Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.Cl[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7]([CH2:16][C:17]2[C:22]([Cl:23])=[CH:21][N:20]=[CH:19][C:18]=2[Cl:24])=[N:6][N:5]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.CCCCCC.C(OCC)(=O)C>CN(C=O)C>[Cl:24][C:18]1[CH:19]=[N:20][CH:21]=[C:22]([Cl:23])[C:17]=1[CH2:16][C:7]1[C:8]2[C:13](=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[N:5][N:6]=1
Reactant: C1COCCN1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(Cl)c2c1
Agent: N#N
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(N3CCOCC3)c2c1
Temperature: 100 °C
Reaction time: 14 h
Yield: 78.7 %

Procedure:
A solution under stirring and dry N2 of 4-chloro-1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazine (1 g, 2.82 mmoles), prepared as described in example 45, in DMF (25 ml), at room temperature, was added with morpholine (0.73 g, 8.46 mmoles) and the temperature was raised to 100° C. After 14 hours the whole was brought to dryness and the solid partitioned between water and CH2Cl2. The organic phase was washed with water, anhydrified and brought to dryness to give a solid which was flash chromatographed (eluent: hexane/ethyl acetate 6:4, then in gradient up to 3:7) to give 0.9 g of the title compound (yield: 79%). m.p.: 179-180° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.C([Cl:11])(=O)C.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30][CH3:31])=[CH:24][CH:23]=2)=O)=[CH:15][CH:14]=1>>[Br:12][C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[C:20](\[Cl:11])/[C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30][CH3:31])=[CH:24][CH:23]=2)=[CH:15][CH:14]=1
Reactant: CC(=O)Cl
Reactant: CCCCc1ccc(C(=O)Cc2ccc(Br)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1ccc(/C(Cl)=C/c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a 2 L three-necked flask containing TFA (231 mL, 3.01 mol) and acetyl chloride (171.4 mL, 2.41 mol) was added in one portion 2-(4-bromophenyl)-1-(4-butylphenyl) ethanone (Ve) (100 g; 0.301 mol) at RT. The reaction mixture was stirred at room temperature overnight and work-up was then similar with those described above. The title compound (m=100 g) was obtained in a 95% yield. Melting point: 59-61° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[CH:15]=2)[C:10]([C:24](=[O:30])[C:25]([O:27]CC)=[O:26])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C1COCC1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[CH:15]=2)[C:10]([C:24](=[O:30])[C:25]([OH:27])=[O:26])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2cc(-c3cccc(Cl)c3)ccc12
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(=O)c1cn(Cc2ccccc2)c2cc(-c3cccc(Cl)c3)ccc12
Yield: 60.3 %

Procedure:
{1-Benzyl-6-(3-chlorophenyl)-1H-indol-3-yl](oxo)acetic acid was prepared from ethyl [1-benzyl-6-(3-chlorophenyl)-1H-indol-3-yl](oxo)acetate (0.489 g, 1.17 mmol), and potassium hydroxide (0.214 g, 3.81 mmol) in THF (10 mL) and water (10 mL), according to the procedure described in Step 4 of Example 5. Crystallization from acetonitrile and drying for 24 hours at 94° C. furnished the title compound as a yellow solid (0.275 g, 60%), mp: 186-188° C. Mass spectrum (−ESI, [M−H]−) m/z 388; 1HNMR (500 MHz, DMSO-d6): δ 13.8-14.2 (br s, 1H), 8.7 (s, 1H), 8.25 (d, 1H, J=8.4 Hz), 8.0 (d, 1H, J=0.76 Hz),7.75 (t, 1H, J=1.8 Hz), 7.65-7.7 (m, 2H), 7.5 (t, 1H, J=7.9 Hz), 7.4 (m, 1H), 7.3-7.4 (m, 4H), 7.25-7.3 (m, 1H), and 5.7 ppm (s, 1H). Elemental Analysis for C23H16ClNO3.0.05 H2O: Calculated: C, 70.70; H, 4.15; N, 3.58. Found: C, 70.45; H, 3.97; N, 3.71.
Reaction SMILES: [Li]CCCC.[CH2:6]([O:13][C:14]1[CH:19]=[C:18](Br)[CH:17]=[CH:16][C:15]=1[O:21][CH3:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:23]([O:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH:34]=[O:35])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>C1COCC1>[CH2:6]([O:13][C:14]1[CH:19]=[C:18]([CH:34]([C:33]2[CH:36]=[CH:37][C:38]([O:39][CH3:40])=[C:31]([O:30][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:32]=2)[OH:35])[CH:17]=[CH:16][C:15]=1[O:21][CH3:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COc1ccc(C=O)cc1OCc1ccccc1
Reactant: COc1ccc(Br)cc1OCc1ccccc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2ccc(OC)c(OCc3ccccc3)c2)cc1OCc1ccccc1
Reaction time: 1 h
Yield: 51.7 %

