Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](Br)[CH:16]=2)[CH:11]=[CH:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:25][N:26]([CH3:38])[C:27]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)=[O:28]>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.CN(C=O)C>[CH2:1]([O:8][N:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:33]3[CH:34]=[C:29]([CH:30]=[CH:31][CH:32]=3)[C:27]([N:26]([CH3:38])[CH3:25])=[O:28])[CH:16]=2)[CH:11]=[CH:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cnc2ccn(OCc3ccccc3)c2c1
Reactant: CN(C)C(=O)c1cccc(B(O)O)c1
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: CN(C)C=O
Product: CN(C)C(=O)c1cccc(-c2cnc3ccn(OCc4ccccc4)c3c2)c1

Procedure:
A solution of 1-(benzyloxy)-6-bromo-1H-pyrrolo[3,2-b]pyridine (60 mg, 0.21 mmol, 1.0 eq), Pd(PPh3)4 (13 mg), 2.0 M K2CO3 (1.0 ml), DMF (1.2 ml), and [3-(dimethylcarbamoyl)phenyl]boronic acid (1.5 eq, 0.315 mmol) were reacted in microwave (110° C.) for 20 minutes. The upper layer was removed with a pipette and filtered, and purified with preparation HPLC to give the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:12][S:13]([C:16]([CH3:21])([CH3:20])[C:17](Cl)=[O:18])(=[O:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29]1([NH2:32])[CH2:31][CH2:30]1>N1C=CC=CC=1>[CH:29]1([NH:32][C:17]([C:16]([S:13]([CH2:12][CH:11]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])(=[O:15])=[O:14])([CH3:21])[CH3:20])=[O:18])[CH2:31][CH2:30]1
Reactant: NC1CC1
Reactant: CC(C)(C(=O)Cl)S(=O)(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C(=O)NC1CC1)S(=O)(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1
Yield: 86.6 %

Procedure:
A solution of 1.07 g (2.5 mmol) of (RS)-2-[[2-[(benzyloxy)carbonyl]-3-phenylpropyl]sulfonyl]-2-methylpropionyl chloride and 0.42 g (7.4 mmol) of cyclopropylamine in 20 ml of pyridine was stirred at room temperature for 2 hours. Thereafter, the reaction solution was evaporated under reduced pressure and the residue was chromatographed on 30 g of silica gel using a 99:1 mixture of methylene chloride and methanol as the eluent. There was obtained 0.96 g of benzyl rac-α-[[[1-(cyclopropylcarbamoyl)-1-methylethyl]sulfonyl]methyl]hydrocinnamate as a yellowish solid, MS: 444 (M)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([N:32]4[CH2:36][CH2:35][C:34]([F:38])([F:37])[CH2:33]4)[C:17]4[CH2:22][CH2:21][CH:20]([C:23]5[CH:28]=[C:27]([F:29])[C:26]([F:30])=[C:25]([F:31])[CH:24]=5)[C:18]=4[N:19]=3)=[CH:9][C:8]=2[O:39][CH3:40])[CH:6]=1>C(=O)=O.CO>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([N:32]4[CH2:36][CH2:35][C:34]([F:37])([F:38])[CH2:33]4)[C:17]4[CH2:22][CH2:21][C@H:20]([C:23]5[CH:28]=[C:27]([F:29])[C:26]([F:30])=[C:25]([F:31])[CH:24]=5)[C:18]=4[N:19]=3)=[CH:9][C:8]=2[O:39][CH3:40])[CH:6]=1
Reactant: COc1cc(Nc2nc3c(c(N4CCC(F)(F)C4)n2)CCC3c2cc(F)c(F)c(F)c2)ccc1-n1cnc(Cl)c1
Agent: O=C=O
Solvent: CO
Product: COc1cc(Nc2nc3c(c(N4CCC(F)(F)C4)n2)CC[C@@H]3c2cc(F)c(F)c(F)c2)ccc1-n1cnc(Cl)c1

