Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14](Br)[C:11]=1[C:12]#[N:13]>>[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)[C:11]=1[C:12]#[N:13]
Reactant: N#Cc1c(N)cccc1Br
Reactant: OB(O)c1ccoc1
Product: N#Cc1c(N)cccc1-c1ccoc1
Yield: 74 %

Procedure:
Prepared as in Example 129c from furan-3-ylboronic acid and 2-amino-6-bromobenzonitrile in 74% yield as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 4.51 (br s, 2H), 6.66 (dd, J=1.2, 8.4 Hz, 1H), 6.78 (dd, J=1.2, 2.0 Hz, 1H), 6.82 (dd, J=1.2, 8.0 Hz, 1H), 7.31 (t, J=8.0 Hz, 1H), 7.50 (t, J=1.6 Hz, 1H), 7.95 (dd, J=1.2, 1.6 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[N+:1]([C:4]1[CH:5]=[N:6][N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1)([O-:3])=[O:2]
Reactant: OB(O)c1ccccc1
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cnn(-c2ccccc2)c1
Temperature: 25 °C

Procedure:
4-Nitro-1H-pyrazole (1 g, 8.84 mmol), phenylboronic acid (2.223 g, 17.69 mmol), copper (II) acetate (2.409 g, 13.27 mmol) and pyridine (2.86 ml, 35.4 mmol) were combined in dichloromethane (40 ml) and the mixture stirred at ambient temperature open to the air with a drying tube. The mixture was filtered through a diatomaceous earth pad washing with dichloromethane; and the filtrate washed with water and brine, dried over MgSO4, filtered and concentrated to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:24][CH3:25])=[CH:5][C:6]2[N:12]([CH3:13])[C:11](=[O:14])[CH2:10][N:9]=[C:8]([C:15]#[C:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:7]=2[CH:23]=1.C(Cl)Cl>CO.[Pd]>[CH3:1][O:2][C:3]1[C:4]([O:24][CH3:25])=[CH:5][C:6]2[N:12]([CH3:13])[C:11](=[O:14])[CH2:10][N:9]=[C:8]([CH2:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:7]=2[CH:23]=1
Reactant: COc1cc2c(cc1OC)N(C)C(=O)CN=C2C#Cc1ccccc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: COc1cc2c(cc1OC)N(C)C(=O)CN=C2CCc1ccccc1
Yield: 5 %

Procedure:
Stir a mixture of 80 mg (0.24 mmol) of 7,8-dimethoxy-1-methyl-5-(2-phenylethynyl)-1,3-dihydro-1,4-benzodiazepin-2-one 132, 15 mg of 10% Pd/C by weight in 5 ml of MeOH and 5 ml of CH2Cl2 under 70 psi of H2 for 48 hours. Filter the suspension on celite, rinse three times with 10 ml of MeOH. Evaporate to dryness and purify by silica chromatography (AcOEt 1/hexane 1, then AcOEt). Yield: 5%. M: 112–115° C. 1H-NMR (CDCl3, 300 MHz): d 2.95–3.07 (m, 4H, CH2CH2), 3.28 (s, 3H, NCH3), 3.87 (s, 3H, OCH3), 3.93 (s, 3H, OCH3), 4.10 (AB system, ? d=0.96, JAB=10.2, 2H, CH2), 6.67 (s, 1H Ar), 6.78 (s, 1H Ar), 7.15–7.25 (m, 5H Ar). Mass: (M+H)+=339.15
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[CH2:10]([OH:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH:21]=[CH:22][CH2:23][CH:24]=[CH:25][CH2:26][CH3:27].CC(C)([O-])C.[K+].C(O)(C)(C)C>C1(C)C=CC=CC=1>[CH2:10]([O:28][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH:21]=[CH:22][CH2:23][CH:24]=[CH:25][CH2:26][CH3:27]
Reactant: O=C(O)c1ccc(Br)o1
Reactant: CCC=CCC=CCC=CCCCCCCCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: CCC=CCC=CCC=CCCCCCCCCOc1ccc(C(=O)O)o1
Temperature: 110 °C

