Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BrH:1].[CH2:2]([CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=2)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCOCC>CO.[Pd]>[BrH:1].[BrH:1].[NH2:24][C:21]1[CH:20]=[CH:19][C:18]([O:17][CH2:16][CH2:15][N:12]2[CH2:11][CH2:10][CH:9]([CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH2:14][CH2:13]2)=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1ccc(OCCN2CCC(Cc3ccccc3)CC2)cc1
Agent: [Pd]
Agent: Br
Solvent: CCOCC
Solvent: CO
Product: Nc1ccc(OCCN2CCC(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 119.9 %

Procedure:
A mixture of 4-benzyl-1-(2-(4-nitrophenoxy)ethyl)piperidine hydrobromide (900 mg, 2.14 mmol) and Pd/C (10%; 100 mg) in MeOH (50 mL) was shaken under H2 (20-30 psi, Parr) for 2.25 h at 25° C. The catalyst was removed by filtration (Celite). The resulting solution was acidified with a dilute solution of HBr in MeOH. The MeOH was removed in vacuo (rotoevap) to give a syrup. Ether (45 mL) was added and the resulting mixture was vigorously stirred at 25° C. for 48 h. A gray suspension was obtained. The solid was collected, washed with ether (3×3 mL) and dried in vacuo (0.005 Torr, 56° C.) to give a beige powder (606 mg, 60%): mp>130° C.; 1H NMR (DMSO-d6) 1.33-1.88 (m, 5 H), 2.38-3.75 (m, 8 H), 4.25-4.45 (m, 2 H), 7.04-7.38 (m, 9 H), 9.49-10.30 (m, 4 H).
Reaction SMILES: C([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:53][O:54][CH3:55])[C:27]([NH:29][CH:30]2[C:37](=[O:38])[N:36]3[CH:31]2[CH2:32][S:33][C:34]([S:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[C:35]3[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:28])[N:25]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(O)=O>[NH2:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:53][O:54][CH3:55])[C:27]([NH:29][CH:30]2[C:37](=[O:38])[N:36]3[CH:31]2[CH2:32][S:33][C:34]([S:46][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)=[C:35]3[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:28])[N:25]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(C)(C)C)=C(Sc3ccccc3)SCC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O=CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(C)(C)C)=C(Sc3ccccc3)SCC12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
A mixture of 200 mg of the product of Step B dissolved in 5 ml of 66% formic acid was stirred for 1 hour at ambient temperature and then was concentrated to dryness under reduced pressure at less than 30° C. The residue was dissolved in a mixture of acetonitrile and methanol and the solvent was evaporated to obtain 110 mg of 1,1-dimethylethyl 7-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamido]-8-oxo-3-phenylthio-4-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylate which after crystallization from ether had an Rf=0.42 (CH2C2 -MeOH (9-1).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][CH2:15][CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[NH:23][CH:22]([C:27]3[C:35]([Br:36])=[CH:34][C:30]4[O:31][CH2:32][O:33][C:29]=4[CH:28]=3)[CH:21]3[CH2:37][CH:38]=[CH:39][CH:20]3[C:19]=2[CH:18]=1)(C)(C)C>ClCCl>[Br:36][C:35]1[C:27]([CH:22]2[CH:21]3[CH2:37][CH:38]=[CH:39][CH:20]3[C:19]3[CH:18]=[C:17]([CH2:16][CH2:15][NH2:14])[CH:26]=[CH:25][C:24]=3[NH:23]2)=[CH:28][C:29]2[O:33][CH2:32][O:31][C:30]=2[CH:34]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc2c(c1)C1C=CCC1C(c1cc3c(cc1Br)OCO3)N2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCc1ccc2c(c1)C1C=CCC1C(c1cc3c(cc1Br)OCO3)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
Triflouroacetic acid (1.2 mL) was added dropwise to a solution of {2-[4-(6-bromo-benzo[1,3]dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-8-yl]-ethyl}-carbamic acid tert-butyl ester (0.15 g, 0.3 mmol) in dichloromethane (1.5 mL), and stirred at rt for 1 h. The reaction mixture was diluted with dichloromethane (15 mL) and washed with cold saturated NaHCO3. Organic layer dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude material was purified by preparative silica gel chromatography using 20% MeOH/DCM and gave the product as a colorless solid (0.115 g, 95%).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.Cl>O.CO>[C:23]([O:22][C:20]([NH:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][N:9]1[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CCOC(=O)C1CCN(Cc2cccc(NC(=O)OC(C)(C)C)c2)CC1
Agent: Cl
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cccc(CN2CCC(C(=O)O)CC2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 1-(3-tert-butoxycarbonylamino-benzyl)-piperidine-4-carboxylic acid ethyl ester (7.6 g, 21.4 mmol) in a mixture of water (90 mL) and MeOH (90 mL) at RT is treated at once with LiOH mono hydrate (922 mg, 22 mmol). The mixture is stirred at RT for 18 h then HCl 1N (22 mmol, 22 mL) is added and the reaction mixture is stirred at RT for 30 min. The solvents are removed under reduce pressure and the crude acid is dried under high vacuum. The crude title compound containing LiCl is used for the next step. LC-MS A: tR=0.56 min; [M+H]+=335.26.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[N:21]=[C:20](Cl)[N:19]=3)[CH2:14][CH2:13]2)=[N:7][CH:6]=1)[CH3:2].[CH3:33][CH:34]1[CH2:38][CH2:37][CH2:36][NH:35]1>CC(N(C)C)=O>[CH2:1]([O:3][C:4](=[O:32])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[CH:23]=[C:22]([C:24]4[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=4)[N:21]=[C:20]([N:35]4[CH2:36][CH2:37][CH2:38][CH:34]4[CH3:33])[N:19]=3)[CH2:16][CH2:17]2)=[N:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cnc(N2CCN(c3cc(-c4ccc(F)cc4)nc(Cl)n3)CC2)c(Cl)c1
Reactant: CC1CCCN1
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cnc(N2CCN(c3cc(-c4ccc(F)cc4)nc(N4CCCC4C)n3)CC2)c(Cl)c1

