Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[NH:8][CH:9]=[N:10][C:4]=2[CH:3]=1.[Cl:11][C:12]1[CH:17]=[N:16][CH:15]=[C:14]([Cl:18])[N:13]=1.[F-].[Cs+].O>CS(C)=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[N:8]([C:14]3[CH:15]=[N:16][CH:17]=[C:12]([Cl:11])[N:13]=3)[CH:9]=[N:10][C:4]=2[CH:3]=1.[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[N:8]=[CH:9][N:10]([C:12]3[CH:17]=[N:16][CH:15]=[C:14]([Cl:18])[N:13]=3)[C:4]=2[CH:3]=1
Reactant: Clc1cncc(Cl)n1
Reactant: Clc1cc2nc[nH]c2cn1
Agent: [Cs+]
Agent: [F-]
Solvent: CS(C)=O
Solvent: O
Product: Clc1cc2c(cn1)ncn2-c1cncc(Cl)n1
Product: Clc1cc2ncn(-c3cncc(Cl)n3)c2cn1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 6-chloro-3H-imidazo[4,5-c]pyridine (4.6 g, 30 mmol), 2,6-dichloropyrazine (6 g, 40.5 mmol) and CsF (9.1 g, 60 mmol) in dry DMSO (80 mL) was stirred at room temperature for 20 h under N2. The mixture was poured into water (50 mL) with stirring. The formed precipitate was collected by filtration. The filter cake was suspended in MeOH (20 mL) and filtered again. The filter cake was collected and dried in vacuum which gave a mixture of title compounds 18a & 17a as a white solid (5.0 g, 62.9%).
Reaction SMILES: ClCCl.[Cl:4][C:5]1[CH:6]=[C:7]([NH:19][C:20]2[C:25]3[C:26]4[CH2:34][CH2:33][C:32]5[N:31]([CH2:35][CH2:36]O)[N:30]=[CH:29][C:28]=5[C:27]=4[S:38][C:24]=3[N:23]=[CH:22][N:21]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.S(Br)([Br:41])=O>O>[Br:41][CH2:36][CH2:35][N:31]1[C:32]2[CH2:33][CH2:34][C:26]3[C:25]4[C:24](=[N:23][CH:22]=[N:21][C:20]=4[NH:19][C:7]4[CH:8]=[CH:9][C:10]([O:11][CH2:12][C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=5)=[C:5]([Cl:4])[CH:6]=4)[S:38][C:27]=3[C:28]=2[CH:29]=[N:30]1
Reactant: OCCn1ncc2c1CCc1c-2sc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: O=S(Br)Br
Solvent: ClCCl
Solvent: O
Product: Clc1cc(Nc2ncnc3sc4c(c23)CCc2c-4cnn2CCBr)ccc1OCc1ccccn1
Temperature: 25 °C