Procedure:
A racemic mixture of N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoropyrrolidin-1-yl)-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine (48 mg, 0.083 mmol from Example 107) was purified using chiral SFC to afford 19.8 mg of peak A (Example 107A) and 17.2 mg of peak B (Example 107B). SFC Method: Chiralpak OJ-H (4.6×250 mm, 5 μM), 25% methanol (0.1% diethylamine) in CO2, 35° C., flow rate 2.0 mL/min for 30 min, absorbance 268 nm, injection 5 μL of 2 mg/mL solution in methanol (multiple stacked injections), tR (peak A)=17.4 min, tR (peak B) 21.2 min. The absolute stereochemistry of individual enantiomers (Examples 107A and 107B) was not determined LC-MS and 1H NMR analytical data for the separated enantiomers was identical to the racemate (Example 107).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][CH:31]4[CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32]4)[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:30][CH:31]4[CH2:32][NH:33][CH2:34]4)[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CC4CN(C(=O)OC(C)(C)C)C4)c4ccc(OC(F)F)cc34)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3nn(CC4CNC4)c4ccc(OC(F)F)cc34)nc12
Reaction time: 1 h
Yield: 41.1 %

Procedure:
To a stirred solution of tert-butyl 3-((3-(7-(tert-butylcarbamoyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-5-(difluoromethoxy)-1H-indazol-1-yl)methyl)azetidine-1-carboxylate (80 mg, 114 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL). After 15 h the mixture was concentrated in vacuo and the residue dissolved in 25 mL of a Jan. 10, 1960 mixture of ammonium hydroxide/methanol/dichloromethane. After 1 h, the mixture was concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-4% methanol containing 10% ammonium hydroxide in dichloromethane) gave 2-(1-azetidin-3-ylmethyl-5-difluoromethoxy-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (22 mg, 41%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@@H:9]([O:13][C:14]1[NH:15][C:16]([NH2:25])=[C:17]2[C:21]([N:22]=1)=[N:20][C:19]([O:23][CH3:24])=[N:18]2)[CH2:10][CH2:11][CH3:12].Br[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][O:33][CH2:32]1>>[CH3:8][C@@H:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]2[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]2[CH2:36][CH2:35][CH2:34][O:33][CH2:32]2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][CH2:11][CH3:12]
Reactant: BrCCCCC1CCCOC1
Reactant: CCC[C@@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@@H](C)Oc1nc(N)c2nc(OC)n(CCCCC3CCCOC3)c2n1

Procedure:
Prepared similarly to Intermediate 213 from 2-{[(1R)-1-methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 3-(4-bromobutyl)tetrahydro-2H-pyran.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[NH2:45][C:46]1[O:50][C:49]([C:51]([O:53][CH3:54])=[O:52])=[CH:48][CH:47]=1>ClCCl.CN(C1C=CN=CC=1)C.O.CN(C=O)C>[CH3:54][O:53][C:51]([C:49]1[O:50][C:46]([NH:45][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10]2)=[O:29])=[CH:47][CH:48]=1)=[O:52]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: COC(=O)c1ccc(N)o1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)o1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (0.5 g, 1.07 mmol) in dichloromethane (5 mL) at 0° C. was added oxalyl chloride (0.11 mL, 1.28 mmol) and DMF (0.03 mL). The reaction mixture was stirred at 0° C. for 3 h, then concentrated. The residue was dissolved into dichloromethane (5 mL), triethylamine (0.45 mL, 3.2 mmol) and DMAP (20 mg, 0.14 mmol) were added, followed by the addition of methyl 5-amino-2-furate (Lancaster) (0.38 g, 2.7 mmol). The reaction mixture was stirred at room temperature for 4 h. Water was added, and the mixture was extracted with dichloromethane twice. The organic layers were combined, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:3) to give rac-5-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-furan-2-carboxylic acid methyl ester as a off white solid (0.1 g, 16%).
Reaction SMILES: [Cl-].C(OC(NCC/C(/N1CCCC1)=C/C(OCC)=O)=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:27][C:28]1[C:32]2[C:33](=[O:37])[NH:34][CH:35]=[CH:36][C:31]=2[O:30][N:29]=1>>[O:30]([C:31]1[CH:36]=[CH:35][C:27]([C:28]2[C:32]3[C:33](=[O:37])[NH:34][CH:35]=[CH:36][C:31]=3[O:30][N:29]=2)=[CH:28][CH:32]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1noc2cc[nH]c(=O)c12
Reactant: CCOC(=O)/C=C(/CCNC(=O)OCc1ccccc1)N1CCCC1
Agent: [Cl-]
Product: O=c1[nH]ccc2onc(-c3ccc(Oc4ccccc4)cc3)c12

