Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH3:20])[C:17]([NH2:19])=[NH:18])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].[OH:25]/[CH:26]=[C:27](/[CH2:32][C:33]1[CH:34]=[N:35][C:36]([O:39][CH3:40])=[N:37][CH:38]=1)\[C:28](OC)=O.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH3:20])[C:17]3[NH:19][CH:28]=[C:27]([CH2:32][C:33]4[CH:34]=[N:35][C:36]([O:39][CH3:40])=[N:37][CH:38]=4)[C:26](=[O:25])[N:18]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:21]([F:22])([F:23])[F:24]
Reactant: COC(=O)/C(=C\O)Cc1cnc(OC)nc1
Reactant: CN(Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1)C(=N)N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ncc(Cc2c[nH]c(N(C)Cc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cn1
Temperature: 130 °C
Yield: 8.9 %

Procedure:
To the solution of N-[(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)methyl]-N-methylguanidine (100 mg, 0.212 mmol) and methyl (2Z)-3-hydroxy-2-{[2-(methyloxy)-5-pyrimidinyl]methyl}-2-propenoate (57.2 mg, 0.255 mmol) in NMP (1 ml) was added K2CO3 (117 mg, 0.850 mmol). It was heated with a microwave reactor at 130° C. for 1.5 h. Purification via MDAP then afforded the title compound as a white solid (10 mg, 8.8% yield). LCMS: rt=3.14 min, [M+H+]=532
Reaction SMILES: [CH3:1]S(C)(=O)=C.[C:6]1([CH:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13][CH:14]=[O:15])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[O:15]1[CH:14]([CH2:13][CH:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:1]1
Reactant: C=S(C)(C)=O
Reactant: O=CCC(c1ccccc1)c1ccccc1
Product: c1ccc(C(CC2CO2)c2ccccc2)cc1

Procedure:
The 1,2-epoxy-4,4-diarylbutane starting materials can alternatively be prepared by reaction of dimethylsulfonium methylide or dimethyloxosulfonium methylide with an appropriate diarylalkyl aldehyde or a diarylalkyl ketone. For example, reaction of an aldehyde such as 3,3-diphenylpropanal with either dimethylsulfonium methylide or dimethyloxosulfonium methylide in approximately equimolar amounts provides 1,2-epoxy-4,4-diphenylbutane. Similarly, reaction of a diarylalkyl ketone such as methyl-(2,2-diphenylethyl) ketone with either dimethylsulfonium methylide or dimethyloxosulfonium methylide provides 1,2-epoxy-4,4-diphenyl-2-methylbutane. Such reactions typically are carried out in a solvent such as dimethyl sulfoxide or tetrahydrofuran, and normally at a reduced temperature of about 0° C. Dimethylsulfonium methylide is prepared by reaction of trimethylsulfonium iodide with methylsulfinylcarbanion, while demethyloxosulfonium methylide is prepared by reaction of trimethyloxosulfonium iodide with sodium hydride. Such reactions are more fully discussed by Corey et al., J. Am. Chem. Soc., 84, 867(1962) and J. Am. Chem. Soc., 84, 3782 (1962).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10]([OH:12])=O.S(Cl)([Cl:15])=O>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10]([Cl:15])=[O:12]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1c(F)cccc1F
Product: O=C(Cl)Cc1c(F)cccc1F
Reaction time: 1 h

Procedure:
75.3 g (0.44 mol) of 2,6-difluorophenylacetic acid are dissolved in 96 ml (156.5 g; 1.32 mol) of thionyl chloride, stirred for 1 hour at 60° and then heated under reflux for 2 hours. The excess thionyl chloride is then distilled off and the residue is fractionated, yielding 79.5 g (95% of the theoretical yield) of 2,6-difluorophenylacetyl chloride.
Reaction SMILES: C(C1[CH:19]=[CH:18][C:6]2[O:7][CH2:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[CH:12][CH3:13])[C:5]=2[CH:4]=1)#N.[C:20]([OH:23])(=[O:22])[CH3:21].Cl>O>[CH:12](=[C:11]1[C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[CH2:8][O:7][C:6]2[CH:18]=[CH:19][C:21]([C:20]([OH:23])=[O:22])=[CH:4][C:5]1=2)[CH3:13]
Reactant: CC(=O)O
Reactant: CC=C1c2ccccc2COc2ccc(C#N)cc21
Agent: Cl
Solvent: O
Product: CC=C1c2ccccc2COc2ccc(C(=O)O)cc21