Procedure:
To 30 mL dichloromethane cooled to 0° C. was added 2-(6-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-4,5-dihydro-3H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-3-yl)ethanol (800 mg, 1.58 mmol), followed by thionyl bromide (1.15 g, 5.54 mmol). The contents were then stirred with warming to rt over a 24 h period, after which time water (5 mL) was added to quench the reaction mixture. The solvent was removed under reduced pressure. The crude residue was diluted with aq. 1M Na2CO3 and vigorously stirred for 1 h. The mixture was extracted with CH2Cl2, and the combined organic layers dried over MgSO4, filtered, and concentrated in vacuo. The resulting solid was triturated with methanol (15 mL) to a light-brown solid (600 mg, 67%) containing 80% of the desired product, and 20% of the aromatized product. A sample of the crude product was purified via reverse phase HPLC to afford the desired product as a white solid. 1H-NMR (DMSO-d6) δ 8.58 (d, 1H), 8.38 (br s, 1H), 8.36 (s, 1H), 7.81 (dd, 1H), 7.78 (s, 1H), 7.70 (s, 1H), 7.44-7.60 (m, 2H), 7.31 (td, 1H), 7.19 (d, 1H), 5.23 (s, 2H), 4.30 (t, 2H), 3.82 (t, 2H), 3.38 (t, 2H), 3.07 (t, 2H); LCMS RT=2.77 min; [M+H]+=567.0.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][C@H:15]([NH:18][C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[C@H:14]([O:29][CH3:30])[CH2:13]2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:31](Cl)(=[O:33])[CH3:32].C(N(CC)CC)C.CO>C(Cl)Cl>[C:31]([NH:1][C:2]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][C@H:15]([NH:18][C:19]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:20])[C@H:14]([O:29][CH3:30])[CH2:13]2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1cc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)ccc1N
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)ccc1NC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl cis(±)-2-amino-5-(4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidin-1-yl)benzoate obtained in Example (185b) (300 mg) was dissolved in methylene chloride (25 ml). Acetyl chloride (0.1 ml) and triethylamine (0.2 ml) were added, and the mixture was stirred at room temperature for one hour. Methanol was added to the reaction solution, followed by concentration under reduced pressure. Then, the residue was diluted with ethyl acetate, washed with water, and then concentrated under reduced pressure to obtain the title compound. The resulting compound was used for the next reaction without purification.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.[CH2:24]([N:26]([CH2:29][CH3:30])[CH2:27]C)C>C1COCC1>[ClH:1].[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[C@@H:14]([NH:13][C:11]([C:9]1[S:10][C:6]3[CH:5]=[C:4]([NH:3][C:11]([NH:13][C:14]4[CH:15]=[CH:30][C:29]([N:26]([CH3:24])[CH3:27])=[CH:18][CH:19]=4)=[O:12])[CH:23]=[CH:22][C:7]=3[CH:8]=1)=[O:12])[CH2:15]2
Reactant: CCN(CC)CC
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Agent: Cl
Solvent: C1CCOC1
Product: CN(C)c1ccc(NC(=O)Nc2ccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc3c2)cc1
Reaction time: 18 h

Procedure:
A solution of 40 mg (0.11 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 2 ml of THF is mixed with 29.8 μl (0.21 mmol) of triethylamine and 34.7 mg (0.21 mmol) of 4-N,N-dimethylaminophenyl isocyanate. After 18 h at room temperature, the product is purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of acetonitrile and 1 N hydrochloric acid (5:1), again concentrated and dried under high vacuum. 21 mg (38.7% of theory) of the title compound are obtained.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Cl:34][C:35]1[C:40]([N+:41]([O-:43])=[O:42])=[CH:39][C:38]([C:44]#[N:45])=[CH:37][C:36]=1[NH:46][C:47](=O)[CH2:48][N:49]([CH2:51][CH2:52][OH:53])[CH3:50]>C1COCC1.CCOC(C)=O.O>[Cl:34][C:35]1[C:40]([N+:41]([O-:43])=[O:42])=[CH:39][C:38]([C:44]#[N:45])=[CH:37][C:36]=1[N:46]1[CH2:47][CH2:48][N:49]([CH3:50])[CH2:51][C:52]1=[O:53]
Reactant: CN(CCO)CC(=O)Nc1cc(C#N)cc([N+](=O)[O-])c1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CN1CCN(c2cc(C#N)cc([N+](=O)[O-])c2Cl)C(=O)C1
Reaction time: 0.17 h
Yield: 35.3 %

Procedure:
To a solution of triphenylphosphine (252 mg, 0.959 mmol) in THF (2 mL) was added DIAD (0.187 mL, 0.959 mmol). The reaction mixture was stirred for 10 min. Then a solution of N-(2-chloro-5-cyano-3-nitrophenyl)-2-((2-hydroxyethyl)(methyl)amino)acetamide (120 mg, 0.384 mmol) in THF (2 mL) was added drop wise. The reaction mixture was then stirred at room temperature for 2 h. LC-MS indicated the desired peak, but the reaction was about ˜80% complete. It was diluted with EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated. Purification via silica gel chromatography (0-100% EtOAc in Hexanes, 12 g) gave 4-chloro-3-(4-methyl-2-oxopiperazin-1-yl)-5-nitrobenzonitrile (40 mg) as a off-white solid.
Reaction SMILES: [C:1]([CH:4]([CH2:17][CH2:18][CH2:19][CH:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:5][CH2:6][CH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[OH2:34].Cl([O-])(=O)(=O)=O.[C:40]([N+:44]1O[C:46]([CH3:49])=[CH:47][CH:48]=1)([CH3:43])([CH3:42])[CH3:41]>C(#N)C>[C:40]([NH:44][C:48](=[O:34])/[CH:47]=[C:46](\[O:13][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][CH2:5][CH:4]([C:1](=[O:3])[CH3:2])[CH2:17][CH2:18][CH2:19][CH:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:16][CH:15]=1)/[CH3:49])([CH3:43])([CH3:42])[CH3:41]
Reactant: Cc1cc[n+](C(C)(C)C)o1
Reactant: O
Reactant: CCCCCC(O)CCCC(CCCc1ccc(C(=O)O)cc1)C(C)=O
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCC(O)CCCC(CCCc1ccc(C(=O)O/C(C)=C\C(=O)NC(C)(C)C)cc1)C(C)=O

Procedure:
A solution of 4-(4-acetyl-8-hydroxytridecyl)benzoic acid (3.62 g., 10 millimole), Example 1, Step F, triethylamine (1.74 ml., 12.5 millimole), and distilled water (18 ml., 1.0 mole) in acetonitrile (100 ml.) is treated with N-t-butyl-5-methylisoxazolium perchlorate (3.0 g., 12.5 millimole). The resulting solution is evaporated in vacuo (water aspirator) at 20°-23° C. for 4 hours providing a tacky residue which is triturated with water (150 ml.) at 0°-5° C. for 15 minutes. After decanting the aqueous phase, the oily residue is dissolved in benzene-ether (1:1) (200 ml.). The organic extract is dried over sodium sulfate, filtered, and evaporated in vacuo at 35°-40° C. providing the desired active ester, N-t-butyl-3-[4-(4-acetyl-8-hydroxytridecyl)benzoyloxy]crotonamide, as a pale yellow oil.
Reaction SMILES: [C:1]1([CH:7]2[CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[CH2:10][C:9]3[CH:16]=[CH:17][CH:18]=[CH:19][C:8]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][O:21][C:22](=[O:25])[CH:23]=[CH2:24].[OH-].C([N+](C)(C)C)C1C=CC=CC=1>CO>[CH3:20][O:21][C:22](=[O:25])[CH2:23][CH2:24][N:13]1[CH2:12][CH:11]2[CH:15]([CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]3[CH:19]=[CH:18][CH:17]=[CH:16][C:9]=3[CH2:10]2)[CH2:14]1
Reactant: C=CC(=O)OC
Reactant: c1ccc(C2c3ccccc3CC3CNCC32)cc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CO
Product: COC(=O)CCN1CC2Cc3ccccc3C(c3ccccc3)C2C1
Reaction time: 4 h

Procedure:
A mixture of 15 g of (3aRS,4SR,9aSR)-3a,4,9,9a-tetrahydro-4-phenyl-benz[f]isoindoline, 5.9 g of acrylic acid methyl ester and 1 cc of a 40% solution of benzyl trimethyl ammonium hydroxide in methanol is stirred at 50° for 4 hours and is then concentrated by evaporation. The evaporation residue is reduced to a slime with silica gel in benzene/ethyl acetate (9:1) and filtration is effected. Upon concentrating the filtrate by evaporation, the title compound, having a M.P. of 75°-76° (after crystallization from ether/petroleum ether), is obtained.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH:13][CH2:14][CH:15]([CH2:17][OH:18])[OH:16].C1C=CC=CC=1.[F:25][C:26]1[CH:27]=[C:28]([N:39]2[CH2:43][C@H:42]([CH2:44][NH:45][C:46](=[O:48])[CH3:47])[O:41][C:40]2=[O:49])[CH:29]=[CH:30][C:31]=1[N:32]1[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1>O>[F:25][C:26]1[CH:27]=[C:28]([N:39]2[CH2:43][C@H:42]([CH2:44][NH:45][C:46](=[O:48])[CH3:47])[O:41][C:40]2=[O:49])[CH:29]=[CH:30][C:31]=1[N:32]1[CH2:33][CH2:34][C:35]2([O:16][CH:15]([CH2:17][OH:18])[CH2:14][O:13]2)[CH2:36][CH2:37]1
Reactant: OCC(O)CO
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)CC3)c(F)c2)C(=O)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)OCC(CO)O4)c(F)c2)C(=O)O1
Temperature: 25 °C
Yield: 84 %

