Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[C:10]=1[CH2:9][NH:8][C:7]1[CH:11]=[CH:12][CH:13]=[N:14][C:6]=1[CH2:5]2.[CH:15]1([C:21]2[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(CC)CC)C>ClCCCl>[CH:15]1([C:21]2[CH:22]=[CH:23][C:24]([C:25]([N:8]3[CH2:9][C:10]4[N:4]([CH:3]=[CH:2][CH:1]=4)[CH2:5][C:6]4[N:14]=[CH:13][CH:12]=[CH:11][C:7]3=4)=[O:26])=[CH:28][CH:29]=2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: c1cnc2c(c1)NCc1cccn1C2
Reactant: O=C(Cl)c1ccc(C2CCCCC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C(c1ccc(C2CCCCC2)cc1)N1Cc2cccn2Cc2ncccc21
Yield: 39.4 %

Procedure:
A mixture of the 9,10-dihydro-4H-3a,5,9-triaza-benzo[f]azulene of Step D (4.67 mmol), 4-cyclohexylbenzoyl chloride (4.90 mmol) and triethylamine (5.1 mmol) in 1,2-dichloroethane was refluxed for three days under nitrogen. The solvent was removed in vacuo and the residue chromatographed on silica gel eluting with a solvent gradient from 5 to 20% of ethyl acetate in hexane to provide the title compound as a tan solid (0.684 g), m.p. 150-152° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][C:10]2[C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=[CH:6][C:5]=2[C:4](=O)[CH2:3]1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:24].[Na+].O>CO>[NH2:24][CH:4]1[CH2:3][C:2]([CH3:17])([CH3:1])[CH2:11][C:10]2[C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=[CH:6][C:5]1=2
Reactant: [BH3-]C#N
Reactant: COC(=O)c1cccc2c1CC(C)(C)CC2=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cccc2c1CC(C)(C)CC2N
Temperature: 60 °C
Yield: 95.6 %

Procedure:
A solution of 3.0 g (13 mmol) of methyl 7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-1-naphthalenecarboxylate (J. Org. Chem. 17 (1976), 2918) in 45 ml of methanol was treated with 10 g (130 mmol) of ammonium acetate and 5.7 g (90 mmol) of sodium cyanoborohydride and heated at 60° C. for 20 hrs. After addition of 10 ml of water, the mixture was completely concentrated in vacuo and the residue was taken up in EA and aqueous ammonia. The organic phase was washed with water, dried over magnesium sulfate and concentrated in a rotary evaporator, and 2.9 g of methyl 5-amino-7,7-dimethyl-5,6,7,8-tetrahydro-1-naphthalenecarboxylate were obtained.
Reaction SMILES: [Na].Cl[C:3]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][O:5][N:4]=1.[CH2:14]([OH:18])[CH2:15][CH2:16][CH3:17]>>[CH2:14]([O:18][C:3]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][O:5][N:4]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCO
Reactant: Clc1nonc1-c1cccnc1
Agent: [Na]
Product: CCCCOc1nonc1-c1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of sodium (150 mg, 6.5 mmol) in 1-butanol (5 ml) was added 3-(3-chloro-1,2,5-oxadiazol-4-yl)pyridine (350 mg, 1.9 mmol). The mixture was stirred at 25° C. for 2 h and evaporated. The residue was dissolved in water and extracted with ether. The combined organic phases were dried and evaporated to give the title compound.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][N:9]([S:12]([NH2:15])(=[O:14])=[O:13])[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].Cl[C:17]1[CH:22]=[C:21]([O:23][CH3:24])[N:20]=[C:19]([S:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=2[F:34])[N:18]=1>>[F:34][C:28]1[C:29]([F:33])=[CH:30][CH:31]=[CH:32][C:27]=1[CH2:26][S:25][C:19]1[N:18]=[C:17]([NH:15][S:12]([N:9]2[CH2:8][CH2:7][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:11][CH2:10]2)(=[O:13])=[O:14])[CH:22]=[C:21]([O:23][CH3:24])[N:20]=1
Reactant: CCS(=O)(=O)N1CCN(S(N)(=O)=O)CC1
Reactant: COc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Product: CCS(=O)(=O)N1CCN(S(=O)(=O)Nc2cc(OC)nc(SCc3cccc(F)c3F)n2)CC1