Procedure:
Reflux a mixture of 2.8 gm of the nitrile of Step A, 50 ml of acetic acid, 5 ml of water and 5 ml of concentrated hydrochloric acid for 140 hours. Cool the reaction mixture, separate the solids by filtration and dry. Recrystallize from toluene to obtain the title product.
Reaction SMILES: Br[C:2]1[C:3]([O:19][CH2:20][CH:21]2[CH2:23][CH2:22]2)=[N:4][C:5]([CH3:18])=[C:6]([CH:17]=1)[C:7]([NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[OH:16])=[O:8].[Cl:24][C:25]1[CH:26]=[CH:27][CH:28]=[C:29](B(O)O)[CH:30]=1>>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([C:2]2[C:3]([O:19][CH2:20][CH:21]3[CH2:23][CH2:22]3)=[N:4][C:5]([CH3:18])=[C:6]([CH:17]=2)[C:7]([NH:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]2[OH:16])=[O:8])=[CH:29][CH:30]=1
Reactant: Cc1nc(OCC2CC2)c(Br)cc1C(=O)N[C@@H]1CCCC[C@H]1O
Reactant: OB(O)c1cccc(Cl)c1
Product: Cc1nc(OCC2CC2)c(-c2ccc(Cl)cc2)cc1C(=O)N[C@@H]1CCCC[C@H]1O

Procedure:
The title compound was synthesized in analogy to the procedure described for the preparation of Example 31c, using 5-bromo-6-cyclopropylmethoxy-N-((1R,2R)-2-hydroxy-cyclohexyl)-2-methyl-nicotinamide and 5-chlorophenyl-boronic acid as starting materials, MS (ISP): 415.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20](O)=[O:21])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:23][CH:24]([C:26]1[S:27][CH:28]=[C:29]([CH2:31][NH2:32])[N:30]=1)[CH3:25]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])=[N:12][CH:11]=[C:10]([CH:9]=2)[C:20]([NH:32][CH2:31][C:29]2[N:30]=[C:26]([CH:24]([CH3:25])[CH3:23])[S:27][CH:28]=2)=[O:21])=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: CC(C)c1nc(CN)cs1
Product: CC(C)c1nc(CNC(=O)c2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)cs1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAS Registry No. 1018782-82-5) and 2-(1-methylethyl)-4-thiazolemethanamine as starting materials, LC-MS (UV peak area/ESI) 98%, 470.090 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[CH:23]=[C:22]([Cl:24])[S:21][C:12]=2[N:13]=[C:14]([C:16]2[O:20][N:19]=[CH:18][CH:17]=2)[N:15]=1>>[O:20]1[C:16]([C:14]2[N:15]=[C:10]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:11]3[CH:23]=[C:22]([Cl:24])[S:21][C:12]=3[N:13]=2)=[CH:17][CH:18]=[N:19]1
Reactant: NCc1ccccc1
Reactant: Clc1cc2c(Cl)nc(-c3ccno3)nc2s1
Product: Clc1cc2c(NCc3ccccc3)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(isoxazol-5-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-benzylamino-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.Cl.[NH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[OH:26].CCN(CC)CC>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[OH:26]
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Reactant: NCc1ccccc1O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1NC(=O)c2ccc(Br)cc2/C1=C/NCc1ccccc1O
Yield: 29.5 %

Procedure:
To a mixture of 6-bromo-4-methoxymethylene-4H-isoquinoline-1,3-dione (194 mg, 0.69 mmol) and 2-aminomethyl-phenol hydrochloride salt (110 mg, 0.69 mmol) in N,N-dimethylformamide (DMF) (5 mL) is added Et3N (0.145 mL, 1.04 mmol). The precipitate is filtered to give 76 mg (30%) of the title compound as a beige solid. MS (ESI) m/z 371.0 (M−H)−1.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[SH:10].C([O-])([O-])=O.[K+].[K+].F[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1>CN(C=O)C.CCOC(C)=O>[F:12][C:2]([F:1])([F:11])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: FC(F)(F)Oc1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Sc2ccccc2OC(F)(F)F)cc1
Temperature: 120 °C
Yield: 73.5 %

