Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:5][NH2:6].[N:15]([C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH:20]=[C:21]([CH3:28])[N:22]=[CH:23]2)=[C:16]=[O:17].N(C1C=CC=C2C=1C=CN=C2)=C=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:5][NH:6][C:16]([NH:15][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH:20]=[C:21]([CH3:28])[N:22]=[CH:23]2)=[O:17]
Reactant: Cc1cc2c(N=C=O)cccc2cn1
Reactant: NCc1ccc(N2CCCC2)c(F)c1
Agent: O=C=Nc1cccc2cnccc12
Product: Cc1cc2c(NC(=O)NCc3ccc(N4CCCC4)c(F)c3)cccc2cn1

Procedure:
The title compound was prepared using the procedure described in Example 61B using 3-fluoro-4-(1-pyrrolidinyl)benzylamine and the product from Example 154A instead of 4-cyanobenzyl alcohol and the product from Example 61A. 1H NMR (300 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.59 (s, 1H), 8.22 (d, 1H, J=7.5 Hz), 7.73 (s, 1H), 7.69 (d, 1H, J=7.5 Hz), 7.50 (t, 1H, J=7.5 Hz), 7.03 (m, 2H), 6.93 (t, 1H, J=6 Hz), 6.72 (m, 1H), 4.24 (d, 2H, J=6 Hz), 3.28 (m, 4H), 2.64 (s, 3H), 1.88 (m, 4H); MS (ESI) 379 (M+H)+; Anal. Calcd for C22H23FN4O: C, 69.82; H, 6.13; N, 14.80. Found: C, 69.76; H, 6.06; N, 14.69.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:22][C:21]([O:23][C@@H:24]3[CH2:28][O:27][C@@H:26]4[C:29](=[O:32])[CH2:30][O:31][C@H:25]34)=[N:20][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.[CH2:33]([Mg]Br)[CH:34]=[CH2:35].CCOCC>C1COCC1>[CH2:35]([C@:29]1([OH:32])[C@H:26]2[O:27][CH2:28][C@@H:24]([O:23][C:21]3[NH:22][C:4]4[C:5]([N:20]=3)=[N:6][C:7]([C:8]3[CH:13]=[CH:12][C:11]([C:14]5[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=5)=[CH:10][CH:9]=3)=[C:2]([Cl:1])[CH:3]=4)[C@H:25]2[O:31][CH2:30]1)[CH:34]=[CH2:33]
Reactant: C=CC[Mg]Br
Reactant: O=C1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2[nH]1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CC[C@@]1(O)CO[C@@H]2[C@H](Oc3nc4nc(-c5ccc(-c6ccccc6)cc5)c(Cl)cc4[nH]3)CO[C@@H]21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A stirred suspension of (3R,3aR,6aS)-3-[[6-chloro-5-(4-phenylphenyl)-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2,3,3a,6a-tetrahydrofuro[3,2-b]furan-6-one (314.3 mg, 0.702 mmol) in THF (7.0 ml) was degassed (3×) and placed under nitrogen after being cooled to 0° C. in an ice bath. Allylmagnesium bromide 1.0 M in ether (1.4 ml, 1.400 mmol) was added to the reaction mixture dropwise over 6 minutes. After 1 hour, the reaction mixture was removed from the ice bath and allowed to warm to room temperature. The reaction mixture was transferred via pipette into saturated aqueous NaHCO3 (50 ml) before being partitioned between EtOAc (100 ml) and water (50 ml). The aqueous layer was extracted with EtOAc (2×50 ml). The organic layers were combined, washed with brine (1×30 ml), dried over MgSO4, filtered, and evaporated under reduced pressure to give a pale yellow residue. The residue was purified by flash chromatography utilizing a 40 g silica RediSep Rf® column and employing a 0-80% EtOAc/hexane gradient. The product fractions were combined and evaporated under reduced pressure to give the title compound as a colorless residue. LC-MS: calculated for C27H24ClN3O4 489.15 observed m/e: 490.19 (M+H)+ (Rt 1.23/2 min); 1H NMR δ (ppm) (CD3OD): 7.81 (s, 1H), 7.70-7-75 (m, 4H), 7.69 (d, J=7.9 Hz, 2H), 7.47 (t, J=7.7 Hz, 2H), 7.36 (t, J=7.4 Hz, 1H), 5.90-5.99 (m, 1H), 5.53 (qt, J=5.5 Hz, J=10.8 Hz, 1H), 5.14 (broad d, J=12.9 Hz, 2H), 4.96 (t, J=5.3 Hz, 1H), 4.10-4.18 (m, 3H), 3.67 (abqt, J=8.5 Hz, J=24.6 Hz, 2H), 2.30-2.38 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[CH2:6][N:7]([C@H:14]1[CH2:20][CH2:19][CH2:18][N:17]([CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[C:16]2[CH:27]=[C:28]([C:32]([F:35])([F:34])[F:33])[C:29]([CH3:31])=[CH:30][C:15]1=2)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[CH2:45]([O:47][C:48](C1CCC(=O)CC1)=[O:49])[CH3:46]>>[CH2:45]([O:47][C:48]([CH:25]1[CH2:26][CH2:22][CH:21]([N:17]2[CH2:18][CH2:19][CH2:20][C@H:14]([N:7]([CH2:6][C:5]3[CH:36]=[C:37]([C:39]([F:42])([F:40])[F:41])[CH:38]=[C:3]([C:2]([F:43])([F:1])[F:44])[CH:4]=3)[C:8]3[N:9]=[N:10][N:11]([CH3:13])[N:12]=3)[C:15]3[CH:30]=[C:29]([CH3:31])[C:28]([C:32]([F:33])([F:34])[F:35])=[CH:27][C:16]2=3)[CH2:23][CH2:24]1)=[O:49])[CH3:46]
Reactant: Cc1cc2c(cc1C(F)(F)F)N(CC1CCCC1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reactant: CCOC(=O)C1CCC(=O)CC1
Product: CCOC(=O)C1CCC(N2CCC[C@H](N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)c3cc(C)c(C(F)(F)F)cc32)CC1