Procedure:
A mixture of 57.0 g (0.300 mole) of 5-bromo-2-furoic acid, 119.0 g (0.450 mole) of 9,12,15-octadecatrienol, and 84 g (0.750 mole) of potassium tert-butoxide in dry toluene is stirred with heating. The tert-butanol formed in the reaction is allowed to distill off, and the mixture is refluxed at 110° C. with stirring for 48 hours. The mixture is allowed to cool, then is acidified with acetic acid and diluted with ice-water. The toluene organic layer is separated, washed with water, then extracted three times with 5% sodium bicarbonate solution. The combined aqueous extracts are cooled and acidified with 10% HCl solution to give 5-(9,12,15-octadecatrien-1-yloxy)-2-furoic acid.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([CH3:14])[N:11]([CH2:15][C:16]4[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=4)[C:19](OC)=[O:20])[C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([CH3:14])[N:11]([CH2:15][C:16]4[CH:17]=[C:18]([CH2:19][OH:20])[CH:23]=[CH:24][CH:25]=4)[C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: COC(=O)c1cccc(Cn2c(C)cc3c2ccc2nnc(C)n23)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc2c(ccc3nnc(C)n32)n1Cc1cccc(CO)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a suspension of methyl 3-[(1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-6-yl)methyl]benzoate (0.96 g, 2.7 mmol, prepared as in Example 26, Step 1) in THF (90 mL) at 0° C. was added dropwise a solution of 1.0 M LiAlH4 in THF (4.0 mL, 4.0 mmol, Aldrich). After 20 minutes, additional 1.0 M LiAlH4 in THF (1.3 mL, 1.3 mmol) was added. After 20 additional minutes, the reaction was quenched by the dropwise addition of water. The reaction was cooled to 0° C. and excess Rochelle's salt was added and stirred until the solution was clear. Sodium sulfate was then added, the mixture was filtered through celite and the solvent was removed in vacuo. Flash chromatography, eluting with a gradient from 0-10% MeOH in DCM afforded product as a light yellow solid (0.61 g, 74%).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[C:6]([CH:10]2[CH2:15][NH:14][CH2:13][CH:12]([NH:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:11]2)[CH:7]=[CH:8][CH:9]=1)[CH3:3].[N:25]1([C:31](Cl)=[O:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C(N(CC)CC)C.O>ClCCl>[N:25]1([C:31]([N:14]2[CH2:15][CH:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([CH:2]([CH3:1])[CH3:3])[CH:5]=3)[CH2:11][CH:12]([NH:16][C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:24])[CH2:13]2)=[O:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: CC(C)c1cccc(C2CNCC(NC(=O)c3ccccc3)C2)c1
Reactant: O=C(Cl)N1CCOCC1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)c1cccc(C2CC(NC(=O)c3ccccc3)CN(C(=O)N3CCOCC3)C2)c1
Temperature: 25 °C

Procedure:
At 0° C., 180 mg (0.54 mmol) of N-{5-[3-(1-methylethyl)phenyl]piperidin-3-yl}benzamide were initially charged in 4 ml of dichloromethane, and 162 mg (1.08 mmol) of morpholine-4-carbonyl chloride and 114 μl (0.81 mmol) of triethylamine were added. The mixture was slowly warmed to RT overnight. Water was added, and the reaction mixture was extracted. The organic phase was dried over magnesium sulphate and concentrated under reduced pressure. The residue was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 121 mg (51% of theory)
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:24][S:25]([C:28]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=1[F:35])(=[O:27])=[O:26].[CH2:36]([NH2:40])[CH:37]([CH3:39])[CH3:38]>>[Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:40][CH2:36][CH:37]([CH3:39])[CH3:38])[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:24][S:25]([C:28]1[C:29]([F:35])=[CH:30][CH:31]=[CH:32][C:33]=1[F:34])(=[O:27])=[O:26]
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2Cl)c(-c2ccnc(Cl)n2)s1
Reactant: CC(C)CN
Product: CC(C)CNc1nccc(-c2sc(C(C)(C)C)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2Cl)n1

