Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][C:4]1=[O:13])[CH3:2].[H-].[Na+].Br[CH2:17][C:18]([O:20]CC)=[O:19]>CN(C=O)C.O>[CH2:1]([CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([CH2:17][C:18]([OH:20])=[O:19])[C:4]1=[O:13])[CH3:2]
Reactant: CCC1Oc2ccccc2NC1=O
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC1Oc2ccccc2N(CC(=O)O)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-ethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (1.5 mmol, 260 mg) in DMF (2 ml) was added NaH (1.8 mmol, 43 mg) and the reaction mixture was stirred at room temperature for 1 h before the dropwise addition of ethyl bromoacetate (1.5 mmol, 250 mg). The reaction mixture was stirred at room temperature overnight, diluted with water and extracted with ethyl acetate. The organic layer was washed with 1N HCl, Sat. NaHCO3, dried over Na2SO4 and evaporated to dryness. The crude compound was dissolved in MeOH (3 ml) and 1 N NaOH (3 ml) and stirred for 2 h at room temperature. The MeOH was removed under reduced pressure and the resulting aqueous solution extracted with EtOAc. The aqueous layer was acidified to pH 2 with 1N HCl and extracted with EtOAc. The organic phase was dried over Na2SO4 and the solvent was evaporated to give the title compound. LC/MS (10% to 99%): M/Z (M+H)+ (obs)=236; tR=2.4.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([CH3:21])[CH:15]=1.C([O-])([O-])=O.[K+].[K+].C(#N)C>O.CC(C)=O>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:2]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=2[C:4]#[N:5])=[C:16]([CH3:21])[CH:15]=1
Reactant: Cc1cc(Cl)ccc1O
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: CC#N
Product: Cc1cc(Cl)ccc1Oc1ccc([N+](=O)[O-])cc1C#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.4 %

Procedure:
In a 250 ml single-neck flask equipped with a magnetic stirrer and a reflux condenser fitted with a nitrogen bubbler were placed 9.73 g (0.0533 moles) of 2-chloro-5-nitrobenzonitrile, 7.83 g (0.0549 moles) of 4-chloro-2-methylphenol, 7.56 g (0.0549 moles) of anhydrous K2CO3, and 75 ml of acetonitrile. The mixture was heated to reflux and held there for 3 hrs. The reaction mixture was then cooled to room temperature and diluted with 150 ml of water. The product separated as a solid. The solid was filtered off, washed thoroughly with water, and air-dried. The air-dried solid was recrystallized from 400 ml of absolute ethanol and a small amount of acetone to give 9.60 g (62% yield) of purified 2-(4-chloro-2-methylphenoxy)-5-nitrobenzonitrile, mp 144.5°-145.5° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:11][N:12]1[CH:16]=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:14]=[N:13]1.CC(N(C)C)=O.C([O-])([O-])=O.[K+].[K+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:11][N:12]1[CH:16]=[C:15]([C:2]2[CH:3]=[C:4]3[CH:10]=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:14]=[N:13]1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cn1cc(-c2cnc3[nH]ccc3c2)cn1
Temperature: 75 °C
Yield: 77.9 %

Procedure:
5-Bromo-1H-pyrrolo[2,3-b]pyridine (1.0 g, 5.05 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (1.17 g. 5.55 mmol) and Pd(dppf)2Cl2 (37 mg, 0.045 mmol) were placed in a N2 charged round bottom flask. DMA (6 mL) was added to the reaction vessel and the solution was bubbled with N2 for 10 minutes. K2CO3 (978 mg, 7.07 mmol) was dissolved in water (6 mL), bubbled with N2 and added to the reaction vessel while maintaining the temperature below room temperature with an ice/water bath. The reaction vessel was bubbled with additional N2 for 10 minutes, fitted with a vigeruex column and N2 line and heated to 75° C. overnight. The reaction was not complete; therefore, additional 1-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-1-pyrazole (1.0 g) and Pd(dppf)2Cl2 (124 mg) were added to the reaction. The solution was heated an additional 4 hours. After this period, water (12 mL) was added to the reaction vessel and the solution was heated for 1 hour at 60° C. The solution was transferred to a separatory funnel with dichloromethane (300 mL) and partitioned from the aqueous layer. The organic layer was dried over Na2SO4, concentrated down on silica gel and purified by flash chromatography (0-10% Methanol/dichloromethane gradient) to afford the title compound (780 mg, 78% yield). MS m/z=199 [M+H+]+
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N:7]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]1[CH3:13])(=[O:3])[CH3:2].[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[C:1]([O:4][CH2:5][CH2:6][N:7]1[C:8]([CH3:13])=[CH:9][C:10]([C:19](=[O:20])[C:18]2[CH:22]=[CH:23][C:15]([Cl:14])=[CH:16][CH:17]=2)=[C:11]1[CH3:12])(=[O:3])[CH3:2]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CC(=O)OCCn1c(C)ccc1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)OCCn1c(C)cc(C(=O)c2ccc(Cl)cc2)c1C
Yield: 34 %