Procedure:
n-BuLi (1.6 M, 5.2 mL) was added to a solution of 2-benzyloxy-4-bromo-1-methoxybenzene (2.10 g, 7.2 mmol) in THF (28 mL) at −78° C. and the resulting yellow solution was stirred at this temperature for 1 h. A solution of 3-benzyloxy-4-methoxybenzaldehyde (1.74 g, 7.2 mmol) in THF (16 mL) was added dropwise at −78° C. and the reaction mixture was stirred at this temperature for 1.5 h and then at room temperature for 2 h. Water (100 mL) was added to the yellow solution and the resulting mixture was extracted with EtOAc (3×100 mL). The combined organics were dried (MgSO4), and solvent was removed in vacuo to give a thick yellow oil which solidified after standing overnight. The crude product was purified by precipitation from EtOAc/hexane to give the title compound (1.70 g, 52%, mp 103-105° C.) as a white solid; δH (270 MHz, CDCl3) 7.42-7.21 (10H, m, ArH), 6.89-6.79 (6H, m, ArH), 5.63 (1H, d, J=3.5, CHOH), 5.06 (4H, s, 2×CH2), 3.86 (6H, s, 2×CH3), 2.02 (1H, d, J=3.5, CHOH); δC (100 MHz, d6-DMSO) 149.2 (2×C), 148.2 (2×C), 137.2 (2×C), 136.6 (2×C), 128.7 (4×CH), 128.0 (2×CH), 127.6 (4×CH), 119.5 (2×CH), 112.6 (2×CH), 111.7 (2×CH), 75.8 (CH), 71.2 (2×CH2), 56.4 (2×CH3); LRMS (FAB+) 456.1 (M+, 45%), 439.1 (85), 349.2 (10), 243.1 (20), 91.1 (100); HRMS (FAB+) Found 456.1944, C29H28O5 requires 456.1937.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][C:5]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(#N)C>[CH2:20]([O:12][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:4]=1[O:3][CH:2]([F:13])[F:1])[CH:8]=[O:9])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccc(OC(F)F)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1ccc(OC(F)F)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 9 g quantity of 4-difluoromethoxy-3-hydroxy benzaldehyde was dissolved in 180 ml of acetonitrile, and 13.1 g of potassium carbonate and 8.6 ml of benzyl bromide were added. The mixture was stirred at room temperature for 4 hours. After insolubles were removed by filtration, the filtrate was concentrated and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to give 11.9 g of colorless oily 3-benzyloxy-4-difluoromethoxybenzaldehyde.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:33]=[CH:32][C:23]([O:24][C:25]2[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=2)=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:34]([O:41][CH2:42][CH2:43][CH2:44]O)([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]>>[CH2:1]([N:8]([CH2:19][C:20]1[CH:33]=[CH:32][C:23]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:44][CH2:43][CH2:42][O:41][Si:34]([C:37]([CH3:38])([CH3:40])[CH3:39])([CH3:35])[CH3:36])[CH:26]=2)=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3cccc(O)c3)cc2)cccc1[N+](=O)[O-]
Reactant: CC(C)(C)[Si](C)(C)OCCCO
Product: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3cccc(OCCCO[Si](C)(C)C(C)(C)C)c3)cc2)cccc1[N+](=O)[O-]

