Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C:10](=[O:14])[C@@H:9]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].[F:35][C:36]([F:50])([F:49])[C:37]1[CH:38]=[C:39]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:40]O.C(=O)(O)[O-].[Na+]>C1COCC1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([O:14][CH2:40][C:39]2[CH:42]=[C:43]([C:45]([F:47])([F:48])[F:46])[CH:44]=[C:37]([C:36]([F:35])([F:49])[F:50])[CH:38]=2)[C@@H:9]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C1OCCN(Cc2ccccc2)[C@H]1c1ccccc1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: O=C([O-])O
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cc(CO[C@H]2OCCN(Cc3ccccc3)[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
A solution of 0.500 g (1.87 mmole) of N-benzyl-3-(S)-phenylmorpholin-2-one (from Example 14) in 10 mL of dry THF was cooled to -75° C. under nitrogen and was treated dropwise with 2.06 mL (2.06 mmole) of a 1M solution of lithium tri(sec-butyl)-borohydride (L-Selectride®) in THF. After stirring the solution at -75° C. for 30 min, a solution of 3,5-bis(trifluoromethyl)benzyl alcohol, trifluoromethanesulfonate ester in toluene was added by cannula so that the internal temperature was maintained below -60° C. The resulting solution was stirred at -75° C. for 1 hr and then between -38° C. and 50° C. for 2 hr. The solution was then poured into a mixture of 25 mL of ethyl acetate and 20 mL of saturated aqueous sodium bicarbonate, and the layers were separated. The aqueous phase was extracted with 2×30 mL of ethyl acetate, the combined organic layers were dried over sodium sulfate, the mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on 130 g of silica eluting with 2 L of 100:5 hexanes:ethyl acetate to give 0.68 g (73%) of an oil, which by 1H NMR is a 20:1 mixture of cis:trans morpholines.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:19]4[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=4)[C:15]([C:16](=[O:18])[CH3:17])=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.CO[CH:28](OC)[N:29]([CH3:31])[CH3:30]>>[CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:19]4[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=4)[C:15]([C:16](=[O:18])[CH:17]=[CH:28][N:29]([CH3:31])[CH3:30])=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(=O)c1c(-c2ccncc2)nn2c(NC3CCCC3)cccc12
Reactant: COC(OC)N(C)C
Solvent: O
Product: CN(C)C=CC(=O)c1c(-c2ccncc2)nn2c(NC3CCCC3)cccc12
Temperature: 25 °C
Yield: 65 %

Procedure:
A solution of 1-[7-(cyclopentylamino)-2-(4-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone (0.3 g, 0.94 mmol) in N,N-dimethylformamide dimethyl acetal (10 mL) was heated at reflux for 3 days. The mixture was allowed to cool to room temperature. Water was added and the resulting mixture was extracted with ethyl acetate. The ethyl acetate phase was dried (magnesium sulfate), filtered and concentrated. The resulting residue was purified by flash chromatography (7:3 ethyl acetate-acetone) to give 1-[7-(cyclopentylamino)-2-(4-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one (0.23 g, 65%) as a colored syrup which was used in the next step without further purification. To a solution of 1-[7-(cyclopentylamino)-2-(4-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one (0.10 g, 0.27 mmol) in tetrahydrofuran (10 mL) was added cyclopentyl guanidine hydrochloride (0.06 g, 0.38 mmol) followed by potassium tert-butoxide (0.085 g, 0.76 mmol). The resulting mixture was heated at reflux for 12 hours. Upon cooling to room temperature, water was added. The mixture was extracted with ethyl acetate. The ethyl acetate phase was washed with brine, dried (magnesium sulfate), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (1:9 methanol-dichloromethane) to give the title compound (89 mg, 75%) as a white solid. 1H NMR (CDCl3): δ 8.64 (d, 2H), 8.04 (d, 1H), 7.58 (m, 3H), 7.28 (t, 1H), 6.32 (d, 1H), 6.02 (d, 1H), 5.95 (d, 1H), 5.03 (d, 1H), 4.22 (m, 1H), 3.97 (m, 1H), 1.2–2.2 (m, 16H); MS m/z 440 (M+1).
Reaction SMILES: [O:1]=[C:2]([CH3:6])[CH2:3][CH2:4][OH:5].[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>O1CCCC1>[O:1]=[C:2]([CH3:6])[CH2:3][CH2:4][O:5][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(=O)CCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)CCOC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.4 %

Procedure:
To 400 ml of tetrahydrofuran in a reactor, 15.0 g (0.17 mol) of 3-oxo-1-butanol and 26.3 g (0.19 mol) of benzoyl chloride were dissolved, followed by drop-wise adding 20.6 g (0.20 mol) of triethylamine under ice-cooling. After the end of drop-wise addition, the reaction liquid was stirred at room temperature for 3 hours. Hydrochloric acid salt of triethylamine was filtered, followed by adding water to the filtrate and extracting with ethyl acetate. The organic layer was washed with water, a saturated aqueous solution of sodium carbonate, water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentrating under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:hexane=1:5 to 1:3) to obtain 31.5 g (yield: 96%) of 3-oxobutylbenzoate.
Reaction SMILES: [C:1]1([C:13]([C:15]2[C:16](=[O:30])[NH:17][C:18](=[O:29])[C:19]=2[C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)=[O:14])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.[H][H]>O1CCCC1.[Pd]>[C:1]1([C:13]([C@H:15]2[C@@H:19]([C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[NH:22][CH:21]=3)[C:18](=[O:29])[NH:17][C:16]2=[O:30])=[O:14])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: [H][H]
Reactant: O=C1NC(=O)C(c2c[nH]c3ccccc23)=C1C(=O)c1cn2c3c(cccc13)CCC2
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C1NC(=O)[C@H](c2c[nH]c3ccccc23)[C@@H]1C(=O)c1cn2c3c(cccc13)CCC2
Yield: 37.1 %

Procedure:
3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-carbonyl)-4-(1H-indol-3-yl)-pyrrole-2,5-dione (500 mg, 1.26 mmol) and 10% Pd—C (300 mg) in anhydrous tetrahydrofuran (60 ml) was stirred at room temperature under 1 atmosphere of hydrogen gas for 1 day. The mixture was filtered through celite and evaporated to dryness. The residue obtained was purified by flash column chromatography (SiO2, 65% EtOAc in hexanes) to yield (±)-cis-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-carbonyl)-4-(1H-indol-3-yl)-pyrrolidine-2,5-dione as a pale yellow powder (186 mg). M.p.=283-285° C.; 400 MHz 1H NMR (DMSO-d6) δ: 11.64 (s, 1H), 11.1 (s, 1H), 8.46 (s, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.42-7.36 (m, 3H), 7.19-6.97 (m, 4H), 4.85 (dd, J=5.0 and 46 Hz, 2H), 4.27-4.15 (m, 2H), 2.98-2.88 (m, 2H), 2.18-2.08 (m, 2H); LCMS: 398 [M+H].
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[O:21][C@H:11]1[CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:22]1([CH3:31])[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][Mg]Br>>[CH2:14]([O:13][CH2:12][C@@H:11]([CH2:31][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28])[C@@H:10]([OH:21])[CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1ccccc1C[Mg]Br
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1O[C@H]1COCc1ccccc1
Product: Cc1ccccc1C[C@H](COCc1ccccc1)[C@@H](O)CO[Si](C)(C)C(C)(C)C

Procedure:
351 mg of (2S,3S)-4-benzyloxy-2,3-epoxy-1-butanol tert-butyldimethylsilyl ether obtained in Example 53, was subjected to Grignard reaction in the same manner as in Example 53 by using 2-tolylmethyl magnesium bromide (0.8M diethyl ether solution). The product was purificated by silica gel column chromatography to obtain 210 mg of (2R,3R)-4-benzyloxy-1-tert-butyldimethylsilyloxy-3-(2-tolylmethyl)-2-butanol as colorless oily substance.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].Cl.[NH2:7][C:8]1[N:9]=[C:10]([C:17]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[C:21]([O:28][CH3:29])[CH:20]=2)=[O:18])[N:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=12>N1C=CC=CC=1.C(OC(C)C)(C)C>[CH3:29][O:28][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[N+:25]([O-:27])=[O:26])[C:17]([C:10]1[N:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]2=[C:8]([NH:7][S:1]([CH3:4])(=[O:3])=[O:2])[N:9]=1)=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C(=O)c2nc(N)c3ccccn23)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: c1ccncc1
Product: COc1cc(C(=O)c2nc(NS(C)(=O)=O)c3ccccn23)ccc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
116 μl (1.49 mmol) of mesyl chloride are added, under a nitrogen atmosphere at a temperature of 5° C., to 0.473 g (1.36 mmol) of (1-aminoimidazo[1,5-a]pyridin-3-yl)(3-methoxy-4-nitrophenyl)methanone hydrochloride obtained in example 76 in 14 ml of pyridine. On completion of the introduction, the mixture is allowed to return to ambient temperature and is stirred for 30 minutes. The reaction medium is poured under 95 ml of 2N hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with water, separated by settling, dried over sodium sulfate and concentrated under reduced pressure. The solid residue obtained is taken up in isopropyl ether, filtered off, washed with isopropyl ether and then dried. 0.40 g of an orange solid is collected. Melting point: 231° C.; 1H NMR (d6-DMSO): 3.24 (3H, s), 4.02 (3H, s), 7.40-7.44 (1H, m), 7.49-7.53 (1H, m), 7.88-7.92 (1H, d), 8.00-8.07 (2H, m), 8.26 (1H, s), 9.75 (1H, d)
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([CH:12]3[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(O)(=O)C.COC(OC)OC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([C@H:12]3[CH2:17][CH2:16][C@H:15]([N:23]4[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]4)[CH2:14][CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CN1CCNCC1
Reactant: O=C1CCC(n2cc(I)c3c(Cl)ncnc32)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: COC(OC)OC
Solvent: CC(Cl)Cl
Product: CN1CCN([C@H]2CC[C@H](n3cc(I)c4c(Cl)ncnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-cyclohexanone (5.6 g, 14.9 mmol), N-methylpiperazine (3.3 mL, 29.8 mmol), acetic acid (2.6 mL, 44.7 mmol), and trimethylorthoformate (9.9 mL, 89.4 mmol) in dichloroethane (100 mL) was stirred at ambient temperature under an atmosphere of nitrogen for 1 hr. Sodium triacetoxyborohydride (14.2 g, 67.05 mmol) was added into the mixture and stirred at ambient temperature under an atmosphere of nitrogen for 18 hours. The solvent was removed under reduced pressure. The residue was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate. The water phase was further extracted with ethyl acetate and the combined organic extracts were dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel using triethylamine/dichloromethane (2:98) followed by methanol/triethylamine/dichloromethane (2:3:95) as mobile phase to yield trans-4-chloro-5-iodo-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidine (1.7 g, 3.7 mmol). 1H NMR (DMSO-d6, 400 MHz) 8.63 (s, 1H), 8.12 (s, 1H), 4.63 (br, 1H), 2.15 (s, 3H), 1.94 (br, 6H), 1.45 (br, 2H) RP-20 HPLC (Hypersil C18, 5 μm, 250×4.6 mm; 25%-100% over 15 min with 0.05 M ammonium acetate, 1 mL/min) Rt 6.17 min.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[Cl:12][S:13](O)(=[O:15])=[O:14].S(Cl)(Cl)=O>>[Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:13]([Cl:12])(=[O:15])=[O:14])=[CH:8][CH:7]=1)=[O:4]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(CCl)Nc1ccccc1
Solvent: O=S(Cl)Cl
Product: O=C(CCl)Nc1ccc(S(=O)(=O)Cl)cc1
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
Chloroacetanilide (4.53 g) is slowly added to chlorosulfonic acid (7.5 mL) at a temperature of 5° C. The solution is heated to 65° C. and thionyl chloride (0.78 mL) is added. After 10 minutes of gas evolution the reaction was cooled to room temperature. The mixture is added to ice/water (2.14 g/3.2 mL) and stirred for 30 minutes. The product was filtered, washed with water (60 mL), placed under vacuum at 50° C. and dried to a constant weight. The product is a white powder, yield: 4.81 g (67%).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[C:8]([C:34]#[N:35])=[CH:7][N:6]=1)(=O)=O.[NH2:36][CH:37]([C:39]1[CH:40]=[CH:41][C:42]([C:45]2([OH:52])[CH2:50][CH2:49][N:48]([CH3:51])[CH2:47][CH2:46]2)=[N:43][CH:44]=1)[CH3:38].[OH-].[Li+]>O1CCCC1>[OH:52][C:45]1([C:42]2[N:43]=[CH:44][C:39]([CH:37]([NH:36][C:5]3[N:10]=[C:9]([C:11]4[C:19]5[C:14](=[N:15][CH:16]=[C:17]([C:20]([F:21])([F:22])[F:23])[CH:18]=5)[NH:13][CH:12]=4)[C:8]([C:34]#[N:35])=[CH:7][N:6]=3)[CH3:38])=[CH:40][CH:41]=2)[CH2:50][CH2:49][N:48]([CH3:51])[CH2:47][CH2:46]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(S(C)(=O)=O)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Reactant: CC(N)c1ccc(C2(O)CCN(C)CC2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(Nc1ncc(C#N)c(-c2c[nH]c3ncc(C(F)(F)F)cc23)n1)c1ccc(C2(O)CCN(C)CC2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 9.4 %

Procedure:
2-(Methylsulfonyl)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile (160.2 mg, 0.255 mmol) was added to a solution of 4-(5-(1-aminoethyl)pyridin-2-yl)-1-methylpiperidin-4-ol (66.01 mg, 0.28 mmol) in tetrahydrofuran (8 mL). The reaction mixture was stirred under nitrogen at room temperature for 18 hours. 1M Lithium hydroxide (1.020 mL of 1 M, 1.020 mmol) was added and the reaction mixture was stirred at room temperature for 4 hours. The crude mixture was partitioned between ethyl acetate and brine. The organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as a white solid (12.5 mg, 9% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])/[CH:4]=[CH:5]/[CH:6]=[CH:7]/[CH2:8][CH:9]([C:17]([O:19]C(C)(C)C)=[O:18])[C:10]([O:12]C(C)(C)C)=[O:11].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:24])/[CH:4]=[CH:5]/[CH:6]=[CH:7]/[CH2:8][CH:9]([C:10]([OH:12])=[O:11])[C:17]([OH:19])=[O:18]
Reactant: COC(=O)/C=C/C=C/CC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)/C=C/C=C/CC(C(=O)O)C(=O)O
Reaction time: 8 h
Yield: 83.1 %

Procedure:
To a stirred solution of 40 (200 mg, 0.59 mmol) in CH2Cl2 (10 mL) was added TFA (1 mL). The reaction was allowed to proceed overnight. Volatiles were removed under reduced pressure to leave 41 as a white solid (112 mg, 0.49 mmol, 83%). 1H-NMR (CD3OD, 400 MHz) δ 7.11 (dd, 1H), 6.33 (dd, 1H), 6.16 (m, 1H), 5.81 (d, 1H), 3.76 (s, 3H), 3.15 (t, 1H), 2.70 (t, 2H).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=1[F:21])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC(Cl)(Cl)[C:44]#[N:45]>CC(N(C)C)=O>[F:21][C:15]1[CH:16]=[C:17]([I:20])[CH:18]=[CH:19][C:14]=1[NH:13][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:7]=1[C:6]1[O:22][C:1]([NH:45][CH3:44])=[N:4][N:5]=1
Reactant: N#CC(Cl)(Cl)Cl
Reactant: CC(=O)NNC(=O)c1ccncc1Nc1ccc(I)cc1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Product: CNc1nnc(-c2ccncc2Nc2ccc(I)cc2F)o1
Temperature: 100 °C
Reaction time: 4 h
Yield: 25.6 %

Procedure:
To a solution of 3-(2-Fluoro-4-iodo-phenylamino)-isonicotinic acid N′-acetyl-hydrazide (400 mg; 0.93 mmol; 1 eq) in DMA (5 mL), PS-Triphenyl-phosphine (1.22 g; 4.66 mmol; 5 eq), Trichloro-acetonitrile (269 mg; 1.86 mmol; 2 eq) and DIEPA (0.49 mL; 2.8 mmol; 3 eq) were added. The reaction mixture was stirred at 100° C. for 4 hrs. The mixture was filtered and the solution was subjected to preparative HPLC to afford the product (98 mg). LC/MS (Method A) [5.03 min; 412(M+1)]
Reaction SMILES: C(OC([N:7]1[C@H:11]([CH:12]([OH:21])[C:13]2[N:14]3[CH:20]=[N:19][CH:18]=[C:15]3[S:16][CH:17]=2)[CH2:10][C@H:9]([S:22][C:23]2[C@H:24]([CH3:40])[C@@H:25]3[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:26]3[C:27]=2[C:28]([O:30]CC=C)=[O:29])[CH2:8]1)=O)C=C.CNC1C=CC=CC=1.ClC1C=CC=CC=1.O>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:38][C@@H:36]([C@H:35]1[C:34](=[O:39])[N:26]2[C:27]([C:28]([OH:30])=[O:29])=[C:23]([S:22][C@H:9]3[CH2:10][C@@H:11]([CH:12]([OH:21])[C:13]4[N:14]5[CH:20]=[N:19][CH:18]=[C:15]5[S:16][CH:17]=4)[NH:7][CH2:8]3)[C@H:24]([CH3:40])[C@H:25]12)[CH3:37]
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](C(O)c3csc4cncn34)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CNc1ccccc1
Solvent: ClCCl
Solvent: Clc1ccccc1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(O)c4csc5cncn45)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 45 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (12.7 mg) is added to a solution of 64.8 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[1-hydroxy-1-(imidazo[5,1-b]thiazol-3-yl)methyl]pyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate (stereoisomer B) and 0.072 ml of N-methylaniline in a mixture of 0.9 ml of dry dichloromethane with 0.9 ml of monochlorobenzene, and the mixture is stirred in an argon atmosphere at room temperature for 70 min. Distilled water (3 ml) is added thereto, the mixture is washed three times with 3 ml of ethyl acetate, and the aqueous layer is filtered, followed by concentration under reduced pressure and freeze drying to give 23 mg of a colorless flocculent material. The colorless flocculent material is successively purified by column chromatography on Diaion CHP-20P (4% aqueous THF solution) and on Cosmosil 5C18-MS (water:methanol=2:1) to give 5.8 mg of the title compound as a colorless flocculent material.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:25])[CH2:23][OH:24])[CH3:21])[C:14]=3[Cl:26])[C:5]2=[N:4][C:3]=1[CH3:27].C(N(CC)CC)C.[S:35](Cl)([CH3:38])(=[O:37])=[O:36]>C(Cl)Cl>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:25])[CH2:23][O:24][S:35]([CH3:38])(=[O:37])=[O:36])[CH3:21])[C:14]=3[Cl:26])[C:5]2=[N:4][C:3]=1[CH3:27]
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CO)c3Cl)cccn2c1Br
