Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13]1)[C:4]1[CH:5]=[N:6][C:7]([NH:10][NH2:11])=[CH:8][CH:9]=1.[C:27]([O:30][CH2:31][CH2:32][O:33][C:34]1[CH:35]=[CH:36][CH:37]=[C:38]2[C:43]=1[N:42]=[C:41]([CH3:44])[CH:40]=[CH:39]2)(=[O:29])[CH3:28].C(O)C.C(O)(=O)C.C(O)(=O)C.I(C1C=CC=CC=1)=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[C:27]([O:30][CH2:31][CH2:32][O:33][C:34]1[CH:35]=[CH:36][CH:37]=[C:38]2[C:43]=1[N:42]=[C:41]([C:44]1[N:6]3[CH:5]=[C:4]([C@@H:3]([N:12]4[CH2:16][CH2:15][C@H:14]([NH:17][C:18]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:24])[CH2:13]4)[C:2]([F:25])([F:1])[F:26])[CH:9]=[CH:8][C:7]3=[N:10][N:11]=1)[CH:40]=[CH:39]2)(=[O:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc(NN)nc2)C(F)(F)F)C1
Reactant: CC(=O)OCCOc1cccc2ccc(C)nc12
Agent: O=C([O-])O
Agent: O=Ic1ccccc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCO
Product: CC(=O)OCCOc1cccc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 63.7 %

Procedure:
A solution of tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (0.48 g, 1.2 mmol) and 2-(2-methylquinolin-8-yloxy)ethyl acetate (0.30 g, 1.2 mmol) in ethanol (5.8 mL, 1.2 mmol) was allowed to stir at ambient temperature for 12 hours. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (5.8 mL) and iodosobenzene diacetate (0.41 g, 1.3 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 hour. Ethyl acetate (20 mL) and saturated sodium bicarbonate (10 mL) were added. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography on a C18 column (0-100% acetonitrile/water) to give the title compound (0.47 g, 66%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.C(Cl)(Cl)Cl.[CH3:24][O:25][CH2:26]Cl>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:24][O:25][CH3:26])=[CH:4][CH:3]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: O
Product: COCOCCc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 103.2 %

Procedure:
To a mixture of 4-bromophenylethyl alcohol (12 g, 59.7 mmol), ethyldiisopropylamine (11.5 g, 89.5 mmol) and chloroform (200 mL), chloromethyl methyl ether (7.2 g, 89.5 mmol) was slowly added at 0° C. The reaction mixture was stirred at 0° C. for 1 hour and at room temperature for 2.5 hours, and then poured into water. After the mixture was extracted twice with chloroform, the combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give bromo-4-(2-methoxymethoxyethyl)benzene (15.1 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH:16]([C:18]1[CH:19]=[N:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH2:17].[OH-].[K+]>CN1C(=O)CCC1>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:17][CH2:16][C:18]3[CH:19]=[N:20][C:21]4[C:26]([CH:27]=3)=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1cnc2ccccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2cnc3ccccc3c2)CCN(C)C1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, 3-vinylquinoline and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[C:5]([O:11][CH3:12])=[CH:4][CH:3]=1.CN(CCN(CCN(C)C)C)C.C([Li])CCC.[CH:30](N1CCOCC1)=[O:31].Cl>C1COCC1>[F:1][C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[CH:30]=[O:31]
Reactant: O=CN1CCOCC1
Reactant: COc1ccc(F)c2c1OCC2
Agent: CN(C)CCN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C=O)c(F)c2c1OCC2
Temperature: -74 °C
Reaction time: 1 h