Procedure:
To a solution of 2-(trifluoromethoxy)benzenethiol (1.035 g, 5.33 mmol) in DMF (15 mL) at 0° C. was added K2CO3 (921 mg, 6.66 mmol). The solution was warmed to ambient temperature over 10 min before 4-fluorobenzonitrile (613 mg, 5.06 mmol) was added at once. The mixture was heated to 120° C. for 16 hours, then was then cooled and poured onto ice. The mixture was diluted with EtOAc, the layers separated, and the organics were washed successively with sat. NaHCO3 and brine (2×). The organics were dried (MgSO4), filtered, and purified by Biotage SP1 (DCM/hexanes gradient) to afford 4-((2-(trifluoromethoxy)phenyl)thio)benzonitrile (1.098 g, 74%) as a golden oil.
Reaction SMILES: [CH2:1]([N:3]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:4](=[O:24])[CH2:5][O:6][C:7]1[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[N:8]=1)[CH3:2].C(O)C>[C].[Pd].C(Cl)(Cl)Cl>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:9]2[N:8]=[C:7]([O:6][CH2:5][C:4]([N:3]([CH2:1][CH3:2])[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:24])[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=2)=[CH:16][CH:17]=1
Reactant: CCN(C(=O)COc1nc(-c2ccc([N+](=O)[O-])cc2)nc(C)c1C)c1ccccc1
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCN(C(=O)COc1nc(-c2ccc(N)cc2)nc(C)c1C)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.6 %

Procedure:
A mixture of 2-[5,6-dimethyl-2-(4-nitrophenyl)-4-pyrimidinyloxy]-N-ethyl-N-phenylacetamide (2.3 g) obtained in Example 164, 5% palladiumcarbon (0.4 g), ethanol (30 ml) and chloroform (10 ml) is stirred at room temperature for three hours under hydrogen atmosphere, and the reaction mixture is filtered. The filtrate is concentrated under reduced pressure, and recrystallized from acetonitrile to give a 1/10 hydrate of the desired compound (2.1 g), m.p. 183-185° C.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:36])[C@@H:14]([NH:23][C:24]([C:26]1[NH:35][C:29]2=[N:30][CH:31]=[C:32]([Cl:34])[CH:33]=[C:28]2[CH:27]=1)=[O:25])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)(C)(C)C>C(Cl)Cl>[Cl:34][C:32]1[CH:33]=[C:28]2[CH:27]=[C:26]([C:24]([NH:23][C@@H:14]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[C:13]([OH:36])=[O:12])=[O:25])[NH:35][C:29]2=[N:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(F)cc1)NC(=O)c1cc2cc(Cl)cnc2[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)O)c1cc2cc(Cl)cnc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Trifluoroacetic acid (1.9 mL, 24.3 mmol) was added to a suspension of 2-(S)-[(5-chloro-1H-pyrrolo[2,3-b]pyridine-2-carbonyl)amino]-3-(4-fluorophenyl)-propionic acid tert-butyl ester (EXAMPLE 281, 507 mg, 1.21 mmol) in DCM (25 mL) and the reaction mixture was stirred at rt for 16 h. Further trifluoroacetic acid (2 mL) was added and the reaction was stirred at rt for 48 h. The solvent was removed in vacuo and the solid partitioned between 1N hydrochloric acid (50 mL) and ethyl acetate (3×30 mL). The combined organic fractions were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo to give the title compound. δH (CD3OD): 3.11 (1H, dd), 3.33 (1H, dd), 4.88 (1H, m), 6.97 (2H, m), 7.06 (1H, s), 7.28 (2H, m), 8.08 (1H, d), 8.29 (1H, d); m/z (ES+)=362 [M+H]+; RT=3.67 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:25][CH2:26][CH2:27][N:28]1[C:36](=[O:37])[C:35]2[N:34](CC=C)[C:33]([Cl:41])=[N:32][C:31]=2[N:30]([CH2:42][CH2:43][CH2:44][C:45]([F:48])([F:47])[F:46])[C:29]1=[O:49])(=O)=O.N1CCOCC1>CN(C=O)C.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>[Cl:41][C:33]1[NH:34][C:35]2[C:36](=[O:37])[N:28]([CH2:27][CH2:26][CH2:25][N:11]3[N:12]=[N:13][C:9]([CH2:8][C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[N:10]3)[C:29](=[O:49])[N:30]([CH2:42][CH2:43][CH2:44][C:45]([F:48])([F:46])[F:47])[C:31]=2[N:32]=1
Reactant: C=CCn1c(Cl)nc2c1c(=O)n(CCCOS(C)(=O)=O)c(=O)n2CCCC(F)(F)F
Reactant: Fc1ccc(Cc2nnn[nH]2)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: [K+]
Solvent: C1COCCN1
Solvent: CN(C)C=O
Product: O=c1c2[nH]c(Cl)nc2n(CCCC(F)(F)F)c(=O)n1CCCn1nnc(Cc2ccc(F)cc2)n1
Temperature: 60 °C

