)-3,3-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (260 mg, 0.398 mmol) prepared in Example 117e, triethylsilane (0.20 mL), trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), to yield the title compound (221 mg, 90%) as a colorless solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:26][NH:27][O:28][CH3:29]>C(Cl)Cl.CCOCC>[CH3:29][O:28][N:27]([CH3:26])[C:10](=[O:12])[CH2:9][C:6]1[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1
Reactant: CNOC
Reactant: CSc1ccc(CC(=O)O)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCOCC
Product: CON(C)C(=O)Cc1ccc(SC)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92.8 %

Procedure:
To a solution of 4-(methylthio)phenylacetic acid (18.3 g, 0.100 mol) in methylene chloride (200 mL) was added 1,1'-carbonyldiimidazole (16.3 g, 0.100 mol) portionwise. The mixture was stirred at room temperature for 20 minutes, and N,O-dimethylhydroxylamine hydrochloride (9.8 g, 0.100 mol) was added. The reaction mixture was stirred overnight at room temperature, diluted with ether (500 mL) and washed successively with 1N hydrochloric acid, saturated aqueous sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated in vacuo to give 20.9 g of N-methoxy-N-methyl-4-(methylthio)-benzeneacetamide as a clear oil (93%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[CH3:10][C:11]1([CH3:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12]1=[O:20]>>[CH3:10][C:11]1([CH3:21])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:1]([O-:4])=[O:2])[CH:18]=2)[NH:13][C:12]1=[O:20]
Reactant: CC1(C)C(=O)Nc2ccccc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC1(C)C(=O)Nc2ccc([N+](=O)[O-])cc21
Reaction time: 0.5 h

Procedure:
A solution of 22 ml. fuming nitric acid in 200 ml. 80% sulphuric acid is added dropwise, with cooling, to a solution of 100 g. (0.62 mol) 3,3-dimethylindolin-2-one in 500 ml. 80% sulphuric acid. The reaction mixutre is then stirred for about 30 minutes, poured on to ice, filtered with suction, washed with water and dried. Yield: 100 g. (78% of theory); m.p. 192°-196° C. (ethyl acetate/heptane).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:14][C@@H:13]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12](=[O:22])[O:11][C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([OH:25])[CH3:24].C1(C)C=CC=CC=1>>[CH2:23]([O:25][C:12]([C@H:13]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:14][C@@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([OH:11])=[O:10])=[O:22])[CH3:24]
Reactant: O=C1OC(=O)[C@H](Cc2ccccc2)C[C@H]1Cc1ccccc1
Reactant: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@H](Cc1ccccc1)C[C@@H](Cc1ccccc1)C(=O)O

Procedure:
The starting material is prepared as follows: 4.0 g of (S,S)-2,4-dibenzylglutaric anhydride is refluxed in 40 ml of ethanol:toluene (3:2) overnight. The reaction mixture is concentrated to yield 4-ethoxycarbonyl-(S,S)-2,4-dibenzylbutyric acid as an oil. Oxalyl chloride (3.5 ml) is added to the solution of 4.5 g of 4-ethoxycarbonyl-(S,S)-2,4-dibenzylbutyric acid in 10 ml of methylene chloride. The mixture is stirred at room temperature overnight and evaporated to yield 4-ethoxycarbonyl-(S,S)-2,4-dibenzylbutyryl chloride, which is used as such without further purification.
Reaction SMILES: [OH:1][C@H:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][C@@H:4]([C:10]([CH3:12])=[CH2:11])[C@@H:3]1[C:13]([O:15][CH3:16])=[O:14].[H-].[Na+].[CH3:19]I>CN(C)C=O>[CH3:19][O:1][C@H:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][C@@H:4]([C:10]([CH3:12])=[CH2:11])[C@@H:3]1[C:13]([O:15][CH3:16])=[O:14]
Reactant: C=C(C)[C@@H]1CCC(C)(C)[C@H](O)[C@H]1C(=O)OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(C)[C@@H]1CCC(C)(C)[C@H](OC)[C@H]1C(=O)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
A mixture of the above alcohol (1.15 g) and sodium hydride (230 mg, 60% dispersion in oil) and methyl iodide (0.6 ml) in dry N,N-dimethylformamide was stirred for 3 hrs at room temperature. The mixture was cooled to 0° C., and reaction was quenched by addition of water. The pH of the mixture was adjusted to pH 7 with 0.1N hydrochloric acid. The mixture was extracted with diethyl ether, and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to give methyl (1S,2R,6R)-2-methoxy-3,3-dimethyl-6-(1-methylvinyl)-cyclohexane-1-carboxylate (1.12 g, 92% yield).
Reaction SMILES: [NH2:1]/[C:2](/OCC)=[CH:3]\[C:4](=O)[C:5]([F:8])([F:7])[F:6].[CH3:13][NH:14][NH2:15]>CCO>[CH3:13][N:14]1[C:2]([NH2:1])=[CH:3][C:4]([C:5]([F:8])([F:7])[F:6])=[N:15]1
Reactant: CCO/C(N)=C/C(=O)C(F)(F)F
Reactant: CNN
Solvent: CCO
Product: Cn1nc(C(F)(F)F)cc1N
Yield: 82.1 %