Procedure:
Prepare the title compound by essentially following the procedures described in the synthesis of (S)-(3,5-Bistrifluoromethylbenzyl)-(1-cyclopentylmethyl-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)amine (Example 3 step 19) by replacing cyclopentanecarboxaldehyde with 4-oxo-cyclohexanecarboxylic acid ethyl ester. Isolate the title compound by chromatography over silica gel, eluting with ethyl acetate/hexane. MS (ES+): 707 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.CC(P(C(C)(C)C)C1[CH-]C=CC=1)(C)C.CC(P(C(C)(C)C)C1[CH-]C=CC=1)(C)C.[Cl-].[Cl-].[Fe+2].[Pd+2]>[Cl:1][C:2]1[CH:7]=[C:6]([N:13]2[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]2)[CH:5]=[CH:4][N:3]=1
Reactant: CN1CCNCC1
Reactant: Clc1cc(I)ccn1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(C)(C)P(c1ccc[cH-]1)C(C)(C)C
Solvent: Cc1ccccc1
Product: CN1CCN(c2ccnc(Cl)c2)CC1
Temperature: 115 °C
Yield: 76.2 %

Procedure:
To a mixture of 2-chloro-4-iodopyridine (300 mg, 1.24 mmol) in toluene (4 mL) was added 1-methylpiperazine (0.14 mL, 1.24 mmol), sodium tert-butoxide (239 mg, 2.44 mmol), [1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride (30 mg, 10% wt) and the suspension was heated to 115° C. under microwave irradiation for 30 minutes. The resulting mixture was concentrated in vacuo and partitioned between DCM (50 mL) and water (50 mL). The organic phase was washed with brine (50 mL), dried (MgSO4), and evaporated in vacuo to give the title compound (200 mg, 77%) as a brown oil. LCMS (ES+) 212.0 (M+H)+, RT 1.78 minutes (70% purity) (Method 2).
Reaction SMILES: Cl[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6](=[O:18])[N:5]([CH3:19])[C:4](=[O:20])[CH:3]=1.[CH3:21][NH:22][CH3:23]>C(O)(C)C>[CH3:21][N:22]([CH3:23])[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6](=[O:18])[N:5]([CH3:19])[C:4](=[O:20])[CH:3]=1
Reactant: Cn1c(=O)cc(Cl)n(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: CNC
Solvent: CC(C)O
Product: CN(C)c1cc(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 80 °C