Procedure:
5-[(4-Fluorophenyl)methyl]-1H-tetrazole (75 mg, 0.4 mmol) was treated with potassium carbonate (100 mg, 0.7 mmol) and DMF (3 ml). The mixture was treated with a solution of 3-[8-chloro-2,6-dioxo-7-(2-propen-1-yl)-3-(4,4,4-trifluorobutyl)-2,3,6,7-tetrahydro-1H-purin-1-yl]propyl methanesulfonate (100 mg, 0.2 mmol) in DMF (0.5 ml). The mixture was stirred and heated at 60° C. 3 hours then cooled and evaporated. The residue was partitioned between chloroform (4 ml) and water (2 cm3). 1 cm3 of saturated aqueous sodium bicarbonate (3 ml) was added to each. The mixture was separated and the organic phase evaporated. The residue was dissolved in anhydrous THF (3 ml) and the mixture degassed by the cautious successive application of vacuum and nitrogen pressure to the mixture. The mixture was treated with tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.008 mmol) and morpholine (0.2 ml, 2.3 mmol) and then stirred in a nitrogen atmosphere for 2 h. The mixture was evaporated and partitioned between chloroform (4 ml) and saturated aqueous ammonium chloride (3 ml). The mixture was separated, and the aqueous phase re-extracted with chloroform. The organic phase was evaporated and the residue dissolved in MeOH (3 ml). The solution was added to the top of a 2 g aminopropyl SPE and washed with MeOH (15 ml). The desired product was eluted from the cartridge with a 3% v/v solution of AcOH in MeOH (20 ml). Product containing fractions were combined and evaporated and the residue subjected to purification by flash column chromatography (gradient elution from 10:1 cyclohexane/EtOAc to EtOAc). Product-containing fractions were combined and evaporated to yield the product as a colourless oil. Trituration in minimal diethyl ether caused the product to solidify and this was thoroughly dried to yield the title compound as a white solid (18.7 mg, 18%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[N:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[CH3:22][C:23]1[O:27][N:26]=[C:25]([C:28]2([NH2:32])[CH2:31][CH2:30][CH2:29]2)[N:24]=1>>[CH3:22][C:23]1[O:27][N:26]=[C:25]([C:28]2([NH:32][C:12]([C:10]3[CH:9]=[N:8][C:7]([N:15]4[CH2:18][C:17]([F:20])([F:19])[CH2:16]4)=[C:6]([O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[N:11]=3)=[O:14])[CH2:31][CH2:30][CH2:29]2)[N:24]=1
Reactant: Cc1nc(C2(N)CCC2)no1
Reactant: O=C(O)c1cnc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: Cl
Product: Cc1nc(C2(NC(=O)c3cnc(N4CC(F)(F)C4)c(OCC4CC4)n3)CCC2)no1

Procedure:
The title compound was synthesized in analogy to Example 8e, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid (Example 8d, 100 mg, 0.35 mmol) and 1-(5-methyl-1,2,4-oxadiazol-3-yl)-cyclobutanamine (CAN 1170897-128-5, 64.42 mg, 0.42 mmol) as starting materials, and isolated (25 mg, 16.95%) as off white solid; LC-MS (UV peak area, ESI) 99.10%, 421.4 (M+H).
Reaction SMILES: [CH2:1]([N:8]([CH2:12][Si](C)(C)C)[CH2:9]OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:17][CH:18]([F:24])/[CH:19]=[CH:20]/[N+:21]([O-:23])=[O:22]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:1]([N:8]1[CH2:12][C@@H:20]([N+:21]([O-:23])=[O:22])[C@H:19]([CH:18]([F:24])[F:17])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=[N+]([O-])/C=C/C(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])[C@@H]1CN(Cc2ccccc2)C[C@H]1C(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 48780.8 %