Procedure:
The product from Example 61F and 1-t-butyldimethylsilyloxypropan-3-ol were processed as in Example 61G to provide the title compound.
Reaction SMILES: ClC1C=CC=CC=1[C@H]([O:10][C:11]1[CH:15]=[C:14]([N:16]2[C:20]3[CH:21]=[CH:22][C:23]([C:25]4[O:26][C:27]([CH3:30])=[N:28][N:29]=4)=[CH:24][C:19]=3[N:18]=[CH:17]2)[S:13][C:12]=1[C:31]([O:33][CH3:34])=[O:32])C.ClC1C(O)=CC=CC=1[C@H](OC1C=C(N2C3C=C(C#N)C=CC=3N=C2)SC=1C(OC)=O)C>>[OH:10][C:11]1[CH:15]=[C:14]([N:16]2[C:20]3[CH:21]=[CH:22][C:23]([C:25]4[O:26][C:27]([CH3:30])=[N:28][N:29]=4)=[CH:24][C:19]=3[N:18]=[CH:17]2)[S:13][C:12]=1[C:31]([O:33][CH3:34])=[O:32]
Reactant: COC(=O)c1sc(-n2cnc3cc(-c4nnc(C)o4)ccc32)cc1O[C@H](C)c1ccccc1Cl
Agent: COC(=O)c1sc(-n2cnc3ccc(C#N)cc32)cc1O[C@H](C)c1cccc(O)c1Cl
Product: COC(=O)c1sc(-n2cnc3cc(-c4nnc(C)o4)ccc32)cc1O
Yield: 81.9 %

Procedure:
The title compound was prepared from methyl 3-{[(1R)-1-(2-chlorophenyl) ethyl]oxy}-5-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxylate (139 mg) using a procedure analogous to Intermediate 3, Step D to give 82.0 mg of the desired product. MS (ESI): 357 [M+H]+.
Reaction SMILES: C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[CH2:13]([C:20](=[CH2:24])[C:21]([OH:23])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[P:25]([O-:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28]>ClCCl.C(OCC)(=O)C>[CH2:27]([O:26][P:25]([CH2:24][CH:20]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:21]([OH:23])=[O:22])([O:29][CH2:30][CH3:31])=[O:32])[CH3:28]
Reactant: CCOP([O-])OCC
Reactant: C=C(Cc1ccccc1)C(=O)O
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOP(=O)(CC(Cc1ccccc1)C(=O)O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
Bis(trimethylsilyl)acetamide (5 g, 0.024 mole, 6 ml) was added, at room temperature, to a solution of benzyl acrylic acid (2 g, 0.012 mole) and diethyl phosphite (3.3 g, 0.024 moles) in dichloromethane (30 ml). The mixture was stirred at ambient temperature for 30 minutes, concentrated in vacuo at room temperature, and the residue was heated at a bath temperature of 100°-110° for 16 hours. The colorless oil reaction mixture was dissolved in ethyl acetate and extracted with 5% sodium bicarbonate (pH 9-10). The aqueous alkaline solution was washed with ether and acidified to a pH of 1-2 with concentrated hydrochloric acid. The colorless oil that separated was extracted into ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a colorless oil (3.6 g).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.[CH3:13][N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.[OH-].[Na+]>C(O)C>[CH3:13][N:14]1[CH2:19][CH2:18][C:17]2[N:1]=[C:2]3[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]3=[CH:4][C:16]=2[CH2:15]1
Reactant: CN1CCC(=O)CC1
Reactant: Nc1ccc([N+](=O)[O-])cc1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1CCc2nc3ccc([N+](=O)[O-])cc3cc2C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 29.4 %

