Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]#C.Cl[CH2:4][Cl:5].[Cl-].[Al+3].[Cl-].[Cl-].[O:10]=[C:11]([CH3:18])[CH2:12][CH2:13][CH2:14][C:15](Cl)=[O:16]>C(Cl)(Cl)(Cl)Cl>[Cl:5]/[CH:4]=[CH:1]/[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C:11](=[O:10])[CH3:18]
Reactant: CC(=O)CCCC(=O)Cl
Reactant: ClCCl
Reactant: C#C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)CCCC(=O)/C=C/Cl
Temperature: 0 °C

Procedure:
Acetylene was passed through 69 ml of carbon tetrachloride contained in a 250 ml three-necked, round-bottomed flask equipped with a gas inlet tube, mechanical stirring, addition funnel and reflux condenser for 5 minutes. Alternately, dichloromethane can also be used as a solvent. The solvent was cooled to 0° C., 7.19 g of aluminum chloride added and acetylene passed through the slurry for an additional 5 minutes. A solution of 5.70 g of 5-ketohexanoylchloride in 6.5 ml of carbon tetrachloride was added dropwise. Acetylene was passed through the stirred mixture for an additional 4.5 hours. The reaction mixture was poured onto an ice-brine mixture, the layers separated and the aqueous layer extracted twice with ether. The combined organic layers were washed with 10% hydrochloric acid, saturated aqueous sodium bicarbonate and brine, dried over MgSO4, filtered and evaporated in vacuo, to yield 2.10 g of a brown oil. This material was bulb-to-bulb distilled (vacuum pump) to yield 1.57 g of a light yellow oil. This material was combined with 1.2 g of crude product from a similar reaction sequence and purified by column chromatography (Silica Gel, 2.5% acetone in dichloromethane) to yield 585 mg of the diketooctene as a yellow oil. The material had the following spectral characteristics: nmr δ 2.15 (s, 3, COCH3), 2.52 (complex, 4, CH2CO), 2.00 (complex, CH2CH2CH2), 6.50 (d, 1, =CHCl), 7.42 (d, J=14Hz, =CHCO); ir λ max 5.85, 6.30, 7.35, 10.70μ.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]#[CH:12])[CH:8]=[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[O:17][CH3:18])([CH3:4])([CH3:3])[CH3:2].C(O[C:23]1[CH:28]=[CH:27][C:26](I)=[C:25]([CH3:30])[C:24]=1[F:31])(=O)C.C(N(CC)CC)C.O1CCCC1.[C:44]([O:47][CH2:48]C)(=[O:46])C>CCCCCC.[Cu]I.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>[CH3:48][O:47][C:44](=[O:46])[CH2:30][C:25]1[CH:26]=[CH:27][C:28]([C:12]#[C:11][C:9]2[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:6]([O:17][CH3:18])=[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=2)=[CH:23][C:24]=1[F:31]
Reactant: CCOC(C)=O
Reactant: CC(=O)Oc1ccc(I)c(C)c1F
Reactant: C#Cc1cc(C(C)(C)C)c(OC)c(C(C)(C)C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C#Cc2cc(C(C)(C)C)c(OC)c(C(C)(C)C)c2)cc1F
Yield: 89 %

Procedure:
Following General Procedure F and using 1,3-di-tert-butyl-5-ethynyl-2-methoxy-benzene (Intermediate 169, 0.087 g, 0.33 mmol), methyl-2-fluoro-4-iodo phenyl acetate (Reagent H, 0.088 g, 0.30 mmol), triethyl amine (5 mL), anhydrous tetrahydrofuran (10 mL), copper(I)iodide (0.02 g, 0. 1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.06 g, 0.085 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 10% ethyl acetate in hexane as the eluent, the title compound (0. 122 g, 89%) was obtained.
Reaction SMILES: F[C:2]1C([B-](C2C(F)=C(F)C(F)=C(F)C=2F)(C2C(F)=C(F)C(F)=C(F)C=2F)C2C(F)=C(F)C(F)=C(F)C=2F)=C(F)C(F)=C(F)C=1F.[Li+].CCOCC.[C:52]([C:56]1[CH:61]=[CH:60][CH:59]=[C:58]([C:62]([CH3:65])([CH3:64])C)N=1)([CH3:55])(C)C>C1(C)C=CC=CC=1.C([Pd]Cl)C=C>[CH2:61]([C:60]12[CH2:64][CH:62]([CH2:58][CH2:59]1)[CH:65]=[CH:2]2)[CH2:56][CH2:52][CH3:55]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)n1
Reactant: Fc1c(F)c(F)c([B-](c2c(F)c(F)c(F)c(F)c2F)(c2c(F)c(F)c(F)c(F)c2F)c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Agent: C=CC[Pd]Cl
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCCCC12C=CC(CC1)C2