Procedure:
The title compound was prepared from 4-ethanesulfonylpiperazine-1-sulfonamide (the product of step i) (0.31 g) and 4-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-methoxypyrimidine (the product of Example 35, step i) (0.25 g) according to the procedure outlined in Example 1, step iv). The crude material was purified by column chromatography using EtOAc/isohexane (1:1) as eluent. Yield: 0.37 g
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1.[CH3:18][N:19]1[C:24]([N:25]2CCCN(C3C=CC=CC=3[N+]([O-])=O)[CH2:27][CH2:26]2)=[CH:23][C:22](=[O:41])[N:21]([CH3:42])[C:20]1=[O:43].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C>[CH3:18][N:19]1[C:24]([NH:25][CH2:26][CH2:27][N:5]([CH2:6][CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH2:4][CH2:3][CH2:2][OH:1])=[CH:23][C:22](=[O:41])[N:21]([CH3:42])[C:20]1=[O:43]
Reactant: Cn1c(N2CCCN(c3ccccc3[N+](=O)[O-])CC2)cc(=O)n(C)c1=O
Reactant: O=[N+]([O-])c1ccc(CCCNCCCO)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC#N
Product: Cn1c(NCCN(CCCO)CCCc2ccc([N+](=O)[O-])cc2)cc(=O)n(C)c1=O
Yield: 109.9 %

Procedure:
N-(3-hydroxypropyl)-3-(4-nitrophenyl)propylamine (0.7 g), 0.53 g of 6-(1-aziridinyl)-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione (compound 6) and 50 mg of p-toluene-sulfonic acid monohydrate were dissolved in 30 ml of acetonitrile, and then the solvent was removed in vacuo. The resultant oil was allowed to react at 80° C. for 3 hours and subjected to silica gel column chromatograph (chloroform/methanol=40:1 (v/v)) for purification: 0.68 g of 1,3-dimethyl-6-{2-[N-(3-hydroxypropyl)-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione was thus obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[CH:7]=O)[CH3:2].[NH2:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1.O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])/[CH:7]=[N:16]/[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1)[CH3:2]
Reactant: N#Cc1ccc(N)cc1
Reactant: CCOc1cc(C=O)ccc1OC(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: CCOc1cc(/C=N/c2ccc(C#N)cc2)ccc1OC(C)C
Yield: 86.9 %

Procedure:
A mixture of 3-ethoxy-4-isopropoxybenzaldehyde (1.78 g, 8.55 mmol), 4-aminobenzonitrile (1.01 g, 8.55 mmol), and 5 g 4 A molecular sieves in 20 mL toluene was refluxed with azeotropic removal of water for 2 h. The mixture was filtered and concentrated to afford 2.29 g of Intermediate 1.1 as a pale yellow solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].[NH:18]1[CH:22]=[CH:21][N:20]=[N:19]1>CN1CCCC1=O>[F:8][C:5]1[CH:6]=[CH:7][C:2]([N:19]2[N:20]=[CH:21][CH:22]=[N:18]2)=[C:3]([C:9](=[O:11])[CH3:10])[CH:4]=1
Reactant: CC(=O)c1cc(F)ccc1F
Reactant: c1c[nH]nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC(=O)c1cc(F)ccc1-n1nccn1
Temperature: 140 °C
Yield: 35 %

Procedure:
To a solution of 2′,5′-difluoroacetophenone (10.0 g, 64 mmol) in 1-methyl-2-pyrrolidinone (10 mL) was added potassium carbonate (8.84 g, 64 mmol) and 1H-1,2,3-triazole (6.64 g, 96 mmol). This mixture was heated to 140° C. for 3 hr, under an atmosphere of nitrogen. After this time, the reaction was cooled and then partitioned between ethyl acetate (300 mL) and aqueous ammonium chloride solution (1M, 100 mL). The organic phase was washed with water (3×200 mL) and then dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with ethyl acetate in heptane (10:90 by volume) to produce the title compound as a brown oil (4.6 g, 35%).
Reaction SMILES: N(OC(C)(C)C)=O.[C:8]([Cu])#[N:9].N[C:12]1[S:13][CH:14]=[C:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:16]=1>C(#N)C>[C:8]([C:12]1[S:13][CH:14]=[C:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:16]=1)#[N:9]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: N#C[Cu]
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: CCOC(=O)Cc1csc(C#N)n1
Reaction time: 2.5 h
Yield: 25.5 %