Procedure:
To a solution of 665 mg of 4-fluoro-7-methoxy-2,3-dihydrobenzofuran and 740 mg of N,N,N′,N′,N″-pentamethyldiethylenetriamine in 15 ml of THF there was added dropwise 1.66 ml of n-butyllithium (2.55 M, hexane solution) at −74° C. The mixture was stirred at −74° C. for 1 hour, and then 500 μl of N-formylmorpholine was added. After further stirring at room temperature for 1 hour, 1N hydrochloric acid was added to the reaction mixture while cooling on ice, and the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (321 mg) as an oil.
Reaction SMILES: Br[C:2]1[N:6]2[C@@H:7]([CH3:14])[CH2:8][N:9]([CH2:12][CH3:13])[C:10](=[O:11])[C:5]2=[C:4]([O:15][CH3:16])[C:3]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].C([Li])CCC.[C:27](OCC)(=[O:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29].OS(O)(=O)=O>C1COCC1>[CH2:31]([O:30][C:28](=[O:29])[C:27]([C:2]1[N:6]2[C@@H:7]([CH3:14])[CH2:8][N:9]([CH2:12][CH3:13])[C:10](=[O:11])[C:5]2=[C:4]([O:15][CH3:16])[C:3]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:33])[CH3:32]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCOC(=O)c1c(OC)c2n(c1Br)[C@@H](C)CN(CC)C2=O
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1c(C(=O)OCC)c(OC)c2n1[C@@H](C)CN(CC)C2=O
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
(S)-Ethyl 6-bromo-2-ethyl-8-methoxy-4-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate (0.70 mol) was dissolved in THF (4500 ml) at 20° C. Molecular sieves (4 Å; 250 g) were added. The mixture was stirred for 30 min at 20° C., and was then cooled to −78° C. A solution of n-Butyllithium (2.5 M; 0.77 mol) was added dropwise below −65° C. The mixture was stirred for 1 h at −78° C. Diethyl oxalate (1.6 mol) in THF (600 ml) was added dropwise below −65° C. and then it was stirred for 3 h. The mixture was poured into a solution of aqueous H2SO4 (4200 ml, 2 M) and THF (3500 ml). The organic layer was separated and the aqueous layer was re-extracted with ethyl acetate (3×2000 ml). The combined organic layers were collected and evaporated. The residue was purified by column chromatography over silica gel (eluent: petroleum ether/ethyl acetate from 100:0 to 1:1). The pure fractions were collected and the organic solvent was evaporated. Yield: 170 g (67% yield).
Reaction SMILES: [BH4-].[Na+].[OH-].[Na+].[Cl:5][C:6]1[C:21]([F:22])=[CH:20][C:9]2[C:10](=[O:19])[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[S:14][C:8]=2[CH:7]=1>O.C(O)C.C1C=CC=CC=1>[Cl:5][C:6]1[C:21]([F:22])=[CH:20][C:9]2[CH:10]([OH:19])[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[S:14][C:8]=2[CH:7]=1
Reactant: O=C1Cc2ccccc2Sc2cc(Cl)c(F)cc21
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Solvent: CCO
Product: OC1Cc2ccccc2Sc2cc(Cl)c(F)cc21
Yield: 94 %

Procedure:
A solution of sodium borohydride (0.42 g) in water (4 ml), containing 15% sodium hydroxide solution (0.1 ml), was added dropwise to a solution of the ketone from the preceding experiment (7.0 g) in a mixture of ethanol (70 ml) and benzene (25 ml). The mixture was refluxed for 3 hours, diluted with water and extracted with benzene. The extract was washed with 5% sodium hydroxide solution and water, dried over sodium sulphate and taken down. The solid residue was crystallized from hexane (30 ml), yielding 6.60 g (94%) of 7-chloro-8-fluoro-10-hydroxy-10,11-dihydrodibenzo(b,f)thiepine, m.p. 86°-87° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[C:3]21[CH2:17][CH2:16]2.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH2:27])=[CH:22][N:21]=1.[OH-].[K+]>CN1C(=O)CCC1>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:27][CH2:26][C:23]3[CH:22]=[N:21][C:20]([C:19]([F:29])([F:18])[F:28])=[CH:25][CH:24]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[C:3]21[CH2:17][CH2:16]2
Reactant: Cc1ccc2[nH]c3c(c2c1)C1(CC1)N(C)CC3
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C(F)(F)F)nc2)CCN(C)C12CC2

