Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:9])=[N:4][CH:5]=[CH:6][C:7]=1Cl.[CH2:10]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1)[CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH3:17]>>[CH2:10]([O:18][C:19]1[CH:20]=[CH:21][C:22]([CH:25]2[CH2:30][CH2:29][CH:28]([NH:31][C:7]3[CH:6]=[CH:5][N:4]=[C:3]([CH3:9])[C:2]=3[Cl:1])[CH2:27][CH2:26]2)=[CH:23][CH:24]=1)[CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH3:17]
Reactant: Cc1nccc(Cl)c1Cl
Reactant: CCOCCOCCOc1ccc(C2CCC(N)CC2)cc1
Product: CCOCCOCCOc1ccc(C2CCC(Nc3ccnc(C)c3Cl)CC2)cc1
Reaction time: 4.5 h
Yield: 28 %

Procedure:
Preparation was carried out analogously to Example 35 from 3,4-dichloro-2-methylpyridine and 4-(4-(3,6-dioxaoctyloxy)phenyl)cyclohexylamine. After 4.5 hours the mixture is worked up. Yield: 28%
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[NH:4][N:3]=1.[CH:11](O)=[O:12]>C1(C)C=CC=CC=1>[C:7]([C:5]1[NH:4][N:3]=[C:2]([NH:1][CH:11]=[O:12])[CH:6]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: O=CO
Reactant: CC(C)(C)c1cc(N)n[nH]1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(NC=O)n[nH]1
Yield: 52.6 %

Procedure:
To 14 g (0.1 mole) of 3-amino-5-t-butylpyrazole prepared in Example 1 were added 16.3 g (0.3 mole) of 85% formic acid and 30 ml of toluene, followed by heating under reflux conditions while separating water by distillation. When a calculated amount of water and an excessive amount of formic acid distilled out, the heating was stopped. The reaction mixture was diluted with water and then concentrated as whole, whereby crystals were precipitated. The crystals were collected by filtration, washed with a sodium carbonate aqueous solution and water, and then dried to obtain 8.8 g of 5-t-butyl-3-formylaminopyrazole. This product was recrystallized from hydrous methanol and found to have a melting point of 204° to 206° C.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C(N(C(C)C)CC)(C)C.[F:14][C:15]([F:44])([F:43])[C:16]1[CH:17]=[C:18]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[CH2:19][N:20]([CH:24]1[CH2:30][CH2:29][CH2:28][NH:27][C:26]2[CH:31]=[C:32]([Cl:35])[CH:33]=[CH:34][C:25]1=2)[C:21](=[O:23])[CH3:22]>C1(C)C=CC=CC=1>[C:21]([N:20]([CH2:19][C:18]1[CH:36]=[C:37]([C:39]([F:40])([F:41])[F:42])[CH:38]=[C:16]([C:15]([F:14])([F:44])[F:43])[CH:17]=1)[CH:24]1[CH2:30][CH2:29][CH2:28][N:27]([C:1]([Cl:4])=[O:2])[C:26]2[CH:31]=[C:32]([Cl:35])[CH:33]=[CH:34][C:25]1=2)(=[O:23])[CH3:22]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCNc2cc(Cl)ccc21
Reactant: O=C(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)Cl)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
Add phosgene (1.1 mmol, 1.93 M solution in toluene) followed by diisopropyl ethylamine (1.1 mmol) to a toluene (15 mL) solution of N-(3,5-Bis-trifluoromethyl-benzyl)-N-(8-chloro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-acetamide (0.50 g, 1.1 mmol) under nitrogen. After stirring at room temperature for 1 h, remove solvent under vacuum. Chromatograph the crude product over silica gel using ethyl acetate/hexane (10-30%) to elute. This provides the title compound (0.55 g, 96%) as an oil which solidifies upon standing: MS (ES+): 527 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[NH:11][CH:10]=[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]2=[O:18].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].O>ClCCl>[CH3:26][S:27]([O:18][C:8]1[C:7]2[C:12](=[C:3]([O:2][CH3:1])[N:4]=[CH:5][CH:6]=2)[N:11]=[CH:10][C:9]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1c[nH]c2c(OC)nccc2c1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)c1cnc2c(OC)nccc2c1OS(C)(=O)=O
Reaction time: 1 h
Yield: 67 %