Procedure:
To a mixture of tert-butyl nitrite (10 mL, 80 mmol) and CuCN (7.28 g, 80 mmol) in anhydrous acetonitrile (30 mL) was added a solution of ethyl 2-(2-aminothiazol-4-yl)acetate (7.5 g, 40 mmol) in anhydrous acetonitrile (20 mL) dropwise over a period of 1 hour at 50° C., then the mixture was stirred at the temperature for 2.5 hours. The mixture was concentrated in vacuo and the residue was purified by a silica gel column chromatography (PETROLEUM ETHER/EtOAc (V/V)=25/1) to give the title compound as yellowish liquid (2 g, 25%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][S@:2](=[O:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[N:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([C:11]#[C:12][Si](C)(C)C)[CH:8]=[N:7][CH:6]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CO>[C:11]([C:9]1[CH:8]=[N:7][CH:6]=[C:5]([CH:10]=1)[C:4]([N:3]=[S@@:2]([CH3:1])(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:17])#[CH:12]
Reactant: C[Si](C)(C)C#Cc1cncc(C(=O)N=[S@@](C)(=O)c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: C#Cc1cncc(C(=O)N=[S@@](C)(=O)c2ccccc2)c1
Temperature: 0 °C

Procedure:
A solution of (S)-N-[methyl(oxo)phenyl-λ6-sulfanylidene]-5-[(trimethylsilyl)ethynyl]nicotinamide (806 mg, 2.3 mmol) in 70 mL THF/methanol (1:1 ratio) at room temperature was degassed with argon. The solution was cooled to 0° C. and K2CO3 (937 mg, 6.8 mmol) added. After 5 minutes the solution was decanted from the solids and partitioned between EtOAc and H2O. The EtOAc layer was washed with brine, dried with anhydrous Na2SO4 and concentrated. The brown oil was purified by chromatography (silica gel, CHCl3/EtOAc) to the title compound as a thick pale orange oil (630 mg, 98%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].Cl.[F:13][C:14]1([F:19])[CH2:18][CH2:17][NH:16][CH2:15]1>N1C=CC=CC=1.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:16]1[CH2:17][CH2:18][C:14]([F:19])([F:13])[CH2:15]1)(=[O:10])=[O:9]
Reactant: FC1(F)CCNC1
Reactant: O=S(=O)(Cl)c1ccccc1Br
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccccc1Br)N1CCC(F)(F)C1
Temperature: 25 °C
Yield: 87.8 %

Procedure:
A solution of 2-bromobenzene-1-sulfonyl chloride (0.300 g, 1.17 mmol) and 3,3-difluoropyrrolidine hydrochloride (0.169 g, 1.17 mmol) in pyridine (5 mL) was stirred for 16 hours at 60° Celsius. The reaction was then cooled to rt, diluted with EtOAc (25 mL), washed with 1 N HCl (2×25 mL), and brine (50 mL). The organic layer was isolated, dried over MgSO4, filtered and concentrated to dryness to yield the title compound (0.335 g, 86%), The product was used without further purification. 1H NMR (500 MHz, CDCl3) δ 8.13-8.09 (m, 1H), 7.80-7.76 (m, 1H), 7.50-7.41 (m, 2H), 3.74 (t, J=12.8, 2H), 3.67 (t, J=7.2, 2H), 2.44-2.35 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[C:12]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:13][CH2:14][C:15]([CH3:17])=O.N1CCCC1>C1(C)C=CC=CC=1>[CH2:20]([O:19][C:12](=[O:18])[CH2:13][CH2:14][C:15]1([CH3:17])[CH2:10][C:9](=[O:11])[C:3]2[CH:4]=[C:5]([OH:8])[CH:6]=[CH:7][C:2]=2[O:1]1)[CH3:21]
Reactant: CCOC(=O)CCC(C)=O
Reactant: CC(=O)c1cc(O)ccc1O
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: CCOC(=O)CCC1(C)CC(=O)c2cc(O)ccc2O1
Yield: 64.2 %

