Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:20][O:21][CH3:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:13]=1.[C:23](Cl)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[C:23]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:20][O:21][CH3:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:13]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(=NOC)c1csc(N)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=NOC)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: -35 °C
Yield: 65 %

Procedure:
2.9 ml of triethylamine were added at -10° C. to a mixture of 4.6 g of the product of Step A in 92 ml of methylene chloride and after cooling to -35° C., 6.1 g of trityl chloride were added thereto. The temperature was allowed to rise to room temperature in about 21/2 hours and the reaction mixture was washed with water and then with 0.5 N hydrochloric acid and finally with aqueous sodium acetate. The mixture was dried and evaporated to dryness. The residue was taken up in ether and the solution was concentrated to dryness again. The residue was dissolved in methanol and water and ether were added to cause crystallization. The mixture was vacuum filtered and the recovered precipitate was washed with ether to obtain 6.15 g of ethyl 2-(2-tritylamino-4-thiazolyl)-2-methoxyiminoacetate melting at 120° C. having the syn configuration.
Reaction SMILES: [CH3:1][C:2](=[CH:5][CH2:6][CH:7]1[CH2:11][CH:10]=[C:9]([CH3:12])[C:8]1([CH3:14])[CH3:13])[CH:3]=[O:4].C(=O)C=CC.CC(C)([O-])C.[K+]>COCCOC>[CH3:1][CH:2]([CH:5]=[CH:6][CH:7]1[CH2:11][CH:10]=[C:9]([CH3:12])[C:8]1([CH3:13])[CH3:14])[CH2:3][OH:4]
Reactant: CC(C=O)=CCC1CC=C(C)C1(C)C
Agent: CC(C)(C)[O-]
Agent: CC=CC=O
Agent: [K+]
Solvent: COCCOC
Product: CC1=CCC(C=CC(C)CO)C1(C)C
Reaction time: 0.25 h

Procedure:
The aldehyde, 2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)but-2-enal, which had been prepared by using the procedure outlined in U.S. Pat. No. 4,052,341 Example IV-1, was reacted essentially following the procedure described in Example I for isomerizing the α,β double bond to the β,γ position. In this case the butenal (19.2 g, 0.1 mole) was reacted with potassium t-butoxide (16.8 g, 0.15 mole) in 1,2-dimethoxyethane (DME, 200 ml) at 15°-20° C. by feeding in the butenal over 30 minutes, stirring for an additional 15 minutes and then rapidly quenching with aqueous 20% acetic acid (75 ml).
Reaction SMILES: [N+]([O-])([O-])=O.[Ag+:5].[NH:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1.O.N>>[NH:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1.[Ag:5]
Reactant: [Ag+]
Agent: N
Agent: O=[N+]([O-])[O-]
Agent: c1ccc2[nH]nnc2c1
Solvent: O
Product: [Ag]

Procedure:
Prepared in the manner that an aqueous ammoniacal silver nitrate solution and benzotriazole (containing ammonia water of 0.2 mol thereto) were added by a double-jet method to an aqueous 10 mol % phenylcarbamoyl gelatin solution at 50° C., and after completion of the addition, its pH was lowered for coagulation and desalting to thereby obtain needle crystals each being 0.1 to 0.2 μm in width and 0.5 to 2 μm in length. ##STR2##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].C([O-])([O-])=O.[K+].[K+].[CH2:16]([O:18][C:19](=[O:24])[C:20](Br)([CH3:22])[CH3:21])[CH3:17].[NH4+].[Cl-]>CN(C)C(=O)C.O>[CH2:16]([O:18][C:19](=[O:24])[C:20]([O:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])([CH3:22])[CH3:21])[CH3:17]
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1Cl
Temperature: 110 °C
Reaction time: 14 h
Yield: 51 %

Procedure:
2,4-Dichlorophenol (448 mg, 2.75 mmol) and K2CO3 (775 mg, 5.61 mmol) were continuously added to 2-bromo-2-methyl-propionic acid ethyl ester (800 mg, 4.10 mmol) in N,N-dimethylacetamide (4 ml) at room temperature. The mixture was stirred at 110° C. for 14 hours, and saturated NH4Cl and H2O were then added, followed by extraction with AcOEt (×2). The organic layers were combined and sequentially washed with H2O and saturated brine, and then dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane/AcOEt) to give 2-(2,4-dichloro-phenoxy)-2-methyl-propionic acid ethyl ester (389 mg, 50%).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][C@@H:10]([CH3:13])[C:11]#[N:12].[F:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]([C:25]3[N:26]=[C:27]4[C:33]([C:34](O)=[O:35])=[CH:32][N:31]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:28]4=[N:29][CH:30]=3)=[N:20][N:21]2[CH3:24])=[CH:17][CH:16]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(#N)C.C(OCC)(=O)C.O>[C:11]([C@H:10]([CH3:13])[CH2:9][NH:8][C:34]([C:33]1[C:27]2[C:28](=[N:29][CH:30]=[C:25]([C:19]3[C:18]4[C:22](=[CH:23][C:15]([F:14])=[CH:16][CH:17]=4)[N:21]([CH3:24])[N:20]=3)[N:26]=2)[N:31]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:32]=1)=[O:35])#[N:12]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Reactant: C[C@@H](C#N)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](C#N)CNC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 36 %

Procedure:
(R)-3-Amino-2-methyl-propionitrile trifluoroacetate (crude from Step 3) was dissolved in acetonitrile (2.8 ml) to which was then added 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (80 mg, 0.18 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (70 mg, 0.22 mmol) and N,N-diisopropylethylamine (0.11 ml, 0.63 mmol). The reaction was stirred at room temperature for 18 h. Additional O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (50 mg, 0.16 mmol) and N,N-diisopropylethylamine (0.11 ml, 0.63 mmol) were added and stirring was continued for 24 h. Water and ethyl acetate were added. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with sodium chloride solution and dried over sodium sulfate. After evaporation, the residue was purified by silica gel chromatography (methanol/dichloromethane) to afford 33 mg (36%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2-cyano-2-methyl-ethyl)-amide. (M+Na)+=530.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].[F:13][C:14]1[CH:15]=[CH:16][C:17](B2OC(C)(C)C(C)(C)O2)=[C:18]2[C:22]=1[C@H:21]([O:23][C:24]1[CH:37]=[CH:36][C:27]3[C@H:28]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH2:29][O:30][C:26]=3[CH:25]=1)[CH2:20][CH2:19]2.BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:7][N:6]([CH3:8])[C:4]([C:3]1[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=1[C:17]1[CH:16]=[CH:15][C:14]([F:13])=[C:22]2[C:18]=1[CH2:19][CH2:20][C@H:21]2[O:23][C:24]1[CH:37]=[CH:36][C:27]2[C@H:28]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH2:29][O:30][C:26]=2[CH:25]=1)=[O:5]
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: CN(C)C(=O)c1ccccc1Br
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5ccccc5C(=O)N(C)C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from 2-bromo-N,N-dimethylbenzamide and methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 9): tR=1.14 min; Mass spectrum (ESI+): m/z=490 [M+H]+.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9]([Br:15])=[CH:8]2)(=O)C.C([O-])([O-])=O.[K+].[K+]>CO.O>[Br:15][C:9]1[CH:10]=[N:11][C:12]2[C:7]([CH:8]=1)=[CH:6][C:5]([OH:4])=[CH:14][CH:13]=2
Reactant: CC(=O)Oc1ccc2ncc(Br)cc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Oc1ccc2ncc(Br)cc2c1
Yield: 90.2 %

Procedure:
A solution of Intermediate A (1 g, 3.76 mmol) and K2CO3 (1.04 g, 7.52 mmol) in MeOH/H2O (5 mL/3 mL) was stirred at rt for 2 hours. The reaction mixture was concentrated under reduced pressure to afford a crude solid which was further purified by washing with water, dried under vacuum to give the title compound as white solid (760 mg, yield 86%). LCMS (method N): [M+H]+=224, tR=2.29 min.
Reaction SMILES: [NH2:1][CH:2]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:3]1[CH:19]=[CH:18][C:6]([O:7][CH2:8][C:9]2[O:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.Cl.[C:27](Cl)(=[O:37])[O:28][C@@H:29]1[CH:34]2[CH2:35][CH2:36][N:31]([CH2:32][CH2:33]2)[CH2:30]1>N1C=CC=CC=1>[C:20]1([CH:2]([NH:1][C:27]([O:28][C@@H:29]2[CH:34]3[CH2:35][CH2:36][N:31]([CH2:32][CH2:33]3)[CH2:30]2)=[O:37])[C:3]2[CH:19]=[CH:18][C:6]([O:7][CH2:8][C:9]3[O:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:10]=3)=[CH:5][CH:4]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)c1ccc(COc2ccc(C(N)c3ccccc3)cc2)o1
Reactant: O=C(Cl)O[C@H]1CN2CCC1CC2
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(COc2ccc(C(NC(=O)O[C@H]3CN4CCC3CC4)c3ccccc3)cc2)o1
Temperature: 25 °C
Reaction time: 72 h
Yield: 64 %

Procedure:
To a stirred solution of methyl 5-((4-(amino(phenyl)methyl)phenoxy)methyl)-furan-2-carboxylate (301 mg, 0.894 mmol) in anhydrous pyridine (5 mL) at 0° C. under nitrogen was added (R)-quinuclidin-3-yl carbonochloridate hydrochloride (243 mg, 1.07 mmol, prepared as previously reported in 16, Step 6) in one portion. The reaction was stirred at room temperature for 3 days. The reaction was quenched by addition of 10% K2CO3 solution, extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with brine, dried over MgSO4, filtered and the solvent removed in vacuo. The residue was purified by silica gel chromatography, eluting with 0-10% 7N methanolic ammonia in ethyl acetate, to give the title compound as a yellow oil (280 mg, 64%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[C:4]([SH:9])[N:3]=1.[Br:10][C:11]1[S:15][C:14]([CH:16]=O)=[CH:13][CH:12]=1.C(O)(=O)C.CN(C=O)C>O>[Br:10][C:11]1[S:15][C:14]([CH:16]=[C:7]2[C:6](=[O:8])[NH:5][C:4](=[S:9])[NH:3][C:2]2=[O:1])=[CH:13][CH:12]=1
Reactant: Oc1cc(O)nc(S)n1
Reactant: O=Cc1ccc(Br)s1
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C1NC(=S)NC(=O)C1=Cc1ccc(Br)s1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 29 %

Procedure:
In a procedure identical to Example 1, 0.144 g (1 mmol) of 4,6-dihydroxy-2-mercaptopyrimidine, and 0.207 g (1 mmol) of 5-bromothiophenecarboxaldehyde in a solution of 2 ml of glacial acetic acid and 4 ml of DMF was heated at 80° C. for 12 hours. Upon cooling to room temperature, the reaction was poured into water and the precipitate collected by filtration. The crude product was washed with water, and the solid boiled in methanol for 1 minute. Filtration provided 92 mg of product as an orange solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][N:5]([CH3:7])[N:6]=1.NC1N(C)N=NN=1.[F:15][C:16]([F:30])([F:29])[C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH:20]=O>C1(C)C=CC=CC=1>[CH3:7][N:5]1[N:4]=[N:3][C:2]([N:1]=[CH:20][C:19]2[CH:22]=[C:23]([C:25]([F:27])([F:28])[F:26])[CH:24]=[C:17]([C:16]([F:15])([F:29])[F:30])[CH:18]=2)=[N:6]1
Reactant: Cn1nnc(N)n1
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cn1nnnc1N
Solvent: Cc1ccccc1
Product: Cn1nnc(N=Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1

Procedure:
A crude mixture of 5-amino-2-methyltetrazole and 5-amino-1-methyltetrazole is treated with 3,5-bis(trifluoromethyl)benzaldehyde (48 mL, 71 g, 0.29 mol) in toluene (780 mL), and the mixture is stirred and refluxed for 5 hours. The resulting mixture is filtered to remove off the insoluble solid (5-amino-1-methyltetrazole), and the residue is washed with hot toluene. The filtrate is concentrated to give crude 2-methyl-N-[3,5-bis(trifluoromethyl)phenylmethylene]-2H-tetrazole-5-amine (70.1 g).
Reaction SMILES: S(Cl)(Cl)=O.CN(C)C=O.[CH:10]1[C:23]2[C:22](=[O:24])[C:21]3[C:16](=[CH:17][C:18]([C:25]([NH2:27])=O)=[CH:19][CH:20]=3)[C:15](=[O:28])[C:14]=2[CH:13]=[CH:12][C:11]=1[C:29]([NH2:31])=O>O>[C:29]([C:11]1[CH:12]=[CH:13][C:14]2[C:15](=[O:28])[C:16]3[C:21](=[CH:20][CH:19]=[C:18]([C:25]#[N:27])[CH:17]=3)[C:22](=[O:24])[C:23]=2[CH:10]=1)#[N:31]
Reactant: NC(=O)c1ccc2c(c1)C(=O)c1ccc(C(N)=O)cc1C2=O
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)C(=O)c1ccc(C#N)cc1C2=O
Reaction time: 0.5 h

Procedure:
Thionyl chloride (10.0 ml) was added to dimethylformamide (100 ml.) at -30° C. with stirring in 1 ml. portions. To the resulting solution, anthraquinone-2,6-dicarboxamide (4.74g.) was added in one portion and the temperature of the mixture was allowed to rise slowly to 5° C. by placing in an ice-bath. After 30 min. at this temperature, the mixture was heated over 30 min. to 65° C. The heterogeneous mixture was then poured into iced water and the solid filtered off, dried, and recrystallised from deimethylsulphoxide, 2.60g. m.p. 392° C. (decomp.) in a sealed, evacuated tube.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]([CH2:20][CH2:21]OS(C)(=O)=O)[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:27]1[CH:31]=[CH:30][N:29]=[CH:28]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.C(#N)C>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]([CH2:20][CH2:21][N:27]2[CH:31]=[CH:30][N:29]=[CH:28]2)[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1c[nH]cn1
Reactant: CS(=O)(=O)OCCC1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=S(=O)(c1ccccc1)c1ccc2c(c1)CCCC2CCn1ccnc1
Yield: 77.4 %

Procedure:
Methanesulfonic acid 2-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-ethyl ester (0.250 g, 0.634 mmol), imidazole (0.173 g, 2.54 mmol), potassium carbonate (0.175 g, 1.27 mmol) and potassium iodide (0.25 g) were added to 50 mL of acetonitrile, and the reaction mixture was refluxed for 16 hours under argon. The reaction mixture was cooled and poured into 300 mL of water, extracted twice with 250 mL of EtOAc, and the combined organic layers were washed with water, saturated brine, and dried (MgSO4). The solvet was removed under reduced pressure to yield an oil that was purified via silica gel column, eluting with MeOH/CHCl3 (5:95). Solvent was removed under reduced pressure to afford 0.180 g (0.491 mmol, 77.5% of 1-[2-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-ethyl]-1H-imidazole as an oil. The oil was recrystallized from EtOH/HC to give 0.130 g of the corresponding hydrochloride salt (0.323 mol, 50.9%). MS: 367 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:8]([CH3:18])[N:7]=1)=[O:5])[CH3:2].[I:19]I.[N+]([O-])([O-])=O.[NH4+].[Ce]>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([I:19])=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:8]([CH3:18])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2ccc(F)cc2)n(C)n1
Reactant: II
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: CC#N
Product: CCOC(=O)c1nn(C)c(-c2ccc(F)cc2)c1I
Temperature: 50 °C
Reaction time: 3 h
Yield: 161.1 %

Procedure:
To a well stirred solution of 2.79 g of 5-(4-Fluoro-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid ethyl ester in 100 ml of Acetonitrile were added 1.71 g of Iodine and 3.70 g of Cerium ammonium nitrate. The mixture was stirred for 3 h at 50° C. The red solution was then allowed to cool and was concentrated in vaccuo. The residue was taken up in 200 ml of Ethyl acetate. The organic phase was successively washed with 5% Sodium bisulfite solution and brine. After drying over Magnesium sulfate and concentration, a beige solid 4.06 g (96%) was obtained which is sufficiently pure and was directly used in the next step. MS: m/e=375.3 ([M+1]+).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH:9]1([O:14][C:15]2[C:16]([O:35][CH3:36])=[CH:17][CH:18]=[C:19]3[C:24]=2[NH:23][C:22](=[O:25])[CH:21]=[C:20]3[NH:26][C:27]2[C:32]([Cl:33])=[CH:31][N:30]=[CH:29][C:28]=2[Cl:34])[CH2:13][CH2:12][CH2:11][CH2:10]1.CN(C=O)C>O>[Br:1][C:21]1[C:22](=[O:25])[NH:23][C:24]2[C:19]([C:20]=1[NH:26][C:27]1[C:32]([Cl:33])=[CH:31][N:30]=[CH:29][C:28]=1[Cl:34])=[CH:18][CH:17]=[C:16]([O:35][CH3:36])[C:15]=2[O:14][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OC1CCCC1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)c(Br)c(=O)[nH]c2c1OC1CCCC1
Reaction time: 4 h