Procedure:
The title compound was prepared from 4-phenoxybenzohydroxyiminoyl chloride, prepared using the procedure described in Jones, Raymond C. F. et al, J. Med. Chem. 2003, 46, 87-96, and ethyl (Z)-5-{[(benzyloxy)carbonyl]amino}-3-tetrahydro-1H-1-pyrrolyl-2-pentenoate, prepared using the procedure described in Natale, Nicholas, R. et al, J. Chem. Soc. Perkins Trans. I, 1999, 765-776, using a manner similar to that described in Natale, Nicholas, R. et al, J. Chem. Soc. Perkins Trans. I, 1999, 765-776 for the preparation of 3-methyl-4,5-dihydroisoxazolo[4,5-c]pyridin-4-one. 1H NMR (DMSO-d6, 400 MHz) δ 8.31 (d, 2H), 7.66 (d, 1H), 7.46 (t, 2H), 7.22 (t, 1H), 7.1-7.15 (m, 5H), 6.82 (d, 1H); Rt=3.03 min (Conditions a), MS m/e: 303 (M−H)−.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[O:15]=[C:16]1[C:25]2([CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:31][CH3:32])[CH:23]=2)[CH2:18][CH2:17]1.[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35].CO>C(OCC)(=O)C>[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:28]3[CH2:29][CH2:30][C:25]4([C:24]5[C:19](=[CH:20][CH:21]=[C:22]([O:31][CH3:32])[CH:23]=5)[CH2:18][CH2:17][C:16]4=[O:15])[CH2:26][CH2:27]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: COc1ccc2c(c1)C1(CCNCC1)C(=O)CC2
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc2c(c1)C1(CCN(C[C@H](O)COc3cccc4[nH]ccc34)CC1)C(=O)CC2

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 3,4-dihydro-2-oxo-7-methoxyspiro[naphthalene-1(2H),4'-piperidine]. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 55% overall yield. FDMS m/e=434 (M+ of free base). α[D]589 =-5.55(c=0.54, methanol).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11](O)=[CH:10][N:9]=1.CI.CN(C)C=O>C(OCC)(=O)C>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([O:4][CH3:1])=[CH:10][N:9]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(Cl)nc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.7 %

Procedure:
Under a nitrogen atmosphere, potassium carbonate (5.52 g) was added to a mixture of 2-chloro-5-hydroxy-pyridine (2.591 g), methyl iodide (1.50 ml) and dimethylformamide (26 ml), and the mixture was stirred at room temperature for 18 hr. To the reaction mixture was added ethyl acetate and the mixture was placed in a separatory funnel. The organic layer was washed 4 times with aqueous ammonium chloride, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (2.403 g, 84%).
Reaction SMILES: [H-].[Na+].O1CCCC1.[F:8][C:9]1[C:14]([N:15]2[C:19]([CH3:20])=[C:18]([C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[C:26](=[O:30])[C:25]([CH3:35])([O:31]C(C)=O)[CH2:24]4)[N:17]=[N:16]2)=[CH:13][CH:12]=[CH:11][N:10]=1>C(OCC)(=O)C>[F:8][C:9]1[C:14]([N:15]2[C:19]([CH3:20])=[C:18]([C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[C:26](=[O:30])[C:25]([OH:31])([CH3:35])[CH2:24]4)[N:17]=[N:16]2)=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: CC(=O)OC1(C)Cc2cc(-c3nnn(-c4cccnc4F)c3C)ccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccc3c(c2)CC(C)(O)C3=O)nnn1-c1cccnc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.5 %

Procedure:
At room temperature, 100 μl of 2M sodium hydride aqueous solution was added to 1 ml solution of tetrahydrofuran with 30 mg of 1-(2-fluoropyridine-3-yl)-4-(2-methyl-2-methylcarbonyloxy-1-oxoindane-5-yl)-5-methyl-1H-[1,2,3]triazole obtained in Example 51. The mixture was stirred at room temperature for 1 hour, diluted with ethyl acetate, washed with water and saturated saline solution, and dried with anhydrous sodium sulfate. The residues obtained by distilling out the solvents under reduced pressure were purified by silicagel column chromatography (hexane:ethyl acetate=80:20) to obtain 10 mg of the above compound as a white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[N:8][C:9](=[S:11])[N:10]=1.[Na].Br[C:14]1[S:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][N:18]=1>>[N+:19]([C:16]1[S:15][C:14]([S:11][C:9]2[N:10]=[C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[NH:7][N:8]=2)=[N:18][CH:17]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1cnc(Br)s1
Reactant: S=C1N=NC(c2cccs2)=N1
Agent: [Na]
Product: O=[N+]([O-])c1cnc(Sc2n[nH]c(-c3cccs3)n2)s1

