Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:28]=[C:27]4[C:18]([N:19]5[CH:24]([C:25](=[O:29])[NH:26]4)[CH2:23][NH:22][CH2:21][CH2:20]5)=[N:17][CH:16]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:30](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][C:15]3[CH:28]=[C:27]4[C:18]([N:19]5[CH:24]([C:25](=[O:29])[NH:26]4)[CH2:23][N:22]([CH3:30])[CH2:21][CH2:20]5)=[N:17][CH:16]=3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc(CN3CCN(c4ccc(Cl)cc4)CC3)cnc2N2CCNCC12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1CCN2c3ncc(CN4CCN(c5ccc(Cl)cc5)CC4)cc3NC(=O)C2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 3.2 %

Procedure:
To a solution of 7-[4-(4-Chloro-phenyl)-piperazin-1-ylmethyl]-1,3,4,10a-tetrahydro-2H,9H-2,4a,5,9-tetraaza-phenanthren-10-one (139 mg, 0.337 mmol) in DMF (3.4 mL) cooled to 0° C. was added potassium carbonate (233 mg, 1.683 mmol) and methyl iodide (2 M in THF, 0.168 mL). The reaction was stirred 1 h at 0° C. and filtered through celite. The filtrate was purified via HPLC (55-90% acetonitrile in water, ammonium bicarbonate buffer). The fractions were combined and concentrated until a white solid precipitated. The precipitate was filtered off and dried in vacuum to afford the title compound (4.6 mg, 3.2%) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.59 (s, 1H), 7.68 (d, J=1.8 Hz, 1H), 7.15-7.28 (m, 2H), 7.01 (d, J=2.0 Hz, 1H), 6.85-6.97 (m, 2H), 4.17-4.30 (m, 1H), 3.88 (dd, J=10.6, 3.3 Hz, 1H), 3.37 (s, 2H), 3.14-3.20 (m, 1H), 3.06-3.14 (m, 4H), 2.84 (d, J=11.6 Hz, 1H), 2.74 (td, J=12.4, 3.0 Hz, 1H), 2.44-2.48 (m, 4H), 2.26 (s, 3H), 1.91-2.02 (m, 2H). [M+H] calc'd for C22H27ClN6O, 427. found, 427.
Reaction SMILES: Cl[C:2](=[O:14])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[N:5]1.[NH2:15][CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1)=[O:18].C([O-])(=O)C.[Na+]>ClCCl.O>[O:14]=[C:2]([NH:15][CH2:16][C:17](=[O:18])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:28])[F:26])[CH:20]=1)[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[N:5]1
Reactant: CCOC(=O)c1cnn(CC(=O)Cl)c1
Reactant: NCC(=O)c1cccc(C(F)(F)F)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cnn(CC(=O)NCC(=O)c2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.9 %

