Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([BH3-])#N.[Na+].[Cl:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([Cl:16])[C:7]=1[N:17]1[N:21]=[C:20]([CH:22]=O)[CH:19]=[N:18]1.[OH-].[K+].[NH2:26][C:27]1[NH:28][C:29]([C:34]#[N:35])=[C:30]([C:32]#[N:33])[N:31]=1>CO>[Cl:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([Cl:16])[C:7]=1[N:17]1[N:21]=[C:20]([CH2:22][NH:26][C:27]2[NH:28][C:29]([C:34]#[N:35])=[C:30]([C:32]#[N:33])[N:31]=2)[CH:19]=[N:18]1
Reactant: N#Cc1nc(N)[nH]c1C#N
Reactant: O=Cc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Agent: [BH3-]C#N
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(NCc2cnn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)n2)[nH]c1C#N
Reaction time: 20 h

Procedure:
Sodium cyanoborohydride (0.05 g) was added to a solution of 2-(2,6-dichloro-4-trifluoromethylphenyl)-1,2,3-triazole-4-carboxaldehyde (0.3 g), potassium hydroxide (0.04 g) and 2-amino-4,5-dicyanoimidazole (0.3 g) in methanol (20 ml). After 20 hours at room temperature, the solvent was evaporated under reduced pressure and the residue purified by silica gel chromatography to give 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-[(4,5-dicyano-1H-imidazol-2-ylamino)methyl]-2H-1,2,3-triazole, m.p. 213°-215°. (Compound 25)
Reaction SMILES: [C:1]1([C:9]([CH:11]([C:13]2[CH:20]=[CH:19][C:16]([O:17][CH3:18])=[CH:15][CH:14]=2)O)=O)[CH:8]=[CH:7][C:4]([O:5][CH3:6])=[CH:3][CH:2]=1.[NH2:21][C:22]([NH2:24])=[S:23]>>[CH3:6][O:5][C:4]1[CH:7]=[CH:8][C:1]([C:9]2[N:21]=[C:22]([SH:23])[NH:24][C:11]=2[C:13]2[CH:20]=[CH:19][C:16]([O:17][CH3:18])=[CH:15][CH:14]=2)=[CH:2][CH:3]=1
Reactant: COc1ccc(C(=O)C(O)c2ccc(OC)cc2)cc1
Reactant: NC(N)=S
Product: COc1ccc(-c2nc(S)[nH]c2-c2ccc(OC)cc2)cc1

Procedure:
27.23 g (0.1 mol) of p-anisoin and 10.8 g (0.15 mol) of thiourea were reacted as in example 10. The yield was 20 g.
Reaction SMILES: II.[CH3:3][CH:4]([OH:19])[CH:5]([OH:18])[C:6]1[N:11]=[C:10]2[C:12]([N:14]=[C:15]([NH2:17])[NH:16][C:9]2=[N:8][CH:7]=1)=[O:13]>>[CH3:3][C@H:4]([OH:19])[C@H:5]([OH:18])[C:6]1[N:11]=[C:10]2[C:12]([N:14]=[C:15]([NH2:17])[NH:16][C:9]2=[N:8][CH:7]=1)=[O:13]
Reactant: CC(O)C(O)c1cnc2[nH]c(N)nc(=O)c2n1
Agent: II
Product: C[C@H](O)[C@H](O)c1cnc2[nH]c(N)nc(=O)c2n1

Procedure:
The resultant phenylhydrazone compound is reacted with an acetylating agent in pyridine to obtain a triacetylated compound, which is then condensed and cyclized with 6-hydroxy-2,4,5-triaminopyrimidine (TAU) in the coexistence of sodium acetate to obtain a biopterin derivative. After oxidized with iodine or other oxidizing agent, the biopterin derivative is subjected to deacetylation (hydrolysis) to produce L-biopterin.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([N:15]3[C:20](=[O:21])[C:19]([CH3:22])=[CH:18][C:17]([CH3:23])=[N:16]3)[C:11]([O:13]C)=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1.[OH-].[Na+]>CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([N:15]3[C:20](=[O:21])[C:19]([CH3:22])=[CH:18][C:17]([CH3:23])=[N:16]3)[C:11]([OH:13])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COC(=O)C(c1ccc2c(c1)OCO2)n1nc(C)cc(C)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C)c(=O)n(C(C(=O)O)c2ccc3c(c2)OCO3)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2.24 g of methyl 2-(1,3-benzodioxol-5-yl)-2-(4,6-dimethyl-2,3-dihydropyridazin-3-on-2-yl)-acetate in 20 ml of methanol is treated with 7.08 ml of 1N sodium hydroxide solution and the mixture is stirred at room temperature for 18 hours. It is worked up in the customary manner and 2-(1,3-benzodioxol-5-yl)-2-(4,6-dimethyl-2,3-dihydropyridazin-3-on-2-yl)acetic acid is obtained, m.p. 165°, EI 302.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([C:20]2[CH:21]=[C:22]([C:26]([CH3:31])([CH3:30])[C:27]([OH:29])=[O:28])[CH:23]=[CH:24][CH:25]=2)[CH:13]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:56][N:57]([CH3:61])[CH2:58][CH2:59]O>C(Cl)Cl>[CH3:56][N:57]([CH3:61])[CH2:58][CH2:59][O:28][C:27](=[O:29])[C:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:14]2[CH:13]=[C:12]([NH:11][CH2:10][CH2:9][C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[N:17]=[C:16]([O:18][CH3:19])[N:15]=2)[CH:21]=1)([CH3:31])[CH3:30]
Reactant: CN(C)CCO
Reactant: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(C)(C)C(=O)O)c2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(C)(C)C(=O)OCCN(C)C)c2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid [100 mg, 0.218 mmol, Example 49(b)] in DCM (2 mL) is treated with HBTU (515.2 mg, 1.35 mmol). The mixture is stirred at room temperature for 2 hours and treated with 2-dimethylamino-ethanol (0.154 mL, 1.53 mmol). After stirring overnight, the mixture is quenched with water and extracted with ethyl acetate. The combined organic layers are washed with brine, dried over sodium sulfate and concentrated. The residue is subjected to silica gel chromatography eluting with 0 to 7.5% MeOH in DCM to obtain 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid 2-dimethylamino-ethyl ester as an oil which is treated with 1M hydrogen chloride in ether affording 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid 2-dimethylamino-ethyl ester dihydrochloride [88 mg, 67%, Example 51] as a solid. LC/MS: RT=2.1 minutes, MS: 531 (M+H). 1H NMR [300 MHz, (CD3)2SO]: □10.16 (1H, br s), 7.3-7.82 (7H, m), 6.62 (1H, s), 4.37 (2H, m), 3.96 (3H, s), 3.68 (2H, m), 3.32 (2H, m), 3 (2H, m), 2.63 (6H, s), 1.6 (6H, s).
Reaction SMILES: C(OC(C1C=C(C2C=CC(C[S:19][CH2:20][CH2:21][OH:22])=CC=2)C=CC=1)=O)C.[CH2:23]([O:25][C:26]([C:28]1[C:29]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40]Br)[CH:35]=2)=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:27])[CH3:24].SCCO.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:23]([O:25][C:26]([C:28]1[C:29]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][S:19][CH2:20][CH2:21][OH:22])[CH:35]=2)=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:27])[CH3:24]
Reactant: CCOC(=O)c1ccccc1-c1cccc(CBr)c1
Reactant: CCOC(=O)c1cccc(-c2ccc(CSCCO)cc2)c1
Agent: O=C([O-])[O-]
Agent: OCCS
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccccc1-c1cccc(CSCCO)c1

Procedure:
3′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid ethyl ester was prepared as described for 4′-(2-hydroxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethyl ester. 3′-Bromomethyl-biphenyl-2-carboxylic acid ethyl ester (5.4 g, 16.92 mmol, 1 eq.). in anhydrous DMF was treated with 2-mercaptoethanol (1.59 g, 20.30 mmol, 1.2 eq.) and potassium carbonate (7.02 g, 50.76 mmol, 3 eq.). When complete, the reaction was worked up as described leaving a light yellow oil.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:17]=[CH:16][C:7]([CH2:8][CH:9]2[S:13][C:12](=[O:14])[NH:11][C:10]2=[O:15])=[CH:6][CH:5]=1.Cl[CH2:19][C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:24]=1.O>CN(C=O)C.C(O)(=O)C>[C:25]1([C:23]2[N:24]=[C:20]([CH2:19][O:3][C:4]3[CH:17]=[CH:16][C:7]([CH2:8][CH:9]4[S:13][C:12](=[O:14])[NH:11][C:10]4=[O:15])=[CH:6][CH:5]=3)[S:21][CH:22]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C1NC(=O)C(Cc2ccc(O)cc2)S1
Reactant: ClCc1nc(-c2ccccc2)cs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: O=C1NC(=O)C(Cc2ccc(OCc3nc(-c4ccccc4)cs3)cc2)S1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
Sodium hydride (60% in oil, 1.2 g) was added to a solution of 5-(4-hydroxybenzyl)-2,4-thiazolidinedione (3.4 g) in DMF (30 ml), and the mixture was stirred at room temperature for 30 minutes, followed by dropwise addition of a solution of 2-chloromethyl-4-phenylthiazole (4.4 g) in DMF (20 ml) at room temperature. The mixture was stirred at room temperature for 1 hour and at 60° C. for 1 hour, poured into water, neutralized with acetic acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4). The solvent was then distilled off and the oily residue was subjected to column chromatography using silica gel (100 g). Elution with benzene-acetone (25:1, v/v) gave 5-[4-(4-phenyl-2-thiazolylmethoxy)benzyl]-2,4-thiazolidinedione (2.9 g, 49.2%). Recrystallization from ethanol gave light-yellow crystals. M.p. 164°-165° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=O)[NH:12]3)[CH2:10][CH:9]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[O:8][C:5]2=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=[S:33])[NH:12]3)[CH2:10][CH:9]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[O:8][C:5]2=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)C2(CC(C3CCCCC3)Oc3ccc(Br)cc32)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: O=C1NC(=S)NC12CC(C1CCCCC1)Oc1ccc(Br)cc12
Temperature: 120 °C
Yield: 66.8 %

Procedure:
A suspension of 6-bromo-2-cyclohexylspiro[chroman-4,4′-imidazolidine]-2′,5′-dione (400 mg, 1.06 mmol) and Lawesson's Reagent (427 mg, 1.06 mmol) in dry 1,4-dioxane (6 mL) was heated at 120° C. in a 10 mL CEM microwave test tube for 30 minutes. The mixture was concentrated in vacuo and the residue was purified by preparative TLC to give 6-bromo-2-cyclohexyl-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (280 mg, 67%). 1H-NMR (CDCl3): 0.78-0.92 (m, 2H), 1.13 (m, 1H), 1.17-1.31 (m, 3H), 1.71 (m, 2H), 1.78 (m, 2H), 1.94 (d, 1H), 2.05 (t, 1H), 2.61 (d, 1H), 4.91 (m, 1H), 6.78 (d, 1H), 7.04 (s, 1H), 7.13 (s, 1H), 7.32 (d, 1H), 9.33 (s, 1H).
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.[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)([O-:14])=[O:13]>>[N+:12]([C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:1][C:2]2[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=2)=[O:20])=[CH:22][CH:23]=1)([O-:14])=[O:13]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc(O)c(C(=O)O)c1
Product: O=C(Nc1ccc(O)c(C(=O)O)c1)c1ccc([N+](=O)[O-])cc1
Yield: 55.8 %

Procedure:
By following the similar procedure in Synthesis Example 1 by using 5-aminosalicylic acid (500 mg, 3.26 mmole) and 4-nitrobenzoyl chloride (700 mg, 3.77 mmole), 550 mg (56% yield) of 5-(4-nitrobenzoyl)aminosalicylic acid was obtained as a pale yellow solid.: mp 270-271° C.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21]([NH:23][C@H:24]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:25]([OH:30])[C:26]([O:28]C)=[O:27])=[O:22])[N:4]=1)#[N:2].O.CCOC(C)=O.Cl>CO.[OH-].[Na+]>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21]([NH:23][C@H:24]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:25]([OH:30])[C:26]([OH:28])=[O:27])=[O:22])[N:4]=1)#[N:2]
Reactant: COC(=O)[C@H](O)[C@@H](Cc1ccccc1)NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: N#Cc1nc(C(=O)N[C@H](Cc2ccccc2)[C@@H](O)C(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
(2R,3R)-Methyl 3-(1-cyano-4-hydroxy-7-phenoxyisoquinoline-3-carboxamido)-2-hydroxy-4-phenylbutanoate (4 mg, 0.01 mmol) was dissolved in MeOH (2 mL) and 2 N NaOH (2 mL). After stirring for 6 hours at room temperature, H2O (15 mL) and EtOAc (15 mL) were added. To the stirred mixture was added 1 N hydrochloric acid until pH was 1. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-30% MeOH/CH2Cl2) to give the title compound in 3 mg. MS: (−) m/z 482.17 (M−1).
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:21][Si](C(C)C)(C(C)C)C(C)C)[CH:14]=[C:15]([F:20])[CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([OH:21])[CH:14]=[C:15]([F:20])[CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC(C)[Si](Oc1cc(F)cc2ccc(-c3nnc4ccccn34)nc12)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Oc1cc(F)cc2ccc(-c3nnc4ccccn34)nc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoro-8-(triisopropylsilyloxy)quinoline (5.00 g, 11.5 mmol) was dissolved in 250 mL of anhydrous THF, followed by cooling to 0° C., then addition of TBAF (4.49 g, 17.2 mmol). Following 1 hour, the reaction was complete by TLC, and the crude reaction partitioned between water and ethyl acetate. The crude work-up was then filtered through standard filter paper with ethyl acetate wash, affording the desired product 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-ol (2.8 g, 9.99 mmol, 87% yield) as a white solid.
Reaction SMILES: [NH2:1][C@@:2]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])[CH2:7][O:6][C@@H:5]([CH2:8][O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:4][C@H:3]1[C@@H:17]([OH:19])[CH3:18].C(OC[C@@H]1OC[C@@](N[C:52]([NH:54][C:55](=[O:62])[C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[S:53])(C2C=CC(F)=CC=2F)[C@H](CO)C1)C1C=CC=CC=1>>[CH2:10]([O:9][CH2:8][C@@H:5]1[O:6][CH2:7][C@@:2]([NH:1][C:52]([NH:54][C:55](=[O:62])[C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)=[S:53])([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])[C@H:3]([C@@H:17]([OH:19])[CH3:18])[CH2:4]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(NC(=S)N[C@@]1(c2ccc(F)cc2F)CO[C@@H](COCc2ccccc2)C[C@H]1CO)c1ccccc1
Reactant: C[C@H](O)[C@@H]1C[C@H](COCc2ccccc2)OC[C@@]1(N)c1ccc(F)cc1F
Product: C[C@H](O)[C@@H]1C[C@H](COCc2ccccc2)OC[C@@]1(NC(=S)NC(=O)c1ccccc1)c1ccc(F)cc1F

Procedure:
The product was prepared from (1 S)-1-[(2R,4R,5S)-5-amino-2-[(benzyloxy)methyl]-5-(2,4-difluorophenyl)tetrahydro-2H-pyran-4-yl]ethanol (C19) according to the general procedure for the synthesis of N-{[(3S,4R,6R)-6-[(benzyloxy)methyl]-3-(2,4-difluorophenyl)-4-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]carbamothioyl}benzamide (C7) in Preparation P1. In this case, after concentration of the reaction mixture in vacuo, the residue was chromatographed on silica gel (Gradient: 0% to 50% ethyl acetate in heptane) to afford the product as a yellow foam. Yield: 13.36 g, 24.71 mmol, 67%. LCMS m/z 539.2 [M−H+].
Reaction SMILES: [CH2:1]([N:8]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2B2OC(C)(C)C(C)(C)O2)[O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:36]1[CH:41]=[CH:40][N:39]=[N:38][CH:37]=1>>[CH2:1]([N:8]([CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[C:36]2[CH:41]=[CH:40][N:39]=[N:38][CH:37]=2)[O:11][CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Brc1ccnnc1
Reactant: CC1(C)OB(c2cccc3c2C[C@H](N(Cc2ccccc2)Cc2ccccc2)CO3)OC1(C)C
Product: c1ccc(CN(Cc2ccccc2)[C@@H]2COc3cccc(-c4ccnnc4)c3C2)cc1
Yield: 62 %

Procedure:
The title compound was synthesized as described for Intermediate example I-48 in 62% yield starting from (3S)-N,N-dibenzyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan -2-yl)chroman-3-amine and 4-bromopyridazine (1.2 equiv). The reaction was irradiated in microwave at 140° C. for 45 min: 1H NMR (400 MHz, CDCl3) δ ppm 9.26 (dd, 1 H), 9.19-9.22 (m, 1 H), 7.38 (dd, 1 H), 7.26-7.34 (m, 8 H), 7.16-7.25 (m, 3 H), 6.91 (d, 1 H), 6.78 (dd, 1 H), 4.36-4.43 (m, 1 H), 4.06 (t, 1 H), 3.64-3.77 (m, 4 H), 3.15-3.25 (m, 1 H), 2.86 (dd, 1 H), 2.57 (ddd, 1 H); MS (ESI) m/z 408[M+H+].
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][CH:35]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)[S:8]([C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[C:12]=1[OH:19])(=[O:10])=[O:9].CCN(CC)CC.Cl[S:44]([C:47]1[CH:48]=[CH:49][C:50]([CH3:56])=[C:51]([CH:55]=1)[C:52]([OH:54])=[O:53])(=[O:46])=[O:45]>C(Cl)Cl>[C:24]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:25]=[CH:26][C:21]([CH2:20][N:7]([CH2:6][C:5]2[CH:4]=[C:3]([CH:35]=[CH:34][CH:33]=2)[CH2:2][NH:1][S:44]([C:47]2[CH:48]=[CH:49][C:50]([CH3:56])=[C:51]([CH:55]=2)[C:52]([OH:54])=[O:53])(=[O:46])=[O:45])[S:8]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[C:12]=2[OH:19])(=[O:10])=[O:9])=[CH:22][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1C(=O)O
Reactant: NCc1cccc(CN(Cc2ccc(-c3ccccc3)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NCc2cccc(CN(Cc3ccc(-c4ccccc4)cc3)S(=O)(=O)c3cc(Cl)cc(Cl)c3O)c2)cc1C(=O)O
Reaction time: 1.17 h
Yield: 58 %

Procedure:
To a solution of N-(3-(aminomethyl)benzyl)-N-(biphenyl-4-ylmethyl)-3,5-dichloro-2-hydroxybenzenesulfonamide (50 mg, 0.095 mmol) and Et3N (0.13 mL) in CH2Cl2 (4 mL) was added a solid of 5-(chlorosulfonyl)-2-methylbenzoic acid (22.24 mg, 0.095 mmol) at rt and it was stirred at it for 70 min. Direct purification of the mixture after concentration by prep HPLC provided the desired product (40 mg, 58.1%) as a white solid after lyophilization. 1H NMR (CD3OD): δ 8.17 (d, J=2.0 Hz, 1H), 7.93 (dd, J=8.3, 2.2 Hz, 1H), 7.56˜6.90 (m, 15H), 6.76 (s, 1H), 4.34 (s, 2H), 4.31 (s, 2H), 3.87 (s, 2H), 2.52 (s, 3H); MS (ESI): (M+H)+=725.
Reaction SMILES: [ClH:1].[NH2:2][CH:3]1[CH:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]2[CH:10]=[C:9]([O:20][CH2:21][CH2:22][N:23]([CH3:33])[S:24]([C:27]3[N:28]=[CH:29][N:30]([CH3:32])[CH:31]=3)(=[O:26])=[O:25])[CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4]1.Br[CH2:35][CH2:36][CH2:37][CH2:38]Br.C(N(CC)CC)C.O>C(#N)C.C(OCC)(=O)C>[ClH:1].[CH2:13]([CH:12]1[C:11]2[CH:10]=[C:9]([O:20][CH2:21][CH2:22][N:23]([CH3:33])[S:24]([C:27]3[N:28]=[CH:29][N:30]([CH3:32])[CH:31]=3)(=[O:26])=[O:25])[CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH:3]1[N:2]1[CH2:38][CH2:37][CH2:36][CH2:35]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CN(CCOc1ccc2c(c1)C(Cc1ccccc1)C(N)CC2)S(=O)(=O)c1cn(C)cn1
Reactant: BrCCCCBr
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN(CCOc1ccc2c(c1)C(Cc1ccccc1)C(N1CCCC1)CC2)S(=O)(=O)c1cn(C)cn1
Temperature: 130 °C
Reaction time: 2 h
Yield: 10 %

Procedure:
N-(2-{[7-Amino-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-N,1-dimethyl-1H-imidazole-4-sulfonamide hydrochloride (98), 1,4-dibromobutane (49.9 mg, 0.231 mmol), and triethylamine (31.2 mg, 0.308 mmol) were dissolved in acetonitrile (3 ml) and stirred for 2 h at 130° C. in the microwave. Water and ethyl acetate were added and the organic phase was separated. After extraction of the aqueous phase with ethylacetate the combined organic layers were washed with saturated NaCl solution, dried over Na2SO4, and concentrated to afford a residue a residue that was purified by flash chromatography (silica gel, MeOH/CH2Cl2 5:95). The residue was transferred to an HCl salt and finally gave the product as a white solid (8.5 mg, 10%) after precipitation from diisopropylether.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].CN1CCOCC1.[C:13]([O:17][C:18]([NH:20][C@H:21]([CH2:25][C:26]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:22](O)=[S:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].C(OC(Cl)=O)(C)C>ClCCl.O1CCCC1>[CH3:5][O:4][N:3]([CH3:2])[C:22](=[S:23])[C@H:21]([NH:20][C:18]([O:17][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:19])[CH2:25][C:26]([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N[C@H](CC(c1ccccc1)(c1ccccc1)c1ccccc1)C(O)=S
Agent: CC(C)OC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CON(C)C(=S)[C@@H](CC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OC(C)(C)C
Temperature: -30 °C

Procedure:
The title compound was synthesized essentially according to the procedure described by O. P. Goel, U. Krolls, M. Stier, and S. Kesten in Organic Syntheses, 1988, 67, 69-75. Thus N,O-dimethyl-hydroxylamine hydrochloride (1.05 g, 10.82 mmol) and N-methyl-morpholine (1.22 mL, 11.14 mmol) were stirred in dichloromethane (6 mL) under nitrogen at 0° C. for 30 min. In a separate flask, 2(R)-tert-butoxycarbonylamino-3-triphenylmethyl-thiopropionic acid (5.02 g, 10.82 mmol) in tetrahydrofuran (11.5 mL, dry) and methylene chloride (45 mL) were cooled to -20° C., and N-methylmorpholine (1.22 mL, 11.14 mmol) and isopropylchloroformate (10.82 mL of 1M solution in toluene) were added via syringe, maintaining the temperature less than -15° C. The reaction was stirred at -30° C., and the suspension of N,O-dimethylhydroxylamine hydrochloride and N-methylmorpholine in methylene chloride added all at once. The cooling bath was removed and the reaction allowed to warm to room temperature over 4 h. The reaction was cooled to 0° C. and quickly washed with two portions of 0.2N hydrochloric acid, two portions of 0.5N sodium hydroxide, and saturated sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered and reduced in vacuo to obtain the title compound as a clear gum, 5.50 g. NMR (300 MHz, DMSO-d6) δ 7.30 (15H, m), 4.43 (1H, br s), 3.56 (3H, s), 2.99 (3H, s), 2.30 (2H, m), 1.36 (9H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([F:39])=[C:14]([C:18]2[C:30]3[C:29]4[C:24](=[CH:25][C:26]([O:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:27][CH:28]=4)[NH:23][C:22]=3[C:21]([C:36](O)=[O:37])=[N:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].F[P-](F)(F)(F)(F)F.[N:49]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.CN1CCOCC1>CN(C=O)C.O>[C:36]([C:21]1[C:22]2[NH:23][C:24]3[C:29]([C:30]=2[C:18]([C:14]2[C:13]([F:39])=[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:17]=[CH:16][CH:15]=2)=[CH:19][N:20]=1)=[CH:28][CH:27]=[C:26]([O:31][CH2:32][CH2:33][O:34][CH3:35])[CH:25]=3)(=[O:37])[NH2:49]
Reactant: COCCOc1ccc2c(c1)[nH]c1c(C(=O)O)ncc(-c3cccc(NC(=O)OCc4ccccc4)c3F)c12
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)ncc(-c3cccc(NC(=O)OCc4ccccc4)c3F)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
A burgundy, homogeneous solution of 4-(3-(benzyloxycarbonylamino)-2-fluorophenyl)-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indole-1-carboxylic acid (0.7 g, 1.322 mmol), ammonium chloride (0.283 g, 5.29 mmol), BOP (0.760 g, 1.719 mmol), DIPEA (1.108 mL, 6.35 mmol) and N-methylmorpholine (0.567 mL, 5.16 mmol) in DMF (8 mL) under nitrogen was stirred. After 2 hr, water (20 mL) was added, and the reaction was stirred at room temperature for 45 min. The precipitate was collected, rinsed with water and dried over Drierite under vacuum to give the desired product (0.6318 g, 1.195 mmol, 90% yield) as a tan solid.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4]Br.[CH2:8]([S:15][C:16]1[N:20]=[C:19]([SH:21])[NH:18][N:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C[O-].[Na+].O>CN(C)C=O.CCOCC>[CH2:8]([S:15][C:16]1[N:20]=[C:19]([S:21][CH2:4][CH:3]([O:6][CH3:7])[O:2][CH3:1])[NH:18][N:17]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COC(CBr)OC
Reactant: Sc1nc(SCc2ccccc2)n[nH]1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: COC(CSc1nc(SCc2ccccc2)n[nH]1)OC
Temperature: 110 °C
Yield: 90.4 %

Procedure:
Bromoacetaldehyde dimethyl acetal (7.8 g) was added portionwise to 3-benzylthio-5-mercapto-1,2,4-triazole (10 g) and sodium methoxide (2.5 g) in dimethylformamide (60 ml) under nitrogen. The mixture was heated at about 110° C. for 5 hours. Addition to water and isolation through ether gave 12.6 g of desired product, mp 73°-76° C.