Procedure:
The title compound was prepared in the manner described in Example 1. Substituting the acid chloride of thiophene-2-carboxylic acid (prepared from the acid and oxalyl chloride) for the benzoyl chloride in Example 1 gave the thiosemicarbazide of thiophene-2-carboxylic acid and then 3-(thien-2-yl)-1,2,4-triazole-5-thione. Reaction of 1.73 g of the sodium salt of the thione with 2.09 g of 2-bromo-5-nitrothiazole as in Example 1 yielded 1 g of 3-[(5-nitrothiazol-2-yl)mercapto]-5-(thien-2-yl)-1,2,4-triazole, an orange solid, MP 179°-181° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]3=[N:14][C:15]4[C:16](=[C:17]([C:22]([O:24][CH3:25])=[O:23])[CH:18]=[CH:19][C:20]=4[Cl:21])[N:12]3[CH2:11][CH2:10][CH2:9]2)=[C:4]([Cl:26])[CH:3]=1.C[O-].[Na+].[C:30](=O)([O-])[O-:31].[K+].[K+].CI>CN(C)C=O.[Cu]I>[Cl:21][C:20]1[CH:19]=[CH:18][C:17]([C:22]([O:24][CH3:25])=[O:23])=[C:16]2[C:15]=1[N:14]=[C:13]1[N:8]([C:5]3[CH:6]=[CH:7][C:2]([O:31][CH3:30])=[CH:3][C:4]=3[Cl:26])[CH2:9][CH2:10][CH2:11][N:12]21
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Br)cc1Cl
Agent: [Cu]I
Agent: C[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)cc1Cl
Temperature: 100 °C
Reaction time: 10 h

Procedure:
To a solution of methyl 1-(4-bromo-2-chlorophenyl)-9-chloro-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxylate (200.0 mg, 0.439 mmol) in N,N-dimethylformamide (2.0 mL) were added copper(I) iodide (125.5 mg, 0.659 mmol) and sodium methoxide (28% wt methanol solution, 1.0 mL). The reaction mixture was stirred at 100° C. for 10 hrs. After cooling, the mixture was filtered through on the pad of celite. The filtrate was diluted with water and extracted with ethyl acetate (×1). The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude product was subject to next step without further purification. The resulting carboxylic acid was dissolved into N,N-dimethylformamide (3.0 mL) and to the mixture were added potassium carbonate (130.9 mg, 0.947 mmol) and methyl iodide (88.5 μL, 1.422 mmol) at 0° C. The reaction mixture was stirred at room temperature for 16.5 hrs. The mixture was quenched with aqueous saturated ammonium chloride and extracted with ethyl acetate (×3). The combined organic layer was washed with water (×2) and brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-35% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless amorphous (121.8 mg, 0.300 mmol, 68% (2 steps)).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[O:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[C:10]([O:12][CH3:13])=[O:11].[C:14](Br)([CH3:17])([CH3:16])[CH3:15].Cl>C(=S)=S>[C:14]([C:9]1[O:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: COC(=O)c1ccco1
Reactant: CC(C)(C)Br
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COC(=O)c1ccc(C(C)(C)C)o1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
AlCl3 (25.4 g, 190 mmol) is added batchwise to methyl furan-2-carboxylate (20.0 g, 159 mmol) and tert.-butylbromide (21.4 mL, 190 mmol) in CS2 (200 mL) while cooling with ice and the mixture is stirred for 6 h at RT. The reaction mixture is poured onto ice water, mixed with conc. hydrochloric acid (25 mL) and stirred for 10 min. Then the aqueous phase is extracted 2× with 200 mL EA. The combined organic phase is dried on Na2SO4, filtered and evaporated down using the rotary evaporator. The methyl 5-tert.-butyl-furan-2-carboxylate thus obtained is used further without any additional purification steps.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10](=[O:12])[NH:9][C:8]=2[CH:13]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:16]I>CN(C=O)C>[CH3:16][N:9]1[C:8]2[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[O:11][C:10]1=[O:12]
Reactant: O=c1[nH]c2cc([N+](=O)[O-])ccc2o1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)oc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A solution of 5-nitro-3H-benzooxazol-2-one (26 g) in DMF (100 mL) was added to a suspension of NaH (60% in mineral oil, 10.71 g) in DMF (100 mL) over a period of 1 hour. Stirring was continued for 45 minutes at r.t. The mixture was cooled to 0° C. and methyl iodide dissolved in DMF (20 mL) was added dropwise over a period of 30 minutes. The mixture was stirred over night at r.t. The reaction mixture was poured into ice/water and extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. CH2Cl2:methanol=4:1 (150 mL) was added to the resulting precipitate and the suspension was stirred for 1 hour at r.t. The solid was filtered off and dried in vacuo. The title compound was obtained as a orange solid (18.33 g, 62%). MS (EI)=194.0 [M+].
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:30])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([OH:28])([CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=1)[CH2:9][C:8]2=[O:29])(=[O:3])[CH3:2].O1CCCC1>[Pd].C(O)C>[C:1]([O:4][C:5]1[C:6]([CH3:30])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=1)([OH:28])[CH2:9][C:8]2=[O:29])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)C(=O)CC(O)(COc1ccc([N+](=O)[O-])cc1)O2
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)C(=O)CC(O)(COc1ccc(N)cc1)O2