Procedure:
A 50 weight percent solution of butylnorbornene (5.0 g, 0.033 mol) was prepared in toluene. Lithium tetrakis(pentafluorophenyl)borate.2.5 Et2O (0.0012 g, 0.0014 mmol) was combined with (allyl)palladiumchloride dimer (100 μl of a 1.4 mmol solution in toluene) and 2,6-di-t-butylpyridine (100 μl of a 2.9 mmol solution in toluene) in toluene and added to the monomer mixture. A polymeric puck formed within 5-10 min at room temperature.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][CH3:16])=[CH:10][C:9]=1[NH:17][C:18]1[C:23]([C:24]#[N:25])=[CH:22][N:21]=[C:20]2[CH:26]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]=O)[CH:30]=3)[S:28][C:19]=12.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CN(C)C=O.C(O)(=O)C>[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][CH3:16])=[CH:10][C:9]=1[NH:17][C:18]1[C:23]([C:24]#[N:25])=[CH:22][N:21]=[C:20]2[CH:26]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[CH:30]=3)[S:28][C:19]=12
Reactant: COc1cc(Nc2c(C#N)cnc3cc(-c4cccc(C=O)c4)sc23)c(Cl)cc1Cl
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(Nc2c(C#N)cnc3cc(-c4cccc(CN5CCOCC5)c4)sc23)c(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 33.3 %

Procedure:
Morpholine (100 μL, 1.15 mmol) is added to a suspension of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(3-formylphenyl)thieno[3,2-b]pyridine-6-carbonitrile (400 mg, 0.88 mmol) in 8 mL of dichloromethane and 2 mL of N,N-dimethylformamide. The reaction mixture is cooled to 0° C. and sodium triacetoxyborohydride (1.0 g, 4.73 mmol) is added. After stirring at 0° C. for 1 hour, 2 drops of acetic acid are added and the reaction mixture is allowed to warm to room temperature and stirred for 2 hours. The reaction is quenched by the addition of water and then partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic layer is washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of 1:1 hexane:ethyl acetate to 5% methanol in ethyl acetate to provide 154 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[3-(morpholin-4-ylmethyl)phenyl]thieno[3,2-b]pyridine-6-carbonitrile as yellow crystals, mp 205-207° C.; 1H NMR (DMSO-d6) δ 2.38 (m, 4H), 3.51 (s, 2H), 3.59 (m, 4H), 3.86 (s, 3H), 7.32-7.48 (m, 3H), 7.64-7.70 (m, 2H), 7.77 (s, 1H), 7.91 (s, 1H), 8.61 (s, 1H), 9.74 (s, 1H); MS 523.1, 525.0 (M−H)−.
Reaction SMILES: [OH2:1].[C:2]1([CH3:12])[CH:7]=[CH:6][C:5](S(O)(=O)=O)=[CH:4][CH:3]=1.[C:13]1([CH3:19])C=CC=C[CH:14]=1>>[CH:5]1[CH:4]=[CH:3][C:2]2[C:7](=[CH:14][CH:13]=[CH:19][C:12]=2[OH:1])[CH:6]=1
Reactant: Cc1ccccc1
Reactant: O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Product: Oc1cccc2ccccc12
Temperature: 90 °C

Procedure:
The compound of the above formula (33) was dissolved in 120 ml of toluene and heated to 90° C. 57.6 g (303.0 mmol) of p-toluenesulfonic acid monohydrate was added to this solution and refluxed for 4 hours. After the reaction, the reaction product was washed in water, the solvent was removed, and the obtained product was purified by column chromatography to obtain a naphthol compound represented by the following formula (34) as 4.4 g (7.6 mmol, yield rate of 75%) of a white solid.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[N:22]=[C:23]([CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([F:39])([F:38])([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[O:24][CH:25]=1.O>CN(C=O)C>[F:37][S:34]([F:35])([F:36])([F:38])([F:39])[C:31]1[CH:32]=[CH:33][C:28](/[CH:27]=[CH:26]/[C:23]2[O:24][CH:25]=[C:21]([CH2:20][O:18][C:15]3[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][N:3]4[CH:7]=[CH:6][N:5]=[N:4]4)=[CH:17][CH:16]=3)[N:22]=2)=[CH:29][CH:30]=1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Reactant: FS(F)(F)(F)(F)c1ccc(C=Cc2nc(CCl)co2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FS(F)(F)(F)(F)c1ccc(/C=C/c2nc(COc3ccc(CCCCn4ccnn4)cc3)co2)cc1
Reaction time: 0.5 h
Yield: 83.6 %

Procedure:
25.0 mg (1.00 mmol) 95% sodium hydride were given to a solution of 217 mg (1.00 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)-phenol in 3.0 ml DMF and stirred for 30 min. 346 mg (1.00 mmol) 4-chloromethyl-2-[2-(4-pentafluorosulfanyl-phenyl)-vinyl]-oxazole were added and stirring continued at r.t. for 24 h. After cautious addition of 10 ml water the mixture was diluted to 60 ml by further addition of water and stirred for 30 min. The resulting precipitate was washed with 3×10 ml water, 2×10 ml methanol/water, diethyl ether and dried to yield 440 mg (84%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[C:8](=[CH:14]/[N:15](C)C)/[C:9]([O:11]CC)=O)[CH:5]=[N:6][CH:7]=1.[NH:18]([C:20]1[N:25]=[CH:24][C:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:22][CH:21]=1)N.C1(C)C=CC(S(O)(=O)=O)=CC=1.[ClH:44]>C(O)C.O1CCOCC1>[ClH:44].[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9](=[O:11])[N:18]([C:20]3[N:25]=[CH:24][C:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:22][CH:21]=3)[NH:15][CH:14]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(NN)nc1
Reactant: CCOC(=O)/C(=C\N(C)C)c1cncc(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CC(C)(C)OC(=O)c1ccc(-n2[nH]cc(-c3cncc(Br)c3)c2=O)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
500 mg (1.7 mmol) of the compound from Example 9A and 350 mg (1.7 mmol) of the compound from Example 15A are dissolved in 2 ml of ethanol, and 58 mg (0.3 mmol) of p-toluenesulfonic acid are added. The mixture is heated under reflux for 24 h and then cooled to RT, and 0.5 ml of a 4 N solution of hydrogen chloride in dioxane is added. The mixture is stirred at RT for 30 min. The precipitate is filtered off, washed with ethanol and diethyl ether and dried under high vacuum.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.OO.C(=O)([O-])[O-:13].[Na+].[Na+]>C(O)(=O)C>[CH3:1][O:2][CH2:3][C:4]1[CH:5]=[N+:6]([O-:13])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: COCc1cccnc1
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: COCc1ccc[n+]([O-])c1
Temperature: 80 °C