Procedure:
To a solution of N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (56.6 g, 0.24 mol) in dry CH2Cl2 (160 ml) was added (E)-3,3-difluoro-1-nitroprop-1-ene (25 g, 0.2 mmol) and a few drops of TFA at 0° C. The resulting mixture was stirred at rt overnight. The mixture was concentrated and purified by flash column chromatography (petroleum ether:EtOAc=100:1 to 25:1) to give the title compound (25 g, 49% yield) as a yellow oil.
Reaction SMILES: Br[C:2]1[C:11]([Br:12])=[CH:10][C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1.[C:13]([Cu])#[N:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:12][C:11]1[C:2]([C:13]#[N:14])=[CH:3][C:4]2[O:9][CH2:8][CH2:7][O:6][C:5]=2[CH:10]=1
Reactant: Brc1cc2c(cc1Br)OCCO2
Reactant: N#C[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc2c(cc1Br)OCCO2
Temperature: 150 °C
Reaction time: 144 h

Procedure:
A mixture of 20.0 g (62.6 mmol) of 6,7-dibromo-2,3-dihydrobenzo[1,4]dioxine, 8.50 g (93.9 mmol) CuCN and 13.0 (93.9 mmol) K2CO3 in 300 mL DMF is stirred at 150° C. for 6 d. The reaction is quenched by the addition of water and extracted with EtOAc. The org. layers are combined and washed with water (3×) and sat. aq. NaCl solution. After drying over Na2SO4, the mixture is filtered and the solvent is removed in vacuo. The resulting residue is purified by column chromatography (silica gel, PE/EtOAc 20/1→10/1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(N(CC)C(C)C)(C)C>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([Cl:9])[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[N:7]=1
Reactant: C1CCNCC1
Reactant: Clc1cc(Cl)nc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Clc1cc(N2CCCCC2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 58.5 %

Procedure:
A mixture of 2,4,6-trichloropyrimidine (5.0 g, 27 mmol) and piperidine (2.3 g, 27 mmol) in tetrahydrofuran (50 mL) and N,N-diisopropylethylamine (3.5 g, 27 mmol) was stirred at room temperature for 24 hours. The solvent was removed and the crude material was purified by flash chromatography on silica gel. The column was eluted with a gradient of hexane to yield ethyl acetate/hexane (1:4). The eluent was removed, giving 2,4-dichloro-6-(1-piperidinyl)pyrimidine (3.67 g, 15.8 mmol, 59%, Rf=0.58 in ethyl acetate/hexane, 1:4).
Reaction SMILES: Br[CH2:2][C@@H:3]([CH3:6])[CH2:4][OH:5].[Br:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([OH:15])=[CH:10][C:9]=1[CH3:16].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[Br:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH2:2][C@@H:3]([CH3:6])[CH2:4][OH:5])=[CH:10][C:9]=1[CH3:16]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: C[C@@H](CO)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1cc(OC[C@@H](C)CO)cc(C)c1Br
Temperature: 25 °C

Procedure:
(S)-3-Bromo-2-methyl-1-propanol (150 mg), 4-bromo-3,5-dimethylphenol (98.5 mg) and potassium carbonate are stirred in 5 mL of acetonitrile at 80° C. for 4 h. The reaction mixture is cooled to room temperature, water is added and the reaction mixture is extracted with diethyl ether. The organic phase is separated, dried over sodium sulfate and concentrated under vacuum to give a solid, used in the next step without further purification. Yield: 130 mg.
Reaction SMILES: [CH2:1]([NH:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([O:22][C:23](=[O:31])[C:24]1[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=1)[CH3:21]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([NH:8][C:9]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[C:19][C:27]3[CH:28]=[CH:29][C:24]([C:23]([O:22][CH2:20][CH3:21])=[O:31])=[CH:25][CH:26]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#Cc1ccc(C2(NCc3ccccc3)CC2)cc1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(C3(NCc4ccccc4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
Using General Procedure F; benzyl-[1-(4-ethynylphenyl)-cyclopropyl]-amine (Intermediate 127, 65.0 mg, 0.27 mmol) and ethyl-4-iodo benzoate (Reagent A, 68.0 mg, 0.27 mmol) in triethyl amine (8 mL) was treated with copper(I)iodide (16.0 mg, 0.08 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (58 mg, 0.08 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-5% EtOAc-hexanes) afforded 90 mg (90%) of the title compound as an orange solid.
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH3:15])[CH:9]=2)[N:5]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:4]1=[O:26].C(N(CC)CC)C.[C:34](Cl)(=[O:36])[CH3:35]>ClCCl>[C:34]([NH:2][N:3]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH3:15])[CH:9]=2)[N:5]([CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)[C:4]1=[O:26])(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: COc1ccc(CCN2C(=O)N(N)CC2c2ccc(C)c(C)c2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CCN2C(=O)N(NC(C)=O)CC2c2ccc(C)c(C)c2)cc1
Reaction time: 0.75 h
Yield: 77.7 %

