Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:17]=[C:16](I)[C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2].[OH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].C(C1C=C(C2C=CC=C(CO)C=2)C2N(C3C=CC=CC=3)C=NC=2C=1)#N>C1(C)C=CC=CC=1.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>[C:1]([C:3]1[CH:17]=[C:16]([C:24]2[CH:25]=[CH:26][C:21]([CH2:20][OH:19])=[CH:22][CH:23]=2)[C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: N#Cc1cc(I)c2c(c1)ncn2-c1ccccc1
Reactant: OCc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#Cc1cc(-c2cccc(CO)c2)c2c(c1)ncn2-c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: N#Cc1cc(-c2ccc(CO)cc2)c2c(c1)ncn2-c1ccccc1

Procedure:
5-Cyano-7-(4-hydroxymethylphenyl)-1-phenylbenzimidazole was prepared from 5-cyano-7-iodo-1-phenylbenzimidazole (1.0 g, 2.90 mmol), 4-hydroxymethylphenylboronic acid (440 mg, 2.90 mmol), tetrakis(triphenylphosphine)palladium(0) (330 mg, 2.90 mmol) and potassium carbonate (2M in water, 2.9 ml, 800 mg, 5.8 mmol) in toluene (8.0 ml) and ethanol (2.0 ml) using the method described for 5-cyano-7-(3-hydroxymethylphenyl)-1-phenylbenzimidazole. 5-Cyano-7-(4-hydroxymethylphenyl)-1-phenylbenzimidazole was obtained as a white solid (711 mg) m/z, 326.3 (M+H)+.
Reaction SMILES: [C:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]#[N:16])=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.[CH3:17]Br.[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[C:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:17])[C:15]#[N:16])=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CCc1ccc(C(=O)c2cccs2)cc1
Reactant: CBr
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC(C#N)c1ccc(C(=O)c2cccs2)cc1
Temperature: 35 °C
Reaction time: 5 h

Procedure:
11.4 parts of 2-[p-(2-thenoyl)phenyl] acetonitrile, 4.9 parts of methyl bromide and 0.13 parts of benzyl triethyl ammonium chloride are added to 30 parts of a 50% sodium hydroxide solution. The whole is stirred vigorously for 5 hours at 35° C. Distilled water is added. The organic layer is separated, washed with distilled water and evaporated. The oily residue is distilled, yielding p-(2-thenoyl)hydratroponitrile.
Reaction SMILES: [O:1]=[C:2]([NH:34][O:35]C1CCCCO1)/[CH:3]=[CH:4]/[C:5]1[CH:6]=[CH:7][C:8]([N:11]([C@@H:19]2[CH2:23][CH2:22][N:21]([CH2:24][C:25]3[C:30]([CH3:32])([CH3:31])[CH2:29][CH2:28][CH2:27][C:26]=3[CH3:33])[CH2:20]2)C(=O)OC(C)(C)C)=[N:9][CH:10]=1.[ClH:42]>CO>[ClH:42].[ClH:42].[OH:35][NH:34][C:2](=[O:1])/[CH:3]=[CH:4]/[C:5]1[CH:10]=[N:9][C:8]([NH:11][C@@H:19]2[CH2:23][CH2:22][N:21]([CH2:24][C:25]3[C:30]([CH3:31])([CH3:32])[CH2:29][CH2:28][CH2:27][C:26]=3[CH3:33])[CH2:20]2)=[CH:7][CH:6]=1
Reactant: CC1=C(CN2CC[C@@H](N(C(=O)OC(C)(C)C)c3ccc(/C=C/C(=O)NOC4CCCCO4)cn3)C2)C(C)(C)CCC1
Agent: Cl
Solvent: CO
Product: CC1=C(CN2CC[C@@H](Nc3ccc(/C=C/C(=O)NO)cn3)C2)C(C)(C)CCC1