Procedure:
Heat a mixture of 5-chloro-6-{4-[2-chloro-6-(4-fluoro-phenyl)-pyrimidin-4-yl]-piperazin-1-yl}-nicotinic acid ethyl ester (1.19 g, 0.0025 mol) and 2-methylpyrrolidine (2.5 mL, 0.025 mol) in DMA at 120° C. for 14 h. Partition the reaction mixture between EtOAc and water. Wash the organic layer with water (1×) and brine (1×), then dry (Na2SO4) and concentrate under reduced pressure. Filter the crude product through a silica gel pad (2 inches deep×3 inches in diameter) eluting with 700 mL of 30% EtOAc/hexanes. Concentrate under reduced pressure to give the title compound as an off-white foam.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:15]=3)[CH:10]=[CH:11][N:12]=2)[CH2:3][CH2:2]1.C1C(=O)N([Br:28])C(=O)C1>C(Cl)Cl>[Br:28][C:10]1[N:9]2[CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:15]=[C:8]2[C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[N:12][CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cn2ccnc(N3CCOCC3)c2n1
Solvent: ClCCl
Product: CCOC(=O)c1cn2c(Br)cnc(N3CCOCC3)c2n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of compound 1c (3.2 g, 9.0 mmol) in DCM (100 mL) at 0° C. was added NBS (1.6 g, 9.0 mmol) portionwise. The reaction mixture was allowed to stir at rt for 10 min, and subsequently was washed with a saturated aqueous sodium bicarbonate (2×100 mL). The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure to give compound 21a as an off-white solid. Mass Spectrum (LCMS, ESI pos.) Calcd. For C13H15BrN4O3: 356.2 (M+H). Found 356.1.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[C:12][CH2:13][O:14][C:15](=[O:17])[CH3:16])(C)(C)C.CC(C)=[O:22].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O>[C:15]([O:14][CH2:13][C:12]#[C:11][CH2:10][CH2:9][CH2:8][C:7]([OH:6])=[O:22])(=[O:17])[CH3:16]
Reactant: CC(=O)OCC#CCCCCO[Si](C)(C)C(C)(C)C
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: CC(=O)OCC#CCCCC(=O)O
Reaction time: 1 h

Procedure:
A solution of crude (28) in acetone (100 mL) was treated with Jones Reagent (18.0 mL, 41.4 mmol, 2.3 M) and cooled with an ice bath. After 1 hour at room temperature, 10 mL isopropyl alcohol was added and the mixture stirred for 15 minutes. The mixture still had a brown color so another 10 mL isopropyl alcohol was added. After another 15 minutes, the color had not changed so the mixture was filtered through celite and the filtrate evaporated in vacuo. The residue was partitioned between 100 mL ether and 100 mL saturated ammonium chloride solution. The aqueous layer was extracted with 100 mL ether and the combined ether solution washed with brine and then dried (MgSO4), filtered and evaporated to leave a yellow oil (6.333 g) that was used directly in the next step.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][O:5][CH2:4][C@H:3]1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].CCN(CC)CC.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl.O>[CH3:23][S:24]([O:1][C@@H:2]1[CH2:7][CH2:6][O:5][CH2:4][C@H:3]1[NH:8][C:9]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:15])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1COCC[C@H]1O
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1COCC[C@H]1OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 101.2 %

Procedure:
Tert-butyl ((3R,4R)-4-hydroxytetrahydro-2H-pyran-3-yl)carbamate (1.6 g, 7.36 mmol) was taken up in CH2Cl2 (20 ml) and cooled to 0° C. followed by addition of Et3N (1.232 ml, 8.84 mmol). After 5 minutes methanesulfonyl chloride (0.631 ml, 8.10 mmol) in DCM (5 ml) was added dropwise. The reaction mixture was stirred at 0° C. for 30 minutes and allowed to warm to ambient temperature while stirring for 2 hours. The reaction mixture was diluted with water and DCM and the layers were separated. The organic layers were combined and washed with water twice, dried over Na2SO4, and the solvent removed in vacuo. The residue was dried under high vacuum overnight to afford recovered (3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl methanesulfonate (2.2 g, 7.45 mmol, 100% yield) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH:5]2[NH:4][C:3]1=[O:10].[H-].[Na+].Cl[C:14]1[N:15]=[N:16][C:17]([C:20]#[C:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:19]=1>CN(C=O)C>[CH3:1][N:2]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH:5]2[N:4]([C:14]2[N:15]=[N:16][C:17]([C:20]#[C:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:19]=2)[C:3]1=[O:10]
Reactant: CN1C(=O)NC2CCCC21
Reactant: Clc1ccc(C#Cc2ccccc2)nn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)N(c2ccc(C#Cc3ccccc3)nn2)C2CCCC21
Yield: 48.1 %

