Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][C@@H:12]([N:14]2[CH2:21][C:20]3[C:16](=[N:17][N:18]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:19]=3)[CH2:15]2)[CH2:11][N:10]([CH2:26][C@@H:27]([OH:29])[CH3:28])[C@@H:9]1[C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[F:37])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C@H:8]1[CH2:13][C@@H:12]([N:14]2[CH2:21][C:20]3[C:16](=[N:17][N:18]([S:22]([CH3:25])(=[O:23])=[O:24])[CH:19]=3)[CH2:15]2)[CH2:11][N:10]([CH2:26][C@@H:27]([OH:29])[CH3:28])[C@@H:9]1[C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[F:37]
Reactant: C[C@H](O)CN1C[C@H](N2Cc3cn(S(C)(=O)=O)nc3C2)C[C@H](NC(=O)OC(C)(C)C)[C@H]1c1cc(F)ccc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](O)CN1C[C@H](N2Cc3cn(S(C)(=O)=O)nc3C2)C[C@H](N)[C@H]1c1cc(F)ccc1F
Reaction time: 1 h

Procedure:
To the product from Step A (18 mg, 0.032 mmol) was added a 1:1 mixture of dichloromethane and trifluoroacetic acid (0.5 mL). The mixture was stirred for 1 h, and the solvent removed in vacuo. The residue was purified by preparative thin layer chromatography (Analtech 1000 μm) and eluted with methanol containing 10% ammonium hydroxide in dichloromethane (10:90) to afford the title compound as a colorless solid. LC/MS 456.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][CH2:14][O:15][CH3:16])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][CH2:33]Cl)=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1.[CH3:35][O:36][CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>COCCO>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][CH2:14][O:15][CH3:16])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][CH2:33][N:40]3[CH2:41][CH2:42][CH:37]([O:36][CH3:35])[CH2:38][CH2:39]3)=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1
Reactant: COC1CCNCC1
Reactant: COCCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCCl)c(OC)cc23)c2c1OCO2
Solvent: COCCO
Product: COCCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCC(OC)CC4)c(OC)cc23)c2c1OCO2
Yield: 78.9 %

Procedure:
This was prepared using the method described in example 13 using N-[5-chloro-7-(4-methoxybut-1-yn-1-yl)-1,3-benzodioxol-4-yl]-7-(3-chloropropoxy)-6-methoxyquinazolin-4-amine (200 mg, 0.40 mmol) and 4-methoxypiperidine (246 mg, 2.14 mmol) in 2-methoxyethanol (4 ml). The crude product was purified by column chromatography on silica using increasing concentrations of methanolic ammonia in dichloromethane as eluent. There was thus obtained the title compound (184 mg, 80%) as a pale yellow solid; NMR Spectrum:(CDCl3) 1.55-1.70 (m, 2H), 1.85-2.00 (m, 2H), 2.10 (quintet, 2H), 2.24 (m, 2H), 2.56 (t, 2H), 2.72 (t, 2), 2.78 (m, 2H), 3.24 (m, 1H), 3.34 (s, 3H), 3.42 (s, 3H), 3.62 (t, 2H), 3.98 (s, 3H), 4.24 (t, 2H), 6.05 (s, 2H), 6.90 (s, 1H), 7.04 (s, 1H), 7.09 (s, 1H), 7.28 (s, 1H), 8.61 (s, 1H); Mass Spectrum: M+H+ 583/585.
Reaction SMILES: [Cl-].[C:2]1([CH:8]([C:14]([O-:16])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:27][CH2:28][NH2:29])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26].N#N.[Cl-].C([NH+](CC)CC)C>O1CCCC1.C(N(CC)CC)C>[C:2]1([CH:8]([C:14]([O-:16])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:27][CH2:28][NH-:29])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: COc1ccc(CCN)cc1OC
Agent: CCOC(=O)C(C(=O)[O-])c1ccccc1
Agent: CC[NH+](CC)CC
Agent: N#N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(CC[NH-])cc1OC

Procedure:
Two hundred ninety-five grams (1.3 mol) of monoethyl phenylmalonate chloride in 500 ml of absolute tetrahydrofuran were added dropwise, at room temperature, to a cooled mixture of 236 gm (1.3 mol) of 2-(3',4'-dimethoxyphenyl)-ethylamine, 171 gm of triethylamine, and 500 ml of absolute tetrahydrofuran, under stirring and in a protective N2 atmosphere. After the reaction ended, the precipitated triethylammonium chloride was suction filtered, the filtrate was concentrated, and the solid residue was distributed between water and methylene chloride. The organic phase was dried over Na2SO4. After the solvent evaporated, the product was recrystallized from ethyl acetate.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][CH:17]=[CH:16]3)[OH:12])=[CH:7][C:6]=1[CH3:23])[CH2:2][CH2:3][CH3:4].O(C1C=C(C=CC=1)CNC(C1C=C2C(=CC=1)NC=C2)=O)C1C=CC=CC=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][CH:17]=[CH:16]3)=[O:12])=[CH:7][C:6]=1[CH3:23])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C(O)c2ccc3ncccc3c2)cc1C
Agent: [Mn+4]
Agent: O=C(NCc1cccc(Oc2ccccc2)c1)c1ccc2[nH]ccc2c1
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CCCCc1ccc(C(=O)c2ccc3ncccc3c2)cc1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 37 %

Procedure:
To a solution of (4butyl-3-methyl-phenyl)-quinoline-6-yl-methanol described in Preparation Example Z+-1 (152 mg, 0.50 mmol) in chloroform (1.0 mL) was added active manganese dioxide (510 mg, 5.0 mmol), and the solution was stirred at room temperature for 5 hours. Manganese dioxide was removed by filtering through Celite pad, the filtrate was concentrated, the residue was purified by silica gel column chromatography (hexane:ethyl acetate), and the title compound (56 mg, 37%) was obtained as a pale yellow oil.
Reaction SMILES: [Mg].[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:17][C:18]1([CH3:25])[CH2:23][CH2:22][CH2:21][C:20](=[O:24])[CH2:19]1>BrC(Br)C.C1COCC1>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:20]2([OH:24])[CH2:21][CH2:22][CH2:23][C:18]([CH3:25])([CH3:17])[CH2:19]2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Brc1ccc(OCc2ccccc2)cc1
Reactant: CC1(C)CCCC(=O)C1
Agent: CC(Br)Br
Agent: [Mg]
Solvent: C1CCOC1
Product: CC1(C)CCCC(O)(c2ccc(OCc3ccccc3)cc2)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 53.4 %

Procedure:
In a RB flask (250 mL) was placed magnesium turnings (2.08 g, 85.9 mmol), which were stirred under vacuum without solvent overnight. To the stirred magnesium turnings was added anhydrous THF (10 mL). To the resulting mixture at 50° C. was added several drops of dibromoethane, followed by 4-benzyloxybromobenzene (11.8 g, 42.9 mmol) in 40 ml of THF. After addition was complete, the reaction mixture was heated at 60° C. for 3 hours until a brownish-grey slurry was formed. The reaction mixture was cooled in an ice-bath and 3,3-dimethyl-cyclohexanone (3.87 g, 30.67 mmol) in THF (15 mL) was added dropwise. The reaction mixture was stirred at room temperature for one hour. The solvent was removed under reduced pressure. The residue was partitioned between EtOAc/aqueous NH4Cl. The aqueous phase was extracted three times with EtOAc. The organic phase was combined and dried (Na2SO4). Silica gel chromatography (EtOAc/heptane) provided 5.08 g of 1-(4-benzyloxy-phenyl)-3,3-dimethyl-cyclohexanol as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([CH3:18])[N:3]=1.[K+].[C:20]([C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH-:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21]>CS(C)=O.O>[C:20]([C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH:33][C:2]2[C:7]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([CH3:18])[N:3]=2)(=[O:31])=[O:32])=[CH:26][CH:25]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)c1ccc(S([NH-])(=O)=O)cc1
Reactant: COc1ccccc1Oc1c(Cl)nc(C)nc1Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccccc1Oc1c(Cl)nc(C)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 64.8 %

