Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[CH3:28][N:29]1[C:33]([NH2:34])=[CH:32][C:31]([CH3:35])=[N:30]1>>[NH2:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:23])([CH3:24])[C@:12]([C:15]2[CH:20]=[C:19]([NH:34][C:33]3[N:29]([CH3:28])[N:30]=[C:31]([CH3:35])[CH:32]=3)[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: Cc1cc(N)n(C)n1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Br)ccc2F)N=C1NC(=O)OC(C)(C)C
Product: Cc1cc(Nc2ccc(F)c([C@@]3(C)N=C(N)N(C)C(=O)C3(C)C)c2)n(C)n1

Procedure:
The coupling of [(S)-4-(5-bromo-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate E8) and 2,5-dimethyl-2H-pyrazol-3-ylamine according to procedure B followed by deprotection yielded the title compound as a black waxy solid. MS (ESI): m/z=373.2 [M+H]+.
Reaction SMILES: Cl.Cl.Cl.[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2[N:13]=[C:14]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[CH:16]=2)[CH:8]=[CH:9][C:10]=1[F:11].[CH:28](=[C:35]1[C:43]2[C:42](Cl)=[N:41][CH:40]=[N:39][C:38]=2[NH:37][C:36]1=[O:45])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CCN(C(C)C)C(C)C>CC(O)C>[CH:28](=[C:35]1[C:43]2[C:42]([N:25]3[CH2:24][CH2:23][CH:22]([C:14]4[N:15]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[CH:16]=[C:12]([C:7]5[CH:8]=[CH:9][C:10]([F:11])=[C:5]([Cl:4])[CH:6]=5)[N:13]=4)[CH2:27][CH2:26]3)=[N:41][CH:40]=[N:39][C:38]=2[NH:37][C:36]1=[O:45])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CN(C)CCn1cc(-c2ccc(F)c(Cl)c2)nc1C1CCNCC1
Reactant: O=C1Nc2ncnc(Cl)c2C1=Cc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CN(C)CCn1cc(-c2ccc(F)c(Cl)c2)nc1C1CCN(c2ncnc3c2C(=Cc2ccccc2)C(=O)N3)CC1

Procedure:
Combine {2-[4-(3-chloro-4-fluoro-phenyl)-2-piperidin-4-yl-imidazol-1-yl]-ethyl}-dimethyl-amine tris hydrochloride (0.5 g; 0.0013 mol; 1.0 equiv); 5-benzylidene-4-chloro-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (0.33 g; 0.0013 mol; 1.0 equiv); DIPEA (1.7 mL 0.0098 mol; 7.6 equiv); 2-propanol (10 mL) and microwave at 100° C. for 30 min. Cool and concentrate in vacuo. Dilute with saturated sodium bicarbonate solution and extract with DCM. Wash organic layer with water and brine and dry over anhydrous sodium sulfate. Concentrate the crude compound and purify by reverse phase HPLC to give the title compound as a mixture of E and Z isomers (0.09 g; 12.2%). MS (ES+): m/z=572 (M+H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][C:6]2=[O:13].[S:14]1[CH:18]=[CH:17][N:16]=[C:15]1[CH:19]=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][C:7](=[CH:19][C:15]1[S:14][CH:18]=[CH:17][N:16]=1)[C:6]2=[O:13]
Reactant: COc1ccc2c(c1)C(=O)CCO2
Reactant: O=Cc1nccs1
Product: COc1ccc2c(c1)C(=O)C(=Cc1nccs1)CO2