Procedure:
Para-toluenesulfonic acid monohydrate (299 mg) and glycerol (0.21 ml) were added successively to a benzene suspension (10 ml) of 500 mg of the (S)-N-{3-[3-fluoro-4-(4-oxo-piperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (Compound No. 7) which was synthesized in Example 3, and the mixture was heated under reflux for 4 h, with water being removed continuously by means of a water separator. After the reaction mixture was cooled to room temperature, a saturated aqueous sodium hydrogencarbonate solution was added and the mixture was stirred. Thereafter, the solution was extracted with methylene chloride and the organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The solvent was evaporated under vacuum and the residue was purified by silica gel column chromatography (solvent: chloroform/methanol=50/1-25/1) to afford the title compound (510 mg) in a yield of 84%.
Reaction SMILES: C([N:8]1[CH2:23][CH2:22][CH2:21][C:11]2=[N:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:19]([OH:20])=[C:10]2[CH2:9]1)C1C=CC=CC=1.Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>>[C:28]1([O:27][C:25]([N:8]2[CH2:23][CH2:22][CH2:21][C:11]3=[N:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:19]([OH:20])=[C:10]3[CH2:9]2)=[O:26])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Oc1c2c(nc3ccccc13)CCCN(Cc1ccccc1)C2
Reactant: O=C(Cl)Oc1ccccc1
Product: O=C(Oc1ccccc1)N1CCCc2nc3ccccc3c(O)c2C1
Yield: 51 %

Procedure:
11-Hydroxy-2,3,4,5-tetrahydro-1H-2-azepino[4,3-b]quinoline-carboxylic acid phenyl ester was prepared analogous to Example 101 from 2-benzyl-11-hydroxy-2,3,4,5-tetrahydro-1H-azepino[4,3-b]quinoline and phenyl chloroformate.
Reaction SMILES: [CH2:1]([CH:8]([C:14](OCC)=[O:15])[C:9](OCC)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH2:1]([CH:8]([CH2:9][OH:10])[CH2:14][OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCC(CO)Cc1ccccc1

Procedure:
Diethyl benzylmalonate is reduced with lithium aluminium hydride to give 2-benzylpropane-1,3-diol (m.p. 64°-65° C.) and esterified with an equimolar amount of benzenesulphochloride in anhydrous pyridine to give 2-benzylpropane-1,3-diol monobenzenesulphonate (oily substance). Reaction thereof with the sodium salt of hexadecanethiol in ethanol gives the desired 2-benzyl-3-hexadecylthiopropan-1-ol (wax-like compound).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:22][CH:21]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:12]=2)[CH:8]=[N:7]1.[CH3:45][C@H:46]1[CH2:48][O:47]1.CCN(C(C)C)C(C)C>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([N:26]5[CH2:27][CH2:28][N:29]([CH2:45][C@@H:46]([OH:47])[CH3:48])[CH2:30][CH2:31]5)=[CH:24][CH:25]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(C)c4)c3)c3cc(-c4ccc(N5CCNCC5)cc4)cnc32)cc1
Reactant: C[C@H]1CO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(C)c4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)cc4)cnc32)cc1
Yield: 62 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-(3-methylbenzyl)-1H-pyrazol-4-yl)-5-(4-(piperazin-1-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (175 mg. 0.244 mmol) was alkylated using (S)-2-methyloxirane (26 mg, 0.488 mmol), DIPEA (171 μL, 0.977 mmol) and ethanol (5 mL) to get 100 mg (62.1% yield) of the titled compound. MS: m/z=661.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]3[CH2:16][CH2:15][N:14]([CH3:17])[C:13](=[O:18])[C:9]3=[C:10]([O:11]C)[C:6]=2[C:5](=[O:19])[N:4]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([Cl:28])[CH:22]=2)[N:3]=1.[CH3:29][C:30](=O)[CH2:31][CH2:32][C:33](=O)[CH3:34].C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[Cl:28][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[F:27])[CH2:20][N:4]1[C:5](=[O:19])[C:6]2[C:10]([OH:11])=[C:9]3[C:13](=[O:18])[N:14]([CH3:17])[CH2:15][CH2:16][N:8]3[C:7]=2[C:2]([N:1]2[C:33]([CH3:34])=[CH:32][CH:31]=[C:30]2[CH3:29])=[N:3]1
Reactant: CC(=O)CCC(C)=O
Reactant: COc1c2n(c3c(N)nn(Cc4ccc(F)c(Cl)c4)c(=O)c13)CCN(C)C2=O
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1nn(Cc2ccc(F)c(Cl)c2)c(=O)c2c(O)c3n(c12)CCN(C)C3=O
Temperature: 120 °C

