Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:21]=[C:20]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[C:19](B4OC(C)(C)C(C)(C)O4)=[CH:18][C:12]=3[C:13]=2[C:14]([NH:16][CH3:17])=[O:15])=[CH:5][CH:4]=1)#[N:2].Cl[C:38]1[CH:39]=[CH:40][C:41]2[O:54][CH2:53][N:44]3[C:45]4[CH:46]=[CH:47][CH:48]=[C:49]([F:52])[C:50]=4[CH:51]=[C:43]3[C:42]=2[N:55]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:21]=[C:20]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[C:19]([C:38]4[CH:39]=[CH:40][C:41]5[O:54][CH2:53][N:44]6[C:45]7[CH:46]=[CH:47][CH:48]=[C:49]([F:52])[C:50]=7[CH:51]=[C:43]6[C:42]=5[N:55]=4)=[CH:18][C:12]=3[C:13]=2[C:14]([NH:16][CH3:17])=[O:15])=[CH:5][CH:4]=1)#[N:2]
Reactant: CNC(=O)c1c(-c2ccc(C#N)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: Fc1cccc2c1cc1n2COc2ccc(Cl)nc2-1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(C#N)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Yield: 21.9 %

Procedure:
To a solution of 2-(4-cyanophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (115 mg, 0.22 mmol), 2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (75 mg, 0.27 mmol) K2CO3 (60 mg, 0.44 mmol), Pd2(dba)3 (30 mg) and X-Phos (30 mg) in dioxane/H2O (3 mL/0.6 mL) was stirred at 100° C. for 3 h. The reaction was filtered to remove the solid and then the mixture was diluted with water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by prep-HPLC to get the product of 2-(4-cyanophenyl)-5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (30 mg, yield: 21%). 1H-NMR (CDCl3, 400 MHz) δ 8.16 (d, J=8.4 Hz, 2H), 7.96 (s, 1H), 7.78 (d, J=8.4 Hz, 2H), 7.70 (s, 1H), 7.23˜7.19 (m, 3H), 7.13 (d, J=8.4 Hz, 2H), 6.87 (m, 1H), 6.14 (d, J=4.4 Hz, 1H), 6.00 (s, 2H), 3.35 (s, 3H), 3.05 (d, J=5.2 Hz, 3H), 2.77 (s, 3H). MS (M+H)+: 622.
Reaction SMILES: [I:1]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[CH2:27]([C@@H:34]1[CH2:38][O:37][C:36](=[O:39])[N:35]1[C:40](=[O:47])[C@@H:41]([CH2:45]O)[CH:42]([CH3:44])[CH3:43])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1(C)C=CC=CC=1>[CH2:27]([C@@H:34]1[CH2:38][O:37][C:36](=[O:39])[N:35]1[C:40](=[O:47])[CH:41]([CH2:45][I:1])[CH:42]([CH3:44])[CH3:43])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: II
Reactant: CC(C)[C@H](CO)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)C(CI)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: 80 °C
Yield: 91 %

Procedure:
Iodine (42 g), triphenylphosphine (47 g) and imidazole (12 g) were added to a solution of 4-(R)-benzyl-3-(2-(R)-hydroxymethyl-3-methylbutanoyl)oxazolidin-2-one (45 g) in toluene (400 ml) and the mixture was heated to 80° C. for 1 h, then cooled and washed with water and saturated brine. The solvent was dried (Na2SO4) and evaporated and the residue filtered through silica (200 g) eluting with diethyl ether-hexane 1:1 to give the title compound as a yellow viscous oil (56.4 g).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[B:23](OC(C)C)([O:28]C(C)C)[O:24]C(C)C.Cl>C1COCC1>[C:1]([NH:5][S:6]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH3:17])=[CH:13][C:14]=1[B:23]([OH:28])[OH:24])(=[O:7])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCc1ccc(S(=O)(=O)NC(C)(C)C)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCc1ccc(S(=O)(=O)NC(C)(C)C)c(B(O)O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2.85 g (11.2 mmol) of N-t-butyl-4-n-propylbenzenesulfonamide (from Step A) in anhydrous THF (20 mL) cooled to -40° C. under N2 was added 2.5M n-BuLi solution (11.2 mL, 2.5 equiv). The mixture was warmed to room temperature and stirred for 2 hours. To the mixture, containing the bright red dianion at 0° C., was added triisopropyl borate (3.9 mL, 1.5 equiv). The next day, 2N HCl (3 mL) was added and the mixture was stirred for 1 hour. The solvent was removed under reduced pressure and the residue was extracted with ethyl acetate. The organic solution was washed with 2N HCl, H2O and brine. The organic phase was dried over anhydrous MgSO4 and concentrated in vacuo to afford the titled compound; Rf =0.5 (1:1 EtOAc-hexane). The material was used in the next step without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[OH:15][C:16]1[CH:17]=[C:18]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[N:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:8][C:7]1[O:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:4][C:3]=1[CH2:2][O:15][C:16]1[CH:17]=[C:18]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[N:20][CH:21]=1
Reactant: COC(=O)c1cncc(O)c1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cncc(OCc2nc(-c3ccccc3)oc2C)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 59.6 %

