Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[C:22]2[C@@H:21]3[C@@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16](=[O:23])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([O:24]C(=O)C)[CH:6]=1)(=O)C.C(Cl)Cl.CO.Cl(O)(=O)(=O)=O>C(OCC)(=O)C>[OH:4][C:5]1[C:22]2[C@@H:21]3[C@@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16](=[O:23])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([OH:24])[CH:6]=1
Reactant: CC(=O)Oc1cc2c(c(OC(C)=O)c1)[C@H]1CC[C@]3(C)C(=O)CC[C@H]3[C@H]1CC2
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@]12CC[C@@H]3c4c(O)cc(O)cc4CC[C@@H]3[C@@H]1CCC2=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 3 g. of 1,3-diacetoxy-8α-estra-1,3,5(10)-trien-17-one in 9 ml. of methylene chloride and 18 ml. of methanol is combined at 0° C. and under nitrogen with 0.23 ml. of perchloric acid (70%) in 1 ml. of methanol; the mixture is then agitated for 3 days at room temperature. Then, the mixture is diluted with ethyl acetate and washed neutral with saturated sodium chloride solution. After drying and evaporation, 2.9 g. of 1,3-dihydroxy-8α-estra-1,3,5(10)-trien-17-one is obtained as an oily substance.
Reaction SMILES: [F:1][CH:2]([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]([O:17]CC)=[O:16])[N:12]=[N:11]2)=[CH:6][CH:5]=1.CO.O.O.[OH-].[Li+]>C1COCC1>[F:20][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[N:12]=[N:11]2)=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1cn(-c2ccc(OC(F)F)cc2)nn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cn(-c2ccc(OC(F)F)cc2)nn1
Temperature: 70 °C
Yield: 107.8 %

Procedure:
To a solution of ethyl 1-(4-(difluoromethoxy)phenyl)-1H-1,2,3-triazole-4-carboxylate (600 mg, 2.12 mmol) in a mixture of THF (7 ml), methanol (7 ml) and water (7 ml) was added lithium hydroxide hydrate (267 mg, 6.36 mmol). The solution was heated to 70° C. for 3 h. Most of the organic solvent was removed under reduced pressure. Water was added and the solution was extracted with methyl tert-butyl ether to remove non-acid material. Then 25% aq. hydrochloric acid was added to reach acidic pH. The product precipitated and the mixture was extracted three times with ethyl acetate. The organic layers were combined, dried (MgSO4) and evaporated to yield a light yellow solid (583 mg, 99%). MS (ISP): 253.9 ([M−H]+); 509.2 ([2M−H]+).
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].[CH3:22][O:23][C:24]1[CH:25]=C([CH:29]=[C:30]([O:32][CH3:33])[CH:31]=1)CN>>[CH3:22][O:23][C:24]1[CH:25]=[C:2]([CH:29]=[C:30]([O:32][CH3:33])[CH:31]=1)[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: NCCNC(=O)c1sccc1Nc1ccnc2[nH]ccc12
Reactant: COc1cc(CN)cc(OC)c1
Product: COc1cc(CNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)cc(OC)c1

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 3,5-dimethoxybenzylamine instead of tert-butyl-2-amino ethyl carbamate. LCMS (ESI) 409 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.53 (1H, br. s.) 10.30 (1H, s) 8.65 (1H, t, J=5.95 Hz) 8.03 (1H, d, J=5.42 Hz) 7.80 (1H, d, J=5.42 Hz) 7.50 (1H, d, J=5.42 Hz) 7.30 (1H, dd, J=3.32, 2.20 Hz) 6.84 (1H, d, J=5.47 Hz) 6.48 (2H, d, J=2.25 Hz) 6.42 (1H, dd, J=3.44, 1.44 Hz) 6.37 (1H, t, J=2.27 Hz) 4.39 (2H, d, J=6.00 Hz) 3.70 (6H, s)
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.O.OS([O-])(=O)=O.[K+]>CS(C)=O>[CH:1]1([CH2:7][C@@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:16])([CH3:15])[CH3:17])[CH:9]=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)CC1CCCCC1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](C=O)CC1CCCCC1
Temperature: 0 °C