Procedure:
To a solution of (3aRS,6aSR)-1-methyl-hexahydro-cyclopentaimidazol-2-one (Example 106, step 3) (55 mg, 0.39 mmol, 1.5 equiv.) in 3 ml of DMF was added 60% sodium hydride suspension in mineral oil (17 mg, 0.42 mmol, 1.6 equiv.). The white suspension was stirred for min. at room temperature. Then 3-chloro-6-(phenylethynyl)pyridazine (CAS 77778-15-5) (56 mg, 0.261 mmol) was added and the reaction was stirred for 1 hour at room temperature. After workup with ethyl acetate/water, drying over magnesium sulfate and concentration in vacuo, the residue was purified by flash chromatography over silica gel eluting with a heptane to 50% ethyl acetate/heptane gradient to yield 40 mg (48% yield) of the title compound as an off-white solid, MS: m/e=319.1 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:15]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17]>>[CH3:29][C:27]1[CH:26]=[CH:25][C:15]([C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:28]=1
Reactant: Cc1ccc(C(=O)Nc2ccccc2)c(N)c1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Product: Cc1ccc(C(=O)Nc2ccccc2)c(Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product from Example 1d (150 mg, 0.84 mmol) was reacted with the product from Example 95c (190 mg, 0.84 mmol) for 6 h following the procedure from Example 1g giving the crude title compound which was purified by silica gel column chromatography eluting with 50:1 CH2Cl2/MeOH providing the title compound (210 mg, 68%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.40 (s, 3H), 2.68 (s, 3H), 6.62 (d, J=6.9 Hz, 1H), 6.98 (t, J=7.3 Hz, 1H), 7.19 (t, J=7.3 Hz, 2H), 7.36 (s, 1H), 7.38 (d, J=8.3 Hz, 1H), 7.52 (d, J=7.3 Hz, 2H), 7.67 (d, J=8.8 Hz, 1H), 7.78 (d, J=8.3 Hz, 1H), 8.40 (d, J=6.9 Hz, 1H), 8.94 (d, J=8.8 Hz, 1H); MS (ESI+) m/z 369 (M+H), ESI− m/z 367 (M−H).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]=[CH:15][C:16]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]2[C:17]=1[CH:18]=[CH:19][CH:20]=[N:21]2.[BH4-].[Na+]>CO.O>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][C:16]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]2[C:17]=1[CH:18]=[CH:19][CH:20]=[N:21]2
Reactant: Oc1ccc(C=NCCCCCCC2CC3C=CC2C3)c2cccnc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Oc1ccc(CNCCCCCCC2CC3C=CC2C3)c2cccnc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
Imine 7 was dissolved in 50 mL of dry methanol and 1 equivalent of NaBH4 (0.136 g, 0.0036 mol) was added in small increments. After the addition was complete, the solution was allowed to stir for 10 minutes at room temperature. The solution was diluted with water and extracted three times with 20 mL of methylene chloride. The combined organic layers were washed with water, NaHCO3, brine, and dried over Na2SO4. The solvent was removed under reduced pressure to yield a brown liquid. Purification by column chromatography (silica gel, 4:1 hexanes/ethyl acetate, then pure ethyl acetate, then 5% methanol in ethyl acetate) gave the product as a pale yellow solid (0.658 g, 50%). 1H NMR (300 MHz, CDCl3) δ8.75 (1H, dd, J=1.09, 4.39); 8.51 (1H, dd, J=1.09, 8.24); 7.46 (1H, dd, J=4.39, 8.24); 7.38 (1H, d, J=7.69); 7.08 (1H, d, J=7.69); 6.11 (1H endo, dd, J=2.74, 5.49); 6.06–5.99 (2H exo, m); 5.90 (1H endo, dd, J=2.74, 5.49); 4.10 (1H, s); 2.73 (2H, s); 2.71 (2H, t, J=7.14); 1.99–1.02 (12H, m); 0.49–0.43 (1H, m). 13C NMR (75 MHz, CDCl3) δ151.8; 147.6; 137.0; 136.3; 133.4; 132.6; 128.0; 127.4; 126.8; 121.8; 109.2; 51.2; 50.0; 49.7; 45.5; 42.7; 38.9; 34.9; 32.6; 30.2; 29.9; 28.8; 27.5. Anal. Calcd for C23H30N2O: C, 78.88; H, 8.63; N, 8.00. Found C: 78.79, H: 8.72, N: 8.00.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([CH2:6][OH:7])[CH2:2]1.[C:8](=O)([O:14]C(C)(C)C)[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].C(=O)=O>C1COCC1>[OH:7][CH2:6][CH:3]1[CH2:4][CH2:5][N:1]([C:8]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:14])[CH2:2]1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: OCC1CCNC1
Agent: O=C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CO)C1
Yield: 100 %

Procedure:
To a boiled solution of pyrrolidin-3-ylmethanol (Preparation 64, 52.4 g, 0.518 mol, 1 eq) in THF (200 mL) was added dropwise under stirring a solution of di-tert-butyl carbonate (114.2 g, 0.523 mol, 1.01 eq) in THF (100-10 mL) during 1.5 h. After carbon dioxide evolution ceased, the mixture was refluxed for 2.5-3 h and cooled to give a yellowish solution. Solvents were removed on a rotary evaporator from this solution. Yellowish viscous oily residue was vacuum-dried to constant weight to give title compound (104 g, 0.518 mol, 100%).
Reaction SMILES: [C:1]([N:5]([CH2:13][CH2:14][C:15]([CH3:20])([CH3:19])[CH2:16][C:17]#[CH:18])[C:6](=[O:12])[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].O1CCOCC1>O>[C:1]([N:5]([CH2:13][CH2:14][C:15]([CH3:20])([CH3:19])[CH2:16][C:17]#[CH:18])[C:6](=[O:12])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCC(C)(C)CCN(C(=O)C(=O)OCC)C(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C#CCC(C)(C)CCN(C(=O)C(=O)O)C(C)(C)C
Temperature: 50 °C
Yield: 106.6 %