Procedure:
To a solution of 1.0 g of 4,6-dichloro-5-(o-methoxyphenoxy)-2-methyl-pyrimidine in 20 ml of DMSO was added 1.76 g of 4-tert.-butyl-benzene sulfonamide potassium salt. The mixture was stirred for 72 h at room temperature. The solution was diluted with 250 ml of water and extracted twice with 200 ml of diehtyl ether. The organic layers were extracted twice with water. The combined aqueous layers were acidified to pH 4 with 5 ml of acetic acid and cooled to 0° C. The precipitated product was filtered off and dried in vacuo to give 1.05 g of 4-tert.-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-benzene sulfonamide as a pale beige powder. LC-MS: tR=5.64 min, [M+1]+=462.51, [M−1]−=460.63.
Reaction SMILES: [F:1][C:2]1[C:3]2[O:14][CH2:13][O:12][C:9]([C:10]=1[F:11])=[CH:8][C:4]=2[C:5](Cl)=[O:6].Cl.[CH3:16][O:17][NH:18][CH3:19].N1C=CC=CC=1>C(Cl)Cl>[CH3:19][N:18]([O:17][CH3:16])[C:5](=[O:6])[C:4]1[CH:8]=[C:9]2[O:12][CH2:13][O:14][C:3]=1[C:2]([F:1])=[C:10]2[F:11]
Reactant: CNOC
Reactant: O=C(Cl)c1cc2c(F)c(F)c1OCO2
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CON(C)C(=O)c1cc2c(F)c(F)c1OCO2
Temperature: 0 °C
Reaction time: 18 h
Yield: 94.8 %

Procedure:
A solution of 14.4 grams (0.065 mole) of 3,4-difluoromethylenedioxybenzoyl chloride in 150 mL of methylene chloride was stirred and cooled to 0° C. To this was added 6.4 grams (0.066 mole) of O,N-dimethylhydroxylamine hydrochloride, followed by the dropwise addition of 11.0 mL (0.136 mole) of pyridine. Upon completion of addition the reaction mixture was stirred at ambient temperature for 18 hours. The reaction mixture was washed with two portions of aqueous 10% hydrochloric acid, two portions of aqueous IN sodium hydroxide, and two portions of an aqueous saturated solution of sodium chloride. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to yield 15.1 grams of N-methyl-N-methoxy-3,4-difluoromethylenedioxybenzamide. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: FC(F)(F)C([O-])=O.[NH3+:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:18])[CH:16]=[CH2:17].CCN(C(C)C)C(C)C.[Br:28][CH2:29][C:30](Cl)=[O:31].C(=O)=O>C1COCC1.ClCCl.CO.C(O)(C)C>[Br:28][CH2:29][C:30]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:18])[CH:16]=[CH2:17])=[O:31]
Reactant: O=C(Cl)CBr
Reactant: C=CC(=O)NCCCCC[NH3+]
Agent: O=C([O-])C(F)(F)F
Agent: O=C=O
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=CC(=O)NCCCCCNC(=O)CBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a suspension of N-(5-ammoniopentyl]acrylamide trifluoracetate (6.12 g, 22.64 mmol) and DIPEA (6.94 ml, 2.2 eq) in THF (120 ml) was added bromoacetyl chloride (2.07 ml, 1.1 eq) through a pressure equalized dropping funnel, over a one hour period and at −60° C. (cardice and isopropanol bath). The reaction mixture was then stirred at room temperature overnight and the completion of the reaction was checked by TLC (dichloromethane:methanol 9:1) the following day. The salts formed during the reaction were filtered off and the reaction mixture evaporated to dryness. The residue was purified by chromatography (neat dichloromethane followed by a gradient of methanol up to 5%). 3.2 g (11.55 mmol, 51%) of the product (N-[5-(2-Bromoacetyl)aminopentyl]acrylamide) were obtained as a white powder. A further recrystallization performed from petroleum ether:ethyl acetate mixture gave 3 g of the product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]3[C:19](Br)=[C:20]([F:23])[CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1.[CH3:25][N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]3[C:19]([C:29]4[CH:28]=[N:27][N:26]([CH3:25])[CH:30]=4)=[C:20]([F:23])[CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(Br)c2n1C
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(-c3cnn(C)c3)c2n1C
Temperature: 140 °C
Yield: 79.6 %

Procedure:
A mixture of 4-Amino-6-[(S)-1-(7-bromo-6-fluoro-1-methyl-1H-benzoimidazol-2-yl)ethylamino]-pyrimidine-5-carbonitrile, (0.10 g, 0.26 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.069 g, 0.33 mmol), tetrakis(triphenylphosphine)palladium(0) (0.015 g, 0.01 mmol) and caesium carbonate (0.17 g, 0.51 mmol) in dioxane (3 mL) and water (1.5 mL) was placed in a sealed tube and degassed with nitrogen for 5 minutes, then heated for 30 minutes at 140° C. by microwave irradiation. The resulting mixture was loaded onto an Isolute® SCX-2 cartridge then washed with MeOH and the product eluted with 2M NH3/MeOH and concentrated in vacuo. The resulting residue was purified by chromatography (SiO2, 0-10% (2M ammonia in methanol) in DCM) then by preparative HPLC (Phenomenex Gemini 5 μm C18 on a 78 min gradient 20-98% 0.1% HCO2H in acetonitrile/water) to give 427 as a white solid (0.081 g, 81%). LCMS (Method K): RT 2.50 min [M+H]+ 392.1. 1H NMR (DMSO-d6, 400 MHz): δ 8.24 (1H, s), 7.92 (1H, s), 7.67-7.59 (2H, m), 7.31 (2H, s), 7.12-7.08 (1H, m), 5.64 (1H, m), 3.93 (3H, s), 3.17 (3H, s), 1.58 (3H, d, J=6.74 Hz)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[N:9][C:8]=2[CH:18]=1)([O-])=O>C(OCC)(=O)C.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]3[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=3)=[N:9][C:8]=2[CH:18]=1
Reactant: O=[N+]([O-])c1ccc2oc(-c3ccncc3)nc2c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc2oc(-c3ccncc3)nc2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 85.9 %

Procedure:
To a solution of 5-nitro-2-(pyridine-4-yl) benzo[d]oxazole 3 (600 mg, 2.48 mmol) in ethyl acetate/MeOH (10 mL) was added catalytic amount of 10% Pd—C under hydrogen atmosphere and stirred it for 6 h at room temperature and filtered by flash column chromatography (100% ethyl acetate) to afford 5-amino-2-(pyridine-4-yl) benzo[d]oxazole 4 (450 mg, 86%) as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ 6.78 (dd, J1=12 Hz, J2=2.4 Hz, 1H), 7.07 (d, J=2 Hz, 1H), 7.40 (d, J=4.8 Hz, 1H), 8.05 (dd, J1=8 Hz, J2=1.6 Hz, 2H), 8.79 (dd, J1=4 Hz, J2=1.6 Hz, 2H), 3.78 (s, 2H).
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:18]=[C:12]2[C:13](=[O:17])[NH:14][CH2:15][CH2:16][N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.Cl[C:60]1[N:65]=[C:64]([O:66][CH3:67])[C:63]([F:68])=[CH:62][N:61]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:68][C:63]1[C:64]([O:66][CH3:67])=[N:65][C:60]([N:14]2[CH2:15][CH2:16][N:11]3[N:10]=[C:9]([CH2:8][O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:18]=[C:12]3[C:13]2=[O:17])=[N:61][CH:62]=1
Reactant: O=C1NCCn2nc(COc3ccccc3)cc21
Reactant: COc1nc(Cl)ncc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Product: COc1nc(N2CCn3nc(COc4ccccc4)cc3C2=O)ncc1F
Temperature: 120 °C
Reaction time: 16 h
Yield: 33 %

