Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8](=[O:22])C2C=C(C)C=CC=2C2C=NN(C)C=2)[C@@H:3]1[CH2:23][N:24]1[C:32](=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]1=[O:34].[C:35]1(C(O)=O)[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37][N:36]=1>>[C:35]1([C:8]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:2]([CH3:1])[C@H:3]2[CH2:23][N:24]2[C:25](=[O:34])[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:32]2=[O:33])=[O:22])[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37][N:36]=1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN2C(=O)c3ccccc3C2=O)c1
Reactant: O=C(O)c1nccc2ccccc12
Product: C[C@@H]1CCCN(C(=O)c2nccc3ccccc23)[C@@H]1CN1C(=O)c2ccccc2C1=O

Procedure:
The title compound was prepared following the same general protocol as described for 2-(((2S,3R)-3-methyl-1-(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoyl)piperidin-2-yl)methyl)isoindoline-1,3-dione in Example A1, using isoquinoline-1-carboxylic acid. ESI-MS (m/z): 414 [M+1]+.
Reaction SMILES: I[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.C([Mg][Cl:16])(C)C.[CH3:17][N:18]([CH:20]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C:22]1=[O:27])[CH3:19].[Cl-].[NH4+]>CCOCC>[ClH:16].[CH3:19][N:18]([CH:20]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C:22]1([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1)[OH:27])[CH3:17]
Reactant: CN(C)C(c1ccccc1)C1CCCCC1=O
Reactant: CC(C)[Mg]Cl
Reactant: Ic1cccc2ccccc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CN(C)C(c1ccccc1)C1CCCCC1(O)c1cccc2ccccc12
Product: Cl
Temperature: -10 °C
Reaction time: 1 h
Yield: 26.9 %

Procedure:
0.824 g (3.24 mmole) of 1-iodonaphthalene were dissolved in 2 ml of ether, cooled to −10° C., and 1.62 ml (3.24 mmole) of isopropylmagnesium chloride (2 M solution in tetrahydro-furan) were added dropwise. After stirring for one hour at 0° C., 0.50 g (2.16 mmole) of the 2-(dimethylaminophenylmethyl)cyclohexanone prepared according to Example 1 and dissolved in 2 ml of ether were added dropwise, and the whole was stirred for 15 hours at RT. The reaction mixture was worked up by adding 2 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 5 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 1.00 g of crude base (129% of theory) was obtained, from which 0.23 g of 2-(dimethylaminophenylmethyl)-1-naphthalene-1-ylcyclohexanol, hydrochloride (17.9% of theory) having a melting point above 250° C. was obtained according to the procedure described in Example 1 (3rd Stage) with chlorotrimethylsilane/water in 2-butanone.
Reaction SMILES: C(O)(=O)C.[F:5][C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[C:12]([C:14]3[C:22]4[N:21]5[CH:23]=[CH:24][CH:25]=[C:20]5[CH:19]([NH2:26])[C:18]=4[CH:17]=[CH:16][CH:15]=3)[NH:11][C:10]=2[CH:27]=1.[NH:28]1[C:32]2[N:33]=[CH:34][CH:35]=[C:36]([C:37](O)=[O:38])[C:31]=2[CH:30]=[CH:29]1.C(N(C(C)C)CC)(C)C>CN1CCCC1=O>[F:5][C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[C:12]([C:14]3[C:22]4[N:21]5[CH:23]=[CH:24][CH:25]=[C:20]5[CH:19]([NH:26][C:37]([C:36]5[C:31]6[CH:30]=[CH:29][NH:28][C:32]=6[N:33]=[CH:34][CH:35]=5)=[O:38])[C:18]=4[CH:17]=[CH:16][CH:15]=3)[NH:11][C:10]=2[CH:27]=1
Reactant: NC1c2cccc(-c3nc4ccc(F)cc4[nH]3)c2-n2cccc21
Reactant: O=C(O)c1ccnc2[nH]ccc12
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1c2cccc(-c3nc4ccc(F)cc4[nH]3)c2-n2cccc21)c1ccnc2[nH]ccc12
Reaction time: 1 h
Yield: 23.2 %