Procedure:
Using the procedure of Example 1, 15 g of 2',5'-dihydroxyacetophenone was condensed with 14.2 g of ethyl levulinate and 12.3 ml of pyrrolidine, in 200 ml of toluene. The crude product (20.5 g) was purified by high pressure liquid chromatography (silica gel; 2:1 hexane-ethyl acetate) giving 17.6 g (64.1%) of racemic-3,4-dihydro-6-hydroxy-2-methyl-4-oxo-2H-1-benzopyran-2-propanoic acid ethyl ester as a yellow oil.
Reaction SMILES: [C:1]1([C:11]2[CH:26]=[CH:25][C:14]3[C@:15]4([CH3:24])[C@@H:20]([CH2:21][CH2:22][C:13]=3[CH:12]=2)[NH:19][C:18](=[O:23])[CH:17]=[CH:16]4)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:27](O)(C)(C)C.CC(C)([O-])C.[K+].CI>C(OCC)(=O)C>[CH3:27][N:19]1[C@H:20]2[C@@:15]([CH3:24])([C:14]3[CH:25]=[CH:26][C:11]([C:1]4[C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[CH:4]=[CH:3][CH:2]=4)=[CH:12][C:13]=3[CH2:22][CH2:21]2)[CH:16]=[CH:17][C:18]1=[O:23]
Reactant: C[C@]12C=CC(=O)N[C@@H]1CCc1cc(-c3cccc4ccccc34)ccc12
Reactant: CC(C)(C)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Product: CN1C(=O)C=C[C@]2(C)c3ccc(-c4cccc5ccccc45)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-8-(1-naphthyl)-10b-methyl-3,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3-one (22 mg, 0.065 mmol), 0.20 mL of t-butanol, and potassium t-butoxide (22 mg, 0.19 mmol). Methyl iodide (0.012 mL, 0.19 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate, and purified by silica gel chromatography (ethyl acetate eluent) to give 16 mg (70%) of the title compound as a yellow solid, upon trituration from diethyl ether/hexanes. mp 172°-173°. FDMS: m/e=353.
Reaction SMILES: [CH2:1]([N:8]([CH2:16][CH:17]1[CH2:21][O:20][CH:19]([O:22][C:23](=O)[C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=2)[CH:18]1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[C:46](OCC)(=O)C>O1CCCC1>[CH2:9]([N:8]([CH2:16][CH:17]1[CH:18]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:19]([O:22][C:23]([C:24]2[CH:25]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=2)=[CH2:46])[O:20][CH2:21]1)[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(C)=O
Reactant: O=C(OC1OCC(CN(Cc2ccccc2)Cc2ccccc2)C1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: O
Product: C=C(OC1OCC(CN(Cc2ccccc2)Cc2ccccc2)C1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 29 %

Procedure:
(2SR, 3SR, 4SR) 3,5-Bis(trifluoromethyl)benzoic acid 4-[(N,N-dibenzylamino)methyl]-3-phenyl-tetrahydrofuran-2-yl ester (Description 7(a); 1.03 g, 1.7 mmol) was azeotroped with tetrahydrofuran (2×10 ml), dissolved in tetrahydrofuran (15 ml) and degassed with Firestone™ valve (×3). Bis(cyclopentadiene) titanium dimethyl (1.8 ml, 2.8M in toluene) was added and the mixture was heated to 60° C. in the dark. Further bis(cyclopentadiene) titanium dimethyl (1 ml) was added and the reaction was left to stand for 18 hours. The reaction was quenched with a slurry of sodium carbonate (4 g), water (2.5 ml) and methanol (50 ml), which caused it to turn yellow, and the reaction was left to stand at 40° C. for 16 hours under nitrogen. The solid was removed by filtration and the solvent removed in vacuo to afford a yellow solid. The solid was dispersed between water (50 ml) and ethyl acetate (40 ml), the aqueous layer was washed with ethyl acetate (3×20 ml) and brine (1×50 ml), and dried over MgSO4. The solvent was removed in vacuo and the product purified by flash column chromatography on silica gel and eluting in increasing concentrations of dichloromethane in hexane (10-100%) to give the title compound (299 mg, yield 29%).
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:30][CH3:31])[C:5]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][CH:13]=[C:12]2[CH2:16][C@H:17]([NH:19][CH2:20][C@@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=1)[OH:22])[CH3:18])=[O:6])[CH3:3].C(N(CC)CC)C.Cl[C:40](Cl)([O:42]C(=O)OC(Cl)(Cl)Cl)Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:30]([N:4]([CH2:2][CH3:3])[C:5]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][CH:13]=[C:12]2[CH2:16][C@H:17]([N:19]1[CH2:20][C@@H:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[O:22][C:40]1=[O:42])[CH3:18])=[O:6])[CH3:31]
Reactant: CCN(CC)C(=O)c1cccc2c(C[C@@H](C)NC[C@H](O)c3cccc(Cl)c3)c[nH]c12
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1cccc2c(C[C@@H](C)N3C[C@@H](c4cccc(Cl)c4)OC3=O)c[nH]c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 247.8 %