Procedure:
A mixture of 4-chloromethyl-5-methyl-2-phenyloxazole (13.4 g), methyl 5-hydroxypyridine-3-carboxylate (9.84 g), anhydrous potassium carbonate (8.90 g) and N,N-dimethylformamide (100 mL) was stirred overnight at 80° C. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (12.42 g, 59%) of methyl 5-(5-methyl-2-phenyl-4-oxazolyl)methoxy-3-pyridinecarboxylate from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 119-120° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([N:7]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)[N:3]=1.[ClH:20].O1CCOCC1>C(OCC)C>[ClH:20].[CH3:1][C:2]1[O:6][N:5]=[C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[N:3]=1
Reactant: Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)no1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1nc(N2CCNCC2)no1
Temperature: 25 °C

Procedure:
To a solution of tert-butyl 4-(5-methyl-1,2,4-oxadiazol-3-yl)piperazine-1-carboxylate (507 mg, 1.890 mmol) in diethyl ether (12 mL) was added HCl, 4N in dioxane (7 mL, 28.0 mmol) and the reaction was stirred at room temperature over the weekend. The precipitate was isolated by filtration, washed with diethylether and dried under reduced pressure after which 330 mg of a white solid were obtained (1.612 mmol, 85%). MS (ESI) m/z=169.2 [M+1]+.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[S:9][CH:10]=[C:11]([CH:13]=O)[N:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[S:15]1[CH2:21][C:19](=[O:20])[N:18]([CH2:22][C:23]([OH:25])=[O:24])[C:16]1=[S:17].[Cl-].[NH4+].N>C(O)C>[CH:1]1([NH:7][C:8]2[S:9][CH:10]=[C:11]([CH:13]=[C:21]3[S:15][C:16](=[S:17])[N:18]([CH2:22][C:23]([OH:25])=[O:24])[C:19]3=[O:20])[N:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)CN1C(=O)CSC1=S
Reactant: O=Cc1csc(NC2CCCCC2)n1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: O=C(O)CN1C(=O)C(=Cc2csc(NC3CCCCC3)n2)SC1=S

Procedure:
The reaction described in Example 1 was repeated, but using 3.0 g of 2-cyclohexylaminothiazole-4-carbaldehyde, 2.27 g of rhodanine-3-acetic acid, 1.7 g of ammonium chloride, 1.7 ml of 28% v/v aqueous ammonia and 60 ml of ethanol giving the title compound as yellowish-brown needles.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:11])[NH:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[H-].[Na+].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[CH3:23]>CN(C)C=O>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[CH2:15][N:4]1[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=[C:2]([CH3:1])[C:3]1=[O:11]
Reactant: Cc1ccc(CBr)c(C)c1
Reactant: Cc1cc([N+](=O)[O-])c[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(Cn2cc([N+](=O)[O-])cc(C)c2=O)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.9 %