Procedure:
A mixture of 42 mg of 5-(6-fluoro-1H-benzimidazol-2-yl)-9H-pyrrolo[1,2-a]indol-9-ylamine acetate obtained according to the preceding stage, 19 mg of 1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid (which can be obtained according to WO 2003/000688), 39 mg of o-((ethoxycarbonyl)cyanomethylene-amino)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TOTU) and 16 μl of diisopropylethylamine in 3 ml of N-methylpyrrolidone is stirred in a 100 ml round-bottomed flask. After 1 hour, the reaction medium is evaporated to dryness, the residue is taken up with 30 ml of a saturated solution of sodium bicarbonate and the aqueous phase is extracted with 4 times 30 ml of ethyl acetate. The combined organic phases are washed with 3 times 30 ml of a saturated solution of sodium chloride, dried over magnesium sulphate, and evaporated to dryness under vacuum. The residue is chromatographed on silica gel (15-40 μm), elution being carried out with a gradient of methanol (2% to 5% v/v) in dichloromethane, and then on a second column of silica gel (15-40 μm), elution being carried out with pure ethyl acetate. 12 mg of 1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid [5-(6-fluoro-1H-benzimidazol-2-yl)-9H-pyrrolo[1,2-a]indol-9-yl]amide are obtained in the form of a brown solid, the characteristics of which are the following:
Reaction SMILES: C([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][CH2:14][C:15]3[C@@:16]4([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[C@:28]([CH3:36])([CH2:29][CH2:30][C:31]=32)[C@@H:19]([C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH:18]=[CH:17]4)[CH2:11]1)(=O)C1C=CC=CC=1>C1COCC1.C(O)C.[O-]CC.[Na+]>[C:38]([CH2:37][C@:16]12[C:15]3[CH2:14][CH2:13][C@@H:12]4[C@:32]([CH3:35])([CH2:33][CH2:34][C@H:10]([OH:9])[CH2:11]4)[C:31]=3[CH2:30][CH2:29][C@:28]1([CH3:36])[C@@H:19]([C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH:18]=[CH:17]2)([O:40][CH2:41][CH3:42])=[O:39]
Reactant: CCOC(=O)C[C@@]12C=C[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CCC1=C2CC[C@H]2C[C@@H](OC(=O)c3ccccc3)CC[C@]12C
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C[C@@]12C=C[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CCC1=C2CC[C@H]2C[C@@H](O)CC[C@]12C

Procedure:
A solution of 3β-benzoyloxy-14α-carbethoxymethyl-5α-cholest-8,15-diene (2.06 g, 3.58 mmole) in THF (90 mL), absolute ethanol (40 mL) and 20% ethanolic sodium ethoxide (5 mL) was heated at 75° C. for one hour. The reaction was partitioned between ethyl ether and iced dilute HCl. The organic layer was washed with water, dried and concentrated to yield the crude 14α-carbethoxymethyl-5α-cholest-8,15-dien-3β-ol. This was dissolved in ethyl acetate (150 mL) and platinum oxide (1 g) was added. The mixture was agitated under an atmosphere of hydrogen for 2 hours. The catalyst was filtered and the concentrated filtrate was flash chromatographed with 2:1 to 1:1 hexane in ethyl acetate to yield 1.59 g of 14α-carbethyoxymethyl-5α-cholest-8-en-3β-ol; mp 72°-73° C. (from CH3CN).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[OH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[CH2:3][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:19][CH:20]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 60 °C
Yield: 84.9 %

Procedure:
To a mixture of 2-(chloromethyl)quinoline hydrochloride (1 g, 4.6 mmol) and methyl p-hydroxyphenylacetate (0.83 g, 5 mmol) in anhydrous dimethylformamide (20 mL), was added potassium carbonate (2.33 g) and the mixture was heated at 60° C. for 8 h. Dimethylformamide was removed, and the residue was partitioned between water and chloroform. The organic phase was dried over sodium sulfate and the solvent was removed, to afford 1.68 g of a crude product that was purified by chromatography on silica gel (ethyl acetatehexane 1:1), to give 1.2 g of the title compound (yield: 84%).
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[F:22][C:23]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:24]=1[NH2:25].[Br:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36](O)=[O:37]>CN(C=O)C>[Br:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([NH:25][C:24]1[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:23]=1[F:22])=[O:37]
Reactant: Nc1ccc(F)cc1F
Reactant: O=C(O)CCCCBr
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(CCCCBr)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 68.5 %

Procedure:
WSC (2.1 g, 11 mmols), and HOBt (1.49 g, 11 mmols) were added to a DMF (30 ml) solution of 2,4-difluoroaniline (1.29 g, 10 mmols) and 5-bromopentanoic acid (2.7 g, 15 mmols), and stirred at room temperature for 12 hours. The reaction mixture was extracted with ether. The organic layer was washed with water, 1 N HCl, an aqueous saturated solution of sodium hydrogencarbonate and saturated saline in that order, and dried with anhydrous magnesium sulfate, and the solvent was evaporated. Then, the residue was purified through preprative thin-layer chromatography (developer: hexane/acetone=5/1), and the resulting crystals were recrystallized from ether-hexane to obtain 2.0 g (yield: 68%) of 5-bromo-N-(2,4-difluorophenyl)pentanamide as colorless needle-like crystals.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[CH3:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][C:26](=[O:32])[NH:27]2>>[CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=[C:25]1[C:24]2[C:28](=[CH:29][CH:30]=[CH:31][C:23]=2[CH3:22])[NH:27][C:26]1=[O:32]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Reactant: Cc1cccc2c1CC(=O)N2
Product: Cc1cccc2c1C(=Cc1[nH]c3c(c1C)C(=O)N(CCN1CCCCC1)CC3)C(=O)N2
Yield: 75.9 %

Procedure:
The title compound was prepared under the same conditions as described in Example 25 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-methyl-1,3-dihydro-indol-2-one (prepared according to U.S. Pat. No. 6,114,371) as starting materials to give 3-methyl-2-(4-methyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-piperidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (41 mg, 75.9%) as a yellow solid.
Reaction SMILES: [I:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.Br[CH2:14][C:15]#[N:16].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(Cl)Cl>[I:1][C:2]1[C:3]([O:12][CH2:14][C:15]#[N:16])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: N#CCBr
Reactant: Oc1cc2ccccc2cc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: N#CCOc1cc2ccccc2cc1I
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.5 %

Procedure:
A mixture of 3-iodo-naphthalen-2-ol (2.0 g, 7.4 mmol), bromoacetonitrile (1.066 g, 8.88 mmol) and potassium carbonate (2.04 g, 14.81 mmol) in three mL of acetonitrile was stirred at room temperature for 16 hours. The reaction mixture was diluted with methylene chloride and filtered. The filtrate was washed with 2% aqueous NaOH solution, water, and saturated brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was crystallized from EtOAc/hexanes to give 2.07 g of (3-iodo-naphthalen-2-yloxy)-acetonitrile, MP=105-107° C., MS (M+H)=309.
Reaction SMILES: [C:1]1([CH3:38])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[NH:14][CH2:13][CH:12]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=3)=[O:24])[C:11]2=[O:37])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:39](Cl)(=[O:43])[CH:40]([CH3:42])[CH3:41].N1C=CC=CC=1>ClCCCl>[C:1]1([CH3:38])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:39](=[O:43])[CH:40]([CH3:42])[CH3:41])[CH2:13][CH:12]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=3)=[O:24])[C:11]2=[O:37])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)C(=O)Cl
Reactant: CCOC(=O)c1cccc(NC(=O)NC2CNc3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)c1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CCOC(=O)c1cccc(NC(=O)NC2CN(C(=O)C(C)C)c3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)c1
Temperature: 25 °C
Yield: 113.9 %

Procedure:
1-[1-(2-Toluoylmethyl)-2-oxo-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea (500 mg) obtained from Step 1 of Example 93 was suspended in 1,2-dichloroethane (10 ml), isobutyryl chloride (114 mg) and pyridine (86 μl) were added thereto at room temperature, and the mixture was refluxed for 2 hours and 30 minutes. The reaction mixture was allowed to cool, washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=2:1), to thereby obtain 647 mg of the titled compound (Yield: 100%).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[NH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[NH2:7]>C(O)C>[NH2:4][C:3]1[N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:7]=[C:1]([CH2:2][C:3]#[N:4])[C:2]=1[C:1]#[N:5]
Reactant: NNc1ccccn1
Reactant: N#CCC#N
Solvent: CCO
Product: N#CCc1nn(-c2ccccn2)c(N)c1C#N
Temperature: 25 °C
Yield: 37.2 %

Procedure:
A solution of malononitrile (19.8 g, 300 mmol) and 2-hydrazinopyridine (16.4 g, 150 mmol) in ethanol (300 mL) was heated under reflux for 12 hours. The solution was cooled to room temperature, and the resulting crystals were collected by filtration. The crystals were purified by silica gel column chromatography (chloroform to 2% methanol/chloroform) to give the title compound (12.5 g, 37% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[C:5]([CH3:13])[C:4]=1[CH:14]([C:16]1[C:21]([Cl:22])=[CH:20][N:19]=[C:18]([Cl:23])[C:17]=1[C:24]([F:27])([F:26])[F:25])[OH:15]>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[C:5]([CH3:13])[C:4]=1[C:14]([C:16]1[C:21]([Cl:22])=[CH:20][N:19]=[C:18]([Cl:23])[C:17]=1[C:24]([F:27])([F:26])[F:25])=[O:15]
Reactant: COc1cc(C)c(C(O)c2c(Cl)cnc(Cl)c2C(F)(F)F)c(OC)c1OC
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: COc1cc(C)c(C(=O)c2c(Cl)cnc(Cl)c2C(F)(F)F)c(OC)c1OC
Yield: 89.1 %

Procedure:
17 ml (25 mmol) of n-butyllithium (1.5 mol/l hexane solution) was dropwise added at 0° C. to a solution having 3.6 ml (25 mmol) of diisopropylamine dissolved in 60 ml of diethyl ether, followed by stirring for 45 minutes. The solution was cooled to −78° C., and a solution having 6.0 g (24 mmol) of 2,3,6-trichloro-5-trifluoromethylpyridine dissolved in 8 ml of diethyl ether was added, followed by stirring for 25 minutes to prepare 2,3,6-trichloro-5-trifluoromethyl-4-pyridyllithium, and then a solution having 5.0 g (24 mmol) of 2,3,4-trimethoxy-6-methylbenzaldehyde dissolved in 12 ml of toluene was added, followed by stirring for 1 hour. 30 ml of water was added to the mixture to terminate the reaction, and the aqueous layer was extracted with ethyl acetate. Then, the organic layer was dried over anhydrous sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure to obtain (2,3,4-trimethoxy-6-methylphenyl)(2,3,6-trichloro-5-trifluoromethyl-4-pyridyl)methanol (melting point 131 to 135° C.). (b) 2.7 ml (19 mmol) of triethylamine and 0.9 g of 5% palladium carbon were added to a solution having 2,3,4-trimethoxy-6-methylphenyl)(2,3,6-trichloro-5-trifluoromethyl-4-pyridyl)methanol obtained in Step (a) dissolved in 200 ml of methanol, followed by stirring under a hydrogen atmosphere for 14 hours. The mixture was subjected to filtration, 30 ml of water was added, and methanol was distilled off under reduced pressure. After extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 2.38 g (yield: 24%) of (2,3,4-trimethoxy-6-methylphenyl)(2,5-dichloro-3-trifluoromethyl-4-pyridyl)methanol (melting point 162 to 165° C.). (c) 14 g of manganese dioxide was added to a solution having 3.5 g (8.2 mmol) of (2,3,4-trimethoxy-6-methylphenyl)(2,5-dichloro-3-trifluoromethyl-4-pyridyl)methanol obtained in Step (b) dissolved in 100 ml of toluene, followed by stirring under reflux with heating for 6 hours. The mixture was cooled and then subjected to filtration, and toluene was distilled off under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 3.1 g (yield: 89%) of 4-(2,3,4-trimethoxy-6-methylbenzoyl)-2,5-dichloro-3-trifluoromethylpyridine (melting point 106 to 109° C.).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[OH:18].[Cl:19][C:20]1[CH:25]=[C:24]([N+]([O-])=O)[CH:23]=[C:22]([Cl:29])[N:21]=1>>[Cl:19][C:20]1[CH:25]=[C:24]([O:18][C:9]2[CH:10]=[CH:11][C:12]([C:14]([F:16])([F:17])[F:15])=[CH:13][C:8]=2[Cl:7])[CH:23]=[C:22]([Cl:29])[N:21]=1
Reactant: O=[N+]([O-])c1cc(Cl)nc(Cl)c1
Reactant: Oc1ccc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: FC(F)(F)c1ccc(Oc2cc(Cl)nc(Cl)c2)c(Cl)c1
Temperature: 0 °C