Procedure:
To a solution of 3-{(2R)-2-[2-(3-chlorophenyl)-(2R)-2-hydroxy-ethylamino]propyl}-1H-indole-7-carboxylic acid diethylamide.hydrochloride (47 mg, 0.1 mmol) and triethylamine (139 μL, 1 mmol) in tetrahydrofuran (3 mL) is added triphosgene (12 mg, 0.04 mmol), and the mixture is stirred at room temperature for 4 hours. To the mixture is added a saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over sodium sulfate, and concentrated. The residue is purified by silica gel column chromatography (methanol/chloroform=1/50) to give 3-{(2R)-2-[(5R)-5-(3-chlorophenyl)-2-oxooxazolidin-3-yl]propyl}-1H-indole-7-carboxylic acid diethylamide (45 mg, yield: 100%).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].O=S(Cl)Cl.[CH3:18][NH2:19]>CN(C)C=O>[CH3:18][NH:19][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([I:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: O=C(O)c1ccc(I)c([N+](=O)[O-])c1
Reactant: CN
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CNC(=O)c1ccc(I)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 62.3 %

Procedure:
10 g (0.034 mol) 4-Iodo-3-nitrobenzoic acid (Compound VI-1) and 50 ml N,N-dimethylformamide were added into a reaction flask, stirred to dissolve, and cooled to below 10° C., and 7.5 ml (0.10 mol) sulfoxide chloride was added. After completion of the dropwise addition, the mixture was warmed to room temperature and reacted for one hour. The reaction mixture was poured into 200 ml aqueous solution of 30% methylamine with low temperature, stirred for 5 minutes to precipitate a solid, and then the mixture was added with 500 ml ice-water, stirred for 10 minutes, filtered. The solid was washed with water and dried to obtain N-methyl-4-iodo-3-nitrobenzamide (Compound VII-1), 6.5 g (0.021 mol), yield 62.3%.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][OH:25])=[CH:18][CH:17]=3)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>>[CH3:26][S:27]([O:25][CH2:24][CH2:23][CH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][C:12]2[N:13]=[C:9](/[CH:8]=[CH:7]/[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:10][CH:11]=2)=[CH:21][CH:20]=1)(=[O:29])=[O:28]
Reactant: OCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)OCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Yield: 92 %

Procedure:
In substantially the same manner as in Reference Example 12, 3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propanol was allowed to react with methanesulfonyl chloride to give 3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl methanesulfonate. The yield was 92%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 111-112° C.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH2:15])=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1.[S:16]1[CH:20]=[CH:19][N:18]=[CH:17]1.C([O-])(=O)C.[K+]>CN(C)C(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:14][C:10]1[CH:9]=[C:8]([C:7]2[N:6]=[C:5]([NH2:15])[CH:4]=[N:3][C:2]=2[C:20]2[S:16][CH:17]=[N:18][CH:19]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: c1cscn1
Reactant: Nc1cnc(Br)c(-c2cccc(F)c2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Nc1cnc(-c2cncs2)c(-c2cccc(F)c2)n1
Temperature: 150 °C
Reaction time: 8 h
Yield: 14.9 %