Procedure:
The title compound is prepared from a mixture of 2′,8′-dimethyl-2′,3′,4′,5′-tetrahydrospiro[cyclopropane-1,1′-pyrido[4,3-b]indole], 2-(trifluoromethyl)-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.[ClH:13].[CH3:14][N:15]([CH:17]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C:27]1=[O:32])[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1)[CH3:16].N.[Cl-].[NH4+]>CCOCC.O>[ClH:13].[CH3:16][N:15]([CH:17]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C:27]1([OH:32])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1)[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1)[CH3:14]
Reactant: CN(C)C(c1ccc(C#N)cc1)C1CCCCC1=O
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: Cl
Agent: N
Agent: [Cl-]
Solvent: O
Solvent: CCOCC
Product: CN(C)C(c1ccc(C#N)cc1)C1CCCCC1(O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 3.3 %

Procedure:
0.34 g (14.0 mmole) of magnesium turnings was stirred in 10 ml of ether of analysis purity. 3.16 g (14.0 mmole) of 4-bromobenzotrifluoride dissolved in 10 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. The base was freed from 3.5 g (12.0 mmole) of the hydrochloride of 4-[dimethylamino-(2-oxocyclohexyl)methyl]benzonitrile obtained according to stage 1 with 30 ml of water and 5 ml of ammonia solution (25 vol. %), extracted three times with 30 ml of ether each time, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator without heating (500 to 10 mbar). 3.0 g (11.7 mmole) of this base were dissolved in 10 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 20 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 20 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 3.52 g of crude base (74.7% of theory) were obtained, from which 0.17 g of 4-{dimethylamino-[2-hydroxy-2-(4-trifluoromethylphenyl)cyclohexyl]methyl}-benzonitrile, hydrochloride (3.3% of theory) having a melting point above 250° C. was obtained according to the procedure described in Example 1 (3rd Stage) with chlorotrimethylsilane/water in 2-butanone.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:7](=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:8]([OH:10])=[O:9])=[O:4].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1>CN(C)C=O>[CH3:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][CH2:2][C:3]([NH:5][C:6]2[C:7](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:8]([OH:10])=[O:9])=[O:4])=[CH:17][CH:18]=1
Reactant: Cc1ccc(N)cc1
Reactant: O=C(CCl)Nc1ccccc1C(=O)O
Solvent: CN(C)C=O
Product: Cc1ccc(NCC(=O)Nc2ccccc2C(=O)O)cc1
Temperature: 90 °C
Yield: 182.9 %

Procedure:
N(chloroacetyl)anthranilic acid 3.2 g (0.02 mol) and p-toluidine 3.4 g (0.005 mol) were dissolved in 4 ml of dimethylformamide and heated at 90° C. for 3 hours. The reaction solution was poured into ice water and deposited crystals were collected by filtration. These crystals were washed with ether and recrystallized from ethanol to obtain N-[(4-methylphenylamino)acetyl]anthranilic acid 2.6 g (yield: 70%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[C:17](=O)([O-])[O-].[Na+].[Na+]>CO>[CH3:17][O:8][C:7](=[O:9])[C:6]1[C:5](=[CH:4][CH:3]=[C:2]([NH2:1])[CH:10]=1)[OH:11]
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(N)ccc1O

Procedure:
A solution of 20.0 g of 5-aminosalicylic acid, 250 ml of methanol and 10 ml of concentrated sulfuric acid is refluxed overnight. The reaction mixture is cooled, made alkaline with dilute aqueous sodium carbonate solution and concentrated. The resulting solid is separated and wshed with water. The solid is then washed with ether, and the ether is evaporated to dryness yielding a brown solid. The aqueous filtrate above is extracted with ether, the extract is dried over anhydrous sodium sulfate, and evaporated yielding a brown solid. The solids are combined and recrystallized from ether to afford 10.7 g of 5-aminosalicylic acid methyl ester.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4](Br)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.C(N(CC)CC)C.Cl.Cl.[NH2:21][CH2:22][CH2:23][NH:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][N:26]=1.O>CS(C)=O>[Br:1][C:2]1[N:3]=[C:4]([NH:21][CH2:22][CH2:23][NH:24][C:25]2[N:26]=[CH:27][C:28]([C:29]#[N:30])=[CH:31][CH:32]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1
Reactant: N#Cc1ccc(NCCN)nc1
Reactant: Brc1cn2ccnc2c(Br)n1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: N#Cc1ccc(NCCNc2nc(Br)cn3ccnc23)nc1
Temperature: 140 °C