Procedure:
A solution of Example 1A (25.8 g,100 mmol), sulfur trioxide pyridine complex (79.6 g, 500 mmol), and triethylamine (69.7 mL, 500 mmol) in DMSO (70 mL) at room temperature was stirred for 30 minutes, cooled to 0° C., treated with water and saturated aqueous KHSO4, and extracted with ethyl acetate. The extract was washed with saturated aqueous KHSO4 and brine, dried (MgSO4), filtered, and concentrated to provide the desired product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:41])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=3)[N:15]([CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[CH:36]=[CH:37][C:38]([OH:40])=[O:39])=[CH:6][CH:5]=1>CO.[Pt]>[CH3:1][O:2][C:3](=[O:41])[C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=3)[N:15]([CH:23]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(OCCc2c(C=CC(=O)O)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Agent: [Pt]
Solvent: CO
Product: COC(=O)c1ccc(OCCc2c(CCC(=O)O)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reaction time: 24 h
Yield: 79.7 %

Procedure:
400 mg of 4-{2-[1-Benzhydryl-2-(2-carboxy-vinyl)-5-chloro-1H-indol-3-yl]-ethoxy}-benzoic acid methyl ester (0.0007M, 1 eq.) was dissolved in 15 mL of methanol. To the solution, 80 mg of 5% platinum on activated carbon was added as a slurry in 5 mL of methanol. The black suspension was placed under a hydrogen atmosphere via a balloon and stirred for 24 hrs. at room temperature. The hydrogen was evacuated and another 80 mg of 5% platinum on activated carbon in 5 mL of methanol was added and the reaction was again placed under a hydrogen atmosphere via a balloon and stirred for another 24 hrs. at room temperature. The reaction was monitored via NMR and at this point complete conversion was indicated. The reaction was filtered through Celite and the filtrate was evaporated to give 4-{2-[1-Benzhydryl-2-(2-carboxy-ethyl)-5-chloro-1H-indol-3-yl]-ethoxy}-benzoic acid methyl ester as a yellow-green solid (320 mg, 79% yield).
Reaction SMILES: [CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=3)=O)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[CH3:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42]N)=[CH:38][CH:37]=1>>[CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]3[C:40]4[C:39](=[CH:38][CH:37]=[C:36]([CH3:35])[CH:41]=4)[NH:42][C:22]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: Cc1ccc(NN)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc([N+](=O)[O-])c3)CC2)c1
Agent: Cl
Product: Cc1ccc2[nH]c(-c3cccc([N+](=O)[O-])c3)c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-(3-{1-[5-(3-nitrophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)propanamide and 4-methylphenylhydrazine hydrochloride: ESMS m/e: 539.2 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)=[O:3].[C:14](N1C=CN=C1)(N1C=CN=C1)=O.CO>C1COCC1>[CH3:14][O:12][C:11](=[O:13])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([S:2]([CH3:1])=[O:3])[CH:5]=1
Reactant: CS(=O)c1cccc(CC(=O)O)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)Cc1cccc(S(C)=O)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 81.4 %

Procedure:
A solution of [3-(methylsulfinyl)phenyl]acetic acid (1.31 g, 6.60 mmol) and carbonyldiimidazole (1.18 g, 7.26 mmol) in 25.0 mL THF was stirred at room temperature for 15 minutes, then methanol (2.1 mL, 52.8 mmol) was added. After 10 minutes the reaction was briefly warmed to near reflux temperature, then allowed to cool to room temperature. After 20 minutes, the reaction was partitioned between EtOAc and NaHCO3/brine mixture. The EtOAc layer was washed with dilute brine, dilute HCl solution, brine, dried with anhydrous Na2SO4 and rotary evaporated to give the title compound as a yellow-orange oil (1.14 g, 82%).
Reaction SMILES: [CH2:1]([N:8]([CH2:12][Si](C)(C)C)[CH2:9]OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1([C@H:23]2[CH2:27][O:26][C:25](=[O:28])[N:24]2[C:29](=[O:38])/[CH:30]=[CH:31]/[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.ClCCl>[CH2:1]([N:8]1[CH2:12][C@H:31]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C@@H:30]([C:29]([N:24]2[C@@H:23]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:27][O:26][C:25]2=[O:28])=[O:38])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=C(/C=C/c1ccccc1)N1C(=O)OC[C@@H]1c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C1OC[C@H](c2ccccc2)N1C(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccccc1
Reaction time: 0.33 h
Yield: 64.7 %