Procedure:
A mixture of 7.74 g of 3-methoxymethylpyridine, 60 ml of acetic acid and 7.5 g of 30% hydrogen peroxide solution was stirred while heating at 80° C. for four hours. The reaction mixture was cooled to room temperature, and then sodium carbonate was added in small portions. The reaction mixture was subjected to filtration, and washed with ethyl acetate. The resultant filtrate was washed with a saturated aqueous solution of sodium hydrogensulfite and a saturated sodium chloride solution, and dried over anhydrous sodium carbonate. Activated carbon was added, followed by filtration through Celite™. The filtrate was concentrated under reduced pressure to give 2.66 g of 3-methoxymethylpyridine N-oxide.
Reaction SMILES: [NH2:1][CH:2]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:3][CH:4]([P:13]([O:18]CC)(=[O:17])[O:14]CC)[P:5]([O:10]CC)(=[O:9])[O:6]CC.Br[Si](C)(C)C>ClCCl>[NH4+:1].[NH4+:1].[NH4+:1].[NH2:1][CH:2]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:3][CH:4]([P:5]([O-:10])(=[O:6])[OH:9])[P:13]([O-:18])(=[O:14])[O-:17]
Reactant: CCCCCC(N)CC(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: CCCCCC(N)CC(P(=O)([O-])[O-])P(=O)([O-])O
Product: [NH4+]
Temperature: 25 °C
Reaction time: 18 h
Yield: 419.8 %

Procedure:
To a solution of tetraethyl 3-aminooctane-1,1-bisphosphonate (0.45 g, 1.12 mmol) in dry dichloromethane (1.1 mL) was added bromotrimethylsilane (1.05 mL, 7.85 mmol) via syringe. After 18 hours, the mixture was concentrated under vacuum. To the residue was added 3N NH4OH (8 mL) which was stirred for 30 minutes at room temperature. The solvent was removed in vacuo and the residue concentrated from methanol (2 mL) to give 0.40 g of 3-aminooctane-1,1-bisphosphonic acid, triammonium salt as a white powder.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=2)[N:3]=1.[F:15][C:16]1[CH:25]=[CH:24][C:19]2[CH:20]([NH2:23])[CH2:21][O:22][C:18]=2[CH:17]=1.C(N(C(C)C)C(C)C)C>CN1CCCC1=O>[F:15][C:16]1[CH:25]=[CH:24][C:19]2[CH:20]([NH:23][C:2]3[CH:11]=[CH:10][C:9]4[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=4)[N:3]=3)[CH2:21][O:22][C:18]=2[CH:17]=1
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Reactant: NC1COc2cc(F)ccc21
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc2nc(NC3COc4cc(F)ccc43)ccc2c1
Temperature: 140 °C
Reaction time: 2 h
Yield: 40.1 %

Procedure:
A mixture of 2-chloro-6-nitro-quinoline (1.6 g, 7.67 mmol) in N-methyl-2-pyrrolidinone (15 ml) with the above described rac-6-fluoro-2,3-dihydro-benzofuran-3-ylamine (1.3 g, 8.43 mmol) and N-ethyldiisopropylamine (1.96 ml, 11.5 mmol) was stirred at 140° C. for 2 h. Cooled to room temperature, poured onto water and extracted twice with Ethyl acetate, dried over sodium sulfate and evaporated totally to give a crude product which was purified by silica gel column chromatography with heptane/dichloromethane followed by trituration with diethyl ether to give the title compound as a yellow solid (1.0 g, 40%); MS (ISP) m/e=326.2 (M+H+).
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][Si](C)(C)C.[CH3:10][N:11]([CH3:16])[S:12](N)(=[O:14])=[O:13].N>S1(C2C(=CC=CC=2)C(=O)N1)(=O)=O.C1(C)C=CC=CC=1>[CH3:10][N:11]([CH3:16])[S:12]([NH:3][Si:2]([CH3:9])([CH3:8])[CH3:1])(=[O:14])=[O:13]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: CN(C)S(N)(=O)=O
Agent: N
Agent: O=C1NS(=O)(=O)c2ccccc21
Solvent: Cc1ccccc1
Product: CN(C)S(=O)(=O)N[Si](C)(C)C
Yield: 140.1 %

Procedure:
3 ml (14.4 mmoles) of hexamethyldisilazane were added to a refluxing mixture of 2.48 g (20 mmoles) of N,N-dimethylsulfamide, 9 mg (0.05 mmole) of saccharin and 30 ml of toluene. By the method described hereinbefore, it was established that the calculated amount of ammonia had been evolved after refluxing for one hour and volatile materials were then evaporated under reduced pressure. The residue was dried to room temperature to obtain 3.96 g (101%) of N,N-dimethyl-N'-trimethylsilylsulfamide melting at 83°-86° C.
Reaction SMILES: Cl.CO[CH2:4][NH2:5].[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:16]([NH:18][CH2:19][C:20]([OH:22])=O)=[O:17])=[CH:10]2.C[CH2:24][O:25]CC>>[CH3:24][O:25][N:5]([CH3:4])[C:20]([CH2:19][NH:18][C:16]([C:11]1[NH:12][C:13]2[C:9]([CH:10]=1)=[CH:8][C:7]([Cl:6])=[CH:15][CH:14]=2)=[O:17])=[O:22]
Reactant: COCN
Reactant: CCOCC
Reactant: O=C(O)CNC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Product: CON(C)C(=O)CNC(=O)c1cc2cc(Cl)ccc2[nH]1

Procedure:
Methoxymethylamine hydrochloride (1.0 mmol) and [(5-chloro-1H-indole-2-carbonyl)-amino]-acetic acid (1.0 mmol) were coupled according to Procedure A. The resulting solid was suspended in ether, filtered and dried: Yield 158 mg, 53%; PBMS 296/298 (MH+, 100%);
Reaction SMILES: [CH2:1]([NH:9][C:10](=[O:19])[CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[OH:12])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:20](Cl)(=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>N1C=CC=CC=1>[CH2:1]([NH:9][C:10](=[O:19])[CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[O:12][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(NCCc1ccccc1)C(O)c1ccccc1
Solvent: c1ccncc1
Product: O=C(NCCc1ccccc1)C(OCc1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
N-phenethyl mandelic amide 51 g is dissolved in 200 ml of pyridine, and benzoyl chloride 42 ml is added with stirring. Exothermic benzoylation takes place immediately and the reaction mixture is cooled externally with a cold water bath. The stirring is continued for 5 hours, and the reaction mixture is mixed with 1 liter of ice water. The product is extracted with 250 ml of chloroform, washed with 300 ml of 5% sodium bicarbonate, followed by 300 ml of 0.5N HCL and is dried over anhydrous sodium sulfate. On evaporation of chloroform a crystalline product is obtained. The crystals are washed with n-hexane and dried. The yield is 85 g.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([Cl:16])=O)=[CH:12][CH:11]=1.C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]=[C:14]([Cl:16])[C:13]2[CH:17]=[CH:18][C:10]([CH3:9])=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: Nc1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(Cl)=Nc2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-(4-bromo-phenyl)-4-methyl-benzimidoyl chloride used is prepared by the following procedure. To a solution of 4-bromoaniline (29.2 mg, 0.17 mmol) and 4-methyl benzoyl chloride (22.5 μL, 0.17 mmol) in dichloromethane was added triethylamine (28 μL, 0.20 mmol). After stirred at room temperature for 30 minutes, the solvent was removed. The residue was added 0.5 mL of thionyl chloride. The reaction mixture was heated at 80° C. for 1 h, concentrated. The product was used in the next step reaction.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[S:19][C:18]2[C:13](=[N:14][CH:15]=[CH:16][C:17]=2[NH:20][C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[NH:26][C:25]([CH3:30])=[CH:24]3)[CH:12]=1>>[CH3:30][C:25]1[NH:26][C:27]2[C:23]([CH:24]=1)=[CH:22][C:21]([NH:20][C:17]1[CH:16]=[CH:15][N:14]=[C:13]3[CH:12]=[C:11]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[S:19][C:18]=13)=[CH:29][CH:28]=2
Reactant: Cc1cc2cc(Nc3ccnc4cc(Br)sc34)ccc2[nH]1
Reactant: OB(O)c1ccccc1
Product: Cc1cc2cc(Nc3ccnc4cc(-c5ccccc5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from phenyl boronic acid and (2-bromothieno[3,2-b]pyridin-7-yl)-(2-methyl-1H-indol-5-yl)-amine by the procedure analogous to example 2 above. 1H NMR (400 MHz, CD3OD) δ8.02 (d, 1H), 7.67 (d, 2H), 7.54 (s, 1H), 7.30 (m, 5H), 6.94 (d, 1H), 6.54 (d, 1H), 6.09 (s, 1H), 2.39 (s, 3H); RP18-HPLC RT: 6.21 minutes; API MS 356 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]([CH3:12])[CH3:11])=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:15][C:16](=[O:28])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([CH3:26])[C:20]=1[CH3:27])C>>[CH:10]([S:9][C:4]1[C:3]([CH2:2][O:25][C:22]2[CH:23]=[CH:24][C:19]([CH2:18][CH2:17][C:16]([OH:28])=[O:15])=[C:20]([CH3:27])[C:21]=2[CH3:26])=[CH:8][CH:7]=[CH:6][N:5]=1)([CH3:12])[CH3:11]
Reactant: CC(C)Sc1ncccc1CCl
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Product: Cc1c(CCC(=O)O)ccc(OCc2cccnc2SC(C)C)c1C
Yield: 78.8 %