Procedure:
8 g (28.9 mmol) of 6,8-dibromoimidazo[1,2-a]pyrazine were dissolved in 80 ml of DMSO, and 16.1 ml (115.6 mmol) of triethylamine and 5.154 g (31.78 mmol) of 6-[(2-aminoethyl)-amino]pyridine-3-carbonitrile (Example 2A) were added. The mixture was heated at 140° C. in a microwave for 1.5 h. The solution was poured into water and the precipitate was filtered off. Washing with water and drying under high vacuum gave 10.3 g (94% of theory) of the product as a solid.
Reaction SMILES: [C:1](O)(=O)[C:2](O)=O.[N:7]([CH:10]1[CH:15]2[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]2)[CH2:11]1)=[N+:8]=[N-:9].C(C(O)=O)#CC(O)=O.C1(C)C(C)=CC=CC=1.C(=O)=O>CC(C)=O>[N:7]1([CH:10]2[CH:15]3[CH2:14][CH2:13][N:12]([CH2:17][CH2:16]3)[CH2:11]2)[CH:2]=[CH:1][N:9]=[N:8]1
Reactant: [N-]=[N+]=NC1CN2CCC1CC2
Reactant: O=C(O)C(=O)O
Agent: O=C(O)C#CC(=O)O
Agent: O=C=O
Solvent: CC(C)=O
Solvent: Cc1ccccc1C
Product: c1cn(C2CN3CCC2CC3)nn1

Procedure:
(±) 3-Azido-1-azabicyclo[2.2.2]octane oxalate salt (D25) (200 mg, 0.0083 mole) in acetone (20 ml) was treated with acetylene dicarboxylic acid (500 mg, 0.0044 mole) and concentrated in vacuo to produce a homogenous gum. Xylene (20 ml) was added and the solution heated to reflux for 10 min when the suspension rapidly darkened and evolved carbon dioxide. The xylene was then removed in vacuo and the residue partitioned between chloroform and saturated aqueous potassium carbonate solution. The organic phase was separated, dried over sodium sulphate and concentrated in vacuo to a gum. Chromatography on alumina in a gradient of 5-30% methanol in ethyl acetate afforded the title compound (E35) which crystallised from 40-60° petrol as needles m.p. 62-65° C. (60 mg, 0.0034 moles, 40%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:12]=[C:13]([NH2:19])[N:14]([CH2:15][CH2:16][CH2:17]Cl)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[H-].[Na+]>CN(C)C(=O)C>[Cl:1][C:2]1[C:11]2[N:12]=[C:13]3[NH:19][CH2:17][CH2:16][CH2:15][N:14]3[C:10]=2[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1nc2c(Cl)nc3ccccc3c2n1CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Clc1nc2ccccc2c2c1nc1n2CCCN1
Reaction time: 0.08 h
Yield: 94.3 %

Procedure:
To a round-bottomed flask containing 4-chloro-1-(3-chloropropyl)-1H-imidazo[4,5-c]quinolin-2-amine (7.92 g, 26.8 mmol) was added N,N-dimethylacetamide (200 mL) and the mixture was stirred for 5 minutes. To the stirred solution was added sodium hydride (60% dispersion in mineral oil, 3.9 g, 80.54 mmol) and the reaction was stirred at 50° C. After 1.5 h the reaction was cooled to ambient and quenched by the careful addition of water (1 L). The reaction was transferred to a separatory funnel and ethyl acetate (1 L) was added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (1 L). The organic layers were combined, washed with water (2×1 L), dried (MgSO4), filtered, and the solvent was evaporated. The resultant product was dried under reduced pressure to afford 6-chloro-8,9,10,11-tetrahydropyrimido[1′,2′:1,2]imidazo[4,5-c]quinoline (6.54 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>N1C=CC=CC=1>[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:10]=2[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]3)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1cc2cccc(N)c2[nH]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2cccc(NS(=O)(=O)c3ccc(C)cc3)c2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.3 %

Procedure:
To a mixture of ethyl 7-amino-1H-indole-2-carboxylate (0.30 g) and pyridine (8 mL) was added 4-methylphenylsulfonyl chloride (0.34 g) at 4° C., and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated, diluted with ethyl acetate, washed with aqueous citric acid solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-hexane to give the title compound (465 mg, yield 88%) as pale-yellow prism crystals. MS:359 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@@H:11]3[CH2:15][CH2:14][C@:13]([CH3:20])([C:16]([O:18][CH3:19])=[O:17])[C:12]3([CH3:22])[CH3:21])=[C:8]([C:23](=[O:25])[NH2:24])[CH:7]=[N:6][N:5]2[CH:26]=1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:23]([C:8]1[CH:7]=[N:6][N:5]2[CH:26]=[C:2]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:3]=[C:4]2[C:9]=1[NH:10][C@@H:11]1[CH2:15][CH2:14][C@:13]([CH3:20])([C:16]([O:18][CH3:19])=[O:17])[C:12]1([CH3:21])[CH3:22])(=[O:25])[NH2:24]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)[C@@]1(C)CC[C@@H](Nc2c(C(N)=O)cnn3cc(Br)cc23)C1(C)C
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: COC(=O)[C@@]1(C)CC[C@@H](Nc2c(C(N)=O)cnn3cc(-c4ccccc4)cc23)C1(C)C
Temperature: 90 °C
Yield: 59.7 %

Procedure:
A solution of (1S,3R)-methyl 3-(6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-ylamino)-1,2,2-trimethylcyclopentanecarboxylate (307 mg, 0.725 mmol) in DMF (4.8 ml) was added into a reaction vial charged with phenylboronic acid (177 mg, 1.450 mmol), 1,1′-bis(di-tert-butylphosphino)ferrocene (34.8 mg, 0.073 mmol) and palladium (II) acetate (16.28 mg, 0.073 mmol), followed by addition of a 2.0 M aqueous potassium phosphate, dibasic solution (1.1 ml, 2.176 mmol). The suspension was purged with nitrogen for 5 minutes. The vial was sealed and heated at 90° C. for 2 hrs. The reaction was cooled to room temperature and diluted with ethyl acetate (20 ml). The ethyl acetate solution was washed with water (3×10 ml), dried with sodium sulfate, filtered, and concentrated under reduced pressure to give a light yellow oil. The crude product was chromatographed on the silica gel column eluted with 0-50% ethyl acetate in hexane, yielding the title compound (182 mg, 0.433 mmol, 59.7% yield) as a white solid. LC/MS found [M+H]+=420.9.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[NH:6][C:7]([C:9]3[C:13]([N+:14]([O-])=O)=[CH:12][NH:11][N:10]=3)=[N:8][C:4]=2[CH:3]=1>C(O)C.[Pd]>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[NH:6][C:7]([C:9]3[C:13]([NH2:14])=[CH:12][NH:11][N:10]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])c1c[nH]nc1-c1nc2cc(Cl)ccc2[nH]1
Agent: [Pd]
Solvent: CCO
Product: Nc1c[nH]nc1-c1nc2cc(Cl)ccc2[nH]1
Reaction time: 3 h
Yield: 143.8 %