Procedure:
N-Benzyl-N-(methoxymethyl)trimethylsilylmethylamine (10.03 g, 40.5 mmol) was added to (S)-4-phenyl-3-[(E)-(3-phenyl-acryloyl)]-oxazolidin-2-one (10.3 g, 35.1 mmol) in toluene (150 mL) at 0° C. and stirred for 20 minutes. Trifluoroacetic acid (9.7 mL) in dichloromethane (125 mL) was added dropwise to the reaction mixture keeping the internal temperature at 0° C. The reaction was stirred at room temperature overnight. The reaction mixture was poured into saturated sodium bicarbonate (200 mL) and extracted with dichloromethane (2×75 mL). The combined organic phases were washed with brine and dried over sodium sulfate. The organic phases were concentrated to give a waxy solid, which was purified by flash silica gel chromatography eluting with ethyl acetate:hexanes (1:9) to give 9.68 g (61%) of (S)-3-((3R,4S)-1-benzyl-4-phenyl-pyrrolidine-3-carbonyl)-4-phenyl-oxazolidin-2-one.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:5]=1[C:6](=[O:19])[CH:7]1[CH:12]([C:13]2=[O:18])CC=CC1)([O-:3])=[O:2].C=CC=C.[N+:24]([C:27]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:28]=1[C:29](=O)[CH:30]=[CH:31][C:32]2=O)([O-:26])=[O:25]>>[N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:5]=1[C:6](=[O:19])[CH:7]=[CH:12][C:13]2=[O:18])([O-:3])=[O:2].[N+:24]([C:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[CH:35][CH:36]=1)([O-:26])=[O:25]
Reactant: O=C1c2cccc([N+](=O)[O-])c2C(=O)C2CC=CCC12
Agent: C=CC=C
Agent: O=C1C=CC(=O)c2c1cccc2[N+](=O)[O-]
Product: O=[N+]([O-])c1cccc2ccccc12

Procedure:
The starting 5-nitro-1,4,4a,9a-tetrahydroanthraquinone of formula II is known and can be prepared e.g. by Diels-Alder reaction of butadiene with 5-nitro-1,4-naphthoquinone. 5-Nitro-1,4-naphthoquinone can in turn be obtained e.g. by electrolytic oxidation of 1-nitronaphthalene or by nitration of 1,4-naphthoquinone.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1.N([O-])=O.[Na+].[BrH:14]>O>[Br:14][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1
Reactant: Cc1ccc(N)cc1O
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(Br)cc1O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 20 %

Procedure:
5-Amino-2-methylphenol (5 g, 0.04 mol) was dissolved in HBr (20 mL) and H2O (20 mL) was added dropwise maintaining a temperature below 0° C. The resulting mixture was stirred for 5 min and a solution of NaNO2 (2.76 g, 0.04 mol) in H2O (7.5 mL) was added dropwise. The mixture was stirred for 30 min below 0° C. Then a solution of cuprous bromide (5.73 g, 0.04 mol) in HBr (7.5 mL) cooled to 0° C. was added dropwise. The resulting mixture was warmed to RT and then refluxed for 2 h. The reaction was cooled and filtered through celite. The filtrate was diluted with water and extracted with EtOAc. The organic extract was dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (2.5% EtOAc-97.5% Hexane) to give the pure title compound (1.57 g, 20%). 1H NMR (500 MHz, CDCl3): δ 6.97 (s, 3H), 4.89 (s, 1H), 2.19 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[CH:12]=[CH:11][N:10]=[C:9]1[N:13]1[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]1.[C:20]1([C:26]#[C:27][C:28](O)=[O:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C>ClCCCl>[C:20]1([C:26]#[C:27][C:28]([NH:19][CH:16]2[CH2:17][CH2:18][N:13]([C:9]3[S:8][CH:12]=[CH:11][N:10]=3)[CH2:14][CH2:15]2)=[O:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NC1CCN(c2nccs2)CC1
Reactant: O=C(O)C#Cc1ccccc1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(C#Cc1ccccc1)NC1CCN(c2nccs2)CC1
Yield: 51.2 %