Procedure:
16.5 gm (0.12 mol) of potassium carbonate were added in portions to an ice-cooled and stirred suspension of 19.65 gm (0.1 mol) of 2-chloro-4-trifluoromethyl-phenol and 19.29 gm (0.1 mol) of 2,6-dichloro-4-nitro-pyridine. The resulting mixture was stirred for 2 hours at room temperature, and was then stirred into 250 ml of ice water. An oil separated out, which crystallized after some time. The crystalline product was collected by suction filtration, washed with water and dissolved in chloroform. The resulting solution was shaken with water, and the organic phase was separated, dried with sodium sulfate and evaporated to dryness. 25.3 gm (75% of theory) of the title compound were obtained as a colorless substance having a melting point of 66° C.
Reaction SMILES: [H-].[Na+].C1COCC1.[CH2:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.F[C:17]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:18]=1[C:19]#[N:20]>CCOC(C)=O>[CH2:8]([O:15][C:17]1[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:28])[F:27])=[CH:21][C:18]=1[C:19]#[N:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCc1ccccc1
Reactant: N#Cc1cc(C(F)(F)F)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1cc(C(F)(F)F)ccc1OCc1ccccc1
Temperature: 60 °C
Yield: 96 %

Procedure:
Intermediate B, Step 1: A 250-mL round bottom flask containing a magnetic stir bar and fitted with a condenser and a inert gas inlet was charged successively with sodium hydride (60% dispersion in mineral oil, 1.32 g, 33.0 mmol), THF (46 mL) and a THF (46 mL) solution of benzyl alcohol (2.86 mL, 27.5 mmol) and 2-fluoro-5-(trifluoromethyl)benzonitrile (5.2 g, 27.5 mmol). The resulting solution was warmed to 60° C. for 3 h, then cooled to RT, diluted with EtOAc (200 mL) and washed with water (2×100 mL) and brine (60 mL). The organic layer was dried (MgSO4) and concentrated on a rotary evaporator to give crude 2-(benzyloxy)-5-(trifluoromethyl)benzonitrile (7.32 g, 26.4 mmol, 96% yield) as a colorless oil. LC/MS [M+H]+=278.07. 1H-NMR (400 MHz, CDCl3) δ=7.89 (s, 1H), 7.78 (d, J=12.0 Hz, 1H), 7.5-7.3 (m, 5H), 7.12 (d, J=8.0 Hz, 1H), 5.31 (s, 2H).
Reaction SMILES: O[CH:2]([CH:16]1[CH2:20][CH2:19][S:18][C:17]1=[O:21])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:21]=[C:17]1[C:16](=[CH:2][C:3]2[CH:8]=[CH:7][C:6]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=2)[CH2:20][CH2:19][S:18]1
Reactant: CCOC(=O)C(C)c1ccc(C(O)C2CCSC2=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)c1ccc(C=C2CCSC2=O)cc1
Reaction time: 1 h
Yield: 88.9 %

Procedure:
Ethyl 2-{4-[hydroxy(2-oxothiolan-3-yl)methyl]phenyl}propionate (300 mg) obtained in Example 32 was dissolved in toluene (3.0 ml), and to the solution was added p-toluenesulfonic acid (200 mg), and stirred for 1 hour under reflux by heating. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to give the title compound (251 mg, 89%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:10])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:12](Cl)([O:14]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1.O>[CH3:10][C:4]1[S:3][C:2]2[NH:1][C:12](=[O:14])[NH:9][C:7](=[O:8])[C:6]=2[CH:5]=1
Reactant: Cc1cc(C(N)=O)c(N)s1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc2c(=O)[nH]c(=O)[nH]c2s1
Temperature: 25 °C

Procedure:
To a stirred solution of Step 2 intermediate (16.5 g, 94.82 mmol) in dry THF (316 ml) was added triphosgene (14.07 g, 47.41 mmol) and the mixture was refluxed for overnight under nitrogen atmosphere. The mixture was cooled to room temperature and diluted with water (200 ml) under stirring. The solid precipitated out was collected by filtration and dried to give 13.8 g of the desired product; 1H NMR (300 MHz, DMSO-d6) δ 2.36 (s, 3H), 6.82 (s, 1H), 11.07 (br. s, 1H), 11.79 (br. s, 1H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:13]3[N:12]=[C:11]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([N:21]([CH3:33])[S:22]([C:25]5[C:26]([CH3:32])=[N:27][N:28]([CH3:31])[C:29]=5Cl)(=[O:24])=[O:23])=[CH:17][CH:16]=4)[NH:10][C:9]=3[C:8](=[O:34])[N:7]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[F:42])[C:6]2=[O:43])[CH2:3][CH2:2]1>CO.[Pd]>[CH:1]1([CH2:4][N:5]2[C:13]3[N:12]=[C:11]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([N:21]([CH3:33])[S:22]([C:25]5[C:26]([CH3:32])=[N:27][N:28]([CH3:31])[CH:29]=5)(=[O:23])=[O:24])=[CH:17][CH:16]=4)[NH:10][C:9]=3[C:8](=[O:34])[N:7]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[F:42])[C:6]2=[O:43])[CH2:3][CH2:2]1
Reactant: Cc1nn(C)c(Cl)c1S(=O)(=O)N(C)c1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Agent: [Pd]
Solvent: CO
Product: Cc1nn(C)cc1S(=O)(=O)N(C)c1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Reaction time: 48 h
Yield: 37 %

Procedure:
A solution of 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonic acid {4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-methyl-amide (prepared as described in Example 18, 20 mg, 0.032 mmol) in methanol (20 mL) at 25° C. was treated with 10% Pd/C (100 mg). The reaction mixture was submitted to hydrogenation conditions in a Parr bomb at 48 psi for 2 d. At this time, the reaction mixture was filtered through a pad of celite and washed with 90/10 methylene chloride/methanol solution (75 mL). The filtrated was concentrated in vacuo. The resulting residue was purified by HPLC (20–60% acetonitrile/water) to afford 1,3-dimethyl-1H-pyrazole-4-sulfonic acid {4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-methyl-amide (7.0 mg, 37%) as white solid; (ES)+-HRMS m/e calculated for C29H30FN7O4S (M+Na)+ 614.1956, found 614.1955.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[C:10]([Cl:23])[CH:9]=1)=[O:6].[NH3:25]>CO>[Cl:23][C:10]1[CH:9]=[C:8]([NH:7][C:5](=[O:6])[CH2:4][C:3]([NH2:25])=[O:2])[CH:13]=[CH:12][C:11]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1
Reactant: N
Reactant: COC(=O)CC(=O)Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Solvent: CO
Product: NC(=O)CC(=O)Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Yield: 100 %

Procedure:
Prepared in analogy to example 3 from N-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-malonamic acid methyl ester and 7M ammonia in methanol. Yield=100%. Colorless solid. MS: m/e=337.1 (M++H).