Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[CH2:2][CH2:3][NH:4][C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[NH:19][CH:20]=[CH:21][C:14]=12)=[O:6].[C:22]([NH:29]CCCN)(OC(C)(C)C)=O>>[NH2:29][CH2:22][CH2:2][CH2:3][NH:4][C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[NH:19][CH:20]=[CH:21][C:14]=12)=[O:6]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: NCCNC(=O)c1sccc1Nc1ccnc2[nH]ccc12
Product: NCCCNC(=O)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid (2-amino-ethyl)-amide using 3-(Boc-amino)-propylamine instead of tert-butyl-2-amino ethyl carbamate. LCMS (ESI) 316 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 12.47 (1H, br. s.) 10.84 (1H, s) 8.66 (1H, t, J=5.56 Hz) 8.04 (1H, d, J=6.83 Hz) 7.87 (3H, d, J=5.27 Hz) 7.36-7.42 (1H, m) 7.30 (1H, d, J=5.27 Hz) 6.81 (1H, br. s.) 6.67 (1H, d, J=7.03 Hz) 3.23 (2H, q, J=6.44 Hz) 2.66-2.82 (2H, m) 1.67-1.81 (2H, m)
Reaction SMILES: C([O:4][CH2:5][CH:6]([O:22][CH2:23][P:24]([O:29][CH2:30][CH3:31])([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][O:8][N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][C:12]([NH:19]C=O)=[N:13][C:14]=2Cl)(=O)C.[NH3:32]>>[NH2:19][C:12]1[N:11]=[C:10]2[C:15]([N:16]=[CH:17][N:9]2[O:8][CH2:7][CH:6]([O:22][CH2:23][P:24]([O:26][CH2:27][CH3:28])([O:29][CH2:30][CH3:31])=[O:25])[CH2:5][OH:4])=[C:14]([NH2:32])[N:13]=1
Reactant: CCOP(=O)(COC(COC(C)=O)COn1cnc2c(Cl)nc(NC=O)nc21)OCC
Reactant: N
Product: CCOP(=O)(COC(CO)COn1cnc2c(N)nc(N)nc21)OCC
Temperature: 25 °C

Procedure:
A solution of 9-[3-acetoxy-2-(diethoxyphosphorylmethoxy)propoxy]-6-chloro-2-formamidopurine (0.16 g, 0.33 mmol) in ethanolic ammonia (5 ml) was heated in a sealed vessel at 120° C. for 5 hours. The solution was allowed to cool to ambient temperature and the solvent was removed under reduced pressure to leave a brown residue. The residue was purified by preparative t.l.c. (dichloromethane:methanol 80:20) to give 2,6-diamino-9-[2-(diethoxyphosphorylmethoxy)-3-hydroxypropoxy]purine as a colourless gum (0.065 g). The gum (0.06 g, 0.15 mmol) was dissolved in dry DMF (1 ml) and trimethylsilyl bromide (0.3 ml, 1.53 mmol) added. After 3 hours at ambient temperature, the solvent was removed under reduced pressure and the residue obtained dissolved in 50% aqueous acetone. Evaporation of the solvent gave a solid which after crystallisation from hot water, gave the title compound as a cream solid (0.014 g, 27%). 1H NMR: δH [(CD3) 2 SO] 3.46-3.60 (2H, m, CH2OH), 3.65-3.85 (3H, m, CHOCH2P), 4.24 (1H, m, NOCHB), 4.42 (1H, m, NOCHA), 6.03 (2H, br. s, D2O exchangeable NH2), 6.88 (2H, br. s, D2O exchangeable NH2), 8.02 (1H, s, H-8), 3.3 (br.s, D2O exchangeable OH, PO(OH)2, water in solvent). m/z (FAB, thioglycerol matrix) 335 (MH+, 6%)
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8]([CH:12]=[CH2:13])[N:7]=1)([CH3:4])([CH3:3])[CH3:2].[O:14]([CH2:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[C:1]([O:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8]([CH2:12][CH2:13][N:25]2[CH2:26][CH2:27][CH:22]([CH2:21][O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:23][CH2:24]2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=Cc1cncc(OC(C)(C)C)n1
Reactant: c1ccc(OCC2CCNCC2)cc1
Solvent: CCO
Product: CC(C)(C)Oc1cncc(CCN2CCC(COc3ccccc3)CC2)n1
Temperature: 80 °C
Reaction time: 96 h