Procedure:
A solution of compound 1-amino-3-[2-(4-methoxy-phenyl)ethyl]-4-(3,4-dimethylphenyl)-2-imidazolidinone hydrochloride (300 mg, 0.80 mmol) in dichloromethane (3.0 mL) is cooled in an ice bath and triethylamine (0.26 mL, 1.8 mmol) is added, followed by dropwise addition of acetyl chloride (0.068 mL, 0.96 mmol). The reaction is stirred in the cold for 45 minutes and washed with 0.1 N aqueous HCl, H2O, 10% aqueous NaHCO3, and brine. The organic phase is dried (Na2SO4) and concentrated under reduced pressure. The residue is purified over silica (2.5% methanol/dichloromethane) to afford 237 mg (78% yield) of the desired compound. 1H NMR (CDCl3) δ 9.18 (s, 1H), 7.12 (m, 3H), 7.07 (d, J=8.4 Hz, 2H), 6.83 (d, J=8.4 Hz), 4.41 (t, J=8.4 Hz, 1H), 3.91 (t, J=8.4 Hz, 1H), 3.81 (s, 3H), 3.71 (m, 1H), 3.59 (t, J=8.1 Hz, 1H), 2.94 (m, 1H), 2.80 (m, 1H), 2.67 (m, 1H), 2.29 (s, 6H), 2.09 (s, 3H). MS 382 (MH+). Anal. Calcd. For C22H27N3O3¼H2O: C, 68.46, H, 7.18; N, 10.89. Found: C, 68.72, H, 6.97; N, 10.85.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16](=[O:30])[C:17]3[CH:22]=[C:21]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[CH:20]=[C:19]([F:29])[CH:18]=3)[CH:12]=[CH:11][C:10]=2[CH3:31])[CH:5]=[CH:4][N:3]=1.[OH-:32].[NH4+]>C(O)=O>[F:29][C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:20]=1)[C:16]([NH:15][C:13]1[CH:12]=[CH:11][C:10]([CH3:31])=[C:9]([CH:14]=1)[NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([OH:32])[N:7]=1)=[O:30]
Reactant: [OH-]
Reactant: Cc1ccc(NC(=O)c2cc(F)cc(N3CCOCC3)c2)cc1Nc1ccnc(Cl)n1
Agent: [NH4+]
Solvent: O=CO
Product: Cc1ccc(NC(=O)c2cc(F)cc(N3CCOCC3)c2)cc1Nc1ccnc(O)n1
Temperature: 65 °C

Procedure:
A mixture of 2-chloro-4-[5-(3-fluoro-5-morpholinobenzamido)-2-methylanilino]pyrimidine (0.1 g) and formic acid (1.0 ml) was stirred and heated to 65° C. for 16 hours. The mixture was allowed to cool to ambient temperature and was poured into a dilute aqueous ammonium hydroxide solution. The resultant precipitate was isolated and washed with anhydrous diethyl ether. There was thus obtained the title compound (0.09 g); NMR Spectrum: (DMSOd6) 2.14 (s, 3H), 3.2 (m, 4H), 3.73 (m, 4H), 5.70 (br m, 1H), 6.95 (m, 1H), 7.09 (m, 1H), 7.19 (m, 1H), 7.25 (s, 1H), 7.4 (m, 1H), 7.5 (m, 1H), 7.68 (m, 1H), 10.14 (s, 1H), 10.5 (broad s, 1H); Mass Spectrum: M+H+ 424.