Procedure:
To a solution containing 0.20 g (1.3 mmol) of 3-methyl-5-nitropyridine-2(1H)-one in 5 ml of N,N-dimethylformamide under a nitrogen atmosphere was added 0.037 g (1.6 mmol) of sodium hydride followed by 0.31 g (1.6 mmol) of 1-bromomethyl-2,4-dimethylbenzene. The reaction was allowed to stir at room temperature for 30 min., quenched with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate. Filtration, removal of solvent and purification of the residue via biotage eluting with 25% ethyl acetate/hexanes gave 0.12 g (34%) of compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([NH:19][NH:20][C:21](=[O:23])[CH3:22])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl>C(#N)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17]2[O:23][C:21]([CH3:22])=[N:20][N:19]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)NNC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nnc(C2CCN(C(=O)OCc3ccccc3)CC2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
A suspension of 2.00 g (6.26 mmol) of 4-(N′-acetyl-hydrazinocarbonyl)-piperidine-1-carboxylic acid benzyl ester in 30 ml acetonitril was treated at RT with 0.69 ml (7.51 mmol) of phosphoroxychloride. The suspension was stirred 1 h at RT and the refluxed for 2 h, evaporated, dissolved in CH2Cl2 and neutralized with aqueous saturated NaHCO3 solution. The aqueous phase was extracted with CH2Cl2 (2×). The organic phase was dried (Na2SO4) and and evaporated to give after flash silica gel column (EtOAc) 1.69 g (89%) of the title compound as light yellow oil. MS: 302.1 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[N:3]=1.C(N(C(C)C)C(C)C)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[CH3:1][C:2]1[C:7]([CH2:8][O:9][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:19])[F:18])=[CH:12][CH:11]=2)[N:3]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.60 g (9.7 mmol) of [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-methanol (example 1M]) were dissolved in 50 ml MeCl2 and cooled down to 0° C. 2.55 ml=1.93 g (14.6 mmol) of N-ethyl diisopropylamine was added, followed by 0.85 ml=1.25 g (10.7 mmol) of methane sulfonylchloride, drop by drop. After stirring for 30 min. at ambient temperature, the reaction mixture was poured into crashed ice and extracted twice with MeCl2. The combined organic phases were washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. This gave 3.44 g of crude title compound as yellow solid.
Reaction SMILES: [C:1]1([C@@H:7]2[NH:11][C@H:10]([CH2:12][O:13][C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32](=[O:45])[NH:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41](O)=[O:42])=[CH:36][C:35]=1[CH3:44].CCN=C=NCCCN(C)C.Cl.O>CN(C=O)C>[Br:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32](=[O:45])[NH:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41]([N:11]2[C@@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][CH2:9][C@H:10]2[CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=2)=[O:42])=[CH:36][C:35]=1[CH3:44]
Reactant: Cc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1Br
Reactant: COC(=O)c1ccc(OC[C@@H]2CC[C@H](c3ccccc3)N2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC[C@@H]2CC[C@H](c3ccccc3)N2C(=O)Cc2ccc(NC(=O)Nc3ccccc3Br)c(C)c2)cc1
Reaction time: 6 h
Yield: 90.6 %

Procedure:
To a stirred solution of methyl 4-[5-(R)-phenyl-2-(S)-pirrolidinylmethoxy]benzoate (125 mg, 0.40 mmol), 4-[N′-(2-bromophenyl)ureido]-3-methylphenylacetic acid (146 mg, 0.40 mmol) and N,N-dimethylaminopyridine (49.0 mg, 0.40 mmol) in DMF (10 ml) was added EDC.HCl (84.1 mg, 0.44 mmol) at rt, and the resulting mixture was stirred for 6 h. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, drying over anhydrous Na2SO4, then concentrated in vacuo. The residue was chromatographed on silica gel with hexane-EtOAc (1:4) as eluent to give methyl 4-[1-[4-[N′-(2-bromophenyl)ureido]-3-methylphenylacetyl]-5-(R)-phenyl-2-(S)-pyrrolidinylmethoxy]benzoate (238 mg, 90%) as a colorless amorphous solid. 1H-NMR (CDCl3) δ1.92 (s, 3 H), 2.09-2.27 (m, 3 H), 2.42-2.50 (m, 1 H), 3.22-3.41 (m, 2 H), 3.88 (s, 3 H), 4.39 (d, J=4.4 Hz, 1 H), 4.64 (brs, 1 H), 5.00 (t, J=6.8 Hz, 1 H), 6.72 (s, 1 H), 6.81-6.93 (series of m, 8 H), 7.22-7.42 (series of m, 6 H), 8.01 (d, J=8.4 Hz, 2 H), 8.13 (d, J=8.0 Hz, 1 H ); MS (FAB) m/z, 656 (M+), 658 (M++2).
Reaction SMILES: C[O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1C=NO.[CH2:15]([N:17](CC)CC)C.CS(Cl)(=O)=O>O1CCCC1>[C:3]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:15]#[N:17])=[CH:8][CH:9]=1)([OH:2])=[O:14]
Reactant: CCN(CC)CC
Reactant: COC(=O)c1ccc(N)cc1C=NO
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: N#CNc1ccc(C(=O)O)cc1
Reaction time: 1 h
Yield: 91.8 %

Procedure:
In 180 ml of tetrahydrofuran was dissolved 17.12 g of 4-amino(N-hydroxyimino)methylbenzoic acid methyl ester. To the solution was added 12.12 g of triethylamine. To the mixture was added dropwise, on an ice-bath, 12.65 g of methanesulfonyl chloride. The mixture was stirred for one hour under the same conditions, followed by concentration under reduced pressure. To the concentrate was added methanol. The resulting crystalline precipitate was collected by filtration, which was dissolved in 100 ml of methanol. To the solution was added, while stirring at room temperature, 100 g of water containing 12 g of sodium hydroxide. Methanol was distilled off under reduced pressure. To the residue was added 700 ml of water. To the mixture was added, while stirring at room temperature, 80 ml of 4N HCl. The resulting crystalline precipitate was collected by filtration to give 13.12 g of the title compound as a colorless crystalline product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([Br:13])=[CH:11][N:10]([CH3:14])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[F:22][C:23]([F:36])([F:35])[O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32](O)=[O:33])=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[Br:13][C:12]1[C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:32](=[O:33])[CH2:31][C:28]3[CH:29]=[CH:30][C:25]([O:24][C:23]([F:35])([F:22])[F:36])=[CH:26][CH:27]=3)[CH:7]=[CH:6][CH:5]=2)=[N:9][N:10]([CH3:14])[CH:11]=1
Reactant: Cn1cc(Br)c(-c2cccc(N)c2)n1
Reactant: O=C(O)Cc1ccc(OC(F)(F)F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1cc(Br)c(-c2cccc(NC(=O)Cc3ccc(OC(F)(F)F)cc3)c2)n1
Temperature: 70 °C
Yield: 67.6 %

Procedure:
A solution of 3-(3-aminophenyl)-4-bromo-1-methylpyrazole (35 mg, 0.14 mmol) and triethylamine (23 μL, 0.17 mmol) in DMF (0.5 mL) was added in one portion to a stirred solution of 4-trifluoromethoxyphenylacetic acid (31 mg, 0.14 mmol), HBTU (53 mg, 0.14 mmol) and HOBT (19 mg, 0.14 mmol) in DMF (1 mL). The mixture was heated at 70° C. for 24 h and then quenched with aqueous sodium bicarbonate solution. Ethyl acetate was added and the organic phase separated, washed with water (.times.3), brine, dried (MgSO4) and evaporated. Chromatography on flash silica (50% EtOAc/hexane) gave the title compound as a colourless solid (43 mg, 68%). m.p. 141.2-142.5° C. (EtOAc/hexane).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[S:9][C:10]([CH:13]([OH:16])[CH2:14][NH2:15])=[CH:11][N:12]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:19]1[C:20]2[S:27][CH:26]=[CH:25][C:21]=2[N:22]=[CH:23][N:24]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[S:9][C:10]([CH:13]([OH:16])[CH2:14][NH:15][C:19]2[C:20]3[S:27][CH:26]=[CH:25][C:21]=3[N:22]=[CH:23][N:24]=2)=[CH:11][N:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ncnc2ccsc12
Reactant: CC(C)(C)OC(=O)Nc1ncc(C(O)CN)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)Nc1ncc(C(O)CNc2ncnc3ccsc23)s1

Procedure:
Compound 62.4 (0.16 mmol), 4-chloro-thieno[3,2-d]pyrimidine (0.16 mmol.) and DIEA (0.28 mmol) is heated in DMA at 90° C. for 5 hours. The reaction mixture is cooled, concentrated and purified by preparative TLC (10% MeOH in EtOAc) to afford {5-[1-hydroxy-2-(thieno[3,2-d]pyrimidin-4-ylamino)-ethyl]-thiazol-2-yl}-carbamic acid tert-butyl ester (compound 62.5).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]1[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19].C1CCN2C(=NCCC2)CC1>N1C=CC=CC=1.Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:16]2[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=2[C:18]([OH:20])=[O:19])[CH2:10][C@@H:9]1[CH3:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: O=C(O)c1ccccc1F
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@H]1CN(c2ccccc2C(=O)O)CCN1C(=O)OC(C)(C)C
Temperature: 150 °C
Reaction time: 48 h
Yield: 55.2 %

Procedure:
To a solution of (S)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (4.10 g, 19.8 mmol) in pyridine (41 mL) is added 2-fluoro-benzoic acid (20.2 g. 140 mmol) followed by DBU (43 ml). The mixture is stirred at 150° C. for 48 h. The mixture is diluted with 600 mL of 2N HCl followed by extraction with EtOAc (3×300 mL). Organics are collected and purified by flash chromoatography to provide 3.50 g, 53% yield of (S)-4-(2-carboxy-phenyl)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:7][O:6][C:5]2([CH:15]([Br:16])[CH2:14][CH2:13][C:12]3[N:11]([S:17]([C:20]4[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=4)(=[O:19])=[O:18])[CH:10]=[CH:9][C:8]2=3)[O:4]1>C(N)(C)C>[CH:12]([NH:11][CH2:2][CH:3]1[CH2:7][O:6][C:5]2([CH:15]([Br:16])[CH2:14][CH2:13][C:12]3[N:11]([S:17]([C:20]4[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=4)(=[O:19])=[O:18])[CH:10]=[CH:9][C:8]2=3)[O:4]1)([CH3:13])[CH3:8]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2CCC(Br)C32OCC(CCl)O2)cc1
Solvent: CC(C)N
Product: Cc1ccc(S(=O)(=O)n2ccc3c2CCC(Br)C32OCC(CNC(C)C)O2)cc1
Yield: 60 %

Procedure:
A solution of 4'-chloromethyl-5-bromo-1-p-toluenesulfonyl-4,5,6,7-tetrahydroindole-4-spiro-[1,3]dioxolane (100 parts) in isopropylamine (890 parts) is placed in a sealed tube and heated on boiling water bath for 7 hours. The reaction mixture is evaporated to remove isopropylamine. The residue is dissolved in dichloromethane, washed with water, dried and concentrated to afford 4'-isopropylaminomethyl-5-bromo-1-p-toluenesulfonyl-4,5,6,7-tetrahydroindole-4-spiro-[1,3]dioxolane in 60% yield. The physical constants are given in Table I, No. 19. yield. The physical constants are given in Table I, No. 19.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[S:24]1[C:28]2=[C:29]([C:33](O)=[O:34])[N:30]=[CH:31][CH:32]=[C:27]2[CH:26]=[CH:25]1>>[NH2:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:33]([C:29]3[N:30]=[CH:31][CH:32]=[C:27]4[CH:26]=[CH:25][S:24][C:28]=34)=[O:34])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: O=C(O)c1nccc2ccsc12
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(N)ccc2F)CCO1
Product: C[C@@]1(c2cc(NC(=O)c3nccc4ccsc34)ccc2F)CCOC(N)=N1

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-carbamic acid tert-butyl ester from experiment F (R3=Me) and thieno[2,3-c]pyridine-7-carboxylic acid followed by deprotection using procedure H yielded the title compound.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:9][C@@H:8]([P:10]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])[CH2:7][C@H:6]1[CH2:24][OH:25])(=[O:4])=[O:3].[CH3:26][S:27](Cl)(=[O:29])=[O:28].Cl>N1C=CC=CC=1>[CH3:1][S:2]([N:5]1[CH2:9][C@@H:8]([P:10]([CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])[CH2:7][C@H:6]1[CH2:24][O:25][S:27]([CH3:26])(=[O:29])=[O:28])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: CS(=O)(=O)N1C[C@@H](P(=O)(C2CCCCC2)C2CCCCC2)C[C@H]1CO
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OC[C@@H]1C[C@H](P(=O)(C2CCCCC2)C2CCCCC2)CN1S(C)(=O)=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 73.8 %

Procedure:
In 20 ml of pyridine was dissolved 1.4 g (3.6 m-mol) of (2S,4S)-N-methanesulfonyl-4-dicyclohexylphosphinyl-2-hydroxymethylpyrrolidine [VIII], and 0.82 g (7.2 m-xol) of methanesulfonyl chloride was added dropwise to the solution under ice-cooling. After stirring the mixture at 0° C. for 3 hours and then at room temperature overnight, 70 ml of 10% hydrochloric acid was added to the mixture under ice-cooling. The mixture was extracted three times with 80 ml of ethyl acetate, and the extract was washed with 30 ml of a saturated solution of sodium hydrogen carbonate and with 30 ml of water and dried over magnesium sulfate. The extract was concentrated under reduced pressure to obtain 1.24 g (yield: 74%) of (2S,4S)-N-methanesulfonyl-4-dicyclohexylphosphinyl-2-methanesulfonyloxymethylpyrrolidine as white crystals. Besides this, 1.88 g (8.52 m-mol) of chlorodiphenylphosphine and 392 mg (17.04 m-mol) of metallic sodium were added to 20 ml of dioxane and the mixture was refluxed in nitrogen atmosphere for 3 hours. After allowing the mixture to stand for cooling, 20 ml of tetrahydrofuran was added to the mixture, and a solution of the previously obtained crystals in 20 ml of dimethylformamide was added dropwise to the mixture at -20° C. to -30° C. lest any air should enter in the reaction system. The mixture was stirred overnight at -20° C. to -30° C. in nitrogen atmosphere, separated from insoluble matters and concentrated under reduced pressure. The residue was extracted three times with 50 ml of ethyl acetate and the extract was washed with 50 ml of water and concentrated under reduced pressure. Using 2.45 g (7.2 m-mol) of 10% hydrogen peroxide, the operation was carried out in the same manner as described in Example 1(e) whereby the title compound was obtained as crystals. Yield 982 mg (80%).
Reaction SMILES: [CH2:1]([C:3]([OH:18])([CH2:16][CH3:17])[C:4]#[C:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=1)=O)[CH3:2].C(NCC)C.C[OH:25]>>[CH2:16]([C:3]1([CH2:1][CH3:2])[C:4](=[O:25])[CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([S:14][CH3:15])=[CH:12][CH:13]=2)[O:18]1)[CH3:17]
Reactant: CCC(O)(C#CC(=O)c1ccc(SC)cc1)CC
Reactant: CO
Solvent: CCNCC
Product: CCC1(CC)OC(c2ccc(SC)cc2)=CC1=O

Procedure:
A solution 10 g of 4-ethyl-4-hydroxy-1-{4-(methylthio)phenyl}-2-hexyn-1-one in 300 ml methanol was stirred in the presence of 4 ml diethylamine at room temperature for 12 hours. Then the solvent was removed in vacuo and the resulting residue was extracted with dilute aqueous HCl and dichloromethane (50 ml×3). The organic layer was washed with brine and then concentrated under reduced pressure to yield 5.6 g of 2,2-diethyl-5-{4-(methylthio)phenyl}-3(2H)-furanone. The crude product was used for the next step without further purification. NMR: δ0.85 (t, J=7.5 Hz, 6H), 1.88 (q, J=7.5 Hz, 4H), 2.54 (s, 3H), 5.96 (s, 1H), 7.31 (d, J=9.0 Hz, 2H), 7.75 (d, J=9.0 Hz, 2H). IR (cm−1): 2971, 1690, 1597, 1487, 1408, 1364, 1162, 1095.