Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]2=[O:20])[C:3]=1[CH3:21].[O:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[C:30]3[NH:36][CH2:35][C:34]4([CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)[C:31]3=[N:32][CH:33]=2)[CH2:24][CH2:23]1>C1(C)C=CC=CC=1>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([N:36]1[C:30]3[C:31](=[N:32][CH:33]=[C:28]([N:25]4[CH2:26][CH2:27][O:22][CH2:23][CH2:24]4)[CH:29]=3)[C:34]3([CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[CH2:35]1)=[C:3]([CH3:21])[C:4]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C:15]1=[O:20])=[N:5]2
Reactant: c1nc2c(cc1N1CCOCC1)NCC21CCOCC1
Reactant: Cc1c(N2CCCCC2=O)nc2cc(F)cc(F)c2c1Br
Solvent: Cc1ccccc1
Product: Cc1c(N2CCCCC2=O)nc2cc(F)cc(F)c2c1N1CC2(CCOCC2)c2ncc(N3CCOCC3)cc21

Procedure:
Prepared according to procedure Y using 1-(4-bromo-5,7-difluoro-3-methylquinolin-2-yl)piperidin-2-one (45.0 mg, 0.130 mmol) and 6′-morpholino-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine] in toluene to give 1-(5,7-difluoro-3-methyl-4-(6′-(4-morpholinyl)-2,3,5,6-tetrahydrospiro[pyran-4,3′-pyrrolo-[3,2-b]pyridin]-1′(2′H)-yl)-2-quinolinyl)-2-piperidinone. 1H NMR (400 MHz, chloroform-d) δ ppm 7.58 (1H, t, J=2.3 Hz), 7.55 (1H, d, J=9.4 Hz), 6.89-7.07 (1H, m), 5.55-6.01 (1H, m), 3.98-4.39 (4H, m), 3.46-3.93 (7H, m), 2.88-3.26 (4H, m), 2.54-2.72 (2H, m), 1.92-2.47 (8H, m), 1.61-1.90 (4H, m). Mass Spectrum (ESI) m/e=550.3 (M+1).
Reaction SMILES: Cl[C:2]1[C:3](=[O:13])[N:4]([CH2:9][CH2:10][S:11][CH3:12])[CH:5]=[C:6]([Cl:8])[N:7]=1.Cl.[Br:15][C:16]1[CH:17]=[C:18]([O:25][CH3:26])[CH:19]=[C:20]2[C:24]=1[NH:23][CH2:22][CH2:21]2>>[Br:15][C:16]1[CH:17]=[C:18]([O:25][CH3:26])[CH:19]=[C:20]2[C:24]=1[N:23]([C:2]1[C:3](=[O:13])[N:4]([CH2:9][CH2:10][S:11][CH3:12])[CH:5]=[C:6]([Cl:8])[N:7]=1)[CH2:22][CH2:21]2
Reactant: CSCCn1cc(Cl)nc(Cl)c1=O
Reactant: COc1cc(Br)c2c(c1)CCN2
Agent: Cl
Product: COc1cc(Br)c2c(c1)CCN2c1nc(Cl)cn(CCSC)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[2-(methylthio)ethyl]-2(1H)-pyrazinone and 7-bromo-5-methoxyindoline hydrochloride as the starting materials. 1H NMR (300 MHz, CDCl3): δ 6.93 (d, J=2.5 Hz, 1 H), 6.88 (s, 1 H), 6.79 (d, J=2.5 Hz, 1 H), 4.36 (t, J=7.7 Hz, 2 H), 4.05 (t, J=7.0 Hz, 2 H), 3.78 (s, 3 H), 3.10 (t, J=7.5 Hz, 2 H), 2.90 (t, J=7.0 Hz, 2 H), 2.17 (s, 3 H); HRMS (CI) calcd for C16H17N3O2SBrCl (M+): 428.9913; found m/z 428.9899.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:19][N:14]4[CH2:15][CH2:16][NH:17][CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[F:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][C:29]=1[C:37]([F:40])([F:39])[F:38]>ClCCl>[CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:19][N:14]4[CH2:15][CH2:16][N:17]([C:32]([C:31]5[CH:35]=[CH:36][C:28]([F:27])=[C:29]([C:37]([F:40])([F:38])[F:39])[CH:30]=5)=[O:33])[CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=C(Cl)c1ccc(F)c(C(F)(F)F)c1
Reactant: c1nc(C2CC2)cnc1O[C@@H]1C[C@H]2CNCCN2C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(F)c(C(F)(F)F)c1)N1CCN2C[C@H](Oc3cnc(C4CC4)cn3)C[C@H]2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of Example 54F (47 mg, 0.18 mmol) and triethylamine (27 mg, 0.27 mmol) in dichloromethane (1 mL) was added 4-fluoro-3-(trifluoromethyl)benzoyl chloride (49 mg, 0.216 mmol). The mixture was stirred at room temperature for 3 hours.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Ca+2].[N:25]([CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N+:36]([O-:38])=[O:37])=[N+]=[N-]>C1C=CC=CC=1>[NH2:25][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N+:36]([O-:38])=[O:37]
Reactant: [N-]=[N+]=NCCc1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: NCCc1ccccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Triphenylphosphine (31.1 g, 0.118 mol) and calcium carbonate (50 mg, 0.5 mmol) were added to a solution of 2-(2-azidoethyl)nitrobenzene (22.8 g, 0.118 mol) in benzene (500 mL). The reaction was stirred at room temperature until complete. The solvent was removed in vacuo, and the residue treated with acetic acid (100 mL) and 48% hydrogen bromide (100 mL) at 100° C. for 1 h. The reaction was cooled and concentrated. Water was added and the solution extracted with methylene chloride. The aqueous layer was made basic by the addition of 5% aqueous sodium hydroxide solution, then extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over sodium sulfate. The title compound was obtained as an oil (8.0 g). MS: m/z=167 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4](Cl)=[O:5].[Br:9][C:10]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[C:13]([NH2:14])=[C:12]([Cl:21])[CH:11]=1.O>C(#N)C>[Br:9][C:10]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[C:13]([NH:14][C:4](=[O:5])[CH2:3][C:2]([CH3:8])([CH3:7])[CH3:1])=[C:12]([Cl:21])[CH:11]=1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: Nc1c(Cl)cc(Br)cc1C(F)(F)F
Solvent: CC#N
Solvent: O
Product: CC(C)(C)CC(=O)Nc1c(Cl)cc(Br)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,3-Dimethylbutanoyl chloride (1.08 g, 8.0 mmol) was added to a solution of 4-bromo-2-chloro-6-(trifluoromethyl)aniline (2.0 g, 7.3 mmol) in acetonitrile (10 mL). The reaction mixture was stirred at room temperature overnight. Water was added, and the mixture was then extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. Purification by column chromatography in dichloromethane afforded the title compound as a powder (1.22 g, 65% over the two steps).
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([OH:18])=[C:10]([C:14](OC)=[O:15])[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].C([NH2:24])=O.C[O-].[Na+].CO.Cl>CN(C=O)C>[CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([OH:18])=[C:10]([C:14]([NH2:24])=[O:15])[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3]
Reactant: CCCN(CCC)C1Cc2cc(O)c(C(=O)OC)cc2C1
Reactant: NC=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCCN(CCC)C1Cc2cc(O)c(C(N)=O)cc2C1
Reaction time: 4 h

Procedure:
To a solution of methyl 2-(dipropylamino)-2,3-dihydro-6-hydroxy-1H-indene-5-caboxylate (86, 0.93 g, 2.9 mmol) and formamide (1.2 mL, 29 mmol) in DMF (20 mL) at 100° C. was added 25% sodium methoxide in methanol (1.3 mL, 5.8 mmol) dropwise. The mixture stirred for 4 h. The reaction was quenched with saturated NaHCO3 and extracted with EtOAc. The organic layer is washed with water, brine dried (MgSO4), filtered and concentrated to give the crude product. Chromatographic purification yielded pure product as an oil that was converted into the HCl salt and crystallized from EtOAc/MeOH to give the title compound 87 as a white solid (m.p. 266-267° C.).
Reaction SMILES: [C:1]1([C:7]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][CH2:19][C:20]3[N:24]([CH3:25])[C:23]4[CH:26]=[CH:27][C:28]([C@@:30]([NH:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])([C:32]([N:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)=[O:33])[CH3:31])=[CH:29][C:22]=4[N:21]=3)=[CH:14][CH:13]=2)=[NH:11])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN1CCN2CCN(C)P1N(C)[CH2:50][CH2:51]2>C(O)CCC>[C:1]1([C:7]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][CH2:19][C:20]3[N:24]([CH3:25])[C:23]4[CH:26]=[CH:27][C:28]([C@@:30]([NH:39][CH2:40][C:41]([O:43][CH2:44][CH2:45][CH2:50][CH3:51])=[O:42])([C:32]([N:34]5[CH2:35][CH2:36][CH2:37][CH2:38]5)=[O:33])[CH3:31])=[CH:29][C:22]=4[N:21]=3)=[CH:14][CH:13]=2)=[NH:11])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN1CCN2CCN(C)P1N(C)CC2
Reactant: CCOC(=O)CN[C@@](C)(C(=O)N1CCCC1)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)c3ccccc3)cc1)n2C
Solvent: CCCCO
Product: CCCCOC(=O)CN[C@@](C)(C(=O)N1CCCC1)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)c3ccccc3)cc1)n2C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 0.3 g (0.53 mmol) of (R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole in 5 ml of n-butanol is mixed with 0.1 g (0.46 mmol) of 2,8,9-trimethyl-1-phospha-2,5,8,9-tetraazabicyclo[3.3.3]undecane and stirred for 1 hour at room temperature. The reaction mixture is purified on silica gel, eluting with ethyl acetate/ethanol/conc. ammonia (50:0.95:0.05 and 20:0.95:0.05). The uniform fractions are combined and concentrated by evaporation.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH:36][CH2:37][CH2:38][O:39][CH3:40])(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[CH3:40][O:39][CH2:38][CH2:37][NH:36][S:33]([C:30]1[CH:31]=[CH:32][C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)=[CH:28][CH:29]=1)(=[O:34])=[O:35]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: COCCNS(=O)(=O)c1ccc(Br)cc1
Product: COCCNS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 4-bromo-N-(2-methoxy-ethyl)-benzenesulfonamide (example B.28) (276 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (400 mg, 70%). MS (ISP) 569.1 [(M+H)+]; mp 185-187° C.
Reaction SMILES: Cl.Cl.[CH3:3][CH:4]([CH3:18])[CH2:5][N:6]([CH2:11][C@H:12]1[CH2:17][NH:16][CH2:15][CH2:14][NH:13]1)[S:7]([CH3:10])(=[O:9])=[O:8].C(N(CC)CC)C.[N+:26]([C:29]1[S:33][C:32]([S:34](Cl)(=[O:36])=[O:35])=[CH:31][CH:30]=1)([O-:28])=[O:27]>C(Cl)Cl>[N+:26]([C:29]1[S:33][C:32]([S:34]([N:16]2[CH2:15][CH2:14][NH:13][C@@H:12]([CH2:11][N:6]([CH2:5][CH:4]([CH3:18])[CH3:3])[S:7]([CH3:10])(=[O:8])=[O:9])[CH2:17]2)(=[O:36])=[O:35])=[CH:31][CH:30]=1)([O-:28])=[O:27]
Reactant: CC(C)CN(C[C@H]1CNCCN1)S(C)(=O)=O
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)s1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CN(C[C@H]1CN(S(=O)(=O)c2ccc([N+](=O)[O-])s2)CCN1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
A 5-mL vial was charged with N-(2-methylpropyl)-N-((2R)-2-piperazinylmethyl)methanesulfonamide dihydrochloride (0.144 g, 0.446 mmol) and CH2Cl2 (2 mL). To this was added triethylamine (0.650 mL, 4.66 mmol) in potions at room temperature followed by drop wise addition of 5-nitrothiophene-2-sulfonyl chloride (0.120 g, 0.525 mmol, Enamine LLC, Monmouth Jct. NJ) in CH2Cl2 (1 mL). The mixture was stirred at room temperature for 15 min and then the reaction mixture was partitioned between water (20 mL) and CH2Cl2 (20 mL). The aqueous phase was extracted with CH2Cl2 (2×20 mL) and the combined organic extracts were washed with saturated aqueous NaCl (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (25 g of silica gel, 0 to 10% (2 M NH3 in MeOH) in CH2Cl2) to afford N-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-2-piperazinyl)methyl)-N-(2-methylpropyl)methanesulfonamide (0.173 g) as a light-brown foam.
Reaction SMILES: [Li]C(C)(C)C.[N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]=1[CH2:15][C:16]([O:18]CC)=O.[NH2:21][C:22]1[C:27]([C:28]#[N:29])=[C:26]([N:30]2[CH2:35][CH2:34][N:33]([CH2:36][CH3:37])[CH2:32][CH2:31]2)[CH:25]=[CH:24][CH:23]=1>C1COCC1>[NH2:29][C:28]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[N:30]2[CH2:31][CH2:32][N:33]([CH2:36][CH3:37])[CH2:34][CH2:35]2)[NH:21][C:16](=[O:18])[C:15]=1[C:7]1[NH:6][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=1
Reactant: CCN1CCN(c2cccc(N)c2C#N)CC1
Reactant: CCOC(=O)Cc1nc2ccccc2[nH]1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCN1CCN(c2cccc3[nH]c(=O)c(-c4nc5ccccc5[nH]4)c(N)c23)CC1
Reaction time: 8 h

Procedure:
t-BuLi (3.1 equivalents) was added to ethyl 2-benzimidazol-2-ylacetate (1.0 equivalent) and 6-amino-2-(4-ethylpiperazinyl) benzenecarbonitrile (1.0 equivalent) in THF at 0° C. The reaction was stirred overnight. The resulting mixture was quenched with NH4Cl (aqueous saturated) and extracted with EtOAc. The combined organic layers were washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo to yield a brown solid. The crude material was triturated with CH2Cl2 and MeOH to provide a tan solid. LC/MS m/z 389.1 (MH+), Rt 1.80 minutes.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:7]=1.[C:22]([NH:25][C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][C:32]=2[NH2:36])[N:27]=1)(=[O:24])[CH3:23]>>[C:22]([NH:25][C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][C:32]=2[NH:36][CH2:11][C:10]([C:13]([F:14])([F:16])[F:15])([OH:17])[CH2:9][C:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:20][CH3:21])([CH3:18])[CH3:19])[N:27]=1)(=[O:24])[CH3:23]
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: CC(=O)Nc1ccc2c(N)cccc2n1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cccc2nc(NC(C)=O)ccc12)C(F)(F)F
Yield: 46.4 %

Procedure:
Analogously to Example 20, 263 mg (0.86 mmol) of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 205 mg (1.0 mmol) of 2-acetylamino-5-aminoquinoline are reacted to form 197 mg of product.
Reaction SMILES: [O:1]1[C:5]2=[N:6][C:7]3[C:13](=O)[O:12][C:10](=[O:11])[C:8]=3[CH:9]=[C:4]2[CH:3]=[CH:2]1.[NH2:15][C:16]([CH3:23])([CH:20]([CH3:22])[CH3:21])[C:17]([NH2:19])=[O:18].CCOCC>C1COCC1>[CH:20]([C:16]1([CH3:23])[C:17](=[O:18])[NH:19][C:13]([C:7]2[N:6]=[C:5]3[O:1][CH:2]=[CH:3][C:4]3=[CH:9][C:8]=2[C:10]([OH:12])=[O:11])=[N:15]1)([CH3:22])[CH3:21]
Reactant: O=C1OC(=O)c2nc3occc3cc21
Reactant: CC(C)C(C)(N)C(N)=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)C1(C)N=C(c2nc3occc3cc2C(=O)O)NC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 27 %

Procedure:
Furo[2,3-b]pyridine-5,6-Dicarboxylic anhydride (2.50 g, 0.013 mol) is suspended in 40 mLs anhydrous THF and (+)-2-amino-2,3-dimethylbutyramide (1.72 g, 0.013 mol) is added. The mixture is stirred under N2 at room temperature for 16 hours. The solution is poured into 150 mLs anhydrous ether, and the resulting solid is collected in 88.6% crude yield. The unpurified adduct is converted to the indicated product in the manner described in Example 38 for the racemic mixture. The (+)-isomer is recrystallized from absolute ethanol, and is isolated in 27.0% yield from the adduct., mp 244°-245° C. [α]D25 =44.5°.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[N:10]([CH2:13][C@@H:14]1[O:18][C:17](=[O:19])[N:16]([C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[C:22]([F:29])[CH:21]=2)[CH2:15]1)=[N+:11]=[N-:12].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:54]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])(=[O:57])[NH:55][NH2:56]>CN(C=O)C>[C:59]([O:58][C:54]([NH:55][NH:56][C:24](=[O:26])[C:23]1[CH:27]=[CH:28][C:20]([N:16]2[CH2:15][C@H:14]([CH2:13][N:10]=[N+:11]=[N-:12])[O:18][C:17]2=[O:19])=[CH:21][C:22]=1[F:29])=[O:57])([CH3:62])([CH3:61])[CH3:60]
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(C(=O)O)c(F)c2)C(=O)O1
Reactant: CC(C)(C)OC(=O)NN
Agent: CN(C)C(On1nnc2cccnc21)=[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: CC(C)(C)OC(=O)NNC(=O)c1ccc(N2C[C@H](CN=[N+]=[N-])OC2=O)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
Diisopropylethylamine (4.67 ml, 0.0268 mol) is added to a mixture of 4-(5(R)-Azidomethyl-2-oxo-oxazolidin-3-yl)-2-fluorobenzoic acid (2.50 g, 0.00892 mol) [prepared according to the procedure described in U.S. Pat. No. 6,239,152] and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (3.73 g, 0.00981 mol) in DMF (30 ml) and stirred for 20 minutes at room temperature. tert-Butyl carbazate (1.30 g, 0.00981 mol) is then added and the mixture stirred at room temperature overnight. The reaction mixture is evaporated under vacuum and the residue diluted with water. The resulting precipitate is filtered and dried under vacuum to give product as a white solid (3.52 g, 99%); 1HNMR (300 MHz, DMSO-d6) δ 1.42 (s, 9H), 3.72-3.76 (m, 2H), 3.81 (dd, J=6.0, 9.3 Hz, 1H), 4.17 (t, J=9.1 Hz, 1H), 4.88-4.96 (m, 1H), 7.43 (dd, J=2.2, 8.8 Hz, 1H), 7.57 (dd, J=2.2, 13.2, 1H), 7.66 (t, J=8.2, 1H), 8.96 (s, 1H), 9.92 (s, 1H); Rf(EtOAc)=0.54; mp 173-5.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[O:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:31]=[CH:30][C:26]([C:27]([O-:29])=O)=[CH:25][CH:24]=2)[CH2:19][CH2:18]1>>[CH3:22][O:17][CH2:18][CH2:19][NH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:27](=[O:29])[C:26]3[CH:25]=[CH:24][C:23]([N:20]4[CH2:19][CH2:18][O:17][CH2:22][CH2:21]4)=[CH:31][CH:30]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(=O)c2ccc(N)cc2)cc1
Reactant: O=C([O-])c1ccc(N2CCOCC2)cc1
Product: COCCNc1ccc(C(=O)c2ccc(NC(=O)c3ccc(N4CCOCC4)cc3)cc2)cc1

Procedure:
Compound 493 was prepared according to the procedure described in Scheme IV from 4,4′-diaminobenzophenone and 4-morpholinobenzoate. [M+H]+ calcd for C27H29N3O4: 460.06; found: 460.12.
Reaction SMILES: [CH:1]1[C:8]([CH2:9][C@H:10]([NH2:14])[C:11]([OH:13])=[O:12])=[CH:7][C:5](=[O:6])[C:3](=[O:4])[CH:2]=1.[NH2:15][C@H:16]([C:19]([OH:21])=[O:20])[CH2:17][SH:18]>>[CH:7]1[C:5]([OH:6])=[C:3]([OH:4])[C:2]([S:18][CH2:17][CH:16]([NH2:15])[C:19]([OH:21])=[O:20])=[CH:1][C:8]=1[CH2:9][CH:10]([NH2:14])[C:11]([OH:13])=[O:12]
Reactant: N[C@@H](CS)C(=O)O
Reactant: N[C@@H](CC1=CC(=O)C(=O)C=C1)C(=O)O
Product: NC(CSc1cc(CC(N)C(=O)O)cc(O)c1O)C(=O)O

Procedure:
The other pathway from dopaquinone to melanin involves the addition of cysteine to dopaquinone to produce 5-S-cysteinyldopa, followed by the oxidation of 5-S-cysteinyldopa to 5-S-cysteinyldopaquinone. A ring closure of the 5-S-cysteinyldopaquinone then yields 7-alanyl-5-hydroxy-3-carboxy-2H-1,4-benzothiazine which is subsequently decarboxylated to yield 7-alanyl-5-hydroxy-2H-1,4-benzothiazine. At this point, the 7-alanyl-5-hydroxy-2H-1,4-benzothiazine is converted to melanin and pheomelanin. Tyrosinase does not play any additional role in this melanin production pathway.
Reaction SMILES: CS(C)=O.[S:5]1[CH:9]=[CH:8][N:7]=[C:6]1[NH:10][C:11](=O)[O:12]C1C=CC=CC=1.[NH2:20][C:21]1[CH:44]=[CH:43][C:24]([O:25][C:26]2[C:35]3[C:30](=[CH:31][C:32]([O:38][CH2:39][CH:40]4[CH2:42][O:41]4)=[C:33]([C:36]#[N:37])[CH:34]=3)[N:29]=[CH:28][CH:27]=2)=[CH:23][C:22]=1[F:45]>O>[C:36]([C:33]1[CH:34]=[C:35]2[C:30](=[CH:31][C:32]=1[O:38][CH2:39][CH:40]1[CH2:42][O:41]1)[N:29]=[CH:28][CH:27]=[C:26]2[O:25][C:24]1[CH:43]=[CH:44][C:21]([NH:20][C:11]([NH:10][C:6]2[S:5][CH:9]=[CH:8][N:7]=2)=[O:12])=[C:22]([F:45])[CH:23]=1)#[N:37]
Reactant: N#Cc1cc2c(Oc3ccc(N)c(F)c3)ccnc2cc1OCC1CO1
Reactant: O=C(Nc1nccs1)Oc1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4nccs4)c(F)c3)ccnc2cc1OCC1CO1
Temperature: 80 °C
Yield: 11.8 %

Procedure:
After adding dimethylsulfoxide (1 ml) and phenyl N-(2-thiazolyl)carbamate (94 mg) to 4-(4-amino-3-fluorophenoxy)-7-oxiranylmethoxyquinoline-6-carbonitrile (100 mg), the mixture was heated at 80° C. for 90 minutes. Water was added and the precipitated crystals were filtered out to obtain the title compound (16 mg) as light yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C@H:13]([CH2:18][OH:19])[C@H:14]([CH2:16][CH3:17])[CH3:15].CCN(CC)CC>CC#N>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C@H:13]([CH2:18][OH:19])[C@H:14]([CH2:16][CH3:17])[CH3:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CC[C@H](C)[C@H](N)CO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@@H](CO)NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-chlorobenzenesulfonyl chloride (1.93 g, 9.1 mmol) in CH3CN (25 mL) and (S)-isoleucinol (1.07 g, 9.1 mmol) was added Et3N (1.91 mL, 13.7 mmol). The reaction mixture was stirred at 25° C. for 30 minutes. The solvent was removed and the oil was dissolved in CH2Cl2 (20 mL). The solution was washed with water (2×20 mL) and dried over Na2SO4. The solvent was removed to give N-4-chloro benzenesulfonyl isoleucinol, which was carried on without further purification.
