Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[C:17]([NH:19][C:20]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=3)=[O:21])[N:16]=[C:15]([NH:29][C:30]([CH:32]([N:34]([CH3:42])[C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH3:33])=[O:31])[CH:14]=2)[C:5]2[N:10]([CH3:11])[N:9]=[C:8]([CH3:12])[C:6]=2[N:7]=1.[CH3:43][O-:44].[Na+].CO>O>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]([NH:19][C:17]2[N:16]=[C:15]([NH:29][C:30]([CH:32]([N:34]([CH3:42])[C:35](=[O:41])[O:36][C:37]([CH3:38])([CH3:39])[CH3:40])[CH3:33])=[O:31])[CH:14]=[C:13]([C:4]3[C:5]4[N:10]([CH3:11])[N:9]=[C:8]([CH3:12])[C:6]=4[N:7]=[C:2]([O:44][CH3:43])[N:3]=3)[CH:18]=2)=[O:21])=[N:23][CH:24]=1
Reactant: C[O-]
Reactant: Cc1nn(C)c2c(-c3cc(NC(=O)c4ccc(Cl)cn4)nc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)c3)nc(Cl)nc12
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1nc(-c2cc(NC(=O)c3ccc(Cl)cn3)nc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)c2)c2c(n1)c(C)nn2C
Temperature: 50 °C
Reaction time: 1.17 h

Procedure:
A mixture of tert-butyl N-{1-[(4-{5-chloro-1,3-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl}-6-(5-chloropyridine-2-amido)pyridin-2-yl)carbamoyl]ethyl}-N-methylcarbamate K63a (54 mg, 88 μmol), sodium methoxide (24 mg, 439 μmol) and methanol (400 μl) is stirred at 50° C. for 70 minutes. At RT water (10 ml) is added and the mixture extracted with DCM. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 30 mg (56%). HPLC-MS: M+H=610; tR=1.12 min (METHOD—2).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:13])=[C:9]([CH:12]=1)[CH:10]=[O:11])=[O:4].[CH3:14][C:15]([CH3:18])([NH2:17])[CH3:16].[S:19](=[O:23])(=[O:22])([OH:21])[OH:20].O>CC(O)C>[S:19]([OH:23])([OH:22])(=[O:21])=[O:20].[CH3:14][C:15]([NH:17][CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:13])=[C:9]([CH:12]=1)[CH:10]=[O:11])=[O:4])([CH3:18])[CH3:16].[CH3:14][C:15]([NH:17][CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:13])=[C:9]([CH:12]=1)[CH:10]=[O:11])=[O:4])([CH3:18])[CH3:16]
Reactant: O=Cc1cc(C(=O)CBr)ccc1O
Reactant: CC(C)(C)N
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)NCC(=O)c1ccc(O)c(C=O)c1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
5-(Bromoacetyl)-2-hydroxybenzaldehyde (10 g) is suspended in 2-propanol (60 ml) under an inert atmosphere and cooled to 0°. To the stirring slurry is added 1,1-dimethylethanamine (13 ml) and the reaction mixture permitted to warm to room temperature and stir for 50 minutes. The solution is then treated with a mixture of concentrated sulfuric acid (3.5 ml), 2-propanol (6.5 ml) and deionized water (5 ml). The reaction mixture is stirred for a further 18 hours whereupon the title compound (10.2 g) is isolated by filtration and dried in vacuo at 50°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9](Cl)(=[O:11])=[O:10])=[CH:4][CH:3]=1.[NH2:13][C@@H:14]1[CH2:29][N:17]2[CH2:18][CH2:19][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][C@@H:16]2[CH2:15]1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([NH:13][C@@H:14]2[CH2:29][N:17]3[CH2:18][CH2:19][N:20]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:21][C@@H:16]3[CH2:15]2)(=[O:11])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN2C[C@@H](N)C[C@H]2C1
Reactant: O=S(=O)(Cl)Cc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN2C[C@@H](NS(=O)(=O)Cc3ccc(Cl)cc3)C[C@H]2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (4-chlorophenyl)methanesulfonyl chloride (1.125 g, 5 mmol) in dichloromethane (10 mL) was added (7S,8aS)-tert-butyl 7-aminohexahydro-pyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (1.400 g, 5.80 mmol) followed by triethylamine (0.758 g, 7.5 mmol). The mixture was stirred at room temperature overnight, and then concentrated. The residue was purified by chromatography on silica gel (ethyl acetate) to give the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.25 (m, 1H), 1.39 (s, 9 H), 1.80 (m, 1 H), 1.95 (m, 1 H), 2.07-2.23 (m, 2 H), 2.89 (m, 3 H), 2.75-3.98 (m, 3 H), 4.32 (s, 2H), 7.43 (m, 5H). MS (ESI) m/z 431 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].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.[NH2:49][N:50]1[CH:54]=[CH:53][CH:52]=[C:51]1[C:55]([NH:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)=[O:56]>CN(C)C=O>[C:58]1([NH:57][C:55]([C:51]2[N:50]([NH:49][C:13]([C@@H:9]3[CH2:10][CH2:11][CH2:12][N:8]3[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:15])[CH:54]=[CH:53][CH:52]=2)=[O:56])[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1
Reactant: Nn1cccc1C(=O)Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
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: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nn1cccc1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
(S)-1-(tert-Butoxycarbonyl)pyrrolidine-2-carboxylic acid (1.80 g, 8.36 mmol) were dissolved in 20 ml of N,N-dimethylformamide and HATU (3.40 g, 8.95 mmol), DIEA (2.60 ml, 14.89 mmol) and 1-amino-N-phenyl-1H-pyrrole-2-carboxamide were added. The resulting solution was stirred at room temperature overnight and the solvent was removed in vacuum. The residue was taken up in ethyl acetate and the organic solution was washed with water and brine, dried over magnesium sulphate, filtered and evaporated to dryness. The crude product was purified by flash chromatography (0% to 30% hexane/AcOEt) to yield 1.90 g (62%) of the title compound as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7].I[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:9]([N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7])[CH2:10][CH3:11]
Reactant: CCCI
Reactant: O=Cc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCn1ccnc1C=O
Temperature: 50 °C
Yield: 95.9 %

Procedure:
1H-imidazole-2-carbaldehyde (800 mg, 8.3 mmol), 1-iodopropane (1.7 g, 10 mmol) and potassium carbonate (1.4 g) were added in DMF (30 mL) and the mixture was heated to 50° C. overnight. Then the mixture was evaporated under reduced pressure, and extracted with ethyl acetate (100 mL×4). The combined organic layers were dried over anhydrous sodium sulfate, concentrated to give 1-propyl-1H-imidazole-2-carbaldehyde (1.1 g). LC-MS (ESI) m/z 139 (M+1)+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([CH:7]1[CH2:14][CH:13]2[CH:15]([N:16]3[CH2:20][CH:19]([CH2:21][OH:22])[C:18]([CH3:24])([CH3:23])[C:17]3=[O:25])[CH:9]([CH2:10][CH2:11][CH2:12]2)[CH2:8]1)=[O:6].Cl[C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][N:28]=1>O1CCCC1.CN1CCCN(C)C1=O>[CH3:3][O:4][C:5]([CH:7]1[CH2:14][CH:13]2[CH:15]([N:16]3[CH2:20][CH:19]([CH2:21][O:22][C:27]4[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][N:28]=4)[C:18]([CH3:23])([CH3:24])[C:17]3=[O:25])[CH:9]([CH2:10][CH2:11][CH2:12]2)[CH2:8]1)=[O:6]
Reactant: COC(=O)C1CC2CCCC(C1)C2N1CC(CO)C(C)(C)C1=O
Reactant: N#Cc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COC(=O)C1CC2CCCC(C1)C2N1CC(COc2ccc(C#N)cn2)C(C)(C)C1=O
Temperature: 25 °C

Procedure:
NaH (0.1 g, 60% in oil, 2.56 mmol) was added in one portion to a stirred and cooled (0° C.) solution of the product of Example 7D (0.48 g, 1.42 mmol) and 6-chloro-nicotinonitrile (0.35 g, 2.56 mmol) in tetrahydrofuran (7 ml) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (7 mL). After the addition, the solution was warmed to room temperature and stirred for another five hours. The dark brown reaction mixture was cooled (0° C.), quenched with acetic acid (0.1 mL), and partitioned with diethyl ether and water. The organic phase was washed with water and brine, dried (MgSO4), filtered, and evaporated. The residue was purified over silica gel using 5-80% ethyl acetate in hexanes to give the titled product as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]([NH:10][NH2:11])=[O:9].[CH2:12]([N:16]=[C:17]=[O:18])[CH:13]([CH3:15])[CH3:14].C(OCC)C>C1COCC1>[Cl:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]([NH:10][NH:11][C:17]([NH:16][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:18])=[O:9]
Reactant: CC(C)CN=C=O
Reactant: Cc1csc(C(=O)NN)c1Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1csc(C(=O)NNC(=O)NCC(C)C)c1Cl
Reaction time: 8 h

Procedure:
1.00 g (5.25 mmol) of 3-chloro-4-methylthien-2-ylcarboxylic acid hydrazide are placed in 10 ml THF at room temperature. 520 mg (5.25 mmol) of isobutyl isocyanate, dissolved in 2 ml THF, are rapidly added dropwise with stirring. The mixture is further stirred overnight at room temperature. For the workup, the reaction mixture is treated with 10 ml diethyl ether, cooled in the water/ice-bath to about 0° C., and the resulting precipitate recovered by filtration, washed with diethyl ether and dried in vacuo. 1.29 g (85% of theory) of the target compound are thus obtained.
Reaction SMILES: Cl.[C:2]1([CH:8]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:14]([C:16]1[CH:31]=[CH:30][C:19]([O:20][C:21]2[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][N:22]=2)=[CH:18][CH:17]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[C:2]1([CH:8]2[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][C:16]3[CH:31]=[CH:30][C:19]([O:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][N:22]=4)=[CH:18][CH:17]=3)[CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Reactant: c1ccc(C2CCCNC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: NC(=O)c1ccc(Oc2ccc(CN3CCCC(c4ccccc4)C3)cc2)nc1
Yield: 314.4 %

Procedure:
Using a method similar to Example 345, using 3-phenyl-piperidine hydrochloric acid salt (0.413 g, 2.09 mmol), 6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1) (0.50 g, 0.417 mmol), sodium triacetoxyborohydride (0.656 g, 3.10 mmol), and acetic acid (0.172 mL, 3.00 mmol) in 1,2-dichloroethane (20.0 mL) provides, after reverse-phase HPLC, 0.508 g (64%) of the title compound as a white solid: mass spectrum (electrospray): m/z=388.1 (M+1); 1H NMR (DMSO-d6): 8.65 (d, 1H, J=2.2 Hz), 8.29 (dd, 1H, J=2.6, 8.8 Hz), 8.05 (s br, 1H), 7.50 (s br, 1H), 7.39 (d, 2H, J=8.4 Hz), 7.35-7.17 (m, 5H), 7.16-7.06 (m, 3H), 3.55 (s, 2H), 2.91 (d, 2H, J=10.6 Hz), 2.80 (t, 1H, J=11.3 Hz), 2.05 (q, 2H, J=8.4 Hz), 1.86 (d, 1H, J=11.3 Hz), 1.81-1.56 (m, 2H), 1.48 (dq, 1H, J=4.0, 12.1 Hz).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][S:9][C@@H:10]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[CH:12]([C:13](=[CH2:30])[CH2:14][C@@H:15]3[C@@H:24]2[CH2:23][CH2:22][C@@:20]2([CH3:21])[C@H:16]3[CH2:17][CH2:18][C:19]2=[O:29])[CH2:11]1)=[O:4].C[N+]1([O-])CC[O:37]CC1>CC#N.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[F:32][C:2]([F:1])([F:31])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][S@@:9]([C@@H:10]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[CH:12]([C:13](=[CH2:30])[CH2:14][C@@H:15]3[C@@H:24]2[CH2:23][CH2:22][C@@:20]2([CH3:21])[C@H:16]3[CH2:17][CH2:18][C:19]2=[O:29])[CH2:11]1)=[O:37])=[O:4]
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CC[C@@H](SCCCNC(=O)C(F)(F)F)CC12
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: CC#N
Product: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CC[C@@H]([S@@](=O)CCCNC(=O)C(F)(F)F)CC12
Yield: 34 %

Procedure:
To a solution of 3α-(3-trifluoroacetamidopropylthio)-6-methyleneandrostane-17-one (Prepn. 82, 286 mg) in dry CH3CN (14 mL), NMO (213 mg) and molecular sieves (4 Å, 280 mg) were added followed by the addition of TPAP (10.6 mg). After 1 h at room temperature the mixture was evaporated to dryness. The residue was purified by flash chromatography (SiO2, n-hexane/acetone 65/35) to give 3α-[(S)-3-trifluoroacetamidopropylsulfinyl]-6-methyleneandrostane-17-one (100 mg, 34% yield). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 9.43 (1H, bb), 4.72 (1H, m), 4.41 (1H, m), 3.24 (3H, m), 2.50-0.86 (24H, m), 0.75 (3H, s), 0.65 (3H, s).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:33])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:30][CH3:31])[CH2:25][CH2:26][CH2:27][CH:28]=[O:29])[C:5]1=[O:32])[CH:2]=[CH2:3].[CH3:34][Mg]Br>C1COCC1.C1(C)C=CC=CC=1>[CH2:1]([C@@:4]1([CH3:33])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@H:24]([CH2:25][CH2:26][CH2:27][CH:28]([OH:29])[CH3:34])[CH2:30][CH3:31])[C:5]1=[O:32])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CCCC=O)C1=O
Reactant: C[Mg]Br
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CCCC(C)O)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-5-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)heptanal prepared above in Step A (138 mg, 0.284 mmol) in THF (2.8 mL) was added 1.4 M methylmagnesium bromide in toluene and THF (75:25) (608 μL, 0.851 mmol) at 0° C. Then the reaction was allowed to warm to rt and stirred for 2 h. The reaction was quenched (sat NH4Cl solution), extracted (2×EtOAc), and washed (sat. aq. NaCl solution). The combined organic layer was dried (Na2SO4) and concentrated under reduced pressure to provide the title compound as a colorless film.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[N+:11]([O-])=O.[H][H]>CCOC(C)=O.[Pd]>[NH2:11][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:3]=1[NH:2][CH3:1])[C:7]#[N:8]
Reactant: CNc1ccc(C#N)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CNc1ccc(C#N)cc1N
Yield: 95.1 %

Procedure:
4-Methylamino-3-nitrobenzonitrile (0.18 g, 1.0 mmol) was dissolved in EtOAc (10 mL) and placed in a closed vessel. 10% Pd/C (50 mg, 5 mol %) was added and the mixture was hydrogenated via a hydrogen-filled balloon that was affixed to the vessel. After 2 h the mixture was filtered through celite and the filtrate was concentrated under reduced pressure to yield the title product (0.14 g, 93%) as an off-white solid, which was used without further purification. 1H-NMR (CDCl3): δ 7.19 (1H, dd), 6.92 (1H, d), 6.57 (1H, d), 4.04 (1H, br s), 3.30 (2H, br s), 2.91 (3H, br s); TLC (5:95 MeOH/DCM Rf 0.33).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH2:16])[CH:12]=[CH:13][C:14]=1[Br:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:18][C:19]([CH3:21])=O>C1CCCCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:24]([O:23][C:17](=[O:22])[CH:18]=[C:19]([NH:16][C:11]1[CH:12]=[CH:13][C:14]([Br:15])=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)[CH3:21])[CH3:25]
Reactant: Nc1ccc(Br)c(OCc2ccccc2)c1
Reactant: CCOC(=O)CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Solvent: O
Product: CCOC(=O)C=C(C)Nc1ccc(Br)c(OCc2ccccc2)c1
Yield: 106.2 %

Procedure:
To a mixture of 3-benzyloxy-4-bromo-phenylamine (55.7 g, 0.168 mol) and ethyl acetoacetate (23.4 mL, 0.185 mol) in cyclohexane was added toluene-4-sulfonic acid monohydrate (0.320 g, 1.68 mmol) The reaction mixture was refluxed during 6 h and the water was azeotropically removed. The reaction mixture was then partitioned between ethyl acetate and an aqueous solution of sodium hydrogenocarbonate. The organic layer was washed with brine, dried over sodium sulfate, filtered and the solvents were evaporated under vacuum. 69.6 g of the title compound were obtained. Black oil, ISP-MS m/e=392.2 ([M+H]+).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:24]1C(C2C=CC=CC=2)=CS[C:25]=1C(OC)=O.C(OCC)(OCC)OCC.C(C1C=CC(N)=CC=1)=C>C(O)(=O)C>[C:17]1([C:16]2[C:10]3[N:9]=[CH:8][N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[C:3]([CH:24]=[CH2:25])[CH:2]=4)[C:12](=[O:13])[C:11]=3[S:14][CH:15]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Agent: C=Cc1ccc(N)cc1
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: C=Cc1cccc(-n2cnc3c(-c4ccccc4)csc3c2=O)c1
Yield: 11.5 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (50 mg, 0.21 mmol), triethyl orthoformate (0.47 ml), 4-vinylaniline (47.5 mg, 0.39 mmol), and acetic acid (0.06 ml) were used to give 8 mg (0.024 mmol, 11.5% yield) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([CH2:15][C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=2[F:24])[C:19]#[N:20])[CH:12]=[CH:11][CH:10]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:35][Si:36]([CH3:45])([CH3:44])[C:37]#[C:38][C:39](OCC)=[O:40]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([CH:15]([C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=2[F:24])[C:19]#[N:20])[C:39](=[O:40])[C:38]#[C:37][Si:36]([CH3:45])([CH3:44])[CH3:35])[CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)C#C[Si](C)(C)C
Reactant: N#Cc1ccc(F)c(Cc2cccc(-c3ccc(F)cc3F)n2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CC(=O)C(c1cccc(-c2ccc(F)cc2F)n1)c1cc(C#N)ccc1F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 417.3 %

Procedure:
To a solution of 3-{[6-(2,4-difluorophenyl)pyridin-2-yl]methyl}-4-fluorobenzonitrile (from Step C above, 30.0 g, 92.3 mmol) in THF (700 mL) was added LiHMDS (276 mL, 276 mmol, 1M solution in THF) via cannula at −78° C. After stirring for 1 hr and 15 min at −78° C., ethyl 3-(trimethylsilyl)prop-2-ynoate (4.01 mL, 21.37 mmol) was added. The reaction was allowed to stir at −78° C. for 1 hr and was allowed to warm to 0° C. over 3 hours. The reaction was quenched with aqueous NH4Cl, extracted with ethyl acetate (2×). The organic layers were combined, washed with 0.5 N HCl, water, brine (2×), dried over MgSO4, and condensed in vacuo to yield a black oil. The crude material was purified via silica gel chromatography (100% CH2Cl2) to give the title compound (40.0 g).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.N1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[N+:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:4]([N:1]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:5]=1[C:6]#[N:7])([O-:14])=[O:13]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: C1CCNC1
Product: N#Cc1c(N2CCCC2)cccc1[N+](=O)[O-]

Procedure:
Prepared as in Example 90c from 2,6-dinitrobenzonitrile and pyrrolidin to give 2-nitro-6-(pyrrolidin-1-yl)benzonitrile which was used in the next step without any further purification. 1H NMR (400 MHz, DMSO-d6) δ 1.97-1.94 (m, 4H), 3.60-3.57 (m, 4H), 7.22 (d, J=8.0 Hz, 1H), 7.41 (d, J=6.8 Hz, 1H), 7.58 (t, J=8.0 Hz, 1H). MS 218 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[CH3:11][NH:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:25].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:11][N:12]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:25])[C:5](=[O:6])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=1
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CNc1cnccc1-c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cccc(Cl)c1
Reaction time: 8 h

Procedure:
3-Chlorobenzoyl chloride (30 mg, 0.17 mmol, CAS RN 618-46-2) was added to a solution of methyl-(4-o-tolyl-pyridin-3-yl)-amine (20 mg, 0.10 mmol, example 1, intermediate a) and DIPEA (30 μL, 0.17 mmol) in CH2Cl2 (1 mL). The reaction mixture was stirred overnight and then loaded directly onto a silica gel column and eluted with 50% EtOAc in n-hexane to yield the title product as a waxy solid (12 mg, 36%). MS (ESI): m/z=337.0 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]3)=[CH:15][CH:14]=2)[N:3]=1.[C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38][C:39]([O:41][CH3:42])=[O:40])#[CH:31].CCN(CC)CC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.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.[Cu]I>[CH3:42][O:41][C:39](=[O:40])[CH2:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[C:30]#[C:31][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]3)=[CH:15][CH:14]=2)[N:3]=1
Reactant: C#Cc1ccccc1CC(=O)OC
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(C3CN(C(=O)OC(C)(C)C)C3)cc2)ncc1C(F)(F)F
Temperature: 120 °C

Procedure:
A suspension of tert-butyl 3-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)azetidine-1-carboxylate (A78) (500 mg, 1.16 mmol), methyl 2-(2-ethynylphenyl)acetate (K1) (244 mg, 1.39 mmol), Et3N (0.60 mL), PdCl2(PPh3)2 (0.041 g, 0.058 mmol), CuI (0.022 g, 0.117 mmol) and PPh3 (0.031 g, 0.117 mmol) in DMF (4 mL) were heated under microwave irradiation at 120° C. for 15 minutes. The resulting mixture was adsorbed onto silica gel and purified using column chromatography (CombiFlash Rf, 40 g SiO2 cartridge, 0-30% EtOAc in cyclohexane) to give the title compound A79 as a yellow foam (0.570 g, 86%); 1H NMR (300 MHz, d6-DMSO) δ 8.65 (s, 1H), 7.70 (d, J=7.7 Hz, 1H), 7.64 (d, J=8.5 Hz, 2H), 7.48-7.33 (m, 6H), 4.35 (t, J=8.6 Hz, 2H), 4.01-3.96 (m, 4H), 3.75-3.72 (m, 4H), 1.49 (s, 9H). LCMS-B: rt 9.160 min; m/z 567 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Cl-].[Al+3].[Cl-].[Cl-].[Br:14]Br>O>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:14])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1ccc(C)c(Cl)c1
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: Cc1cc(Br)c(C)cc1Cl

Procedure:
400 parts of 2-chloro-p-xylene (b.p.=183° to 184° C.) and 2 parts of anhydrous aluminum chloride were charged into a 1-liter four-necked flask provided with a reflux condenser, a thermometer, a stirrer and a dropping funnel, to which 360 parts of bromine was dropwisely added over a period of 5 hours to carry out the reaction at 35° to 60° C. Water was added to the reaction liquid to wash the same with the thus added water and to remove the catalyst, and then the oil layer was cooled. The separated crystals were filtered, and washed with methanol to obtain 377 parts of 2-chloro-5-bromo-p-xylene having a melting point of 60° to 64° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)(=[O:17])=[O:16])[CH2:12][O:13][CH3:14])[C:5]([C:8](Cl)=[O:9])=[N:6][CH:7]=1.[C:29]([O:33][C:34]([N:36]1[CH:40]=[CH:39][C:38]([NH:41][CH:42]([CH3:44])[CH3:43])=[N:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]>C1COCC1>[C:29]([O:33][C:34]([N:36]1[CH:40]=[CH:39][C:38]([N:41]([C:8]([C:5]2[C:4]([N:11]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:26])([F:28])[F:27])[CH:19]=3)(=[O:17])=[O:16])[CH2:12][O:13][CH3:14])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[O:9])[CH:42]([CH3:44])[CH3:43])=[N:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)Nc1ccn(C(=O)OC(C)(C)C)n1
Reactant: COCN(c1cc(Cl)cnc1C(=O)Cl)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(=O)N(c1ccn(C(=O)OC(C)(C)C)n1)C(C)C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carbonyl chloride (100 mg, 0.2 mmol), 3-isopropylamino-pyrazole-1-carboxylic acid tert-butyl ester (54 mg, 0.24 mmol), TEA (0.88 mL) in THF was stirred at RT for 2 hours and then purified by flash column to give 3-({5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carbonyl}-isopropyl-amino)-pyrazole-1-carboxylic acid tert-butyl ester.