Procedure:
A mixture of 4-amino-2-(3-chloro-4-fluorobenzyl)-10-methoxy-8-methyl-7,8-dihydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (100 mg, 246 μmol), hexan-2,5-dione (34 mg, 296 μmol), and toluenesulfonic acid (catalytic amount) in toluene (2 mL) was heated in a sealed tube in an oil bath at 120° C. for one hour. The product mixture was concentrated under vacuum. The residue was partitioned between dichloromethane and aqueous sodium bicarbonate. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a 0-30% methanol in ethyl acetate gradient. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: [CH2:1]([S:8][CH:9]([CH:27]([O:30][CH3:31])[O:28][CH3:29])[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([OH:23])=[CH:18][C:17]=2[N+:24]([O-:26])=[O:25])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:39](Cl)(=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41]>O1CCCC1.C(OCC)(=O)C>[C:39]([O:23][C:19]1[CH:20]=[C:21]2[C:16](=[C:17]([N+:24]([O-:26])=[O:25])[CH:18]=1)[NH:15][C:14]([C:12]([NH:11][CH2:10][CH:9]([S:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:27]([O:28][CH3:29])[O:30][CH3:31])=[O:13])=[CH:22]2)(=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COC(OC)C(CNC(=O)c1cc2cc(O)cc([N+](=O)[O-])c2[nH]1)SCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(OC)C(CNC(=O)c1cc2cc(OC(=O)C(C)(C)C)cc([N+](=O)[O-])c2[nH]1)SCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a solution of N-[2-(benzylthio)-3,3-dimethoxypropyl]-5-hydroxy-7-nitro-1H-indole-2-carboxamide (1.0 g) in tetrahydrofuran (10 mL) were added dropwise triethylamine (0.38 mL) and pivaloyl chloride (0.30 mL) under ice-cooling. The mixture was stirred overnight at room temperature, diluted with ethyl acetate, washed with water, 1N hydrochloric acid and saturated brine, dried (MgSO4), and concentrated. The residue was purified by basic silica gel column chromatography (hexane:ethyl acetate=1:1) to give the title compound (1.18 g, yield 99%) as a pale-yellow amorphous powder.
Reaction SMILES: [N:1]1([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([OH:32])([C:22]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:24]([CH3:31])[CH:23]=4)[C:18]([F:21])([F:20])[F:19])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[O:7])C=CN=[CH:2]1.[CH:33]1(N)C[CH2:34]1>N1C=CC=CC=1.CCOCC>[CH:2]1([NH:1][C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([OH:32])([C:22]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:24]([CH3:31])[CH:23]=4)[C:18]([F:20])([F:21])[F:19])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[O:7])[CH2:34][CH2:33]1
Reactant: NC1CC1
Reactant: Cn1cc(C(O)(c2ccc3c(cnn3C(=O)n3ccnc3)c2)C(F)(F)F)c2ccccc21
Solvent: CCOCC
Solvent: c1ccncc1
Product: Cn1cc(C(O)(c2ccc3c(cnn3C(=O)NC3CC3)c2)C(F)(F)F)c2ccccc21
Reaction time: 8 h

Procedure:
To a solution of imidazol-1-yl-{5-[2,2,2-trifluoro-1-hydroxy-1-(1-methyl-1H-indol-3-yl)ethyl]indazol-1-yl}-methanone (0.145 mmol) in 1 mL of pyridine was added cyclopropylamine (1.45 mmol). The mixture was stirred overnight, diluted with ether, washed with water and brine and dried over magnesium sulfate. The volatiles were removed in vacuo and the residue purified by flash silica gel chromatography using 33% ethyl acetate in hexanes. The product-rich fractions were concentrated in vacuo to provide the title compound, m.p. 116° C.-118° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:16])[CH:14]=[O:15])[CH:7]=[CH:6]2.CC1C=CC=C(C)[N+]=1[O-:25].C(OO)(=O)C>C(OCCCC)(=O)C.C(OCC)(=O)C>[CH3:16][C@H:13]([C:14]([OH:25])=[O:15])[C:8]1[CH:7]=[CH:6][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:10]=2[CH:9]=1
Reactant: COc1ccc2cc([C@H](C)C=O)ccc2c1
Reactant: Cc1cccc(C)[n+]1[O-]
Agent: CC(=O)OO
Solvent: CCOC(C)=O
Solvent: CCCCOC(C)=O
Product: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Yield: 98.3 %