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18]>>[Cl:14][C:15]1[CH:16]=[C:17]([NH:18][S:2]([C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=2)(=[O:4])=[O:3])[CH:19]=[CH:20][CH:21]=1
Reactant: Nc1cccc(Cl)c1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Product: O=C(O)c1ccc(S(=O)(=O)Nc2cccc(Cl)c2)cc1

Procedure:
4-(chlorosulfonyl)benzoic acid (22) (553 mg, 2.60 mmol) was treated with 3-chloroaniline (800 mg, 6.3 mmol) using method A to give 4-(N-(3-chlorophenyl)sulfamoyl)benzoic acid as an off white solid. Yield: 382 mg (49%). 1H-NMR: 10.73 (s, 1H), 8.09 (d, J=8.5 Hz, 2H), 7.88 (d, J=8.5 Hz, 2H), 7.27 (t, J=8.5 Hz, 1H), 7.13-7.04 (m, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:10]=1[CH2:11]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:27])=O>>[CH2:1]([O:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:10]=1[CH2:11][Cl:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: O=S(Cl)Cl
Product: ClCc1ccc(OCc2ccccc2)cc1OCc1ccccc1

Procedure:
That is, 2,4-dihydroxybenzaldehyde [IV] is benzylated with benzyl chloride to produce 2,4-dibenzyloxybenzaldehyde [V], then [V] is reduced with sodium borohydride to produce 2,4-dibenzyloxybenzyl alcohol [VI] and then, [VI] is chlorinated with thionyl chloride to produce 2,4-dibenzyloxybenzyl chloride [VII]. Then, [VII] is allowed to react with sodium cyanide to obtain 2,4-dibenzyloxyphenyl acetonitrile [VIII], thereafter [VIII] is hydrolyzed with an alkali to produce 2,4-dibenzyloxyphenylacetic acid [IX], then this [IX] is chlorinated with thionyl chloride to produce 2,4-dibenzyloxyphenylacetyl chloride [X] and further, this [X] is allowed to react with L-asparagine or glutamine p-nitrophenyl ester to obtain [IIa].
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[CH:12]=[C:11]([CH:13]=[O:14])[N:10]=[CH:9]1.[C:15]1([C:21](Cl)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O>[C:21]([N:8]1[CH:12]=[C:11]([CH:13]=[O:14])[N:10]=[CH:9]1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1c[nH]cn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.7 %

Procedure:
Triethylamine (3.05 ml, 21.86 mmol) was added to a solution of 1H-imidazole-4-carbaldehyde (2 g, 20.82 mmol) and triphenylmethyl chloride (5.80 g, 20.82 mmol) in N,N-dimethylformamide (20 ml). The reaction mixture was stirred at room temperature for 18 hours. The crude mixture was concentrated in vacuo and partitioned between ethyl acetate and water. The organic phase was washed dried over sodium sulfate, filtered and concentrated in vacuo. The residue was recrystallised from dichloromethane and hexanes to afford the title compound as a cream solid (4.7 g, 67% yield).