Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.[NH2:11][CH:12]([CH3:16])[C:13]([NH2:15])=O.N1C=CC=CC=1.Cl.C(N=C=NCCCN(C)C)C>>[C:13]([CH:12]([NH:11][C:5](=[O:7])[C:4]1[CH:3]=[CH:2][N:10]=[CH:9][CH:8]=1)[CH3:16])#[N:15]
Reactant: Cc1cc(C(=O)O)ccn1
Reactant: CC(N)C(N)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Product: CC(C#N)NC(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
To a mixture of 2-methylisonicotinic acid (2.00 g, 15 mmol) and 2-aminopropanamide (3.7 g, 29 mmol) in pyridine (15 ml, 15 mmol) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (5.6 g, 29 mmol). The resulting mixture was allowed to stir at rt overnight. The mixture was concentrated, to the residue was added 10% methanol/DCM (80 mL). The white precipitate was collected and the residue was purified by CombiFlash using 0-10% methanol/DCM as the eluent to give 2.14 g of N-(1-cyanoethyl)isonicotinamide 22B. LCMS (ES+) m/z 208.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[S:18][C:17]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[O:19][C:20]3[CH:21]=[CH:22][C:23]4[C:27]([C:28](O)=[O:29])=[C:26]([CH3:31])[S:25][C:24]=4[CH:32]=3)[CH:11]=2)=[O:9])[CH2:4]1.[NH2:33][CH2:34][CH2:35][CH2:36][OH:37].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[OH:37][CH2:36][CH2:35][CH2:34][NH:33][C:28]([C:27]1[C:23]2[CH:22]=[CH:21][C:20]([O:19][C:16]3[CH:15]=[CH:14][N:13]=[C:12]4[CH:11]=[C:10]([C:8]([N:5]5[CH2:6][CH2:7][C@@H:3]([O:2][CH3:1])[CH2:4]5)=[O:9])[S:18][C:17]=34)=[CH:32][C:24]=2[S:25][C:26]=1[CH3:31])=[O:29]
Reactant: CO[C@@H]1CCN(C(=O)c2cc3nccc(Oc4ccc5c(C(=O)O)c(C)sc5c4)c3s2)C1
Reactant: NCCCO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@@H]1CCN(C(=O)c2cc3nccc(Oc4ccc5c(C(=O)NCCCO)c(C)sc5c4)c3s2)C1
Yield: 23.3 %

Procedure:
This material was prepared from the reaction of 6-[(2-{[(3R)-3-methoxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridin-7-yl)oxy]-2-methylbenzo[b]thiophene-3-carboxylic acid 123b (130 mg, 0.278 mmole) with 3-amino-1-propanol (106 μL, 1.39 mmole), N,N-diisopropylethylamine (0.15 mL, 0.83 mmole), and HBTU (263 mg, 0.694 mmole) in a manner similar to that previously described for example 117 to give a yellow solid (34 mg, 23%). 1H NMR (DMSO-d6, 300 MHz) δ 8.58 (1H, d, J=5.27 Hz), 8.36 (1H, t, J=5.65 Hz), 8.06 (1H, s), 7.96 (1H, d, J=2.07 Hz), 7.83 (1H, d, J=8.85 Hz), 7.33 (1H, dd, J=2.07, 8.85 Hz), 6.75 (1H, d, J=5.27 Hz), 4.51 (1H, t, J=5.18 Hz), 4.13–3.82 (3H, m), 3.62 (2H, m), 3.50 (2H, m), 3.39–3.30 (2H, m), 3.27, 3.24 (3H, s), 2.60 (3H, s), 2.18–1.93 (2H, m), 1.71 (2H, quintet, J=6.6 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.C1(S([N:19]2[C:23]3=[N:24][CH:25]=[CH:26][CH:27]=[C:22]3[C:21]([C:28]3[CH:33]=[CH:32][N:31]=[C:30](Cl)[N:29]=3)=[CH:20]2)(=O)=O)C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:30]2[N:29]=[C:28]([C:21]3[C:22]4[C:23](=[N:24][CH:25]=[CH:26][CH:27]=4)[NH:19][CH:20]=3)[CH:33]=[CH:32][N:31]=2)=[CH:5][CH:4]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Reactant: COc1ccc(N)cc1
Product: COc1ccc(Nc2nccc(-c3c[nH]c4ncccc34)n2)cc1
Yield: 40.9 %

Procedure:
Using the procedure of example 1, p-anisidine (100 mg) was reacted with compound 1f (100 mg) to provide compound 5 (35 mg, 41%). 1H NMR (400 MHz, CD3OD) δ 8.73 (d, J=8.0 Hz, 1H), 8.27 (m, 2H), 8.07 (s, 1H), 7.55 (d, J=9.0 Hz, 2H), 7.18 (dd, J=8.0 Hz, 4.8 Hz, 1H), 7.06 (d, J=5.6 Hz, 1H), 6.96 (d, J=9.0 Hz, 2H), 3.86 (s, 3H). MS (ESI) m/z: 318 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][N:7]=[CH:6][C:5]=2[S:4][CH:3]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][CH2:19]O>>[Br:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:19][CH2:18][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=3)[N:7]=[CH:6][C:5]=2[S:4][CH:3]=1