Procedure:
Using the procedure described in Example 161A Step 3, (E)-4-amino-4-ethoxy-1,1,1-trifluorobut-3-en-2-one (2.34 g, 12.78 mmol) and methylhydrazine (0.645 g, 14 mmol) were reacted in EtOH (10 mL) at 95° C. for 8 hours, and purified by silica gel chromatography with 30-40% EtOAc/hexane as eluants to afford 1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-amine as solid (1.733 g, 68.3%). MP: 100-101° C.; 1H NMR (300 MHz, CDCl3) δ 5.80 (s, 1H), 3.71 (s, 3H), 3.62 (br, 2H); LC-MS (ESI) m/z 166 (M+H)+.
Reaction SMILES: [Li][CH2:2]CCC.[C:6]([C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])(=O)[CH3:7]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:7]=[C:6]([C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])[CH3:2]
Reactant: CC(=O)c1cccc(C#N)c1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C(C)c1cccc(C#N)c1
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To the methyl triphenylphosphoniumbromide (4.3 grn, 12 mmol) in THF at 0° C., n-BuLi (1.6M, 7.5 ml, 12 mmol) was added and stirred for 30 min. Then 3-acetylbenzonitrile in THF was slowly added and the reaction mixture was stirred at 0° C. for further 3 h. Then reaction mixture was quenched with aqeous ammonium chloride and diluted with ethyl acetate. Organic layer was washed with water, brine and dried. Crude residue after column purification yielded 3-(prop-1-en-2-yl)benzonitrile in 86% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH3:14].C([Li])CCC.[O:20]1[C:22]([CH3:39])([CH2:23][CH2:24][CH2:25][CH:26]([CH3:38])[CH2:27][CH2:28][CH2:29][CH:30]([CH3:37])[CH2:31][CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH2:21]1.O>O1CCCC1>[CH3:12][O:11][C:6]1[C:7]([CH3:10])=[C:8]([CH3:9])[C:3]([O:2][CH3:1])=[C:4]([CH3:14])[C:5]=1[CH2:13][CH2:39][C:22]([CH3:21])([OH:20])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:38])[CH2:27][CH2:28][CH2:29][CH:30]([CH3:37])[CH2:31][CH2:32][CH2:33][CH:34]([CH3:35])[CH3:36]
Reactant: CC(C)CCCC(C)CCCC(C)CCCC1(C)CO1
Reactant: COc1c(C)c(C)c(OC)c(C)c1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1c(C)c(C)c(OC)c(CCC(C)(O)CCCC(C)CCCC(C)CCCC(C)C)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
1.8 g (9 mmol) of 2,5-dimethoxy-1,3,4,6-tetramethylbenzene were dissolved in 100 ml of tetrahydrofuran, treated with 1 g (9 mmol) of potassium tert.butylate and subsequently 6 ml (9.5 mmol) of n-butyllithium (1.6 molar) were added dropwise at room temperature. Thereafter, the mixture was stirred at room temperature for 30 minutes, treated dropwise with 2.7 g (9 mmol) of (2RS,6RS,10RS)-1,2-epoxy-2,6,10,14-tetramethylpentadecane and stirred at room temperature for 16 hours. Thereupon, HYFLO and 200 ml of water were added, the mixture was then filtered and washed with water. The residue was stirred up with diethyl ether and sodium sulphate, filtered, washed with diethyl ether and concentrated. There were obtained 3.8 g of (3RS,7RS,11RS)-1-(2,5-dimethoxy-3,4,6-trimethylphenyl)-3,7,11,15-tetramethyl-3-hexadecanol.