Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[C:17]([O:21][C:22](=[O:53])[N:23]([CH2:36][CH2:37][NH:38][S:39]([C:42]1[C:43]2[CH:44]=[CH:45][N:46]=[CH:47][C:48]=2[CH:49]=[C:50](Br)[CH:51]=1)(=[O:41])=[O:40])[CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)([CH3:20])([CH3:19])[CH3:18]>CN(C=O)C.CO.CCOC(C)=O>[C:17]([O:21][C:22](=[O:53])[N:23]([CH2:36][CH2:37][NH:38][S:39]([C:42]1[C:43]2[CH:44]=[CH:45][N:46]=[CH:47][C:48]=2[CH:49]=[C:50]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)[CH:51]=1)(=[O:40])=[O:41])[CH2:24][CH2:25][CH2:26][C:27]1[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: OB(O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N(CCCc1ccc([N+](=O)[O-])cc1)CCNS(=O)(=O)c1cc(Br)cc2cnccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(CCCc1ccc([N+](=O)[O-])cc1)CCNS(=O)(=O)c1cc(-c2ccc(O)cc2)cc2cnccc12
Temperature: 85 °C
Yield: 90.2 %

Procedure:
Add Pd(dppb)Cl2 (0.0051 g, 0.0085 mmol), 4-hydroxyphenylboronic acid (0.0258 g, 0.187 mmol) and 2M Na2CO3 (0.21 ml, 0.425 mmol) to [2-(7-bromo-isoquinoline-5-sulfonylamino)-ethyl]-[3-(4-nitro-phenyl)-propyl]-carbamic acid tert-butyl ester, (0.101 g, 0.170 mmol) in 3 ml DMF and 0.75 ml MeOH. Heat the reaction mixture at 85° C. for 1 h, then dilute with EtOAc (20 ml) and wash with H2O (2×20 ml) and brine (10 ml). Concentrate the organic layer and chromatograph on silica gel using a gradient of 0-2% MeOH in CH2Cl2 to give 0.093 g of {2-[7-(4-hydroxy-phenyl)-isoquinoline-5-sulfonylamino]-ethyl}-[3-(4-nitro-phenyl)-propyl]-carbamic acid tert-butyl ester, as a yellow solid in 90% yield. ES Positive Ion MS [M+H]+ ion observed: m/z 607. (Used in Example 98).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[C:3]([C:12]([OH:14])=O)=[CH:2]1.S(Cl)([Cl:17])=O>>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[C:3]([C:12]([Cl:17])=[O:14])=[CH:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1coc2ccccc2c1=O
Product: O=C(Cl)c1coc2ccccc2c1=O
Yield: 90 %

Procedure:
In accordance with the procedure described in Example 5-a), chromone-3-carboxylic acid (3.8 g, 20 mmol) was treated with thionyl chloride (1.73 ml) to obtain the desired compound (3.76 g, 90%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[CH:9]=[CH:8][C:7]=1OCCCCCO.C(N(CC)CC)C.CS(Cl)(=O)=O>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)CCc1cc(C(C)=O)ccc1OCCCCCO
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)CCc1cccc(C(C)=O)c1
Temperature: 0 °C
Reaction time: 1.33 h

Procedure:
A solution of 0.62 g (2 mmol) of 2-[(5-hydroxypentyl)oxy]-5-acetylbenzenepropanoic acid methyl ester and 2 mL of triethylamine, in 6 mL of ethyl acetate was stirred with ice-bath cooling while 0.6 mL of methanesulfonyl chloride was added dropwise. The resulting mixture was stirred at 0°-5° C. for 1.33 hr and then poured into ice--3N HCl. Work-up with ethyl acetate in the usual manner gave 0.96 g of 2-[[5-(methylsulfonyl)oxy]pentyl]oxy]-5-acetylbenzenepropanoic acid methyl ester as an oil which was used without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CC(C)([O-])C.[K+].CS(OCC1CCCCC1)(=O)=O.Cl>CC(OC)(C)C.O>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH:2]([NH2:1])[CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: NCc1ccccn1
Reactant: O=Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: CS(=O)(=O)OCC1CCCCC1
Agent: Cl
Solvent: O
Solvent: COC(C)(C)C
Product: NC(CC1CCCCC1)c1ccccn1
Reaction time: 8 h
Yield: 40.2 %

Procedure:
To 465 g (4.3 moles) of 2-(aminomethyl) pyridine was added with stirring 456 g (4.3 moles) of benzaldehyde. The temperature was increased to 70°-80° C. The mixture was diluted with 2 L of MTBE and the water was removed by stirring the solution with 200 g of sodium sulfate overnight. The mixture was filtered and washed with 2 L of MTBE. To remove the remaining water, 100 g of molecular sieves were added. To the mixture was added 483 g (4.3 moles) potassium t-butoxide in portions followed by 842 g (4.38 moles) of cyclohexylmethyl methanesulfonate. After 10-20 hours, the mixture was hydrolyzed by the addition of 5 L water containing 720 mL of hydrochloric acid. The organic phase was separated and discarded. The aqueous phase was washed with 0.5 L of methylene chloride and basified with 0.5 L of ammonium hydroxide. The product was extracted with petroleum ether to yield 452 g of crude mine. The amine was purified by vacuum distillation at 88° C. and 0.5 Torr to give 353 g (35%) of 1-(R,S)-(2-pyridyl)-2-cyclohexylethylamine.
Reaction SMILES: [C:1]1([C@@H:7]([N:9]2[C@@H:14]([C:15]([O:17]CC)=[O:16])[C@H:13]3[CH2:20][C@@H:10]2[CH2:11][CH2:12]3)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[OH-].[Na+]>O1CCCC1>[C:1]1([C@@H:7]([N:9]2[C@@H:14]([C:15]([OH:17])=[O:16])[C@H:13]3[CH2:20][C@@H:10]2[CH2:11][CH2:12]3)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)[C@H]1[C@@H]2CC[C@@H](C2)N1[C@@H](C)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H](c1ccccc1)N1[C@H]2CC[C@H](C2)[C@@H]1C(=O)O
Temperature: 65 °C
Reaction time: 21 h
Yield: 82.5 %

Procedure:
To a solution of ethyl (1S, 3R, 4R)-2-[(S)-1-phenylethyl]-2-azabicyclo[2.2.1]heptane-3-carboxylate (601 mg, 2.20 mmol) in tetrahydrofuran (12 ml)-methanol (6 ml) was added 1N sodium hydroxide (12 ml) and the mixture was stirred at 65° C. for 21 hours. The reaction mixture was neutralized and the water phase was concentrated. The residue was dissolved in chloroform and dried over magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (0–15% methanol/chloroform), to give (1S, 3R, 4R)-2-[(S)-1-phenylethyl]-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (445 mg, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15]>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:11][C:12]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:13]=2[C:14]([O:16][CH3:17])=[O:15])=[O:7])=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: COC(=O)c1cc(Cl)ccc1N
Product: COC(=O)c1cc(Cl)ccc1NC(=O)c1ccc(Cl)nc1

Procedure:
The title compound was prepared from 6-chloronicotinoyl chloride and methyl 2-amino-5-chlorobenzoate as a white solid as described in Example 1. 1H NMR (CDCl3): 12.13 (s, 1H), 9.06 (d, J=3.0, 1H), 8.86 (d, J=9.3, 1H), 8.29-8.25 (m, 1H), 8.08 (d, J=2.4, 1H), 7.60-7.57 (m, 1H), 7.50 (d, J=8.4, 1H), 3.99 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[CH2:4][C:5]1[C:6](=[O:18])[O:7][C:8]2[C:13]([C:14]=1[CH3:15])=[CH:12][C:11]([Cl:16])=[C:10]([OH:17])[CH:9]=2.[I-].[CH3:25][N:26]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:27](N1C=C[N+](C)=C1)=[O:28]>>[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[CH2:4][C:5]1[C:6](=[O:18])[O:7][C:8]2[C:13]([C:14]=1[CH3:15])=[CH:12][C:11]([Cl:16])=[C:10]([O:17][C:27](=[O:28])[N:26]([CH3:25])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH:9]=2
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Reactant: Cc1c(Cc2c(Cl)cccc2Cl)c(=O)oc2cc(O)c(Cl)cc12
Agent: [I-]
Product: Cc1c(Cc2c(Cl)cccc2Cl)c(=O)oc2cc(OC(=O)N(C)c3ccccc3)c(Cl)cc12

Procedure:
The title compound was prepared from 3-(2,6-dichloro-benzyl)-6-chloro-7-hydroxy-4-methyl-2H-chromen-2-one and 3-(methyl-phenyl-carbamoyl)-1-methyl-3H-imidazol-1-ium iodide. HPLC-MS m/z=502 (M+1), Rt: 5.68 min.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([NH:17]S(C(C)(C)C)=O)[C:11]2[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.Cl>CO.O1CCOCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([NH2:17])[C:11]2[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(CC(NS(=O)C(C)(C)C)c2cnn(C)c2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc(C)cc(CC(N)c2cnn(C)c2)c1
Yield: 77 %

Procedure:
A solution of RS 2-methyl-propane-2-sulfinic acid [2-(3,5-dimethyl-phenyl)-1-(1-methyl-1H-pyrazol-4-yl)-ethyl]-amide (2.0 g) in methanol (12 ml) was treated with a solution of hydrogenchloride in dioxane (12 ml, 4 N) at room temperature overnight. The reaction mixture was quenched with aqueous potassium carbonate solution and adjusted to pH 8-9, extracted and the organic phases dried over magnesium sulfate. After evaporation of the solvent a yellowish oil was obtained in 77% yield (1.05 g).
Reaction SMILES: C1COCC1.[Cl:6][C:7]1[C:11]([CH3:12])=[CH:10][S:9][C:8]=1[C:13]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.O.[NH2:22][NH2:23].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Cl:6][C:7]1[C:11]([CH3:12])=[CH:10][S:9][C:8]=1[C:13]1([C:18]([NH:22][NH2:23])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Cc1csc(C2(C(=O)Cl)CCCC2)c1Cl
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1csc(C2(C(=O)NN)CCCC2)c1Cl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
DMF (a catalytic amount) was added to a thionyl chloride (15 ml) solution of 1-(3-chloro-4-methyl-2-thienyl)cyclopentanecarboxylic acid (1.59 g), followed by stirring at 75° C. for 30 minutes. The reaction solution was subjected to evaporation under reduced pressure to obtain 1-(3-chloro-4-methyl-2-thienyl)cyclopentanecarbonyl chloride. A THF (20 ml) solution of 1-(3-chloro-4-methyl-2-thienyl)cyclopentanecarbonyl chloride was added dropwise to a THF (20 ml) solution of hydrazine monohydrate (12.6 ml) at 0° C., followed by stirring at 0° C. for 3 hours. After the reaction solution and chloroform were added to a saturated aqueous sodium hydrogen carbonate solution, the organic layer was separated. The organic layer washed with brine and, after drying over anhydrous sodium sulfate and filtration, the solvent was removed by evaporation under reduced pressure to obtain 1.65 g of 1-(3-chloro-4-methyl-2-thienyl)cyclopentanecarbohydrazide (pale yellow solid).
Reaction SMILES: [NH2:1][CH:2]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])[CH:20]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)[OH:4].[C:32]1([C:43](O)=[O:44])[CH:33]=[CH:34][CH:35]=[C:36]2[CH2:42][CH2:41][CH2:40][CH:39]=[CH:38][C:37]=12.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[OH:4][CH:3]([C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:9][CH:10]=1)[CH:2]([NH:1][C:43]([C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[CH2:42][CH2:41][CH2:40][CH:39]=[CH:38][C:37]=12)=[O:44])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:30])([F:31])[CH:27]([F:28])[F:29])[CH:20]=1
Reactant: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(Oc2ccccc2)cc1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(Oc2ccccc2)cc1)c1cccc2c1C=CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.2 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-(phenyloxy)phenyl)-3-(3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)-1-propanol (300 mg, 0.69 mmol) in acetonitrile (16 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (130 mg, 0.69 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (198 mg, 1.03 mmol) and 1-hydroxy-1H-benzotriazole (106 mg, 0.69 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave the title compound (285 mg, 68%).
Reaction SMILES: [CH2:1]([C@@H:8]1[C@@H:16]([O:17][Si](C(C)C)(C(C)C)C(C)C)[C@H:15]([CH3:28])[O:14][C:13](=[O:29])[C@@H:12]([N:30]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:11][O:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[Na+]>C1COCC1>[CH2:1]([C@@H:8]1[C@@H:16]([OH:17])[C@H:15]([CH3:28])[O:14][C:13](=[O:29])[C@@H:12]([N:30]([C:31]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:37])[C:38](=[O:39])[O:40][C:41]([CH3:44])([CH3:42])[CH3:43])[CH2:11][O:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[Si](O[C@@H]1[C@@H](Cc2ccccc2)COC[C@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)O[C@H]1C)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@@H]1OC(=O)[C@@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)COC[C@H](Cc2ccccc2)[C@H]1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72.4 %

Procedure:
To a solution of tert-butyl N-[(3S,7S,8R,9S)-7-benzyl-9-methyl-2-oxo-8-triisopropylsilyloxy-1,5-dioxonan-3-yl]-N-tert-butoxycarbonylcarbamate (5.77 g, 9.07 mmol, 1.00 equiv) in THF (91 ml) was added tetrabutylammonium fluoride (TBAF; 1M in THF, 18 ml, 18 mmol, 2.0 equiv). The resulting solution was stirred at room temperature for 1.5 h, poured into 100 mL sat'd sodium chloride (NaCl), extracted with EtOAc (3×100 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated to provide an oil. Purification by automated silica gel column chromatography provided tert-butyl N-[(3S,7S,8R,9S)-7-benzyl-8-hydroxy-9-methyl-2-oxo-1,5-dioxonan-3-yl]-N-tert-butoxycarbonylcarbamate (3.15 g, 72.4%) as a solid white foam: IR (ATR) 3489, 2980, 2934, 1740, 1703, 1496, 1476, 1454, 1393, 1367, 1307, 1254, 1210, 1168, 1145, 1121, 1041, 909, 850, 729, 701 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.31-7.27 (m, 2H), 7.23-7.16 (m, 3H), 5.21 (dd, J=8.8, 4.8 Hz, 1H), 5.06-4.91 (m, 1H), 4.16 (dd, J=12.1, 4.8 Hz, 1H), 3.89 (dd, J=12.1, 8.8 Hz, 1H), 3.77 (d, J=9.9 Hz, 1H), 3.55-3.42 (m, 2H), 3.00 (dd, J=13.8, 5.0 Hz, 1H), 2.57 (dd, J=13.8, 9.4 Hz, 1H), 2.26 (d, J=7.8 Hz, 1H), 2.10 (s, 1H), 1.50 (s, 18H), 1.47 (d, J=6.5 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 169.75, 152.71, 139.53, 129.10, 128.49, 126.28, 83.15, 77.20, 76.51, 71.67, 57.69, 47.63, 36.34, 27.95, 18.58; HRMS-ESI (m/z) [M+Na]+ calc'd for C25H37NNaO8; 502.2411 found 502.2418.
Reaction SMILES: [OH:1][C@H:2]1[CH2:15][C@@H:14]([O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[C@H:13](/[CH:23]=[CH:24]/[CH:25]([O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])[C@H:3]1[CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].CC(C)=O.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CCOCC>[CH3:30][C:29]([CH3:31])=[CH:28][CH2:27][CH2:26][CH:25]([O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1)/[CH:24]=[CH:23]/[C@@H:13]1[C@@H:3]([CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:2](=[O:1])[CH2:15][C@H:14]1[O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1
Reactant: CC(C)=CCCC(/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1OC1CCCCO1)OC1CCCCO1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: CC(C)O
Product: CC(C)=CCCC(/C=C/[C@H]1[C@H](OC2CCCCO2)CC(=O)[C@@H]1C/C=C\CCCC(=O)O)OC1CCCCO1
Reaction time: 0.17 h

Procedure:
At -20°, a solution of 2.6 g. of the alcohol obtained according to (d) in 33 ml. of acetone was combined with 2.72 ml. of Jones reagent and stirred for 30 minutes at this temperature. Thereafter, 3.3 ml. of isopropanol was added dropwise thereto, the mixture was stirred for another 10 minutes at -20°, diluted with ether, and washed three times with water. The organic phase was dried over magnesium sulfate and concentrated under vacuum, thus obtaining 2 g. of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:44])[C@@H:4]([NH:14][C:15]([C:17]1[CH:21]=[C:20]([O:22][CH2:23][C:24]([N:26]2[CH2:30][CH2:29][CH2:28][C@H:27]2[C:31](=[O:37])[NH:32][CH2:33][CH:34]2[CH2:36][CH2:35]2)=[O:25])[N:19]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:18]=1)=[O:16])[CH2:5][CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[Li+].[OH-]>C1COCC1>[C:10]([O:9][C:7](=[O:8])[CH2:6][CH2:5][C@H:4]([NH:14][C:15]([C:17]1[CH:21]=[C:20]([O:22][CH2:23][C:24]([N:26]2[CH2:30][CH2:29][CH2:28][C@H:27]2[C:31](=[O:37])[NH:32][CH2:33][CH:34]2[CH2:35][CH2:36]2)=[O:25])[N:19]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:18]=1)=[O:16])[C:3]([OH:44])=[O:2])([CH3:13])([CH3:11])[CH3:12]
Reactant: COC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NCC2CC2)n(-c2ccccc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NCC2CC2)n(-c2ccccc2)n1)C(=O)O
Reaction time: 2 h

Procedure:
To a solution of 2.0 g (S)-2-({5-[2-((S)-2-(Cyclopropylmethyl-carbamoyl)-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-pentanedioic acid 5-tert-butyl ester 1-methyl ester in 13 ml THF were added 78 mg LiOH (as solution in 4 ml water). After 2 h the reaction mixture was neutralized with Amberlite IR-120, filtrated and washed with methanol.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[C:9]([C:11]1[N:12]=[C:13]([CH3:22])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:10])#[CH:2].Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>CN(C=O)C.[Cu]I.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>[CH3:22][C:13]1[S:14][C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:11]([C:9]([N:4]2[CH2:5][CH2:6][CH2:7][CH2:8][CH:3]2[C:1]#[C:2][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:10])[N:12]=1
Reactant: C#CC1CCCCN1C(=O)c1nc(C)sc1-c1ccccc1
Reactant: Brc1ccccc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)N2CCCCC2C#Cc2ccccc2)c(-c2ccccc2)s1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A solution of (2-ethynylpiperidin-1-yl)(2-methyl-5-phenyl-1,3-thiazol-4-yl)methanone (25 mg, 0.081 mmol), bromobenzene (23 mg, 0.15 mmol), CuI (4.6 mg, 0.024 mmol), and triethylamine (0.15 mL, 1.1 mmol) in DMF (0.5 mL) was purged subsurface with nitrogen. Palladium tetrakis (9.3 mg, 0.0081 mmol) was added and the reaction was heated at 90° C. overnight. The reaction was stirred over excess Quadrapure TU overnight, then filtered and dried. The residue was subjected to purification via reverse phase HPLC to provide the title compound which gave a high resolution mass spectrum (ES+) m/z of 387.1527, calculated for M+H+ [C24H22N2OS: 387.1526].
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[NH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:13]>P(Cl)(Cl)(Cl)=O>[Cl:13][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=[CH:2][N:3]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2ccccc12
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2ccccc12

Procedure:
4-Quinazolone (5 g, 34.2 mmol), phosphorus pentachloride (10.26 g, 47.9 mmol) and phosphorus oxychloride (40 ml) were refluxed for two hours at 115-118 C. The phosphorus oxychloride was removed in vacuo and the residue was extracted in ether. The entire mixture was then poured into a vessel containing crushed ice and again extracted with ether. The ether layer was then washed with sodium bicarbonate and dried. The ether was then removed under reduced pressure and the crude material was recrystallized from hexanes to afford the product.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)=[O:5])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:29][C:30]1[CH:35]=[N:34][CH:33]=[C:32](Cl)[N:31]=1>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1([C:32]2[CH:33]=[N:34][CH:35]=[C:30]([Cl:29])[N:31]=2)[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:7]1)=[O:5])[CH3:2]
Reactant: Clc1cncc(Cl)n1
Reactant: CCOC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(c2cncc(Cl)n2)CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (90 g, 350.1 mmol) in dry THF (180 mL) at 0° C. was slowly added sodium-bis-(trimethylsilyl)-amide (1 M in THF, 450 mL, 450 mmol). The reaction mixture was stirred at the same temperature for 0.5 hr before it was slowly added to a solution of 2,6-dichloropyrazine (60 g, 401.6 mmol) in dry THF (180 mL) under argon. The resulting reaction mixture was stirred at 0° C. for 1 hr, and then allowed to warm up to room temperature, and quenched by the addition of satd. aq. solution of NH4Cl (360 mL). The organic layer was dried over anhy. Na2SO4, filtered, and concentrated in vacuo to afford a crude title product. It was then used directly in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([F:28])=[CH:10][C:11]3[C:21](=[O:22])[C:20]([C:23]([O:25]CC)=[O:24])=[CH:19][N:13]4[C@@H:14]([CH3:18])[CH2:15][O:16][C:17]=2[C:12]=34)[CH:5]=[C:4]([CH3:29])[N:3]=1.C([O-])(=O)C.[Na+]>Cl>[CH3:29][C:4]1[CH:5]=[C:6]([C:8]2[C:9]([F:28])=[CH:10][C:11]3[C:21](=[O:22])[C:20]([C:23]([OH:25])=[O:24])=[CH:19][N:13]4[C@@H:14]([CH3:18])[CH2:15][O:16][C:17]=2[C:12]=34)[CH:7]=[C:2]([CH3:1])[N:3]=1
Reactant: CCOC(=O)c1cn2c3c(c(-c4cc(C)nc(C)c4)c(F)cc3c1=O)OC[C@@H]2C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: Cc1cc(-c2c(F)cc3c(=O)c(C(=O)O)cn4c3c2OC[C@@H]4C)cc(C)n1
Yield: 62.1 %

Procedure:
A mixture of 0.52 g ethyl (S)-10-(2,6-dimethyl-4-pyridinyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate and 10 ml 1M hydrochloric acid was heated at reflux for one hour. The reaction mixture was cooled, poured into sodium acetate solution and extracted with chloroform. The extract was dried (sodium sulfate) and concentrated, and the residue was recrystallized from methanol to give 300 mg (S)-10-(2,6-dimethyl-4-pyridinyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid, colorless powder, m.p. 305°-308° C., [α]D25 =-39.8°.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18]N)=[CH:14][CH:13]=1>C(O)(=O)C>[CH2:8]([O:7][C:1]([C:2]1[C:16]2[C:15](=[CH:14][CH:13]=[C:12]([O:11][CH3:10])[CH:17]=2)[NH:18][C:3]=1[CH3:5])=[O:6])[CH3:9]
Reactant: COc1ccc(NN)cc1
Reactant: CCOC(=O)CC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)[nH]c2ccc(OC)cc12
Temperature: 110 °C
Reaction time: 16 h

Procedure:
Ethyl acetoacetate (5.5 ml, 43.15 mmol) was added into a solution of (4-methoxy-phenyl)-hydrazine (5.0 g, 28.63 mmol) in glacial acetic acid (500 ml) at room temperature. The mixture was heated at 110° C. for 2 hours, and kept at room temperature for 16 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between dichloromethane and 1 N sodium hydroxide solution. The organic extract was dried (anhydrous sodium sulfate) and concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel eluting with 2% methanol in dichloromethane to give 5-Methoxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester as a dark solid, (3.18 g, 47%). 1H NMR (CDCl3) δ:1.44 (t, 3H, J=7.1 Hz), 2.70 (s, 3H), 3.87 (s, 1H), 4.39 (q, 2H, J=7.1 Hz), 6.82(dd, 1H, J=8.8 Hz, 2.5 Hz), 7.17 (d, 1H, J=8.8 Hz), 7.63 d, 1H, J=2.5 Hz), 8.38 (bs, 1H). M−H: 232.