Procedure:
A solution of 500 mg (1.68 mmol) 1-(thiazol-2-yl)piperidin-4-amine trifluoroacetate, 332 mg (2.02 mmol) 3-phenylpropiolic acid and 1.17 ml DIPEA in DCE (20 ml) was stirred for 5 h at RT. Subsequently, the reaction solution was washed with water and a sat. aqueous Na2CO3 soln and dried over MgSO4. After filtering and concentration in vacuo, column chromatography (SiO2, chloroform) was performed on the residue, yielding 267 mg (0.86 mmol, 51%) 3-phenyl-N-(1-(thiazol-2-yl)piperidin-4-yl)propiolamide. MS [MH+] 312.1
Reaction SMILES: [F:1][C:2]1[CH:32]=[C:31]([N+:33]([O-])=O)[CH:30]=[CH:29][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[N:16][C:17](=[O:28])[N:18]([CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:19]=3)[S:13][C:6]=12.[NH4+].[Cl-]>C(O)C.O.[Fe]>[NH2:33][C:31]1[CH:30]=[CH:29][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]3[CH:11]=[C:12]([C:14]4[CH:15]=[N:16][C:17](=[O:28])[N:18]([CH2:20][CH2:21][N:22]5[CH2:23][CH2:24][O:25][CH2:26][CH2:27]5)[CH:19]=4)[S:13][C:6]=23)=[C:2]([F:1])[CH:32]=1
Reactant: O=c1ncc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)cn1CCN1CCOCC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(Oc2ccnc3cc(-c4cnc(=O)n(CCN5CCOCC5)c4)sc23)c(F)c1
Temperature: 80 °C
Reaction time: 0.75 h

Procedure:
To a solution the compound 415 (81 mg, 0.16 mmol) in ethanol (1 mL) and water (0.5 mL) was added NH4Cl (9 mg, 0.16 mmol) and iron powder (73 mg, 1.30 mmol). The mixture was stirred at 80° C. for 45 min, filtered through celite, and the solvent was evaporated to give title compound (416). MS (m/z): 468.1 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]=[C:12]([NH:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[NH:13][C:14]1[C:23]([CH3:24])=[C:22]2[C:17]([CH:18]=[CH:19][CH:20]=[N:21]2)=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[C:37]1C(C)=C2C(C=CC=N2)=CC=1.C(N=C(S)N(C(OCC1C=CC=CC=1)=O)C(OCC1C=CC=CC=1)=O)C>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]=[C:12]([NH:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[NH:13][C:14]1[C:23]([CH2:24][CH3:37])=[C:22]2[C:17]([CH:18]=[CH:19][CH:20]=[N:21]2)=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(NC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)ccc2cccnc12
Reactant: Cc1c(N)ccc2cccnc12
Agent: CCN=C(S)N(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1c(NC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)ccc2cccnc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7-[N2,N3-Bis(benzyloxycarbonyl)guanidino]-8-methylquinoline. To a pale yellow solution of 500 mg of 7-amino-8-methylquinoline in 20 mL of tetrahydrofuran are added 1.18 g of ethyl N,N-bis(benzyloxy-carbonyl)pseudothiourea and 1.01 g of mercuric acetate and the mixture is stirred at room temperature for 1 hour. The suspension is diluted with ethyl acetate and the organic layer is washed with water followed by brine. The aqueous layers are extracted with ethyl acetate; the combined organic layers are dried over magnesium sulfate, filtered and rotary evaporated. The residue is purified by flash column chromatography on silica gel, eluting with 50% ethyl acetate/hexanes and recrystallization from hexanes/methylene chloride to provide 1.257 g of 7-[N2,N3-bis(benzyloxycarbonyl)guanidino]-8-ethylquinoline as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[C:5]([Cl:10])=[CH:4][N:3]=1.[N+:11]([C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=O)=[CH:16][CH:15]=1)([O-])=O>>[Cl:10][C:5]1[C:6]([Cl:9])=[C:7]2[NH:8][C:18]([C:17]3[CH:21]=[CH:22][C:14]([NH2:11])=[CH:15][CH:16]=3)=[N:1][C:2]2=[N:3][CH:4]=1
Reactant: Nc1ncc(Cl)c(Cl)c1N
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Product: Nc1ccc(-c2nc3ncc(Cl)c(Cl)c3[nH]2)cc1