Procedure:
N-Bromosuccinimide (0.104 g, 0.585 mmol) was added to a solution of 4-(3,5-dichloropyridin-4-ylamino)-8-(cyclopentyloxy)-7-methoxyquinolin-2(1H)-one (0.246 g, 0.585 mmol, Example 1) and anhydrous DMF (3 mL) at 0° C. After 4 h at 0° C., the mixture was poured into water, and the precipitate was filtered. Saturated sodium thiosulfate solution (1 mL) was added to a solution of the filter cake and methanol (5 mL). After the dibromo intermediate was consumed by LCMS, the mixture was diluted with water and extracted with EtOAc. The organic extract was dried, filtered, and concentrated to give 3-bromo-8-(cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one: 1H NMR (400 MHz, DMSO-d6): δ 10.56 (s, 1H), 8.88 (br s, 1H), 8.42 (s, 2H), 7.62 (d, 1H), 7.04 (d, 1H), 4.98 (m, 1H), 3.89 (s, 3H), 1.84-1.51 (m, 8H); MS (ESI): 497.8.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C:8]1[N:9]=[CH:10][S:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[Cl:24][C:25]1[C:26]([F:36])=[CH:27][C:28]([F:35])=[C:29]([S:31](Cl)(=[O:33])=[O:32])[CH:30]=1.[Cl-].[NH4+]>O1CCCC1>[C:1]([O:5][C:6](=[O:13])[N:7]([S:31]([C:29]1[CH:30]=[C:25]([Cl:24])[C:26]([F:36])=[CH:27][C:28]=1[F:35])(=[O:33])=[O:32])[C:8]1[N:9]=[CH:10][S:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1cc(Cl)c(F)cc1F
Reactant: CC(C)(C)OC(=O)Nc1cscn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(Cl)c(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
To a solution of thiazol-4-yl-carbamic acid tert-butyl ester (Preparation 3, 503 mg, 2.51 mmol) in tetrahydrofuran (5.0 mL) cooled to −78° C. was added lithium hexamethyldisilazide (1.0 M in tetrahydrofuran, 2.76 mL, 2.76 mmol). The reaction mixture was stirred for 30 minutes at ambient temperature then cooled to −78° C. A solution of 5-chloro-2,4-difluorobenzenesulfonyl chloride (620.5 mg, 2.51 mmol) in tetrahydrofuran (5.0 mL) was added slowly via a syringe. After the addition was complete, the reaction mixture was allowed to warm gradually to ambient temperature. After 24 hours, the reaction mixture was poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo onto diatomaceous earth. The residue was purified by automated silica gel flash chromatography (0% to 5% ethyl acetate in dichloromethane gradient elution) to afford the title compound as a white solid (733 mg).
Reaction SMILES: C([O-])(=O)C.[CH2:5]([N+:12]1[CH:16]=[CH:15][NH:14][C:13]=1[CH2:17][CH:18]1[O:23][C:22]2[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=2[O:20][CH2:19]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[S:28](=[O:32])(=[O:31])([OH:30])[OH:29]>>[S:28](=[O:30])(=[O:29])([OH:32])[OH:31].[CH2:5]([N:12]1[CH:16]=[CH:15][N:14]=[C:13]1[CH2:17][CH:18]1[O:23][C:22]2[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=2[O:20][CH2:19]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: c1ccc(C[n+]2cc[nH]c2CC2COc3ccccc3O2)cc1
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Product: c1ccc(Cn2ccnc2CC2COc3ccccc3O2)cc1