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([CH2:10][N:11]3[C:16]4([CH2:21][CH2:20][N:19]([C:22]5[CH:31]=[N:30][C:29]6[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=6)[N:23]=5)[CH2:18][CH2:17]4)[CH2:15][CH2:14][CH2:13][C:12]3=[O:32])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH3:35]I.O>C1COCC1>[CH3:35][N:1]1[C:9]2[C:4](=[C:5]([CH2:10][N:11]3[C:16]4([CH2:17][CH2:18][N:19]([C:22]5[CH:31]=[N:30][C:29]6[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=6)[N:23]=5)[CH2:20][CH2:21]4)[CH2:15][CH2:14][CH2:13][C:12]3=[O:32])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C1CCCC2(CCN(c3cnc4ccccc4n3)CC2)N1Cc1cccc2[nH]ccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1ccc2c(CN3C(=O)CCCC34CCN(c3cnc5ccccc5n3)CC4)cccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
The title compound was synthesized from 1-((1H-indol-4-yl)methyl)-9-(quinoxalin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one (prepared according to method G) via methylation as follows: NaH (7 mg, 0.18 mmol, 60% in mineral oil) was added to an ice-cold solution of 1-((1H-indol-4-yl)methyl)-9-(quinoxalin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one (synthesized according to method G) (25 mg, 0.06 mmol) in THF (5 mL). The resulting mixture was stirred at rt for 10 min. The mixture was cooled to 0° C., methyl iodide (26 mg, 0.18 mmol) was added at 0° C. and stirring was continued at 0° C. for 1 h. Then the mixture was allowed to warm to rt over a period of 1 h. The mixture was poured into water and the solution was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, filtered and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure. The product was purified by preparative reversed phase HPLC (column Zorbax eclipseXDB C18 21.2×150 mm 5 ♀m, flow 20 mL/min, eluent: gradient water/acetonitrile) to yield the title compound (13 mg, 50%). [1H NMR (300 MHz, CDCl3) ♀ ppm 8.49 (s, 1H), 7.88 (d, 1H), 7.68-7.50 (m, 2H), 7.45-7.35 (m, 1H), 7.21-7.08 (m, 2H), 6.95 (d, 1H), 6.73 (d, 1H), 6.35 (d, 1H), 4.98 (s, 2H), 4.40 (d, 2H), 3.78 (s, 3H), 3.15 (t, 2H), 2.68 (t, 2H), 2.25-2.05 (m, 4H), 2.00-1.85 (m, 2H), 1.80-1.70 (m, 2H); LCMS RtF=1.50 min, [M+H]+=440.0].
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:18]=[C:17]4[C:13]([CH:14]=[N:15][N:16]4[S:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)(=[O:21])=[O:20])=[C:12]([C:28]4[NH:32][N:31]=NN=4)[CH:11]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Cl:33][CH2:34][C:35](Cl)=[O:36]>C(Cl)(Cl)Cl>[Cl:33][CH2:34][C:35]1[O:36][C:28]([C:12]2[CH:11]=[C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[CH:3]=[CH:2][NH:1]4)[CH:18]=[C:17]3[C:13]=2[CH:14]=[N:15][N:16]3[S:19]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)(=[O:20])=[O:21])=[N:32][N:31]=1
Reactant: O=S(=O)(c1ccccc1)n1ncc2c(-c3nnn[nH]3)cc(-c3cccc4[nH]ccc34)cc21
Reactant: O=C(Cl)CCl
Solvent: ClC(Cl)Cl
Product: O=S(=O)(c1ccccc1)n1ncc2c(-c3nnc(CCl)o3)cc(-c3cccc4[nH]ccc34)cc21
Temperature: 100 °C
Yield: 15.2 %