Procedure:
By at procedure similar to Examples 258 and 259 but starting from 2,3-diamino-4,5-dichloropyridine (Example 206a) and 4-nitrobenzoyl chloride, the title compound was obtained.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[N:10]=[C:9]([NH2:11])[CH:8]=[CH:7][N:6]=1.Cl[C:13]1[S:14][C:15]([C:18]#[N:19])=[CH:16][N:17]=1>C1COCC1>[CH3:3][O:4][C:5]1[N:10]=[C:9]([NH:11][C:13]2[S:14][C:15]([C:18]#[N:19])=[CH:16][N:17]=2)[CH:8]=[CH:7][N:6]=1
Reactant: N#Cc1cnc(Cl)s1
Reactant: COc1nccc(N)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1nccc(Nc2ncc(C#N)s2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A flame dried flask under argon (g) was charged with sodium hydride (33 mg, 60% dispersion, 0.83 mmol) and 1.5 mL anhydrous THF. 2-Methoxy-pyrimidin-4-ylamine (26 mg, 0.21 mmol) was added slowly. After the resulting bubbling ceased, 2-chloro-thiazole-5-carbonitrile (30 mg, 0.21 mmol) was added and the reaction was heated to reflux. After 2 hours, the reaction was cooled to room temperature, the THF was removed in vacuo, and the mixture was diluted with water and adjusted to pH 7 with 1M HCl (aq). The resulting precipitate was filtered, washed with water and air dried. The resulting solid was purified by flash column chromatography (eluted with a gradient 85:15 hexane/EtOAc to EtOAc) to give a pure sample of the title compound. 1H-NMR (300 MHz, DMSO-d6) 12.61 (s, 1H), 8.36 (d, 1H, J=6.4 Hz), 6.73 (d, 1H, J=5.6 Hz), 4.02 (s, 3H). mp>250.
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[C:10]([C:16]([OH:18])=O)[NH:11]3)[CH2:4][CH2:3][CH2:2]1.[NH2:19][CH:20]1[CH2:25][CH2:24][C:23]([CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][C@H:32]([OH:35])[C@@H:31]([CH3:36])[CH2:30]2)([OH:26])[CH2:22][CH2:21]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[OH:26][C:23]1([CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][C@H:32]([OH:35])[C@@H:31]([CH3:36])[CH2:30]2)[CH2:24][CH2:25][CH:20]([NH:19][C:16]([C:10]2[NH:11][C:12]3[C:8]([CH:9]=2)=[C:7]([O:6][CH2:5][CH:1]2[CH2:2][CH2:3][CH2:4]2)[CH:15]=[CH:14][CH:13]=3)=[O:18])[CH2:21][CH2:22]1
Reactant: O=C(O)c1cc2c(OCC3CCC3)cccc2[nH]1
Reactant: C[C@H]1CN(CCC2(O)CCC(N)CC2)CC[C@@H]1O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(CCC2(O)CCC(NC(=O)c3cc4c(OCC5CCC5)cccc4[nH]3)CC2)CC[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-cyclobutylmethoxy-1H-indole-2-carboxylic acid (16a) (140 mg, 0.383 mmol), (3S,4S)-1-[2-(4-amino-1-hydroxy-cyclohexyl)-ethyl]-3-methyl-piperidin-4-ol (14) (103 mg, 0.421 mmol) and DIEA (0.263 ml, 1.532 mmol) in 5 ml of DMF is treated with solid TBTU (139 mg, 0.421 mmol). The mixture is stirred for 2 h at rt and then evaporated. The crude residue is dissolved in EtOAc and extracted with 1M-HCl. The aqueous layer is separated, its pH adjusted to 14 and extracted 3-times with DCM. The organic layers are dried over sodium sulphate and evaporated. The crude product is then purified by chromatography on silicagel using methanol and DCM (saturated with ammonia) from 1:99 to 5:95.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:23])=[C:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[NH:9][C:10]=1[CH:11]=[CH:12][CH2:13][CH2:14][Br:15])=[O:5])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:23])=[C:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[NH:9][C:10]=1[CH2:11][CH2:12][CH2:13][CH2:14][Br:15])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C=CCCBr)[nH]c(C(=O)OC(C)(C)C)c1C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1c(CCCCBr)[nH]c(C(=O)OC(C)(C)C)c1C
Yield: 67.6 %