Procedure:
Following the same procedure as described in Preparation 24, 7 g of 6-acetoxy-2-hydroxy-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)chroman-4-one (prepared as described in Preparation 43) were treated with 5 g of 10% w/w palladium-on-carbon, 100 ml of tetrahydrofuran and 100 ml of ethanol, to give the title compound.
Reaction SMILES: [H-].[Na+].C([O:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([OH:17])=[C:12]([CH3:18])[C:11]=1[CH3:19])(=O)C(C)(C)C.[CH3:20][O:21][CH2:22]Cl>O1CCCC1>[CH3:20][O:21][CH2:22][O:17][C:13]1[C:14]([CH3:16])=[CH:15][C:10]([OH:9])=[C:11]([CH3:19])[C:12]=1[CH3:18]
Reactant: Cc1cc(OC(=O)C(C)(C)C)c(C)c(C)c1O
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1c(C)cc(O)c(C)c1C
Reaction time: 0.5 h

Procedure:
Sodium hydride (8.51 g, 55% suspension in mineral oil) was added to a solution of 4-hydroxy-2,3,5-trimethylphenol pivalate (35.4 g) in tetrahydrofuran (300 ml) at room temperature. The mixture was stirred for 30 minutes. To the reaction mixture was added dropwise methoxymethyl chloride (15.7 g). This mixture was stirred at room temperature for 1 hour. The solvent of the reaction mixture was evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in methanol (100 ml) and to this solution was added dropwise a solution of potassium hydroxide (16.8 g) in methanol (100 ml). The mixture was stirred at room temperature and concentrated under reduced pressure. The residue was neutralized with 3N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column using hexane:ethyl acetate=5:1 as the eluant to afford the title compound (27.5 g, Rf=0.16: thin layer chromatography on a silica gel plate using hexane:ethyl acetate=4:1 as the eluant).
Reaction SMILES: [CH2:1]([O:5][CH:6]([P:15](=[O:22])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])[P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].[CH2:29](Br)[CH2:30][CH2:31][CH3:32]>C(O)(C)(C)C.C(OCC)(=O)C>[CH2:1]([O:5][C:6]([P:15](=[O:22])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])([P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Reactant: CCCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: CCCCOC(CCCC)(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Reaction time: 0.5 h

Procedure:
Tetraethyl (n-butoxymethylene)-bisphosphonate (1.2 g) was added to a stirred solution of potassium tert-butoxide (0.37 g) in tert-butanol (5 ml). After 30 minutes at room temperature, butyl bromide (0.36 ml) was added, and the mixture was refluxed for 8 hours. After cooling, the mixture was diluted with ethyl acetate and washed with water. The organic phase was dried and evaporated to give an oil which was purified by chromatography to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[S:17][C:16]([C:18]([O:20][CH3:21])=[O:19])=[CH:15][CH:14]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:13]2[S:17][C:16]([C:18]([O:20][CH3:21])=[O:19])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: COC(=O)c1ccc(Br)s1
Product: COC(=O)c1ccc(-c2ccc(OC)cc2)s1
Yield: 62.6 %

Procedure:
Following General Procedure B, 4-methoxyphenylboronic acid (2.7 g, 18 mmol) was reacted with methyl 5-bromothiophene-2-carboxylate (2.0 g, 9.0 mmol) to afford the desired product (1.4 g, 61%): 1H NMR (300 MHz, CDCl3) δ 7.71 (d, J=3.9 Hz, 1H), 7.53 (td, J=9.7, 2.5 Hz, 2H), 7.14 (d, J=3.9 Hz, 1H), 6.89 (td, J=9.7, 2.5 Hz, 2H), 3.87 (s, 3H), 3.80 (s, 3H).