Procedure:
In 1,2-dichloroethane, 2-(2,5-dimethylpyrrol-1-yl)ethyl acetate was reacted with p-chlorobenzoyl chloride in the presence of aluminum chloride at room temperature for 18 hours to afford compound (340) in a yield of 34.0%.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:17]=[CH:16][C:7]([CH2:8][CH:9]2[S:13][C:12](=[O:14])[NH:11][C:10]2=[O:15])=[CH:6][CH:5]=1.Cl[CH2:19][C:20]1[N:40]([CH3:41])[C:23]2=[N:24][C:25]([S:28][C:29]3[CH:34]=[C:33]([CH3:35])[C:32]([N+:36]([O-:38])=[O:37])=[C:31]([CH3:39])[CH:30]=3)=[CH:26][CH:27]=[C:22]2[N:21]=1>CN(C)C=O>[CH3:39][C:31]1[CH:30]=[C:29]([S:28][C:25]2[N:24]=[C:23]3[N:40]([CH3:41])[C:20]([CH2:19][O:3][C:4]4[CH:17]=[CH:16][C:7]([CH2:8][CH:9]5[S:13][C:12](=[O:14])[NH:11][C:10]5=[O:15])=[CH:6][CH:5]=4)=[N:21][C:22]3=[CH:27][CH:26]=2)[CH:34]=[C:33]([CH3:35])[C:32]=1[N+:36]([O-:38])=[O:37]
Reactant: Cc1cc(Sc2ccc3nc(CCl)n(C)c3n2)cc(C)c1[N+](=O)[O-]
Reactant: O=C1NC(=O)C(Cc2ccc(O)cc2)S1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Sc2ccc3nc(COc4ccc(CC5SC(=O)NC5=O)cc4)n(C)c3n2)cc(C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a suspension of sodium hydride (0.12 g, 55% w/w) in N,N-dimethylformamide (6 ml) was added 5-(4-hydroxybenzyl)thiazolidine-2,4-dione (0.31 g). The mixture was stirred at room temperature for 20 minutes. To the reaction mixture was added dropwise a solution of 2-chloromethyl-5-(3,5-dimethyl-4-nitrophenylthio)-3-methyl-3H-imidazo[4,5-b]pyridine (0.51 g) in anyhdrous N,N-dimethylformamide (14 ml). The mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated and neutralized with 3N hydrochloric acid and sodium bicarbonate and then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed on a silica gel column using ethyl acetate as the eluant to afford the desired compound (0.39 g, Rf=0.60: thin layer chromatography on a silica gel plate using ethyl acetate as the eluant).
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[O:7][CH2:8][C@@H:9]([NH:31][C:32]([C:34]([CH3:37])([CH3:36])[CH3:35])=[O:33])[CH2:10][C@H:11]([C:15](=O)[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=1)[CH:12]([CH3:14])[CH3:13])([CH3:4])([CH3:3])[CH3:2]>C(O)C.C(O)(=O)C.[Pd]>[C:1]([O:5][C:6](=[O:38])[O:7][CH2:8][C@@H:9]([NH:31][C:32]([C:34]([CH3:35])([CH3:37])[CH3:36])=[O:33])[CH2:10][C@H:11]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=1)[CH:12]([CH3:13])[CH3:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: COCCCOc1cc(C(=O)[C@@H](C[C@@H](COC(=O)OC(C)(C)C)NC(=O)C(C)(C)C)C(C)C)ccc1OC
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: COCCCOc1cc(C[C@@H](C[C@@H](COC(=O)OC(C)(C)C)NC(=O)C(C)(C)C)C(C)C)ccc1OC