Reactant: OCCc1ccccn1
Reactant: O=c1[nH]ncc2scc(Br)c12
Product: O=c1c2c(Br)csc2cnn1CCc1ccccn1
Yield: 76.3 %

Procedure:
The title compound was prepared in analogy to the process described in Example 3.4 starting from 3-bromo-5H-thieno[2,3-d]-pyridazin-4-one and 2-pyridin-2-yl-ethanol. Yield: 76.3%.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH2:14][C:15]3[CH:16]=[C:17]([CH:20]4OCC[O:21]4)[S:18][CH:19]=3)[CH:5]=[CH:4][C:3]1=2.Cl.CO>C1COCC1>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([CH2:14][C:15]3[CH:16]=[C:17]([CH:20]=[O:21])[S:18][CH:19]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(Cc3csc(C4OCCO4)c3)ccc21
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(Cc3csc(C=O)c3)ccc21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A round bottom flask was mixed with 2-{4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)methyl]-2-thienyl}-1,3-dioxolane (5.1 g, 14.3 mmol), 3.0 N HCl (50 mL), methanol (20 mL) and THF (30 mL). The reaction mixture stirred for 6 hours at room temperature and was concentrated to one half volume. The resulting mixture was partitioned between water and ether. The ether layer was dried over MgSO4 and concentrated to dryness. The resulting oil showed an inseparable impurity by TLC from the starting material. The product was used without further purification (2.7 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH3:18][O:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[C:23]([OH:30])[CH:24]=[CH:25][CH:26]=2)[N:21]=1>>[CH3:18][O:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[C:23]([O:30][C:2]3[CH:7]=[C:6]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=4)[N:5]=[CH:4][N:3]=3)[CH:24]=[CH:25][CH:26]=2)[N:21]=1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Reactant: COc1ccc2cccc(O)c2n1
Product: COc1ccc2cccc(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)c2n1

Procedure:
The title compound was prepared from 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine (Example 2(a), Method A) and 2-methoxy-quinolin-8-ol (prepared according to Ataev, A; et al. Teoreticheskaya i Eksperimental'naya Khimya 1980, 16 (2), 243-249) under the conditions of Example 6. Mp: 158.5-161° C. MS (ESI, pos. ion) m/z: 398 (M+1).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li].[CH3:15][C:16]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[C:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1.O>O1CCCC1.[Cl-].[Cl-].C1(C(=[Hf+2](C2C3C=CC=CC=3C3C2=CC=CC=3)C2C=CC=C2)C)C=CC=CC=1>[CH:17]1([C:16]2[CH:15]=[CH:25][CH:26]=[CH:27][C:22]=2[CH2:23][CH2:24][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH2:18][CH2:19][CH:20]=[CH:21]1
Reactant: CC(=C1C=CC=C1)c1ccccc1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: CC(c1ccccc1)=[Hf+2](C1C=CC=C1)C1c2ccccc2-c2ccccc21
Agent: [Cl-]
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Product: C1=CC(c2ccccc2CCC2c3ccccc3-c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
(Phenyl(methyl)methylene)(9-fluorenyl)(cyclopentadienyl)hafnium dichloride ##STR12## A solution of 67.8 mmol of lithium-fluorene in 50 cm3 of tetrahydrofuran was added to a solution of 11.4 g (67.8 mmol) of 6-methyl-6-phenyl-fulvene in 40 cm3 of tetrahydrofuran at room temperature. After the mixture had been stirred at room temperature for 2 hours, 60 cm3 of water were added. The substance obtained after this addition was filtered off with suction, washed with diethyl ether and dried under an oil pump vacuum. 19.1 g (84.2%) of 2,2-cyclopentadienyl(9-fluorenyl)ethylbenzene were obtained (correct elemental analyses; 1H-NMR spectrum).
Reaction SMILES: [CH3:1][CH:2]([CH3:29])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21](=O)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[CH3:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[NH:38]N>>[CH3:1][CH:2]([CH3:29])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[C:34]4[C:33](=[C:32]([CH3:31])[CH:37]=[CH:36][CH:35]=4)[NH:38][C:21]=3[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCC(=O)c3ccccc3)CC2)c1
Reactant: Cc1ccccc1NN
Agent: Cl
Product: Cc1cccc2c(CCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c(-c3ccccc3)[nH]c12

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-{3-[1-(4-oxo-4-phenylbutyl)-4-piperidinyl]phenyl}propanamide and 1-(2-methylphenyl)hydrazine hydrochloride: ESMS m/e: 480.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[CH2:9]2)=[CH:4][CH:3]=1.[CH3:27][S:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)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>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:12]1[CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[S:28][CH3:27])=[CH:3][CH:4]=2)[CH2:9][C:10]([C:20]([F:25])([F:26])[C:21]([F:22])([F:24])[F:23])=[N:11]1
Reactant: FC(F)(F)C(F)(F)C1=NN(c2ccccc2Cl)C(c2ccc(Br)cc2)C1
Reactant: CSc1ccccc1B(O)O
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: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccccc1-c1ccc(C2CC(C(F)(F)C(F)(F)F)=NN2c2ccccc2Cl)cc1
Yield: 57.2 %

Procedure:
A solution of 5-(4-bromo-phenyl)-1-(2-chloro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (100.0 mg, 0.19 mmol) prepared in Step 3 of Preparation 1, 2-(methylthio)phenylboronic acid (80.0 mg, 0.28 mmol), Pd(PPh3)4 (26 mg, cat.), and a 2N sodium carbonate solution (0.6 mL) in N,N-dimethylformamide (5 mL) was stirred at 80° C. for 6 hours. The reaction mixture was concentrated under reduced pressure and then diluted with ethyl acetate. The organic layer was washed with distilled water, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/20) to give 54.0 mg of 1-(2-chloro-phenyl)-5-(2′-methylsulfanyl-biphenyl-4-yl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole as a pale yellow liquid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][C@H:12]([CH3:17])[C:13]([O:15]C)=O)[CH:4]=[CH:3][CH:2]=1.[NH2:18][CH2:19][C@@H:20]([OH:32])[CH2:21][N:22]1[CH2:31][CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1>CCO>[CH2:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:30][CH2:31][N:22]1[CH2:21][C@@H:20]([OH:32])[CH2:19][NH:18][C:13](=[O:15])[C@H:12]([O:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:1]=[CH:2][CH:3]=[CH:4]2)[CH3:17]
Reactant: COC(=O)[C@@H](C)Oc1cccc2cccnc12
Reactant: NC[C@@H](O)CN1CCc2ccccc2C1
Solvent: CCO
Product: C[C@@H](Oc1cccc2cccnc12)C(=O)NC[C@H](O)CN1CCc2ccccc2C1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 51.3 %

Procedure:
To a stirred mixture of (R)-methyl 2-(quinolin-8-yloxy)propanoate (100 mg, 0.433 mmol) in EtOH (1 mL) was added (R)-1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl) propan-2-ol (89.2 mg, 0.433 mmol). The mixture was stirred in a sealed tube in a microwave apparatus at 120° C. for 0.5 hour. After cooling to room temperature the solvent was evaporated, and the residue was first purified by prep-TLC and then prep-HPLC to afford the title compound (90 mg, yield: 51%). 1H NMR (400 MHz, METHANOL-d4)8 ppm 8.89 (br. S., 1H), 8.29-8.42 (m, 1H), 7.49-7.65 (m, 3H), 7.28 (d, J=5.52 Hz, 1H), 6.89-7.13 (m, 4H), 5.01-5.13 (m, 1H), 4.10-3.84 (m, 1H), 3.45-3.60 (m, 2H), 3.35-3.43 (m, 2H), 2.81 (d, J=3.01 Hz, 2H), 2.65 (br. S., 2H), 2.34-2.49 (m, 2H) 1.71 (d, J=6.78 Hz, 3H), LCMS (m/z): 406.2 [M+H]+
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([CH3:26])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:16]=1>>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:15]2[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:12]3[CH:25]=[C:24]([CH3:26])[S:23][C:13]=3[N:14]=2)[CH:18]=1
Reactant: Cc1cc2c(Cl)nc(-c3cccnc3)nc2s1
Reactant: NCCc1ccccc1
Product: Cc1cc2c(NCCc3ccccc3)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyridin-3-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-phenethylamino-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH:13]1[CH:14]=[C:15]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]3[CH:33]=[CH:34][C:35]4[CH2:42][CH2:41][C:39](=[O:40])[NH:38][C:36]=4[CH:37]=3)[CH2:23][CH2:22]2)[C:16]([Cl:20])=[C:17]([Cl:19])[CH:18]=1.[CH3:43][O:44][C:45](Cl)=[O:46]>>[Cl:20][C:16]1[C:17]([Cl:19])=[CH:18][CH:13]=[CH:14][C:15]=1[N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]2[CH:37]=[C:36]3[C:35]([CH2:42][CH2:41][C:39](=[O:40])[N:38]3[C:45]([O:44][CH3:43])=[O:46])=[CH:34][CH:33]=2)[CH2:23][CH2:22]1
Reactant: COC(=O)Cl
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: COC(=O)N1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc21
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of diisopropylamine (0.99 mL, 7.02 mmol) in 2-methyltetrahydrfuran (33 mL) at −5° C. was added n-BuLi (2.67 mL, 2.5 M in hexanes, 6.69 mmol) slowly. After 20 minutes, the reaction was cooled to −78° C. and aripiprazole (1.50 g, 3.34 mmol) was added. After a further 10 minutes, methylchloroformate (0.65 mL, 8.36 mmol) was added. The reaction was held at −78° C. for 2 hours before allowing to warm to room temperature. After 2 hours the reaction was quenched with saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (2×30 mL). The organics were combined, washed with saturated aqueous sodium hydrogen carbonate solution (30 mL), brine (30 mL), dried over MgSO4 and concentrated. The crude product was purified by column chromatography on silica eluting with 1:1 ethyl acetate to dichloromethane to 10% methanol in 1:1 ethyl acetate to dichloromethane to give the product. The product was triturated in heptane to remove aliphatic impurities and then filtered to afford Compound-74 (0.824 g) as a colorless solid.
Reaction SMILES: CNCCNC.Br[C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH:29]4[CH2:31][CH2:30]4)=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])=[C:10]([F:32])[CH:9]=1.[CH2:33]([O:40][CH2:41][N:42]1[C:46](=[O:47])[CH:45]([CH3:48])[NH:44][C:43]1=[O:49])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu]I.O.O1CCOCC1>[CH2:33]([O:40][CH2:41][N:42]1[C:46](=[O:47])[CH:45]([CH3:48])[N:44]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[C:27]([CH3:28])=[CH:26][C:25]([CH:29]5[CH2:31][CH2:30]5)=[CH:24][N:23]=4)[CH2:18][CH2:17]3)=[O:15])=[C:10]([F:32])[CH:9]=2)[C:43]1=[O:49])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC1NC(=O)N(COCc2ccccc2)C1=O
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2F)CC1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)N(COCc4ccccc4)C(=O)C3C)cc2F)CC1

Procedure:
1,4-Dioxane (12 mL) and N,N′-dimethylethylenediamine (86 μL) were added to a mixture of (4-bromo-2-fluorophenyl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (325 mg) described in Preparation Example 121, 3-benzyloxymethyl-5-methylimidazolidine-2,4-dione (225 mg) described in Preparation Example 206, cesium carbonate (521 mg) and copper(I) iodide (76 mg), and the mixture was stirred with heating under reflux for 10 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title is compound (270 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:10]=[C:4]2[N:3]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O>>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:12]=[C:13]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[C:26]([F:37])([F:36])[F:25])[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:10]=[C:4]2[N:3]=1
Reactant: Cc1ccn2c(-c3cccc(OS(=O)(=O)C(F)(F)F)c3)cnc2n1
Reactant: OB(O)c1ccccc1C(F)(F)F
Product: Cc1ccn2c(-c3cccc(-c4ccccc4C(F)(F)F)c3)cnc2n1
Yield: 35.4 %

Procedure:
Trifluoromethanesulfonic acid 3-(7-methylimidazo[1,2-a]pyrimidin-3-yl)phenyl ester (0.1 g, 0.28 mmol) was coupled to 2-trifluoromethylbenzeneboronic acid (52 μl, 0.59 mmol) as described in Example 21 to give 7-methyl-3-(2′-trifluoromethylbiphenyl-3-yl)-imidazo[1,2-a]pyrimidine as a white solid (35 mg): δH (400 MHz, CDCl3) 2.65 (3H, s), 6.77 (1H, d, J 7), 7.39 (1H, m), 7.48-7.62 (6H, m), 7.78 (1H, d, J 7.2), 7.82 (1H, s), 8.52 (1H, d, J 7); m/z (ES+) 354 (M++H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[F:14].[Si]([C:19]#[CH:20])(C)(C)C.CCN(CC)CC.C([O-])([O-])=O.[K+].[K+]>CO.CCOC(C)=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C1COCC1>[C:19]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[F:14])#[CH:20]
Reactant: Fc1cc(-c2ccncc2)ccc1Br
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C#Cc1ccc(-c2ccncc2)cc1F
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
4-(4-bromo-3-fluorophenyl)pyridine (55 mg, 0.218 mmol), CuI (5.8 mg, 0.031 mmol), PdCl2(PPh3)2 (23 mg, 0.033 mmol) were placed in a μwave tube under an atmosphere of N2. TMS acetylene (46 μL, 0.327 mmol), Et3N (121 μL, 0.873 mmol) and THF (1.1 mL) were added and the mixture was heated to 100° C. for 20 min and then cooled to ambient temperature. The mixture was filtered through a silica gel pack and washed with EtOAc. Combined eluents were evaporated under reduced pressure to give crude TMS acetylenic product as a solid. The crude material from step 1 was dissolved in MeOH (in some cases 20% EtOAc was added to increase solubility) and 3 eq of K2CO3 added and the mixture stirred for 30 min. To the mixture was added water and extracted with EtOAc. The combined organic layers were dried, filtered and evaporated. The residue was purified by column chromatography on silica to afford the title compound 29 mg (0.146 mmol).
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([NH:9][C@H:10]2[C@@H:15]([NH:16]C(=O)OC(C)(C)C)[CH2:14][CH2:13][S:12](=[O:25])(=[O:24])[CH2:11]2)=[CH:5][C:4]=1[NH:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([CH3:35])[N:28]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:16][C@H:15]1[CH2:14][CH2:13][S:12](=[O:25])(=[O:24])[CH2:11][C@H:10]1[NH:9][C:6]1[CH:5]=[C:4]([NH:26][C:27]2[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([CH3:35])[N:28]=2)[C:3]([C:1]#[N:2])=[N:8][CH:7]=1
Reactant: COc1cc(C)nc(Nc2cc(N[C@@H]3CS(=O)(=O)CC[C@@H]3NC(=O)OC(C)(C)C)cnc2C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C)nc(Nc2cc(N[C@@H]3CS(=O)(=O)CC[C@@H]3N)cnc2C#N)c1
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl rel-[(3S,4S)-3-({6-cyano-5-[(4-methoxy-6-methylpyridin-2-yl)amino]pyridin-3-yl}amino)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl]carbamate (56 mg, 0.11 mmol) in DCM (2 mL) was added TFA (1 mL). After 30 minutes, the reaction mixture was concentrated under reduced pressure to afford rel-5-{[(3S,4S)-4-amino-1,1-dioxidotetrahydro-2H-thiopyran-3-yl]amino}-3-[(4-methoxy-6-methylpyridin-2-yl)amino]pyridine-2-carbonitrile, which was used directly in the next step without purification. MS ESI calc'd. for C18H23N6O3S [M+H]+ 403. found 403.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([C:13]([CH3:27])([CH3:26])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([Cl:25])=[CH:22][C:23]=2I)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Cl:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([C:13]([CH3:27])([CH3:26])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([Cl:25])=[CH:22][C:23]=2[C:32]2[CH:33]=[CH:34][C:35]([F:37])=[CH:36][C:31]=2[Cl:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1I
Reactant: OB(O)c1ccc(F)cc1Cl
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: [Na+]
Solvent: C1COCCO1
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1-c1ccc(F)cc1Cl
Yield: 96 %

Procedure:
2-[3,5-bis(trifluoromethyl)phenyl]-N-(6-chloro-4-iodo-3-pyridinyl)-N ,2-dimethylpropanamide (200 mg, 0.363 mmol), 2-chloro-4-fluorobenzene boronic acid (82 mg, 0.472 mmol), sodium carbonate (0.4 mL, 2M solution), tetrakistriphenylphosphinepalladium (4 mg, 0.00363 mmol) in dioxan (2 mL) were heated together in the microwave at 110° C. for 30 minutes. The mixture was partitioned between EtOAc and Brine. The Aqueous layer was extracted with EtOAc ×3. The combined extracts were dried and evaporated. The residue was purified on a 25+M column eluting with 0-50% EtOAc/Pet Et2O. Impurities still seen. Sent to MDAP for purification to afford the title compound in a 96% yield.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][N:15]=2)[C:10]([OH:12])=O)[NH:5][CH:4]=[C:3]1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.[CH2:64]([NH2:71])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1>CN(C=O)C>[CH2:64]([NH:71][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][N:15]=[C:7]([N:6]2[C:2](=[O:1])[C:3]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[CH:4][NH:5]2)[CH:8]=1)[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1
Reactant: O=C(O)c1ccnc(-n2[nH]cc(-c3cccnc3)c2=O)c1
Reactant: NCc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)c1ccnc(-n2[nH]cc(-c3cccnc3)c2=O)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
60.0 mg (213 μmol) of the compound from Example 41 are dissolved in 24 ml DMF, 2.6 mg (21 μmol) 4-N,N-dimethylaminopyridine, 65.9 mg (510 μmol) N,N-diisopropylethylamine and 265 mg (510 μmol) (benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate are added and the mixture is stirred at RT for 45 min. 68.3 mg (638 μmol) benzylamine are added and the mixture is stirred overnight at RT. To bring the conversion to completion, a further 65.9 mg (510 μmol) N,N-diisopropylethylamine and 265 mg (510 μmol) (benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate are added, the mixture is stirred at RT for 45 min, a further 68.3 mg (638 μmol) benzylamine are added and the mixture is then stirred overnight at RT. It is concentrated and the residue is purified by means of preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid).