Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[C:5]([CH3:12])[CH:6]=[CH:7][C:8]=2[CH3:11])[CH:3]1O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH2:10][C:9]2[C:4]([CH:3]=1)=[C:5]([CH3:12])[CH:6]=[CH:7][C:8]=2[CH3:11]
Reactant: Cc1ccc(C)c2c1CC(C)C2O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1=Cc2c(C)ccc(C)c2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
9.06 g of 2,4,7 trimethylindanol (51.4 mmol) were dissolved in 100 ml of toluene in a 250 ml, 2-neck flask equipped with magnetic stirring bar, Dean-Stark separator and bubble condenser. 0.15 g of p-toluenesulphonic acid monohydrate (0.78 mmol, 0.015 eq) were added, and the solution was heated to reflux, distilling the toluene-H2O azeotrope. After about 2 h, the temperature increased toward the boiling point of toluene, and after a few drops of pure toluene distillate, the reaction was stopped by cooling to room temperature and treating the solution with 100 ml of saturated NaHCO3 aqueous solution. The organic phase was extracted with Et2O with the standard procedure, the combined organic phases were washed with H2O and then dried with Na2SO4. After filtration, the solvents were evaporated under reduced pressure to give 7.24 g of an off-white waxy product (yield: 89%).
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([NH:18][C:19]3[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=3)[N:16]=2)[N:11](COCC[Si](C)(C)C)[CH:10]=1)=[O:8])([CH3:5])[CH3:4].FC(F)(F)C(O)=O>ClCCl.CO.[OH-].[NH4+]>[OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([NH:18][C:19]3[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=3)[N:16]=2)[NH:11][CH:10]=1)=[O:8])([CH3:5])[CH3:4]
Reactant: Cn1cc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)CO)cn3COCC[Si](C)(C)C)cn1
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: Cn1cc(Nc2cnc3[nH]cc(C(=O)NC(C)(C)CO)c3n2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.3 %

Procedure:
To a solution of N-(1-hydroxy-2-methylpropan-2-yl)-2-(1-methyl-1H-pyrazol-4-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (26 mg, 56.6 mol) in dichloromethane (1 mL) was added trifluoroacetic acid (129 mg, 87.2 μL, 1.13 mmol) and the mixture stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo and the residue obtained diluted with dichloromethane (1 mL), methanol (0.5 mL) and ammonium hydroxide (0.15 mL) and stirred at room temperature for 2 h. The mixture was concentrated and triturated with water. The solid was collected by filtration and washed with water and ether to give N-(1-hydroxy-2-methylpropan-2-yl)-2-(1-methyl-1H-pyrazol-4-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (12 mg, 36.4 mol, 64%) as a brown solid. 1H NMR (400 MHz, DMSO-d) δ ppm: 12.19 (s, 1H), 9.16 (s, 1H), 8.01 (s, 1H), 7.91 (d, J=3.0, 1 H), 7.86 (s, 1H), 7.70 (s, 1H), 7.49 (s, 1H), 5.15 (t, J=5.7, 1 H), 3.82 (s, 3H), 3.57 (d, J=5.9, 2 H), 1.37 (s, 9H); MS (EI/CI) m/z: 330.2 [M+H].
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3](=[O:18])[N:4]1[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:5]1=[N:6]2.[CH3:19][CH:20]1[CH2:25][CH2:24][CH:23]([C:26](Cl)=[O:27])[CH2:22][CH2:21]1>>[CH3:19][CH:20]1[CH2:25][CH2:24][CH:23]([C:26]([N:11]2[C:5]3=[N:6][C:7]4[C:2]([C:3](=[O:18])[N:4]3[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]2=3)=[CH:1][CH:10]=[CH:9][CH:8]=4)=[O:27])[CH2:22][CH2:21]1
Reactant: CC1CCC(C(=O)Cl)CC1
Reactant: O=c1c2ccccc2nc2[nH]c3ccccc3n12
Product: CC1CCC(C(=O)n2c3ccccc3n3c(=O)c4ccccc4nc23)CC1

Procedure:
6-(4-Methylcyclohexanoyl)benzimidazo[2,1-b]quinazolin-12(6H)one is prepared with benzimidazo[2,1-b]quinazolin-12(6H)one and 4-methylcyclohexanoyl chloride.
Reaction SMILES: CS(C)=O.C([Li])CCC.[Br-].[C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:13])=[O:12].[N:38]1[CH:43]=[CH:42][CH:41]=[C:40]([N:44]2[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:46]([CH:53]=O)=[CH:45]2)[CH:39]=1>O>[C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH:53][C:46]1[C:47]2[C:52](=[CH:51][CH:50]=[CH:49][CH:48]=2)[N:44]([C:40]2[CH:39]=[N:38][CH:43]=[CH:42][CH:41]=2)[CH:45]=1)([OH:13])=[O:12]
Reactant: O=Cc1cn(-c2cccnc2)c2ccccc12
Reactant: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)CCCCC=Cc1cn(-c2cccnc2)c2ccccc12
Reaction time: 0.5 h

Procedure:
A solution of dimsyllithium (from 80 ml of dimethylsulfoxide and 13 ml of 2.1M n-butyllithium) is stirred under nitrogen at room temperature, and 6.2 g of 5-carboxypentyltriphenylphosphonium bromide is added in portions. The reaction mixture is stirred for 30 minutes and 3.0 g of N-(3-pyridyl)indole-3-carboxaldehyde is added. After 18 hours at room temperature, the reaction mixture is diluted with 240 ml of water and extracted with 100 ml of ethyl acetate. The aqueous phase is neutralized with 1.1 ml of concentrated hydrochloric acid and extracted with ethyl acetate. The extracts are dried over sodium sulfate and evaporated to an oil which is triturated with ether to give a semi-solid which is recrystallized from methanol to yield 3-(6-carboxyhex-1-enyl)-N-(3-pyridyl)indole, m.p. 124°-125°.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:23])[NH:8][CH2:9][CH2:10][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:14][C:15]=2[CH3:16])=[C:5]([C:24]([O:26]CC)=[O:25])[CH:4]=[N:3]1.[Li+].[OH-].Cl>C1COCC1.C(O)C>[CH3:1][N:2]1[C:6]([C:7](=[O:23])[NH:8][CH2:9][CH2:10][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:14][C:15]=2[CH3:16])=[C:5]([C:24]([OH:26])=[O:25])[CH:4]=[N:3]1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)NCCc1nc(-c2ccccc2)oc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1CCNC(=O)c1c(C(=O)O)cnn1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
To a solution of ethyl 1-methyl-5-(2-(5-methyl-2-phenyloxazol-4-yl)ethylcarbamoyl)-1H-pyrazole-4-carboxylate (407 mg, 1.06 mmol) in THF (3.00 mL) and Ethanol (1.5 mL) was added LiOH (1M aqueous solution, 2.13 mL, 2.13 mmol) at 0-5° C. The reaction mixture was stirred at RT for 2 h and poured into HCl (1 M, 2.15 mL). The resulting thick suspension was filtered and the filtrate was extracted with dichloromethane (3×50 mL). The organic layers were combined, dried over MgSO4 and concentrated in vacuo to give 341 mg (90.4%) off-white solid as crude product which was used without any further purification.
Reaction SMILES: [CH3:1][CH:2]([CH:5]([CH3:8])[CH:6]=[CH2:7])[CH:3]=[O:4].[CH2:9]=[O:10].[OH-].[Na+]>>[CH3:1][C:2]([CH:5]([CH2:6][CH3:7])[CH3:8])([CH2:9][OH:10])[CH2:3][OH:4]
Reactant: C=CC(C)C(C)C=O
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Product: CCC(C)C(C)(CO)CO

Procedure:
50 g. of 2,3-dimethyl-pent-4en-aldehyde is added to 100 ml. of 37% formaldehyde in a 250 ml. round bottom flask. 70 g. of a 50% w/w solution of sodium hydroxide is dripped into the mixture with stirring and the temperature maintained at 35°-40° C. with an ice bath. When the addition is complete the mixture is stirred one-half hour at room temperature and the two layers separated. The aqueous layer is extracted with 75 ml. ethyl acetate and the extract combined with the organic layer. The organic layer is washed twice with 100 ml. of water. The organic layer is placed in a Parr hydrogenation bottle and diluted to 150 ml. with methanol. 1 g. wet Raney Nickle catalyst is added and the mixture reduced at 50 p.s.i. until no more hydrogen is absorbed. The catalyst is removed by filtration and the filtrate concentrated and distilled. A yield of 45.4 g. of 2-methyl-2(sec butyl)-1,3-propanediol BP 139°-140° C. at 10 mm. pressure and refractive index ND22 =1.4610 is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([NH:10][C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[N:8]([CH3:9])[C:4]=2[C:3]=1[C:21]#[N:22].[OH:23]S(O)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>CCOCC>[NH2:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([NH:10][C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[N:8]([CH3:9])[C:4]=2[C:3]=1[C:21]([NH2:22])=[O:23]
Reactant: O=S(=O)(O)O
Reactant: Cn1c(Nc2c(Cl)cccc2Cl)nc2ccc(N)c(C#N)c21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: Cn1c(Nc2c(Cl)cccc2Cl)nc2ccc(N)c(C(N)=O)c21
Temperature: 105 °C
Yield: 66 %

Procedure:
A mixture of 5-amino-3-methyl-2-(2,6-dichlorophenylamino)-3H-benzimidazole-4-carbonitrile (Example 6) (1 g, 3 mmol) and conc. H2SO4 (8 mL) was warmed to 100-110° C. for 1 h and monitored by TLC for the disappearance of starting material. The mixture was cooled and poured onto a mixture of crushed ice, sodium carbonate, and ether. The precipitate was filtered, washed with water, dissolved in MeOH-methylene chloride, treated with carbon (decolorizing charcoal), dried (MgSO4), filtered, and concentrated in vacuo. The aqueous filtrate was washed with EtOAc (3×30 mL). The combined organic layers were washed with brine (25 mL), which was then extracted with EtOAc (20 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated to yield 190 mg of a crude product. This was combined with the solid product and triturated with ether-methylene chloride to afford 5-amino-2-(2,6-dichlorophenylamino)-3-methyl-3H-benzoimidazole-4-carboxylic acid amide (700 mg, 66%). The filtrate was chromatographed on silica gel to afford an additional 128 mg (12%) of product.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1.C([O-])(=O)C.[Na+].[OH-].[NH4+].[Cl-].[NH4+].[S:23]1[CH:27]=[CH:26][N:25]=[C:24]1[NH:28][S:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH2:38])=[NH:37])=[CH:34][CH:33]=1)(=[O:31])=[O:30]>CN(C=O)C.CCOC(C)=O>[Cl:12][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[Cl:11])[CH2:4][C:3]1[N:37]=[C:36]([C:35]2[CH:34]=[CH:33][C:32]([S:29]([NH:28][C:24]3[S:23][CH:27]=[CH:26][N:25]=3)(=[O:31])=[O:30])=[CH:40][CH:39]=2)[NH:38][CH:2]=1
Reactant: N=C(N)c1ccc(S(=O)(=O)Nc2nccs2)cc1
Reactant: O=C(CBr)Cc1ccc(Cl)c(Cl)c1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=S(=O)(Nc1nccs1)c1ccc(-c2nc(Cc3ccc(Cl)c(Cl)c3)c[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75.6 %

Procedure:
To a solution of 1-bromo-3-(3,4-dichloro-phenyl)-propan-2-one (4.1 mmol) in DMF (20 mL) was added sodium acetate (21 mmol) and the mixture was stirred for 2 hr at room temperature before concentrated ammonium hydroxide (5 mL) and ammonium chloride (1 g) were added. After the reaction mixture was stirred for 10 min, 4-(thiazol-2-ylsulfamoyl)-benzamidine (4.1 mmol) was added and the mixture was stirred at 60° C. overnight. After cooled to room temperature, the mixture was diluted with AcOEt (200 mL) and the resulting organic solution was washed with brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by column chromatography to give 4-[4-(3,4-dichloro-benzyl)-1H-imidazol-2-yl]-N-thiazol-2-yl-benzenesulfonamide (3.1 mmol), which was converted to its sodium salt by reacting with NaOH solution (0.999 N).
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:22][CH2:21][C:8]2=[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[S:10][C:11]([S:12][CH:13]([CH3:15])[CH3:14])=[C:7]2[C:6]1=[O:23])(=O)[CH3:2].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH:13]([S:12][C:11]1[S:10][C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:8]2[CH2:21][CH2:22][C:5]3[N:4]=[C:1]([CH3:2])[O:23][C:6]=3[C:7]=12)([CH3:14])[CH3:15]
Reactant: CCOC(=O)c1sc(SC(C)C)c2c1CCC(NC(C)=O)C2=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1sc(SC(C)C)c2c1CCc1nc(C)oc1-2
Yield: 100.1 %

Procedure:
A mixture of ethyl 5-acetylamino-4,5,6,7-tetrahydro-3-isopropylthio-4-oxobenzo[c]thiophene-1-carboxylate (1.00 g), phosphorus oxychloride (1.29 g) and toluene (30 ml) was refluxed under heating for 1.5 hours; the solution obtained was concentrated under reduced pressure, diluted with a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with water and dried (MgSO4), after which the solvent was distilled off to yield ethyl 4,5-dihydro-8-isopropylthio-2-methylthieno[3,4-g]benzoxazole-6-carboxylate (0.95 g, 100%), which was then recrystallized from ethyl acetate-hexane. Yellow prisms. Melting point 62-63° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[N:7]([CH2:12][CH3:13])[C:6](=[O:14])[C:5]2([CH3:16])[CH3:15].[N+:17]([C:20]1[C:21]([C:25](O)=O)=[N:22][NH:23][CH:24]=1)([O-:19])=[O:18].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[CH2:12]([N:7]1[C:8]2[CH:9]=[C:10]3[N:11]=[C:25]([C:21]4[C:20]([N+:17]([O-:19])=[O:18])=[CH:24][NH:23][N:22]=4)[NH:1][C:2]3=[CH:3][C:4]=2[C:5]([CH3:15])([CH3:16])[C:6]1=[O:14])[CH3:13]
Reactant: CCN1C(=O)C(C)(C)c2cc(N)c(N)cc21
Reactant: O=C(O)c1n[nH]cc1[N+](=O)[O-]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4[N+](=O)[O-])nc3cc21
Temperature: 150 °C
Reaction time: 6 h

Procedure:
5,6-Diamino-1-ethyl-3,3-dimethyl-1,3-dihydro-indol-2-one (5.00 g, 22.80 mmol), and 4-nitro-pyrazole carboxylic acid (3.58 g, 22.80 mmol) were mixed with polyphosphoric acid (22.34 g, 228.0 mmol) and phosphorus pentoxide (1.63 g, 11.4 mmol) and stirred under nitrogen at 150° C. for 6 h. It was quenched with ice water (250 ml) and the resulting suspension was adjusted to pH 5 by adding aqueous ammonia. The crude microcrystalline solid was dissolved in ethyl acetate (400 mL). The organic layer was separated and the aqueous layer was further extracted with ethyl acetate (4×400 mL). After evaporation of the solvent, the crude product was purified by HPLC (High Performance Liquid Chromatography). 5-Ethyl-7,7-dimethyl-2-(4-nitro-1H-pyrazol-3-yl)-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one was obtained as an orange solid (2.47 g, 32%).
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](=O)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[CH3:33][C:34]1[CH:39]=[CH:38][C:37]([NH:40]N)=[CH:36][CH:35]=1>>[CH3:1][CH:2]([CH3:31])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]3[C:38]4[C:37](=[CH:36][CH:35]=[C:34]([CH3:33])[CH:39]=4)[NH:40][C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: Cc1ccc(NN)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(=O)c3ccccc3)CC2)c1
Agent: Cl
Product: Cc1ccc2[nH]c(-c3ccccc3)c(CCCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-{3-[1-(6-oxo-6-phenylhexyl)-4-piperidinyl]phenyl}propanamide and 1-(4-methylphenyl)hydrazine hydrochloride: ESMS m/e: 508.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][CH:3]=1.Cl[N:12]1C(=O)[CH2:15][CH2:14][C:13]1=O.C(N)C#C.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[CH:15]=[C:14]([CH2:13][NH2:12])[O:8][N:7]=2)=[CH:4][CH:3]=1
Reactant: ON=Cc1ccc(Cl)cc1
Reactant: O=C1CCC(=O)N1Cl
Agent: C#CCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NCc1cc(-c2ccc(Cl)cc2)no1
Yield: 110.2 %