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)COS(C)(=O)=O)c3Cl)cccn2c1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-bromo-8-[2,6-dichloro-3-(N-glycoloyl-N-methylamino)benzyloxy]-2-methylimidazo[1,2-a]pyridine (700 mg) and triethylamine (269 mg) in methylene chloride (14 ml) was added mesyl chloride (224 mg) under ice-cooling, and the mixture was stirred for 1 hour at ambient temperature. The reaction mixture was washed with water twice and brine, dried over magnesium sulfate and concentrated in vacuo to give the residue of 3-bromo-8-[2,6-dichloro-3-(N-mesyloxyacetyl-N-methylamino)benzyloxy]-2-methylimidazo[1,2-a]pyridine. The residue was dissolved in N,N-dimethylformamide (7 ml) and potassium phthalimide (362 mg) was added thereto at ambient temperature under N2 atmosphere. The mixture was stirred for 1 day, and water was added thereto. The precipitate was collected by filtration and dried to give 3-bromo-8-[2,6-dichloro-3-(N-methyl-N-phthalimidoacetylamino)benzyloxy]-2-methylimidazo[1,2-a]pyridine (629 mg).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([C:17]2[CH:30]=[CH:29][C:28]3[C:27](=[O:31])[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([CH3:35])[C:25]=4[N+:32]([O-])=O)[C:20](=[O:36])[C:19]=3[C:18]=2[NH2:37])=[O:16])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C1(C)C=CC=CC=1.[H][H]>[Pd].C(O)C>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]([C:17]2[CH:30]=[CH:29][C:28]3[C:27](=[O:31])[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([CH3:35])[C:25]=4[NH2:32])[C:20](=[O:36])[C:19]=3[C:18]=2[NH2:37])=[O:16])=[CH:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCc1ccc(OC(=O)c2ccc3c(c2N)C(=O)c2ccc(C)c([N+](=O)[O-])c2C3=O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCCCCc1ccc(OC(=O)c2ccc3c(c2N)C(=O)c2ccc(C)c(N)c2C3=O)cc1

Procedure:
A suspension of 0.426 g of 1-amino-6-methyl-5-nitro-2-anthraquinonecarboxylic acid p-heptylphenyl ester, 50 ml of toluene, 50 ml of ethanol and 0.10 g of palladium/barium carbonate catalyst poisoned with 2 wt.% lead was hydrogenated at room temperature until the hydrogen uptake came to a standstill. The mixture was filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica gel with methylene chloride as the eluent. Recrystallization from methylene chloride/hexane, yielded 0.334 of 1,5-diamino-6-methyl-2-anthraquinonecarboxylic acid p-heptylphenyl ester as violet crystals; m.p. (C-N) 163.7°-165.7° C., cl.p. (N-I) 190.9°-191.4° C., nematic; E277 =15280, E524 =14700.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][N:15]2C(OC(C)(C)C)=O)=[N:4][CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([O:12][CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)=[N:4][CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:7]=1
Reactant: COC(=O)c1cnc(OCC2CCCN2C(=O)OC(C)(C)C)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cnc(OCC2CCCN2)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.2 %

Procedure:
To a stirred solution of methyl 3-chloro-2-[[1-(tert-butoxycarbonyl)-2-pyrrolidinyl]methoxy]pyridine-5-carboxylate (235.6 mg, 0.635 mmol) in CH2Cl2 (5.0 mL) was added TFA (1.0 mL) at 0° C., and the reaction mixture was stirred at room temp for 2 hr. The solvent was removed under a reduced pressure. The residue was made basic by the addition of 1N NaOH and extracted with CHCl3. The extract was dried over Na2SO4, concentrated under a reduced pressure to afford 172.3 mg (q.y.) methyl 3-chloro-2-[(2-pyrrolidinyl)methoxy]pyridine-5-carboxylate as a pale yellowish oil. 1H-NMR (400 MHz, CDCl3) δ1.55-1.63 (m, 1HR), 1.76-1.99 (m, 3H), 2.93-2.99 (m, 1H), 3.02-3.08 (m, 1H), 3.57-3.62 (m, 1H), 3.92 (s, 3H), 4.33 (dd, J=7.3, 10.7 Hz, 1H), 4.44 (dd, J 4.4, 10.7 Hz, 1H), 8.21 (d, J=2.0 Hz, 1H), 8.67 (d, J=2.0 Hz, 1H); MS (FAB) m/z 271 (M++1).