Procedure:
To a stirred solution of tert-butyl (5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridinyl){(3R)-1-[(2,6,6-trimethyl-1-cyclohexen-1-yl)methyl]-3-pyrrolidinyl}carbamate (80 mg) in methanol (1 mL) was added 4N hydrogen chloride in methanol (3 mL) at ambient temperature and the mixture was stirred at the same temperature for fifteen minutes. The mixture was concentrated in vacuo and the mixture was dissolved in dioxane (1 mL). To this solution was added 4N hydrogen chloride in dioxane (3 mL) and the mixture was stirred at ambient temperature for two hours. The reaction mixture was concentrated in vacuo and the resulting solid was triturated with acetonitrile to give (2E)-N-hydroxy-3-[6-({(3R)-1-[(2,6,6-trimethyl-1-cyclohexen-1-yl)methyl]-3-pyrrolidinyl}amino)-3-pyridinyl]acrylamide dihydrochloride (40 mg) as a pale tan amorphous solid.
Reaction SMILES: Br[C:2]1[C:3]([F:23])=[C:4]([F:22])[C:5]2[C:15](=[O:16])[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][N:7]3[C@@H:8]([CH3:12])[CH2:9][O:10][C:11]=1[C:6]=23.[CH3:24][C:25]1[CH:30]=[C:29]([Sn](C)(C)C)[CH:28]=[C:27]([CH3:35])[N:26]=1.CN(C)P(N(C)C)(N(C)C)=O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:24][C:25]1[CH:30]=[C:29]([C:2]2[C:3]([F:23])=[C:4]([F:22])[C:5]3[C:15](=[O:16])[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][N:7]4[C@@H:8]([CH3:12])[CH2:9][O:10][C:11]=2[C:6]=34)[CH:28]=[C:27]([CH3:35])[N:26]=1
Reactant: Cc1cc([Sn](C)(C)C)cc(C)n1
Reactant: CCOC(=O)c1cn2c3c(c(Br)c(F)c(F)c3c1=O)OC[C@@H]2C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1COCCO1
Product: CCOC(=O)c1cn2c3c(c(-c4cc(C)nc(C)c4)c(F)c(F)c3c1=O)OC[C@@H]2C
Yield: 16.6 %

Procedure:
To a mixture of 14.08 g ethyl (S)-10-bromo-8,9-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate, 10.91 g 2,6-dimethyl-4-trimethylstannylpyridine and 6.3 ml hexamethylphosphoramide in 200 ml dioxane under nitrogen was added 1.27 g dichlorobis(triphenylphosphine)palladium. The reaction mixture was heated at reflux for 24 hrs. Most of the solvent was then removed in vacuo and the residue was extracted with ethyl acetate and water, and then with chloroform. The organic extracts were combined and concentrated. The residue was chromatographed on silica gel using as eluant chloroform and chloroform containing increasing amounts of methanol (1-3%). There was thereby obtained 2.5 g pure ethyl (S)-10-(2,6-dimethyl-4-pyridinyl)-8,9-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate, light yellow solid, m.p. 295°-297° C., [α]D25 =-34.4° (1% in chloroform).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:34]1[CH:43]=[CH:42][C:37]2[N:38]=[C:39]([CH3:41])[S:40][C:36]=2[CH:35]=1)[C:9]1[N:20]2[C:16](=[CH:17][CH:18]=[N:19]2)[N:15]=[C:14]2[C:10]=1[CH2:11][CH2:12][N:13]2[C@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I:44]N1C(=O)CCC1=O>C1COCC1>[I:44][C:17]1[CH:18]=[N:19][N:20]2[C:16]=1[N:15]=[C:14]1[C:10]([CH2:11][CH2:12][N:13]1[C@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]1)=[C:9]2[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:34]1[CH:43]=[CH:42][C:37]2[N:38]=[C:39]([CH3:41])[S:40][C:36]=2[CH:35]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1nc2ccc(N(C(=O)OC(C)(C)C)c3c4c(nc5ccnn35)N([C@H]3CCCN(C(=O)OC(C)(C)C)C3)CC4)cc2s1
Solvent: C1CCOC1
Product: Cc1nc2ccc(N(C(=O)OC(C)(C)C)c3c4c(nc5c(I)cnn35)N([C@H]3CCCN(C(=O)OC(C)(C)C)C3)CC4)cc2s1
Reaction time: 3 h
Yield: 93.1 %