Procedure:
A mixture of 5-bromo-6-(3-fluorophenyl)pyrazin-2-amine (Preparation 1, 100 mg, 0.37 mmol), thiazole (0.06 mL, 0.88 mmol) and potassium acetate (54 mg, 0.56 mmol) in N,N-dimethylacetamide (1 mL) was degassed with argon. The catalyst Pd(PPh3)4 (23 mg, 0.02 mmol, 5 mol %) was added and degassing was repeated. The mixture was heated to 150° C. in a sealed tube and stirred overnight. The mixture was cooled and ethyl acetate and aqueous NH4Cl were added. The aqueous layer was extracted with ethyl acetate. The organic layer was dried and concentrated. The residue was purified by flash silica gel chromatography (hexanes/EtOAc 1:1) to give the title compound (15 mg, 15%) as a yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:10]([CH2:15][CH3:16])[S:11]([CH3:14])(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>C(OCC)(=O)C.CO>[CH3:19][N:20]([CH3:22])[CH:21]=[CH:2][C:1]([C:4]1[CH:5]=[C:6]([N:10]([CH2:15][CH3:16])[S:11]([CH3:14])(=[O:12])=[O:13])[CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CCN(c1cccc(C(C)=O)c1)S(C)(=O)=O
Reactant: COC(OC)N(C)C
Solvent: CO
Solvent: CCOC(C)=O
Product: CCN(c1cccc(C(=O)C=CN(C)C)c1)S(C)(=O)=O
Yield: 88.6 %

Procedure:
1.1 g (4.56 mmol) of N-(3-acetyl-phenyl)-N-ethyl-methanesulfonamide were dissolved in 10 ml of N,N-dimethylformamide dimethylacetal and the resultant solution was refluxed for 18 hours. The excess of volatile reagent was removed by reduced pressure distillation to yield a crude which was chromatographied over silica gel using a gradient of ethyl acetate/methanol as eluent. 1.2 g of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethyl-methanesulfonamide as a yellowish-white solid were obtained (yield 88.6%)
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].N1C=CC=CC=1.O[C@H:23]1[CH2:28][CH2:27][O:26][C:24]1=[O:25]>ClCCl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C@H:23]1[CH2:28][CH2:27][O:26][C:24]1=[O:25])(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C1OCC[C@@H]1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C1OCC[C@@H]1OS(=O)(=O)C(F)(F)F
Reaction time: 0.08 h
Yield: 61.2 %

Procedure:
Trifluoromethanesulfonic anhydride (1.65 mL) was gently added to a solution of pyridine (0.83 mL) in dichloromethane mL) at 0° C., and the mixture was stirred for 5 minutes at the same temperature. Subsequently, (S)-2-hydroxybutyrolactone (1.0 g) was added dropwise thereto over 10 minutes at 0° C., followed by stirring for 12 hours at the same temperature. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified through silica gel column chromatography (n-hexane/ethyl acetate=2/1), to thereby yield a colorless oil (1.40 g, 61.2%).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH:11]=[CH:10][C:9](=[O:12])[CH:8]=[CH:7]1)C.O.[NH2:15][NH2:16]>C(O)C>[O:12]=[C:9]1[CH:10]=[CH:11][N:6]([CH2:5][C:4]([NH:15][NH2:16])=[O:3])[CH:7]=[CH:8]1
Reactant: NN
Reactant: CCOC(=O)Cn1ccc(=O)cc1
Solvent: O
Solvent: CCO
Product: NNC(=O)Cn1ccc(=O)cc1

Procedure:
As described for example 112a, (4-oxo-4H-pyridin-1-yl)-acetic acid ethyl ester (Bambury, Ronald E.; Edwards, Michael Louis; Miller, Laird Foulis. 4-Oxo-1-pyridinylpeniclliin and -cephalosporin derivatives. Ger. Offen. (1975)) in ethanol was reacted with hydrazine hydrate (1.2 equivalents) at rt for 72 h. The mixture was concentrated and crystallized from ethanol/diisopropylether and the title compound was obtained as a yellow solid (yield: 98%). MS: m/e=168.3 [M+H]+.