Procedure:
A solution of 5-chloro-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole [91 mg, Example 239(a)] in ethanol (40 mL), under nitrogen, was treated with palladium on carbon (spatula tip, 5%). The mixture was stirred under hydrogen for 3 hours and then filtered through Celite. The filter pad was washed well with dichloromethane. The combined filtrate and washings were evaporated to give 3-(5-chloro-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine (116 mg). LC-MS (METHOD A): RT=2 minutes; 234 (M+H)+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[CH:15][C:16]([C:19]#[C:20][C:21]3[CH:30]=[CH:29][C:24]([O:25][CH2:26][CH2:27][OH:28])=[CH:23][CH:22]=3)=[N:17][CH:18]=2)=[CH:9][CH:8]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:1][S:2]([O:28][CH2:27][CH2:26][O:25][C:24]1[CH:23]=[CH:22][C:21]([C:20]#[C:19][C:16]2[CH:15]=[N:14][C:13]([C:10]3[CH:9]=[CH:8][C:7]([Cl:6])=[CH:12][CH:11]=3)=[CH:18][N:17]=2)=[CH:30][CH:29]=1)(=[O:4])=[O:3]
Reactant: OCCOc1ccc(C#Cc2cnc(-c3ccc(Cl)cc3)cn2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)OCCOc1ccc(C#Cc2cnc(-c3ccc(Cl)cc3)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.62 mL (7.98 mmol) of methanesulfonic acid chloride was added dropwise at RT to a solution of 700 mg (2.00 mmol) of 2-{4-[5-(4-chlorophenyl)pyrazin-2-ylethynyl]phenoxy}ethanol and 0.65 mL (7.98 mmol) of pyridine in 20 mL of DCM and the mixture was then stirred overnight at RT. After the addition of another 0.33 mL (3.99 mmol) of pyridine and 0.32 mL (4.12 mmol) of methanesulfonic acid chloride, the reaction mixture was stirred for a further 2 hours at RT in the ultrasound bath. The solution was diluted with 30 mL DCM, and the organic phase was separated off, washed three times with 60 mL of water, and dried over magnesium sulfate. After the desiccant and solvent had been eliminated, the residue was purified by chromatography (silica gel, DCM). Yield: 600 mg (70% of theoretical); C21H17ClN2O4S (M=428.889); calc.: molpeak (M+H)+:429/431 (Cl); found: molpeak (M+H)+:429/431 (Cl); Rf value: 0.30 (silica gel, DCM/MeOH 9:1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:36])[C@@H:12]([NH:21][C:22](=[O:35])[C@@H:23]([C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:34])[CH3:33])=[CH:27][CH:26]=2)[NH2:24])[C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[S:8][CH:9]=1)=[O:4].[O:37]=[C:38](Cl)OC(Cl)(Cl)Cl>ClCCl.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:36])[C@@H:12]([N:21]2[C:22](=[O:35])[C@@H:23]([C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:34])[CH3:33])=[CH:27][CH:26]=3)[NH:24][C:38]2=[O:37])[C@H:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH3:14])[S:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1csc(NC(=O)[C@@H](NC(=O)[C@H](N)c2ccc(NC(C)=O)cc2)[C@@H](C)c2ccccc2)n1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1csc(NC(=O)[C@H]([C@@H](C)c2ccccc2)N2C(=O)N[C@H](c3ccc(NC(C)=O)cc3)C2=O)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 119.9 %

Procedure:
Crude 2-{(2S,3S)-2-[(R)-2-(4-acetylamino-phenyl)-2-amino-acetylamino]-3-phenyl-butyrylamino}-thiazole-4-carboxylic acid methyl ester (≈0.175 mmol) was dissolved in dichloromethane (10 mL) and diisopropylethyllamine (72 μL, 0.41 mmol) was added. The resulting mixture was added to an ice cooled solution of diphosgene (13 μL, 0.109 mmol) in dichloromethane (10 mL). The reaction mixture was stirred for 15 minutes, diluted with ethyl acetate (100 mL) and washed with 0.2M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, brine and dried over sodium sulfate. The solution was filtered and the solvent removed in vacu. The residue was purified by chromatography over silica gel gradient eluted from 50% to 100% ethyl acetate in hexanes to afford 2-{(2S,3S)-2-[(R)-4-(4-acetylamino-phenyl)-2,5-dioxo-imidazolidin-1-yl]-3-phenyl-butyrylamino}-thiazole-4-carboxylic acid methyl ester (70 mg, 74%).