Procedure:
The compound (3.2 g) obtained in Example 115c and 2-amino-1-[3-(trifluoromethyl)phenyl]ethanone (2.88 g) were dissolved in dichloromethane (120 mL) and water (40 ml), and an aqueous solution (40 mL) of sodium acetate (2.46 g) was added dropwise under cooling in an ice bath. The reaction mixture was stirred at room temperature overnight, and the organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: petroleum ether-ethyl acetate) to give the title compound (0.92 g) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C@@:8]2([CH3:15])[NH:13][C:12](=[S:14])[CH2:11][O:10][CH2:9]2)[CH:7]=1.[Cl:17][C:18]1[C:19]([CH:26]=O)=[N:20][N:21]([CH:23]([F:25])[F:24])[CH:22]=1.[B][B][B][B][B][B][B][B][B][B]>CO>[Cl:17][C:18]1[C:19]([CH2:26][NH:1][C:2]2[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C@@:8]3([CH3:15])[NH:13][C:12](=[S:14])[CH2:11][O:10][CH2:9]3)[CH:7]=2)=[N:20][N:21]([CH:23]([F:25])[F:24])[CH:22]=1
Reactant: O=Cc1nn(C(F)F)cc1Cl
Reactant: C[C@@]1(c2cc(N)ccc2F)COCC(=S)N1
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Product: C[C@@]1(c2cc(NCc3nn(C(F)F)cc3Cl)ccc2F)COCC(=S)N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 5 ml-reaction tube under an inert atmosphere a mixture of (R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-morpholine-3-thione (48 mg, 0.2 mmol) and 4-chloro-1-difluoromethyl-1H-pyrazole-3-carbaldehyde (20 mg, 0.11 mmol) in methanol (0.3 ml) was stirred at room temperature for 1 hour. Then decaborane (24 mg, 0.2 mmol) was added in one portion and the mixture warmed to 45° C. for 15 hours. For the workup, the light yellow solution was quenched with sodium carbonate (10% solution), the methanol removed at reduced pressure and then the residue extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulphate, then evaporated at reduced pressure. The crude product was purified by preparative HPLC using a gradient of water (+0.1% triethylamine) and acetonitrile (90:10 to 10:90). The (R)-5-{5-[(4-chloro-1-difluoromethyl-1H-pyrazol-3-ylmethyl)-amino]-2-fluoro-phenyl}-5-methyl-morpholine-3-thione was obtained as a colourless foam (49 mg, 60%); (calculated) C16H16ClF3N4OS [404.84]; (found) [M+H]+=405.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]([OH:9])=O.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][C:43]=1[CH3:44])[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:34]=2)[N:31]=1>CN(C)C=O.CN(C)C(=O)C>[CH:38]1([C:36]([NH:35][C:33]2[N:34]=[C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]4[CH:41]=[CH:42][C:43]([CH3:44])=[C:22]([NH:21][C:7]([C:6]5[O:5][CH:4]=[N:3][C:2]=5[CH3:1])=[O:9])[CH:23]=4)=[N:31][N:30]3[CH:32]=2)=[O:37])[CH2:39][CH2:40]1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Reactant: Cc1ncoc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1NC(=O)c1ocnc1C
Yield: 85.5 %

Procedure:
In the same manner as in Example 259 and using 4-methyl-1,3-oxazole-5-carboxylic acid (77 mg, 0.60 mmol), tetrahydrofuran (10 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (62 μL, 0.72 mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.46 mmol) and N,N-dimethylacetamide (7 mL) as starting materials, the title compound (170 mg, 83%) was obtained as a white solid.
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH:22]1([NH2:25])[CH2:24][CH2:23]1>CS(C)=O>[CH:22]1([NH:25][C:2]2[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[CH2:24][CH2:23]1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Cl)nc2c1
Reactant: NC1CC1
Solvent: CS(C)=O
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(NC3CC3)nc2c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Into a 20-mL sealed tube, was placed methyl 3-chloro-2-phenylquinoxaline-6-carboxylate (200 mg, 0.67 mmol, 1.00 equiv), cyclopropanamine (10 mL), DMSO (1 mL). The resulting solution was stirred overnight at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with H2O. The resulting solids were collected by filtration and applied onto a silica gel column with PE/EA (50:1). This resulted in 182.4 mg (83%) of methyl 3-(cyclopropylamino)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: C(=O)([O-])O.[NH4+:5].Cl[CH2:7][C:8]([NH:10][C@H:11]([C:20]([OH:22])=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)=[O:9]>N.O>[NH2:5][CH2:7][C:8]([NH:10][C@H:11]([C:20]([OH:22])=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)=[O:9]
Reactant: [NH4+]
Reactant: O=C(CCl)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: N
Agent: O=C([O-])O
Solvent: O
Product: NCC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Temperature: 40 °C
Reaction time: 5 h

Procedure:
Ammonium hydrogencarbonate (1289 g) was dissolved in a mixture of 4000 ml of 28% aqueous ammonia and 1000 ml of distilled water at 35° C. To the solution were added 700 g (2.72 mol) of N-chloroacetyl-L-tyrosine and 700 ml of distilled water, followed by stirring at 40° C. for 5 hours. The reaction mixture was concentrated under reduced pressure to remove excess ammonia and then adjusted to pH 5.5 with concentrated hydrochloric acid at 45° C., followed by gradual cooling. After crystals were deposited, the mixture was ice-cooled and the crystals were isolated by filtration to give 600 g (489 g on anhydrous basis, 2.05 mol, 75.4%) of crude crystals of N-glycyl-L-tyrosine.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[CH2:4][C:5]#[CH:6].Cl[CH2:9][C:10]([N:12]1[CH2:31][CH2:30][C:15]2[N:16]=[C:17]([NH:20][CH:21]3[CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22]3)[N:18]=[CH:19][C:14]=2[CH2:13]1)=[O:11].C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:3]([O:7][CH2:9][C:10]([N:12]1[CH2:31][CH2:30][C:15]2[N:16]=[C:17]([NH:20][CH:21]3[CH2:22][C:23]4[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:29]3)[N:18]=[CH:19][C:14]=2[CH2:13]1)=[O:11])[CH2:4][C:5]#[CH:6]
Reactant: C#CCCO
Reactant: O=C(CCl)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCCOCC(=O)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Temperature: 23 °C
Reaction time: 0.33 h
Yield: 76.6 %

Procedure:
To sodium hydride (60 wt % in mineral oil, 1.58 g, 39.6 mmol) in tetrahydrofuran (50 mL) at 23° C., add 3-butyn-1-ol (7.93 g, 8.59 mL, 113.2 mmol) dropwise, then stir at 23° C. for 20 minutes. Add this solution to 2-chloro-1-[2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]ethanone (9.70 g, 28.3 mmol) in tetrahydrofuran (150 mL) at 23° C. and stir for one hour. Pour the reaction mixture into 50% saturated aqueous sodium bicarbonate solution. Separate the organic layer and further extract the aqueous layer with ethyl ether (×2) and ethyl acetate (×2). Combine the organic extracts and wash with brine, then dry over anhydrous sodium sulfate, filter, and concentrate. Purify the resulting crude product by silica gel column chromatography (gradient elution: 20% ethyl acetate in hexanes to 100% ethyl acetate) to give the title compound (8.16 g, 77%). MS (m/z): 377 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[NH:15][N:14]=[N:13][N:12]=2)=[O:9])[CH:5]=[N:4][CH:3]=1.O.[OH-].[Na+].[NH2:19][C:20]1[C:21]([CH3:26])=[CH:22][CH:23]=[CH:24][CH:25]=1>CS(C)=O>[CH3:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[NH:19][C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[NH:15][N:14]=[N:13][N:12]=2)=[O:9])[CH:5]=[N:4][CH:3]=1
Reactant: O=C(Nc1nnn[nH]1)c1cncc(Cl)n1
Reactant: Cc1ccccc1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccccc1Nc1cncc(C(=O)Nc2nnn[nH]2)n1

Procedure:
To a suspension of 1.13 g of 6-chloro-N-(1H-5-tetrazolyl)pyrazine-2-carboxamide in 5 ml of dimethylsulfoxide, 5.35 ml of o-toluidine was added, and the mixture was heated for 24 hours at 100°-110 ° C. Water and 10%-sodium hydroxide aqueous solution were added to the reaction mixture, and the aqueous alkaline solution was washed with chloroform. Aqueous layer was filtered and the filtrate was adjusted with 10%-hydrochloric acid to pH 3. The precipitate was collected by filtration, and recrystalized from a mixture of dimethylformamide and ethanol affording 0.19 g of the desired compound as dark yellow crystals, m.p. 277°-282° C. (decomp.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[CH2:7][CH2:8][C@H:9]([NH:13][C:14]([C:16]1[CH:20]=[C:19]([O:21][CH2:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[N:18]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:17]=1)=[O:15])[C:10]([OH:12])=O)([CH3:4])([CH3:3])[CH3:2].[N:36]1([C:42]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[O:43])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.C(N1CCOCC1)C.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O>CN(C=O)C.C(OCC)(=O)C>[CH2:45]([O:44][C:42]([N:36]1[CH2:41][CH2:40][N:39]([C:10](=[O:12])[C@@H:9]([NH:13][C:14]([C:16]2[CH:20]=[C:19]([O:21][CH2:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[N:18]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:17]=2)=[O:15])[CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:35])[CH2:38][CH2:37]1)=[O:43])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1cc(OCC(=O)C(C)(C)C)n(-c2ccccc2)n1)C(=O)O
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1cc(OCC(=O)C(C)(C)C)n(-c2ccccc2)n1)C(=O)N1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
To a solution of 3.5 g (S)-2-{[5-(3,3-dimethyl-2-oxo-butoxy)-1-phenyl-1H-pyrazole-3-carbonyl]-amino}-pentanedioic acid 5-tert-butyl ester in 11 ml DMF were added 1.36 ml benzyl 1-piperazinecarboxylate, 3.61 ml N-ethylmorpholine and 2.3 g TOTU. After 2 h the reaction mixture was diluted with ethyl acetate and extracted with aqueous NaHCO3 and aqueous LiCl (4% w/w). The crude product product obtained after evaporation of the solvent (4.4 g) was used in the subsequent reaction.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH3:8])[NH:5][C:6]=1[Br:7].C(=O)([O-])[O-].[Na+].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C=O)C>[CH2:15]([N:3]1[C:2]([Br:1])=[C:6]([Br:7])[N:5]=[C:4]1[CH3:8])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: Cc1nc(Br)c(Br)[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(Br)c(Br)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4,5-dibromo-2-methylimidazole (3.0 g, 12.5 mmol) in 25 mL DMF add sodium carbonate (2.0 g, 18.8 mmol) and benzyl bromide (1.64 mL, 13.8 mmol). Stir the solution at room temperature for 72 hours. Pour the reaction into water and extract with EtOAc. Wash the organic layer with water, saturated aqueous sodium chloride, and dry over sodium sulfate. Filter the mixture and concentrate to 3.8 g crude oil. Purify the oil by radial chromatography eluting with 40% EtOAc in hexanes. Concentrate the appropriate fractions to 3.1 g (75%) of the title compound as a colorless oil. MS(ES+): m/z=331.0 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:10]([C:21]2[C:26]([F:27])=[CH:25][CH:24]=[C:23]([F:28])[C:22]=2[F:29])[C:11]2[C:12]([CH3:20])=[CH:13][C:14]([C:17]([NH2:19])=[O:18])=[N:15][CH:16]=2)=[O:9])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:38])C=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:10]([C:21]2[C:26]([F:27])=[CH:25][CH:24]=[C:23]([F:28])[C:22]=2[F:29])[C:11]2[C:12]([CH3:20])=[CH:13][C:14]([C:17]([NH2:19])=[O:18])=[N:15][CH:16]=2)(=[O:38])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(C(N)=O)ncc1C(c1c(F)ccc(F)c1F)S(=O)c1ccc(F)cc1
Solvent: ClCCl
Product: Cc1cc(C(N)=O)ncc1C(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 60 %

Procedure:
To a solution of 5-[[(4-fluorophenyl)sulfinyl](2,3,6-trifluorophenyl)methyl]-4-methylpyridine-2-carboxamide (106 mg, 0.25 mmol) in methylene chloride (5 ml), 3-chloroperbenzoic acid (66 mg, 0.25 mmol) was added at 0° C. After stirring for 5 days at room temperature, the reaction mixture was washed with 1 N aqueous sodium hydroxide. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to preparative thin-layer chromatography (developed with hexane:ethyl acetate=2:3, eluted with methylene chloride:methanol=4:1). The obtained fraction was concentrated under reduced pressure, and the resulting residue was washed with a mixed solvent of ethanol and diethyl ether, and was collected by filtration, to obtain the title compound (67 mg, 0.15 mmol, 61%) as a white solid.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:10]=[C:11]2[S:16][CH2:15][CH:14](O)[N:12]2[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.S(Cl)(Cl)=O>ClCCl>[CH2:1]([S:8][C:9]1[N:10]=[C:11]2[S:16][CH:15]=[CH:14][N:12]2[N:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CSc2nc(SCc3ccccc3)nn21
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: c1ccc(CSc2nc3sccn3n2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The product from stage (b) (7.9 g) was dissolved in dichloromethane (50 ml) and was treated with pyridine (2.7 g), then with thionyl chloride (4.2 g) in dichloromethane (5 ml) dropwise with stirring at 5°-10° C. After 3 hours stirring at room temperature, the solution was washed with water, dilute hydrochloric acid, aqueous sodium bicarbonate solution and water again, dried and run down to give the desired product as a brown oil which was recrystallise from ethanol to give pure product, mp 91°-93° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][CH:28]=1)=O>>[Br:33][C:30]1[CH:31]=[CH:32][C:27]([C:25]2[N:12]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=3)[S:13][CH:24]=2)=[CH:28][CH:29]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Product: O=C(O)c1cc(-c2nc(-c3ccc(Br)cc3)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Yield: 68 %

Procedure:
4-[4-(4-Bromo-phenyl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid (205 mg, 68%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 2,4′-dibromoacetophenone (available from Alfa Aesar) using the procedure described for the preparation of Example 1. 1H NMR (300 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.57 (d, J=1.9 Hz, 1H), 8.34 (s, J=8.3, 1H), 8.25 (dd, J=8.0, 2.0 Hz, 1H), 8.14 (dd, J=8.1, 1.1 Hz, 1H), 8.03 (d, J=8.6 Hz, 1H), 7.62-7.81 (m, 4H), 7.40-7.47 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[C:7]12([C:17](Cl)=[O:18])[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[NH:1][C:17]([C:7]12[CH2:16][CH:11]3[CH2:10][CH:9]([CH2:15][CH:13]([CH2:12]3)[CH2:14]1)[CH2:8]2)=[O:18]
Reactant: Nc1nccs1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1nccs1)C12CC3CC(CC(C3)C1)C2
Temperature: 65 °C
Reaction time: 4 h
Yield: 76.2 %

Procedure:
To a solution of 2-aminothiazole (6.1 g, 61 mmol) in 250 mL of THF at 0° C. was added a solution of adamantane-1-carbonyl chloride (11 g, 55 mmol) in 25 mL of THF, followed by triethylamine (17 mL, 0.12 mol). The mixture was warmed to 65° C., stirred for 4 hours, and then allowed to cool to ambient temperature. The mixture was diluted with ethyl acetate and washed twice with water and brine. The aqueous washings were combined and extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (SiO2, 20-40% ethyl acetate/hexanes gradient) afforded 11 g (78%) of the title compound. 1H NMR (CDCl3, 300 MHz) δ ppm 1.68-1.85 (m, 6H), 1.97 (d, J=3.1 Hz, 6H), 2.12 (s, 3H), 6.96 (d, J=3.7 Hz, 1H), 7.44 (d, J=3.4 Hz, 1H), 8.92 (s, 1H); MS (DCI/NH3) m/z 263 (M+H)+.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]([CH3:33])([C:30](O)=[O:31])[CH2:20][C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[NH:23][CH:22]=3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.FC1C(O)=C(F)C(F)=C(F)C=1F.C1(N=C=NC2CCCCC2)CCCCC1.[CH:61]1[CH:66]=[CH:65][C:64]([CH2:67][CH2:68][NH2:69])=[CH:63][CH:62]=1>C(OCC)(=O)C>[NH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]([CH2:20][C:19]([NH:18][C:16](=[O:17])[O:15][CH2:14][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)([CH3:33])[C:30](=[O:31])[NH:69][CH2:68][CH2:67][C:64]2[CH:65]=[CH:66][CH:61]=[CH:62][CH:63]=2)=[CH:22]1
Reactant: CC(Cc1c[nH]c2ccccc12)(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: NCCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CCOC(C)=O
Product: CC(Cc1c[nH]c2ccccc12)(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 34.3 %

Procedure:
To a solution of N-[(9H-fluoren-9-ylmethyloxy)carbonyl]-α-methyl-DL-tryptophan (8.80 g, 20 mmol) in dry ethyl acetate (350 mL) was added pentafluorophenol (3.68 g, 20 mmol) and stirred for 10 minutes. The reaction mixture was cooled to 0° C. and a solution of dicyclohexylcarbodiimide (20 mmol) in ethyl acetate (25 mL) was added dropwise. This solution was stirred for one hour at 0° C. then at room temperature for four hours before leaving it at 4° C. overnight. The mixture was filtered and the precipitate washed with cold ethyl acetate (30 mL) and a solution of 2-phenethylamine (2.66 g, 22 mmol) in ethyl acetate (30 mL) was added dropwise to the combined filtrates. The mixture was left to stir for 48 hours at room temperature. The reaction mixture was filtered and the residue washed with cold ethyl acetate (2×30 mL) to give the title compound (3.73 g, 75%). The filtrates were combined and the solvent removed in vacuo and taken up again in ethyl acetate (5 mL) to give a second crop of 1.67 g (15%), a total of 90% yield as a white solid, mp 179°-181° C. (EtOAc); IR (film) 1708, 1652 cm-1 ; NMR (DMSO d6) δ1.30 (3H, s), 2.64 (2H, t, J 7.2Hz), 3.2-3.3 (4H, m), 4.19 (1H, t, J 6.7Hz), 4.25-4.40 (2H, m), 6.9-7.9 (20 H, m), 10.8 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=3)[CH:12]([C:27]([NH2:29])=O)[CH2:11]2)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[Br:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=3)[CH:12]([CH2:27][NH2:29])[CH2:11]2)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Br)cc(N2CCN(Cc3ccc(OC)c(OC)c3)C(C(N)=O)C2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COc1cc(Br)cc(N2CCN(Cc3ccc(OC)c(OC)c3)C(CN)C2)c1

Procedure:
In a manner similar to Preparation 2, react 4-(3-bromo-5-methoxyphenyl)-1-[(3,4-dimethoxyphenyl)methyl]-2-piperazinecarboxamide with lithium aluminum hydride to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[CH:6]=1.C(N(CC)CC)C.Cl[C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23]>C(Cl)Cl>[Cl:27][C:26]([Cl:29])([Cl:28])[CH2:25][O:24][C:22](=[O:23])[NH:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[CH:6]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Cc1ccc(-n2cc(N)cn2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(-n2cc(NC(=O)OCC(Cl)(Cl)Cl)cn2)cc1
Yield: 94.3 %

Procedure:
Intermediate 6b (150 mg, 0.87 mmol) dissolved in DCM (10 mL) was cooled using an ice bath, and then treated sequentially with triethylamine (0.18 mL, 1.30 mmol) and trichloroethyl chloroformate (0.15 mL, 1.08 mmol). The mixture was stirred with cooling for 45 min, then evaporated to dryness. Residue was purified by FCC, eluting with 0-30% ethyl acetate in cyclohexane, to give the title compound as a beige solid (286 mg, 95%). LCMS (Method 3): Rt 4.25 min, m/z 348/350/352 [MH+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:13][C:12](=[S:14])[N:11]3[N:15]=[CH:16][CH:17]=[C:10]3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:18]I.Cl>[OH-].[Na+].CO>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([S:14][CH3:18])[N:11]3[N:15]=[CH:16][CH:17]=[C:10]3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: S=c1[nH]c(-c2cccc(Br)c2)cc2ccnn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSc1nc(-c2cccc(Br)c2)cc2ccnn12
Yield: 36 %

Procedure:
To a solution of 5-(3-bromo-phenyl)-6H-pyrazolo[1,5-c]pyrimidine-7-thione (compound E3)(3.73 g) in 2M aqueous NaOH (6 ml) and methanol (100 ml) methyl iodide (0.785 ml) is added at ambient temperature. After 30 min at this temperature further methyl iodide (0.785 ml) is added After 60 min the mixture is neutralized with 2M hydrochloric acid and evaporated The residue is partitioned between dichloromethane and water and the organic phase is washed twice with water. The organic phase is dried over sodium sulfate and the crude product is purified by silica gel flash chromatography. A yellow solid (1.4 g, 36%) is obtained