Procedure:
To a stirred solution of 3.32 g (15.5 mmol) of (S)-2-(6-methoxy-2-naphthyl)propionaldehyde (98.8% pure by GC) in n-butyl acetate (15.5 mL) cooled in a wet-ice bath (ca. 2° C.) was added 1.91 g (15.5 mmol) of 2,6-dimethylpyridine N-oxide (2,6-lutidine N-oxide). To this solution was then added slowly dropwise 1.77 g (23.2 mmol) of a 20.4 weight percent solution of peracetic acid in ethyl acetate, at a rate slow enough such that the reaction temperature did not exceed 10° C. (ca. 30 min). After the initial exotherm, the temperature returned to 2° C., and the reaction was maintained at this temperature for an additional 2 hours. Conversion of aldehyde at this time was ca. 99%, as monitored by GC (DB-1 column). The reaction solution was transferred into a separatory funnel, was diluted with n-butyl acetate (70 mL), and was washed with a 5% aqueous solution of sodium thiosulfate (Na2S2 O3, 15 mL). The butyl acetate layer was further washed with water (50 mL), and the combined water washes were back-extracted with n-butyl acetate (30 mL). The combined butyl acetate layers were extracted with two portions of a 5% aqueous solution of sodium hydroxide (NaOH, 65 mL each). The combined NaOH solutions of sodium naproxenate were acidified to pH=1 with a 5% aqueous solution of hydrochloric acid, precipitating the naproxen acid. The mixture was cooled in a wet-ice bath, and then was vacuum filtered through a #1 Whatman filter. The filter cake was washed with cold water (50 mL) and the white solid thus obtained was dried in a vacuum oven 60 hours at 55° C. (25 mm Hg), giving 3.51 g (98.4%) of naproxen.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9](O)=[O:10])[CH:5]=[CH:6][CH:7]=1.CO>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(F)c1
Solvent: C1CCOC1
Solvent: CO
Product: OCCc1cccc(F)c1
Temperature: 0 °C

Procedure:
Borane-dimethyl sulfide complex (9.15 ml, 96.5 mmol) is added dropwise and then faster as gas evolution slowed, to an ice-cooled mixture of 3-fluorophenyl acetic acid (XXXIX, 4.96 g, 32.2 mmol) in THF (30 ml). After 2 hr methanol is added dropwise over the course of several hours. The solvents are then removed under reduced pressure and methanol is again added and removed under reduced pressure. The methanol addition/removal is repeated three times and then the residue is partitioned between dichloromethane and aqueous sodium bicarbonate. The organic layers are dried over sodium sulfate and concentrated to give 2-(3-fluorophenyl)ethanol (LXV), MS (m/z) 140; IR (neat) 1590, 1046, 1450, 1141, 782, 1488 and 691 cm-1.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:5][CH:4]=1.Cl.[CH3:28][NH:29][CH2:30][C:31]#[N:32].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:31]([CH2:30][N:29]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:5][CH:4]=1)[CH3:28])#[N:32]
Reactant: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CCl)cc3)c2)cc1
Reactant: CNCC#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CN(C)CC#N)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 59 %

Procedure:
In DMF (3ml) was dissolved (E)-N-[4-(chloromethyl)-phenyl]-3-(4-methylphenyl)cinnamamide (200mg), and to the solution were added methylaminoacetonitrile hydrochloride (77mg) and potassium carbonate (382mg). The mixture was stirred at room temperature for 14 hours, and to the mixture was added water (50ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropylether to give (E)-N-[4-[N-(cyanomethyl)-N-methylaminomethyl]phenyl]-3-(4-methylphenyl)-cinnamamide (Compound 64) (129mg) as colorless crystals.