Procedure:
1.56 g (10 mmol) of p-chlorobenzaldoxime was dissolved in 40 ml of dried dichloromethane in a erlenmeyer flask equipped with a magnetic stirrer, and 1.7 g (12 mmol) of N-chlorosuccinimide was added slowly. The reaction mixture was stirred until completely dissolved. The system was heated slightly for 20 min. Then, 0.56 g (10 mmol) of propargyl amine was introduced and 1.2 g (12 mmol) of triethylamine was added dropwise, which caused the emission of white smog. The reaction mixture was heated under reflux for 2 h, and then purified by column chromatography on silica gel using petroleum ether (b.p. 60-90° C.)—ethyl acetate (v:v=4:1) as eluant, to obtain 2.3 g of the product as yellow solid. The yield was 62%.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[O:10][C:3]=12.[NH2:23][CH2:24][C:25]1[C:26]([N:31]([CH3:36])[S:32]([CH3:35])(=[O:34])=[O:33])=[N:27][CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:36][N:31]([C:26]1[C:25]([CH2:24][NH:23][C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]4[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=4)[O:10][C:3]=23)=[CH:30][CH:29]=[CH:28][N:27]=1)[S:32]([CH3:35])(=[O:34])=[O:33]
Reactant: COc1cc(-c2cc3nccc(Cl)c3o2)cc(OC)c1OC
Reactant: CN(c1ncccc1CN)S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(-c2cc3nccc(NCc4cccnc4N(C)S(C)(=O)=O)c3o2)cc(OC)c1OC
Temperature: 110 °C
Reaction time: 1 h
Yield: 33.8 %

Procedure:
To a dry 10 mL microwave vial with stirbar was added 7-chloro-2-(3,4,5-trimethoxyphenyl)furo[3,2-b]pyridine (50.00 mg; 0.16 mmol; 1.00 eq.), N-(3-aminomethyl-pyridin-2-yl)-N-methyl-methanesulfonamide (40.40 mg; 0.19 mmol; 1.20 eq.), chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl-tert.-butyl ether adduct (2.59 mg; 0.003 mmol; 0.02 eq.), and potassium carbonate (30.26 mg; 0.22 mmol; 1.40 eq.). The vial was sealed and flushed with N2. The reagents were suspended in tert.-BuOH (1.00 ml) and the reaction mixture was heated to 110° C. with stirring for 1 h. The reaction mixture was cooled to room temperature and concentrated on a rotary evaporator. The crude mixture was purified by Biotage chromatography (20-100% EtOAc/hex KP-NH SNAP column) to afford the title compound as a beige solid (27 mg, 34%). (HPLC (method F): 90%, RT: 4.62 min); MS (m/z) 499 [M+H]+, RT: 2.5 min.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:13][C@@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]1[NH:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.C(N(CC)CC)C.[OH-].[Na+]>ClCCl>[O:4]=[C:2]1[N:20]([CH:21]2[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]2)[C@@H:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C@H:14]2[NH:13]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N[C@@H]2CCCC[C@H]2N)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)N[C@@H]3CCCC[C@H]32)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 141.8 %

Procedure:
A solution of triphosgene (7.2 g, 24.2 mmol) in dichloromethane (300 mL) was added with a solution of tert-butyl 4-{[(1R,2R)-2-aminocyclohexyl]amino}piperidine-1-carboxylate (18 g, 60 mmol) and triethylamine in dichloromethane (600 mL) drop wise over a period of 1 h and stirred at room temperature for 22 h. An additional amount of triphosgene (8 g) and triethylamine (13 mL) were added and stirred at room temperature for another 22 h. An aqueous solution of sodium hydroxide (0.5N 200 mL) was added to the reaction mixture, layers were separated, and the aqueous layer was extracted with dichloromethane (2×100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to afford the crude product which was triturated with diethylether (80 mL) to give the title compound as white solid (11.1 g, 56%). 1H NMR (300 MHz, METHANOL-D4): δ ppm 4.25-4.05 (m, 2H), 3.80-3.65 (m, 1H), 3.10-2.90 (m, 2H), 2.85-2.65 (m, 2H), 2.20-1.90 (m, 2H), 1.90-1.55 (m, 4H), 1.55-1.30 (m, 11H)
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:12](Cl)(=[O:14])[CH3:13].C(N(CC)CC)C>ClCCl>[C:12]([NH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)Cl
Reactant: Nc1ccc2c(c1)NC(=O)C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc2c(c1)NC(=O)C2
Reaction time: 4 h
Yield: 76.3 %

Procedure:
To a mixture of 6-amino-2-oxindole (1 g) and acetyl chloride (0.79 g) in 10 ml of dichloromethane at 0° C. was added triethylamine (1 g). The mixture was brought to room temperature and stirred for 4 hours protected from atmospheric moisture with a dry-tube. The solvent was then evaporated and the residue was recrystallized from methanol to give 0.98 g (77%) of 6-acetylamino-2-oxindole as a beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]4[CH:19]=[CH:20][C:21]([C:23](O)=[O:24])=[CH:22][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([CH2:41][NH2:42])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([CH2:41][NH:42][C:23]([C:21]2[CH:20]=[CH:19][C:13]3[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:10]([NH:9][C:7]4[S:8][C:4]5[CH:3]=[C:2]([Cl:1])[CH:27]=[CH:26][C:5]=5[N:6]=4)=[N:11][C:12]=3[CH:22]=2)=[O:24])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: COCCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCC3CCN(C(=O)OC(C)(C)C)CC3)ccc21
Yield: 59.8 %

Procedure:
4-({[2-(6-Chloro-benzothiazol-2-ylamino)-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carbonyl]-amino}methyl)-piperidine-1-carboxylic acid tert-butyl ester (160 mg) was prepared by following General Procedure F starting from 2-(6-Chloro-benzothiazol-2-ylamino)-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carboxylic acid (180 mg), 4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (150 mg), HBTU (200 mg), and DIEA (1.2 mL) in DMF (2 mL).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:16])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:17][C:18]1[CH:19]=[C:20]([N:37]2[CH2:41][C@H:40]([CH2:42][N:43]3[CH:47]=[CH:46][N:45]=[N:44]3)[O:39][C:38]2=[O:48])[CH:21]=[CH:22][C:23]=1[C:24]1[CH:25]=[N:26][C:27]([C:30]2[CH2:34][C@@H:33]([CH2:35]O)[O:32][N:31]=2)=[CH:28][CH:29]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:16])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:35][C@H:33]1[O:32][N:31]=[C:30]([C:27]2[CH:28]=[CH:29][C:24]([C:23]3[CH:22]=[CH:21][C:20]([N:37]4[CH2:41][C@H:40]([CH2:42][N:43]5[CH:47]=[CH:46][N:45]=[N:44]5)[O:39][C:38]4=[O:48])=[CH:19][C:18]=3[F:17])=[CH:25][N:26]=2)[CH2:34]1)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO)C3)nc2)c(F)c1
Reactant: CN(CCCCC(=O)O)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(CCCCC(=O)OC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The crude carbamate prepared as above (2 g, 8.6 mmol), (5R)-3-(3-fluoro-4-{6-[(5S)-5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl]pyridin-3-yl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 1: 1 g, 2.28 mmol), 4-dimethylaminopyridine (0.05 g, 0.4 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.28 g, 6.67 mmol) were combined in DMF (10 ml). The suspension was allowed to stir for 16 hours at room temperature, diluted with ethyl acetate, washed with water, and dried over magnesium sulfate. The residue obtained upon filtration and evaporation was purified via chromatography (silica gel, 0.5 to 5% methanol in dichloromethane). Evaporation of the product containing fractions and trituration of the resulting solid with diethyl ether yielded the title compound as an off-white solid (1.28 g), melting point: 121° C.