Procedure:
A mixture of 250 mg of 24d, 250 mg of KOH, 3 ml of dioxane and 1 ml of water was heated at oil bath at 50° C. for 1 hr. The mixture was poured onto water and extracted once with heptane/ether 1/1. The aqueous phase was acidified with cold 1N HCl to pH3 and extracted with ethyl acetate. The organic extract was once washed with sat. NaCl and dried and concentrated, to give 240 mg of 24e, as colorless oil. NMR (CDCl3) δ 1.00 (s, 6, 2×CH3), 1.50 (s, 9, tertC4H9), 2.00 (t, 1, acetylene), 1.70 (m, 2, CH2), 2.10 (m, 2, CH2), 3.71 (m, 2, CH2).
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=1)[OH:4])#[N:2].[Cl:18][C:19]([Cl:29])=[CH:20][C@@H:21]1[C@H:23]([C:24](Cl)=[O:25])[C:22]1([CH3:28])[CH3:27].N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:18][C:19]([Cl:29])=[CH:20][C@@H:21]1[C@H:23]([C:24]([O:4][CH:3]([C:1]#[N:2])[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:6]=2)=[O:25])[C:22]1([CH3:27])[CH3:28]
Reactant: N#CC(O)c1cccc(Oc2ccccc2)c1
Reactant: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 106.1 %

Procedure:
A mixture of 468.6 g (2.08 moles) (cyano)(3-phenoxyphenyl)methanol and 2500 ml toluene was placed in a flask and heated to 40° C. During an 80-85 minute period, 509 g (2.24 moles) of (cis)-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarbonyl chloride prepared as described in Step B, and 186 g (2.35 moles) of pyridine were added under nitrogen. Upon completion of the addition, the reaction mixture was stirred 2.5 hours at 40° C. After cooling, the reaction mixture was washed successively with 1000 ml of water, 1000 ml of 1 N hydrochloric acid, 1000 ml of 1 N sodium hydroxide, twice with water, and once with an aqueous solution of sodium chloride. After being dried over magnesium sulfate, the solution was filtered through Celite and the solvent stripped using a rotary evaporator. Residual solvent was removed in a vacuum oven. A total of 918.3 g of 93.6% (cyano)(3-phenoxyphenyl)methyl cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylate was obtained.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]3[CH:17]=[N:18][C:19]([C:20](OCC)=[O:21])=[C:9]3[N:8]=2)[CH2:3][CH2:2]1.C([NH2:28])(=O)C.C[O-].[Na+]>CN(C)C=O.CO.C(O)(C)C>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]3[CH:17]=[N:18][C:19]([C:20]([NH2:28])=[O:21])=[C:9]3[N:8]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ncn2c1nc(N1CCOCC1)c1ccccc12
Reactant: CC(N)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: NC(=O)c1ncn2c1nc(N1CCOCC1)c1ccccc12
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A stirred mixture of ethyl 5-morpholino-imidazo[1,5-a]quinazoline-3-carboxylate (2.0 g) and acetamide (1.2 g) in 20 ml of dry dimethylformamide was heated to 80° C. 30% sodium methoxide in methanol (1 ml) was added and the mixture was stirred at 100° C. for 2 hours, cooled to room temperature and diluted with isopropanol (20 ml). Crystals were filtered off, washed with isopropanol (15 ml), water (20 ml) and diethyl ether (10 ml), and dried to give the title compound as yellow crystals, m.p. >300° C. Yield 1.3 g.
Reaction SMILES: C([O-])(=O)C.[Na+].[C:6]([O:9][C:10](=[O:12])[CH3:11])(=[O:8])[CH3:7].[CH3:13][N:14]([CH3:21])[N:15]=[CH:16][C:17]([CH2:19][CH3:20])=[CH2:18].BrC1C(OC(=O)C=1)=O>C(Cl)Cl>[CH3:13][N:14]([CH3:21])[N:15]1[CH:16]=[C:17]([CH2:19][CH3:20])[CH2:18][C:7]2[C:6]([O:9][C:10](=[O:12])[C:11]1=2)=[O:8]
Reactant: CC(=O)OC(C)=O
Reactant: C=C(C=NN(C)C)CC
Agent: CC(=O)[O-]
Agent: O=C1C=C(Br)C(=O)O1
Agent: [Na+]
Solvent: ClCCl
Product: CCC1=CN(N(C)C)C2=C(C1)C(=O)OC2=O
Reaction time: 1 h

Procedure:
A mixture of sodium acetate (14.76 g, 180.0 mmol) and acetic anhydride (150 ml) is heated, under N2, to 120° for 10 min., and is then chilled to 10°. 2-Ethyl-2-propenal dimethylhydrazone (11.36 g, 90.0 mmol) is added, followed by addition of bromomaleic anhydride (16.41 g, 92.7 mmol) and the reaction mixture is stirred at 10° for ca. 1 hour. The mixture is then diluted with methylene chloride and filtered, and the solid is rinsed with methylene chloride until colorless. The filtrate is concentrated to remove the solvent and to give 1,4-dihydro-1-dimethylamino-5-ethyl-2,3-pyridine-dicarboxylic anhydride.
Reaction SMILES: [CH3:1][CH:2]([SH:6])[CH:3]([SH:5])[CH3:4].Cl[CH2:8][C:9](=O)[CH2:10][CH3:11]>>[CH2:10]([C:9]1[S:5][CH:3]([CH3:4])[CH:2]([CH3:1])[S:6][CH:8]=1)[CH3:11]
Reactant: CC(S)C(C)S
Reactant: CCC(=O)CCl
Product: CCC1=CSC(C)C(C)S1
Yield: 53 %

Procedure:
The procedure of Example 1(a) is followed using 2,3-butanedithiol and 1-chloro-2-butanone to give 2-ethyl-5,6-dihydro-5,6-dimethyl-1,4-dithiin as a colorless oil, b.p. 55°-58°/0.03-0.05 mm, yield 53%. NMR 1.08 (3t), 1.36 (6d), 2.18 (2q), 2.7-3.1 (2m), 5.78 (1s, broadened) (CDCl3). IR 3000 (shoulder), 2955, 1570, 1440, 1365, 1110, 825, 705.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:11]=[C:10]([CH2:12][CH3:13])[N:9]([C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)[N:8]=2)[CH:2]=1.[CH2:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH:22]1[CH:30]=O.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH2:12]([C:10]1[N:9]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][CH2:30][CH:22]3[CH2:21][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:23]3)=[CH:18][CH:19]=2)[N:8]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:11]=1)[CH3:13]
Reactant: O=CC1Cc2ccccc2C1
Reactant: CCc1cc(-c2cccnc2)nn1-c1ccc(N)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCc1cc(-c2cccnc2)nn1-c1ccc(NCC2Cc3ccccc3C2)cc1

Procedure:
A solution of 3-(3-pyridyl)-5-ethyl-1-(4′-aminophenyl)pyrazole (185 mg, 0.7 mmol) and indane 2-carboxaldehyde (0.96 mmol, 140 mg) in methanol (9 mL) and acetic acid (1 mL) was stirred at room temperature for 30 min. Sodium cyanoborohydride (124 mg, 2 mmol) was added and stirring continued at room temperature. After 3 h the solvent was evaporated under vacuum, the residue was taken up in sodium bicarbonate solution (50 mL), and extracted with methylene chloride (3×50 mL). The combined organic extracts were washed with water, dried over anhydrous sodium sulfate, and evaporated. Chromatography of the residue over silica gel (eluant, 35% ethyl acetate in methylene chloride) gave the title compound which was taken up in 50% aqueous acetonitrile containing 1% trifluoroacetic acid and lyophilized to give a light yellow solid. 1H NMR (DMSO-d6) δ 1.2 (3H, t, J=7.5 Hz), 2.63 (2H, q, J=7.5 Hz), 2.7-2.76 (3H, m), 3.05-3.12 (4H, m), 6.71 (2H, d, J=8.7 Hz), 6.98 (1H, s), 7.12-7.14 (2H, m), 7.21-7.24 (4H, m), 7.84-7.88 (1H, m), 8.65 (1H, br, d, J=8.2 Hz), 8.71 (1H, d, J=5.1 ),9.2 (1H, s).
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH3:11])[C:7]([OH:9])=O)(=[O:3])[CH3:2].[NH2:19][C@H:20]([C:22]([OH:24])=[O:23])[CH3:21]>>[CH2:10]([O:23][C:22](=[O:24])[C@H:20]([CH3:21])[NH:19][C:7](=[O:9])[CH:6]([CH2:5][S:4][C:1](=[O:3])[CH3:2])[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH3:11])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)SCC(C(=O)O)C(C)c1ccc(F)cc1
Reactant: C[C@H](N)C(=O)O
Product: CC(=O)SCC(C(=O)N[C@@H](C)C(=O)OCc1ccccc1)C(C)c1ccc(F)cc1
Yield: 73 %

Procedure:
Working as in Example 60, but starting with 2-acetylthiomethyl-3-(4-fluorophenyl)butanoic acid and benzyl esters of alanine, the title compound is obtained in a yield of 73% as an oil having the characteristics: