Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@H:1]1([C:8]([OH:10])=[O:9])[CH2:4][C@@H:3]([C:5]([OH:7])=[O:6])[CH2:2]1.[CH2:11](O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[CH2:11]([O:6][C:5]([C@@H:3]1[CH2:4][C@H:1]([C:8]([OH:10])=[O:9])[CH2:2]1)=[O:7])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)[C@H]1C[C@@H](C(=O)O)C1
Reactant: OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)[C@H]1C[C@@H](C(=O)OCc2ccccc2)C1
Reaction time: 8 h

Procedure:
To a solution of cis-cyclobutane-1,3-dicarboxylic acid (4.00 g, 27.75 mmol), benzyl alcohol (2.87 mL, 27.75 mmol) and DMAP (0.339 g, 2.78 mmol) in DMF (80 mL) was added WSC (5.59 mL, 30.53 mmol) at room temperature, and the mixture was stirred overnight. The reaction mixture was poured into water, and the pH of the mixture was adjusted to 2 to 3 with 1N hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give crude cis-3-((benzyloxy)carbonyl)cyclobutanecarboxylic acid (5.93 g, 25.3 mmol, 91%) as a colorless oil. This compound was used for the next step without purification.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:3]=1.Cl.[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20].C(N(CC)CC)C>C(#N)C>[CH3:22][O:21][C:19](=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][S:8]([C:4]1[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: COC(=O)CCCCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)CCCCCNS(=O)(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
Pyridine-3-sulfonyl chloride hydrochloride (92c) (1.8 g, 5.0 mmol) was added to a solution of methyl 6-aminohexanoate hydrochloride (91) (1.82 g, 10 mmol) and triethylamine (3.03 g, 30 mmol) in acetonitrile (30 ml). The mixture was stirred for 1 hour at ambient temperature, filtered and solvents were removed under reduced pressure. The oily product was dissolved in water (15 ml) and extracted with ethyl ether (50 ml). The extract was dried (Na2SO4) and the solvents were removed under reduced pressure. The title compound (1.09 g, 76%) was obtained as oil and was used for the next step without an additional purification. 1H NMR 5H (90 MHz, DMSO-d6) δ: 0.80-1.51 (6H, m, CH2); 1.83 (2H, t, J=6.5 Hz, CH2); 2.76 (2H, t, J=6.5 Hz, CH2N); 3.58 (3H, s, CH3); 7.54 (1H, dd, J=5.0 Hz, J=8.2 Hz, C5HN); 8.12 (1H, dt, J=2.0 Hz, J=8.2 Hz, C5HN); 8.61 (1H, dd, J=2.0 Hz, J=5.0 Hz, C5HN); 8.81 (1H, d, J=2.0 Hz, C5HN).
Reaction SMILES: O.NN.[Br:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[C:7]([Cl:15])[CH:6]=1.[C:16]([O-])(=O)C.[Na+].CI>C1COCC1.CCO>[Br:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:16])(=[O:13])=[O:12])=[C:7]([Cl:15])[CH:6]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1Cl
Reactant: CC(=O)[O-]
Agent: NN
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CCO
Product: CS(=O)(=O)c1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.4 %

Procedure:
Hydrazine monohydrate (1.51 mL, 48 mmol) was added to a cooled 0° C. solution of 4-bromo-2-chlorobenzenesulfonyl chloride (5 g, 17.2 mmol) dissolved in THF (50 mL). The reaction was stirred at room temperature for 2 hours and then the solvent was removed in vacuo to give a white solid. The solid was dissolved in EtOH (100 mL) and treated with sodium acetate (6.56 g, 80 mmol) followed by methyl iodide (4.9 mL, 79 mmol). The reaction mixture was refluxed for 18 hours. The solvent was removed in vacuo to give a residue that was partitioned between 1 N HCl and EtOAc. The organic layer was dried over MgSO4 and concentrated. The crude mixture was purified by flash column chromatography to give the product (1.5 g, 32%). 1H NMR (300 MHz, CDCl3): δ 3.26 (s, 3 H), 7.63 (dd, J=8.5, 1.9 Hz, 2 H), 7.74 (d, J=1.9 Hz, 1 H), 8.02 (d, J=8.5 Hz, 1 H).
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([OH:12])[CH3:11].[ClH:13]>O1CCOCC1>[ClH:13].[CH2:10]([O:12][C:8](=[NH:9])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:11]
Reactant: CCO
Reactant: N#CCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=N)Cc1ccccc1
Yield: 100 %