Procedure:
To a THF solution (1.5 mL) of tert-butyl (S)-3-[8-{tert-butoxycarbonyl-(2-methylbenzothiazol-6-yl)amino}-6,7-dihydro-1,4,5,8a-tetraaza-s-indacen-5-yl]piperidine-1-carboxylate (97.6 mg, 0.161 mmol), N-iodosuccinimide (43.5 mg, 0.193 mmol) was added at room temperature and the mixture was stirred for 3 hr. After the reaction, the reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and then brine and dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was removed under reduced pressure and the residue was purified with column chromatography (30% ethyl acetate-hexane) to obtain the title compound (109.7 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:18])=[CH:3][CH2:4][C:5]1[C:15](=[O:16])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:7](=[O:8])[C:6]=1[OH:17].S(=O)(=O)(O)O>C(Cl)Cl>[CH3:1][C:2]1([CH3:18])[O:16][C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:7]([C:6](=[O:17])[C:5]=2[CH2:4][CH2:3]1)=[O:8]
Reactant: CC(C)=CCC1=C(O)C(=O)c2ccccc2C1=O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC1(C)CCC2=C(O1)c1ccccc1C(=O)C2=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
17.4 g (0.10M) of 2-hydroxy-1,4-naphthoquinone was dissolved in 120 ml of DMSO, and 0.88 g (0.11M) of LiH was gradually added thereto. Here, this should be done with care because hydrogen evolves. The reaction solution was stirred, and after confirming no further production of hydrogen, was additionally stirred for another 30 min. Then, 14.8 g (0.11M) of methallyl bromide (1-bromo-2-methylpropene) and 3.35 g (0.025M) of LiI were gradually added thereto. The reaction solution was heated to 45° C. and then stirred vigorously for 12 hours at that temperature. The reaction solution was cooled below 10° C., and 80 g of ice was first added and 250 ml of water was then added. Thereafter, 25 ml of concentrated HCl was gradually added to maintain the resulting solution at an acidic pH>1. 200 ml of CH2Cl2 was added to the reaction mixture which was then shaken vigorously to separate two layers. The aqueous layer was extracted once again with addition of 70 ml of CH2Cl2 and was combined with the previously extracted organic layer. Two materials were confirmed to be formed newly by TLC and were subsequently used without any particular separation process. The organic layer was concentrated by distillation under reduced pressure, dissolved again in xylene and then refluxed for 8 hours. In this process, two materials on TLC were combined into one, thereby obtaining a relatively pure Lapachol derivative. The thus-obtained Lapachol derivative was mixed with 80 ml of sulfuric acid and stirred vigorously at room temperature for 10 min, and 200 g of ice was added thereto to complete the reaction. 80 ml of CH2Cl2 was added to the reaction materials which were then shaken vigorously. Thereafter, a CH2Cl2 layer was separated and washed with 5% NaHCO3. An aqueous layer was extracted once again using 50 ml of CH2Cl2, washed with 5% NaHCO3 and combined with the previously extracted organic layer. The organic layer was dried over MgSO4 and concentrated to give impure β-Lapachone derivative (Compound 4). The thus-obtained β-Lapachone derivative was recrystallized from isopropanol, thereby obtaining 12.21 g of pure Compound 4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[NH2:6].C(=O)([O-])[O-].[Na+].[Na+].[Cl:18][CH2:19][CH2:20][CH2:21][S:22](Cl)(=[O:24])=[O:23]>C1(C)C(C)=CC=CC=1>[CH3:11][O:10][C:8]1[CH:7]=[C:5]([NH:6][S:22]([CH2:21][CH2:20][CH2:19][Cl:18])(=[O:24])=[O:23])[CH:4]=[C:3]([O:2][CH3:1])[CH:9]=1
Reactant: COc1cc(N)cc(OC)c1
Reactant: O=S(=O)(Cl)CCCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: COc1cc(NS(=O)(=O)CCCCl)cc(OC)c1
Yield: 30.1 %

Procedure:
3,5-Dimethoxyaniline (34.62 g, 0.226 mol) in xylene (500 mL) containing suspended sodium carbonate (12.0 g, 0.113 mol) was treated with 3-chloropropane sulfonyl chloride (40.0 g, 0.226 mol) added dropwise with stirring. Stirring was continued for twenty-four hours and the solvent was stripped to provide a black partially crystalline gum. Filtration through dry-column silica gel combined with crystallization from ethyl acetate/hexane provided N-(3,5-dimethoxyphenyl)-3-chloro-1-propanesulfonamide (20 g), m.p. 68°-71° C.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].C(Cl)(=[O:13])CCC>>[C:5]([OH:13])(=[O:6])[CH2:7][CH2:8][CH3:1].[C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2]
Reactant: CCCC(=O)Cl
Agent: Oc1ccc(O)cc1
Product: CCCC(=O)O

Procedure:
According to the same procedure as described in Preparation 6, hydroquinone and butyryl chloride were reacted and the reaction mixture was extracted with ethyl acetate. The ethyl acetate extract was thoroughly washed with water and the solvent was removed. The residue was distilled under a reduced pressure to give hydroquinone monobutyrate. b.p. 150°-153° C./3 mmHg.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=3)[C:6]=2[N:7]=1.[CH3:20][NH:21][CH3:22]>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:21]([CH3:22])[CH3:20])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=3)[C:6]=2[N:7]=1
Reactant: CNC
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1F
Solvent: CO
Product: CN(C)c1nc(Cl)nc2c1CCC2c1ccc(F)c(F)c1
Yield: 31.8 %

Procedure:
A solution of 2,4-dichloro-7-(3,4-difluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (446 mg, 1.481 mmol) and excess dimethylamine (2.222 mL, 4.44 mmol) in MeOH (6 mL) was stirred at rt for 30 min. The solvent was removed in vacuum and the crude product was purified by column chromatography on silica gel to afford 2-chloro-7-(3,4-difluorophenyl)-N,N-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (146 mg, 0.471 mmol, 31.8% yield). LC-MS (M+H)+=310.2.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([S:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]([CH2:22][NH2:23])[CH2:17][CH2:16][CH2:15]3)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[CH2:24]([O:31][C:32]([N:34]([CH2:36][C:37](O)=[O:38])[CH3:35])=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.ON1C2C=CC=CC=2N=N1.CC[N+](CCCN(C)C)=C=N.C(N(CC)CC)C>C(Cl)Cl>[CH2:24]([O:31][C:32](=[O:33])[N:34]([CH2:36][C:37](=[O:38])[NH:23][CH2:22][CH:18]1[C:19]2[C:14](=[CH:13][C:12]([S:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([F:2])[CH:4]=3)(=[O:11])=[O:10])=[CH:21][CH:20]=2)[CH2:15][CH2:16][CH2:17]1)[CH3:35])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCC1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Reactant: CN(CC(=O)O)C(=O)OCc1ccccc1
Agent: CC[N+](=C=N)CCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CC(=O)NCC1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21)C(=O)OCc1ccccc1
Yield: 51.1 %

Procedure:
C-[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-methylamine hydrochloride (0.2 gms, 0.56 mmole), (Benzyloxycarbonyl-methyl-amino)-acetic acid (0.15 gms, 0.67 mmole), 1-hydroxybenzotriazole (0.11 gms, 0.84 mmole), 0.16 gms N-(3-dimethylaminopropyl)-N-ethylcarbodiimide (0.16 gms, 0.84 mmole) and triethylamine (0.50 ml, 3.36 mmole) in 30 mL methylene chloride and was stirred at room temperature for 24 hours. The reaction was quenched with 0.2 ml water, and the entire mixture was absorbed on to silica gel and medium pressure chromatography, eluting with ethyl acetate, gave 0.15 gms of ({[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-carbamoyl}-methyl)-methyl-carbamic acid benzyl ester as an oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][C:23]([F:26])([F:25])[F:24])[C:15]=3[N:14]=[C:13](Cl)[C:12]=2[CH2:11][CH2:10]1)[CH3:2].[NH2:28][CH2:29][CH2:30][CH2:31][OH:32]>>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][C:23]([F:26])([F:25])[F:24])[C:15]=3[N:14]=[C:13]([NH:28][CH2:29][CH2:30][CH2:31][OH:32])[C:12]=2[CH2:11][CH2:10]1)[CH3:2]
Reactant: NCCCO
Reactant: CCc1ccccc1N1CCc2c(Cl)nc3c(OC(F)(F)F)cccc3c21
Product: CCc1ccccc1N1CCc2c(NCCCO)nc3c(OC(F)(F)F)cccc3c21

Procedure:
1-(2-Ethylphenyl)-4-chloro-6-trifluoromethoxy-2,3-dihydropyrrolo[3,2-c]quinoline(801 mg, 2.0 mmol) was dissolved in 3-amino-1-propanol(10 ml) in the pressure tube, then reacted at the same condition of Step 3 in the Example 10 to obtain 560 mg of desired compound as solid in 62% of yield.
Reaction SMILES: O=[C:2]([C:9]1SC=[CH:12][CH:13]=1)[CH2:3][C:4]([O:6][CH2:7]C)=O.S1C=CC=C1C1C=CN=C(N)N=1.C[C:27]1([CH3:35])[O:32][C:31](=[O:33])[CH2:30][C:29](=[O:34])O1.COC1C=CC(C(O)=O)=CC=1>>[O:34]=[C:29]([C:9]1[CH:2]=[CH:3][C:4]([O:6][CH3:7])=[CH:12][CH:13]=1)[CH2:30][C:31]([O:32][CH2:27][CH3:35])=[O:33]
Reactant: CCOC(=O)CC(=O)c1cccs1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: COc1ccc(C(=O)O)cc1
Agent: Nc1nccc(-c2cccs2)n1
Product: CCOC(=O)CC(=O)c1ccc(OC)cc1

Procedure:
This material is prepared by a method analogous to that described for preparation of ethyl 3-oxo-3-(2-thienyl)propanoate in preparation of 1D, starting from 2,2-dimethyl-1,3-dioxane-4,6-dione and 4-methoxybenzoic acid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](O)[C:5]([CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=2[O:20][CH3:21])=[C:4]([CH3:22])[N:3]=1.P(Cl)(Cl)([Cl:25])=O>>[NH2:1][C:2]1[N:7]=[C:6]([Cl:25])[C:5]([CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=2[O:20][CH3:21])=[C:4]([CH3:22])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc(Cc2c(C)nc(N)nc2O)c(OC)c1
Product: COC(=O)c1ccc(Cc2c(C)nc(N)nc2Cl)c(OC)c1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
The product from step (ii) (8.6 g) was added to phosphorous oxychloride (50 ml) and the resulting suspension stirred at 100° C. for 15 h. The reaction mixture was allowed to cool and the phosphorous oxychloride evaporated under reduced pressure. The residue was diluted with water (100 mL) and the suspension adjusted to pH 7 with NaHCO3. The mixture was heated at 50° C. for 1 h and allowed to cool. The solid was collected by filtration, washed with water, EtOAc and dried under vacuum to give the subtitle compound 9.05 g.
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[C:5]([F:12])=[CH:4][C:3]=1[CH2:13]OC1CCCCO1.P(Br)(Br)[Br:22]>C1(C)C=CC=CC=1>[Br:22][CH2:13][C:3]1[CH:4]=[C:5]([F:12])[C:6]2[O:7][CH2:8][CH2:9][O:10][C:11]=2[C:2]=1[F:1]
Reactant: Fc1cc(COC2CCCCO2)c(F)c2c1OCCO2
Reactant: BrP(Br)Br
Solvent: Cc1ccccc1
Product: Fc1cc(CBr)c(F)c2c1OCCO2
Temperature: 25 °C
Reaction time: 15 h
Yield: 160 %

Procedure:
To a solution of 5,8-difluoro-6-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2,3-dihydro-1,4-benzodioxine (785 mg, 2.74 mmol) in toluene (5 mL) was added phosphorous tribromide (155 μl, 1.65 mmol) and the solution was stirred at room temperature for 15 hrs. The solution was concentrated in-vacuo, and the residue was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in-vacuo to afford 700 mg, 2.64 mmol (96%) of 6-(bromomethyl)-5,8-difluoro-2,3-dihydro-1,4-benzodioxine as a pale yellow oil. 1H NMR (400 MHz, CDCl3): 6.68 (q, 1H), 4.33 (s, 2H), 4.35 (s, 4H); GC/MS (EI) for C9H7O2F2Br: 265 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:15]2[CH:16]=[N:17][N:18]([CH:20]([C:22]3[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=3)[CH3:21])[CH:19]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:7]=1.[OH-].[NH4+:32]>C1COCC1.CN(C=O)C.C(OCC)(=O)C.O>[CH3:1][C:2]1[CH:3]=[C:4]([C:15]2[CH:16]=[N:17][N:18]([CH:20]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([NH2:32])=[O:27])=[CH:24][CH:23]=3)[CH3:21])[CH:19]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)[CH:7]=1
Reactant: [NH4+]
Reactant: Cc1cc(Nc2ncccn2)cc(-c2cnn(C(C)c3ccc(C(=O)O)cc3)c2)c1
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(Nc2ncccn2)cc(-c2cnn(C(C)c3ccc(C(N)=O)cc3)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(1H-Benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (101 mg, 0.315 mmol) was added to a solution of 4-(1-(4-(3-methyl-5-(pyrimidin-2-ylamino)phenyl)-1H-pyrazol-1-yl)ethyl)benzoic acid (105 mg, 0.263 mmol) in THF (5.0 mL) and DMF (1.0 mL). Ammonium hydroxide (0.15 mL, 1.05 mmol) was then added and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (100 mL) and water (10 mL). The organic layer was separated and washed with water (2×10 mL) followed by brine (10 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to afford the crude product residue. The crude product residue was purified by column chromatography on silica (0-100% [5% methanol in ethyl acetate]/hexanes) to afford racemic 4-(1-(4-(3-methyl-5-(pyrimidin-2-ylamino)phenyl)-1H-pyrazol-1-yl)ethyl)benzamide. MS ESI calcd. for C23H23N6O [M+H]+ 399. found 399. 1H NMR (500 MHz, DMSO-d6) δ 9.46 (s, 1H), 8.46 (d, J=5.0 Hz, 2H), 8.22 (s, 1H), 7.92 (s, 1H), 7.82 (s, 1H), 7.79 (d, J=6.5 Hz, 2H), 7.71 (s, 1H), 7.41 (s, 1H), 7.36-7.26 (m, 3H), 7.00 (s, 1H), 6.80 (t, J=5.0 Hz, 1H), 5.70-5.64 (m, 1H), 2.27 (s, 3H), 1.83 (d, J=7.0 Hz, 3H).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[CH2:8][N:7]3[CH:15]=[CH:16][CH:17]=[C:6]3[C:5]=12.P(Cl)(Cl)(Cl)=O.CN(C)[CH:25]=[O:26]>>[N:1]1[CH:2]=[CH:3][N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[CH2:8][N:7]3[CH:15]=[C:16]([CH:25]=[O:26])[CH:17]=[C:6]3[C:5]=12
Reactant: c1ccc2c(c1)Cn1cccc1-c1nccn1-2
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cc2n(c1)Cc1ccccc1-n1ccnc1-2
Reaction time: 2 h

Procedure:
9H-Imidazo[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine (8.00 g, 36.1 mmoles) was heated in dry dimethylformamide (120 mL) at 120° C. in the presence of phosphoryl chloride (10.4 g, 6.32 mL). After 2 hours, the reaction mixture was poured onto ice-water and then extracted several times with chloroform. The combined extracts were washed with water, brine, dried and evaporation of solvent gave a tan residual solid. Crystallization of the solid form toluene-hexane gave 9H-imidazo[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine-12-carboxaldehyde (3.57 g): mp 203°-205° C.; Anal. Calcd for C15H11N3O: C, 72.27% H, 4.45% N, 16.86%, Found: C, 72.08% H, 4.51% N, 16.77%.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[N:8]2[C:16]([CH2:19][CH2:20][CH2:21][N:22]3[CH:26]=[C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:24]=[N:23]3)=[N:17][N:18]=[C:7]12)[CH2:2][CH2:3][CH2:4][CH3:5].[Br:33]N1C(=O)CCC1=O>C1COCC1>[Br:33][C:12]1[NH:11][C:10]2[C:9](=[O:15])[N:8]3[C:16]([CH2:19][CH2:20][CH2:21][N:22]4[CH:26]=[C:25]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH:24]=[N:23]4)=[N:17][N:18]=[C:7]3[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:14]=2[N:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2c(CCCn3cc(-c4ccccc4)cn3)nnc12
Solvent: C1CCOC1
Product: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(CCCn3cc(-c4ccccc4)cn3)nnc12
Temperature: 70 °C
Reaction time: 1 h
Yield: 38.3 %

Procedure:
To a solution of 9-pentyl-3-[3-(4-phenyl-1H-pyrazol-1-yl)propyl]-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one (234 mg, 0.543 mmol) in THF (45 ml) at room temperature was added N-bromosuccinimide (145 mg, 0.814 mmol). After stirring at 70° C. for 1 hour, the reaction mixture was concentrated and then purified by preparative LCMS to give the desired product (106 mg, 38%) as white solid. LCMS calculated for C23H26BrN8O (M+H): 509.1, 511.1; found: 509.0, 511.1.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][NH2:12].C(N(CC)CC)C>C1COCC1>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][NH:12][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: COc1cccc(CN)c1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cccc(CNS(C)(=O)=O)c1
Reaction time: 18 h
Yield: 94.8 %

Procedure:
Methanesulfonyl chloride (4.170 g, 36.4 mmol) was added to a solution of 3-methoxybenzylamine (5.000 g, 36.4 mmol) and triethylamine (3.946 g, 39.0 mmol) in THF (100 mL) at room temperature. The mixture was stirred for 18 h and the insolubles were removed by filtration. The organic solution was concentrated to a yellow oil which was purified by flash chromatography (6:4 hexanes:EtOAc to 1:1 hexanes:EtOAc) to yield N-(3-methoxy-benzyl)-methanesulfonamide (7.431 g). 1H NMR (400 MHz, CDCl3) δ 7.26 (m, 1H), 6.92-6.82 (m, 3H), 4.62 (m, 1H), 4.28 (d, 2H), 3.80 (s, 3H), 2.87 (s, 3H); MS 214 (M-1).