Procedure:
1-Benzyl-2-(1,4-benzodioxan-2-ylmethyl)imidazolium acetate (1.0 g) is dissolved in 50 ml 50% aqueous sulfuric acid, and the solution evaporated to dryness. The product is suspended in ethanol and filtered, air dried and recrystallized from methanol/acetone to yield 1-benzyl-2-(1,4-benzodioxan-2-ylmethyl)imidazole bisulfate.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[CH:11][S:12][C:3]=12.[CH:13]([N-]C(C)C)(C)C.[Li+].CCCCCCC.O1CCCC1.C(C1C=CC=CC=1)C.IC>O1CCCC1>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[C:11]([CH3:13])[S:12][C:3]=12
Reactant: N#Cc1cnc2ccsc2c1Cl
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Product: Cc1cc2ncc(C#N)c(Cl)c2s1
Reaction time: 0.67 h

Procedure:
To a solution of 7-chlorothieno[3,2-b]pyridine-6-carbonitrile (500 mg, 2.57 mmol) in 15 mL of tetrahydrofuran at −78° C. is added dropwise 2.0 M lithium diisopropylamide in heptane/tetrahydrofuran/ethylbenzene (1.6 mL, 3.21 mmol). After stirring for 40 minutes, iodomethane (616 mg, 0.27 mL, 4.34 mmol) is added dropwise over 7 minutes. The reaction mixture is stirred at −78° C. for 5 hours, then the mixture is partitioned between 20 mL of dichloromethane and 10 mL of water. The organic layer is washed with a saturated aqueous ammonium chloride solution, followed by saturated aqueous sodium chloride, then dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of 5% ethyl acetate in hexane to 20% ethyl acetate in hexane to provide 274 mg of 7-chloro-2-methylthieno[3,2-b]pyridine-6-carbonitrile as a white solid, mp 163-164° C.; 1H NMR (DMSO-d6) 82.73 (s, 3H), 7.55 (s, 1H), 9.03 (s, 1H); MS 209.0, 211.1 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([I:12])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:14])([CH3:13])[C@H:3]1[OH:15].[C:16]([C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O)(OC)=[O:17].C([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[CH3:14][C:4]1([CH3:13])[C@@H:3]([OH:15])[C@H:2]([N:1]2[CH2:22][C:21]3[C:20](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:16]2=[O:17])[C:7]2[CH:8]=[C:9]([I:12])[CH:10]=[CH:11][C:6]=2[O:5]1
Reactant: CC1(C)Oc2ccc(I)cc2[C@@H](N)[C@@H]1O
Reactant: COC(=O)c1ccccc1C=O
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CC1(C)Oc2ccc(I)cc2[C@@H](N2Cc3ccccc3C2=O)[C@@H]1O
Temperature: 25 °C
Yield: 94.4 %

Procedure:
To a solution of 5.48 g (17.2 mmol) of trans-4-amino-3,4-dihydro-2,2-dimethyl-6-iodo-2H-1-benzopyran-3-ol as prepared in Example 1 in methanol (34 mL) containing 3.38 g (20.6 mmol) of 2-carbomethoxybenzaldehyde was added 68.7 mL (34.4 mmol) of 0.5 M zinc chloride-modified sodium cyanoborohydride in methanol, prepared according to the method of Kim et. al. L. Org. Chem. 50 (11), 1927 (1985). The reaction mixture was refluxed for 3 h, cooled to room temperature and quenched with water (375 mL). The reaction mixture was extracted into 20% THF/CH2Cl2, and the extracts were dried over MgSO4. Purification was achieved by flash chromatography (CH2Cl2 :MeOH:NH4OH (94.75: 3.5: 1.75) to give 7.07 g of the title compound as a white solid. An analytical sample, mp 224°-228° C., was obtained by additional flash chromatography using (25% Et 2 O-CH2Cl2): 1H-NMR (DMSO-d6 ; 300 MHz) δ7.79 (d, 1 H), 7.53-7.68 (m, 3 H), 7.46 (dd, 1 H), 7.02 (s, 1 H), 6.67 (d, 1 H), 5.75 (d, 1 H), 5.1 (bs, 1 H), 4.5 (br d, 1 H), 4.1 (br, d 1 H), 3.89 (br, 1 H), 1.45 (s, 3 H), and 1.22 ppm (s, 3 H); mass spectrum (CI), m/e 436, 435, 417, 402. Anal. Calcd. for C19H18INO3. 1 H2O: C, 51.36; H, 4.31; N, 3.15 Found: C, 51.62; H, 4.04; N, 2.95.