Procedure:
6-(1H-Indol-4-yl)-1-(phenylsulfonyl)-4-(1H-tetrazol-5-yl)-1H-indazole (1.41 g, 3.19 mmol) was slurried into anhydrous chloroform (20 ml), treated with chloroacetyl chloride (1.023 ml, 12.78 mmol) and heated at 100° C. in a Biotage Initiator microwave for 30 mins, the mixture was split into 4 batches for the microwave reaction. The mixtures were allowed to cool to room temperature and the resultant precipitate collected by filtration to give the title compound as a yellow/brown solid (0.237 g). LCMS (Method A): Rt 1.25 mins, MH+490.
Reaction SMILES: [C:1](=[O:8])([O:5][CH2:6][CH3:7])OCC.[H-].[Na+].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][CH:13]=1>C1C=CC=CC=1>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]([C:1]([O:5][CH2:6][CH3:7])=[O:8])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:16][CH:17]=1
Reactant: CCOC(=O)OCC
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCOC(=O)C(C(=O)OCC)c1ccc(Br)cc1
Yield: 89.2 %

Procedure:
Under argon flow, 10.85 g of diethyl carbonate was dissolved in 60 ml of benzene, and 2.75 g of 60% sodium hydride was added and the mixture was heated to reflux. A solution of 5.58 g of ethyl 4-bromophenylacetate/20 ml of benzene was added dropwise to the solution over 1 hour, and the mixture was heated to reflux for 1 hour. After cooling, ice-cold water was added dropwise to the reaction solution slowly. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane: ethyl acetate=10:1) to provide 6.45 g of the objective compound as colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(N[C:14]1[CH:19]=CC(O)=C(CC=C)[CH:15]=1)(=O)C>>[CH2:19]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[OH:1])[CH:6]=[O:7])[CH:14]=[CH2:15]
Reactant: O=Cc1ccc(O)cc1
Reactant: C=CCc1cc(NC(C)=O)ccc1O
Product: C=CCc1cc(C=O)ccc1O

Procedure:
The starting 3-allyl 4-hydroxybenzaldehyde was prepared from 4-hydroxybenzaldehyde using the method described in Example 1 for the preparation of 4-acetamido-2-allylphenol.
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][NH2:5].[CH2:6]([CH2:10][C:11](=O)[CH3:12])[C:7]([CH3:9])=O.C([O-])(=O)C.[K+]>C(O)(=O)C.O>[Br:2][CH2:3][CH2:4][N:5]1[C:11]([CH3:12])=[CH:10][CH:6]=[C:7]1[CH3:9]
Reactant: CC(=O)CCC(C)=O
Reactant: NCCBr
Agent: Br
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(C)n1CCBr
Temperature: 80 °C
Reaction time: 2 h
Yield: 46.8 %

Procedure:
To a solution of 2-bromoethylamine hydrobromide (20.5 g, 0.1 mol) and acetonylacetone (12.5 ml, 0.1 mol) in acetic acid (10 ml) was added potassium acetate (10 g, 0.1 mol), and the mixture was stirred for 1 h at 20° C. and for 2 h at 80° C. The reaction mixture was diluted with water (150 ml) and extracted with diethyl ether (150 ml). The extract was washed with brine and concentrated in vacuo to afford an oily residue. The residue was distilled at 60-64° C./0.5 mm of mercury to afford the title compound as a colourless oil (9.45 g, 47%).
Reaction SMILES: C[O:2][C:3]1[CH:10]=[C:9]([O:11]C)[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].[C:13](Cl)(=[O:15])[CH3:14].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[C:13]([C:8]1[C:9]([OH:11])=[CH:10][C:3]([OH:2])=[C:4]([CH:7]=1)[CH:5]=[O:6])(=[O:15])[CH3:14]
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cc(C=O)c(O)cc1O
Temperature: 0 °C

Procedure:
To a mixture of 49.8 g of 2,4-dimethoxybenzaldehyde, 23.6 ml of acetyl chloride, and 1000 ml of methylene chloride cooled to approximately 0° C. were added 119.7 g of aluminum chloride with stirring under a nitrogen atmosphere. The reaction was allowed to warm to room temperature while stirring overnight. The mixture was added to a slurry of ice and concentrated hydrochloric acid. The organic layer was separated and washed with a saturated sodium chloride solution, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by high pressure liquid chromatography over silica gel eluting with a 0-40% ethyl acetate in hexane gradient. The appropriate fractions were pooled and concentrated to provide 5.85 g of the desired title intermediate, m.p.=142°-143° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[N:5]=[C:4]1[CH2:12][OH:13])[CH3:2].O[C:15]1[CH:47]=[CH:46][C:18]([CH2:19][CH:20]2[S:24][C:23](=[O:25])[N:22]([C:26]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]2=[O:45])=[CH:17][CH:16]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1>[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[N:5]=[C:4]1[CH2:12][O:13][C:15]1[CH:47]=[CH:46][C:18]([CH2:19][CH:20]2[S:24][C:23](=[O:25])[N:22]([C:26]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]2=[O:45])=[CH:17][CH:16]=1)[CH3:2]
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCn1c(CO)nc2cccnc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: CCn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2cccnc21

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 0.5 g of 3-ethyl-2-hydroxymethylimidazo[5,4-b]pyridine (prepared as described in Preparation 28), 1.313 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 0.77 ml of tributylphosphine, 0.712 g of 1,1'-(azodicarbonyl)dipiperidine and 80 ml of benzene were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a 1:3 by volume mixture of hexane and ethyl acetate as the eluent, to give 300 mg of the title compound having Rf=0.55 (on silica gel thin layer chromatography using a 1:3 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: [NH2:1][N:2]1[C:10]2[C:6]([N:7]3[N:13]([CH3:14])[C:12](=[O:15])[N:11]([CH2:16][CH2:17][OH:18])[CH:8]3[N:9]=2)=[C:5]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:4]=[CH:3]1.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.CCCCCC>N1C=CC=CC=1>[CH3:34][C:24]1[CH:29]=[CH:28][C:27]([S:30]([O:18][CH2:17][CH2:16][N:11]2[CH:8]3[N:9]=[C:10]4[C:6]([N:7]3[N:13]([CH3:14])[C:12]2=[O:15])=[C:5]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:4]=[CH:3][N:2]4[NH2:1])(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: CN1C(=O)N(CCO)C2N=C3C(=C(c4ccco4)N=CN3N)N21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CCCCCC
Product: Cc1ccc(S(=O)(=O)OCCN2C(=O)N(C)N3C4=C(c5ccco5)N=CN(N)C4=NC23)cc1
Temperature: 26 °C
Reaction time: 16 h
Yield: 79.1 %

Procedure:
A mixture of 5-amino-8-(2-furyl)-3-(2-hydroxyethyl)-1-methyl-[1,2,4]triazolo[5,1-f]purin-2-one obtained in step 6 (3.5 g, 11 mmol), p-toluene sulphonylchloride (5.2 g, 27 mmol) were taken in pyridine (30 ml) and stirred at 25-27° C. for 16 hours. To the reaction mixture hexane (100 ml) was added and solid obtained was filtered off and washed with water (100 ml) followed by hexane (100 ml) to obtain 2-[5-amino-8-(2-furyl)-1-methyl-2-oxo-[1,2,4]triazolo[5,1-f]purin-3-yl]ethyl 4-methylbenzenesulfonate (4.1 g, 78%) as a brown solid.
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([C:22]([OH:24])=[O:23])[CH:14]([C:18]([F:21])([F:20])[F:19])[O:15]2)=[CH:10][C:9]=1[Cl:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([C:22]([OH:24])=[O:23])[C@@H:14]([C:18]([F:20])([F:21])[F:19])[O:15]2)=[CH:10][C:9]=1[Cl:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1=Cc2cc(Cl)c(Cc3ccccc3)cc2OC1C(F)(F)F
Solvent: CO
Product: O=C(O)C1=Cc2cc(Cl)c(Cc3ccccc3)cc2O[C@@H]1C(F)(F)F

Procedure:
A racemic mixture of the compound prepared in Example 9k, Step 3 was chirally resolved using the same protocol as for Example 9d, Step 1 as peak 1 with retention time 4.27 min: ESHRMS m/z 367.0343 (M−H, C18H11ClF3O3, Calc'd 367.0329). 1HNMR (DMSO-d6/400 MHz) 13.34 (brs, 1H), 7.81 (s, 1H), 7.61 (s, 1H), 7.25-7.29 (m, 2H), 7.17-7.19 (m, 3H), 6.99 (s, 1H), 5.89 (q, 1H, J=7.1 Hz), 4.00 (s, 2H). [a]25589=−1.4 degrees (in MeOH).