Procedure:
Following a procedure analogous to the procedure described in Example 18, Step B using N-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide (0.15 g, 0.28 mmol) and isobutylamine (0.15 g, 2.01 mmol), the title compound was obtained as a yellow solid (0.078 g, 45.4% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.81 (s, 1H), 8.01 (d, J=5.1 Hz, 1H), 7.62-7.71 (m, 1H), 7.49-7.53 (m, 1H), 7.45 (t, J=7.7 Hz, 1H), 7.29-7.39 (m, 2H), 7.21 (t, J=9.1 Hz, 2H), 5.65 (d, 1H), 3.03 (br. s., 2H), 1.84 (dt, J=13.4, 6.7 Hz, 1H), 1.40 (s, 9H), 0.88 (d, J=6.6 Hz, 6H). MS (ESI) 592.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:13]C(OC(C)(C)C)=O)[CH2:5][CH2:6][N:7]([CH2:9][CH2:10][O:11][CH3:12])[CH3:8].[ClH:22]>>[ClH:22].[ClH:22].[CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH2:13])[CH2:5][CH2:6][N:7]([CH2:9][CH2:10][O:11][CH3:12])[CH3:8]
Reactant: COCCN(C)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Agent: Cl
Product: COCCN(C)CC[C@H](N)C(=O)OC

Procedure:
(S)-2-tert-Butoxycarbonylamino-4-[(2-methoxyethyl)-methylamino]-butyric acid methyl ester (0.086 g, 0.28 mmol) was treated with HCl (1 mL of 4M in dioxane) and sonicated. The mixture was concentrated and dried under high vacuum to provide the product.
Reaction SMILES: C[C:2]1[S:6][C:5]([CH2:7]Br)=[N:4][C:3]=1[Br:9].[H-].[Na+].[NH:12]1[CH2:16][CH2:15][CH2:14][C:13]1=[O:17]>C1COCC1.CN(C=O)C>[Br:9][C:3]1[N:4]=[C:5]([CH2:7][N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])[S:6][CH:2]=1
Reactant: Cc1sc(CBr)nc1Br
Reactant: O=C1CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C1CCCN1Cc1nc(Br)cs1
Yield: 79 %

Procedure:
A solution of methyl 4-bromo-2-(bromomethyl)thiazole (prepared according to the procedure reported in US 2010/298388), (0.50 g, 1.94 mmol) in THF (5 ml) was added to a solution of sodium hydride (0.12 g 60% in paraffin oil, 2.92 mmol) and pyrrolidin-2-one (0.20 g, 2.33 mmol) in DMF (5 ml) at 0° C. under stirring. The reaction mixture was stirred at room temperature for 30 minutes. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with water (5 ml). The mixture was then extracted with ethyl acetate (2×50 ml). The combined organic layer was dried over anhydrous Na2SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain a crude product; the crud product was further purified by flash column chromatography using 60% ethyl acetate in hexanes as an eluent to obtain the title compound (0.40 g, 79%). MS: m/z 262 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:29][N:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37](N2C=CN=C2)=[O:38])=[CH:32][C:31]1=[O:44]>C(Cl)Cl>[CH3:29][N:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]([N:9]2[CH2:10][CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:28])=[O:38])=[CH:32][C:31]1=[O:44]
Reactant: Cn1ccc(NC(=O)n2ccnc2)cc1=O
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Product: Cn1ccc(NC(=O)N2CC(CC(C)(C)C)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)cc1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (15.8 mg, 0.0373 mmol) and imidazole-1-carboxylic acid (1-methyl-2-oxo-1,2-dihydro-pyridin-4-yl)-amide (76.3 mg, 0.105 mmol) in CH2Cl2 (1.5 mL) was stirred at rt for 1 day. The reaction mixture was then purified by flash column to rac (2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carboxylic acid (1-methyl-2-oxo-1,2-dihydro-pyridin-4-yl)-amide (19.7 mg, 92.1%). HRMS (ES+) m/z Calcd for C29H28Cl2F2N4O2+H [(M+H)+]: 573.1630; Found: 573.1629.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]([O:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.O.O>[C:32]([O:31][C:29]([NH:28][CH2:27][CH2:26][CH2:25][O:24][C:20]1[N:19]=[C:18]([O:17][C:13]2[CH:14]=[C:15]([CH3:16])[C:7]3[CH:6]([CH2:5][C:4]([OH:36])=[O:3])[O:10][B:9]([OH:11])[C:8]=3[CH:12]=2)[CH:23]=[CH:22][N:21]=1)=[O:30])([CH3:34])([CH3:35])[CH3:33]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3ccnc(OCCCNC(=O)OC(C)(C)C)n3)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Oc2ccnc(OCCCNC(=O)OC(C)(C)C)n2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Yield: 71.2 %