Procedure:
Combine benzyl cyanide (1.0 g, 8.50 mmol), ethanol (0.4 g, 8.50 mmol) and 4N hydrogen chloride in dioxane (8 mL) and stir the reaction mixture at ambient temperature for 17 h. Evaporate the solvent and triturate the residue with diethyl ether to obtain the desired intermediate as a white solid (1.7 g, 100%).
Reaction SMILES: [C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:11][C@@H:10]([NH:25]C(OC(C)(C)C)=O)[C:9]1=[O:33])=[O:6])([CH3:4])([CH3:3])[CH3:2].Cl.O.C(OCC)C>C(O)C>[C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:11][C@@H:10]([NH2:25])[C:9]1=[O:33])=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(C2CCCCC2)c2ccccc2N(CC(=O)C(C)(C)C)C1=O
Agent: Cl
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: CC(C)(C)C(=O)CN1C(=O)[C@H](N)CN(C2CCCCC2)c2ccccc21
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 93.3 %

Procedure:
To a solution of 63.5 g of (R)-1-tert-butylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine in 100 ml of ethanol was added 100 ml of 6N hydrochloric acid. The mixture was stirred at 60° C. for 1.5 hours. After the reaction mixture was cooled to room temperature, a mixed solvent of water and diethyl ether (1:1) was added. The aqueous layer was separated, neutralized with a 6N aqueous solution of sodium hydroxide, and then extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure, whereby 46.3 g of (R)-(−)-1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine was obtained.
Reaction SMILES: CC(OC([NH:8][C@H:9]([C:16]([OH:18])=[O:17])[CH2:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])=O)(C)C.[CH2:19]([O:26][C:27](=[O:33])[C@@H:28]1[CH2:32][CH2:31][CH2:30][NH:29]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl.O1CCOCC1.C(Cl)(Cl)[Cl:42].C(OCC)C>O1CCOCC1.CO>[CH3:15][S:12]([CH2:11][CH2:10][C@H:9]([NH2:8])[C:16]([OH:18])=[O:17])(=[O:13])=[O:14].[ClH:42].[CH2:19]([O:26][C:27](=[O:33])[C@@H:28]1[CH2:32][CH2:31][CH2:30][NH:29]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCS(C)(=O)=O)C(=O)O
Reactant: ClC(Cl)Cl
Agent: Cl
Agent: O=C(OCc1ccccc1)[C@@H]1CCCN1
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: CO
Product: CS(=O)(=O)CC[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-Boc-L-methionine sulfone-L-proline-O-benzyl ester (23.5 g, 50 mmole) in dry dioxane (300 mL) was added 100 mL of a 4M HCl/dioxane solution. The mixture was then stirred at room temperature for 1 hour until the starting material disappeared as shown by thin layer chromatography analysis (silica, 10% chloroform in methanol). Diethyl ether was added to the mixture to precipitate the title compound as a white hydrochloride salt. The mixture was filtered on a Buchner funnel and the solid was then dried under high vacuum to give 20.16 g (100%) of the title compound as a white solid.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[C:13](=[O:29])[N:14]([CH:21]1[CH2:26][CH2:25][C:24](=[O:27])[NH:23][C:22]1=[O:28])[C:15]2=[O:20].[C:30](Cl)(=[O:39])[C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1>C1COCC1>[O:28]=[C:22]1[CH:21]([N:14]2[C:13](=[O:29])[C:12]3[C:16](=[CH:17][CH:18]=[CH:19][C:11]=3[CH2:10][NH:9][C:30](=[O:39])[C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[C:15]2=[O:20])[CH2:26][CH2:25][C:24](=[O:27])[NH:23]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)NCc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.2 %

Procedure:
Triethylamine (0.5 g, 5.0 mmol) was added slowly to a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.0 mmol) and p-anisoyl chloride (0.5 g, 2.8 mmol) in THF (30 mL) at 5-10° C. After 10 minutes, the mixture was stirred at room temperature overnight. The reaction was quenched with methanol (1 mL), and the mixture was concentrated. The residue was stirred with 1N HCl (30 mL) for 1 hour then filtered. The solid was slurried with hot ethanol (15 mL) to give N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-4-methoxy-benzamide (0.6 g, 71%) as a white solid: mp 193-195° C.; 1H NMR (DMSO-d6) δ 2.06-2.10 (m, 1H), 2.50-2.65 (m, 2H), 2.84-2.97 (m, 1H), 3.83 (s, 3H, OCH3), 4.93 (d, J=5.7 Hz, 2H, CH2), 5.14-5.21 (dd, J=5.4 and 12.7 Hz, 1H, CH), 7.04 (d, J=8.8 Hz, 2H, Ar), 7.69-7.86 (m, 3H, Ar), 7.89 (d, J=8.7 Hz, 2H, Ar), 9.01 (t, J=5.7 Hz, 1H, NH), 11.15 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.99, 30.94, 38.25, 48.87, 55.36, 113.57, 121.80, 126.10, 127.06, 129.15, 131.51, 133.00, 134.77, 139.63, 161.75, 166.08, 166.99, 167.56, 169.85, 172.77; Anal. calcd. for C22H19N3O6+0.34H2O: C, 61.81; H, 4.64; N, 9.83. Found: C, 61.77; H, 4.54; N, 9.63.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=O)[NH:2]1.O=P(Cl)(Cl)[Cl:13].Cl>O>[Cl:13][C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][N:2]=1
Reactant: O=c1[nH]sc2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Solvent: O
Product: Clc1nsc2ccccc12
Reaction time: 1.5 h

Procedure:
A mixture of 1,2-benzisothiazole-3(2H)-one (Example 1, 818 g, 5.414 moles) and POCl3 (1114 g, 7.26 moles) was heated to 120° over about two hours. HCl evolution began at about 70°. Heat was continued at 120° for another 1.5 hours. The hot solution was poured into 8 liter of H2O at 25°. The temperature was not allowed to exceed 50°. After 30 minutes, the mixture was cooled to 25° (ice addition) and extracted with methylene chloride (4 liter). A dark oil was obtained by evaporation of the methylene chloride in vacuo. This oil was extracted with Skelly B (3×1 liter and 2×500 mL). The turbid extract was treated with Darco G-60 (30 g) and Celite A-545 (20 g) before filtering. The filtrate was evaporated in vacuo to give 743.9 g, 81%, of a yellow oil which readily crystallized. Distillation of the oil at reduced pressure gave 707 g, 77%, b.p. 80°-85° at 0.75 Torr., of colorless distillate which readily crystallized, m.p. 39°-41°.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@H:17]([F:29])[CH2:16][O:15]2)[N:6]=1.[C:40]1(B2OC(C)(C)C(C)(C)O2)[CH2:44][CH2:43][CH2:42][CH:41]=1>>[NH2:32][C:4]1[S:3][C:2]([C:40]2[CH2:44][CH2:43][CH2:42][CH:41]=2)=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:30])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@H:17]([F:29])[CH2:16][O:15]1)=[O:31]
Reactant: CC1(C)OB(C2=CCCC2)OC1(C)C
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: Cn1ncc(NC(=O)c2nc(C3=CCCC3)sc2N)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6S)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 95), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane gave 333. 1H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 7.85 (s, 1H), 7.34 (s, 2H), 6.20-6.15 (m, 1H), 4.80 (dd, J=10.4, 3.7 Hz, 1H), 4.50-4.29 (m, 1H), 4.27-4.16 (m, 1H), 4.12-3.95 (m, 1H), 3.74 (s, 3H), 2.79-2.69 (m, 2H), 2.07-1.99 (m, 1H), 1.97-1.86 (m, 2H), 1.81-1.66 (m, 4H). LCMS (ES+) m/z 421 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([C:13]([O:15]CC)=[O:14])[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.Cl>[OH-].[Na+].C1COCC1.CO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([C:13]([OH:15])=[O:14])[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1Cc2ccc(Cl)cc2NC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1Cc2ccc(Cl)cc2NC1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.9 %

Procedure:
IN Aqueous sodium hydroxide solution (60 ml) was added dropwise to a mixed solution of ethyl 7-chloro-2-oxo -1,2,3,4-tetrahydro-3-quinolinecarboxylate (14.39 g) in THF (180 ml) and methanol (120 ml) at 0° C. The reaction mixture was stirred at room temperature for 24 hours. 1N Hydrochloric acid (70 ml) was added dropwise to the reaction mixture at 0° C., which was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried and concentrated. The obtained crude crystals were washed with IPE to obtain the entitled compound (12.15 g).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH3:3].O1[CH2:13][C@@H:6]1[C@@H:7]([CH3:12])[CH2:8][C:9]([O-:11])=[O:10].[Cl-].[NH4+]>CCOCC.[Cu](I)I>[CH3:12][C@@H:7]1[C@@H:6]([CH2:13][CH2:1][CH2:2][CH3:3])[O:11][C:9](=[O:10])[CH2:8]1
Reactant: [Li]CCC
Reactant: C[C@@H](CC(=O)[O-])[C@H]1CO1
Agent: I[Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCCC[C@H]1OC(=O)C[C@@H]1C
Temperature: -50 °C
Yield: 75.9 %

Procedure:
In 20 ml of anhydrous ether, 1.98 g of copper iodide (10.4 mmol were suspended. To the resultant suspension, 20.8 ml of n-propyl lithium solution (1 N, 20.8 mmol) were added dropwise under an argon atmosphere with cooling at -50° C. The reacted solution was added dropwise to 25 ml of anhydrous ether solution containing 1.0 g of epoxide (6.94 mmol) obtained in step [C'] under an argon atmosphere at -60° C. Next, the temperature of the reacted solution was raised from -60° C. to -20° C. over three hours. After that, the solution was poured into a saturated aqueous ammonium chloride solution, followed by stirring for thirty minutes. Next, the solution was filtered to remove insoluble substances. The obtained filtrate was extracted with ether. The resultant extract was then washed with water and a saturated aqueous sodium chloride aqueous solution, in this order, dried with anhydrous magnesium sulfate, and filtered. The obtained filtrate was concentrated, and the obtained residue was dissolved in 20 ml of methanol. To the obtained solution was then added 20 ml of a 10% aqueous sodium hydroxide solution, followed by stirring at room temperature for three hours. Next, the methanol in the solution as distilled off under reduced pressure, and the obtained residue was extracted twice with diethyl ether and then the organic layer was separated from the obtained extract. Also, the residual aqueous layer was acidified with dilute hydrochloric acid, and then extracted five times with diethyl ether. The obtained extract was combined with the organic layer obtained before. The combined organic layer was dried with anhydrous magnesium chloride, and concentrated to obtain a crude product. This crude product was purified via silica gel column chromatography (n-hexane:ethyl acetate=10:1 to 5:1), and distilled under reduced pressure to obtain 823 mg of trans-whisky lactone (yield: 76.2%). This product exhibited the same physical properties as that of the trans-whisky lactone obtained in Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[C:10](Cl)=[CH:9][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[N:7][C:6]=12.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[CH2:32][CH2:33][NH2:34])=[O:25])([CH3:22])([CH3:21])[CH3:20].C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[CH2:32][CH2:33][NH:34][C:10]1[N:5]2[N:4]=[CH:3][C:2]([Br:1])=[C:6]2[N:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[CH:9]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: Clc1ccccc1-c1cc(Cl)n2ncc(Br)c2n1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCN
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCCCC1CCNc1cc(-c2ccccc2Cl)nc2c(Br)cnn12
Temperature: 75 °C
Yield: 78.7 %

Procedure:
3-Bromo-7-chloro-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidine (400 mg, 1.166 mmoles) (prepared as described in Preparative Example 129) was dissolved in anhydrous 1,4-dioxane (5.7 mL). 2-Aminoethylpiperidine-1-carboxylic acid tert-butyl ester (266 mg, 1.166 mmoles) and diisopropyl ethylamine (0.409 mL, 2.33 mmoles) were added and the mixture was heated at 75° C. for 48 h. Additional diisopropyl ethylamine (0.204 mL, 1.166 mmoles) was added and the heating was continued for a total of 58 h. The solution was evaporated to dryness and the residue was chromatographed on a silica gel column (15×5 cm) using dichloromethane followed by 0.3% (10% conc. ammonium hydroxide in methanol)-dichloromethane as the eluant to give 2-{[3-bromo-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino]ethyl}piperidine-1-carboxylic acid tert-butyl ester (491.1 mg, 79%): FABMS: m/z 534.1 (MH+); HRESIMS: m/z 534.12797 (MH+). Calcd. for C24H30N5O2BrCl: m/z 534.12714; δH (CDCl3) 1.50 (1H, m, CH2), 1.51 (9H, s, COOC(CH3)3), 1.57 (2H, m, CH2), 1.68 (2H, m, CH2), 1.76 (2H, m, CH2), 2.24 (1H, bm, CH2), 2.82/3.40/3.54/4.08/4.51 (5H, m, CH/CH2), 6.34 (1H, s, H6), 7.41 (2H, m, Ar—H), 7.51 (1H, m, Ar—H), 7.76 (1H, m, Ar—H) and 8.08 ppm (1H, s, H2); δC (CDCl3) CH3: 28.5, 28.5, 28.5; CH2: 19.2, 25.5, 29.2, 29.2, 39.2, 67.1; CH: ˜47.4, 87.1, 127.1, 130.1, 130.1, 131.6, 143.9; C: 80.0, 83.0, 132.1, 138.9, 145.7, 146.2, 158.0.
Reaction SMILES: C(O[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([N:19]2[CH:23]=[CH:22][N:21]=[C:20]2[CH3:24])=[C:16]([F:18])[CH:17]=1)=O)C1C=CC=CC=1.C([Li])CCC.[CH2:30]([O:34][C:35](=[O:39])CCC)[C@@H:31]1[O:33]C1.C(=O)(O)[O-].[Na+]>O1CCCC1.CN1CCCN(C)C1=O.C(OCC)(=O)C>[F:18][C:16]1[CH:17]=[C:12]([N:11]2[CH2:9][C@H:30]([CH2:31][OH:33])[O:34][C:35]2=[O:39])[CH:13]=[CH:14][C:15]=1[N:19]1[CH:23]=[CH:22][N:21]=[C:20]1[CH3:24]
Reactant: Cc1nccn1-c1ccc(NC(=O)OCc2ccccc2)cc1F
Reactant: CCCC(=O)OC[C@H]1CO1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Solvent: CCOC(C)=O
Product: Cc1nccn1-c1ccc(N2C[C@H](CO)OC2=O)cc1F
Reaction time: 0.5 h
Yield: 44.5 %

Procedure:
5-Benzyloxycarbonylamino-2-(2-methylimidazol-1-yl)fluorobenzene (54 g, 0.166 M) was dissolved in a mixture of dry tetrahydrofuran (600 ml) and 1,3-dimethyl-tetrahydropyrimidin-2-one (100 ml) under nitrogen, cooled to −70°, and treated with a solution of n-butyllithium (1.6M in isohexane, 114 ml), over 30 minutes. After stirring for 30 minutes at −70°, a solution of (R)-glycidylbutyrate (26.35 g, 0.183 M) in dry tetrahydrofuran (50 ml) was added over 15 minutes. Stirring was continued for 16 hours allowing the temperature to rise to ambient. The mixture was treated with aqueous sodium bicarbonate (5%, 500 ml) and ethyl acetate (800 ml), the organic layer separated, and the aqueous extracted with further ethyl acetate (3×750 ml). The combined extracts were dried (magnesium sulfate) and evaporated, and the resulting oil triturated with diethyl ether. The resulting solid was recrystallisd from isopropanol to give the title compound (21.5 g).
Reaction SMILES: [Cl:1][CH:2]([C:7](=[O:23])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:3]([O:5][CH3:6])=[O:4].ClC(C(=O)CC)C(OC)=O.C(Cl)Cl.P>[Ru].CO>[Cl:1][CH:2]([C@H:7]([OH:23])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:3]([O:5][CH3:6])=[O:4]
Reactant: CCCCCCCCCCCCCCCC(=O)C(Cl)C(=O)OC
Agent: [Ru]
Agent: CCC(=O)C(Cl)C(=O)OC
Agent: P
Solvent: CO
Solvent: ClCCl
Product: CCCCCCCCCCCCCCC[C@@H](O)C(Cl)C(=O)OC
Yield: 95.3 %

Procedure:
In a 500 ml Hastelloy-made autoclave having been purged with nitrogen were put 100 g (0.2886 mol) of the methyl 2-chloro-3-oxooctadecanoate (VII) prepared in (1) above, 2 ml of a methylene chloride solution of 260 mg (0.144 mol) of a ruthenium-optically active phosphine complex Ru2Cl4 [(+)-Tol-BINAP]2NEt3, and 300 ml of methanol, and the mixture was allowed to react at 50° C. under a hydrogen pressure of 30 atm for 18 hours. Methanol was removed by evaporation to give 95.8 g (0.275 mol; yield: 95.3%) of the title compound (VIII) (melting point: 39-40° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.Cl[CH2:25][C:26]([C:28]1[O:29][CH:30]=[CH:31][C:32]=1[CH2:33][O:34][CH3:35])=[O:27]>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:25]=1[C:26]([C:28]1[O:29][CH:30]=[CH:31][C:32]=1[CH2:33][O:34][CH3:35])=[O:27]
Reactant: COCc1ccoc1C(=O)CCl
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Product: COCc1ccoc1C(=O)c1[nH]c2cc(Cl)ccc2c1CC(=O)OC

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-4-chloro-2-(penylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and 2-chloroacetyl-3-(methoxymethyl)furan*.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7][N:8]2CO[CH2:11][N:10](C)[C:9]2=[N:15][N+:16]([O-:18])=[O:17])=[CH:5][N:6]=1.[OH-].[Na+]>Cl>[Cl:1][C:2]1[S:3][C:4]([CH2:7][NH:8][C:9]([NH:10][CH3:11])=[N:15][N+:16]([O-:18])=[O:17])=[CH:5][N:6]=1
Reactant: CN1COCN(Cc2cnc(Cl)s2)C1=N[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CNC(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 5.0 g of 5-(2-chlorothiazol-5-ylmethyl)-3-methyl4-nitroimino-perhydro-1,3,5-oxadiazine and 20 ml of concentrated hydrochloric acid is stirred for 2 hours at 80° C. The reaction mixture is cooled to 5° C., adjusted to a pH of about 5 with concentrated caustic soda solution and filtered. The filtering residue is mixed with diethyl ether/ethyl acetate 1:1 (v:v) and filtered again. The title compound is thus obtained.
Reaction SMILES: [S:1]([N:11]1[C:19]2[C:14](=[C:15]([CH2:20][N:21]3[C:26]4([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH2:25][CH2:24][CH2:23][C:22]3=[O:32])[CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].Cl[C:34]1[CH:43]=[N:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:35]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:35]1[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:42]=[CH:43][C:34]=1[N:29]1[CH2:30][CH2:31][C:26]2([N:21]([CH2:20][C:15]3[CH:16]=[CH:17][CH:18]=[C:19]4[C:14]=3[CH:13]=[CH:12][N:11]4[S:1]([C:4]3[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=3)(=[O:2])=[O:3])[C:22](=[O:32])[CH2:23][CH2:24][CH2:25]2)[CH2:27][CH2:28]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(CN4C(=O)CCCC45CCNCC5)cccc32)cc1
Reactant: Clc1cnc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(CN4C(=O)CCCC45CCN(c4cnc6ccccc6n4)CC5)cccc32)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 103 %

Procedure:
To a stirred solution of 1-((1-tosyl-1H-indol-4-yl)methyl)-1,9-diazaspiro[5.5]undecan-2-one (TFA salt) (0.11 g, 0.201 mmol) in 5.0 mL DMF, 2-chloroquinoxaline (0.04 g, 0.241 mmol) and K2CO3 (0.084 g, 0.603 mmol) were added and the reaction mixture was stirred for 6 h at 80° C. under a nitrogen atmosphere. The reaction mixture was quenched with ice-cold water and extracted with ethyl acetate (2×25 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield the title compound as a pale yellow solid (0.120 g). LCMS RtA=0.512, [M+H]+=579.9