Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([OH:17])[CH3:16])[N:8]=2)=[CH:5][N:4]([CH:18]([CH3:20])[CH3:19])[N:3]=1.[CH3:21][C:22]1[NH:39][C:25]2=[N:26][CH:27]=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:29]=[C:24]2[C:23]=1[CH3:40].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:21][C:22]1[NH:39][C:25]2=[N:26][CH:27]=[C:28]([C:2]3[C:6]([C:7]4[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([OH:17])[CH3:16])[N:8]=4)=[CH:5][N:4]([CH:18]([CH3:20])[CH3:19])[N:3]=3)[CH:29]=[C:24]2[C:23]=1[CH3:40]
Reactant: Cc1[nH]c2ncc(B3OC(C)(C)C(C)(C)O3)cc2c1C
Reactant: CC(C)n1cc(-c2ccnc(NC[C@H](C)O)n2)c(I)n1
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: CCO
Solvent: Cc1ccccc1
Product: Cc1[nH]c2ncc(-c3nn(C(C)C)cc3-c3ccnc(NC[C@H](C)O)n3)cc2c1C
Temperature: 85 °C
Reaction time: 8 h
Yield: 23.6 %

Procedure:
To a solution of (2S)-1-(4-(3-iodo-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol (B-1-3) (0.34 g, 0.885 mmol) in toluene (30 mL) and EtOH (10 mL) were added 2,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (B-6-5) (0.7 g, 1.77 mmol in theory) and 2 N aq. Na2CO3 (1.3 mL). The resulting mixture was degassed under N2 for 2 minutes. Then Pd(PPh3)4 (68 mg, 0.058 mmol) was added and the mixture was degassed again. The reaction was heated to 80-90° C. and stirred overnight. The mixture was cooled. The organic layer was separated and concentrated. The residue was purified by prep. HPLC to afford (2S)-1-(4-(3-(2,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol (B-6) (0.170 mg, 23.6%) as a light yellow solid.
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:17])[C:9]1=[O:18].[S:19]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20]1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[S:19]1[CH:23]=[CH:22][C:21]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[C:9]2=[O:18])=[CH:20]1
Reactant: OB(O)c1ccsc1
Reactant: O=C1Nc2ccccc2C1=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1C(=O)N(c2ccsc2)c2ccccc21
Reaction time: 8 h
Yield: 4.7 %

Procedure:
Triethylamine (56.9 mL, 0.408 mol), was added to a mixture of 1H-indole-2,3-dione (15.0 g, 0.102 mol), copper (II) acetate (46.0 g, 0.255 mol), and 3-thienylboronic acid (19.6 g, 0.153 mol) in CH2Cl2 (500 mL). The reaction mixture was stirred overnight, filtered through Celite®, rinsed with EtOAc/hexane (1:1, 300 mL), and concentrated in vacuo. The crude product was purified by column chromatography on silica using Hexane/EtOAc (1:1), giving the desired product (1.1 g, 50%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[CH:8]=[C:7]([NH2:14])[C:6]=1[NH2:15])[CH3:2].COC(C1C2N=C(N)[NH:26][C:25]=2C=CC=1)=O.BrC#N>CO>[CH2:1]([O:3][C:4]([C:5]1[C:6]2[N:15]=[C:25]([NH2:26])[NH:14][C:7]=2[CH:8]=[C:9]([O:11][CH2:12][CH3:13])[CH:10]=1)=[O:16])[CH3:2]
Reactant: CCOC(=O)c1cc(OCC)cc(N)c1N
Reactant: COC(=O)c1cccc2[nH]c(N)nc12
Agent: N#CBr
Solvent: CO
Product: CCOC(=O)c1cc(OCC)cc2[nH]c(N)nc12

Procedure:
4.0 g (17.9 mmol) of 2,3-diamino-5-ethoxy-benzoic acid ethyl ester was subjected to a similar cyclization condition as illustrated in intermediate A by using 5.7 g (53.7 mmol) of BrCN in methanol to produce 2-amino-6-ethoxy-1H-benzoimidazole-4-carboxylic acid ethyl ester. LCMS: 250 (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: C1CCOC1
Solvent: O
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: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[I:9][CH2:10][C@H:11]1[NH:14][C:13](=[O:15])[CH2:12]1.C(N(CC)CC)C>CN(C)C=O>[Si:5]([N:14]1[C@H:11]([CH2:10][I:9])[CH2:12][C:13]1=[O:15])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7]
Reactant: O=C1C[C@@H](CI)N1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)N1C(=O)C[C@H]1CI
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
t-butyldimethylchlorosilane (7.51 g, 49.8 mmol) is added in one portion to an ice-cold, stirring solution of (4S)-4-iodomethyl-azetidin-2-one (10.0 g, 47.4 mmol) and triethylamine (5.04 g, 49.8 mmol) in anhydrous dimethylformamide (100 ml). A voluminous white precipitate forms almost immediately. The reaction mixture is stirred at 0°-5° for 1 hour and then allowed to warm to room temperature. Most of the solvent is removed under vacuum to give a residue which is partitioned between diethyl ether (250 ml) and water. The ethereal phase is washed with 2.5 N hydrochloride acid (50 ml), water (3×50 ml), and brine, dried with magnesium sulfate, filtered, and evaporated under vacuum to provide (4S)-1-(t-butyldimethylsilyl)-4-iodomethyl-azetidin-2-one (15.1 g) as a white solid. Recrystallization from petroleum ether-ethyl ether gives the product as colorless plates, mp 71°-72°; n.m.r. (CDCl3), δ3.8 (m,1), δ2.6-3.6 (2 overlapping d of AB, 4) δ1.0 (S,9), δ0.3 (S,6), δ0.25 (S,6).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH:8]([C:12]1[S:13][CH:14]=[C:15]([CH2:17][S:18][CH2:19][CH2:20][NH:21][C:22]([NH:26][CH3:27])=[N:23][C:24]#[N:25])[N:16]=1)[C:9]([NH2:11])=[NH:10]>N1C=CC=CC=1.O>[C:5]([N:10]=[C:9]([NH2:11])[NH:8][C:12]1[S:13][CH:14]=[C:15]([CH2:17][S:18][CH2:19][CH2:20][NH:21][C:22]([NH:26][CH3:27])=[N:23][C:24]#[N:25])[N:16]=1)(=[O:7])[CH3:6]
Reactant: CNC(=NC#N)NCCSCc1csc(NC(=N)N)n1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CNC(=NC#N)NCCSCc1csc(NC(N)=NC(C)=O)n1
Reaction time: 2 h

Procedure:
Acetic anhydride (0.39 g.) was added to a stirred suspension of 2 -guanidino-4-[2-(2-cyano-3-methylguanidino)ethylthiomethyl]thiazole (1.10 g.) in pyridine (6 ml.) at room temperature. After stirring for two hours, the mixture was diluted with water (50 ml.), extracted with methylene chloride (3×30 ml.) and the combined extracts washed with water (100 ml.) and dried over magnesium sulphate. The solution was filtered and evaporated to dryness to leave a gum which was purified by column chromatography (silica column, eluted with ethyl acetate/ethanol/ammonia (s.g. 0.880) 6:1:1 v/v/v) to give 2-(2-acetylguanidino)-4-[2-(2-cyano-3-methylguanidino)ethylthiomethyl]thiazole as an amorphous solid. The n.m.r. spectrum in d6 dimethyl sulphoxide using tetramethylsilane as internal standard had the following resonances (δ): 2.1 (3H, singlet); 2.7 (5H, multiplet); 3.3 (multiplet, obscured by H2O); 3.7 (2H, singlet); 6.8 (1H, singlet); 7.0 (2H, broad multiplet; 9.0 (2H, very broad) and 10.7 (1H, broad).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:21]=[C:20]([NH:22][CH2:23][CH2:24][NH2:25])[N:19]2[CH:26]=[CH:27][N:28]=[C:18]2[CH:17]=1.F[C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][N:31]=1.C(=O)(O)[O-].[K+]>CS(C)=O>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:21]=[C:20]([NH:22][CH2:23][CH2:24][NH:25][C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][N:31]=2)[N:19]2[CH:26]=[CH:27][N:28]=[C:18]2[CH:17]=1
Reactant: Fc1ccc(C(F)(F)F)cn1
Reactant: NCCNc1nc(-c2ccc(Cl)cc2Cl)cc2nccn12
Agent: O=C([O-])O
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: FC(F)(F)c1ccc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cc3nccn23)nc1
Temperature: 130 °C

Procedure:
50 mg (0.155 mmol) of the amine (Example 8A) are introduced into 3 ml of dry DMSO, 51.2 mg (0.31 mmol) of 2-fluoro-5-(trifluoromethyl)pyridine and 31.1 mg (0.31 mmol) of potassium bicarbonate are added, and the mixture is heated at 130° C. under argon for 16 h. Purification by preparative HPLC results in 22 mg (30% of theory) of the product as a solid.
Reaction SMILES: CN(C)C=O.Cl[CH2:7][CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([O:20][C:21]3[C:22]([CH3:31])=[N:23][C:24]4[C:29]([CH:30]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:32][CH3:33].C(=O)([O-])[O-].[K+].[K+].[NH:40]1[CH2:45][CH2:44][CH2:43][CH:42]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH2:41]1>O>[CH3:33][O:32][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:10]=1[O:9][CH2:8][CH2:7][N:40]1[CH2:45][CH2:44][CH2:43][CH:42]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH2:41]1)[N:17]=[CH:16][CH:15]=[C:14]2[O:20][C:21]1[C:22]([CH3:31])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCl
Reactant: CCOC(=O)C1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCCN(CCOc2cc3nccc(Oc4cc5ccccc5nc4C)c3cc2OC)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 55.1 %

Procedure:
N,N-Dimethylformamide (1 ml) was added to 7-(2-chloro-ethoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline (compound 353) (50 mg), potassium carbonate (53 mg), and ethyl piperidine-3-carboxylate (60 mg), and the mixture was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (36 mg, yield 54%).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1[C:21]([F:22])=[C:20]([CH3:23])[CH:19]=[CH:18][C:17]=1[CH2:24]O>>[F:15][C:16]1[C:21]([F:22])=[C:20]([CH3:23])[CH:19]=[CH:18][C:17]=1[CH2:24][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: Cc1ccc(CO)c(F)c1F
Product: Cc1ccc(COc2ccnn2-c2cc(C#N)ccn2)c(F)c1F

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (2,3-difluoro-4-methylphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 2.32 (3H, s), 5.28 (2H, s), 5.80 (1H, s), 6.98 (1H, d, J=6.8 Hz), 7.11 (1H, d, J=7.2 Hz), 7.40 (1H, d, J=5.2 Hz), 7.58 (1H, s), 8.01 (1H, s), 8.70 (1H, d, J=4.8 Hz). [M+H] Calc'd for C17H12F2N4O, 327; Found, 327.
Reaction SMILES: [CH2:1]1CCC(N=C=NC2CCCCC2)C[CH2:2]1.[C:16]([O:20][C:21]([NH:23][CH2:24][P:25]([CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])(=[O:27])[OH:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C(O)C>C1COCC1>[C:16]([O:20][C:21]([NH:23][CH2:24][P:25]([CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])(=[O:26])[O:27][CH2:1][CH3:2])=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCP(=O)(O)CNC(=O)OC(C)(C)C
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCO
Solvent: C1CCOC1
Product: CCOP(=O)(CNC(=O)OC(C)(C)C)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 34.2 %

Procedure:
DCC (190 mg, 0.92 mmol) in THF (4 ml) is added dropwise in the course of 4 minutes to a solution of the phosphinic acid 1 (270 mg, 0.83 mmol) in dry THF (4 ml) and abs. ethanol (0.30 ml, 5.15 mmol) which is boiling under reflux. After 1.5 hours (checking by TLC), the reaction solution is cooled to room temperature and filtered. The filter residue is washed with ether. The filtrate is extracted with water (2×20 ml). The organic phase is dried over Na2SO4 and concentrated under reduced pressure. After purification by column chromatography on silica gel (ethyl acetate/heptane=3:2), the phosphinic acid ester 3 (100 mg, 34% of theory) is obtained. M.p. 117.5°-120° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH:17]=[CH:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]Br)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1.[ClH:34].COC1C=C(C2[C@H]3[C@H](CCCC3)C(=O)N(CCN3C=CN=C3)N=2)C=CC=1OC>>[ClH:34].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH:17]=[CH:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:29]3[CH:33]=[CH:32][N:31]=[CH:30]3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: c1c[nH]cn1
Reactant: COc1ccc(C2=NN(CCCCCCBr)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC
Agent: COc1ccc(C2=NN(CCn3ccnc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(CCCCCCn3ccnc3)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC

Procedure:
Prepared from compound 117 and imidazole as described for compound 113. Purified by chromatography and crystallized as the hydrochloride from tetrahydrofurane. M.p. 183° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N+:9]([O-:11])=[O:10].C(N(C(C)C)CC)(C)C.Cl.[CH3:22][O:23][CH2:24][CH2:25][CH2:26][CH2:27][NH2:28]>C(#N)C>[F:8][C:4]1[C:3]([N+:9]([O-:11])=[O:10])=[C:2]([CH:7]=[CH:6][CH:5]=1)[NH:28][CH2:27][CH2:26][CH2:25][CH2:24][O:23][CH3:22]
Reactant: O=[N+]([O-])c1c(F)cccc1F
Reactant: COCCCCN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COCCCCNc1cccc(F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 90 h
Yield: 66.6 %

Procedure:
To a solution of 1,3-difluoro-2-nitrobenzene (3.00 g) and diisopropylethylamine (7 μl) in acetonitrile (30 ml) was added a solution of 4-methoxybutan-1-amine hydrochloride (2.51 g) in acetonitrile (10 ml), and the mixture was stirred at room temperature for 90 hr. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (2:98-25:75) was concentrated under reduced pressure to give the object product (2.90 g).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:33])[NH:5][CH2:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:31])([CH3:30])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:15][C:14]=2[OH:32])[CH:10]=[CH:11][CH:12]=1)[CH3:2].IC.[C:36]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([NH:3][C:4](=[O:33])[NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:31])([CH3:30])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:29])[C:25]([CH3:27])([CH3:26])[CH3:28])=[CH:15][C:14]=2[O:32][CH3:36])[CH:8]=1)[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCNC(=O)NCc1cccc(-c2ccc(C(C)(C)CCCNC(=O)C(C)(C)C)cc2O)c1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCNC(=O)NCc1cccc(-c2ccc(C(C)(C)CCCNC(=O)C(C)(C)C)cc2OC)c1
Temperature: 70 °C
Yield: 63 %

Procedure:
A mixture of 35 (0.23 g, 0.508 mmol, 1.0 eq), iodomethane (0.13 mL, 2.1 mmol, 4.1 eq), and K2CO3 (0.56 g, 4.06 mmol, 8.0 eq) in acetone (5 mL) was heated to 70° C. for 24 hours. LC/MS showed complete conversion. Acetone was removed under reduced pressure, and the residue was partitioned in water/ethyl acetate. The aqueous layer was extracted with ethyl acetate (2×20 mL), and the combined organic layer was washed by water (20 mL), brine (20 mL) and dried over anhydrous K2CO3. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (neutral aluminum gel, 0-3% methanol in dichloromethane). Yield: 63%, 99% pure. M+1=468
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([O:16]C)=O)[CH:9]=2)[CH2:3][CH2:2]1.[NH2:18][CH2:19][CH: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>CO>[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][CH:20]([OH:32])[CH2:19][NH:18][C:14](=[O:16])[C:10]1[CH:9]=[C:8]([NH:7][CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[CH:13]=[CH:12][N:11]=1
Reactant: COC(=O)c1cc(NC2CCOCC2)ccn1
Reactant: NCC(O)CN1CCc2ccccc2C1
Solvent: CO
Product: O=C(NCC(O)CN1CCc2ccccc2C1)c1cc(NC2CCOCC2)ccn1
Yield: 34.7 %

Procedure:
To a solution of compound methyl 4-((tetrahydro-2H-pyran-4-yl)amino)picolinate (50 mg, 0.21 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (44 mg, 0.21 mmol) in MeOH (2 mL) was stirred at 100° C. under microwave heating for 3 h. The reaction mixture was purified by prep-HPLC to give the title compound (29.9 mg, Yield 34.4%). 1H NMR (400 MHz, CD3OD): δ 7.95 (d, J=5.6 Hz, 1H), 7.26 (d, J=2.4 Hz, 1H), 7.13-7.05 (m, 3H), 7.03-6.98 (m, 1H), 6.62 (dd, J=2.4, 5.6 Hz, 1H), 4.07 (quin, J=6.0 Hz, 1H), 4.01-3.93 (m, 2H), 3.72 (s, 2H), 3.66-3.60 (m, 1H), 3.60-3.57 (m, 1H), 3.57-3.52 (m, 2H), 3.49-3.42 (m, 1H), 2.95-2.89 (m, 2H), 2.87-2.81 (m, 2H), 2.65 (d, J=6.0 Hz, 2H), 1.97 (d, J=12.8 Hz, 2H), 1.59-1.47 (m, 2H). LCMS (m/z): 411.1 (M+1).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:27])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:18]=[CH:17][N:16]=[C:15](OC4C=CC=CC=4)[C:14]3=[O:26])[CH:7]=2)[CH2:3][CH2:2]1.[C:28]1([SH:34])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[CH:1]1([NH:4][C:5](=[O:27])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:18]=[CH:17][N:16]=[C:15]([S:34][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:14]3=[O:26])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(Oc2ccccc2)c1=O
Reactant: Sc1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(Sc2ccccc2)c1=O
Temperature: 120 °C

Procedure:
A mixture of N-cyclopropyl-4-methyl-3-(2-oxo-3-phenoxy-1(2H)-pyrazinyl)-benzamide (Example 116, 55 mg), benzenethiol (0.1 mL) and THF (1 mL) was heated under an atmosphere of nitrogen within a microwave for 90 minutes at 120° C. Purification by preparative HPLC (Gemini column, 0.1% ammonia:acetonitrile eluent) afforded the title compound as a solid (32 mg).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([CH2:8][C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[F:16])=[CH:6][CH:7]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:27][Si:28]([CH3:37])([CH3:36])[C:29]#[C:30][C:31](OCC)=[O:32]>C1COCC1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([CH:8]([C:9]2[C:10]([F:16])=[CH:11][CH:12]=[CH:13][C:14]=2[F:15])[C:31](=[O:32])[C:30]#[C:29][Si:28]([CH3:37])([CH3:36])[CH3:27])=[CH:6][CH:7]=1
Reactant: Fc1cccc(F)c1Cc1ccc(Cl)nn1
Reactant: CCOC(=O)C#C[Si](C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CC(=O)C(c1ccc(Cl)nn1)c1c(F)cccc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 111 %

Procedure:
To a solution of 3-chloro-6-(2,6-difluorobenzyl)pyridazine (5.7 g, 23.7 mmol) in THF (300 mL) was added LHMDS (71.2 mL, 71.2 mmol, 1M solution in THF) via cannula at −78° C. After stirring for 0.5 hr at −78° C., ethyl 3-(trimethylsilyl)propynoate (6.66 mL, 35.5 mmol) was added. The reaction was allowed to warm from −78° C. to −10° C. over 3 hours. The reaction was known to be complete by LCMS analysis; and then quenched with aqueous NH4Cl, extracted with ethyl acetate. The organic layers were combined, washed with 0.5 N HCl, water, brine, dried over MgSO4, and condensed in vacuo to yield an oil. The crude material was purified via silica gel chromatography (EtOAc/Hex) to yield the title compound (9.6 g).
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:16]1([C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:23][CH2:24]Cl)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>O1CCCC1>[C:16]1([C:22]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:23][CH2:24][S:1][C:2]2[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1cc(C(F)(F)F)ccc1S
Reactant: ClCC=C(c1ccccc1)c1ccccc1
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(F)(F)F)ccc1SCC=C(c1ccccc1)c1ccccc1
Yield: 85.2 %

Procedure:
A solution of 2.19 g (9.86 mmol) of methyl 2-mercapto-5-trifluoromethylbenzoate, 2.29 g (10.0 mmol) of 1,1-diphenyl-3-chloro-1-propene, and 1.67 g (11.0 mmol) of diazabicycloundecene (DBU) in 10 ml tetrahydrofuran was stirred for 60 minutes at room temperature. The solution was partitioned between ether and water and the ether layer was washed with water, dried over MgSO4 and evaporated. The residue was chromatographed (20% CH2Cl2 -hexane) on silica to afford 3.6 g (85%) of a clear oil. NMR (CDCl3, 90 MHz) 3.67 (d, 2H, J=8, CH2), 3.92 (s, 3H, --OCH3), 6.05 (t, 1H, J=8), 6.9-7.6 (m, 12H), 8.13 (s, 1H).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9](/[CH:15]=[C:16](\[CH3:20])/[C:17]([OH:19])=[O:18])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.OS(O)(=O)=O.[CH3:26]O>>[CH3:26][O:18][C:17](=[O:19])/[C:16](/[CH3:20])=[CH:15]/[C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:8]=1
Reactant: CO
Reactant: COc1ccc(/C=C(\C)C(=O)O)cc1OC1CCCC1
Agent: O=S(=O)(O)O
Product: COC(=O)/C(C)=C/c1ccc(OC)c(OC2CCCC2)c1
Temperature: 25 °C
Yield: 96 %

Procedure:
The carboxylic acid thus obtained (610 mg, 2.2 mmol) was dissolved in 10 mL of methanol and 3 drops of con. H2SO4 was added. The resulting solution was heated to reflux for 20 hr, cooled to room temperature, and partitioned between sat. NaHCO3 and CH2Cl2. The aqueous layer was extracted with CH2Cl2 (2×) and the combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure to an oil. Silica gel chromatography (4:1, hexanes:ethyl acetate) afforded (E)-methyl-3-(3-cyclopentoxy-4-methoxyphenyl)-2-methyl-prop-2-en-oate as a colorless solid (610 mg, 96%). 1H-NMR (300 MHz): d 2.15 (d, 3, J=1.2), 3.81 (s, 3), 3.88 (s, 3), 7.63 (s, 1). Anal. Calcd for C17H22O4 : C, 70.32; H, 7.64. Found: C, 70.44; H, 7.72.