Procedure:
To a solution of {6-[2-(3-tert-butoxycarbonylamino-propoxy)-pyrimidin-4-yloxy]-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl}-acetic acid ethyl ester (0.45 g, 0.89 mmol) in THF:H2O (1:1, 6 mL) at 0° C. was added a solution of LiOH (0.043 g, 1.79 mmol) in water (1 mL). The solution was allowed to warm to room temperature over 3 hours then acidified to pH 4 with 1N HCl and extracted with EtOAc (2×10 mL). The organic extracts were dried and concentrated in vacuo to give crude {6-[2-(3-tert-Butoxycarbonylamino-propoxy)-pyrimidin-4-yloxy]-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl}-acetic acid (0.3 g) which was used without further purification. MS (ESI) m/z=472 [M−H]−.
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3]([O:5]CC)=O.[I:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[CH3:20])[NH2:16]>C(O)C>[I:12][C:13]1[CH:14]=[C:15]([NH:16][C:3](=[O:5])[CH2:2][C:1]([NH:16][C:15]2[CH:17]=[CH:18][C:19]([CH3:20])=[C:13]([I:12])[CH:14]=2)=[O:9])[CH:17]=[CH:18][C:19]=1[CH3:20]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1ccc(N)cc1I
Solvent: CCO
Product: Cc1ccc(NC(=O)CC(=O)Nc2ccc(C)c(I)c2)cc1I
Temperature: 210 °C
Yield: 81.3 %

Procedure:
A mixture of diethyl malonate (16.0 g, 100 mmol) and 3-iodo-4-methylaniline (46.6 g, 200 mmol) was heated at 210° C. for 20 min, allowing the liberated ethanol to evaporate. After cooling the solid formed was triturated in hot ethanol (200 mL) to afford the title compound (43.4 g, 81%). Light brown solid, ISP-MS: m/e=535.0 ([M+H]+).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH2:11][O:12][CH3:13])=[N:10][C:5]2=[N:4][CH:3]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][C:16]=1[C:30]1[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=1>>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([CH2:11][O:12][CH3:13])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:17][C:16]=1[C:30]1[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COCc1ccn2c(Br)cnc2n1
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccccc3C#N)c2)OC1(C)C
Product: COCc1ccn2c(-c3ccc(F)c(-c4ccccc4C#N)c3)cnc2n1
Yield: 60 %

Procedure:
3-Bromo-7-methoxymethylimidazo[1,2-α]pyrimidine (121 mg, 0.50 mmol) was coupled with 2′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 1 to give 2′-fluoro-5′-(7-methoxymethylimidazo[1,2-α]pyrimidin-3-yl)biphenyl-2-carbonitrile (108 mg, 60%) as a white powder: δH (400 MHz, CDCl3) 3.50 (3H, s), 4.66 (2H, s), 7.19 (1H, d, J 7), 7.39-7.41 (1H, m), 7.53-7.64 (4H, m), 7.69-7.73 (1H, m), 7.85 (1H, dd, J 8 and 1), 7.87 (1H, s), 8.82 (1H, d, J 7); m/z (ES+) 359 (M++H).
Reaction SMILES: [CH3:1][S:2][C:3](SC)=[N:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:15][SiH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:10][CH:9]=1)(=[O:7])=[O:6].[CH2:35]1[C:39]2([CH2:43][CH2:42][CH2:41][CH2:40]2)[CH2:38][N:37]=[N:36]1>N1C=CC=CC=1>[C:17]([SiH2:16][O:15][C:14]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:11]1[CH:10]=[CH:9][C:8]([S:5]([N:4]=[C:3]([N:36]2[N:37]=[CH:38][C:39]3([CH2:43][CH2:42][CH2:41][CH2:40]3)[CH2:35]2)[S:2][CH3:1])(=[O:7])=[O:6])=[CH:13][CH:12]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: C1CCC2(C1)CN=NC2
Reactant: CSC(=NS(=O)(=O)c1ccc(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)cc1)SC
Solvent: c1ccncc1
Product: CSC(=NS(=O)(=O)c1ccc(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)cc1)N1CC2(C=N1)CCCC2
Temperature: 90 °C
Yield: 153 %

Procedure:
To 15 mL pyridine, 400 mg N-(bis-methylsulfanyl-methylene)-4-(tert-butyl-diphenyl-silanyloxymethyl)-benzenesulfonamide and 111 mg 2,3-diaza-spiro[4.4]non-2-ene were added. The mixture was heated for two nights at 90° C. degrees, concentrated under reduced pressure and dried in vacuo to provide 700 mg of product (LC-MS Rt 3.91 min) which was used in the subsequent step without purification. 1H NMR (400 MHz, CDCl3) δ ppm 1.10-1.12 (m, 9H), 1.63-1.94 (m, 8H), 4.82 (s, 2H), 7.01 (s, 1H), 7.65-7.71 (m, 4H), 7.92-7.96 (m, 2H).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[CH:3]=1.[NH:18]1[CH:22]=[CH:21][CH:20]=[N:19]1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.[Cu]I>[CH:9]1([N:6]2[C:7](=[O:8])[C:2]([N:18]3[CH:22]=[CH:21][CH:20]=[N:19]3)=[CH:3][C:4]([C:14]([O:16][CH3:17])=[O:15])=[CH:5]2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: COC(=O)c1cc(Br)c(=O)n(C2CCCC2)c1
Reactant: c1cn[nH]c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(-n2cccn2)c(=O)n(C2CCCC2)c1
Temperature: 100 °C

Procedure:
A mixture of methyl 5-bromo-1-cyclopentyl-6-oxo-1,6-dihydropyridine-3-carboxylate (300 mg, 1.00 mmol), pyrazole (23 mg, 0.34 mmol), K2CO3 (99 mg, 0.72 mmol), CuI (9.1 mg, 0.048 mmol), N1—N2-dimethylethane-1,2-diamine (5 uL, 0.048 mmol) in toluene (3 mL) was heated to 100° C. for 17 h. The mixture was brought to RT and quenched with saturated NH4Cl, brine, dried over MgSO4 and chromatographed on silica gel using 3:1 hexanes:ethylacetate to afford the title compound as a white solid. MS m/z: 288 (M+1).
Reaction SMILES: C([N:8]1[CH:12]=[C:11]([C:13]2[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]3[C:19](=[O:30])[N:18]([CH2:31][CH2:32][CH3:33])[C:17]([N:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)=[N:16][C:15]=3[N:14]=2)[CH:10]=[N:9]1)C1C=CC=CC=1.CS(C)=O.CC([O-])(C)C.[K+].[NH4+].[Cl-]>C1COCC1>[CH2:31]([N:18]1[C:19](=[O:30])[C:20]2[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:13]([C:11]3[CH:12]=[N:8][NH:9][CH:10]=3)=[N:14][C:15]=2[N:16]=[C:17]1[N:34]1[CH2:35][CH2:36][CH2:37][CH2:38]1)[CH2:32][CH3:33]
Reactant: CCCn1c(N2CCCC2)nc2nc(-c3cnn(Cc4ccccc4)c3)n(COCC[Si](C)(C)C)c2c1=O
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCCn1c(N2CCCC2)nc2nc(-c3cn[nH]c3)n(COCC[Si](C)(C)C)c2c1=O
Reaction time: 18 h
Yield: 69.2 %

Procedure:
A mixture of 8-(1-Benzyl-1H-pyrazol-4-yl)-1-propyl-2-pyrrolidin-1-yl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (0.154 g, 0.29 mmol), and DMSO (0.2 ml, 2.9 mmol) was taken in THF (10 ml). 0.5M solution of KOtBu (4 ml, 2.0 mmol) in THF was added at 0° C. and stirred for 18 hours. After adding saturated NH4Cl solution, the compound was extracted with ethyl acetate (2×10 ml). Organic layer was washed with brine (2×10 ml), dried over Na2SO4. Solvent was evaporated and purified by preparative TLC to get pure 1-Propyl-8-(1H-pyrazol-4-yl)-2-pyrrolidin-1-yl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one as white solid (89 mg, 70%)
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[CH2:22][C@H:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@@H:20]([CH2:29][OH:30])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(C(C)C)CC)(C)C>ClCCl>[C:11]([O:15][C:16]([N:18]1[CH2:22][C@H:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C@@H:20]([CH:29]=[O:30])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1C[C@H](CO)[C@@H](c2ccccc2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](c2ccccc2)[C@@H](C=O)C1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 70.1 %

Procedure:
Oxalyl chloride (3.3 mL, 2M in CH2Cl2, 6.42 mmol) was stirred in dichloromethane (3 mL) in a three-necked flask. The reaction mixture was cooled to −78° C., and dimethyl sulfoxide (0.91 mL, 12.85 mmol) was added so that the internal temperature did not exceed −65° C. The reaction mixture was then stirred for 15 minutes. The (3R,4S)-3-hydroxymethyl-4-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester (713 mg, 2.57 mmol) in dichloromethane (6 mL) was added dropwise keeping the internal temperature below −65° C. and then stirred for 15 minutes. Diisopropylethylamine (4.5 mL, 25.7 mmol) was added keeping the internal temperature below −65° C. and then stirred for 20 minutes. The cooling bath was removed and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to give a colorless oil, which was purified by flash silica gel chromatography eluting with ethyl acetate: hexanes (1:4) to give 496 mg (70%) of (3R,4S)-3-formyl-4-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].N[C@@H]1C[CH2:26][CH2:25][CH2:24][C@H:23]1[OH:28].N#N.IC1CCOC1.Cl>CC(O)C.[Ni](I)I>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:25]2[CH2:24][CH2:23][O:28][CH2:26]2)=[CH:4][CH:3]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: OB(O)c1ccc(Br)cc1
Agent: I[Ni]I
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Solvent: CC(C)O
Product: Brc1ccc(C2CCOC2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 648.1 %

Procedure:
A mixture of 4-bromophenylboronic acid (1.7 g, 8.1 mmol), nickel iodide (102 mg, 0.32 mmol), solid sodium hexamethyldisilazide (1.6 g, 8.1 mmol) and trans-2-aminocyclohexanol (49.0 mg, 0.32 mmol) was sealed in a microwave vial, diluted with dry i-PrOH (7 mL), and evacuated/backfilled with N2 three times. The reaction mixture was stirred at room temperature for 5 minutes, treated with a solution of 3-iodotetrahydrofuran (800 mg, 4.04 mmol) in i-PrOH (1 mL) and evacuated/backfilled with N2. The reaction mixture was subjected to microwave irradiation at 80° C. for 20 minutes. The cooled reaction mixture was poured into 0.3N HCl (30 mL) and extracted with heptane/EtOAc (2:1, 3×20 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give a yellow solid. The crude material was purified by flash chromatography (0-5% EtOAc/Heptane) to give the title compound (471 mg, 51% yield) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J=8.39 Hz, 2H), 7.11 (d, J=8.39 Hz, 2H), 4.09 (t, J=8.00 Hz, 1H), 4.04 (td, J=8.39, 4.69 Hz, 1H), 3.89 (q, J=8.00 Hz, 1H), 3.65-3.70 (m, 1H), 3.34 (quin, J=7.66 Hz, 1H), 2.35 (dtd, J=12.37, 7.77, 7.77, 4.68 Hz, 1H), 1.94 (dq, J=12.37, 8.04 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([OH:17])=O)[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:60][CH:61]1[CH2:66][CH2:65][CH2:64][CH:63]([NH2:67])[CH2:62]1>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:67][CH:63]3[CH2:64][CH2:65][CH2:66][CH:61]([CH3:60])[CH2:62]3)=[O:17])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1
Reactant: CC1CCCC(N)C1
Reactant: C[C@@H]1CC[C@H](C(=O)O)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1CCCC(NC(=O)[C@H]2CC[C@@H](C)N(c3cc(-c4ccc(C#N)c(F)c4)nc(N)n3)C2)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.4 %

Procedure:
To a solution of (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid (170 mg, 0.478 mmol) and HATU (218 mg, 0.574 mmol) in DMF (3 mL) was added Hunig's base (0.167 mL, 0.957 mmol), and the mixture was stirred at room temperature for 5 minutes. Then 3-methylcyclohexanamine (54.2 mg, 0.478 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. LCMS showed reaction was completed. The reaction was poured onto water, and the formed solid was filtered, washed by water, and dried to give the yellow title compound (186 mg). LC-MS (ES) m/z=451 [M+H]+.