Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12]C)=[O:11])[C:3]=1I.[C:15](=O)([O-])[O-:16].[Cs+].[Cs+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>[Cu]I.CO>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([OH:12])=[O:11])[C:3]=1[O:16][CH3:15]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1I
Agent: [Cu]I
Agent: [Cs+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CO
Product: COc1c(C(=O)O)nc(Cl)c(F)c1N
Temperature: 65 °C
Reaction time: 12 h

Procedure:
To a dry 1 liter (L) flask was added methyl 4-amino-6-chloro-5-fluoro-3-iodopicolinate (50 g, 151 mmol) and cesium carbonate (Cs2CO3; 99 g, 303 mmol). CH3OH (378 mL) was added, and the solution was sparged with nitrogen for 10 min. 1,10-Phenanthroline (6.00 g, 30.3 mmol) and copper(I) iodide (CuI; 2.88 g, 15.13 mmol) were added, and the flask was fitted with a reflux condenser and heated to 65° C. under nitrogen. After 12 h, CuI (2.88 g, 15.13 mmol) was again added to the reaction mixture, and heating was continued until consumption of the iodopicolinate was observed. The reaction mixture was cooled to room temperature, filtered through Celite, and concentrated in vacuo. To the crude residue was added EtOAc (100 mL) and H2O (100 mL). The layers were separated, and the aqueous phase was acidified to pH=2 with concentrated (conc) HCl and subsequently extracted with EtOAc (3×100 mL). The organic extracts were combined, washed with satd aq NaCl, dried (Na2SO4), filtered, and concentrated in vacuo to afford 4-amino-6-chloro-5-fluoro-3-methoxypicolinic acid.
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([O:11][C:12]([NH:14][C@H:15]([C:21]([O:23]C)=[O:22])[CH2:16][O:17][CH:18]([CH3:20])[CH3:19])=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.S([O-])(O)(=O)=O.[K+]>O1CCCC1.O>[CH2:4]([O:11][C:12]([NH:14][C@H:15]([C:21]([OH:23])=[O:22])[CH2:16][O:17][CH:18]([CH3:20])[CH3:19])=[O:13])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)[C@H](COC(C)C)NC(=O)OCc1ccccc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)OC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reaction time: 8 h

Procedure:
Lithium hydroxide monohydrate (0.078 g, 1.86 mmol) was added to a stirred solution of methyl N-[(benzyloxy)carbonyl]-O-isopropyl-L-serinate (0.432 g, 1.47 mmol) in a mixture of tetrahydrofuran/water (10 ml, 1:1) at 0° C. The reaction mixture was stirred overnight, acidified with a 10% w/v aqueous solution of potassium hydrogensulfate and extracted with EtOAc (2×30 ml). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated to give N-[(benzyloxy)carbonyl]-O-isopropyl-L-serine as a clear colourless oil, (0.346 g, 84%); 1H NMR Spectrum: (CDCl3) 1.14 (m, 6H), 3.64 (m, 2H), 3.95 (m, 1H), 4.49 (m, 1H), 5.14 (s, 2H), 5.62 (d, 1H), 7.36 (m, 5H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[S:6].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>C1COCC1>[C:24]([O:23][C:21]([CH2:20][CH:4]([CH2:3][CH2:2][CH3:1])[C:5]([O:7][CH3:8])=[S:6])=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCCCC(=S)OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC(CC(=O)OC(C)(C)C)C(=S)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.1 %

Procedure:
To a −78° C. solution of methyl 4-methylthiobutyrate (1.48 g, 10.0 mmol) in THF (20 mL) was added sodium bis(trimethylsilyl)amide (1.0 M in THF, 11 mL). After 30 min, tert-butyl bromoacetate (2.34 g, 12.0 mmol) was added to the reaction, and the reaction mixture was gradually warmed to the room temperature over 6 hours. The reaction mixture was then partitioned between ethyl acetate (80 mL) and water (20 mL). The organic layer was washed with water (2×20 mL), brine (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography with 5% ethyl acetate in hexane to give the title compound (1.21 g, 46%).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6](OCC)=[O:7])=[CH:4][C:3]=1[I:13].[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[NH2:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[I:13]
Reactant: CCOC(=O)c1ccc(N)c(I)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: Nc1ccc(CO)cc1I
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 4-amino-3-iodobenzoate (8.0 g) in CH2Cl2 (56 mL) cooled to 0° C. is added diisobutylaluminum hydride in CH2Cl2 (110 mL of a 1M solution). The reaction is stirred at 0° C. for 2 h then quenched by the addition of MeOH (50 mL). To this is added 1N HCl (100 mL). The mixture is concentrated to remove the organics. The aqueous solution is extracted with CH2Cl2 (3×). The combined organic layers are dried over Na2SO4, filtered and condensed. The resulting residue is adsorbed onto silica and chromatographed (Biotage flash 40M, eluent CH2Cl2 (2L), 1% MeOH/CH2Cl2 (2L), 2% MeOH/CH2Cl2). Fractions homogeneous by TLC are combined and condensed to afford (4-amino-3-iodophenyl)methanol.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:21]=[CH:22][C:23]3[O:27][CH2:26][CH2:25][C:24]=3[CH:28]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[C:30]([Cu])#[N:31]>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:30]#[N:31])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:21]=[CH:22][C:23]3[O:27][CH2:26][CH2:25][C:24]=3[CH:28]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2ccc(Oc3ccc4c(c3)CCO4)cc2c1O
Reactant: N#C[Cu]
Product: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3ccc4c(c3)CCO4)cc2c1O

Procedure:
Prepared in analogy to example 31g from 1-bromo-6-(2,3-dihydro-benzofuran-5-yloxy)-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester and CuCN. ESI MS (m/z): 405 (M+H)+.
Reaction SMILES: O1CCCC1.[Cl-].[Al+3].[Cl-].[Cl-].[C:10]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]2[C:22](=[O:23])[CH2:21][C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[S:18][C:17]=2[CH:28]=1)#[N:11].[N-:29]=[N+:30]=[N-:31].[Na+]>O>[NH:29]1[C:10]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]3[C:22](=[O:23])[CH2:21][C:20]4[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=4[S:18][C:17]=3[CH:28]=2)=[N:11][N:31]=[N:30]1
Reactant: N#CCc1ccc2c(c1)Sc1ccccc1CC2=O
Reactant: [N-]=[N+]=[N-]
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1Cc2ccccc2Sc2cc(Cc3nnn[nH]3)ccc21

Procedure:
Add to 25 cc. of tetrahydrofuran cooled in an ice bath 1.59 gm. (11.9 mmole) of aluminum chloride, 1.33 gm. (5.25 mmole) of 3-cyanomethyl-10,11-dihydro-11-oxodibenzo[b,f]thiepin and 1.55 gm. (23.8 mmole) of sodium azide. Reflux the mixture for 19 hours, cool, dilute with water and acidify. Extract the mixture into ethyl acetate and evaporate. Triturate the residue in ether and separate the title product by filtration.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2([C:15]#[N:16])[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[FH:17].[FH:18].F.C(N(CC)CC)C>C(Cl)Cl>[F:17][C:11]1([F:18])[CH2:12][CH2:13][C:8]([C:5]2[CH:6]=[N:7][C:2]([F:1])=[CH:3][CH:4]=2)([C:15]#[N:16])[CH2:9][CH2:10]1
Reactant: N#CC1(c2ccc(F)nc2)CCC(=O)CC1
Reactant: F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CC1(c2ccc(F)nc2)CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
To a stirred suspension of diethylamino difluorosulfiinium tetrafluoroborate salt (23.8 g, 0.104 mol) in dry DCM (100 mL) at room temperature was added 1-(6-fluoro-pyridin-3-yl)-4-oxo-cyclohexanecarbonitrile (12 g, 0.052 mol) followed by triethylamine trihydrofluoride (25.12 g, 0.156 mol) under a nitrogen atmosphere. The reaction mixture was stirred overnight at room temperature. The resulting mixture was then quenched with saturated aq. NaHCO3 solution (300 mL), stirred for 10 minutes, and the resulting mixture was extracted with DCM (3×100 mL). The combined organic layer was washed with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (eluting with a gradient elution of between 2-10% EtOAc in petroleum ether) to afford the title compound (8 g, yield: 64%). 1H NMR (CDCl3 400 MHz): 6 ppm 8.40-8.35 (m, 1H), 7.95-7.84 (m, 1H), 7.05-6.96 (m, 1H), 2.40-2.10 (m, 8H).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([NH:13][C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=1)=[O:6].[C:18](Br)#[C:19][CH3:20]>>[CH3:17][N:2]([CH3:1])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([N:13]([CH2:20][C:19]#[CH:18])[C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=1)=[O:6]
Reactant: CC(=O)Nc1cccc(C(=O)C=CN(C)C)c1
Reactant: CC#CBr
Product: C#CCN(C(C)=O)c1cccc(C(=O)C=CN(C)C)c1

Procedure:
An 11.61 g portion of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]acetamide was reacted with propynyl bromide as described in Example 6, giving N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-2-propynylacetamide, mp 98°-101° C.
Reaction SMILES: [H-].[Na+].C(OP([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:24]=O.O>O1CCCC1>[CH3:17][C:11](=[CH:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=Cc1ccccn1
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C)=Cc1ccccn1
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
Sodium hydride (ca. 60%, 2.0 g, 50.0 mmol) was suspended in tetrahydrofuran (20 ml), and a solution of ethyl 2-(diethylphosphono)propionate (11.7 g, 49.1 mmol) in tetrahydrofuran (8 ml) was added thereto under ice cooling condition. The mixture was stirred for 0.5 hr. Successively, a solution of 2-pyridinecarbaldehyde (5.0 g, 46.7 mmol) in tetrahydrofuran (8 ml) was added to the mixture. The mixture was stirred at 0° C. for 14 hrs, combined with water, concentrated under reduced pressure to the half amount and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel (80 g) column chromatography. The fractions eluted with hexane-ethyl acetate (3:1, v/v) were collected and concentrated to give the titled compound (7.8 g, 87%).
Reaction SMILES: [K+].[C:2]([O:6][C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:24][CH:25]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:26]([O-])=[O:27])=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].Cl.[NH2:40][CH2:41][C:42]#[N:43]>>[C:42]([CH2:41][NH:40][C:26]([CH:25]([O:24][CH:23]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:20]1[CH:19]=[CH:18][C:17]([C:15]([N:12]2[CH2:11][CH2:10][N:9]([C:7]([O:6][C:2]([CH3:3])([CH3:4])[CH3:5])=[O:8])[CH2:14][CH2:13]2)=[O:16])=[CH:22][CH:21]=1)[CH2:29][CH:30]([CH3:32])[CH3:31])=[O:27])#[N:43]
Reactant: CC(C)CC(OC(c1ccccc1)c1ccc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1)C(=O)[O-]
Reactant: N#CCN
Agent: Cl
Agent: [K+]
Product: CC(C)CC(OC(c1ccccc1)c1ccc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1)C(=O)NCC#N

Procedure:
Using the same procedure as described in step 3, 2-[(4-{[4-(tert-butoxycarbonyl)piperazin-1-yl]carbonyl}phenyl)(phenyl)methoxy]-4-methylpentanoic acid potassium salt from step 4 (0.55 g, 1.1 mmol) was coupled with amino acetonitrile HCl salt. The crude product was chromatographed on silica gel using 5% methanol in dichloromethane to afford the title compound as a white solid.
Reaction SMILES: Cl[CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([OH:14])=[O:13])[CH2:4]1.CC(Cl)(C)C.[Cl-].CN1CCCC1=[O:27]>C([O-])(=O)C.C([N+](CCCC)(CCCC)CCCC)CCC>[OH:27][CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([OH:14])=[O:13])[CH2:4]1
Reactant: CC1(C)O[C@H](CCl)C[C@H](CC(=O)O)O1
Reactant: CN1CCCC1=O
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: CC(C)(C)Cl
Product: CC1(C)O[C@H](CO)C[C@H](CC(=O)O)O1
Temperature: 85 °C
Reaction time: 0.75 h

Procedure:
Solid tetrabutylammonium acetate obtained as above (111 g, 0.368 mole) was added in one portion to a mechanically stirred solution of the chloride (4R-cis)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxane-4-acetic acid, 1,1-dimethylethyl ester prepared in step (d) above (35 g, 0.125 mole) in HPLC grade 1-methyl-2-pyrrolidinone (504 ml) under argon. The resulting solution was stirred at 85° C. (internal temperature). After 30 to 60 minutes the reaction mixture became homogeneous and brown in color. The progress of the reaction was followed by TLC and GC analysis. (TLC: Rf=0.63 for the chloride starting material; Rf =0.54 for the title compound (silica gel, Ethyl acetate:Hexane, 1:1, visualization by Ce(SO4)2 spray). GC: Rt =7.20 minutes (starting material) and 8.66 minutes (title compound).) After 11 hours the reaction was completed.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[CH:18]=[C:17]([C:19]([OH:21])=O)[S:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[NH:28]1[CH2:33][CH2:32][CH:31]([OH:34])[CH2:30][CH2:29]1>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[C:13]4[CH:18]=[C:17]([C:19]([N:28]5[CH2:33][CH2:32][CH:31]([OH:34])[CH2:30][CH2:29]5)=[O:21])[S:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: OC1CCNCC1
Reactant: O=C(O)c1cc2c(N3CCOCC3)nc(-c3cccc4[nH]ncc34)nc2s1
Product: O=C(c1cc2c(N3CCOCC3)nc(-c3cccc4[nH]ncc34)nc2s1)N1CCC(O)CC1

Procedure:
45 mg of 2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidine-6-carboxylic acid 14 was coupled to piperidin-4-ol via General Procedure B. The product was purified via reverse phase HPLC to give 46.6 mg of 123 MS (Q1) 465.1 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]([CH:17]([CH3:21])[C:18](O)=[O:19])[C:9]2[CH:16]=[CH:15][C:12]([O:13][CH3:14])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])=[CH:28][CH:27]=1>>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]([CH:17]([CH3:21])[C:18]([N:32]([CH2:33][CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])[C:29]2[CH:28]=[CH:27][C:26]([O:25][CH3:24])=[CH:31][CH:30]=2)=[O:19])[C:9]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[CH:15][CH:16]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)CCCNc1ccc(OC)cc1
Reactant: COc1ccc(N(C(=O)c2ccc(Cl)cc2)C(C)C(=O)O)cc1
Product: COC(=O)CCCN(C(=O)C(C)N(C(=O)c1ccc(Cl)cc1)c1ccc(OC)cc1)c1ccc(OC)cc1

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-2-(p-anisidino)propionic acid and methyl 4-(p-anisidino)butyrate and suitable processing produces methyl N-[N-(p-chlorobenzoyl)-2-(p-anisidino)propionyl]-4-(p-anisidino)butyrate (oil), saponification of which and processing of the reaction product yields N-[N-(p-chlorobenzoyl)-2-(p-anisidino)propionyl]-4-(p-anisidino)butyric acid (M.P. 135° to 137°).
Reaction SMILES: CC1C=CN=C(NC2C=CC=C(C3OC(C4C=CC=CC=4)=NC=3)N=2)C=1.I[C:27]1[O:28][C:29]([C:32]2[CH:33]=[C:34]([NH:38][C:39]3[CH:44]=[C:43]([CH3:45])[CH:42]=[CH:41][N:40]=3)[CH:35]=[CH:36][CH:37]=2)=[CH:30][N:31]=1.[F:46][C:47]([F:60])([F:59])[C:48]1[CH:49]=[C:50](/[CH:54]=[CH:55]/B(O)O)[CH:51]=[CH:52][CH:53]=1.C([O-])([O-])=O.[K+].[K+]>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.O.C1COCC1>[CH3:45][C:43]1[CH:42]=[CH:41][N:40]=[C:39]([NH:38][C:34]2[CH:35]=[CH:36][CH:37]=[C:32]([C:29]3[O:28][C:27]([CH:55]=[CH:54][C:50]4[CH:51]=[CH:52][CH:53]=[C:48]([C:47]([F:46])([F:59])[F:60])[CH:49]=4)=[N:31][CH:30]=3)[CH:33]=2)[CH:44]=1
Reactant: Cc1ccnc(Nc2cccc(-c3cnc(I)o3)c2)c1
Reactant: OB(O)/C=C/c1cccc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccnc(Nc2cccc(-c3cnc(-c4ccccc4)o3)n2)c1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccnc(Nc2cccc(-c3cnc(C=Cc4cccc(C(F)(F)F)c4)o3)c2)c1
Yield: 72 %

Procedure:
Prepared as for (4-methyl-pyridin-2-yl)-[6-(2-phenyl-oxazol-5-yl)-pyridin-2-yl]-amine above using [3-(2-Iodo-oxazol-5-yl)-phenyl]-(4-methyl-pyridin-2-yl)-amine, trans-2-(3-trifluoromethylphenyl)vinylboronic acid, K2CO3 and Pd(PPh3)4 in a 2:1 mixture by volume of THF and water to give (4-methyl-pyridin-2-yl)-(3-{2-[2-(3-trifluoromethyl-phenyl)-vinyl]-oxazol-5-yl}-phenyl)-amine as a pale yellow solid (72%). 1H NMR (400 MHz, DMSO-d6) δ 9.26-8.94 (m, 1H), 8.15 (s, J=8.6 Hz, 1H), 8.11-8.06 (m, 3H), 7.76-7.63 (m, 5H), 7.43 (d, J=16.5 Hz, 1H), 7.40-7.29 (m, 2H), 6.68 (s, 1H), 6.64 (d, J=5.2 Hz, 1H), 2.25 (s, 3H). (ESI+) m/z 422 (M+H)+. Retention time=3.84 mins (method 1).
Reaction SMILES: [O:1]=[C:2]1[O:6][CH:5]([C:7]2[S:8][C:9]3[CH:15]=[C:14]([N:16]4[CH2:20][CH:19]([CH2:21][O:22][CH3:23])[O:18][C:17]4=[O:24])[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH2:4][CH2:3]1.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1>[OH:6][CH:5]([C:7]1[S:8][C:9]2[CH:15]=[C:14]([N:16]3[CH2:20][CH:19]([CH2:21][O:22][CH3:23])[O:18][C:17]3=[O:24])[CH:13]=[CH:12][C:10]=2[N:11]=1)[CH2:4][CH2:3][CH2:2][OH:1]
Reactant: COCC1CN(c2ccc3nc(C4CCC(=O)O4)sc3c2)C(=O)O1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: COCC1CN(c2ccc3nc(C(O)CCCO)sc3c2)C(=O)O1
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 79.5 %

Procedure:
3.48 g of the 3-[2-(5-oxotetrahydrofuran-2-yl)-benzothiazol-6-yl]-5-methoxymethyl-2-oxazolidinone obtained in the Example 5 was dissolved in 20 ml of anhydrous tetrahydrofuran and the solution was cooled to -50° C. 30 ml of a 1.0M solution of diisobutylaluminum hydride in tetrahydrofuran was added dropwise thereto. After stirring for 30 min followed by ordinary treatment and recrystallization, 2.8 g of 3-[2-(1,4-dihydroxybutyl)benzothiazol-6-yl]-5-methoxymethyl-2-oxazolidinone was obtained.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[S:10][C:11]([C:14](=O)[CH3:15])=[CH:12][CH:13]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[NH2:17][C:18]([NH2:20])=[S:19]>CCO.CCOC(C)=O>[CH2:1]([O:3][P:4]([C:9]1[S:10][C:11]([C:14]2[S:19][C:18]([NH2:20])=[N:17][CH:15]=2)=[CH:12][CH:13]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(OCC)c1ccc(C(C)=O)s1
Reactant: NC(N)=S
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOP(=O)(OCC)c1ccc(-c2cnc(N)s2)s1
Temperature: 25 °C
Yield: 15.9 %

Procedure:
To a solution of (5-acetyl-thiophen-2-yl)-phosphonic acid diethyl ester (1.13 g, 4.31 mmol) in EtOH (80 ml) was added CuBr2 (959 mg, 8.62 mmol). The reaction mixture was then refluxed for 3 hr, diluted with EtOAc, quenched by adding sat. NaHCO3. After layers were separated, the org. layer was collected and the aqueous layer was further extracted with EtOAc once. Combined organic layers were dried over MgSO4, filtrated, and concentrated. The residue was then dissolved in EtOH/EtOAc (4 ml/16 ml) and treated with thiourea (394 mg, 5.17 mmol). The reaction mixture was then heated to reflux for 1 hr, cooled to r.t., and concentrated down. The residue was partitioned between EtOAc and water. The organic layer was collected, dried over MgSO4, filtrated, concentrated, and purified by Biotage to give the final compound (218 mg, 15.9%). 1H NMR (300 MHz, DMSO-d6): δ 7.50 (m, 2H), 7.23 (s, 2H), 7.10 (s, 1H), 4.02 (m, 4H), 1.21 (m, 6H). LC-MS m/z=263.4 [C7H7N2O3PS2+H]+.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]([C:10]3[N:11]=[N:12][N:13]([C:15]4[CH:16]=[C:17]([CH:39]=[CH:40][C:41]=4[CH3:42])[C:18]([NH:20][C:21]4[CH:26]=[C:25]([C:27]([CH3:31])([CH3:30])[CH2:28][OH:29])[CH:24]=[C:23]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[C:22]=4[O:37][CH3:38])=[O:19])[CH:14]=3)=[CH:6][N:5]=2)[CH2:3][CH2:2]1.[C:43](C1N(C)C(C2(C)CC2)=NC=1)#C>>[OH:29][CH2:28][C:27]([C:25]1[CH:24]=[C:23]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[C:22]([O:37][CH3:38])=[C:21]([NH:20][C:18](=[O:19])[C:17]2[CH:39]=[CH:40][C:41]([CH3:42])=[C:15]([N:13]3[CH:14]=[C:10]([C:7]4[N:8]([CH3:9])[C:4]([C:1]5([CH3:43])[CH2:3][CH2:2]5)=[N:5][CH:6]=4)[N:11]=[N:12]3)[CH:16]=2)[CH:26]=1)([CH3:31])[CH3:30]
Reactant: C#Cc1cnc(C2(C)CC2)n1C
Reactant: COc1c(NC(=O)c2ccc(C)c(-n3cc(-c4cnc(C5CC5)n4C)nn3)c2)cc(C(C)(C)CO)cc1NS(C)(=O)=O
Product: COc1c(NC(=O)c2ccc(C)c(-n3cc(-c4cnc(C5(C)CC5)n4C)nn3)c2)cc(C(C)(C)CO)cc1NS(C)(=O)=O

Procedure:
Example 134 was prepared in the same manner as 3-[4-(2-cyclopropyl-3-methyl-3H-imidazol-4-yl)-1,2,3-triazol-1-yl]-N-[5-(2-hydroxy-1,1-dimethyl-ethyl)-3-methane-sulfonylamino-2-methoxy-phenyl]-4-methyl-benzamide (Example 133) with 1.5 equivalents of 5-ethynyl-1-methyl-2-(1-methyl-cyclopropyl)-1H-imidazole. ESI MS m/z 608 [C30H37N7O5S+H]+.
Reaction SMILES: C([O:4][CH:5]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[CH:11]=1)[C:6]([F:9])([F:8])[F:7])(=O)C.Br[CH2:18][C:19](=O)[CH3:20].C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>C(O)CCC.O>[F:9][C:6]([F:7])([F:8])[CH:5]([C:10]1[CH:15]=[CH:14][N:13]2[CH:18]=[C:19]([CH3:20])[N:16]=[C:12]2[CH:11]=1)[OH:4]
Reactant: CC(=O)CBr
Reactant: CC(=O)OC(c1ccnc(N)c1)C(F)(F)F
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CCCCO
Product: Cc1cn2ccc(C(O)C(F)(F)F)cc2n1
Temperature: 130 °C
Reaction time: 24 h
Yield: 40 %

Procedure:
In n-butanol (2 mL) was dissolved 1-(2-aminopyridin-4-yl)-2,2,2-trifluoroethyl acetate (53.2 mg, 0.227 mmol) obtained in Step 2. Bromoacetone (0.042 mL, 0.45 mmol) was added and the mixture was stirred at 130° C. for 24 hours. A saturated aqueous sodium bicarbonate solution and water were added to the reaction mixture. Extraction with ethyl acetate and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure and the residue was dissolved in methanol (2.0 mL). Potassium carbonate (31.4 mg, 0.227 mmol) was added and the mixture was stirred at room temperature for 18 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture. Extraction with ethyl acetate and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=5/1) to give Compound A30 (20.7 mg, 40% yield).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.Cl.Cl.[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[C:22]([CH3:32])[CH:21]=1.[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][N:29]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]5[CH2:13][CH2:14][CH2:15][C@H:8]5[C:7](=[O:16])[NH:6][C:5]=4[CH:4]=3)[CH2:28][CH2:27]2)=[C:22]([CH3:32])[CH:21]=1
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Reactant: Cc1cc(F)ccc1N1CCNCC1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: Cc1cc(F)ccc1N1CCN(Cc2cnc3c(c2)NC(=O)[C@@H]2CCCN32)CC1
Temperature: 105 °C
Yield: 56.8 %

Procedure:
(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (100 mg, 0.456 mmol), 1-(4-fluoro-2-methylphenyl)piperazine dihydrochloride (122 mg, 0.456 mmol), (cyanomethyl)trimethylphosphonium iodide (166 mg, 0.684 mmol) and N,N-diisopropylethylamine (0.398 ml, 2.281 mmol) were suspended in propiononitrile (Volume: 1.370 ml) and heated in a closed vial at 90-120° C. for 4 h. The reaction mixture became a dark brown solution. It was cooled to room temperature, concentrated in vacuo, dissolved in DMSO (2 mL) and purified using HPLC (basic, 45-95% ACN in water, basic). The fractions were concentrated in vacuo and the resulting solid was recrystallized from water-MeOH (2:1, 6 mL) and dried in vacuum to afford (S)-3-((4-(4-fluoro-2-methylphenyl)piperazin-1-yl)methyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (102.3 mg, 0.259 mmol, 56.7% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.80-2.02 (m, 3 H) 2.09-2.20 (m, 1 H) 2.23 (s, 3 H) 2.37-2.49 (m, 4 H) 2.77 (br. s., 4 H) 3.34-3.44 (m, 3 H) 3.52-3.65 (m, 1 H) 3.93-4.03 (m, 1 H) 6.88-7.07 (m, 4 H) 7.62 (s, 1 H) 10.44 (s, 1 H). [M+H] calc'd for C22H26FN5O, 396; found, 396.