Procedure:
By the method of Example 1, 6-methoxy-4-chromanone (3.97 g, 0.0223 mol) and 2-thiazolecarbaldehyde (3.00 g, 0.0265 mol) were converted to present title product which was recrystallized from methanol, 1.20 g (20%), m.p. 130-132° C., tlc (1:19 CH3OH:CH2Cl2) Rf 0.67.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:23])[CH:15]=[CH:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH2:5][CH2:4]1.[C:24]1([N:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:31](Cl)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>ClCCl>[C:24]1([N:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:31]([N:3]2[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:23])[CH:15]=[CH:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH2:5][CH2:4]2)=[O:32])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(C=Cc1cccnc1)NCCCCC1CCNCC1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Product: O=C(C=Cc1cccnc1)NCCCCC1CCN(C(=O)N(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6.5 g (18.0 mmol) N-[4-(piperidin-4-yl)-butyl]-3-(pyridin-3-yl)-acrylamide dihydrochloride (K22.142) and 5.77 ml (41.4 mmol) TEA are placed in 70 ml abs. dichlormethane and cooled to ca. 0° C. under moisture exclusion. 4.58 g (19.8 mmol) N,N-diphenylcarbamic acid chloride are dissolved in 20 ml abs. dichlormethane and added dropwise. The mixture is stirred at RT overnight without further cooling. 4 ml (28.7 mmol) TEA are added and the red colored suspension is stirred a further 2 hours at RT. Subsequently, the batch is washed with 80 ml water. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum. The residue is chromatographically purified over silica gel with CHCl3/CH3OH (98/2) and crystallized twice, each from 60 ml acetic acid ethyl ester, after drawing off the solvent. Beige colored crystals with a MP of 132–134° C.; yield: 5.3 g (60%).
Reaction SMILES: [C:1]([C:5]1[CH:18]=[C:17]2[C:19]3=[C:20]4[C:10]([CH:11]=[CH:12][CH:13]=[C:14]4[CH:15]=[CH:16]2)=[CH:9][CH:8]=[C:7]3[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:21]N1C(=O)CCC1=O>O1CCCC1>[Br:21][C:13]1[C:14]2[C:20]3=[C:19]4[C:17](=[CH:16][CH:15]=2)[CH:18]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=[C:7]4[CH:8]=[CH:9][C:10]3=[CH:11][CH:12]=1
Reactant: CC(C)(C)c1cc2ccc3cccc4ccc(c1)c2c34
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CC(C)(C)c1cc2ccc3ccc(Br)c4ccc(c1)c2c34
Temperature: 30 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
To a mixed solution of 120 g (content 79.2%) of 2-t-butylpyrene, and 3000 ml of tetrahydrofuran was added 69.66 g of N-bromosuccinimide under a nitrogen stream. This mixed solution was stirred at 30° C. for about 3 hours, and concentrated, 500 ml of methanol was added, and the mixture was stirred for about 1 hour, and filtered. To the resulting solid was added 500 ml of hexane, and the mixture was heated and stirred for about 1 hour, and filtered. After the resultant was vacuum dried, 106.9 g of 1-bromo-7-t-butylpyrene was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([C:11](=O)[CH2:12]Cl)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[NH2:16][C:17]([NH2:19])=[S:18]>C(O)C>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([C:11]1[N:16]=[C:17]([NH2:19])[S:18][CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(C(=O)CCl)C(=O)OCC
Reactant: NC(N)=S
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)c1csc(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.2 %