Procedure:
Palladium (II) acetate (2.79 mg, 0.012 mmol) was added to a stirred suspension of 2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (100 mg, 0.41 mmol), cesium carbonate (0.18 g, 0.57 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (17 mg, 0.037 mmol) and 2-chloro-5-fluoro-4-methoxypyrimidine (0.2 g, 1.23 mmol) in a sealed tube and under nitrogen. The reaction mixture was stirred at 120° C. for 16 hours. The solvent was evaporated in vacuo and the crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 100/0). The desired fractions were collected and the solvents evaporated in vacuo to yield 5-(5-fluoro-4-methoxy-pyrimidin-2-yl)-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (50 mg, 33% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 4.10 (s, 3H), 4.41-4.57 (m, 4H), 5.12 (s, 2H), 6.93-7.04 (m, 3H), 7.09 (s, 1H), 7.27-7.34 (m, 2H), 8.28 (d, J=2.3 Hz, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][O:24][CH2:23]4)[CH2:18][C@@H:17]3[CH3:26])=[CH:12][N:11]=2)[C:5](=[O:8])[NH:6][N:7]=1.[C:27]([O:30][CH2:31][C:32]1[C:33]([N:47]2[CH2:58][CH2:57][N:56]3[C:49](=[CH:50][C:51]4[CH2:52][C:53]([CH3:60])([CH3:59])[CH2:54][C:55]=43)[C:48]2=[O:61])=[N:34][CH:35]=[CH:36][C:37]=1B1OC(C)(C)C(C)(C)O1)(=[O:29])[CH3:28].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>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].C(#N)C.O>[C:27]([O:30][CH2:31][C:32]1[C:33]([N:47]2[CH2:58][CH2:57][N:56]3[C:49](=[CH:50][C:51]4[CH2:52][C:53]([CH3:60])([CH3:59])[CH2:54][C:55]=43)[C:48]2=[O:61])=[N:34][CH:35]=[CH:36][C:37]=1[C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][O:24][CH2:23]4)[CH2:18][C@@H:17]3[CH3:26])=[CH:12][N:11]=2)[C:5](=[O:8])[NH:6][N:7]=1)(=[O:29])[CH3:28]
Reactant: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(Cl)n[nH]c2=O)nc1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C5COC5)C[C@@H]4C)cn3)c(=O)[nH]n2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 90 °C
Yield: 31.3 %

Procedure:
A 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 253d (172 mg, 0.46 mmol), (3-(acetoxymethyl)-2-(7,7-dimethyl-1-oxo-3,4,7,8-tetrahydro-1H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2(6H)-yl)pyridin-4-yl)boronic acid 199e (0.91 g, 2.29 mmol), Pd(dppf)Cl2 (36 mg, 0.050 mmol), K3PO4 (195 mg, 0.92 mmol), sodium acetate (75 mg, 0.050 mmol), water (0.5 mL), and acetonitrile (10 mL). After three cycles of vacuum/argon flush, the mixture was heated at 90° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 20:1 ethyl acetate/methanol to afford the 253e (100 mg, 31%) as brown solid. MS-ESI: [M+H]+ 694.3.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:12]([C:17]#[N:18])C(OC)=O)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Cl-].[Na+].ClCCl>O.CS(C)=O>[Cl:1][C:2]1[C:3]([CH2:12][C:17]#[N:18])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: COC(=O)C(C#N)c1ncc(C(F)(F)F)cc1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: N#CCc1ncc(C(F)(F)F)cc1Cl
Temperature: 160 °C

Procedure:
314 g (1.13 mol, 1 eq.) of methyl [3-chloro-5-(trifluoromethyl)-2-pyridinyl]-(cyano)acetate and 22 g (0.38 mol, 0.33 eq.) of sodium chloride are dissolved in a solution of 44 mL of water and 1.1 L of dimethyl sulphoxide. The reaction medium is stirred and heated at 160° C. Once all gas has been given off, the medium is cooled to ambient temperature. 1 L of water and 0.5 L of dichloromethane are added. After separation, the aqueous phase is extracted twice with 0.5 L of dichloromethane. The organic phase is washed twice with 0.5 L of water and dried over magnesium sulphate. After concentration, the crude product is diluted in 100 mL of dichloromethane and eluted with an ethyl acetate/heptane mixture (20/80) on a bed of silica. The filtrate is concentrated so as to produce [3-chloro-5-(trifluoromethyl)-2-pyridinyl]acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9](Cl)=[O:10])[CH:5]=[CH:6][CH:7]=1.[Cl:12][C:13]([Cl:22])([Cl:21])[C:14]([C:16]1[NH:17][CH:18]=[CH:19][CH:20]=1)=[O:15].[Cl-].[Cl-].[Cl-].[Al+3]>ClCCl>[Cl:22][C:13]([Cl:12])([Cl:21])[C:14]([C:16]1[NH:17][CH:18]=[C:19]([C:9](=[O:10])[CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH:20]=1)=[O:15]
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Reactant: O=C(Cl)Cc1cccc(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(Cc1cccc(Cl)c1)c1c[nH]c(C(=O)C(Cl)(Cl)Cl)c1
Reaction time: 2 h