Procedure:
3-Chloromethyl-2-isopropylsulfanyl-pyridine (25 mg, 0.12 mmol) obtained in Step C of Preparation Example 1 and 3-(4-hydroxy-2,3-dimethyl-phenyl)-propionic acid ethyl ester (30 mg, 0.13 mmol) obtained in Step D of Preparation Example 43 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (34 mg, 85%).
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][S:7]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1)(=[O:9])=[O:8].C([Li])CCC.[CH3:34][C:35]([CH3:37])=[O:36].FC(F)(F)C(O)=O>C1COCC1.CCCCCC>[OH:36][C:35]([CH3:37])([CH3:34])[CH:10]([C:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)=[CH:15][CH:16]=1)[S:7]([NH2:6])(=[O:8])=[O:9]
Reactant: CC(C)=O
Reactant: COc1ccc(CNS(=O)(=O)Cc2ccc(N3CCOCC3)cc2)c(OC)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCC
Product: CC(C)(O)C(c1ccc(N2CCOCC2)cc1)S(N)(=O)=O
Reaction time: 0.17 h

Procedure:
Under inert gas, 0.264 g of N-(2,4-dimethoxybenzyl)-C-(4-morpholin-4-ylphenyl)methanesulfonamide was initially charged in 3 ml of THF and then, at −78° C., 0.85 ml of a 1.6 N butyllithium solution in hexane was added dropwise. The reaction mixture was stirred for 10 minutes and then 0.22 ml of acetone was added dropwise. The mixture was stirred at constant temperature for 30 minutes, 0.102 ml of trifluoroacetic acid was added and the mixture was allowed to come to room temperature. The solvent was removed under reduced pressure. The residue was dissolved in 4 ml of dichloromethane, and 1.2 ml of trifluoroacetic acid was added. After stirring at room temperature for 16 h, the crude product was purified in a purification laboratory by means of preparative HPLC. This gave the product with a molecular weight of 428.43 g/mol (C14H22N2O4S).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([F:17])=[C:5]([C:9]([N+:14]([O-:16])=[O:15])=[C:10](F)[C:11]=1[F:12])[C:6]([OH:8])=[O:7].[OH-].[NH4+:19]>>[NH2:19][C:10]1[C:9]([N+:14]([O-:16])=[O:15])=[C:5]([C:4]([F:17])=[C:3]([O:2][CH3:1])[C:11]=1[F:12])[C:6]([OH:8])=[O:7]
Reactant: [NH4+]
Reactant: COc1c(F)c(F)c([N+](=O)[O-])c(C(=O)O)c1F
Agent: [OH-]
Product: COc1c(F)c(N)c([N+](=O)[O-])c(C(=O)O)c1F
Yield: 80 %