Procedure:
4.96 g of ethyl 8-methoxy-1,7-naphthyridin-4(1H)-one-3-carboxylate and 4.2 ml of triethylamine were dissolved into 70 ml of dichloromethane, and a solution of methanesulfonyl chloride (1.85 ml) in dichloromethane (10 ml) was added dropwise at a temperature of 0° C. to 5° C. The resulting mixture was stirred for 1 hour at the same temperature. Water was added, and the resulting mixture was extracted with dichloromethane three times, and the organic phase was washed with water and then brine, dried over magnesium sulfate and distilled under reduced pressure. Ether was added to the residue to give 4.4 g (67%) of the titled compound as yellow crystals.
Reaction SMILES: CC([O-])(C)C.[K+].[N+:7]([C:10]1[CH:18]=[C:17]2[C:13]([CH:14]=[N:15][NH:16]2)=[CH:12][CH:11]=1)([O-:9])=[O:8].Cl[CH2:20][CH2:21][N:22]([CH3:24])[CH3:23].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:23][N:22]([CH3:24])[CH2:21][CH2:20][N:16]1[C:17]2[C:13](=[CH:12][CH:11]=[C:10]([N+:7]([O-:9])=[O:8])[CH:18]=2)[CH:14]=[N:15]1
Reactant: CN(C)CCCl
Reactant: O=[N+]([O-])c1ccc2cn[nH]c2c1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN(C)CCn1ncc2ccc([N+](=O)[O-])cc21

Procedure:
0.11 mol of potassium tert-butylate is added to a solution of 0.11 mol (20 g) of 6-nitroindazole in 400 ml of tetrahydrofuran. After total dissolution, a solution of 0.24 mol (27 g) of 2-chloroethyl-N,N-dimethylamine in 300 ml of toluene is added. The reaction medium is heated at reflux for 3 hours. After cooling, 300 ml of a 10% sodium carbonate solution are added. The mixture is diluted with ethyl acetate and decanted, and the aqueous phase is extracted with dichloromethane. After concentration of the organic phases, the residue is purified by chromatography on silica gel using a dichloromethane/methanol mixture (98/2) as eluant to yield the expected compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]3[CH:29]=[CH:28][C:27]4[C:26]([CH3:31])([CH3:30])[CH2:25][CH2:24][C:23]([CH3:33])([CH3:32])[C:22]=4[CH:21]=3)[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>>[N:11]1([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]3[CH:29]=[CH:28][C:27]4[C:26]([CH3:31])([CH3:30])[CH2:25][CH2:24][C:23]([CH3:33])([CH3:32])[C:22]=4[CH:21]=3)[N:15]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccnc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)n2)CC1
Agent: Cl
Product: CC1(C)CCC(C)(C)c2cc(-c3nccc(N4CCNCC4)n3)ccc21

Procedure:
The above compound is prepared analogously to FS201 starting from 4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidin-4-yl]piperazine-1-carboxylic acid tert-butyl ester. Product is the hydrochloride.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.CC1(C)C(C)(C)OB([C:15]2[CH:29]=[CH:28][C:18]([O:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:17][CH:16]=2)O1.[Cl-].[K+].C([O-])([O-])=O.[Na+].[Na+]>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.CCO.C1(C)C=CC=CC=1>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[C:15]1[CH:29]=[CH:28][C:18]([O:19][CH2:20][C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])=[CH:17][CH:16]=1
Reactant: Brc1nccs1
Reactant: CC(C)(C)OC(=O)COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
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: [Cl-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)COc1ccc(-c2nccs2)cc1
Temperature: 100 °C
Yield: 95 %

Procedure:
To a solution of 2-bromothiazole (265 μL, 2.97 mmol), tert-butyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)acetate (1.19 g, 3.56 mmol), KCl (664.7 mg, 8.91 mmol) in a 4:1 mixture of toluene (20 mL)/EtOH (5 mL) was added an aqueous solution of Na2CO3 2M (11.8 mL). The flask was evacuated and re-filled with nitrogen three times and then, tetrakis(triphenylphosphine)palladium (0) (346.2 mg, 0.30 mmol) was added. The reaction mixture was heated to 100° C. for 4 h. When the reaction was completed, inorganic solids were removed by filtration through Celite® and washing with several portions of dichloromethane, then the solvent was evaporated. The residue was absorbed onto silica then subjected to flash chromatography (SiO2, hexane: ethyl acetate (AcOEt), 9:1) to afford 825.2 mg of de tert-butyl 2-(4-(thiazol-2-yl)phenoxy)acetate as a white solid (95% yield). RMN1H (CDCl3, 400 MHz): δ 7.95-7.86; (m, 2H), 7.81; (d, J=3.3 Hz, 1H), 6.99-6.85; (m, 1H), 4.57; (s, 2H), 1.49; (s, 1H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[C@@H:20](O)[CH3:21]>>[Br:1][C:2]1[CH:3]=[C:4]([O:11][C@@H:20]([C:14]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=2[F:12])[CH3:21])[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1
Reactant: C[C@H](O)c1cc(F)ccc1F
Reactant: O=[N+]([O-])c1ncc(Br)cc1O
Product: C[C@@H](Oc1cc(Br)cnc1[N+](=O)[O-])c1cc(F)ccc1F
Reaction time: 1 h

Procedure:
The title compound was prepared by a similar method to that of preparation 18 using commercially available 5-bromo-3-hydroxy-2-nitro-pyridine and (S)-1-(2,5-difluoro-phenyl)-ethanol except the reaction time was 1 hr and crude reaction purified by chromatography on silica gel eluting with ethyl acetate in heptane (50:50) to give a yellow oil (21.0 g, 93%).
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11]([OH:20])(=[O:19])[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[SH:14]>[Cu].[Zn].[OH-].[Na+]>[S:14]([C:13]1[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=1[C:11]([OH:20])=[O:19])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1S
Reactant: O=C(O)c1ccc(I)cc1
Agent: [Cu]
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc(Sc2ccccc2C(=O)O)cc1

Procedure:
First, 2,4′-thiobis(benzoic acid) was prepared. A mixture of 4-iodobenzoic acid (55.7 g, 225 mmol), thiosalicylic acid (34.6 g, 225 mmol), copper powder (15 g, 236 mmol), zinc powder (3 g, 46 mmol), and 2.5 M aqueous sodium hydroxide (400 mL) was heated at reflux for 5 h and then cooled to ambient. The reaction mixture was filtered, and the filtrate was acidified with concentrated HCl. The precipitate was collected and washed with water, then dissolved and filtered. The filtrate was concentrated to deposit 2,4′-thiobis(benzoic acid), mass 50 g (81% of theory).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:6]=1)=[O:4].[OH-].[Li+]>O1CCCC1.CO>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:7]2[C:8](=[O:11])[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6]2)=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(=O)n(Cc2ccc(OC)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Cn2cc(C(=O)O)ccc2=O)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of methyl coumalate (1 g, 6.49 mmol, 1 eq) in ethanol (30 mL) was added p-anisidine (0.79 g, 6.49 mmol, 1 eq). The reaction mixture was heated to reflux for 16 h. After this time, the solvent was removed under reduced pressure, and the residue was purified by column chromatography eluting with 3:2 ethyl acetate/hexane to afford 1-(4-methoxy-benzyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid methyl ester. Mass Spec m/z=260 [M+H+]. To a solution of 1-(4-methoxy-benzyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (400 mg, 1.54 mmol, 1 eq) in 3:1 tetrahydrofuran/methanol (20 mL) was added lithium hydroxide (148 mg, 6.17 mmol, 4 eq). The mixture was stirred at rt for 48 h then heated to 50° C. for 16 h. After this time, the mixture was concentrated under reduced pressure and partitioned between water and ethyl acetate. The aqueous layer was acidified with a 2N aqueous solution of hydrochloric acid then extracted with ethyl acetate. The organic layers were combined and washed with water, dried (MgSO4), filtered and concentrated under reduced pressure to afford 1-(4-methoxy-benzyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid, which is used without further purification.
Reaction SMILES: Cl.[CH:2]1[C:12]2[CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[N:7]([CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH2:23][C@H:22]([C:26]([OH:28])=[O:27])[CH2:21]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:29](N(CC)CC)C.CS(Cl)(=O)=O.COC(=O)CC1CCNC1>C1COCC1>[CH3:29][O:28][C:26](=[O:27])[CH2:22][CH:23]1[CH2:24][CH2:25][N:20]([CH2:19][CH2:18][CH2:17][N:7]2[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH2:10][CH2:11][C:12]3[CH:2]=[CH:3][CH:4]=[CH:5][C:6]2=3)[CH2:21]1
Reactant: CCN(CC)CC
Reactant: O=C(O)[C@H]1CCCN(CCCN2c3ccccc3CCc3ccccc32)C1
Agent: COC(=O)CC1CCNC1
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)CC1CCN(CCCN2c3ccccc3CCc3ccccc32)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 27 %

Procedure:
3-(10,11-Dihydro-5H-dibenzo[b,f]azepin-5-yl)-1-propanol (2.0 g, 0.0079 mol, prepared as described in example 10) was dissolved in dry THF (25 ml) under an atmosphere of nitrogen, and triethylamine (2.75 ml) was added. Methanesulfonyl chloride (0.61 ml, 0.0079 mol) was added dropwise and when addition was complete the reaction mixture was stirred for 45 minutes. The mixture was filtered and 3-pyrrolidinacetic acid methyl ester (2.4 g, 0.012 mol) was added to the filtrate. The mixture was heated at reflux temperature for 4 h and then stirred at room temperature for 48 h. Triethylamine (2.2 ml) was added and the mixture was heated at reflux temperature for 24 h. After cooling to room temperature the solvent was removed by evaporation in vacuo. The residue was purified by column chromatography on silica gel (125 g) using a mixture of dichloromethane and methanol (9:1) as eluent, affording 0.9 g (27%) of 1-(3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-1-propyl)-3-pyrrolidinacetic acid methyl ester as an oil. Rf : 0.15 (SiO2 ; dichloromethane/methanol/acetic acid=20:2:1).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][N:14]3[CH2:19][CH2:18][NH:17][C@@H:16]([CH3:20])[C:15]3=[O:21])=[CH:10][CH:11]=2)[N:6]=[CH:5][CH:4]=1.Br[CH2:23]/[CH:24]=[CH:25]/[C:26]1[S:27][C:28]([Cl:31])=[CH:29][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][N:14]3[CH2:19][CH2:18][N:17]([CH2:23][CH:24]=[CH:25][C:26]4[S:27][C:28]([Cl:31])=[CH:29][CH:30]=4)[C@@H:16]([CH3:20])[C:15]3=[O:21])=[CH:10][CH:11]=2)[N:6]=[CH:5][CH:4]=1
Reactant: C[C@@H]1NCCN(Cc2ccc3c(Cl)ccnc3c2)C1=O
Reactant: Clc1ccc(/C=C/CBr)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C[C@H]1C(=O)N(Cc2ccc3c(Cl)ccnc3c2)CCN1CC=Cc1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
(S)-1-(4-chloroquinolin-7-ylmethyl)-3-methylpiperazin-2-one hydrochloride (0.25 g, 1.0 mmol), EXAMPLE 91, is treated with 2-(3-Bromo-(E)-propenyl)-5-chloro-thiophene (0.35 g 1.2 mmol), EXAMPLE 17, and potassium carbonate (0.5 g, 3 mmol). The resulting suspension is sonicated for 10 minutes then stirred vigorously for 16 h at ambient temperature. The reaction mixture is poured into water and extracted with ethyl acetate (2×150 mL). The organic layer is washed with water (4×200 mL), dried over sodium sulfate and concentrated. The residue is chromatographed (3% methanol/methylene chloride) to give the title compound (0.31 g, 0.73 mmol).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6])#[N:2]>CO.[Pd]>[NH2:6][C:5]1[CH:4]=[C:3]([CH:9]=[CH:8][CH:7]=1)[CH2:1][NH2:2]
Reactant: N#Cc1cccc(N)c1
Agent: [Pd]
Solvent: CO
Product: NCc1cccc(N)c1
Yield: 99.9 %

Procedure:
3-Cyanoaniline (0.50 g, 4.23 mmol) in 100 mL of MeOH was stirred overnight at room temperature under a H2 environment in the presence of 10% Pd/C (100 mg). The Pd/C was removed by filtration through a pad of Celilte, and the resulting filtrate was concentrated under reduced pressure to give 0.516 g (˜100%) of 100A as a thick oil. The product was used without any further purification.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[F:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:54]=[CH:53][C:33]([CH2:34][C:35]3([C:41]([NH:43][CH2:44][CH:45]([OH:52])[CH2:46][C:47]([CH3:51])([CH3:50])[CH2:48][CH3:49])=[O:42])[CH2:39][CH2:38][C:37](=[O:40])[NH:36]3)=[CH:32][CH:31]=2)=[N:28][CH:29]=1>C(Cl)Cl>[CH3:50][C:47]([CH3:51])([CH2:48][CH3:49])[CH2:46][C:45](=[O:52])[CH2:44][NH:43][C:41]([C:35]1([CH2:34][C:33]2[CH:53]=[CH:54][C:30]([C:27]3[CH:26]=[CH:25][C:24]([F:23])=[CH:29][N:28]=3)=[CH:31][CH:32]=2)[CH2:39][CH2:38][C:37](=[O:40])[NH:36]1)=[O:42]
Reactant: CCC(C)(C)CC(O)CNC(=O)C1(Cc2ccc(-c3ccc(F)cn3)cc2)CCC(=O)N1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCC(C)(C)CC(=O)CNC(=O)C1(Cc2ccc(-c3ccc(F)cn3)cc2)CCC(=O)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dess-Martin periodinane (355 mg, 0.84 m mol) was added to an ambient temperature solution of 2-[4-(5-fluoropyridin-2-yl)benzyl]-N-(2-hydroxy-4,4-dimethylhexyl)-5-oxopyrrolidine-2-carboxamide (185 mg, 0.42 mmol) in methylene chloride (5 mL). After stirring at ambient temperature for 2 hr, the reaction mixture was quenched with saturated aqueous sodium bicarbonate/saturated aqueous sodium thiosulfate (1:1) was and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (sodium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 20-60% acetone/methylene chloride afforded N-(4,4-dimethyl-2-oxohexyl)-2-[4-(5-fluoropyridin-2-yl)benzyl]-5-oxopyrrolidine-2-carboxamide.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]#[C:13][Si](C)(C)C)[C:5]2[O:6][CH:7]([CH3:9])[CH2:8][C:4]=2[C:3]=1[N:18]1[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[N:20]([CH3:29])[C:19]1=[O:30].[F-].[K+]>C(O)C>[C:12]([C:10]1[C:5]2[O:6][CH:7]([CH3:9])[CH2:8][C:4]=2[C:3]([N:18]2[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[N:20]([CH3:29])[C:19]2=[O:30])=[C:2]([F:1])[CH:11]=1)#[CH:13]
Reactant: CC1Cc2c(c(C#C[Si](C)(C)C)cc(F)c2-n2c(=O)cc(C(F)(F)F)n(C)c2=O)O1
Agent: [F-]
Agent: [K+]
Solvent: CCO
Product: C#Cc1cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c2c1OC(C)C2
Reaction time: 8 h
Yield: 79.7 %

Procedure:
3-{5-Fluoro-2-methyl-7-[2-(trimethylsilyl)-1-ethynyl]-2,3-dihydrobenzo[b]furan-4-yl}-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (0.39 g) was dissolved in ethanol (4 ml). To this solution, an aqueous solution (0.3 ml) of potassium fluoride (84 mg) was added dropwise at room temperature, and the mixture was stirred for further 8 hours. After the reaction, ethanol was distilled off under reduced pressure, extracted with ethyl acetate, washed with water, and then dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off and the resulting oily substance was purified by chromatography on silica gel (ethyl acetate:n-hexane=1:3 v/v) to obtain the objective 3-[7-(1-ethynyl)-5-fluoro-2-methyl-2,3-dihydrobenzo[b]furan-4-yl]-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (0.26 g).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Br[C:21]1[CH:22]=[C:23]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([CH3:45])([CH3:44])[O:38][SiH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH:32]=2)[N:24]2[C:29]=1[C:28]([NH2:30])=[N:27][CH:26]=[N:25]2.[CH2:46]([N:53]1[CH:61]=[C:60]2[C:55]([CH:56]=[C:57](B3OC(C)(C)C(C)(C)O3)[CH:58]=[CH:59]2)=[N:54]1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C([O-])([O-])=O.[Na+].[Na+]>CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1.C1(C)C=CC=CC=1>[CH2:46]([N:53]1[CH:61]=[C:60]2[C:55]([CH:56]=[C:57]([C:21]3[CH:22]=[C:23]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([CH3:45])([CH3:44])[O:38][SiH2:39][C:40]([CH3:43])([CH3:41])[CH3:42])[CH:32]=4)[N:24]4[C:29]=3[C:28]([NH2:30])=[N:27][CH:26]=[N:25]4)[CH:58]=[CH:59]2)=[N:54]1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cccc(-c2cc(Br)c3c(N)ncnn23)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CC(C)(C)[SiH2]OC(C)(C)c1cccc(-c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)c1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 65.6 %

Procedure:
Pd(OAc)2 (11 mg, 0.05 mmol) was suspended in a degassed mixture of 3:2 toluene:dioxane and PPh3 (52 mg, 0.20 mmol) was added. The mixture was stirred for 10 minutes and then the product from step 3 (433 mg, 1.00 mmol) and Intermediate C (434 mg, 1.30 mmol) were added followed by 2.5 mL of 2M aqueous Na2CO3 solution. The mixture was heated to 90° C. overnight. The reaction was allowed to cool to rt and partitioned between water and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by Isco® (Redi-sep 40, eluting with 75-100% EtOAc/Hexanes) to provide 368 mg (66%) of the title compound as an off-white solid. 1H-NMR (DMSO-d6) 8.44 (s, 1H), 7.98 (s, 1H), 7.84 (s, 1H), 7.82 (m, 1H), 7.74 (d, 1H), 7.56 (s, 1H), 7.50-7.39 (m, 2H), 7.31 (t, 1H), 7.26-7.12 (m, 5H), 7.08 (d, 1H), 7.00, (s, 1H), 5.57 (s, 2H), 4.64 (s, 2H) 0.82 (s, 9H), 0.01 (s, 6H); LC-MS [M+H]+=561.5, RT=3.65 min.
Reaction SMILES: [CH3:1][CH:2]([CH:6]([Ge:8]([Cl:11])([Cl:10])[Cl:9])[CH3:7])[C:3](O)=[O:4].S(Cl)([Cl:14])=O>>[CH3:1][CH:2]([CH:6]([Ge:8]([Cl:11])([Cl:10])[Cl:9])[CH3:7])[C:3]([Cl:14])=[O:4]
Reactant: O=S(Cl)Cl
Reactant: CC(C(=O)O)C(C)[Ge](Cl)(Cl)Cl
Product: CC(C(=O)Cl)C(C)[Ge](Cl)(Cl)Cl
Yield: 90.4 %

Procedure:
28.0 g (0.1 mol) of 2-methyl-3-(trichlorogermyl)butanoic acid was treated with 100 ml of thionyl chloride and then distilled under reduced pressure to obtain 27.0 g (yield: 90.4%) of 2-methyl-3-(trichlorogermyl)-butanoyl chloride as a light yellow fraction having a boiling point of 99° to 100° C./6 mmHg.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[S:7][C:6]=2[CH:14]=1.[CH3:15][Sn:16](C)([CH3:39])[C:17]1C=CC2C3C=CC(CO[Si](C(C)(C)C)(C)C)=CC=3OC=2C=1>>[CH3:15][Sn:16]([CH3:39])([CH3:17])[C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[S:7][C:6]=2[CH:14]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc2c(c1)oc1cc([Sn](C)(C)C)ccc12
Reactant: Brc1ccc2c(c1)sc1ccccc12
Product: C[Sn](C)(C)c1ccc2c(c1)sc1ccccc12
Yield: 82 %

Procedure:
Using the procedure described in Example 316, but substituting 3-bromodibenzothiophene for the bromodibenzofuran 10 of Example 316, provided the title compound in 82% yield.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[C:18]([CH3:19])=[CH:17][N:16]=[C:15]([Cl:20])[N:14]=1)(C(C)(C)C)(C)C.[H-].[Na+].I[CH3:24]>CN(C=O)C>[Cl:20][C:15]1[N:14]=[C:13]([N:12]([CH3:24])[CH2:11][CH2:10][CH2:9][OH:8])[C:18]([CH3:19])=[CH:17][N:16]=1
Reactant: Cc1cnc(Cl)nc1NCCCO[Si](C)(C)C(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cnc(Cl)nc1N(C)CCCO
Reaction time: 0.5 h
Yield: 35.8 %

Procedure:
To a solution of N-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-2-chloro-5-methyl-4-pyrimidinamine (Example 340, 5.00 g, 15.8 mmol) in DMF (60 mL) was added portionwise NaH (0.95 g, 60% dispersion in mineral oil, 23.7 mmol) [H2 evolution]. The heterogeneous mixture was stirred for 30 min, then iodomethane (1.97 mL, 31.7 mmol) was added. After 3 h of stirring at rt, the excess NaH was quenched by the slow addition of a saturated solution of NH4Cl [H2 evolution]. The product was extracted with Et2O. The combined organic layers were then dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified using a pad of silica gel (3:1 hexanes/EtOAc) and the desired fractions were concentrated under reduced pressure. The resulting silyl derivative was dissolved in a mixture of ethanol (46 mL) and HCl (4.2 mL of a 2 N aqueous solution), and stirred at rt until the reaction was complete (6-10 h). The reaction mixture was then concentrated under reduced pressure, diluted with EtOAc, and washed with a saturated solution of NaHCO3 and brine. The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (3:1 hexanes/EtOAc) to yield the title compound (1.22 g, 62%). 1H NMR (400 MHz, CDCl3) δ 1.83 (qt, 2H), 2.32 (s, 3H), 3.19 (s, 3H), 3.56 (t, 2H), 3.69 (t, 2H), 7.70 (s, 1H).