Procedure:
To a solution of 2-amino-5-nitrobenzaldehyde (1.00 g, 6.02 mmol) and 1-methyl-4-piperidinone (0.89 ml, 7.22 mmol) in ethanol (108 ml) was added a 4N aqueous sodium hydroxide solution (9.0 ml) at room temperature, and the mixture was stirred at 60° C. for 1 hour. The solvent was distilled off under reduced pressure, ethyl acetate was added to the resulting oil, the mixture was washed with an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After the solvent was concentrated under reduced pressure, the resulting residue was purified by alumina column chromatography (developing solvent: ethyl acetate), and converted into powders with diisopropyl ether to obtain 2-methyl-8-nitro-1,2,3,4-tetrahydrobenzo[b][1,6]naphthyridine (430 mg).
Reaction SMILES: ClC1N=C(Cl)N=C(NC2NN=C(C3CC3)C=2)N=1.N1CCOCC1.[Cl:24][C:25]1[N:30]=[C:29]([NH:31][C:32]2[NH:36][N:35]=[C:34]([CH:37]3[CH2:39][CH2:38]3)[CH:33]=2)[N:28]=[C:27]([N:40]2[CH2:44][CH2:43]C[C@@:41]2(C)[C:45](NC2C=NC(F)=CC=2)=[O:46])[N:26]=1>>[Cl:24][C:25]1[N:26]=[C:27]([N:40]2[CH2:44][CH2:43][O:46][CH2:45][CH2:41]2)[N:28]=[C:29]([NH:31][C:32]2[CH:33]=[C:34]([CH:37]3[CH2:39][CH2:38]3)[NH:35][N:36]=2)[N:30]=1
Reactant: C[C@@]1(C(=O)Nc2ccc(F)nc2)CCCN1c1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1
Agent: Clc1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1
Solvent: C1COCCN1
Product: Clc1nc(Nc2cc(C3CC3)[nH]n2)nc(N2CCOCC2)n1

Procedure:
Compound 112A was prepared from 1A and morpholine as described for 1C. LC/MS [M+H]+: 322/324; Ret time (Method F): 2.81 min.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].C([O-])([O-])=O.[K+].[K+].[CH3:11][C:12](=[O:17])[CH2:13][C:14](=[O:16])[CH3:15]>CC(C)=O>[CH2:3]([CH:13]([C:12](=[O:17])[CH3:11])[C:14](=[O:16])[CH3:15])[C:2]#[CH:1]
Reactant: CC(=O)CC(C)=O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCC(C(C)=O)C(C)=O
Temperature: 60 °C
Reaction time: 24 h
Yield: 80.4 %

Procedure:
The mixture of propargyl bromide (0.32 g, 2.70 mmol), K2CO3 (2.22 g, 16.10 mmol), and 2,4-pentane-dione (1.34 g, 13.40 mmol) in acetone (30 mL) was stirred for 24 hrs at 60° C. After filtration and removal of solvent under reduced pressure, the crude residue was purified by flash chromatography (hexane) to give 22 as colorless liquid (0.30 g, 69%). 1HNMR (400 MHz, CDCl3) δ 2.03-2.04 (t, J=5.28 Hz, 1H), 2.22 (s, 3H), 2.25 (s, 3H), 2.68-2.71 (m, 2H), 3.84-3.87 (t, J=15.08 Hz, 1H); 13CNMR (100 MHz, CDCl3) δ 14.45, 29.33, 29.41, 68.70, 70.79, 86.13, 202.18, 202.63.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C>[CH2:15]([O:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][CH:8]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1cccc(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Oc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Yield: 70.7 %

Procedure:
To a stirring solution of resorcinol (58 mmol, 6.4 g) in acetonitrile (25 mL) was added potassium carbonate (5.8 mmol, 0.801 g). The solution was then heated to reflux for 1 hour. At this time, benzyl bromide (5.8 mmol, 1 g) in acetonitrile (33 mL) was added to the refluxing mixture. The reaction was monitored by TLC until all benzyl bromide was consumed. At this time the reaction mixture was cooled to room temperature and filtered through a fitted funnel. The mother liquor was then evaporated to an oil and taken up in ethyl acetate (200 mL). The organic layer was extracted with three 15 mL portions of aqueous 1N HCl followed by one 10 mL portion of brine. The organic layer was dried over magnesium sulfate and evaporated to dryness. The crude mixture was purified via flash chromatography to yield 0.819 g (4.1 mmol) of the title product. 1H NMR (300 MHz, CDCl3) δ 7.57-7.33 (m, 5H), 7.15 (t, J=8.2, 1H), 6.59 (dd, J=2.0, 7.9, 1H), 6.52-6.41 (m, 2H), 5.10 (s, 1H), 5.03 (s, 2H). 13C NMR (75 MHz, CDCl3) δ 160.70, 156.84, 137.04, 130.48, 128.86, 128.29, 127.79, 108.36, 107.66, 102.72, 70.29.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][C:3]=1C(OC)=O.CN1CCNCC1.O>CN1CCCC1=O>[NH2:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1
Reactant: COC(=O)c1sc2ccccc2c1N
Agent: CN1CCNCC1
Solvent: CN1CCCC1=O
Solvent: O
Product: Nc1csc2ccccc12
Temperature: 178 °C

Procedure:
To a solution of methyl 3-aminobenzothiophene-2-carboxylate [prepared by the method of J. R. Beck, J. Org. Chem. 1972, 37, 3224] (6.5 g, 31.4 mmol) in N-methylpyrrolidinone (30 ml) was added 1-methylpiperazine and the reaction mixture was heated to 178° C. for 4 h. After cooling the mixture was poured into water and the product extracted with diethyl ether (3×100 ml), the extracts were washed with water (1×100 ml) and brine (1×100 ml), combined and dried (MgSO4). Concentration of the extracts yielded 3-aminobenzothiophene (5.9 g), which was used without purification. To a solution of 3-aminobenzothiophene (5 g, 32 mmol) in N-methylpyrrolidinone (50 ml) was added piperazine (8.7 g, 102 mmol) and the mixture heated to reflux under nitrogen for 14h. Cooled and poured into water and extracted with dichloromethane (4×100 ml). The extracts were washed with brine (50 ml), combined and dried (MgSO4). On concentration of the extracts a white solid came out of solution which was collected by filtration to yield the title compound (0.78 g, more product left in solution); δH (DMSO-d6 +TFA), 3.3 (8H, m, 4×piperazinyl CH2), 7.08 (1H, s, 3-H), 7.39 (2H, m, 2×ArH), 7.83 (1H, m, ArH), 7.95 (1H, m, ArH), and 9.30 (1H, br s, NH).
Reaction SMILES: [NH2:1][C@@H:2]([C:13]1[NH:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1)[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH2:24]1[C:29](=[O:30])[N:28]([O:31][C:32](ON2C(=O)CCC2=O)=[O:33])[C:26](=[O:27])[CH2:25]1>C(#N)C>[O:27]=[C:26]1[CH2:25][CH2:24][C:29](=[O:30])[N:28]1[O:31][C:32]([NH:1][C@@H:2]([C:13]1[NH:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1)[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)=[O:33]
Reactant: N[C@H](Cc1c[nH]c2ccccc12)c1nc(-c2ccccc2)c[nH]1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: CC#N
Product: O=C(N[C@H](Cc1c[nH]c2ccccc12)c1nc(-c2ccccc2)c[nH]1)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.5 %

Procedure:
302.4 mg (1 mmol) of 2-{(1R)-1-amino-2-[indol-3-yl]ethyl}-4-phenyl-1H-imidazole previously dissolved in 20 mL of anhydrous acetonitrile was added dropwise to a solution of N,N′-disuccinimidylcarbonate (528 mg, 2 mmol, DSC) in 20 mL of anhydrous acetonitrile during 1.5 hour. After a further 4 hours of stirring at room temperature, the solvent was evaporated in vacuo and the residue redissolved in 30 mL of chloroform. Excess DSC was then discarded and the organic layer washed with water (4×30 mL), dried over MgSO4 and concentrated to obtain a brown solid (215 mg, 49%). 1H-NMR (CDCl3, 100 MHz) δ: 8.22 (brs, 1H); 8.1-7.08 (m, 12H); 5.9 (br s, 1H); 4.97 (dd, J=3.6 and 9.3 Hz, 1H); 3.75 (dd, J=3.6 and 14.8 Hz, 1H), 3.06 (dd, J=9.7 and 14.6 Hz, 1H); 2.96 (s, 2H); 2.89 (s, 2H). LC/MS: m/z=329 ((M+H)−SuOH.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][OH:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cr](O)(O)(=O)=O.O>CC(C)=O>[C:1]([C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1cccc(CO)c1
Agent: O=[Cr](=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: O=Cc1cccc(C(=O)c2ccccc2)c1
Reaction time: 0.08 h

Procedure:
3-Benzoylbenzyl alcohol (2.0 g) in acetone (10 ml) was treated dropwise at 15°-20° C. with chromic acid solution. After stirring for 5 minutes, water (50 ml) was added and the mixture extracted with ether. The ethereal solution was washed with saturated Na2CO3, saturated NaCl, dried (Na2SO4), evaporated and distilled; b.p. 160°-170° C./0.08 mm, (1.1 g).
Reaction SMILES: CC(C)([O-])C.[K+].[Br-].[CH3:8][O:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH:41]=[CH:40][C:39]([O:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[C:49](=O)[C:50]([O:52][CH3:53])=[O:51])=[N:38]2)=[CH:33][CH:32]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH:41]=[CH:40][C:39]([O:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3/[C:49](=[CH:8]\[O:9][CH3:10])/[C:50]([O:52][CH3:53])=[O:51])=[N:38]2)=[CH:33][CH:32]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)C(=O)c1ccccc1Oc1ccn(-c2ccc(Cl)cc2)n1
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Br-]
Solvent: C1CCOC1
Product: CO/C=C(/C(=O)OC)c1ccccc1Oc1ccn(-c2ccc(Cl)cc2)n1

Procedure:
A solution of 0.38 g of potassium tert-butoxide in 3 ml of tetrahydrofuran was added dropwise at not more than 5° C to a suspension of 1.4 g of methoxymethyltriphenylphosphonium bromide ("Wittig reagent") in 15 ml of anhydrous tetrahydrofuran. 1.0 g of methyl 2-[1-(4-chlorophenyl)-3-pyrazolyloxy]phenylglyoxalate (cf. Ex. 1) in 5 ml of tetrahydrofuran was added to the dark red suspension, and the batch was allowed to come to room temperature. Wittig reagent was metered in twice more until all of the keto ester had reacted. For working-up, the batch was stirred into 20% by weight of aqueous citric acid and the mixture was extracted three times with methyl tert-butyl ether. The combined organic phases were washed until neutral, dried over sodium sulfate and subsequently concentrated. The crude product (3.2 g) was chromatographed over silica gel (eluent: toluene/ethyl acetate, 95/5). The resulting E/Z mixture was separated by medium-pressure chromatography on silica gel (eluent heptane/ethyl acetate, 9/1→7/3). This gave 0.5 g of the title compound and 0.15 g of the Z isomer.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[CH:10]=[C:9]([C:11]3[CH:12]=[C:13]([CH:20]=[CH:21][C:22]=3[CH3:23])[C:14]([NH:16][CH:17]3[CH2:19][CH2:18]3)=[O:15])[S:8][C:7]=12.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][C:25]1=[O:30].C(N(CC)C(C)C)(C)C>CN1C(=O)CCC1.O>[CH:17]1([NH:16][C:14](=[O:15])[C:13]2[CH:20]=[CH:21][C:22]([CH3:23])=[C:11]([C:9]3[S:8][C:7]4=[C:2]([N:27]5[CH2:28][CH2:29][NH:24][C:25](=[O:30])[CH2:26]5)[N:3]=[N:4][CH:5]=[C:6]4[CH:10]=3)[CH:12]=2)[CH2:19][CH2:18]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1cc2cnnc(Cl)c2s1
Reactant: O=C1CNCCN1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1cc2cnnc(N3CCNC(=O)C3)c2s1
Temperature: 180 °C

Procedure:
The title compound was prepared by a method similar to that described in Example 2. 3-(7-chlorothieno[2,3-d]pyridazin-2-yl)-N-cyclopropyl-4-methylbenzamide (100 mg, 291 μmol), piperazin-2-one (44 mg, 436 μmol) and N,N-diisopropylethylamine (152 μl, 873 μmol) were combined in NMP (2 ml) and heated to 180° C. for 18 hrs. The mixture was cooled to RT, diluted with H2O and filtered. The solids were washed with H2O and air-dried. Both the solid and solution were collected, dissolved in DMSO and purified with reverse-phase chromatography (Phenomenex Synergi 4m Max RP 80 A column, 150×21 mm, 20 ml/min, 10-95% CH3CN/H2O, 0.1% TFA, 10.5 min gradient). The residue was purified with reverse-phase chromatography (Phenomenex Synergi 4m Max RP 80 A column, 150×21 mm, 20 ml/min, 10-95% CH3CN/H2O, 0.1% TFA, 10.5 min gradient) to afford the title compound. MS (ESI, pos. ion) m/z: 408 (M+1).
Reaction SMILES: [S:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:5]=1)[C:2]#N.[C-]#N.[Na+]>CO>[CH3:2][S:1][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([C:11]([F:12])([F:13])[F:14])[CH:5]=1
Reactant: N#CSc1ccc(N)c(C(F)(F)F)c1
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Product: CSc1ccc(N)c(C(F)(F)F)c1
Yield: 96.5 %

Procedure:
A solution of 4-thiocyano-2-trifluoromethylaniline (1.09 g., 0.005 mole) and sodium cyanide (0.125 g., 0.0025 mole) in methanol (50 ml) is refluxed for about 16 hours. Methanol is removed from the cool reaction mixture by evaporation under reduced pressure, the residue is taken up in methylene chloride, washed with water and dried. Removal of the drying agent and solvent gives the product as a yellow oil (1 g., 91 percent yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[C@@H:5]1[O:7][CH2:6]1)[CH3:2].[Cl-].[NH4+].[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:8])[C@H:5]([OH:7])[CH2:6][N:11]=[N+:12]=[N-:13])[CH3:2]
Reactant: CCOC(=O)[C@H]1CO1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](O)CN=[N+]=[N-]
Temperature: 75 °C
Yield: 69.1 %

Procedure:
Ethyl-(2R)-2,3-epoxyproprionate (0.5 g, 4.3 mmol), ammonium chloride (0.253 g, 4.73 mmol), and sodium azide (0.336 g, 5.17 mmol) were combined in DMF (8 mL), and the mixture was heated at 75° C. for 14 hours. The reaction was cooled to room temperature, and was partitioned between water and ether/hexanes (1:1 v/v). The phases were separated, and the organic phase was washed once each with water, brine, dried over MgSO4, filtered, and concentrated to an oil, which was purified by flash chromatography (silica gel/hexanes: 10% ethyl acetate) to give (R)-ethyl-3-azido-2-hydroxypropionate as a clear oil (0.47 g, 2.97 mmol, 69% yield). Rf 0.27 (hexanes: 10% EtOAc, v/v, p-anisaldehyde); MS m/e [M+Na]+ calcd 182.1, found 182.0.