Procedure:
To a suspension of 6-chloro-3-methyl-1-(3-(trifluoromethyl)phenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 56) (301 mg) in isopropyl alcohol (10 ml) was added 50% aqueous dimethyl amine solution (0.5 ml) and the resulting mixture was stirred at 80° C. for two and a half hours. The reaction solutions were concentrated under reduced pressure, and to the residue were added water and methanol, and the resulting mixture was stirred. The precipitated solids were collected by filtration, and washed with water and diethylther to afford 6-(dimethylamino)-3-methyl-1-(3-(trifluoromethyl)phenyl)pyrimidin-2,4(1H,3H)-dione (220 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5](=O)[CH:6]([Cl:10])[C:7](=O)[CH3:8])[CH3:2].[NH2:13][C:14]1[CH:18]=[CH:17][NH:16][N:15]=1.N1CCCCC1>CC#N.CCO>[CH2:1]([O:3][C:4]([C:5]1[C:6]([Cl:10])=[C:7]([CH3:8])[N:15]2[N:16]=[CH:17][CH:18]=[C:14]2[N:13]=1)=[O:12])[CH3:2]
Reactant: Nc1cc[nH]n1
Reactant: CCOC(=O)C(=O)C(Cl)C(C)=O
Solvent: CCO
Solvent: CC#N
Solvent: C1CCNCC1
Product: CCOC(=O)c1nc2ccnn2c(C)c1Cl
Temperature: 90 °C
Yield: 19.8 %

Procedure:
3-Chloro-2,4-dioxo-pentanoic ethyl ester (0.325 g, 1.685 mmol) is added to a solution of 3-aminopyrazole (0.14 g, 1.685 mmol) and piperidine (0.18 mL, 1.85 mmol) in MeCN (15 mL), and the reaction mixture heated at 90° C. for 17 hours. After cooling to room temperature, the reaction mixture is diluted with EtOH and concentrated. Purification by flash chromatography (0.5% MeOH in methylene chloride) gives 80 mg (20%) desired product. 1H NMR (400 mHz, CD3OD) δ 8.27 (d, 1H), 6.84 (d, 1H), 4.48 (q, 2H), 2.97 (s, 3H), 1.42 (t, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[F:6][C:7]([F:18])([F:17])[C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](Cl)=[O:12].Cl>CC#N.[OH-].[Na+]>[F:6][C:7]([F:17])([F:18])[C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:12]
Reactant: NCC(=O)O
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
To a rapid stirring solution of glycine (15.014 g, 0.20 mol) in MeCN (400 mL) and 2 M NaOH (250 mL) at 0° C. was slowly added a solution of 3-(trifluoromethyl)-benzoyl chloride (41.714 g, 0.20 mol) in 75 mL of MeCN over 30 min. The cloudy yellow solution was stirred at 0° C. for 30 min. The reaction mixture was acidified with 3 M HCl to pH=3, followed by removal of MeCN on rotary evaporator. The resulting mixture was then extracted with EtOAc (400 mL×3). The combined organic layers were dried, filtered and concentrated to give a light yellow solid (48.53 g), which was triturated with toluene (500 mL). After filtration, the solid product was washed with cold toluene until the filtrate was colorless. After dried under high vacuum over the weekend, a white powder product: 44.60 g (90%) was afforded. MS (M+H+)=248.1. 1H NMR (DMSO-d6) δ 12.70 (br s, 1H), 9.17 (m, 1H), 8.20 (dd, 2H), 7.94 (dd, 1H), 7.78 (m, 1H), 3.97 (d, 2H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(OC(N(C)C)=[N+](C)C)[C:12]2N=CC=C[C:11]=2N=N1.[NH2:25][C:26]1[N:27]=[C:28]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:29]2[CH:34]=[C:33]([C:35]([OH:37])=O)[S:32][C:30]=2[N:31]=1.C(N(C(C)C)CC)(C)C.Cl.C(NCC)C>CN(C)C=O>[CH2:12]([NH:8][C:35]([C:33]1[S:32][C:30]2[N:31]=[C:26]([NH2:25])[N:27]=[C:28]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:29]=2[CH:34]=1)=[O:37])[CH3:11]
Reactant: Nc1nc(-c2ccccc2)c2cc(C(=O)O)sc2n1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCNCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1cc2c(-c3ccccc3)nc(N)nc2s1
Temperature: 100 °C

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.380 g, 1.0 mmol) was added to 2-amino-4-phenyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (0.187 g, 0.69 mmol). This mixture was suspended in dimethylformamide (DMF) (5.0 ml) and diisopropylethylamine (0.696 ml; 4.0 mmol) added to afford a yellow solution. Diethylamine hydrochloride (0.122 g; 5.0 mmol) was added and the reaction mixture was heated for ten minutes at 100° C. in a sealed vial in a microwave synthesiser. DMF was removed in vacuo and the residue was partitioned between ethyl acetate (30 ml) and water (30 ml). The phases were separated and the organic phase was washed with saturated sodium chloride solution and dried over sodium sulphate. Mixture was filtered and the filtrate solvents were removed in vacuo to leave a yellow solid which was adsorbed onto silica gel and purified by flash chromatography on silica gel (20 g), eluting with a solvent gradient of 15 to 50% ethyl acetate in hexane. This affords 2-amino-4-phenyl-thieno[2,3-d]pyrimidine-6-carboxylic acid ethylamide as a pale yellow solid (0.051 g; 25%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][NH:14][CH3:15])=[CH:11][C:10]=1[Br:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](Cl)(=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>ClCCl>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][N:14]([CH3:15])[C:19](=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:11][C:10]=1[Br:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCC(=O)Cl
Reactant: CNCc1ccc(OCc2ccccc2)c(Br)c1
Solvent: ClCCl
Product: CCCCCCCC(=O)N(C)Cc1ccc(OCc2ccccc2)c(Br)c1
Yield: 98.3 %

Procedure:
In a manner similar to that of Example 37(e), by reacting 9.9 g (32 mmol) of N-(4-benzyloxy-3-bromo benzyl)-N-methylamine with 5.3 g (32 mmol) of octanoyl chloride in 90 ml of dichloromethane, 13.6 g (97%) of the expected product are obtained in the form of a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:16]([CH3:18])[CH3:17]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:16]([CH3:18])[CH3:17])=[CH:4][CH:3]=1
Reactant: CC(C)I
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)Oc1ccc(Br)cc1
Temperature: 25 °C
Yield: 92 %

Procedure:
A mixture of 4-bromophenol (7.0 g, 40.0 mmol, 1 eq) dimethylsulfoxide (20 mL), and potassium carbonate (11.0 g, 80.0 mmol, 2.0 eq) was stirred at room temperature then 2-iodopropane (5.2 mL, 1.3 eq) was added. The mixture was heated to 60° C. overnight, cooled to room temperature and treated with water (200 mL). The reaction was extracted with dichloromethane, dried (sodium sulfate) and concentrated in vacuo. The crude was purified by flash chromatography eluting with cyclohexane to afford the title compound as a colorless oil (7.9 g, 92%);
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[CH:9])=[C:6](/[N:10]=[N:11]/N(CC)CC)[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:4]([CH:24]([OH:26])[CH3:25])[CH:3]=1>ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]([OH:26])[CH3:25])[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:6]2[C:7]=1[CH:8]=[CH:9][N:11]=[N:10]2
Reactant: C#Cc1c(Cl)cc(C(C)O)c(-c2cccc(F)c2)c1/N=N/N(CC)CC
Solvent: Clc1ccccc1Cl
Product: CC(O)c1cc(Cl)c2ccnnc2c1-c1cccc(F)c1
Yield: 75.8 %

Procedure:
A solution of 1-{4-chloro-6-[(1E)-3,3-diethyltriaz-1-en-1-yl]-5-ethynyl-3′-fluorobiphenyl-2-yl}ethanol (2.3 g, 6.1 mmol) in 1,2-dichlorobenzene (59 mL) was heated in the microwave at 200° C. for 15 minutes. The reaction mixture was concentrated to give a black residue. Purification by flash column chromatography using acetonitrile in dichloromethane (0%-30%) gave the desired product (1.4 g, 74% for 2 steps). LCMS for C16H13ClFN20 (M+H)+: m/z=303.1; Found: 302.9.
Reaction SMILES: C(O[K])(C)(C)C.[C:7](=[O:14])([O:11][CH2:12][CH3:13])OCC.C1(C)C=CC=CC=1.[C:22]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)(=[O:24])[CH3:23]>O>[CH2:12]([O:11][C:7](=[O:14])[CH2:23][C:22](=[O:24])[C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)[CH3:13]
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1cccs1
Agent: CC(C)(C)O[K]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)CC(=O)c1cccs1
Temperature: 62.5 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
A 71.1 g (0.63 mol) portion of tert-butoxy potassium was added to 194.7 g (1.65 mol) of diethyl carbonate at 60 to 65° C. and stirred at 60 to 65° C. for 1 hour, and then 180 ml of toluene solution containing 50 g (0.40 mol) of 2-acetylthiophene was added dropwise thereto at 75 to 80° C. and stirred at 75 to 80° C. for 2 hours. The reaction solution was cooled down to room temperature, mixed with 725 g of water, extracted with 600 ml of ethyl acetate, washed with saturated brine, concentrated and then distilled under a reduced pressure to obtain 65.2 g of 3-oxo-3-(2-thienyl)propionic acid ethyl ester (yield 83%).
Reaction SMILES: [C:1]([Si:5]([CH3:9])([CH3:8])[O:6][NH2:7])([CH3:4])([CH3:3])[CH3:2].[CH:10]1[CH:19]=[C:18]2[C:20]([O:22][C:23](=O)[C:16]3=[C:17]2[C:12](=[CH:13][C:14]([N+:25]([O-:27])=[O:26])=[CH:15]3)[CH:11]=1)=[O:21]>N1C=CC=CC=1>[Si:5]([O:6][N:7]1[C:23](=[O:22])[C:16]2[CH:15]=[C:14]([N+:25]([O-:27])=[O:26])[CH:13]=[C:12]3[C:17]=2[C:18](=[CH:19][CH:10]=[CH:11]3)[C:20]1=[O:21])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:9])[CH3:8]
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])cc3cccc1c23
Reactant: CC(C)(C)[Si](C)(C)ON
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)ON1C(=O)c2cccc3cc([N+](=O)[O-])cc(c23)C1=O
Yield: 85.1 %

Procedure:
O-(tert-Butyldimethyl-silyl)hydroxylamine (1.8 g, 12.3 mmol) was added to a solution of 3-nitro-1,8-naphthalic anhydride (2.0 g, 8.2 mmol) in 50 mL of pyridine. The solution was refluxed for 4 hours and concentrated in vacuo. Purification as described in Example A-1 gave 2.6 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[CH3:25][N:26]([CH3:36])[C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl>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.C(O)C.C(COC)OC>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([C:31]3[CH:30]=[CH:29][CH:28]=[C:27]([N:26]([CH3:36])[CH3:25])[CH:32]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: CN(C)c1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: COCCOC
Product: CC(NC(=O)c1coc(-c2cccc(N(C)C)c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Temperature: 140 °C
Reaction time: 0.33 h
Yield: 16.6 %

Procedure:
In a 5 ml glass tube were placed 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol), 3-dimethylaminophenyl boronic acid (60 mg, 0.30 mmol), Cs2CO3 (129 mg, 0.40 mmol), Pd(PPh3)2Cl2(7 mg, 0.01 mmol), dimethoxyethane (0.8 mL), ethanol (0.2 mL), and a magnetic stir bar. The mixture was stirred at 140° C. for 20 minutes under microwave irradiation, acidified with 3N HCl, and extracted twice with EtOAc. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was triturated with ether to give title compound (10 mg, 16%).
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8](Cl)[CH:7]=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[C:3]=1[C:4]#[N:5].[C:24]1([OH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:9]=[C:8]([O:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=[C:6]([C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)cc(Cl)nc1Cl
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)cc(Oc2ccccc2)nc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 101 %

Procedure:
A mixture of 2,6-dichloro-4-(4-phenoxyphenyl)nicotinonitrile (51 mg, 0.149 mmol, from Step 2 of Example 8), phenol (15.47 mg, 0.164 mmol) and cesium carbonate (97 mg, 0.299 mmol) in DMSO (1.5 mL) was stirred at room temperature for 15 h. The mixture was diluted with ethyl acetate (60 mL), washed with water (2×5 mL), brine (5 mL), dried (MgSO4) and concentrated. Silica gel chromatography, eluting with 0% to 20% ethyl acetate in hexanes, gave 2-chloro-6-phenoxy-4-(4-phenoxyphenyl)nicotinonitrile as a white solid (60 mg, 75% yield). 1H NMR (500 MHz, CDCl3) δ ppm 7.52-7.73 (2H, m), 7.37-7.52 (4H, m), 7.25-7.36 (1H, m), 7.20-7.24 (1H, m), 7.08-7.18 (4H, m), 6.87 (1H, s); MS (ES+) m/z: 399 (M+H); LC retention time: 4.283 min (analytical HPLC Method A).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([O:9][CH3:10])=[CH:4][N:3]=1.[CH2:11]([Mg]Cl)[CH3:12].C[Mg]Cl.Cl>C1COCC1.C(CC(=O)C)(=O)C.[Fe+3].C(OCC)C>[Cl:1][C:2]1[N:7]=[C:6]([CH2:11][CH3:12])[C:5]([O:9][CH3:10])=[CH:4][N:3]=1
Reactant: COc1cnc(Cl)nc1Cl
Reactant: CC[Mg]Cl
Agent: [Fe+3]
Agent: C[Mg]Cl
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(=O)CC(C)=O
Product: CCc1nc(Cl)ncc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,4-Dichloro-5-methoxypyrimidine (5 g) was dissolved in THF (50 ml), and while cooling, iron(III) acetylacetone (985 mg) and ethyl magnesium chloride (0.91 M: 36.9 ml) were then added to the solution. The obtained mixture was stirred at room temperature overnight. Thereafter, iron(III) acetylacetone (985 mg) and methyl magnesium chloride (0.91 M: 36.9 ml) were added to the reaction solution further twice. A 1 N hydrochloric acid aqueous solution was added to the reaction mixture, and liquid separation and extraction were then carried out with diethyl ether. The organic layer was dried over magnesium sulfate, and the solvent was then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-heptane:ethyl acetate), so as to obtain the title compound (1 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Br:14])=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].[C:15](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.ClCCl>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Br:14])=[CH:11][CH:12]=2)[N:7]([CH3:15])[CH:6]=1)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1c[nH]c2cc(Br)ccc12
Agent: [K+]
Solvent: ClCCl
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cn(C)c2cc(Br)ccc12
Reaction time: 1.5 h
Yield: 99.4 %

Procedure:
To a mixture of 6-bromo-1H-indole-3-carboxylic acid methyl ester (100 mg, 0.394 mmol), potassium carbonate (163 mg, 1.18 mmol) in DMF is added iodomethane (30 μL, 0.47 mmol). The reaction mixture is stirred for 1.5 h. Additional iodomethane (10 μL) is added and the reaction is stirred for 30 minutes. The reaction mixture is diluted with dichloromethane and filtered. The filtrate is concentrated under high vacuum, diluted with ethyl acetate, and concentrated to give the title compound (105 mg, 99%). ES/MS m/e 270.0 (M+2).
Reaction SMILES: [C:1]([N:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].O.[NH2:19][NH2:20].[BH4-].[Na+].N>CO.C(Cl)Cl>[CH2:4]([O:3][C:1]([N:11]1[CH2:16][CH2:15][CH:14]([NH:19][NH2:20])[CH2:13][CH2:12]1)=[O:2])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NN
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: N
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: NNC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.8 %

Procedure:
A solution of 1-CBZ-4-piperidone (2.92 g, 12.5 mmol) and hydrazine hydrate (2.01 mL, 18.8 mmol) in MeOH (25 mL) was stirred at 50° C. for 30 min, then cooled to RT and NaBH4 (1.18 g, 31.3 mmol) added (CARE: gas evolution and exotherm to −45° C.). The solution was stirred at RT for 30 min, then 50° C. for 18 h. The cooled solution was concentrated in vacuo, suspended in water (25 mL) and extracted with DCM (2×25 mL). The combined organics were passed through a hydrophobic frit and concentrated in vacuo to leave a clear oil. FCC, using 0-10% [2H NH3 in MeOH] in DCM, gave the title compound as a clear oil (1.80 g, 58%). LCMS (Method 3): Rt 2.03 min, m/z 250 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][N:18]2[CH:23]=[CH:22][C:21]([NH:24][CH2:25]C)=[N:20][C:19]2=[O:27])=[CH:4][CH:3]=1.ClC1C=CN(CC2N3C=CC=CC3=NC=2C2C=CC(Cl)=CC=2)C(=O)N=1.CN>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][N:18]2[CH:23]=[CH:22][C:21]([NH:24][CH3:25])=[N:20][C:19]2=[O:27])=[CH:6][CH:7]=1
Reactant: CCNc1ccn(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)c(=O)n1
Agent: CN
Agent: O=c1nc(Cl)ccn1Cc1c(-c2ccc(Cl)cc2)nc2ccccn12
Product: CNc1ccn(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)c(=O)n1

Procedure:
The title compound was prepared according to the experimental for compound 132 from 4-chloro-1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2(1H)-one and methylamine. M/e− 366 for C19H17ClN5O (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.42 (d, J=6.6 Hz, 1H), 7.68 (d, J=8.4 Hz, 2H), 7.62 (m, 1H), 7.46 (d, 8.4 Hz, 2H), 7.28 (d, J=7.7 Hz, 1H), 6.86 (t, J=6.9 Hz, 1H), 6.64 (d, J=7.3 Hz, 1H), 5.51 (s, 2H), 5.41 (d, J=7.3 Hz, 1H), 5.24 (bs, 1H), 2.98 (s, 3H) ppm.