Procedure:
After dissolving 471 mg of 2-tert-butoxy-6-vinylpyrazine and 505 mg of 4-(phenoxymethyl)piperidine in 10 ml of ethanol, the mixture was stirred for 4 days at 80° C. The reaction solution was concentrated under reduced pressure and the residue was purified by NH silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain 2-tert-butoxy-6-[2-(4-phenoxymethylpiperidino)ethyl]pyrazine.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:7])[S:5][CH:6]=1.[CH:8]1([C:11](Cl)=[O:12])[CH2:10][CH2:9]1.O>N1C=CC=CC=1>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:11]([CH:8]2[CH2:10][CH2:9]2)=[O:12])[S:5][CH:6]=1
Reactant: Cc1csc(N)n1
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Solvent: O
Product: Cc1csc(NC(=O)C2CC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-methylthiazol-2-amine (20.4 g) in pyridine (80 ml) under an ice bath was added dropwise cyclopropanecarbonyl chloride (19.7 ml) and the resulting reaction was stirred at room temperature (RT) overnight. A half volume of pyridine was removed using a rotary evaporator to afford a residue, to which water (100 ml) was added. Filtration, washing with water (3×100 ml) and drying under vacuum afforded N-(4-methylthiazol-2-yl)cyclopropanecarboxamide as a white solid (29.92 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)([C:10]2[CH:11]=[C:12]3[C:17](=[C:18]([Br:20])[CH:19]=2)[N:16]=[CH:15][CH:14]=[C:13]3[Br:21])O)=[CH:4][CH:3]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:10]2[CH:11]=[C:12]3[C:17](=[C:18]([Br:20])[CH:19]=2)[N:16]=[CH:15][CH:14]=[C:13]3[Br:21])=[CH:27][CH:26]=1
Reactant: OC(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)c1cc(Br)c2nccc(Br)c2c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(C(c2ccc(Cl)cc2)c2cc(Br)c3nccc(Br)c3c2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To solution of bis(4-chlorophenyl)(4,8-dibromoquinolin-6-yl)methanol (175 mg, 0.325 mmol) and triethylsilane (0.208 mL, 1.3 mmol) in CH2Cl2 was added slowly TFA (0.35 mL, 4.57 mmol). The resulting mixture was stirred for 4 hr at room temperature. The reaction was diluted with CH2Cl2 and washed with Na2CO3 to make the aqueous layer basic. The organics were concentrated and purified by silica column (15% EtOAc/hexanes) chromatography to yield 6-(bis(4-chlorophenyl)methyl)-4,8-dibromoquinoline. (M+H)+: 520, 523, 528.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][NH:14][C@H:15]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16]([CH3:19])([CH3:18])[CH3:17].NN>C(O)C>[NH2:3][CH2:12][CH2:13][NH:14][C@H:15]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16]([CH3:18])([CH3:19])[CH3:17]
Reactant: CC(C)(C)OC(=O)[C@@H](NCCN1C(=O)c2ccccc2C1=O)C(C)(C)C
Agent: NN
Solvent: CCO
Product: CC(C)(C)OC(=O)[C@@H](NCCN)C(C)(C)C
Temperature: 75 °C
Yield: 90.2 %

Procedure:
The product of Example 111-2 (87 g, 241.6 mmol) was taken up in ethanol (2 L) in a 3-necked, 3L round bottom flask equipped with mechanical stirring under N2. Hydrazine (anhydrous, 68.3 mL, 2.17 mol, 9 equivalents) was added. The reaction mixture was heated to 75° C., which resulted in the formation of a very thick suspension. The addition of more ethanol was necessary in order to continue effective stirring. The reaction was stirred for 1 hour at 75° C. until consumption of starting material was complete as determined by HPLC. The thick suspension was cooled to ambient temperature and quenched with 1 L of 0.5N NaOH solution. The mixture was diluted with 0.5N NaOH (2 L) and extracted with dichloromethane (2×2 L). The combined organic layer was washed with brine (1 L), dried over MgSO4, filtered and concentrated to oil. The oil was chased with heptanes to remove ethanol and pump dried to afford light yellow oil (50.2 g, 93.2% yield). 1H NMR (CDCl3): δ 2.73(m, 4H), 2.45(m, 1H), 1.64(s, 9H), 0.96(s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:5]2.[OH-].[K+].[CH3:20][CH:21]1[CH2:26][C:25](=[O:27])[O:24][C:23](=[O:28])[CH2:22]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:25](=[O:27])[CH2:26][CH:21]([CH3:20])[CH2:22][C:23]([OH:28])=[O:24])[C:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:5]2
Reactant: CC1CC(=O)OC(=O)C1
Reactant: CC(C)CCCCc1cc2cc(Cl)ccc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)CCCCc1cc2cc(Cl)ccc2n1C(=O)CC(C)CC(=O)O
Reaction time: 0.5 h

Procedure:
To the solution of 5-chloro-2-(5-methyl-hexyl)-1H-indole in DMSO was added KOH at RT and was stirred for 30 minutes. Then to this mixture, 4-methyl-dihydro-pyran-2,6-dione was added and stirred for 3 hours. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The product was purified by column chromatography.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:20])[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH2:7][CH2:6]1.[O:21]=[C:22]1[NH:26][C:25]([C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])=[C:24]([C:34](O)=[O:35])[S:23]1>>[Cl:19][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[Cl:18])[O:11][CH:8]1[CH2:9][CH2:10][N:5]([CH2:4][C@H:3]([OH:20])[CH2:2][NH:1][C:34]([C:24]2[S:23][C:22](=[O:21])[NH:26][C:25]=2[C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])=[O:35])[CH2:6][CH2:7]1
Reactant: O=C(O)c1sc(=O)[nH]c1C(F)(F)C(F)(F)F
Reactant: NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Product: O=C(NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1)c1sc(=O)[nH]c1C(F)(F)C(F)(F)F
Yield: 26.5 %

Procedure:
Prepared as Example 1 using (2R)-1-amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.158 g) and 2-oxo-4-(pentafluoroethyl)-2,3-dihydro-1,3-thiazole-5-carboxylic acid (0.130 g) to yield the title compound as a colourless solid (0.074 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH3:19])[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[C:7]([S:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[N:6]=2.O[C:21]1[CH:53]=[CH:52][C:24]([CH2:25][CH:26]2[S:30][C:29](=[O:31])[N:28]([C:32]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]2=[O:51])=[CH:23][CH:22]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH3:19][N:4]1[C:5]2=[N:6][C:7]([S:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:8][CH:9]=[C:10]2[N:11]=[C:3]1[CH2:2][O:1][C:21]1[CH:53]=[CH:52][C:24]([CH2:25][CH:26]2[S:30][C:29](=[O:31])[N:28]([C:32]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]2=[O:51])=[CH:23][CH:22]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1c(CO)nc2ccc(Sc3ccccc3)nc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2ccc(Sc3ccccc3)nc21

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 0.70. g of 2-hydroxymethyl-3-methyl-5-phenylthioimidazo[5,4-b]pyridine (prepared as described in Preparation 90), 1.20 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 0.64 ml of tributylphosphine, 0.65 g of 1,1'-(azodicarbonyl)dipiperidine and 25 ml of toluene were used, and that the product was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.61 g of the title compound, melting at 90-95° C. (softening).
Reaction SMILES: [CH:1]1([CH:4]=O)[CH2:3][CH2:2]1.[CH3:6][C:7]([S@@:10]([NH2:12])=[O:11])([CH3:9])[CH3:8]>C(Cl)Cl.[O-]S([O-])(=O)=O.[Cu+2]>[CH:1]1([CH:4]=[N:12][S@:10]([C:7]([CH3:9])([CH3:8])[CH3:6])=[O:11])[CH2:3][CH2:2]1
Reactant: CC(C)(C)[S@@](N)=O
Reactant: O=CC1CC1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)[S@](=O)N=CC1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
The title compound was prepared according to a general procedure described by G. Liu, D. A. Cogan, T. D. Owens, T. P. Tang, and J. A. Ellman J. Org. Chem. 1999, 64, 1278: A mixture of cyclopropanecarboxaldehyde (35.0 g, 0.5 mol), (S)-(−)-2-methyl-2-propanesulfinamide (30 g, 0.25 mol) and anhydrous CuSO4 (120 g, 0.75 mol) in CH2Cl2 (1500 mL) was stirred at room temperature overnight. The reaction mixture was filtered and evaporated to give the title compound (39 g, yield 95%), which was used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:13][C:6]1[N:2]([CH3:1])[C:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][C:5]=1[CH3:7]
Reactant: CCOC(=O)c1cc(C)cn1C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc(C)c(Br)n1C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of ethyl 1,4-dimethyl-1H-pyrrole-2-carboxylate (63 mg, 0.377 mmol) in CHCl3 (3.5 mL) at 0° C. was added N-bromosuccinimide (67.1 mg, 0.377 mmol). The reaction was stirred at 0° C. for 15 min. The reaction was warmed to room temperature and stirred overnight. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative TLC (1000 μm, hexanes/EtOAc (9:1)) to give ethyl 5-bromo-1,4-dimethyl-1H-pyrrole-2-carboxylate. LCMS calc.=245.0. found=245.9 (M+H)+. 1H NMR (500 MHz, CDCl3): δ 6.83 (s, 1H); 4.27 (q, J=7.1 Hz, 2H); 3.91 (s, 3H); 2.05-2.02 (m, 3H); 1.34 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Li+].[OH-].[Cl:3][C:4]1[CH:8]=[C:7]([C:9]([NH:11][CH2:12][CH2:13][OH:14])=[O:10])[NH:6][C:5]=1[C:15]([O:17]C)=[O:16]>C1COCC1.CO>[Cl:3][C:4]1[CH:8]=[C:7]([C:9]([NH:11][CH2:12][CH2:13][OH:14])=[O:10])[NH:6][C:5]=1[C:15]([OH:17])=[O:16]
Reactant: COC(=O)c1[nH]c(C(=O)NCCO)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NCCO)c1cc(Cl)c(C(=O)O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.7 %

Procedure:
LiOH (2 mL, 2 mmol) was added to a solution of methyl 3-chloro-5-{[(2-hydroxyethyl)amino]carbonyl}-1H-pyrrole-2-carboxylate (0.082 g, 0.33 mmol) in THF (2 mL) and methanol (2 mL). The solution was stirred at RT overnight. The solvent was evaporated and the residue partitioned between EtOAc and 1 N HCl. The organic layer was separated, dried over MgSO4, filtered and evaporated to afford very little solid. The aqueous layer was evaporated to a residue and the salts extracted with methanol. The methanol was evaporated to afford the title compound (0.042 g, 54%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.16 (br. s., 1H), 8.40 (t, 1H), 6.61-7.10 (m, 1H), 3.45 (t, 2H), 3.26 (q, 2H).
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][C:10]=1[CH3:11])(=[O:3])[CH3:2].[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([NH:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][C:10]=1[CH2:11][Br:12])(=[O:3])[CH3:2]
Reactant: CC(=O)NCc1sccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)NCc1sccc1CBr

Procedure:
N-Acetyl-2-aminomethyl-3-methylthiophene is dissolved in carbon tetrachloride and treated with an equimolar amount of N-bromosuccinimide and a catalytic amount of dibenzoyl peroxide. The mixture is heated to reflux for 3 hours while irradiating with a 250 watt light. The mixture is cooled and the precipitated succinimide removed by filtration. The filtrate is washed with saturated sodium bisulphite solution, dried over magnesium sulfate and evaporated to yield the title compound.
Reaction SMILES: C([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[NH:12][N:11]=1)(=O)N.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].C[N:40](C)[CH:41]=[O:42]>>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[N:14]=[C:10]3[N:11]([C:41](=[O:42])[NH:40][C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=43)[N:12]=2)=[CH:20][CH:19]=1
Reactant: CN(C)C=O
Reactant: NC(=O)c1ccccc1-c1n[nH]c(-c2ccc(Cl)cc2)n1
Agent: CC(=O)[O-]
Agent: [Pb+4]
Product: O=c1[nH]c2ccccc2c2nc(-c3ccc(Cl)cc3)nn12

Procedure:
Seven grams of 3-(2-Carbamoylphenyl)-5-(4-chlorophenyl)-1H-1,2,4-triazole are dissolved in dry dimethylformamide (180 ml) at 50° C. Lead tetraacetate (10.4 g) is added under stirring and the reaction mixture is stirred under nitrogen for ten minutes. The reaction mixture is quenched in crushed ice (500 ml) containing concentrated hydrochloric acid (50 ml). The white solid which forms is collected, washed thoroughly with cold water and recrystallized from 2-methoxyethanol to afford 2-(4-chlorophenyl)-[1,2,4]-triazolo[1,5-c]quinazolin-5(6H)one, mp 315°-318°.
Reaction SMILES: [CH2:1]([C:4]1([OH:27])[C@@H:8]([NH:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:7][N:6]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:5]1)[CH:2]=[CH2:3].B1C2CCCC1CCC2.OO.CC([O-])=[O:41].[Na+].O>C1COCC1.O>[CH2:13]([O:12][C:10]([NH:9][C@H:8]1[CH2:7][N:6]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:5][C:4]1([OH:27])[CH2:1][CH2:2][CH2:3][OH:41])=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(=O)[O-]
Reactant: C=CCC1(O)CN(C(=O)OC(C)(C)C)C[C@@H]1NC(=O)OCc1ccccc1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](NC(=O)OCc2ccccc2)C(O)(CCCO)C1
Reaction time: 48 h

Procedure:
To a solution of 0.85 g of allyl alcohol of step C in 20 mL of anhydrous THF was added a solution of 15 mL of 0.5 N 9-BBN. The reaction was stirred for 2 days. Water (0.5 mL) was added followed with 1 mL of 30% H2O2 and 1 mL of NaOAc/water. After being stirred for 1 h, the organic phase was separated. The water solution was neutralized with HCl and extracted with EtOAc twice. The combined organic phase was dried over Na2SO4. Solvent was removed under vacuum. Column chromatography on silica gel using pure EtOAc as eluent provided 0.80 g of the title compound. MS (M+H)+ 395.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Si:11]([O:18][C@@H:19]1[CH2:24][CH2:23][C@H:22]([CH2:25][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:21][CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C1C[O:39]CC1>>[Si:11]([O:18][C@@H:19]1[CH2:20][CH2:21][C@H:22]([CH:25]([OH:39])[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:23][CH2:24]1)([C:14]([CH3:16])([CH3:17])[CH3:15])([CH3:13])[CH3:12]
Reactant: C1CCOC1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](CC(=O)OCc2ccccc2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](C(O)C(=O)OCc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
A 1.0 M sodium bistrimethylsilylamide solution in THF (3.3 ml, 3.25 mmol) was added to anhydrous THF (5.0 ml), and the mixture was cooled to −78° C. A solution of benzyl 2-(cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)acetate (1.0 g, 2.76 mmol) in anhydrous THF (10 ml) was added dropwise to the mixture over 20 min. The mixture was stirred at −78° C. for 30 min, and a solution of n-benzyl-benzenesulfonyloxaziridine (860 mg, 3.25 mmol) in anhydrous THF (7 ml) was added dropwise over 30 min. The mixture was stirred at −78° C. for one hr, was quenched with a saturated aqueous ammonium chloride solution, and was extracted with ether. The organic layer was washed with water and saturated brine, was dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. The residue was chromatographed on silica gel column (hexane:ethyl acetate=93:7) to give the title compound as a yellow oil (650 mg, yield 63%).
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:11]([CH2:18][C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([F:28])[CH:26]=4)[N:21]([CH2:29][C:30]([OH:32])=[O:31])[C:20]=3[CH3:33])=[N:12][C:13](SC)=[N:14][CH:15]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C>[Ni].O>[C:1]1([S:7]([C:10]2[C:11]([CH2:18][C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([F:28])[CH:26]=4)[N:21]([CH2:29][C:30]([OH:32])=[O:31])[C:20]=3[CH3:33])=[N:12][CH:13]=[N:14][CH:15]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CSc1ncc(S(=O)(=O)c2ccccc2)c(Cc2c(C)n(CC(=O)O)c3ccc(F)cc23)n1
Agent: [Ni]
Solvent: CCO
Solvent: O
Product: Cc1c(Cc2ncncc2S(=O)(=O)c2ccccc2)c2cc(F)ccc2n1CC(=O)O
Temperature: 60 °C
Reaction time: 0.75 h
Yield: 32 %

Procedure:
A mixture of [3-(5-benzenesulfonyl-2-methylsulfanylpyrimidin-4-ylmethyl)-5-fluoro-2-methylindol-1-yl]acetic acid (0.20 g), ethanol (12 mL) and water (12 mL) was treated with Raney Nickel 2800 (0.050 g), and the resulting reaction mixture was stirred at 60° C. for 45 minutes. The mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified by preparative reverse-phase HPLC, eluting with a mixture of acetonitrile and water (1:19 to 49:1 by volume) to afford the title compound as an off-white solid (0.058 g).
Reaction SMILES: N1C2C(=CC=CC=2)C=C1.[CH2:10]([N:18]1[C:26]2[C:21](=[C:22]([CH3:41])[C:23]([CH2:35][C:36]([O:38]CC)=[O:37])=[C:24]([CH3:34])[C:25]=2[NH:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])[CH:20]=[CH:19]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[OH-].[Na+]>CCO.O>[CH2:10]([N:18]1[C:26]2[C:21](=[C:22]([CH3:41])[C:23]([CH2:35][C:36]([OH:38])=[O:37])=[C:24]([CH3:34])[C:25]=2[NH:27][C:28](=[O:33])[C:29]([CH3:30])([CH3:31])[CH3:32])[CH:20]=[CH:19]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCn1ccc2c(C)c(CC(=O)OCC)c(C)c(NC(=O)C(C)(C)C)c21
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc2[nH]ccc2c1
Solvent: O
Solvent: CCO
Product: CCCCCCCCn1ccc2c(C)c(CC(=O)O)c(C)c(NC(=O)C(C)(C)C)c21
Temperature: 60 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
0.70·1.10 (3H, br-t, —(CH2)7CH3), 1.10- 1.70 (15H, m, —CH2 CH3, —(CH2)6CH3), 1.38 (9H, s, —C(CH3)3), 2.21 (3H, s, —CH3), 2.47 (3H, s, —CH3), 3.79 (2H, m, —CH2 CO2—), 3.90·4.30 (4H, m, —CH2 CH3, >NCH2—), 6.42 (1H, t, J=3.5 Hz, Indole C3—H), 6.91 (1H, t, J=3.5 Hz, Indole C2—H), 7.12 (1H, br, —CONH—). (3) N-(1-Octyl-5-ethoxycarbonylmethyl-4,6-dimethylindol-7-yl)-2,2-dimethylpropanamide (3.5 g) was dissolved in EtOH (50 ml), and a solution of NaOH (1.6 g) in water (20 ml) was added, which was followed by stirring at 60° C. for 1 hr. EtOH was evaporated under reduced pressure, and the residue was dissolved in water (20 ml), and washed with AcOEt (10 ml). The aqueous layer was neutralized with 2N HCl and extracted with AcOEt (50 ml). The AcOEt layer was washed successively with saturated brine and dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure to give 2.0 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:27]3[N:31]([CH3:32])[CH:30]=[N:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[OH:20])[CH:8]=2)[N:3]=1.[CH3:33][NH2:34].[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>CCO.CN(C=O)C>[Cl:1][C:2]1[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:10]([NH:34][CH3:33])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:27]3[N:31]([CH3:32])[CH:30]=[N:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[OH:20])[CH:8]=2)[N:3]=1.[C:37]([OH:39])([C:36]([F:41])([F:40])[F:35])=[O:38]
Reactant: CN
Reactant: Cn1cncc1C(O)(c1ccncc1)c1ccc2nc(Cl)c(-c3ccccc3)c(Cl)c2c1
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CNc1c(-c2ccccc2)c(Cl)nc2ccc(C(O)(c3ccncc3)c3cncn3C)cc12
Temperature: 80 °C

Procedure:
A mixture of (2,4-dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)pyridin-4-ylmethanol (28 mg, 0.0607 mmol, Example 16), 33% MeNH2 in EtOH (0.8 mL), and trifluoroacetic acid (0.050 mL, 0.653 mmol) was heated at 80° C. for 17 hours. After cooling to room temperature, the mixture was diluted with DMF and purified by reverse phase HPLC (water/acetonitrile/0.1% TFA) to give the title compound. 1H NMR (400 MHz, MeOH-d4) δ 9.08 (s, 1H), 8.74-8.83 (m, 2H), 8.49 (d, J=1.71 Hz, 1H), 7.98 (dt, J=1.93, 6.91 Hz, 3H), 7.86 (d, J=8.80 Hz, 1H), 7.47-7.55 (m, 3H), 7.35-7.46 (m, 2H), 7.25 (d, J=1.47 Hz, 1H), 3.69 (s, 3H), 2.58 (s, 3H); MS m/e 456.1 [M+H]+.