Procedure:
In a dry flask, 3-chlorophenylacetyl chloride (1 equivalent) was combined with 2-trichloroacetyl pyrrole (1 equivalent) in a minimum amount of dichloromethane (DCM). To the resulting solution, at ambient temperature, was added aluminum trichloride (1 equivalent). After 2 hours, the reaction mixture was applied directly onto a silica gel column. Gradient elution with 10% ethyl acetate to 50% ethyl acetate in hexanes provided the title compound 1. HPLC Method A, Rt=15 minutes.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][CH3:13])=[CH:9][CH:10]=2)[C:5](=[O:14])[N:4]([CH:15]([CH3:17])[CH3:16])[N:3]=1.[H-].[Na+].[CH3:20][O:21][CH2:22][C:23](Cl)=[O:24].O>CN(C=O)C>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([N:12]([CH3:13])[C:23](=[O:24])[CH2:22][O:21][CH3:20])=[CH:9][CH:10]=2)[C:5](=[O:14])[N:4]([CH:15]([CH3:17])[CH3:16])[N:3]=1
Reactant: CNc1ccc2c(Br)nn(C(C)C)c(=O)c2c1
Reactant: COCC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCC(=O)N(C)c1ccc2c(Br)nn(C(C)C)c(=O)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
4-Bromo-2-isopropyl-7-methylamino-2H-phthalazin-1-one (0.5 g, 1.69 mmol) was dissolved in DMF (5 ml). To this was added NaH (60%, 0.19 g, 5.1 mmol) as a suspension in DMF (2 ml). The mixture was stirred at RT for 30 min then methoxyacetyl chloride (0.27 g, 2.5 mmol) was added dropwise and the reaction mixture was stirred at RT for 24 hours. After this time, water (10 ml) was added cautiously, the mixture was extracted with EtOAc (3×10 ml), the organic layers were combined, dried (MgSO4), filtered and concentrated under vacuum. Flash column chromatography (elution: 50% hexane, 50% EtOAc) gave the title compound (0.47 g, 76% yield) as a white solid.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[CH:14][C:13]=3[C:24]([F:27])([F:26])[F:25])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.OC1CCNC1.[NH:34]1[CH2:39][CH2:38][CH:37]([CH2:40][OH:41])[CH2:36][CH2:35]1>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:19]=[CH:20][N:21]=[C:22]([N:34]5[CH2:39][CH2:38][CH:37]([CH2:40][OH:41])[CH2:36][CH2:35]5)[CH:23]=4)=[CH:14][C:13]=3[C:24]([F:25])([F:26])[F:27])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: FC(F)(F)c1cc(-c2ccncc2)ccc1Sc1ccc2c(c1)OCCO2
Reactant: OCC1CCNCC1
Agent: OC1CCNC1
Product: OCC1CCN(c2cc(-c3ccc(Sc4ccc5c(c4)OCCO5)c(C(F)(F)F)c3)ccn2)CC1

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 118 (0.033 g, 0.0779 mmol) and 3-hydroxypyrrolidine with 4-piperidinemethanol. A yellow solid 122 was obtained (0.0284 g, 57%). 1H-NMR (CDCl3, 400 MHz) δ 1.41-1.51 (m, 2H), 1.86-1.95 (m, 1H), 1.97-2.04 (m, 2H), 3.23-3.31 (m, 2H), 3.57 (d, J=5.8 Hz, 2H), 4.28-4.34 (m, 4H), 4.36-4.41 (m, 2H), 6.92 (d, J=6.6 Hz, 1H), 6.93-6.97 (m, 2H), 7.05 (dd, J=1.8 Hz, 8.4 Hz, 1H),7.09 (d, J=1.8 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.82 (s, 1H), 8.25 (d, J=6.6 Hz, 1H); MS (APCI) m/z 503 (M+H)+.