Procedure:
2.0 g (8 mmol) of 3-methoxy-6-nitro-2,4,5-trifluoro-benzoic acid was treated with ammonium hydroxide to produce 1.6 g (6.45 mmol, 80%) of 3-amino-4,6-difluoro-5-methoxy-2-nitro-benzoic acid. LCMS: 249 (M+1)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[N:6]=[CH:5]2.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[CH:32])=[N:29][CH:30]=2)=[CH:21][CH:20]=1>>[IH:1].[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[C:32][C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[N:7]([CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[N:6]=[CH:5]4)=[N:29][CH:30]=2)=[CH:23][CH:24]=1
Reactant: Ic1ccc2c(cnn2CCN2CCCC2)c1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: Clc1ccc(-c2ccc(C#Cc3ccc4c(cnn4CCN4CCCC4)c3)nc2)cc1
Product: I

Procedure:
Prepared according to general working method I from 5-iodo-1-(2-pyrrolidin-1-yl-ethyl)-1H-indazole (230 mg, 0.67 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (144 mg, 0.67 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=3)[C@H:11]([CH2:20][N:21]3[N:25]=[N:24][C:23]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)=[N:22]3)[O:10][C:9]2=[O:32])=[CH:4][CH:3]=1.[C:33](=O)([O-])[O-].[K+].[K+].I[CH:40]([CH3:42])[CH3:41]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH:40]([CH3:42])[CH3:41])[CH:14]=3)[C@H:11]([CH2:20][N:21]3[N:25]=[N:24][C:23]([C:26]4[CH:27]=[N:28][C:29]([CH3:33])=[CH:30][CH:31]=4)=[N:22]3)[O:10][C:9]2=[O:32])=[CH:4][CH:3]=1
Reactant: O=C1O[C@@H](Cn2nnc(-c3cccnc3)n2)[C@H](c2cccc(O)c2)N1c1ccc(Cl)cc1
Reactant: O=C([O-])[O-]
Reactant: CC(C)I
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nnn(C[C@@H]3OC(=O)N(c4ccc(Cl)cc4)[C@H]3c3cccc(OC(C)C)c3)n2)cn1
Temperature: 50 °C

Procedure:
A small reaction tube fitted with screw cap containing a septa is charged with (4S,5S)-3-(4-chlorophenyl)-4-(3-hydroxyphenyl)-5-((5-(pyridin-3-yl)-2H-tetrazol-2-yl)-methyl)oxazolidin-2-one (25 mg, 0.055 mmol) and DMF (0.5 mL). Potassium carbonate (25 mg, 0.18 mmol) and 2-iodopropane (18 μL, 0.18 mmol) are then added and the vessel is heated to 50° C. for 4 h, then cooled to room temperature. The reaction is quenched with water, and extracted with EtOAc, dried over MgSO4, filtered and concentrated. The title compound is then obtained after flash chromatography (12 g Redisep, 30-50% EtOAc/hexanes). 1H NMR (acetone-d6, 400 MHz) δ 9.22 (br, s 1H), 8.72 (br, s, 1H), 8.33 (ddd, J=8.0, 1.8, 1.8 Hz, 1H), 7.52 (dd, J=7.9, 4.8 Hz, 1H), 7.46-7.42 (m, 2H), 7.32 (t, J=7.6 Hz, 1H), 7.27-7.24 (m, 2H), 7.09 (app t, J=1.9 Hz, 1H), 7.04 (d, J=7.7 Hz, 1H), 6.86 (ddd, J=8.3, 2.5, 0.8 Hz, 1H), 5.72 (d, J=5.0 Hz, 1H), 5.51 (dd, J=14.7, 5.9 Hz, 1H), 5.44 (dd, J=14.7, 4.1 Hz, 1H), 5.12 (ddd, J=5.8, 5.0, 4.2 Hz, 1H), 4.60 (septet, J=6.0 Hz, 1H), 1.24 (d, J=6.0 Hz, 3H, 1.21 (d, J=6.0 Hz, 3H); HPLC-MS calculated C25H23ClN6O3 (M+H+) 491.2, found 491.2.