Procedure:
To a solution of 2-(chloroacetyl)malonic acid diethyl ester in ethanol (8 parts) is added thiourea (1.9 equivalents). After stirring at room temperature for 2 hours, the mixture is let stand overnight. The reaction mixture is concentrated, diluted with water, and neutralized with aqueous sodium hydrogen carbonate to give 2-(2-amino-4-thiazolyl)malonic acid diethyl ester. Yield: 79.2%. mp. 99.5°-100.5° C.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16](O)=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:23]=[CH:22][O:21][CH:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[CH2:56]([O:58][C:59](=[O:71])[C@H:60]([CH2:62][C:63]1[CH:68]=[CH:67][C:66]([C:69]#[N:70])=[CH:65][CH:64]=1)[NH2:61])[CH3:57]>CS(C)=O>[CH2:56]([O:58][C:59](=[O:71])[C@@H:60]([NH:61][C:16]([C:14]1[CH:13]=[CH:12][C:11]2[N:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:8]([C:19]3[CH:23]=[CH:22][O:21][CH:20]=3)=[N:9][C:10]=2[CH:15]=1)=[O:17])[CH2:62][C:63]1[CH:68]=[CH:67][C:66]([C:69]#[N:70])=[CH:65][CH:64]=1)[CH3:57]
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(C#N)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](Cc1ccc(C#N)cc1)NC(=O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
The carboxylic acid of example 2 (0.060 g, 0.20 mmol) and TBTU (1.3 equiv., 0.26 mmol, 0.084 g) were dissolved in DMSO (0.6 mL) and DIEA (5 equiv., 1.0 mmol, 0.18 mL) was added followed by (S)-4-cyanophenylalanine ethyl ester hydrochloride (1.3 equiv., 0.26 mmol, 0.065 g). The mixture was stirred at room temperature for 1 h and quenched with water. The precipitated solid was collected by filtration, washed with water and dried. The title amide (0.081 g) was obtained as a beige solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[Cl:9].[CH2:10]([O:12][CH2:13][CH2:14][CH2:15]O)[CH3:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:15][CH2:14][CH2:13][O:12][CH2:10][CH3:11])=[CH:4][C:3]=1[Cl:9]
Reactant: Oc1ccc(Br)c(Cl)c1
Reactant: CCOCCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOCCCOc1ccc(Br)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.1 %

Procedure:
To a solution of 4-bromo-3-chlorophenol (10.0 g), 3-ethoxypropanol (6.0 g) and triphenylphosphine (15.2 g) in tetrahydrofuran (50 ml) was added dropwise under nitrogen atmosphere at 0° C. diethylazodicarbonate (40% toluene solution, 25.2 g) for 15 minutes, and the mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. To the residue was added diethylether, and insoluble materials were filtered off. The filtrate was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/hexane 1:5) and distilled under reduced pressure (1.5 mmHg, 190° C.) to give colorless oil of 4-bromo-3-chloro-(3-ethoxypropoxy)benzene (11.2 g).
Reaction SMILES: C(O)(=O)C.[N+:5](/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)([O-:7])=[O:6].[BH4-].[Na+]>CS(C)=O>[N+:5]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)([O-:7])=[O:6]
Reactant: O=[N+]([O-])/C=C/c1ccc(Nc2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])CCc1ccc(Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
To an acetic acid (3.2 mL) and dimethyl sulfoxide (54 mL) solution of (4-((E)-2-nitro-vinyl)-phenyl)-phenyl-amine (3.2 g, 13.4 mmol) described in Manufacturing Example 69-1-2 was added sodium borohydride (811 mg, 21.4 mmol) at room temperature while cooling appropriately. This mixture was stirred for 1 hour at room temperature. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=4:1-2:1) to obtain the title compound (2.01 g, 62%).
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:11]=[C:12]([C:16]([N+:19]([O-:21])=[O:20])=[CH:17][N:18]=1)[C:13]([OH:15])=O)[CH2:3][CH2:2]2.[NH2:22][CH2:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:11]=[C:12]([C:16]([N+:19]([O-:21])=[O:20])=[CH:17][N:18]=1)[C:13]([NH:22][CH2:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26])=[O:15])[CH2:3][CH2:2]2
Reactant: O=C(O)c1cc(N2CCN3CCC2CC3)ncc1[N+](=O)[O-]
Reactant: CC(C)(CN)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(CO)CNC(=O)c1cc(N2CCN3CCC2CC3)ncc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
To a solution of 2-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-5-nitroisonicotinic acid (Intermediate 29A) (2.0 g, 6.8 mmol) in DMF (25 mL) was added 3-amino-2,2-dimethylpropan-1-ol (0.85 g, 8.2 mmol), triethylamine (1 g, 10.3 mmol) and HATU (3.16, 10.3 mmol) under nitrogen, reaction then stirred overnight. The reaction mixture was concentrated and purified by HPLC to afford 2-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-N-(3-hydroxy-2,2-dimethylpropyl)-5-nitroisonicotinamide.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:17])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[N:8]([CH:13]1[CH2:15][CH2:14]1)[C:7]2=[O:16].[CH:18]([NH2:21])([CH3:20])[CH3:19]>CN1C(=O)CCC1>[Br:1][C:2]1[C:3]([F:17])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:21][CH:18]([CH3:20])[CH3:19])[N:8]([CH:13]1[CH2:15][CH2:14]1)[C:7]2=[O:16]
Reactant: CC(C)N
Reactant: O=c1c2ccc(F)c(Br)c2nc(Cl)n1C1CC1
Solvent: CN1CCCC1=O
Product: CC(C)Nc1nc2c(Br)c(F)ccc2c(=O)n1C1CC1
Yield: 92.1 %

Procedure:
A slurry of 8-bromo-2-chloro-3-cyclopropyl-7-fluoroquinazolin-4(3H)-one (721; 0.080 g, 0.252 mmol) in isopropylamine (Aldrich; 0.541 ml, 6.30 mmol) and 0.2 mL NMP was heated in a sealed tube in a biotage initiator microwave to 100° C. for 20 min. The reaction was partitioned between water and EtOAc. The organic layer was washed with water once, satd aq NaCl once, and the organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 8-bromo-3-cyclopropyl-7-fluoro-2-(isopropylamino)quinazolin-4(3H)-one (0.079 g, 0.232 mmol, 92% yield) as a brown solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.89 (1H, dd, J=8.8, 6.5 Hz), 7.01 (1H, t, J=8.7 Hz), 6.85 (1H, d, J=7.6 Hz), 4.41 (1H, dq, J=13.6, 6.7 Hz), 2.64-2.79 (1H, m), 1.30 (6H, d, J=6.7 Hz), 1.19-1.27 (2H, m), 0.71-0.79 (2H, m). m/z (ESI, +ve ion) 340.0/342.0 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[O:8][N:7]=[C:6]([C:9]([OH:11])=O)[CH:5]=1)(=[O:3])[CH3:2].[NH2:12][C@@H:13]([CH3:30])[CH2:14][N:15]1[CH:19]=[CH:18][C:17]([C:20]2[CH:27]=[C:26]([F:28])[C:23]([C:24]#[N:25])=[C:22]([Cl:29])[CH:21]=2)=[N:16]1>>[C:1]([C:4]1[O:8][N:7]=[C:6]([C:9]([NH:12][C@@H:13]([CH3:30])[CH2:14][N:15]2[CH:19]=[CH:18][C:17]([C:20]3[CH:27]=[C:26]([F:28])[C:23]([C:24]#[N:25])=[C:22]([Cl:29])[CH:21]=3)=[N:16]2)=[O:11])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C(=O)O)no1
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Product: CC(=O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)no1
Yield: 16.09 %

Procedure:
(S)-5-acetyl-N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)-propan-2-yl)isoxazole-3-carboxamide was prepared using the method of Example 34(d) starting from 5-acetylisoxazole-3-carboxylic acid (0.200 g, 1.292 mmol) and (s)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.3 g, 1.076 mmol). The product was purified by Flash-chromatography. Yield 16.09%. 1H-NMR (400 MHz; CDCl3): δ 1.26 (d, 3H), 2.65 (s, 3H), 4.26 (dd, 1H), 4.46 (dd, 1H), 4.61 (m, 1H), 6.64 (d, 1H), 7.29 (s, 1H), 7.51 (d, 1H), 7.63 (dd, 1H), 7.85 (s, 1H), 8.04 (d, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.O>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: O=C1CCCCN1Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: C1=C(N2CCCC2)CCN(Cc2ccccc2)C1

Procedure:
A solution of N-benzyl piperidone (20.0 g, 53 mmol) and pyrrolidine (14.0 mL, 80 mmol) in 300 mL of toluene was warmed at reflux overnight with azeotropic removal of water. The reaction mixture was then cooled and concentrated under reduced pressure. The resultant dark oil was dissolved in 200 mL of ether, dried over magnesium sulfate, filtered and concentrated under reduced pressure.
Reaction SMILES: [F:1][C:2]([F:14])=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13].[OH-:15].[Na+].OO.O>C(Cl)Cl>[F:1][C:2]([F:14])=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:15]
Reactant: C=CCCCCCCCCC=C(F)F
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: OCCCCCCCCCCC=C(F)F
Temperature: 20 °C
Reaction time: 60 h

Procedure:
With stirring, 14.5 grams (0.072 mole) of 1,1-difluorododec-1,11-diene was cooled to 0° C., and 25 ml (0.025 mole--1M in tetrahydrofuran) of borane·tetrahydrofuran complex was added dropwise. Upon completion of addition the reaction mixture was stirred for 30 minutes during which time the reaction mixture temperature was at 8°-12° C. After this time 25 ml of aqueous 3N sodium hydroxide was added dropwise. This was followed by 30 ml of aqueous 30% hydrogen peroxide. During the initial peroxide addition the exothermic reaction caused the reaction mixture temperature to rise to 30°-35° C. The reaction mixture was cooled to approximately 20° C., and the peroxide addition was continued. Upon completion of addition the reaction mixture was stirred at ambient temperature for 30 minutes, and then it was warmed to 45°-50° C. where it stirred for one hour. After this time it was allowed to cool to ambient temperature where it stood for 60 hours. The reaction mixture was shaken with 100 ml of water and 50 ml of methylene chloride. The methylene chloride layer was separated, and the water layer was extracted with two 50 ml portions of methylene chloride. The combined methylene chloride extracts were washed with 25 ml of water and 25 ml of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was distilled under reduced pressure yielding 7.6 grams of 12,12-difluoro-11-dodecenol; b.p. 80-85/0.2 mm. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]([NH:5][C:6]1([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:25][C:24]4[C:23]5=[N:33][N:34]=[C:35]([C:36]6[N:41]=[CH:40][CH:39]=[CH:38][N:37]=6)[N:22]5[CH:21]=[CH:20][C:19]=4[N:18]=3)=[CH:13][CH:12]=2)[CH2:9][C:8](=[O:10])[CH2:7]1)=[O:4].C[Si]([C:48]#[N:49])(C)C.O>C(Cl)Cl.[I-].[Zn+2].[I-]>[C:48]([C:8]1([OH:10])[CH2:9][C:6]([NH:5][C:3](=[O:4])[C:2]([F:42])([F:1])[F:43])([C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:26]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)=[CH:25][C:24]4[C:23]5=[N:33][N:34]=[C:35]([C:36]6[N:41]=[CH:40][CH:39]=[CH:38][N:37]=6)[N:22]5[CH:21]=[CH:20][C:19]=4[N:18]=3)=[CH:15][CH:16]=2)[CH2:7]1)#[N:49]
Reactant: O=C1CC(NC(=O)C(F)(F)F)(c2ccc(-c3nc4ccn5c(-c6ncccn6)nnc5c4cc3-c3ccccc3)cc2)C1
Reactant: C[Si](C)(C)C#N
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: O
Product: N#CC1(O)CC(NC(=O)C(F)(F)F)(c2ccc(-c3nc4ccn5c(-c6ncccn6)nnc5c4cc3-c3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2,2,2-trifluoro-N-(3-oxo-1-{4-[9-phenyl-3-(2-pyrimidinyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutyl)acetamide (4-2) (25 mg, 0.043 mmol), trimethylsilyl cyanide (0.012 mL, 0.086 mmol), and zinc iodide (1.4 mg, 0.0043 mmol) in CH2Cl2 (1.0 mL) was stirred at room temperature for 1 hour. To the mixture was added water, extracted with CHCl3, washed with brine, dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by preparative TLC, eluting with 10% MeOH in CHCl3 to give N-(3-cyano-3-hydroxy-1-{4-[9-phenyl-3-(2-pyrimidinyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutyl)-2,2,2-trifluoroacetamide (4-10) as a yellow solid. MS (M+H)+: observed=607, calculated=607.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=1[C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1)=[O:11].Cl[C:27]1[N:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=1>>[Cl:33][C:30]1[CH:29]=[N:28][C:27]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=2[C:20]2[N:21]=[CH:22][CH:23]=[CH:24][N:25]=2)=[O:11])=[N:32][CH:31]=1
Reactant: C[C@@H]1CCCN(C(=O)c2cc(F)c(F)cc2-c2ncccn2)[C@@H]1CN
Reactant: Clc1cnc(Cl)nc1
Product: C[C@@H]1CCCN(C(=O)c2cc(F)c(F)cc2-c2ncccn2)[C@@H]1CNc1ncc(Cl)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(4,5-difluoro-2-(pyrimidin-2-yl)phenyl)methanone and 2,5-dichloropyrimidine. ESI-MS (m/z): 459 [M+1]+.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C:6]1([C:12]([OH:14])=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:15]O>>[NH2:5][C:6]1([C:12]([O:14][CH3:15])=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: NC1(C(=O)O)CCCCC1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C1(N)CCCCC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
51 ml of thionyl chloride were added in portions at −5° C. to 50 g (350 mmol) of 1-aminocyclohexane-1-carboxylic acid in 1.25 l of methanol. The reaction mixture was subsequently stirred at room temperature for 5 hours and allowed to stand overnight at room temperature. The methanol was removed in vacuo, the residue was mixed with water, and the aqueous solution was adjusted to pH 9 using saturated sodium carbonate solution and extracted twice with dichloromethane. The organic phase was dried over sodium sulfate and, after filtration, the solvent was removed in vacuo. Yield: 36.35 g (66%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH2:12][C:13](=[N:15][OH:16])[NH2:14])[C:6]=2[C:5](=[O:17])[NH:4][C:3]1=[O:18].[C:19](OCC)(=O)[CH3:20].[Na]>C(O)C>[CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH2:12][C:13]3[N:14]=[C:19]([CH3:20])[O:16][N:15]=3)[C:6]=2[C:5](=[O:17])[NH:4][C:3]1=[O:18]
Reactant: CCOC(C)=O
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2CCC(N)=NO
Agent: [Na]
Solvent: CCO
Product: Cc1nc(CCn2cnc3c2c(=O)[nH]c(=O)n3C)no1
Reaction time: 5 h

Procedure:
A mixture of 2.52 g of 3-(3-methyl-xanthine-7-yl)propionic acid amide oxime, 4.0 ml of ethyl acetate and a solution of 0.46 g of metallic sodium in 25 ml of ethanol is heated to boiling under stirring for 5 hours. The hot reaction mixture is filtered and the filtrate is evaporated. The residue is treated with 20 ml of water, the pH is adjusted to 7 and the precipitated product is crystallized from water. Thus 1.7 g of 3.7-dihydro-3-methyl-7-(2-[5-methyl-1,2,4-oxadiazole-3-yl]-ethane-1-yl)-1H-purine-2,6-dione are obtained, m.p.: 258°-260° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1I.[CH3:21][C:22]([CH3:28])=[C:23](B(O)O)[CH3:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.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>[CH3:24][C:23]([C:11]1[CH:12]=[C:13]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=[CH:15][C:10]=1[C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[F:1])=[C:22]([CH3:28])[CH3:21]
Reactant: CC(C)=C(C)B(O)O
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(I)c1
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: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C(C)=C(C)C)c1
Temperature: 90 °C
Reaction time: 18 h
Yield: 51 %

Procedure:
To a stirred solution of 66.15D (0.231 g, 0.60 mmol) in DMF (4.00 mL) at 23° C. was added 3-methylbut-2-en-2-ylboronic acid (0.14 g, 1.2 mmol, commercially available from Aldrich), and potassium carbonate (0.25 g, 1.8 mmol). Tetrakis(triphenylphosphine)palladium (0.069 g, 0.060 mmol) was then added to the reaction. The mixture was heated to 90° C. and stirring was continued for 18 hours. The reaction was then cooled to room temperature, diluted with water and extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was then purified on silica gel (0-10% EtOAc in hexanes) to yield 69.12A as a colorless oil (0.100 g, 51% yield).