Procedure:
Carbonic acid (2S,4S)-2-tert-butylcarbonylamino-4-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-5-methyl-hexylester tert-butyl ester (2.67 g) is dissolved in 25 mL of a mixture of ethanol/acetic acid, 2/1 at room temperature. Palladium metal, 10% on charcoal (0.3 g) is added and the suspension placed under an atmosphere of hydrogen at a pressure of 5 bar. Hydrogenation is continued for 3 days at 50° C. with periodic addition of more catalyst. The reaction mixture is filtered and the solvent removed to give an oil. The oil is purified by chromatography on silica-gel eluting with hexane/ethyl acetate mixtures. The product fractions are combined and the solvent is removed to give the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[CH:36][CH:35]=[CH:34][C:4]=1[CH2:5][N:6]1[C:11](=[O:12])[C:10]([C:13]([OH:15])=[O:14])=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:8]2[O:24][C:25]3[CH:30]=[C:29]([N+:31]([O-])=O)[CH:28]=[CH:27][C:26]=3[C:7]1=2>CO.[Ni]>[NH2:31][C:29]1[CH:28]=[CH:27][C:26]2[C:7]3[N:6]([CH2:5][C:4]4[CH:34]=[CH:35][CH:36]=[CH:37][C:3]=4[O:2][CH3:1])[C:11](=[O:12])[C:10]([C:13]([OH:15])=[O:14])=[C:9]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=4)[C:8]=3[O:24][C:25]=2[CH:30]=1
Reactant: COc1ccc(-c2c(C(=O)O)c(=O)n(Cc3ccccc3OC)c3c2oc2cc([N+](=O)[O-])ccc23)cc1
Agent: [Ni]
Solvent: CO
Product: COc1ccc(-c2c(C(=O)O)c(=O)n(Cc3ccccc3OC)c3c2oc2cc(N)ccc23)cc1

Procedure:
A solution of 1 g of 1,2-dihydro-1-(2-methoxybenzyl)-4-(4-methoxyphenyl)-2-oxo-7-nitrobenzofuro[3,2-b]pyridine-3-carboxylic acid, m.p. 245°, prepared analogously to Examples 1 and 2, in 25 ml of methanol is hydrogenated to completion on 1 g of Raney nickel at normal pressure and 20°. The mixture is filtered, the solvent is removed and 7-amino-1,2-dihydro-1-(2-methoxybenzyl)-4-(4-methoxyphenyl)-2-oxobenzofuro[3,2-b]pyridine-3-carboxylic acid, m.p. 268°, is obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[CH:3]=1.[NH2:19][N:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1>>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[CH:3]=[C:2]([NH:19][N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1)([CH3:18])=[O:16]
Reactant: CP(C)(=O)c1ccc(Nc2cc(Cl)ncn2)cc1
Reactant: CN1CCN(N)CC1
Product: CN1CCN(Nc2cc(Nc3ccc(P(C)(C)=O)cc3)ncn2)CC1

Procedure:
The compound is prepared as in Example 59 by reacting 6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine with 1-Amino-4-methyl-piperazine.
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][CH2:4][Mg]Cl.[CH3:8][C@H:9]1[CH2:11][O:10]1.[NH4+].[Cl-]>C1COCC1.[Cu]I>[CH3:1][C:2]([CH3:7])=[CH:3][CH2:4][CH2:8][C@@H:9]([OH:10])[CH3:11]
Reactant: C[C@H]1CO1
Reactant: CC(C)=CC[Mg]Cl
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)=CCC[C@H](C)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-Methylbut-2-enylmagnesium chloride, 0.50 M in THF (100 mL, 50 mmol) was cooled to 0° C., CuI (952 mg, 5.0 mmol), then (S)-2-methyl-oxirane (1.752 mL, 25.0 mmol) in anhydrous THF (12 mL) was slowly added to the stirred reaction mixture via syringe pump at a rate of 16 mL/h over 45 min to give a dark suspension which was stirred at 0° C. under an Argon atm for 1 h, then allowed to slowly warm to RT over several h. After stirring at RT for 18 h the reaction mixture was poured into sat aqueous NH4Cl (75 mL), the mixture was extracted with Et2O (3×100 mL), the organic extracts were combined, washed with water (100 mL), brine (100 mL), dried with MgSO4, and solvent was evaporated in vacuo (30 mm Hg) at 25° C. to give an oil which was purified by SiO2 flash chromatography to give the title compound as an oil in 2 fractions (2.2 g, 69%). H1 NMR (CDCl3): • 5.14 (m, 1H), 3.82 (m, 1H), 3.08 (m, 1H), 1.69 (s, 3H), 1.62 (s, 2H), 1.48 (m, 2H), 1.19 (d, 3H, J=6 Hz).
Reaction SMILES: ClC[C:3]([N:5]([CH2:16][CH:17]1[C:25]2[C:20](=[CH:21][C:22]([C:26]#[N:27])=[CH:23][CH:24]=2)[CH2:19][CH2:18]1)[CH2:6][CH2:7][NH:8][C:9](=O)OC(C)(C)C)=[O:4].CCO.C([O-])([O-])=O.[K+].[K+]>Cl.O1CCOCC1>[O:4]=[C:3]1[CH2:9][NH:8][CH2:7][CH2:6][N:5]1[CH2:16][CH:17]1[C:25]2[C:20](=[CH:21][C:22]([C:26]#[N:27])=[CH:23][CH:24]=2)[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)NCCN(CC1CCc2cc(C#N)ccc21)C(=O)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: C1COCCO1
Product: N#Cc1ccc2c(c1)CCC2CN1CCNCC1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of tert-Butyl (2-{(chloroacetyl)[(5-cyano-2,3-dihydro-1H-inden-1-yl)methyl]amino}ethyl)carbamate (125 mg, 0.32 mmol) in HCl/dioxane (20 mL) was stirred at RT for 12 hours and then concentrated to dryness. To the residue was added 2 mL EtOH and K2CO3 (300 mg, 2.0 mmol). The resulting mixture was heated to reflux for 4 hours before cooled to RT and filtered. The filtrate was concentrate and the residue was partitioned between EtOAc and water. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to dryness to give 1-[(2-Oxopiperazin-1-yl)methyl]indane-5-carbonitrile. MS m/z: 256 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[CH2:12][NH:11][CH2:10][CH2:9][C:5]=2[N:6]=[CH:7][N:8]=1.Br[C:14]1[CH:15]=[C:16]([Cl:22])[C:17]([O:20][CH3:21])=[N:18][CH:19]=1.CC(C)([O-])C.[Na+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C(O[Pd]OC(=O)C)(=O)C.CCCCCCC.COC(C)(C)C.C1(C)C=CC=CC=1.C(O)(C)(C)C>[Cl:22][C:16]1[CH:15]=[C:14]([N:11]2[CH2:10][CH2:9][C:5]3[N:6]=[CH:7][N:8]=[C:3]([O:2][CH3:1])[C:4]=3[CH2:12]2)[CH:19]=[N:18][C:17]=1[O:20][CH3:21]
Reactant: COc1ncc(Br)cc1Cl
Reactant: COc1ncnc2c1CNCC2
Agent: CC(=O)O[Pd]OC(C)=O
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Solvent: CC(C)(C)O
Product: COc1ncc(N2CCc3ncnc(OC)c3C2)cc1Cl
Temperature: 110 °C
Reaction time: 2 h
Yield: 18.8 %

Procedure:
To a glass vial was added 4-methoxy-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (WO 2008/130481, p 47) (0.273 g, 1.65 mmol), 5-bromo-3-chloro-2-methoxypyridine (0.368 g, 1.65 mmol), sodium tert-butoxide (318 mg, 3.31 mmol), diacetoxypalladium (0.037 g, 0.17 mmol), X-Phos (0.079 g, 0.17 mmol) and anhydrous toluene/tert-butanol, 5/1 (6 mL). The vial was flushed with a stream of argon for 15 sec and capped. The mixture was heated with stirring for 2 h at 110° C. then allowed to cool to room temperature and stirred at rt for 5 days. Diluted with CH2Cl2 (10 mL) and water (2 mL), filtered through a celite pad. The organic phase was separated by filtering through a phase separation tube and concentrated in vacuo. Purified by flash chromatography on silica gel with heptane/EtOAc 100/0 to 0/100 to give 6-(5-chloro-6-methoxy-pyridin-3-yl)-4-methoxy-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine as a yellow solid (95 mg, 19% yield) LCMS: [M+H]+=307.0/308.9, Rt(3)=1.62 min.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:21][CH2:22][N:23]([CH3:25])[CH3:24]>CN(C)C=O>[CH3:24][N:23]([CH3:25])[CH2:22][CH2:21][N:7]1[CH:6]=[C:5]2[C:9]([CH:10]=[CH:11][CH:12]=[C:4]2[N+:1]([O-:3])=[O:2])=[N:8]1
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCn1cc2c([N+](=O)[O-])cccc2n1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
4-Nitroindazole (1.00 g, 6.13 mmol) was dissolved in 20 mL of N,N-dimethylformamide and potassium carbonate (2.50 g, 18.1 mmol) was added. The mixture was stirred for 30 minutes and then (2-chloro-ethyl)-dimethyl-amine hydrochloride (1.33 g 9.23 mmol) was added. The reaction mixture was heated to 60° C. for 6 hours, cooled to room temperature. The mixture was filtered through a plug of silica gel and rinsed with triethylamine/ethyl acetate (1/4). The filtrate was concentrated in vacuo to remove N,N-dimethylformamide and the residue purified by flash chromatography (silica gel, triethylamine/ethyl acetate 1/30). 1H NMR (300 MHz, DMSO-d6) ppm 2.19 (s, 6H), 2.84 (t, 2H, J=6.44) 4.65 (t, 2H, J=6.44), 7.49 (dd, 1H, J1=8.48, J2=7.8), 8.18(m, 1H), 8.20 (m, 1H), 8.91 (s, 1H); MS (DCI/NH3) m/z 235 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.I[C:36]1[C:46]([CH3:47])=[CH:45][C:39]([C:40]([N:42]([CH3:44])[CH3:43])=[O:41])=[CH:38][C:37]=1[CH3:48].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C1(C)C=CC=CC=1>[CH3:43][N:42]([CH3:44])[C:40]([C:39]1[CH:38]=[C:37]([CH3:48])[C:36]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[C:10]3[C:6]=2[CH2:7][CH2:8][C@H:9]3[O:11][C:12]2[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=2)=[C:46]([CH3:47])[CH:45]=1)=[O:41]
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(C(=O)N(C)C)cc(C)c1I
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(C(=O)N(C)C)cc5C)ccc(F)c43)ccc21
Temperature: 120 °C
Reaction time: 5 h

Procedure:
In a microwave vial, methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (75 mg), 4-iodo-N,N,3,5-tetramethylbenzamide (97 mg), K3PO4 (102 mg) and dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (S-Phos) (7 mg) are suspended in toluene (2 mL) and water (0.2 mL) and purged for 10 minutes with argon. Palladium-(II)-acetate (4 mg) are added, the vial is sealed and the mixture is stirred at 120° C. for 5 hours. After cooling to ambient temperature the mixture is partitioned between ethyl acetate and water. The organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 100:0→80:20) to give the title compound. Yield: 70 mg; LC (method 25): tR=1.41 min; Mass spectrum (ESI+): m/z=518 [M+H]+.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:14][C:15]([F:24])([F:23])[C:16]1[N:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[F:11][C:10]([F:13])([F:12])[C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([O:22][C:19]2[CH:20]=[N:21][C:16]([C:15]([F:24])([F:14])[F:23])=[CH:17][CH:18]=2)[CH:9]=1
Reactant: N#Cc1ccc(C(F)(F)F)cc1F
Reactant: Oc1ccc(C(F)(F)F)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(C(F)(F)F)cc1Oc1ccc(C(F)(F)F)nc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 87.3 %

Procedure:
A mixture of 2-fluoro-4-(trifluoromethyl)benzonitrile (0.19 g, 1.0 mmol), 6-(trifluoromethyl)pyridin-3-ol (0.16 g, 1.0 mmol), and Cs2CO3 (0.33 g, 1 mmol) in DMF (10 mL) was stirred at 60° C. for 18 hours. The reaction was diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine and water, dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on silica gel with 0-15% ethyl acetate in hexanes to give 4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyridin-3-yloxy)benzonitrile (0.29 g, 87% yield). LC/MS: m/z 333.5 (M+H)+ at 1.83 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:26][C:27]([NH:29][CH:30]([CH:44]([CH3:46])[CH3:45])[CH:31]([O:36][Si](C(C)(C)C)(C)C)[C:32]([F:35])([F:34])[F:33])=[O:28])[C:10](=[O:25])[C:11]([NH:14][C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[O:16])=[CH:12][N:13]=2)=[CH:4][CH:3]=1.CO>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:26][C:27]([NH:29][CH:30]([CH:44]([CH3:46])[CH3:45])[CH:31]([OH:36])[C:32]([F:34])([F:35])[F:33])=[O:28])[C:10](=[O:25])[C:11]([NH:14][C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=3)=[O:16])=[CH:12][N:13]=2)=[CH:4][CH:3]=1
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccc(F)cc2)ncc(NC(=O)OCc2ccncc2)c1=O)C(O[Si](C)(C)C(C)(C)C)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CC(C)C(NC(=O)Cn1c(-c2ccc(F)cc2)ncc(NC(=O)OCc2ccncc2)c1=O)C(O)C(F)(F)F

Procedure:
2-[2-(4-Fluorophenyl)-6-oxo-5-(4-pyridylmethoxycarbonylamino)-1,6-dihydro-1-pyrimidinyl]-N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)acetamide was subjected to a procedure similar to that described in Example 2.d. Chromatography with methanol:dichloromethane (gradient, 5:95, 7:93) as the eluent, gave 2-[2-(4-fluorophenyl)-6-oxo-5-(4-pyridylmethoxycarbonylamino)-1,6-dihydro-1-pyrimidinyl]-N-(3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl)acetamide as a white solid; MS: m/z=552(M+1).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH3:14])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:21])[N:6]2[CH2:15][CH:16]1[CH2:20][CH2:19][O:18][CH2:17]1.[ClH:22].[CH2:23](OCC)C>O1CCOCC1>[ClH:22].[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:23])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:21])[N:6]2[CH2:15][CH:16]1[CH2:20][CH2:19][O:18][CH2:17]1
Reactant: CCCOc1nc(N)c2[nH]c(=O)n(CC3CCOC3)c2n1
Reactant: CCOCC
Agent: Cl
Solvent: C1COCCO1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CC3CCOC3)c2n1

Procedure:
To 6-Amino-2-(propyloxy)-9-(tetrahydro-3-furanylmethyl)-7,9-dihydro-8H-purin-8-one (52.6 mg) was added an excess of 4N hydrogen chloride in 1,4-dioxane (1 mL). The resultant solution was evaporated under reduced pressure (after 5 minutes) to give a colourless gum containing some crystals. To this material was added diethyl ether to triturate out the 1,4-dioxane, giving a free flowing solid on scratching. After evaporation to dryness under reduced pressure for 2 hours (water bath at 50° C., minimum vacuo ˜38 mbar) gave the title compound (61 mg) an off-white free flowing solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:17][C:16](=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:17]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:29])([F:30])[F:31])=[CH:23][CH:22]=2)[C:16](=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: COc1cccc(OC)c1C1CCCCC(=O)N1
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1ccc(OC(F)(F)F)cc1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 7-(2,6-dimethoxyphenyl)azepan-2-one with commercially available 1-(bromomethyl)-4-(trifluoromethoxy)benzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.98 min.; [M+H]+: 424.20 g/mol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:11]=O.[NH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17].C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl.CCOC(C)=O.CO>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH2:11][NH:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]
Reactant: Nc1ccccc1C(=O)O
Reactant: O=Cc1c[nH]c2c(F)cccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C(O)c1ccccc1NCc1c[nH]c2c(F)cccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 7-fluoro-1H-indole-3-carbaldehyde (200 mg, 1.23 mmol), 2-amino-benzoic acid (168 mg, 1.23 mmol) and p-toluenesulfonic acid (20 mg, 10% W/W) was heated a reflux in toluene (5 mL) for 4 h. The mixture was cooled to RT and diluted with CH2Cl2. NaBH4 (51.4 mg) was added followed by MeOH (2 mL). The mixture was stirred for 1 h. The reaction mixture was diluted with EtOAc (10 mL) and extracted with water (2×10 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo affording the titled compound as a light yellow solid. ESI MS: (M−1)=283. Calc'd for C16H13FN2O2-284.29.