Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:13])=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:16]I>CN(C=O)C>[NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:13])=[CH:7][C:8](=[O:12])[N:9]2[CH3:16])=[CH:4][CH:3]=1
Reactant: CI
Reactant: Cc1cc(=O)[nH]c2cc(N)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(=O)n(C)c2cc(N)ccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 68 %

Procedure:
To a solution of 7-amino-4-methyl-1H-quinolin-2-one (87 mg, 0.5 mmol) in dry DMF (2 ml) was added sodium hydride (24 mg, 60% disp. in oil, 0.6 mmol) followed by methyl iodide (38 μl, 0.6 mmol) and the reaction stirred at room temperature for 1.5 h. After quenching with water the mixture was extracted with EtOAc and the combined extracts were dried over MgSO4 and concentrated in vacuo to give the crude product. Purification by SPE column chromatography, eluting with 0-10% MeOH/EtOAc gradient gave title compound (64 mg) which was used in the next step without further purification. 1H NMR (250 MHz, CDCl3) δ (ppm): 7.47 (d, 1H), 6.59 (m, 2H), 6.55 (d, 1H), 4.45 (br, 2H), 3.61 (s, 3H), 2.38 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[CH:8]=[C:7]2[CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[O:25][CH3:26])([OH:3])=O.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.Cl.[F:47][C:48]([F:55])([F:54])[CH2:49][CH:50]([CH3:53])[CH2:51][NH2:52]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:26][O:25][C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][C:15]=1[CH2:14][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([C:1](=[O:3])[NH:52][CH2:51][CH:50]([CH3:53])[CH2:49][C:48]([F:55])([F:54])[F:47])[CH:5]=2)[N:9]([CH3:13])[CH:8]=1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1ccc(Cc2cn(C)c3ccc(C(=O)O)cc23)c(OC)c1
Reactant: CC(CN)CC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Cc2cn(C)c3ccc(C(=O)NCC(C)CC(F)(F)F)cc23)c(OC)c1
Yield: 81.6 %

Procedure:
A solution of methyl 4-(5-carboxy-1-methylindol-3-ylmethyl)-3-methoxybenzoate (2.0 g), 4-dimethylaminopyridine (0.71 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.3 g), triethylamine (1.0 mL) and 4,4,4-trifluoro-2-methylbutylamine hydrochloride (1.2 g) in methylene chloride (28 mL) was stirred under a nitrogen atmosphere for 18 hours. The mixture was diluted with methylene chloride, washed (10% (w/v) hydrochloric acid, water and brine), dried (MgSO4), and evaporated. The resulting ivory foam was purified by flash chromatography, eluting with 1:1 ethyl acetate:hexane to afford methyl 3-methoxy-4-[1-methyl-5-(2-methyl-4,4,4-trifluorobutylcarbamoyl)indol-3-ylmethyl]benzoate as a white powder (2.2 g, 82%); mp 168°-170° C.; partial NMR (300 MHz, CDCl3): 1.12 (d, 3H, CHCH3), 2.00 (m, 1H), 2.22 (m, 2H), 3.34-3.52 (m, 2H, NCH2), 3.75 (s, 3H, NCH3), 3.90 (s, 3H, CO2CH3), 3.93 (s, 3H, OCH3), 4.13 (s, 2H, CH2), 6.21 (t, 1H, NH), 6.82 (s, 1H, indole-H(2)), 8.02 (s, 1H, indole-H(4)).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][C:12]3[C:14]([N:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=2)=[CH:5][CH:4]=1)[CH3:2].Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[C:28]([N+:33]([O-:35])=[O:34])[CH:27]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][C:12]3[C:14]([N:18]4[CH2:19][CH2:20][N:21]([CH2:25][C:26]5[CH:31]=[CH:30][C:29]([F:32])=[C:28]([N+:33]([O-:35])=[O:34])[CH:27]=5)[CH2:22][CH2:23]4)=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: O=[N+]([O-])c1cc(CBr)ccc1F
Reactant: CCc1ccc(-c2nc3cccc(N4CCNCC4)c3[nH]2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ccc(-c2nc3cccc(N4CCN(Cc5ccc(F)c([N+](=O)[O-])c5)CC4)c3[nH]2)cc1
Reaction time: 1 h
Yield: 33.8 %

Procedure:
2-(4-Ethyl-phenyl)-7-piperazin-1-yl-1H-benzoimidazole (200 mg, 0.65 mmol) and 4-bromomethyl-1-fluoro-2-nitro-benzene (152 mg, 0.65 mmol) were stirred together with DIEA (83 mg, 0.6.5 mmol) in DMF (4 ml) at room temperature. After 1 h, the reaction is complete and it was purified by HPLC Method E to yield the title product (100 mg (34%), 0.22 mmol). 1H NMR (DMSO-d6): δ=12.71 (s, 1H), 8.15 (m, 1H), 8.04 (d, J=8.2 Hz, 2H), 7.83 (m, 1H), 7.59 (m, 1H), 7.34 (d, J=8.2 Hz, 2H), 7.08 (m, 2H), 6.52 (dd, J=6.64, 1.94 Hz, 1H), 3.69 (s, 2H), 3.65 (bs, 4H), 2.75 (bs, 6H), 1.32 (t, J=7.6 Hz, 3H). Calculated mass=457.43, [M+H]+=458.
Reaction SMILES: [C:1]1([CH2:7][C:8]2([NH2:26])[CH2:17][CH2:16][CH2:15][C:14]3[N:13]=[C:12]([O:18]CC4C=CC=CC=4)[CH:11]=[CH:10][C:9]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(O)C.[ClH:31].[H][H]>C(O)C.[Pd]>[ClH:31].[NH2:26][C:8]1([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:17][CH2:16][CH2:15][C:14]2[NH:13][C:12](=[O:18])[CH:11]=[CH:10][C:9]1=2
Reactant: NC1(Cc2ccccc2)CCCc2nc(OCc3ccccc3)ccc21
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CC(C)O
Product: NC1(Cc2ccccc2)CCCc2[nH]c(=O)ccc21
Yield: 28 %

Procedure:
A mixture of 5,6,7,8-tetrahydro-5-(phenylmethyl)-2-(phenylmethoxy)-5-quinolinamine (19.1 g) and 10% palladium-on-carbon (1.5 g) in ethanol (1 l) was acidified to about pH 2-3 with 2propanol/hydrochloric acid solution. The mixture was shaken on Parr hydrogenation apparatus, starting at 55 psi of hydrogen, until hydrogen uptake ceased. The catalyst was removed by filtration, the filtrate was neutralized with 4-polyvinylpyridine and concentrated. The residue was triturated with a mixture of methanol and ethyl acetate. The precipitate was collected and recrystallized form water/methanol/ethyl acetate to afford 4.6 g (28%) of product, mp 235°-238° C. (dec), in two crops.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([O:9][CH3:10])=[CH:4][C:3]=1[F:11].[Li]CCCC.[N:17]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[N:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].N#N>C1COCC1>[F:11][C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[C:7]([F:8])[C:2]=1[N:17]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[NH:18][C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20]
Reactant: COc1cc(F)c(Br)c(F)c1
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(F)c(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 103.5 %

Procedure:
In an oven-dried, N2-purged round bottom, 4-bromo-3,5-difluoroanisole (500 mg, 2.24 mmol) was dissolved in anhydrous THF (11 mL) and brought to −78° C. nBuLi (0.96 mL, 2.44 M in THF, 2.35 mmol) was added over 2 min. This was stirred for 5 min and then a solution di-tert-butyl azodicarboxylate (542 mg, 2.35 mmol) in anhydrous THF (3 mL) in an oven-dried, N2-purged pear flask was added in one portion via syringe. The reaction was removed from the ice bath and allowed to warm to room temperature over 30 min. The reaction, a clear solution, was quenched by the addition of aq. sat. NH4Cl. The material was extracted with two portions of ethyl acetate and the combined organics were dried over MgSO4 and concentrated in vacuo. Purification by silica gel flash chromatography (ethyl acetate in heptane) gave di-tert-butyl 1-(2,6-difluoro-4-methoxyphenyl)hydrazine-1,2-dicarboxylate (0.868 g, impure with ethyl acetate) as a clear oil. 1H NMR (400 MHz, CDCl3, δ): 6.48 (d, J=10.1 Hz, 2H) 3.73-3.85 (m, 3H) 1.36-1.60 (m, 18H).
Reaction SMILES: CC(C)([O-])C.[K+].S([CH2:17][N+:18]#[C-])(C1C=CC(C)=CC=1)(=O)=O.CO.[C:22]([Si:26]([CH3:38])([CH3:37])[O:27][CH:28]1[CH2:35][CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30][CH2:29]1)([CH3:25])([CH3:24])[CH3:23]>COCCOC>[C:22]([Si:26]([CH3:38])([CH3:37])[O:27][CH:28]1[CH2:35][CH2:34][CH2:33][CH:32]([C:17]#[N:18])[CH2:31][CH2:30][CH2:29]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)(C)[Si](C)(C)OC1CCCC(=O)CCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC1CCCC(C#N)CCC1
Temperature: 25 °C

Procedure:
Potassium tert-butoxide (30.4 mL, 1 M in tetrahydrofuran, 30.4 mmol) was added drop wise to a stirred and cooled (0° C.) solution of tosylmethyl isocyanide (4.74 g, 24.27 mmol) in dry DME (40 mL). After ten minutes, dry methanol (0.98 mL, 24.28 mmol) was added and followed by a solution of the product of Example 5B (3.11 g, 12.14 mmol) in DME (10 mL). The resulting solution was allowed to warm to room temperature and then heated (45° C.) for thirty minutes. After cooling, the reaction mixture was partitioned with diethyl ether and water. The organic phase was washed with brine, dried (MgSO4), filtered, and evaporated. The residue was purified over silica gel using 2-10% diethyl ether in hexanes to give the title compound as an oil.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:15])[C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[I:21]I.S(S([O-])=O)([O-])(=O)=O.[K+].[K+]>C(Cl)Cl.C1COCC1>[C:1]1([NH:7][C:8](=[O:15])[C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[I:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: II
Reactant: O=C(Nc1ccccc1)c1ccncc1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(Nc1ccccc1)c1ccncc1I
Temperature: -69 °C
Reaction time: 14 h

Procedure:
Into a 4-necked RBF equipped with an overhead stirrer and a J-Kem internal temperature probe was placed N-phenylisonicotinamide (35.1 g, 0.18 mol) and anhydrous THF (700 ml). All material appeared to go into solution. This mixture was cooled to −69° C. in a dry ice/IPA bath. To this was slowly added nBuLi (156 ml of a 2.5 M in Hexanes) in two portions. While adding the first equivalent of nBuLi, an exotherm was observed raising the temperature to approx. −41° C. The orange reaction mixture was slightly heterogeneous. This was allowed to slowly warm to 12° C. over 2 h. This mixture was re-cooled to −70° C. At this point, a THF solution (175 ml) of iodine (47.2 g, 0.19 mol) was added. This was allowed to warm and stirred at room temperature for 14 h. To this solution was added 150 ml of a saturated solution of potassium meta-bisulfite and diluted with CH2Cl2. The two layers were separated and the organic layer was extracted with brine. The two layers were separated and the organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to give a black oil. This material was purified by SiO2 column chromatography using 40% ethyl acetate/Hexane as eluent. Concentration gave 38.6 g (67% th) of an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:20]([C:23]2[CH:24]=[N:25][C:26]([Cl:29])=[CH:27][CH:28]=2)(=[O:22])=[O:21])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.ClC1C=C(C=CC=1)C(OO)=[O:35]>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:20]([C:23]2[CH:24]=[N:25][C:26]([Cl:29])=[CH:27][CH:28]=2)(=[O:22])=[O:21])[CH:5]=[CH:6][C:7]=1[S:8]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)=[O:35]
Reactant: O=S(=O)(Nc1ccc(Sc2ccc3ccccc3c2)c(Cl)c1)c1ccc(Cl)nc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=S(c1ccc2ccccc2c1)c1ccc(NS(=O)(=O)c2ccc(Cl)nc2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.7 %

Procedure:
To a solution of 6-Chloro-pyridine-3-sulfonic acid [3-chloro-4-(naphthalen-2-ylsulfanyl)-phenyl]-amide (94, 55 mg, 0.12 mmol) in CH2Cl2 (2 mL), was added dropwise a solution of m-chloroperoxybenzoic acid (mCPBA, Aldrich, 36 mg, 0.12 mmol) in CH2Cl2 (1 mL). The resulting mixture was stirred at ambient temperature for 1 hour and diluted with EtOAc (60 mL). The organic layer was washed with saturated aqueous NaHCO3 solution (50 mL), twice with brine solution (50 mL), dried over Na2SO4, and concentrated under vacuum. The crude solid was chromatographed (10–25% EtOAc in hexane) to yield 17 mg (30%) of 103 as an off white solid.
Reaction SMILES: [CH3:1][Mg+].[Br-].[CH3:4][O:5][C:6](=[O:29])[C:7]1[CH:12]=[C:11]([C:13](=[O:15])[CH3:14])[C:10]([NH:16][CH:17]=[O:18])=[C:9]([F:19])[C:8]=1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][C:22]=1[F:28]>CCOCC.C1COCC1>[CH3:4][O:5][C:6](=[O:29])[C:7]1[CH:12]=[C:11]([C:13]([OH:15])([CH3:1])[CH3:14])[C:10]([NH:16][CH:17]=[O:18])=[C:9]([F:19])[C:8]=1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][C:22]=1[F:28]
Reactant: C[Mg+]
Reactant: COC(=O)c1cc(C(C)=O)c(NC=O)c(F)c1Nc1ccc(Br)cc1F
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1cc(C(C)(C)O)c(NC=O)c(F)c1Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of MeMgBr (3.20 equiv., 3.0 M solution in diethyl ether) in ether is added a solution of 5-acetyl-2-(4-bromo-2-fluorophenylamino)-3-fluoro-4-formylamino-benzoic acid methyl ester (1.00 equiv.) in THF at 0° C. The reaction mixture is warmed to room temperature and stirred for 16 hours. The reaction is quenched with saturated aqueous NH4Cl and diluted with EtOAc. The organic layer is washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that is used directly without further purification.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]([OH:15])=[O:14])=[N:4][NH:3]1.[OH-].[Na+].[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>CO>[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:3]2[N:4]=[C:5]([CH2:12][C:13]([OH:15])=[O:14])[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]2=[O:1])=[CH:21][CH:20]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: O=C(O)Cc1n[nH]c(=O)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1nn(Cc2ccc(Br)cc2)c(=O)c2ccccc12
Yield: 16.4 %

Procedure:
1,2-Dihydro-1-oxophthalazin-4-ylacetic acid (2.0 g.) was added to a solution of sodium hydroxide (0.9 g.) in methanol (50 ml.). A clear solution was obtained on slight warming, which was treated with 4-bromobenzyl bromide (2.6 g.). The mixture was then heated under reflux for 3 hours and then evaporated. The residue was treated with water (60 ml.) and the solution obtained was extracted with ether (3×60 ml.). The aqueous phase was then acidified to pH 2 with concentrated hydrochloric acid and the acid mixture extracted with ethyl acetate (150 ml.). The extracts were washed with water (50 ml.), dried (MgSO4) and evaporated. The solid obtained was recrystallised from a 1:4 v/v mixture of ethyl acetate and petrol (60-80) to give 2-(4-bromobenzyl)-1,2-dihydro-1-oxophthalazin-4-ylacetic acid (0.6 g.), m.p. 179°-181° C.
Reaction SMILES: NC1C=CC=CC=1C(O)=O.C(N)=O.[N+]([O-])(O)=O.S(=O)(=O)(O)O.O[C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([N+:34]([O-:36])=[O:35])[CH:32]=2)[N:27]=[CH:26][N:25]=1.S(Cl)([Cl:39])=O>>[Cl:39][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([N+:34]([O-:36])=[O:35])[CH:32]=2)[N:27]=[CH:26][N:25]=1
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1ccc2ncnc(O)c2c1
Agent: Nc1ccccc1C(=O)O
Agent: O=S(=O)(O)O
Solvent: O=[N+]([O-])O
Solvent: NC=O
Product: O=[N+]([O-])c1ccc2ncnc(Cl)c2c1

Procedure:
In brief, 2-aminobezoic acid substituted by a reactive group (G in Scheme 3), is reacted with formamide, at 160° C., for 3 hours. The resulting 4-hydroxyquinazolinesubstituted by the reactive group is then reacted with a mixture of nitric acid and sulfuric acid, to thereby obtain 4-hydroxy-6-nitroquinazoline substituted by the reactive group. The reactive 4-hydroxy-6-nitroquinazoline is thereafter reacted with thionyl chloride, so as to obtain 4-chloro-6-nitroquinazoline substituted by a reactive group. In these compounds, the nitro group serves as a first reactive group and G is a second reactive group.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[OH-].[K+].[C:36](=[O:44])([O:40][CH:41]([CH3:43])[CH3:42])[O:37][CH2:38]Cl>CN(C=O)C.CCOC(C)=O>[C:36](=[O:44])([O:40][CH:41]([CH3:43])[CH3:42])[O:37][CH2:38][N:14]1[C:11]2=[N:12][CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:9]=[C:10]2[C:16]([C:17](=[O:18])[C:19]2[C:24]([F:25])=[CH:23][CH:22]=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[C:20]=2[F:33])=[CH:15]1
Reactant: CC(C)OC(=O)OCCl
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(COC(=O)OC(C)C)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Temperature: 10 °C
Reaction time: 3 h
Yield: 42.3 %

Procedure:
To a mixture of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.2 g, 0.41 mmol) and KOH (46 mg, 0.82 mmol) in DMF (1.5 mL) was added a solution of chloromethyl isopropyl carbonate (62 mg, 0.41 mmol) in DMF (0.5 mL) over 30 min. The reaction mixture was stirred at 10° C. for 3 h, then diluted with EtOAc (40 mL) and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=2/1) to afford the title compound as a white solid (105 mg, 43%). The title compound was characterized by LC-MS and 1H NMR as shown below:
Reaction SMILES: Br[C:2](Br)=[CH:3][CH:4]1[CH2:7][CH:6]([CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:5]1.C([Li])CCC.[CH2:19]([O:26][CH2:27][CH2:28][CH2:29][CH:30]([C:39](=[O:44])NCOC)[CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:19]([O:26][CH2:27][CH2:28][CH2:29][CH:30]([C:39](=[O:44])[C:2]#[C:3][CH:4]1[CH2:7][CH:6]([CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:5]1)[CH2:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)CC1CC(C=C(Br)Br)C1
Reactant: COCNC(=O)C(CCCOCc1ccccc1)CC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)CC1CC(C#CC(=O)C(CCCOCc2ccccc2)CC(=O)OC(C)(C)C)C1
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
1-(2,2-dibromovinyl)-3-(2,2-dimethylpropyl)cyclobutane (5 g) and tetrahydrofuran (50 mL) were mixed. To the mixture was added n-butyllithium (1.65 M in hexane) (20.5 mL) dropwise at −78° C. The mixture was stirred at ice temperature for 30 min. and a solution of tert-butyl 6-benzyloxy-3-(methoxymethylcarbamoyl)hexanoate (4.13 g) in tetrahydrofuran (25 mL) was added dropwise to the mixture. After stirring at ice temperature for 20 min., saturated aqueous ammonium chloride was added to the reaction mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, then dried over magnesium sulfate. The magnesium sulfate was filtered off and the filtrate was concentrated in vacuo. The resultant residue was purified by silica gel column chromatography (Eluent: ethyl acetate/hexane=1/20) to give the title compound (3.45 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([Cl:10])=[CH:8][C:7](N)=[CH:6][C:5]=1[Cl:12].N([O-])=[O:15].[Na+].O>Cl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([OH:15])=[CH:6][C:5]=1[Cl:12]
Reactant: COC(=O)c1c(Cl)cc(N)cc1Cl
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)c1c(Cl)cc(O)cc1Cl
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 54.8 %

Procedure:
4-Amino-2,6-dichlorobenzoic acid methyl ester (0.5 g) was suspended in 20% HCl (25 mL) and stirred for 30 min then cooled to 0-5° C. After slow addition of NaNO2 (188 mg), the mixture was stirred for 30 min at that temperature and added to boiling water (50 mL) . The mixture was then refluxed for 2 h, allowed to cool to room temperature and extracted with AcOEt, dried (MgSO4), filtered and evaporated. The residue was purified by preparative TLC (silica gel; eluent: CH2Cl2) to give 2,6-dichloro-4-hydroxybenzoic acid methyl ester (275 mg).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH2:11].[C:12](=O)([O-])[O-].[Na+].[Na+]>CO>[CH3:12][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([OH:1])[C:3]=1[NH2:11]
Reactant: O=C([O-])[O-]
Reactant: Nc1c(O)cccc1C(=O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccc(O)c1N
Yield: 83 %

Procedure:
To a solution of 1.0 g (6.53 mmol) of 3-hydroxyanthranilic acid in 15 mL of methanol was added 5.0 mL of BF3 -methanol complex and the resulting solution was heated to reflux for 24 h. After cooling to room temperatue the reaction mixture was poured into saturated sodium carbonate solution and then extracted with ether. The combined organics were washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide 0.90 g (83%) of the desired product as a brown solid. Electrospray Mass Spec: 167.8 (M+H)+
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH:8]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:6]=1)(=O)=O.[NH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1>CC#N>[CH3:20][S:17]([C:14]1[CH:15]=[CH:16][C:11]([C:9]2[CH:8]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:6]=[C:5]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[N:10]=2)=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nc(S(C)(=O)=O)n2)cc1
Reactant: NCc1ccccn1
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nc(NCc3ccccn3)n2)cc1
Yield: 80 %

Procedure:
To a stirred solution of 2-(methylsulfonyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine (0.10 g, 0.26 mmol) in MeCN (4 ml) was added 2-(aminomethyl)-pyridine (0.14, 5 eq) and the resultant solution heated under reflux for 3 h. The cooled reaction mixture was concentrated in vacuo and purified by SPE chromatography using chloroform, diethyl ether, ethyl acetate, acetone and methanol as the eluotropic series of solvents. Concentration in vacuo of the combined fractions containing pure product gave the title compound as a colourless solid (0.086 g, 80%).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]=[C:13]3[CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:29]([O-])([O-])=O.[Cs+].[Cs+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:29][N:15]1[C:16]2[C:12](=[CH:11][C:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:8])=[O:9])=[CH:18][CH:17]=2)[C:13]([CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[CH:14]1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)NCCc1c[nH]c2ccc(S(=O)(=O)c3ccccc3)cc12
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: Cn1cc(CCNC(=O)OC(C)(C)C)c2cc(S(=O)(=O)c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 67.7 %

Procedure:
A solution of tert-butyl 2-[5-(phenylsulfonyl)-1H-indol-3-yl]ethylcarbamate (0.58 g, 1.46 mmol) in acetone (25.0 mL) was treated with Cs2CO3 (1.85 g, 5.68 mmol) and dimethyl sulfate (0.80 mL, 8.45 mmol). The reaction was stirred at room temperature for 3.5 hours then filtered. The filtrate was concentrated in vacuo and subjected to column chromatography (silica gel, 30% EtOAc/hexane) to give 0.41 g (68%) of a colorless solid as the title compound: mp 127.4-130.6° C.; 1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.93 (d, J=7.1 Hz, 1H), 7.65-7.55 (m, 5H), 7.35 (s, 1H), 6.93 (br, 1H), 3.77 (s, 3H), 3.20-3.18 (m, 2H), 2.86-2.82 (m, 2H), 1.37 (s, 9H); 13C NMR (100 MHz, DMSO-d6) δ 155.5, 142.7, 138.3, 132.8, 130.5, 130.0, 129.4, 127.0, 126.7, 119.7, 119.3, 113.4, 110.7, 77.4, 41.1, 32.5, 28.1, 24.9; IR (diffuse reflectance) 1676, 1531, 1450, 1366, 1316, 1303, 1286, 1177, 1152, 1144, 1103, 797, 726, 692, 626 cm−1; HRMS (FAB) calcd for C22H26N2O4S+H 414.1613, found 414.1619; Anal. Calcd for C22H26N2O4S: C, 63.74; H, 6.32; N, 6.76. Found: C, 63.78; H, 6.39; N, 6.80.