Procedure:
5-(4-Bromo-but-1-enyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 60b (30 mg, 0.08 mmol) was dissolved in 3 ml of ethanol under stirring, and added with palladium on activated carbon (6 mg, 5%) to the solution at room temperature. The reaction mixture was stirred for 45 minutes under a hydrogen atmosphere. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was filtered, concentrated under reduced pressure to obtain the title compound 5-(4-bromo-butyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 60c (21 mg, yield 70%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7](I)=[C:6]([O:11][CH2:12][C:13]([CH3:15])=[CH2:14])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>CN(C=O)C.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[C:13]([CH2:15][C:27]3[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=3)([CH3:14])[CH2:12][O:11][C:6]=2[CH:5]=1)=[O:16]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: C=C(C)COc1cc(C(=O)OC)ccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)OCC2(C)Cc1ccc(Cl)cc1
Yield: 36.9 %

Procedure:
A solution of 4-Iodo-3-(2-methyl-allyloxy)-benzoic acid methyl ester (455 mg, 1.37 mmol) in DMF (15 mL) were added Potassium carbonate (379 mg, 2.74 mmol), Tetrabutylammonium chloride (380 mg, 1.37 mmol), Palladium acetate (25.6 mg, 0.136 mmol) in DMF (5 mL) and 4-Chlorophenylboronic acid, (256 mg, 1.64 mmol) was submitted to microwave irradiation at 140° C. for 21 minutes. The resulting mixture was filtered over silica, washed with water, dried over MgSO4 and concentrated. Column chromatography (silica gel, heptane/CH2Cl2: 5/5) afforded 160 mg (37%) of the title compound as a slightly brown oil.
Reaction SMILES: [C:1]([Si:5]([CH3:63])([CH3:62])[O:6][C@H:7]1[C@@H:11]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C@H:10]([N:20]2[CH:25]=[CH:24][C:23](=[O:26])[N:22]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[C:21]2=[O:36])[O:9][C@@H:8]1[C@@H:37]([OH:61])[C@H:38]([N:46](CC1C=CC=CC=1)CC1C=CC=CC=1)[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[NH2:46][C@@H:38]([C@@H:37]([C@@H:8]1[C@@H:7]([O:6][Si:5]([C:1]([CH3:2])([CH3:3])[CH3:4])([CH3:63])[CH3:62])[C@@H:11]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:14])[CH3:15])[C@H:10]([N:20]2[CH:25]=[CH:24][C:23](=[O:26])[N:22]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[C:21]2=[O:36])[O:9]1)[OH:61])[C:39]([O:41][C:42]([CH3:44])([CH3:43])[CH3:45])=[O:40]
Reactant: COc1ccc(Cn2c(=O)ccn([C@@H]3O[C@H]([C@@H](O)[C@@H](C(=O)OC(C)(C)C)N(Cc4ccccc4)Cc4ccccc4)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(Cn2c(=O)ccn([C@@H]3O[C@H]([C@@H](O)[C@H](N)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Yield: 20.7 %

Procedure:
tert-Butyl (2S,3S)-3-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl-(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)-tetrahydro-2-furanyl]-2-(dibenzylamino)-3-hydroxy-propanoate (850 mg, 0.942 mmole, obtained from Reference Example 4) was hydrogenated using 10% palladium on carbon in methanol (10 ml) under atmospheric pressure. The catalyst was removed and the volatile was removed in vacuo. The residue was chromatographed (flash column, silica gel, methylene chloride:methanol:diethyl ether=95:2:3) to give the recovered starting material (248 mg, 29%) and tert-butyl (2S,3S)-2-amino-3-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl-(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)-tetrahydro-2-furanyl]-3-hydroxypropanoate (141 mg, 21%) as a white amorphous solid.