Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([N:8]([CH:34]([CH3:36])[CH3:35])[C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[CH:17]2[CH2:26][CH2:25][C:24]3[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=3[CH2:18]2)=O)=[CH:4][CH:3]=1.[N:39]1([C:47](=O)[CH2:48]Cl)[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>>[N:39]1([CH2:47][CH2:48][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][N:8]([CH:34]([CH3:36])[CH3:35])[C:9]3[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=3[CH:17]3[CH2:26][CH2:25][C:24]4[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=4[CH2:18]3)=[CH:37][CH:38]=2)[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)cc2)C(C)C)c1
Reactant: O=C(CCl)N1CCCCCCC1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(N(Cc2ccc(OCCN3CCCCCCC3)cc2)C(C)C)c1
Yield: 61.7 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8tetrahydronaphthalen-2-yl ester (30 mg) and 1-azocan-1-yl-2-chloroethanone (22 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (20 mg) was obtained.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:7]([C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:18][CH:17]=1
Reactant: COc1ccc(N)cc1
Reactant: CCOC(=O)C(=O)c1cccn1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C(=Nc1ccc(OC)cc1)c1cccn1C
Yield: 58 %

Procedure:
To a solution of 4.0 g ethyl 1-methylpyrrole-2-glyoxylate and 2.96 g p-anisidine in 20 ml toluene is added 24 mg p-toluenesulfonic acid. Heating at reflux for 4 days with water being removed with a Dean-Stark trap is followed by washing successively with aqueous hydrochloric acid, aqueous sodium bicarbonate and brine. After drying, evaporation of the solvent affords a dark solid. Recrystallization from isopropanol gives a 58% yield of ethyl α-(4-methoxyphenylimino)-1-methylpyrrole-2-acetate, m.p. 83°-85° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[Cl:11])=[O:5])C.[Li+].[OH-]>CO.O>[C:12]([N:9]1[C:10]([Cl:11])=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CCOC(=O)c1cnn(C(C)(C)C)c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)n1ncc(C(=O)O)c1Cl
Yield: 91 %

Procedure:
To a solution of 1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid ethyl ester (5 g, 21.7 mmol) in methanol (50 mL) and water (50 mL) was added LiOH (0.63 g, 26.3 mmol). The reaction mixture was stirred at reflux overnight and then concentrated under reduced pressure to remove the methanol. The residue was diluted with water, acidified to pH 2 with concentrated HCl (4 mL), and extracted with ethyl acetate. The organic extracts were evaporated in vacuo to give 1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid (4 g, 91%) which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][C:12]([OH:14])=[O:13].[N+:15]([O-])([OH:17])=[O:16]>C(O)(=O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:15]([O-:17])=[O:16])[C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][C:12]([OH:14])=[O:13]
Reactant: COc1ccc(OC)c(CC(=O)O)c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: COc1cc([N+](=O)[O-])c(OC)cc1CC(=O)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69 %

Procedure:
A solution of of 2,5-dimethoxyphenylacetic acid (1.00 g, 5.10 mmol) in 10 mL of acetic acid was added 6.5 mL of 1.0M HNO3 in acetic acid. The reaction was stirred at ambient temperature for 10 min, and diluted with 75 mL of water. The yellow precipitate was collected and washed with water (3×10 mL), then dried on the filter. Recrystallization from 20 mL of 2-propanol gave 846 mg (69%) of the titled compound as fine yellow crystals.
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[S:14])[NH:9][CH2:10][C:11](N)=[O:12].[CH2:16](I)[CH3:17]>>[CH2:16]([S:14][C:8]1[N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:15])[C:11](=[O:12])[CH2:10][N:9]=1)[CH3:17]
Reactant: CCI
Reactant: Cc1ccccc1NC(=S)NCC(N)=O
Product: CCSC1=NCC(=O)N1c1ccccc1C
Yield: 57.9 %

Procedure:
The title compound was prepared by the procedure described in Example 6 using 11.2 g of 2-[3-(2-tolyl)-thioureido]-acetamide and 15.6 g of ethyl iodide. Crystallization from ethyl acetate afforded the hydrochloride salt of the title compound as a white solid (6.8 g), m.p. 156°-158° C. (dec.). Anal. Calcd. for. C12H14N2O S. HCl: C, 53.23; H, 5.58; N, 10.34. Found: C, 52.96; H, 5.49; N, 10.25. Mass spectrum (EI, M.+) m/z 234. 1H-NMR (DMSO-d6 ; 400 MHz) 88.75 (broad s, 2H), 7.43 (m, 2H), 7.35 (m, 1H), 7.30 (m, 1H), 4.53 (q, 2H), 3.18-3.20 (m, 2H), and 1.29 ppm (t, 3H).
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].C(=O)([O-])O.[NH4+]>O.C(#N)C>[C:1]([NH:4][C@H:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(Cc1cccc(C#N)c1)NC(C)=O
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)[C@@H](Cc1cccc(C#N)c1)NC(C)=O
Temperature: 20 °C
Reaction time: 24 h
Yield: 47.4 %

Procedure:
The process is performed as in Example 2, starting with 11.39 g of ethyl (2RS)-2-acetylamino-3-(3-cyanophenyl)propanoate, 17.39 g of ammonium hydrogen carbonate and 0.1 g of α-chymotrypsin in 200 cm3 of water and 70 cm3 of acetonitrile. After stirring for 24 hours at a temperature in the region of 20° C. and an identical work-up, 5.40 g of ethyl (2R)-2-acetylamino-3-(3-cyanophenyl)propanoate are obtained in the form of a beige-colored solid. (Rf=0.76 in a 40/10/20 by volume mixture of n-butanol/acetic acid/water, on a Merck 60F254R silica plate).
Reaction SMILES: [NH:1]([C:8]1[C:13]([Cl:14])=[CH:12][N:11]=[C:10](Cl)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:16][CH:17]([CH2:27][NH:28][CH:29]([CH3:31])[CH3:30])[CH2:18][O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1.Cl>C(O)CCC.CO>[NH:1]([C:8]1[C:13]([Cl:14])=[CH:12][N:11]=[C:10]([NH:24][C:23]2[CH:25]=[CH:26][C:20]([O:19][CH2:18][CH:17]([OH:16])[CH2:27][NH:28][CH:29]([CH3:30])[CH3:31])=[CH:21][CH:22]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncc(Cl)c(Nc2ccccc2)n1
Reactant: CC(C)NCC(O)COc1ccc(N)cc1
Agent: Cl
Solvent: CO
Solvent: CCCCO
Product: CC(C)NCC(O)COc1ccc(Nc2ncc(Cl)c(Nc3ccccc3)n2)cc1
Temperature: 100 °C
Yield: 41.3 %

Procedure:
4-Anilino-2,5-dichloropyrimidine (Method 7, 241 ma, 1.0 mmol) was dissolved in n-butanol (20 ml) and methanol (4 ml). 4-[2-Hydroxy-3-(isopropylamino)propoxy]aniline (obtained as described in Pharmazie 1980, 35, 278; 202 mg, 0.9 mmol) and ethereal hydrogen chloride (1.0M; 2 ml, 2.0 mmol) were added and the solution was heated at 100° C. for 20 hours, allowed to cool to ambient temperature and then concentrated to a volume of 5 ml. The solution was loaded on a Varian Mega Bond Elut column and the column was eluted with 0-4% 2.0M methanolic ammonia solution in DCM. Concentration of the appropriate fractions and recrystallization of the residue from acetonitrile gave the product as a white solid (159 mg, 41%). NMR: 1.0 (d, 6H), 2.5-2.6 (m, 1H), 2.65-2.75 (m, 2H), 3.8-3.95 (m, 3H), 4.9 (br s, 1H), 6.8 (d, 2H), 7.1 (t, 1H), 7.35 (t, 2H), 7.45 (d, 2H), 7.65 (d, 2H), 8.1 (s, 1H), 8.7 (s, 1H), 9.1 (s, 1H); MS (MH+): 428, 430.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[NH:11][C:12]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[NH:11][C:12]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[S:29]
Reactant: COc1ccc(OC)c(NC(=O)C2CCCCC2)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(OC)c(NC(=S)C2CCCCC2)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 81.4 %

Procedure:
1.46 g (5.54 mmol) of N-(2,5-dimethoxyphenyl)cyclohexanecarboxamide is put into solution in 40 ml of anhydrous toluene. The solution is taken to 100° C., and 3.34 g (8.26 mmol; 1.5 eq.) of Lawesson's reagent are added to the reaction medium which is then maintained under stirring at 100° C. for 4 hours. After returning to ambient temperature, the solution is poured into 50 ml of iced water and extracted using toluene. The organic phases are dried over magnesium sulphate and the solvent is evaporated off. The N-(2,5-dimethoxyphenyl)cyclohexanecarbothioamide is then purified by chromatography on a silica column (eluent: dichloromethane/heptane: 1/1 then 3/2). 1.26 g (yield=81%) of product is obtained in the form of yellow oil.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[CH2:19][C:20](=O)[CH2:21][C:22](OC)=[O:23]>>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[CH2:19][C:20]1[CH:21]=[C:22]([OH:23])[N:1]([C:3]2[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: COC(=O)CC(=O)Cc1c(F)cccc1F
Reactant: N#Cc1ccnc(NN)c1
Product: N#Cc1ccnc(-n2nc(Cc3c(F)cccc3F)cc2O)c1

Procedure:
The title compound was prepared from 2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and methyl 4-(2,6-difluorophenyl)-3-oxobutanoate according to the procedure for the preparation of Example 158, part A.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:16](OC(=O)C)(=[O:18])[CH3:17]>C(Cl)(Cl)Cl>[C:16]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccc(Br)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-bromophenol (25 g, 0.145 mol) in 100 ml of chloroform was added at 0° C. with triethylamine (20.1 ml) and acetic anhydride (16.4 ml) stirring at room temperature for 2 h. After that the mixture was washed with a 0.2M HCl solution, dried and the solvent was evaporated off under reduced pressure, thereby obtaining the title compound as a colourless oil (quantitative yield).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH:6]([C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([CH3:16])[CH:9]=1)=[O:7]>>[CH:6]([C:8]1[CH:15]=[CH:14][C:11]([C:12]([NH2:13])=[O:2])=[C:10]([CH3:16])[CH:9]=1)=[O:7]
Reactant: Cc1cc(C=O)ccc1C#N
Reactant: O=S(=O)(O)O
Product: Cc1cc(C=O)ccc1C(N)=O
Temperature: 25 °C
Reaction time: 108 h

Procedure:
In 0.40 g of 4-formyl-2-methylbenzonitrile, 7 mL of concentrated sulfuric acid was added, and stirred at room temperature for 4.5 days. After the completion of the reaction, the reaction mixture was poured in 20 mL of ice water, extracted with ethyl acetate (15 mL×2). The combined organic phases were washed with water, and dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was washed with 5 mL of diisopropyl ether to obtain 0.26 g of the aimed product as white crystal.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([Br:14])[CH:12]=2)[N:7]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:6]=1[CH3:24])=[O:4].C1C(=O)N([Br:32])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>ClCCCl.CCCCC>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([Br:14])[CH:12]=2)[N:7]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:6]=1[CH2:24][Br:32])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c(C)n(S(=O)(=O)c2ccccc2)c2ncc(Br)cc12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCCl
Solvent: CCCCC
Product: COC(=O)c1c(CBr)n(S(=O)(=O)c2ccccc2)c2ncc(Br)cc12
Temperature: 25 °C
Yield: 94.2 %

Procedure:
To a solution of 1-benzenesulfonyl-5-bromo-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid methyl ester (0.42 g, 1.0 mmol) in 1,2-dichloroethane (9 mL) were added NBS (0.20 g, 1.1 mmol) and AIBN (30 mg, 0.2 mmol) and the reaction mixture was heated under reflux for 45 minutes. The reaction mixture was allowed to cool to ambient temperature and was diluted with pentane (4.0 mL), the solid was removed by filtration and the liquors were then concentrated in vacuo. The resultant residue was purified by chromatography (silica, 5 g cartridge, Si-SPE, 30-100% DCM in pentane) to afford the title compound as a white solid (0.46 g, 90%). LCMS (Method B): RT=4.55 min, M+H+=489.
Reaction SMILES: [F:1][C:2]1[C:10]2[N:9]=[C:8]([C@@H:11]([NH2:13])[CH3:12])[N:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][N:25]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[C:10]2[N:9]=[C:8]([C@@H:11]([NH:13][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:12])[N:7]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](N)c1nc2c(F)cccc2n1-c1ccccc1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2c(F)cccc2n1-c1ccccc1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A mixture of (S)-1-(4-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine from Example 15 (0.407 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (122 mg, 0.509 mmol) and DIPEA (0.444 mL, 2.55 mmol) in n-butanol (3 mL) was stirred in a sealed vial for 20 h at 100° C. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in EtOAc). The product containing fractions were concentrated in vacuo and the resulting residue was dissolved in EtOAc (10 mL) and stirred with 2N HCl (10 mL) for 15 min. Volatiles were removed under reduced pressure and the residue was dissolved in MeOH (2 mL) and triturated with diethyl ether affording 136 as a beige powder (126 mg, 78%). LCMS: RT 3.47 min [M+H]+ 374.0. 1H NMR (DMSO, 400 MHz): δ 10.03 (1H, s), 8.66 (1H, s), 8.55 (1H, s), 7.68-7.38 (5H, m), 7.28-7.21 (1H, m), 7.13 (1H, dd, J=10.91, 7.98 Hz), 6.94 (1H, dd, J=8.11, 0.82 Hz), 5.68-5.59 (1H, m), 1.72 (3H, d, J=6.85 Hz)
Reaction SMILES: [NH:1]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:2]([C:11]([NH:13][C@@H:14]([C:19]([NH:21][CH2:22][C:23]([O:25]CC)=[O:24])=[O:20])[CH2:15][CH2:16][S:17][CH3:18])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[OH-].[Na+].Cl.CN(C=O)C>CO>[NH:1]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:2]([C:11]([NH:13][C@@H:14]([C:19]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:20])[CH2:15][CH2:16][S:17][CH3:18])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: CCOC(=O)CNC(=O)[C@@H](CCSC)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CSCC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
In 30 ml of MeOH is dissolved 2.8 g of BOC-Tyr-(D)-Met-Gly-OEt. After cooling, 12 ml of N-aqueous sodium hydroxide solution is added, and the mixture is stirred at room temperature for 1 hour. After cooling, 60 ml of 0.2 N-aqueous hydrochloric acid solution is added, and the precipitated crystals are collected by filtration, followed by washing with cold water. Thus obtained is 2.3 g of the desired product, m.p. 184°-186° C., Rf1 =0.24, [α]D21 +13.3° (c=0.46, DMF).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4](Cl)=[O:5].[OH:12][C:13]1[CH:14]=[C:15]([B:19]([OH:21])[OH:20])[CH:16]=[CH:17][CH:18]=1.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([O:12][C:13]1[CH:14]=[C:15]([B:19]([OH:21])[OH:20])[CH:16]=[CH:17][CH:18]=1)=[O:5]
Reactant: OB(O)c1cccc(O)c1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Oc1cccc(B(O)O)c1)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
To make compound (6a), a solution of 2,6-dichlorobenzoyl chloride (29 μL, 0.2 mmol) in 5 mL of dried THF was added dropwise to an ice-cold solution of 3-hydroxyphenylboronic acid (21 mg, 0.15 mmol), dried triethyl amine (42 μL, 0.3 mmol) and 10 mL of dried THF. The reaction mixture was stirred at room temperature overnight and then evaporated to dryness. It was dissolved in 25 mL of ethyl acetate and washed with 1N aqueous HCl, 10% aqueous NaHCO3, saturated brine solution, dried (Na2SO4) and then concentrated. The residue was purified by flash chromatography eluting with MeOH-ethyl acetate (1:10) to give 38 mg (81% yield) of desired compound as a white powder, mp: 238° C.(dec). 1H-NMR (400 MHz, 5% D2O in d6-DMSO): δ7.08–7.19 [m, 1H, Ar—H], 7.22–7.30 [m, 1H, Ar—H], 7.22–7.30 [m, 1H, Ar—H], 7.42–7.50 [m, 1H, Ar—H], 7.54–7.60 [m, 1H, Ar—H], 7.60–7.68 [m, 2H, Ar—H], 7.73–7.78 [m, 3H, Ar—H].
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[NH:12][CH:11]=1.N1C=CC=CC=1.[C:26]1([CH2:32][S:33](Cl)(=[O:35])=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[N:7]=[C:6]([NH:8][S:33]([CH2:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:35])=[O:34])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[NH:12][CH:11]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: Cc1cnc2[nH]cc(Cc3ccc(N)nc3F)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cnc2[nH]cc(Cc3ccc(NS(=O)(=O)Cc4ccccc4)nc3F)c2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 15.5 %

Procedure:
In a vial, 6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine (137, 157 mg, 0.614 mmol) was mixed with 4 mL of dichloromethane and pyridine (149 μL, 1.84 mmol) and cooled to 0° C. in an ice water bath. Phenyl-methanesulfonyl chloride (139, 0.234 g, 1.23 mmol) was added and the reaction stirred at 0° C. for 1 hour, then warmed to room temperature and stirred overnight. Aqueous saturated sodium bicarbonate was added and extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with 0-10% methanol in dichloromethane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a yellow solid (P-2181, 39 mg). MS (ESI) [M+H]+=411.1.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)([O-:3])=[O:2].[Cl-].C[Al+]C.Cl[C:18](=[O:26])[CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(Cl)Cl>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6]([C:18](=[O:26])[CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:7][NH:8]2)([O-:3])=[O:2]
Reactant: CCOC(=O)CCC(=O)Cl
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Agent: C[Al+]C
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)CCC(=O)c1c[nH]c2cccc([N+](=O)[O-])c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-nitroindole (2.00 g, 12.3 mmol) in CH2Cl2 (60 mL) at 0° C. was added dimethylaluminum chloride (1 M in hexanes, 14.8 mL, 14.8 mmol) and the mixture was stirred for 30 min. Ethyl 4-chloro-4-oxobutyrate (2.44 g, 14.8 mmol) was added dropwise and the resulting mixture was allowed to warm slowly to ambient temperature and stirred for 18 h. The reaction mixture was carefully quenched with 10% aqueous citric acid (150 mL) and extracted with CH2Cl2 (3×150 mL).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[CH:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[S:9][C:8]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:4][CH:3]=1.C[Si](C)(C)N[Si](C)(C)C.[Na].O1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])S1(=O)=O>CN(C)C=O.O1CCCC1>[C:43]([O:42][C:40]([NH:37][CH2:38][CH2:39][CH:6]([C:7]1[CH:11]=[C:10]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[S:9][C:8]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:24][CH:23]=1)=[O:41])([CH3:46])([CH3:45])[CH3:44].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:11]=[C:10]([N:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)[S:9][C:8]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCOS1(=O)=O
Agent: CCOC(=O)c1sc(N2CCOCC2)cc1Cc1ccc(Cl)cc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(N2CCOCC2)cc1C(CCNC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 64 %

Procedure:
Glasswares were flame-dried before use. A solution of ethyl 3-(4-chlorobenzyl)-5-morpholin-4-ylthiophene-2-carboxylate (0.872 g, 2.38 mmol) in N,N-dimethylformamide (16.0 mL) and tetrahydrofuran (4.00 mL) was cooled to −78° C. with vigorous stirring. The solution was evacuated under highvac and purged with argon (×4). 1.00 M Sodium hexamethyldisilazane in tetrahydrofuran (2.62 mL, 2.62 mmol) was added; the solution turned deep purple. The mixture was stirred at −78° C. under argon for 10 min. A solution of tert-butyl 1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (1.06 g, 4.77 mmol) in N,N-dimethylformamide (4.00 mL) was added dropwise over −1 min. The solution turned light red, and then slightly dark green in −1 min. In 15 min, the reaction was warmed to 0° C., and then in 1 h, it was warmed to rt. After 15 min of stirring at rt, the reaction was quenched and distributed between NH4Cl saturated solution and EtOAc. The aqueous layer was extracted with EtOAc (×2). The combined organic layer was washed with 10% LiCl aqueous solution (×2) and brine, dried, and concentrated. Purification on a silica gel column (continuous gradient from 5% EtOAc/hexanes to 25% EtOAc/hexanes over 30 min) provided 776 mg of ethyl 3-{3-[(tert-butoxycarbonyl)amino]-1-(4-chlorophenyl)propyl}-5-(morpholin-4-yl)thiophene-2-carboxylate (64% yield) and 303 mg of unreacted ethyl 3-(4-chlorobenzyl)-5-morpholin-4-ylthiophene-2-carboxylate (35% yield). LCMS: (AA) ES+ 510, 512; 1H NMR (400 MHz, CDCl3) δ 7.24-7.21 (s, 4H), 5.88-5.82 (s, 1H), 5.21-5.11 (t, J=7.8 Hz, 1H), 5.06-4.94 (s, 1H), 4.34-4.22 (qd, J=7.1, 2.8 Hz, 2H), 3.83-3.73 (t, J=4.9 Hz, 4H), 3.29-3.19 (s, 1H), 3.22-3.12 (t, J=4.9 Hz, 4H), 2.99-2.85 (m, 1H), 2.25-2.12 (d, J=6.6 Hz, 1H), 2.12-2.06 (s, 1H), 1.47-1.41 (s, 9H), 1.36-1.31 (m, 3H).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([C:12](=[O:19])[CH:13]([CH3:18])[CH2:14][C:15]([OH:17])=[O:16])=[CH:11][C:5]=2[O:4][CH2:3]1.[C:20](Cl)(=O)C>CO>[O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([C:12](=[O:19])[CH:13]([CH3:18])[CH2:14][C:15]([O:17][CH3:20])=[O:16])=[CH:11][C:5]=2[O:4][CH2:3]1
Reactant: CC(=O)Cl
Reactant: CC(CC(=O)O)C(=O)c1ccc2c(c1)OCC(=O)N2
Solvent: CO
Product: COC(=O)CC(C)C(=O)c1ccc2c(c1)OCC(=O)N2

Procedure:
4-(3,4-Dihydro-3-oxo-1,4(2H)-benzoxazin-7-yl)-4-Oxo-3-methylbutyric acid (5 g) was suspended in methanol (50 ml) and acetyl chloride (0.5 ml) added. The mixture was heated on a steam bath until all of the solid dissolved. The solvent was evaporated at reduced pressure providing the ester as a white foam which was recrystallized from ethyl acetate-methanol to give the product as white crystals, yield 5 g, mp 95°-98° C.