Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[C:26]=1[C:32](=[O:34])[CH3:33])(=O)C.[O:35]1[CH:39]=[CH:38][C:37]2[CH:40]=[C:41]([CH:44]=O)[CH:42]=[CH:43][C:36]1=2.[OH-].[K+]>[Pt].C(O)C>[C@@H:6]1([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[C:26]=2[C:32](=[O:34])[CH2:33][CH2:44][C:41]2[CH:42]=[CH:43][C:36]3[O:35][CH:39]=[CH:38][C:37]=3[CH:40]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: O=Cc1ccc2occc2c1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2cccc(O)c2C(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Pt]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(CCc1ccc2occc2c1)c1c(O)cccc1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
To a mixture of 2'-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-6'-hydroxyacetophenone (1500 mg), benzo[b]furan-5-carbaldehyde (545 mg) and ethanol (15 ml) is added dropwise a 50% aqueous potassium hydroxide solution (3 ml), and the mixture is stirred at room temperature overnight. The mixture is subjected to catalytic hydrogenation by using as a catalyst 10% platinum on activated carbon (303 mg) under atmospheric pressure. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. To the residue are added toluene and water, and the mixture is stirred. The aqueous layer is collected by filtration, acidified with a 10% hydrochloric acid under ice-cooling, and extracted with ethyl acetate. The obtained organic layer is washed with water, dried, and evaporated to remove the solvent. The residue is purified by silica gel column chromatography to give 2'-(β-D-glucopyranosyloxy)-6'-hydroxy-3-(5-benzo[b]furanyl)propiophenone (982 mg). The physical properties of this product are the same as those of the compound of Example 1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:3]=[C:2]([OH:1])[CH:11]=[C:10]([O:12][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:9]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(O)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(O)cc(OCc2ccccc2)c1
Temperature: 25 °C
Yield: 30.7 %

Procedure:
To a solution of methyl 3,5-dihydroxybenzoate (15.0 g, 89.21 mmol) in 350 mL of acetone was added potassium carbonate (13.56 g, 98.13 mmol) followed by benzyl bromide (11.2 mL, 93.6 mmol). And the mixture refluxed for 3 h. After cooling to rt the solids were filtered and the filtrate was evaporated. The residue was chromatographed on silica gel using an EtOAc-hexane gradient to afford 7.08 g (31%) of 3-benzyloxy-5-hydroxybenzoic acid methyl ester. 1H NMR (300 MHz, DMSO-d6) δ 3.81 (s, 3H), 5.10 (s, 2H), 6.64-6.66 (m, 1H), 6.97-7.01 (m, 2H), 7.35-7.45 (m, 5H), 9.89 (br s, 1H).
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][C:7]([N+:13]([O-])=O)=[CH:8][CH:9]=2)[CH2:4]1>CO.[Pd]>[ClH:1].[CH3:2][N:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][C:7]([NH2:13])=[CH:8][CH:9]=2)[CH2:4]1
Reactant: CN1CCc2ccc([N+](=O)[O-])cc2C1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN1CCc2ccc(N)cc2C1

Procedure:
2-Methyl-7-nitro-1,2,3,4-tetrahydroisoquinoline hydrochloride was dissolved in methanol and hydrogenated at 50 psi in the presence of a catalytic quantity of 10% Pd-C. After 1 h the mixture was filtered through glass and evaporated to provide 2-methyl-1,2,3,4-tetrahydroisoquinolin-7-ylamine hydrochloride, m.p. 137-138° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.C(OCC)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>[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=2)=[CH:19][CH:18]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CC(CNS(C)(=O)=O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc(C(C)CNS(C)(=O)=O)cc2)cc1
Temperature: 100 °C
Yield: 42.1 %

Procedure:
To a degassed solution of 1.4 g (4.7 mmol) of the product of Example 1, 1.0 g (7.1 mmol) of 4-methylbenzeneboronic acid, 1.0 g (7.1 mmol) of potassium carbonate in 30 mL of toluene, and 10 mL of water was added 0.3 g (0.2 mmol) of tetrakis(triphenylphosphine)palladium(0). The mixture was heated to 100° C. for 2 hr, cooled to ambient temperature and the organic portion was separated. The aqueous portion was extracted three times with ethyl acetate and the combined organic portions were dried (MgSO4), filtered and concentrated in vacuo. The residue was chromatographed on silica gel (30% ethyl acetate/hexane) to afford an off-white solid. The solid was suspended in diethyl ether, filtered and dried in vacuo to afford 0.6 g (43%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([O:8]C(OC(C)(C)C)=O)=O)([CH3:4])([CH3:3])[CH3:2].[CH3:16][NH:17][NH2:18].CO.ClCCl>CO>[C:1]([O:5][C:6]([N:17]([CH3:16])[NH2:18])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CNN
Solvent: ClCCl
Solvent: CO
Product: CN(N)C(=O)OC(C)(C)C
Temperature: 5 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
Di-tert-butyl-dicarbonate (0.23.69 g, 108.5 mmol) in methanol (40 mL) was added dropwise over a period of 1.5 h to a solution of methylhydrazine (5.00 g, 106.4 mmol) in methanol (20 mL) cooled to ˜5° C. When the addition was complete, tlc (10% methanol/dichloromethane) indicated that the reaction was complete. The reaction mixture was stored at −20° C. overnight, and then the solvent was evaporated to give N-methyl-hydrazinecarboxylic acid tert-butyl ester (14.34 g, 92%) as a colorless oil which was used directly in the subsequent step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:18])C=1.[OH-].[Na+]>ClCCl>[CH3:8][C:7]1[C:2]([CH:1]=[O:18])=[N:3][CH:4]=[C:5]([CH3:9])[CH:6]=1
Reactant: Cc1cnc(C)c(C)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1cnc(C=O)c(C)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 79.2 %

Procedure:
In dichloromethane (15.0 ml), 2,3,5-trimethyl-pyridine (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (1.29 g) was dissolved. After having been cooled to 0° C., the reaction solution was added with m-chloroperbenzoic acid (2.53 g), followed by stirring at room temperature for 1.5 hours. The reaction solution was added with a 1 mol/l sodium hydroxide aqueous solution and then subjected to extraction with chloroform. Subsequently, the organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate. The drying agent was filtrated out and the solvent was then distilled off, followed by dissolving the resultant residue in dichloromethane (25.0 ml). The reaction solution was added with trifluoroacetic anhydride (2.8 ml) and the whole was refluxed under heating for 3.5 hours. After the reaction solution was cooled to room temperature, the solvent was distilled off. The resultant residue was dissolved in methanol (60.0 ml). After having been cooled to 0° C., the reaction solution was added with a 12.5% sodium methoxide/methanol solution to adjust the solution to pH 10, and the whole was stirred at room temperature for 16.5 hours. After the solvent was distilled off, the residue was added with distilled water and subjected to extraction with chloroform. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate. The drying agent was filtrated out and the solvent was then distilled off, followed by dissolving the residue in chloroform (30.0 ml). The reaction solution was added with manganese dioxide (chemically processed product) (6.10 g) and then stirred at room temperature for 18 hours. The reaction solution was filtrated through Celite. The solvent in the filtrate was distilled off and the resultant residue was then purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (1.14 g) as a yellow oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][O:9]2)=[CH:4][C:3]=1[Cl:11].[NH2:12][CH2:13][CH2:14][OH:15]>C1COCC1.[Cl-].[Na+].O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:9])[CH2:10][NH:12][CH2:13][CH2:14][OH:15])=[CH:4][C:3]=1[Cl:11]
Reactant: NCCO
Reactant: Clc1cc(C2CO2)ccc1Br
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OCCNCC(O)c1ccc(Br)c(Cl)c1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a stirred solution of (RS)-2-(4-bromo-3-chlorophenyl)oxirane (15.2 g) in THF (40 ml) was added 2-aminoethanol (35.1 ml) and the mixture was stirred at room temperature for 7 hours. The reaction mixture was then poured into brine and extracted twice with EtOAc. The combined organic layers was dried over Na2SO4 and concentrated in vacuo to afford (RS)-1-(4-bromo-3-chlorophenyl)-2-(2-hydroxyethylamino)ethanol (19.0 g) as a yellow oil which was used in the next step without further purification. MS (ISP): 298.1 ([{81Br37Cl}M+H]+), 296.0 ([{79Br37Cl/81Br35Cl}M+H]+), 293.9 ([{79Br35Cl}M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: Oc1ccccc1Cl
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccccc1Cl
Temperature: 25 °C
Reaction time: 7 h
Yield: 95 %

Procedure:
To a stirred solution of 2-chlorophenol (6, 20.0 g, 156 mmol) in acetone (300 mL) under nitrogen at ambient temperature were added potassium carbonate (23.7 g, 171 mmol) and ethyl bromoacetate (7, 26.0 g, 156 mmol). The reaction mixture was then heated to reflux and stirred at this temperature under nitrogen for 7 hours. After cooling to ambient temperature, the reaction mixture was filtered to remove insolubles. The filtrate was then concentrated under reduced pressure to give 8 as highly viscous, light yellow oil (32.0 g, 95% yield, 95% pure by LCMS and 1H NMR), 1H NMR (400 MHz; CDCl3): δ 7.16 (m, 1H); 7.03 (m, 1H); 6.76 (m, 1H); 6.71 (m, 1H); 4.90 (s, 2H); 4.12 (q, 2H); 1.33 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][CH:3]=1.[Cl:11]N1C(=O)CCC1=O>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:11])=[N:7][OH:8])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=Cc1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: ON=C(Cl)c1ccc(F)cc1
Temperature: 50 °C

Procedure:
A solution of 4-fluorobenzaldehyde oxime (222 mg, 1.60 mmol) dissolved in 3 mL of DMF was treated with N-chlorosuccinimide (212 mg, 1.60 mmol) and the reaction mixture was heated at 50° C. for 3 hours. The reaction mixture was diluted with 25 mL of ethyl acetate and then washed with H2O (4×20 mL). The organic portion was washed with brine, dried over Na2SO4, filtered and concentrated to give 4-fluoro-N-hydroxybenzenecarboximidoyl chloride as a white solid. The material was dissolved in 10 mL of CH2Cl2 and the solution was cooled to 0° C. A solution of (11S)-11-ethynyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline (190 mg, 0.76 mmol) dissolved in 3 mL of CH2Cl2 was then added followed by triethylamine (318 μL, 2.29 mmol). The reaction was allowed to warm to ambient temperature overnight. The reaction mixture was concentrated and chromatography (0-2% methanol/CHCl3) gave (11R)-11-[3-(4-fluorophenyl)isoxazol-5-yl]-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline as a light-brown solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7](=O)[C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1)[CH3:2].[CH:14]1[C:19]([NH:20][NH2:21])=[CH:18][CH:17]=[C:16]([S:22]([NH2:25])(=[O:24])=[O:23])[CH:15]=1.Cl>O>[CH2:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7](=[N:21][NH:20][C:19]3[CH:18]=[CH:17][C:16]([S:22]([NH2:25])(=[O:23])=[O:24])=[CH:15][CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: CCc1ccc2c(c1)NC(=O)C2=O
Agent: Cl
Solvent: O
Product: CCc1ccc2c(c1)NC(=O)C2=NNc1ccc(S(N)(=O)=O)cc1
Yield: 79 %

Procedure:
The title compound was prepared from 6ethyl-1H-indole-2,3-dione (Krantz and Young, 1989, U.S. Pat. No. 4,873,232) and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G in 79% yield: 1H NMR (DMSO-d6): δ 1.16 (t, J=7.5 Hz, 3H), 2.60 (q, J=7.5 Hz, 2H), 6.74 (s, 1H), 6.89 (d, J=7.5 Hz, 1H), 7.22 (s, 2H), 7.46 (d, J=7.5 Hz, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.75 (d, J=8.7 Hz, 2H), 11.02 (s, 1H), 12.70 (s, 1H); APCI−MS m/z 343 (M−H)−. Anal. Calcd for C16H16N4O3S.0.32 H2O: C, 54.88, H, 4.79; N, 16.00; S, 9.16. Found C, 54.81, H, 4.59; N, 16.06; S, 9.04.
Reaction SMILES: [N:1]([CH:4]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1)=[N+]=[N-]>CO.[Pd]>[NH2:1][CH:4]1[CH2:5][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CC(N=[N+]=[N-])C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(N)C1

Procedure:
A solution of 3-azido-1-(t-butoxycarbonyl)azetidine (3.44 g, 17.4 mmol) (obtained as described in Reference Example 57(2)) in methanol (170 ml) was subjected to catalytic hydrogenation in the presence of 10% palladium on charcoal (3.44 g) at room temperature for 2 hours. After checking the completion of the reaction, the reaction mixture was filtered in order to remove the catalyst. The filtrate was concentrated under reduced pressure to give 3-amino-1-t-butoxycarbonylazetidine as a crude product. This product was dissolved in methylene chloride (170 ml), and chloroformic acid p-nitrobenzyl ester (5.63 g, 26.1 mmol) and triethylamine (3.66 ml, 26.1 mmol) were added thereto in an ice bath. The mixture was stirred at room temperature overnight. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane: ethyl acetate (1:1→1:2) as the eluant to afford 1-t-butoxycarbonyl-3-(p-nitrobenzyloxycarbonylamino)azetidine (4.84 g, yield 79%) as a colorless oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-])=O)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]>CO.[Ni]>[CH2:18]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH2:15])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:19]
Reactant: CCN(CC)CCn1ccc2cc([N+](=O)[O-])ccc21
Agent: [Ni]
Solvent: CO
Product: CCN(CC)CCn1ccc2cc(N)ccc21
Reaction time: 2 h

Procedure:
650 mg (2.487 mmol) of diethyl-[2-(5-nitro-indol-1-yl)-ethyl]-amine was added to a suspension of 200 mg Raney-Ni in 10 mL MeOH and the mixture was hydrogenated for 2 hours at RT under 20 psi H2 atmosphere. The catalyst was filtered off and the filtrate evaporated down i. vac.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([O:17]C)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH3:19]>B(Br)(Br)Br.C(Cl)Cl>[C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH3:19]
Reactant: COc1cccc2c1cc(C)n2Cc1ccccc1-c1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc2c(O)cccc2n1Cc1ccccc1-c1ccccc1
Yield: 54.8 %

Procedure:
By the method used in Example 1, Part D, 1.6 g (4.9 mmol) of 1-([1,1'-biphenyl]-2-ylmethyl)-4-methoxy-2-methyl-1H-indole was O-demethylated by treating it with 20 mL of 1M BBr3 /CH2Cl2. The crude product was chromatographed on silica gel and eluted with 20% EtOAc/hexane to give 841 mg (55% yield) of 1-([1,1'-biphenyl]-2-ylmethyl)-4-hydroxy-2-methyl-1H-indole.
Reaction SMILES: [Cl-].[CH3:2][C:3]1[S:32][C:6]2=[N:7][C:8]([CH2:12][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:9][C:10](=[O:11])[N:5]2[CH:4]=1.[H-].[Na+].[CH:35]1([CH2:38][O:39][C:40]2[C:47]([O:48][CH3:49])=[CH:46][CH:45]=[CH:44][C:41]=2[CH:42]=O)[CH2:37][CH2:36]1.C1(COC2C(OC)=CC=CC=2/C=C/C2N=C3SC=CN3C(=O)C=2I)CC1>CS(C)=O>[CH:35]1([CH2:38][O:39][C:40]2[C:47]([O:48][CH3:49])=[CH:46][CH:45]=[CH:44][C:41]=2/[CH:42]=[CH:12]/[C:8]2[N:7]=[C:6]3[S:32][C:3]([CH3:2])=[CH:4][N:5]3[C:10](=[O:11])[CH:9]=2)[CH2:36][CH2:37]1
Reactant: Cc1cn2c(=O)cc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc2s1
Reactant: COc1cccc(C=O)c1OCC1CC1
Agent: COc1cccc(/C=C/c2nc3sccn3c(=O)c2I)c1OCC1CC1
Agent: [Cl-]
Agent: [H-]
Solvent: CS(C)=O
Product: COc1cccc(/C=C/c2cc(=O)n3cc(C)sc3n2)c1OCC1CC1

Procedure:
A stirred suspension of Step 2 intermediate (1.0 g, 2.096 mmol) in dry DMSO (12 ml) was treated with NaH (92 mg, 2.306 mmol) and 2-(cyclopropylmethoxy)-3-methoxybenzaldehyde (475 mg, 2.306 mmol) according to the procedure described in Step 3, Intermediate 2 to yield a crude solid which was purified by column chromatography using 2% ethyl acetate in DCM to afford the 600 mg of the desired compound as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.31-0.32 (m, 2H), 0.53-0.55 (m, 2H), 0.84-0.86 (s, 1H), 2.42 (s, 1H), 3.74-3.76 (m, 2H), 3.79 (s, 3H), 6.25 (s, 1H), 7.00-7.16 (m, 2H), 7.31-7.33 (m, 1H), 7.80 (s, 1H), 8.06-8.11 (m, 1H); ESI-MS (m/z) 369.24 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:3]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22].C1C(=O)N([I:30])C(=O)C1.FC(F)(F)C(O)=O.[NH4+].[Cl-]>CN(C=O)C>[F:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:3]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:30])=[CH:18][C:17]=1[F:22]
Reactant: COC(=O)c1cc2scnc2c(F)c1Nc1ccccc1F
Reactant: O=C1CCC(=O)N1I
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)c1cc2scnc2c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 4-fluoro-5-((2-fluorophenyl)amino)benzo[d]thiazole-6-carboxylate (1.963 g, 6.14 mmol) in DMF (10 mL) was added NIS (1.5 g, 6.5 mmol) followed by trifluoroacetic acid (0.5 mL). After stirring for 4 h at ambient temperature, the reaction was treated by saturated NH4Cl (aq.). The aqueous layer was extracted with ethyl acetate (150 mL×3). The combined organic layer was washed with water (100 mL×3) and brine (100 mL) sequentially, dried over Na2SO4, filtered and concentrated in vacuo. After purification by flash column chromatography on silica gel (petroleum ether/ethyl acetate, 10:1, v/v), the desired product was obtained as white solid (1.889 g, 69% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.03 (s, 1H), 8.10 (s, 1H), 7.93 (s, 1H), 7.18-6.72 (m, 3H), 3.91 (s, 3H).
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[NH2:10][C:11]1[N:16]=[C:15]([NH2:17])[C:14]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:13]([CH2:25][CH3:26])[N:12]=1.[OH-].[NH4+]>>[NH2:10][C:11]1[N:16]=[C:15]([NH2:17])[C:14]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[C:22]([N+:6]([O-:9])=[O:7])[CH:23]=2)=[C:13]([CH2:25][CH3:26])[N:12]=1
Reactant: O=[N+]([O-])O
Reactant: CCc1nc(N)nc(N)c1-c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: CCc1nc(N)nc(N)c1-c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
Concentrated sulfuric acid, 90 mL, and 70% nitric acid, 90 mL, were stirred together during which time the mixture warmed to about 65° C. The mixture was allowed to cool to about 50° C., and 30.0 grams (0.12 mole) of 2,4-diamino-6-ethyl-5-(4-chlorophenyl)pyrimidine (commercially available) was added portionwise during a 45 minute period, while maintaining the reaction mixture temperature at about 50°-53° C. Upon completion of addition, the reaction mixture was stirred for one hour, while still maintaining the reaction mixture temperature at about 50° C. After this time, the reaction mixture was cooled and poured into ice. The resultant mixture was cooled further and, with stirring, was made basic with concentrated ammonium hydroxide. A precipitate was collected by filtration, rinsed with water and dried, yielding 35.4 grams of 2,4-diamino-6-ethyl-5-(4-chloro-3-nitrophenyl)pyrimidine, mp 220°-223° C., dec. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH2:7])=[N:3]1.[CH2:8]([CH2:12][C:13](=O)[CH3:14])[C:9]([CH3:11])=O.O>C1(C)C=CC=CC=1.CC(O)=O>[CH3:14][C:13]1[N:7]([C:4]2[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=2)[C:9]([CH3:11])=[CH:8][CH:12]=1
Reactant: CC(=O)CCC(C)=O
Reactant: Cn1ccc(N)n1
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1ccn(C)n1

