Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.S(Cl)([Cl:14])=O.[OH-].[Na+]>>[F:1][C:2]1[C:3]([C:9]([Cl:14])=[O:11])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(O)c1ncc(Cl)cc1F
Reactant: O=S(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(Cl)c1ncc(Cl)cc1F
Temperature: 90 °C
Reaction time: 5 h

Procedure:
71.38 g of 3-fluoro-5-chloro-2-pyridinecarboxylic acid (Example P4) are placed in a round-bottomed flask and heated to 90° C. 59 ml of thionyl chloride are added dropwise from a dropping funnel over a period of 30 minutes, and the gas formed is introduced into sodium hydroxide solution. Stirring is then carried out for 5 hours at 100° C., after which the thionyl chloride is distilled off at normal pressure. After the addition of 50 ml of dry toluene, 20 ml thereof are distilled off. The resulting solution is poured into 200 ml of n-hexane and stirred overnight. After cooling in an ice-bath, the mixture is filtered and the filtration residue is washed twice with n-hexane. 68.7 g of the desired compound are obtained in the form of a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]([NH2:19])=O)[CH2:11][CH2:10]1.B.O1CCCC1.Cl.[OH-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][NH2:19])[CH2:13][CH2:14]1
Reactant: COc1ccccc1N1CCN(CCC(N)=O)CC1
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccccc1N1CCN(CCCN)CC1
Temperature: 67 °C
Yield: 87.7 %

Procedure:
3-[4-(2-Methoxyphenyl)piperazin-1-yl]propionamide (3 g, 11.4 mmol) was suspended in 30 mL of freshly distilled THF and borane-tetrahydrofuran complex (17.5 mL, 1M in THF, 17.5 mmol) was added at a rate such that the reaction temperature remained below 26° C. The mixture was stirred at gentle reflux (67° C.) for 6.5 hours, with additional borane-tetrahydrofuran complex (6 mL, 4 mL and 4 mL) added after 1, 3.5 and 5 hours, respectively. The mixture was cooled to 22° C. and then hydrochloric acid (20 mL, 6N, 120 mmol) was added at a rate such that the reaction temperature did not exceed 35° C. The mixture was heated at reflux for 20 minutes and cooled to room temperature and then 50% sodium hydroxide was added at a rate such that the reaction temperature did not exceed 60° C. The aqueous layer was separated and extracted with THF (2×25 mL). The combined organic layers were dried (K2CO3) and filtered. The filtrate was concentrated under reduced pressure to give 3-[4-(2-methoxyphenyl)-piperazin-1-yl]propylamine (2.5 g, 10 mmol) as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:24])=[CH:4][C:5]([Cl:23])=[C:6]([NH:8][CH:9]([CH3:22])[C:10]([O:12][CH:13]2[CH:17]([O:18][C:19](=[O:21])[CH3:20])[CH2:16][O:15][CH2:14]2)=[O:11])[CH:7]=1.[C:25]1(=O)[O:30][C:28](=[O:29])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.C(O)(=O)C>O>[Cl:23][C:5]1[CH:4]=[C:3]([F:24])[C:2]([N:1]2[C:28](=[O:29])[C:27]3=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]3[C:25]2=[O:30])=[CH:7][C:6]=1[NH:8][CH:9]([CH3:22])[C:10]([O:12][CH:13]1[CH:17]([O:18][C:19](=[O:21])[CH3:20])[CH2:16][O:15][CH2:14]1)=[O:11]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(=O)OC1COCC1OC(=O)C(C)Nc1cc(N)c(F)cc1Cl
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)OC1COCC1OC(=O)C(C)Nc1cc(N2C(=O)c3ccccc3C2=O)c(F)cc1Cl
Yield: 89.8 %

Procedure:
A mixture of 1.62 g of 4-acetoxytetrahydrofuran-3-yl 2-[(5-amino-2-chloro-4-fluorophenyl)amino]propionate, 0.80 g of phthalic anhydride, and 10 ml of acetic acid was heated under reflux for 3 hours while stirring. Water was added to the reaction mixture, and the semi-solid formed was collected by filtration, dissolved in ethyl acetate, washed successively with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate-hexane=2:3) to give 1.98 g of the title compound (Table 1, Compound No. 32).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:12]=[C:13]([CH2:17][C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])[CH:14]=[CH:15][CH:16]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:26]1([N:36]=[C:37]=[O:38])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1>C(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:37]([NH:36][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28][CH:27]=2)=[O:38])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C:18]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[O:19])[CH:12]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(N)n(-c2cccc(CC(=O)N3CCOCC3)c2)n1
Reactant: O=C=Nc1cccc2ccccc12
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc3ccccc23)n(-c2cccc(CC(=O)N3CCOCC3)c2)n1

Procedure:
A mixture of Example L (0.2 g, 0.58 mmol) and 1-naphthylisocyanate (0.10 g, 0.6 mmol) in dry CH2Cl2 (4 ml) was stirred at RT under N2 for 18 h. The solvent was removed in vacuo and the crude product was purified by column chromatography using ethyl acetate/hexane/CH2Cl2 (3/1/0.7) as the eluent (0.11 g, off-white solid) to yield 1-{3-tert-butyl-1-[3-(2-morpholino-2-oxoethyl)phenyl]-1H-pyrazol-5-yl}-3-(naphthalene-1-yl)urea. mp: 194-196; 1H NMR (200 MHz, DMSO-d6): δ 9.07 (1H, s), 8.45 (s, 1H), 8.06-7.93 (m, 3H), 7.69-7.44 (m, 7H), 7.33-7.29 (d, 6.9 Hz, 1H), 6.44 (s, 1H), 3.85 (m, 2H), 3.54-3.45 (m, 8H), 1.31 (s, 9H); MS:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([C:9]2[CH2:10][NH:11][CH2:12][CH2:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.[CH:17](I)([CH3:19])[CH3:18]>[Ag]=O.CC(C)=O>[CH:17]([N:11]1[CH2:12][CH2:13][CH:14]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=2)[CH2:10]1)([CH3:19])[CH3:18]
Reactant: CC(C)I
Reactant: FC(F)(F)c1cccc(C2=CCCNC2)c1
Agent: O=[Ag]
Solvent: CC(C)=O
Product: CC(C)N1CCC=C(c2cccc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 2.2 g of 3-(3-trifluoromethyl-phenyl)-1,2,5,6-tetrahydropyridine, 18 ml of acetone, 1.18 g of silver oxide and 1.4 ml of isopropyl iodide was stirred for 12 hours at room temperature and after the addition of 0.7 ml of isopropyl iodide and 0.5 g of silver oxide, the mixture was stirred another 3 hours at room temperature and was filtered. The filtrate was evaporated to dryness to obtain 2.9 g of raw product which was chromatographed over silica gel. Elution with an 85-10-5 cyclohexane-chloroform-triethylamine mixture yielded 2.21 g of 1-isopropyl-3-(3-trifluoromethyl-phenyl)-1,2,5,6-tetrahydropyridine in the form of a yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[CH:23][CH:22]=3)[S:18][C:19]=2[CH3:20])=[CH:8][C:7]=1[CH3:33].[OH-:35].[Na+].Cl>O1CCCC1.C(OCC)(=O)C>[CH3:33][C:7]1[CH:8]=[C:9]([O:12][CH2:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[CH:23][CH:22]=3)[S:18][C:19]=2[CH3:20])[CH:10]=[CH:11][C:6]=1[CH2:5][CH2:4][C:3]([OH:34])=[O:2].[C:9]([O:12][CH2:13][CH3:14])(=[O:35])[CH3:8]
Reactant: COC(=O)CCc1ccc(OCCc2nc(-c3ccc(-c4cccnc4)cc3)sc2C)cc1C
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(OCCc2nc(-c3ccc(-c4cccnc4)cc3)sc2C)ccc1CCC(=O)O

Procedure:
3-(2-Methyl-4-{2-[5-methyl-2-(4-pyridin-3-yl-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-propionic acid methyl ester (47 mg, 0.100 mmol) is dissolved in tetrahydrofuran (1 mL) and 5N sodium hydroxide (1 mL) solution is added at room temperature. The reaction is heated to reflux and monitored by HPLC. Upon complete conversion, the reaction is allowed to cool to room temperature and neutralized with 5N hydrochloric acid (1 mL), diluted with ethyl acetate, and extracted. The organic layer is washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The pure 3-(2-Methyl-4-{2-[5-methyl-2-(4-pyridin-3-yl-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-propionic acid (40 mg, 0.087 mmol) may also be obtained by recrystalization from ethyl acetate (87% yield). MS (ES): 459.2 (M++1). Alternatively, the acid may be obtained after reversed phase preparative HPLC as the hydrochloride salt.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14](Br)[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C(OCC)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=2)[C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([F:28])[CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)Nc1ccc(C(Br)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: OB(O)c1cccc(F)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)Nc1ccc(C(c2cccc(F)c2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reaction time: 3 h

Procedure:
To a solution of compound 88 (0.30 g, 0.625 mmoles) and tetrakis(triphenyl phosphine), palladium(0) (50 mg) in toluene (degassed, 5 mL) was added 3-fluorophenyl boronic acid (0.182 g, 1.3 mmoles) in ethanol (degassed, 5 mL) followed by 0.75 mL 2M Na2CO3 (aq) (1.5 mmoles). The reaction was allowed to proceed at 80° C. for 3 hrs under argon. The reaction was diluted with water and diethyl ether and vortexed. The organic phase was isolated and evaporated to give a crude product. The crude product was purified by silica gel chromatography (0-50% EtOAc in hexanes) to give the product (compound 92) as a white powder (0.166 g, 58% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].F[C:22]1[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([O:26][CH3:27])=[O:25])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccccc1F
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1N1CCCC(NC(=O)OC(C)(C)C)C1
Temperature: 130 °C
Reaction time: 8 h
Yield: 19.8 %

Procedure:
3-(tert-Butoxycarbonylamino)piperidine (7.07 g, 35.3 mmol) was dissolved in N,N-dimethylformamide (120 mL). To this solution, potassium carbonate (9.80 g, 70.9 mmol) and methyl 2-fluorobenzoate (5.0 mL, 39.2 mmol) were added and the mixture was stirred at 130° C. for 8 hours. Subsequently, the mixture was allowed to cool, diluted with ethyl acetate, and washed sequentially with water and brine. The washed product was dried over sodium sulfate and the solvent was evaporated. Purification of the resulting residue by silica gel column chromatography (hexane:ethyl acetate=10:1->5:1) gave 2.34 g (20%) of the desired compound as a yellow oil.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([NH2:23])=[CH:22][C:17]=3[N:16]=[C:15]2[CH2:24][CH3:25])=[CH:10][CH:9]=1)(=[O:4])[CH2:2][CH3:3].[CH3:26][S:27](Cl)(=[O:29])=[O:28].N1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[C:1]([O:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([NH:23][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:22][C:17]=3[N:16]=[C:15]2[CH2:24][CH3:25])=[CH:12][CH:13]=1)(=[O:4])[CH2:2][CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCC(=O)OCCc1ccc(-n2c(CC)nc3cc(N)ccc32)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=O)OCCc1ccc(-n2c(CC)nc3cc(NS(C)(=O)=O)ccc32)cc1
Reaction time: 6 h
Yield: 88 %

Procedure:
To a stirred solution of 2-[4-(5-amino-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl propionate (step 4, 1.18 g, 3.50 mmol) in dichloromethane (20 mL) was added methanesulfonyl chloride (0.40 mL, 5.25 mmol) and pyridine (0.42 mL, 5.25 mmol) at room temperature. After stirring for 6 h, the mixture was poured into 10% aqueous citric acid (100 mL) and extracted with ethyl acetate (100 mL). The aqueous layer was made basic with saturated aqueous sodium bicarbonate (100 mL) and extracted with ethyl acetate (100 mL). The combined organic extracts were washed with brine (100 mL) and dried (MgSO4), and concentrated to afford 1.28 g (88%) of the title compound as brown amorphous: 1H-NMR (CDCl3) δ 8.47 (1H, s), 7.66 (1H, d, J=1.7 Hz), 7.50 (2H, d, J=8.4 Hz), 7.42 (1H, dd, J=2.0, 8.8 Hz), 7.41 (2H, d, J=8.4 Hz), 7.09 (1H, d, J=8.8 Hz), 4.39 (2H, t, J=7.0 Hz), 3.09 (2H, t, J=6.8 Hz), 3.00 (2H, q, J=7.7 Hz), 2.36 (2H, q, J=7.7 Hz), 1.42 (3H, t, J=7.7 Hz), 1.15 (3H, t, J=7.5 Hz).
Reaction SMILES: C1COCC1.[C:6]1([C:12]([C:14]2[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=2)=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CO>C1(C)C=CC=CC=1>[C:6]1([C@H:12]([C:14]2[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=2)[OH:13])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: Cn1nccc1C(=O)c1ccccc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CO
Product: Cn1nccc1[C@H](O)c1ccccc1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-3,3-diphenyl-1-methylpyrrolidine[1,2-c]-1,3,2-oxazaborole 1M in toluene (7.5 ml, 7.5 mmol) cooled to -10° C., under an argon atmosphere, a solution of catecolborane 1M in THF (100 ml, 100 mmol) is added dropwise. To the resulting mixture a solution of phenyl-(1-methyl-1H-pyrazol-5-yl)ketone, III (9.30 g, 50 mmol) in dry toluene is added. Once the addition has been completed the mixture is stirred for 1 hour at -10° C. and then over night at room temperature. Next, MeOH (10 ml) is carefully added while stirring, which is maintained for 6 hours. The reaction mixture is concentrated to half the volume, washed successively with water and with a solution of saturated NaCl, dried and the solvent evaporated to yield an oil which is purified on a silicagel column, eluted with a mixture of ethyl acetate: petrol ether (7:3) to give (R)-(+)-phenyl-(1-methyl-1H-pyrazol-5-yl)methanol, (+)-II (7.82 g, 83%), whose optical purity as determined by chiral HPLC is 99%. M.p. 81-83° C.; [α]D =+16.6 (c=1.0, CHCl3).
Reaction SMILES: [F:1][CH:2]([F:11])[C:3](=O)[CH2:4][C:5](OCC)=[O:6].C(O)=O.[CH3:15][NH:16][NH2:17]>C(OC)(C)(C)C>[CH3:15][N:16]1[C:5]([OH:6])=[CH:4][C:3]([CH:2]([F:11])[F:1])=[N:17]1
Reactant: CCOC(=O)CC(=O)C(F)F
Reactant: CNN
Solvent: O=CO
Solvent: COC(C)(C)C
Product: Cn1nc(C(F)F)cc1O
Temperature: 5 °C
Reaction time: 20 h
Yield: 95 %

Procedure:
166 g (1 mol) of ethyl difluoroacetoacetate are initially charged in 500 ml of methyl tert-butyl ether, and 140 g of formic acid are added. After the mixture has been cooled to 5° C., 119 g of methylhydrazine are added in 40% aqueous solution. The mixture is stirred at 22° C. for a further 20 h. The phases are separated, and the organic phase is washed with 200 ml of water and dried over MgSO4. After the solvent has been removed under reduced pressure, 148 g of the product are obtained as a yellow solid with an m.p. of 133° C. and a purity of 95%. Yield 95%.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][C:5]1[N:6]=[C:7]([C:14]([NH2:16])=O)[N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12>P(Cl)(Cl)(Cl)=O>[F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][C:5]1[N:6]=[C:7]([C:14]#[N:16])[N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12
Reactant: NC(=O)c1nc(Cc2ccccc2F)c2ncccn12
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1nc(Cc2ccccc2F)c2ncccn12
Temperature: 120 °C
Reaction time: 2 h

Procedure:
150 ml of phosphoryl chloride was added to 9.100 g (33.67 mmol) of 8-(2-fluorobenzyl)imidazo[1,5-a]pyrimidine-6-carboxamide and it was stirred for 2 h at 120° C. The reaction mixture was concentrated in the rotary evaporator and the residue was mixed with water. The solid was filtered with suction, washed with a little water and dried under high vacuum. 8.02 g (92% of theor.) of the target compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[N+:11]([O-])([OH:13])=[O:12]>OS(O)(=O)=O>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1
Reactant: Nc1ncccc1[N+](=O)[O-]
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Nc1ncc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 2-amino-3-nitropyridine (8.74 g, 63 mmol) in conc. H2SO4 (50 mL) at 0° C. was added HNO3 (3.10 mL, d=1.49) drop-wise over 10 min. The mixture was warmed to r.t. for 20 min then heated to 50° C. for 90 min. The reaction mixture was cooled and poured into 400 g of ice. The resulting precipitate was filtered, washed with cold water, and air dried to give 2-amino-3,5-dinitropyridine as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[C:9]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1)([OH:11])=[O:10].C(C(C#N)=C(C#N)C#N)#N>CC(N(C)C)=O>[C:9]([C:12]1[CH:19]=[CH:18][C:15]([C:16]2[S:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)=[CH:14][CH:13]=1)([OH:11])=[O:10]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: Nc1ccccc1S
Agent: N#CC(C#N)=C(C#N)C#N
Solvent: CC(=O)N(C)C
Product: O=C(O)c1ccc(-c2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 2-aminothiophenol (300 mg, 2.4 mmol) in DMA (3 mL) was added to resin-bound 4-carboxybenzaldehyde (subn. 0.60 mmol/g, 400 mg, 0.24 mmol), followed by TCNE (307 mg, 2.4 mmol). The suspension was shaken at 25° C. for 24h. The resin was filtered, washed with DMA and DCM, and dried under high vacuum. The resin-bound benzothiazole was cleaved from the solid support with 20% (v/v) TFA in DCM (2×5 mL, 15 min) and the combined filtrates were evaporated to give the title compound. 1H NMR (d6-DMSO) δ 7.52 (t, 1H, J=7.6 Hz), 7.60 (t, 1H, J=7.0 Hz), 8.12 (d, 2H, J=8.4 Hz), 8.23 (d, 2H, J=8.4 Hz), 8.00-8.40 (m, 2H). MS (API-ES+) m/z 256 (M+H).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([OH:12])[CH2:9][C:10]#[CH:11].C1(NC2CCCCC2)CCCCC1.C(#N)C>[Cu]I.CCOCC>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[C:11]#[C:10][CH2:9][CH2:8][OH:12]
Reactant: Brc1ncccn1
Reactant: C#CCCO
Agent: [Cu]I
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: CC#N
Solvent: CCOCC
Product: OCCC#Cc1ncccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.2 %

Procedure:
A mixture of 2-bromopyrimidine (5.0 g), 3-butynol (2.20 g), dicyclohexylamine (6.87 g), copper (I) iodide (50 mg), BTPC (380 mg) and acetonitrile (50 ml) was stirred at room temperature under nitrogen for 16 h. Ether (150 ml) was added, the mixture filtered and the filtrate evaporated in vacuo. Purification of the residue by FCC eluting with ether and ether-methanol (1-3%) followed by System C (5:1) afforded the title compound as a pale yellow solid (4.29 g) m.p. 58°-64°, t.l.c. (System C, 99:1) Rf 0.08
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH:3]=[CH2:4].[C:6]([O:9][C@@H:10]1[C@@H:33]([O:34][C:35](=[O:37])[CH3:36])[C@H:32]([O:38][C:39](=[O:41])[CH3:40])[C@@H:31]([CH2:42][O:43][C:44](=[O:46])[CH3:45])[O:30][C@H:11]1[O:12][C:13]1[C:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][C:20]=2[CH3:26])=[C:16]([CH:27]([CH3:29])[CH3:28])[NH:15][N:14]=1)(=[O:8])[CH3:7].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:6]([O:9][C@@H:10]1[C@@H:33]([O:34][C:35](=[O:37])[CH3:36])[C@H:32]([O:38][C:39](=[O:41])[CH3:40])[C@@H:31]([CH2:42][O:43][C:44](=[O:46])[CH3:45])[O:30][C@H:11]1[O:12][C:13]1[C:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22](/[CH:4]=[CH:3]/[CH2:2][CH2:1][OH:5])=[CH:21][C:20]=2[CH3:26])=[C:16]([CH:27]([CH3:29])[CH3:28])[NH:15][N:14]=1)(=[O:8])[CH3:7]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(Br)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: C=CCCO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CCO)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 90 °C
Yield: 50.6 %

Procedure:
Add 3-buten-1-ol (6.1 mL, 70 mmol) to a solution of 4-(4-bromo-2-methylbenzyl)-5-(propan-2-yl)-1H-pyrazol-3-yl 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside (15 g, 23.5 mmol) in acetonitrile (200 mL) and triethylamine (50 mL). Degas the solution with nitrogen over 10 minutes. Add tri-o-tolylphosphine (1.43 g, 4.7 mmol) and palladium acetate (526 mg, 2.35 mmol). After refluxing at 90° C. for 2 hours, cool and concentrate to remove the solvent under reduced pressure. Purify the resulting residue by flash chromatography (silica gel, gradient ethyl acetate/hexanes from 20-80% over 20 min, 330 g column) to provide the title compound (7.5 g, 11.9 mmol). MS (m/z): 631.2 (M+1), 629.2 (M−1).
Reaction SMILES: [CH3:1][C@:2]1([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:6][CH2:5][N:4]([C@@H](C2C=CC=CC=2)C)[CH2:3]1>O1CCOCC1.[OH-].[Pd+2].[OH-]>[CH3:1][C@:2]1([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:6][CH2:5][NH:4][CH2:3]1
Reactant: C[C@H](c1ccccc1)N1CC[C@](C)(NC(=O)OC(C)(C)C)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@@]1(C)CCNC1
Temperature: 50 °C
Yield: 99.9 %

Procedure:
tert-Butyl {(3S)-3-methyl-1-[(1R)-1-phenylethyl]pyrrolidin-3-yl}carbamate (I-344) (406 mg, 1.33 mmol) was dissolved in 1,4-dioxane (13 ml), then palladium hydroxide catalyst (20 wt. % on carbon) (100 mg) was added, followed by stirring in an oil bath at 50° C. Under hydrogen atmosphere far 5 hours. The reaction liquid was filtered, and the filtrate was concentrated under reduced pressure to obtain the entitled compound (266 mg, 100%) as a colorless oily substance.
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[Br:12][C:13]1[CH:14]=[CH:15][C:16](F)=[N:17][CH:18]=1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[Br:12][C:13]1[CH:18]=[N:17][C:16]([O:11][C:8]2[CH:9]=[N:10][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=2)=[CH:15][CH:14]=1
Reactant: Fc1ccc(Br)cn1
Reactant: CC(C)Oc1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)Oc1ccc(Oc2ccc(Br)cn2)cn1
Yield: 0 %

Procedure:
The mixture of Example 68B (1.0821 g, 7.064 mmol), 5-bromo-2-fluoropyridine (1.245 g, 7.074 mmol, 1.0 eq.), and K2CO3 (1.17 g, 8.47 mmol, 1.2 eq.) in dimethylsulfoxide (8 mL) was heated to 160° C. under microwave for 30 min. The reaction mixture was poured into water. The aqueous layer was extracted with ether (1×). The ether layer was washed with 10% NaOH (1×), brine (1×), dried over MgSO4, filtered and concentrated. The product was purified on silica gel eluting with ethyl acetate: hexane gradient to give the desired product as a solid (0.845 mg, 39%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:14]3=[C:15]([C:17](=[O:20])[CH:18]=[CH:19][N:13]3[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]2=3)[CH:16]=1)([OH:3])=[O:2].[CH3:21][Si](C=[N+]=[N-])(C)C>O1CCCC1.CO>[CH3:21][O:2][C:1]([C:4]1[CH:5]=[C:6]2[C:14]3=[C:15]([C:17](=[O:20])[CH:18]=[CH:19][N:13]3[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]2=3)[CH:16]=1)=[O:3]
Reactant: O=C(O)c1cc2c(=O)ccn3c4ccccc4c(c1)c23
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc2c(=O)ccn3c4ccccc4c(c1)c23
Reaction time: 1.5 h
Yield: 48 %

Procedure:
2-carboxy-4H-pyrido[3,2,1-jk]carbazole-4-one (500 mg) produced in Example 175 was suspended in tetrahydrofuran (100 ml), and methanol (several drops) was added to the suspension. Trimethylsilyldiazomethane (2M hexane solution, 1 ml) was added dropwise at room temperature, and the mixture was stirred for 90 minutes. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel flash column chromatography (eluent: ethyl acetate) to obtain the title compound (250 mg, 48%).