Procedure:
To a solution of 1-methyl-1H-pyrazol-3-amine (9.5 g, 98 mmol) and acetonylacetone (11.2 g, 98 mmol) in toluene (150 mL), AcOH (1.5 mL) is added, heated to reflux with a water separator until the formation of water ceased. Concentrated to dry. The residue is purified by flash column to give product.
Reaction SMILES: [Cl:1][C:2]1[N:13]=[CH:12][CH:11]=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[CH3:14][Mg]Cl>O1CCCC1>[Cl:1][C:2]1[C:3]([C:4](=[O:5])[CH3:14])=[CH:10][CH:11]=[CH:12][N:13]=1
Reactant: CON(C)C(=O)c1cccnc1Cl
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(=O)c1cccnc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
A solution of 2-chloro-N-methoxy-N-methyl-nicotinamide (23.6 g, 118 mmol) in tetrahydrofuran (350 mL, 0.34M) at 0° C. was treated dropwise via an addition funnel with methyl magnesium chloride (3.0M solution in tetrahydrofuran, 100 mL, 300 mmol). The reaction became a very thick opaque white mixture and was diluted with additional tetrahydrofuran (150 mL). The reaction was stirred at 0° C. for 1 h. At this time, the reaction was carefully quenched with water (250 mL) and then partitioned between additional water (250 mL) and ethyl acetate (250 mL). The aqueous layer was back extracted with ethyl acetate (2×250 mL). The combined organics were washed with a saturated aqueous sodium chloride solution (250 mL), dried over magnesium sulfate, filtered, rinsed with ethyl acetate, and concentrated in vacuo. Flash chromatography (AnaLogix Intelliflash 280, 400 g silica gel column, 25-50% ethyl acetate/hexanes) afforded 1-(2-chloro-pyridin-3-yl)-ethanone (13.17 g, 72%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH3:11]O>S(=O)(=O)(O)O>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:11])=[O:7])=[CH:4][N:3]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(N)nc1

Procedure:
6-Aminonicotinic acid (2 g, 22 mmol) was dissolved in methanol (10 ml) and sulphuric acid (0.5 ml). The solution was refluxed over-night and the solvent was evaporated under vacuum. The crude product was dissolved in water-EtOAc and made alkaline by aqueous sodium hydrogencarbonate. Extraction by EtoAc yielded the pure intermediate depicted above (2.3 g, 70%).