Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:8](=[O:9])[N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17](=[O:26])[C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=3)[CH:11]=2)[C:6]2[N:27]=[CH:28][CH:29]=[CH:30][C:5]=2[N:4]=1.[C:31]1([C:37]2[NH:38][CH:39]=[CH:40][N:41]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[C:31]1([C:37]2[N:41]([CH2:2][C:3]3[C:8](=[O:9])[N:7]([C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17](=[O:26])[C:18]5[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=5)[CH:11]=4)[C:6]4[N:27]=[CH:28][CH:29]=[CH:30][C:5]=4[N:4]=3)[CH:40]=[CH:39][N:38]=2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: c1ccc(-c2ncc[nH]2)cc1
Reactant: O=C(Nc1cccc(-n2c(=O)c(CBr)nc3cccnc32)c1)c1cc(Cl)cc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-n2c(=O)c(Cn3ccnc3-c3ccccc3)nc3cccnc32)c1)c1cc(Cl)cc(Cl)c1
Yield: 16.2 %

Procedure:
The solution of 2-bromomethyl-4-[3-(3,5-dichlorobenzoylamino)phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (285 mg) and 2-phenylimidazole (734 mg) in N,N-dimethylformamide (30 ml) was stirred for 3 hours at 80° C. The mixture was poured into aqueous sodium hydrogencarbonate (150 ml) and extracted by ethyl acetate (150 mg). The organic layer was evaporated and chromatographed to obtain 2-[(2-phenylimidazol-1-yl)methyl]-4-[3-(3,5-dichlorobenzoylamino)phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (52 mg) in brown powder form.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[N:3]=1.[C:14]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][OH:20])#[N:15]>>[C:14]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][O:20][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[N:3]=1)#[N:15]
Reactant: Clc1cncc(N2CCNCC2)n1
Reactant: N#Cc1cccc(CO)c1
Product: N#Cc1cccc(COc2cncc(N3CCNCC3)n2)c1

Procedure:
Starting materials, 2-chloro-6-(1-piperazinyl)pyrazine and 3-cyanobenzyl alcohol. Fragmenting mass analysis supports the stated structure. Purity 90% (HPLC). HRMS m/z calcd for C16H17N5O (M)+ 295.1433, found 295.1431.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][S:7][CH2:6][C@@H:5]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[N:4]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:3]1=[O:22].Br[CH:24]([CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:25]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:26]>C(OCC)(=O)C.C(Cl)Cl>[CH2:28]([O:27][C:25]([CH:24]([NH:1][C@H:2]1[CH2:8][S:7][CH2:6][C@@H:5]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[N:4]([CH2:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C:3]1=[O:22])[CH2:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:26])[CH2:29][CH2:30][CH3:31]
Reactant: CCCCOC(=O)C(Br)CCc1ccccc1
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)CSC[C@H]1c1cccs1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCOC(=O)C(CCc1ccccc1)N[C@H]1CSC[C@@H](c2cccs2)N(CC(=O)OC(C)(C)C)C1=O

Procedure:
345 mg of t-butyl α-[6(R)-amino-5-oxo-3(S)-(2-thienyl)perhydro-1,4-thiazepin-4-yl]acetate [prepared as described in Example 16(g)] were N-alkylated with 450 mg of butyl 2-bromo-4-phenylbutyrate in the same manner as in Example 1(h). The reaction product was then subjected to silica gel column chromatography using a 1:40 by volume mixture of ethyl acetate and methylene chloride as eluent, to separate it into two isomers, A and B (ascribed to the asymmetric carbon atom to which the phenethyl group is attached).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:16][C:17]([CH3:19])=[CH2:18])=[C:4]2[C:8](=[C:9]([CH3:12])[C:10]=1[CH3:11])[N:7](C=O)[CH:6]([CH3:15])[CH2:5]2.[ClH:20]>C(O)C>[ClH:20].[CH3:18][C:17]1([CH3:19])[O:1][C:2]2[C:3](=[C:4]3[C:8](=[C:9]([CH3:12])[C:10]=2[CH3:11])[NH:7][CH:6]([CH3:15])[CH2:5]3)[CH2:16]1
Reactant: C=C(C)Cc1c(O)c(C)c(C)c2c1CC(C)N2C=O
Agent: Cl
Solvent: CCO
Product: Cc1c(C)c2c(c3c1NC(C)C3)CC(C)(C)O2
Yield: 52 %

Procedure:
To a solution of 2,3-dihydro-5-hydroxy-2,6,7-trimethyl-4-(2-methyl-2-propen-1-yl)-1H-indole-1 carbaldehyde (0.26 g, 1.0 mmol) in ethanol (3 mL) was added concentrated hydrochloric acid (0.5 mL), and the mixture was heated to reflux for 1 hour. The reaction mixture was treated with active carbon, filtered, and concentrated under reducer pressure. The residue was recrystallized from ethanol-diethyl ether to obtain 0.14 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([F:32])([F:31])[C:13]2[N:18]=[CH:17][C:16]([CH:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[OH:20])=[CH:15][CH:14]=2)[CH2:11][O:10]1.[NH:33]1[CH:37]=[N:36][N:35]=[N:34]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([CH2:11][N:33]1[CH:37]=[N:36][N:35]=[N:34]1)[C:12]([F:31])([F:32])[C:13]1[CH:14]=[CH:15][C:16]([CH:19]([OH:20])[C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:30])[F:29])=[CH:23][CH:22]=2)=[CH:17][N:18]=1
Reactant: c1nnn[nH]1
Reactant: OC(c1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)C2(c3ccc(F)cc3F)CO2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC(c1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)C(O)(Cn2cnnn2)c2ccc(F)cc2F)nc1
Temperature: 65 °C
Reaction time: 16 h
Yield: 178.1 %

Procedure:
To a stirred solution of (6-((2-(2,4-difluorophenyl)oxiran-2-yl)difluoromethyl)pyridin-3-yl)(4-(trifluoromethyl)phenyl)methanol (AM; 600 mg, 0.32 mmol) in dry DMF (10 mL) was added 1H-tetrazole (138 mg, 1.97 mmol) followed by K2CO3 (181 mg, 1.31 mmol) at RT under inert atmosphere. The resulting reaction mixture was gradually heated up to 65° C. and stirred for 16 h; progress of the reaction was monitored by TLC. The reaction mixture was cooled to RT, diluted with ice-cold water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 35-40% EtOAc/hexanes) afforded 72 (diastereomeric mixture; 300 mg, 0.57 mmol, 43%) as an off-white solid. 1H NMR (500 MHz, CDCl3; mixture of diastereomers): δ 8.73 (s, 2H), 8.54 (s, 1H), 8.48 (s, 1H), 7.83 (d, J=8.0 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.64 (d, J=8.0 Hz, 4H), 7.62-7.58 (m, 4H), 7.50-7.44 (m, 4H), 7.42-7.39 (m, 2H), 6.81-6.74 (m, 2H), 6.72-6.64 (m, 2H), 5.99-5.93 (m, 2H), 5.48-5.40 (m, 2H), 5.20-5.12 (m, 2H), 2.78 (s, 1H), 2.70 (s, 1H). MS (ESI): m/z 528 [M+H]+.
Reaction SMILES: [CH3:1][C@H:2]1[C@@:6]([CH3:8])([OH:7])[CH2:5][CH2:4][NH:3]1.[F:9][C:10]1[CH:17]=[C:16](F)[CH:15]=[C:14]([F:19])[C:11]=1[C:12]#[N:13].C(=O)([O-])[O-].[Li+].[Li+]>>[F:9][C:10]1[CH:17]=[C:16]([N:3]2[CH2:4][CH2:5][C@@:6]([OH:7])([CH3:8])[C@@H:2]2[CH3:1])[CH:15]=[C:14]([F:19])[C:11]=1[C:12]#[N:13]
Reactant: C[C@@H]1NCC[C@]1(C)O
Reactant: N#Cc1c(F)cc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: C[C@@H]1N(c2cc(F)c(C#N)c(F)c2)CC[C@]1(C)O

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-2,3-dimethylpyrrolidin-3-ol 0.5 oxalate (300 mg), 2,4,6-trifluorobenzonitrile (882 mg) and lithium carbonate (276 mg), the title compound was obtained as a colorless solid (yield: 263 mg, yield: 56%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH2:10])=[O:4].[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>N1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH:10][C:22](=[O:23])[C:21]1[CH:25]=[CH:26][C:18]([Cl:17])=[CH:19][CH:20]=1)=[O:4]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N
Solvent: c1ccncc1
Product: COC(=O)c1sc(-c2ccccc2)cc1NC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.1 %

Procedure:
To mixture of methyl-3-amino-5-phenylthiophene-2-carboxylate (100 mg, 0.428 mmol) in anhydrous pyridine (4.3 ml) was added p-chlorobenzoyl chloride (71 μl, 0.556 mmol). The mixture was stirred for 3 hours at room temperature and concentrated. Purification chromatography (silica gel, hexane to hexane:ethyl acetate; 95:5) gave 145 mg (91% yield) of 3-(4-Chloro-benzoylamino)-5-phenyl-thiophene-2-carboxylic acid methyl ester. 1H NMR (CDC3, 400 MHz) 8.54 (s, 1H), 7.99-7.96 (m, 2H), 7.73-7.71 (m, 2H); 7.52-7.50 (m, 2H), 7.46-7.39 (m, 3H), 3.95 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10]2)=[CH:5][CH:4]=1.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2CCC(=O)C2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C2CCC(O)C2)cc1
Reaction time: 0.5 h

Procedure:
To a RT solution of 3-(4-methoxyphenyl)cyclopentanone (Step B) (482.5 mg, 2.54 mmol) in MeOH (5 ml) was added sodium borohydride (96 mg, 2.54 mmol). The reaction mixture was stirred under nitrogen for 30 minutes, then, concentrated, added water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to afford the title compound as a mixture of diastereomers that was used without further purification. Mass spectrum (ESI) 175.3 (M+1 minus 18).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:14][C:15]([F:50])([F:49])[C:16]1[CH:17]=[C:18]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:19][N:20]1[CH2:25][C:24]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=2)([CH2:26][CH2:27]OS(C)(=O)=O)[CH2:23][O:22][C:21]1=[O:41].[I-].[K+].Cl>CCOCC.CN(C=O)C>[ClH:39].[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:27][CH2:26][C:24]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=3)[CH2:23][O:22][C:21](=[O:41])[N:20]([CH2:19][C:18]3[CH:17]=[C:16]([C:15]([F:49])([F:50])[F:14])[CH:44]=[C:43]([C:45]([F:47])([F:46])[F:48])[CH:42]=3)[CH2:25]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: CS(=O)(=O)OCCC1(c2ccc(Cl)c(Cl)c2)COC(=O)N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C1OCC(CCN2CCC(Cc3ccccc3)CC2)(c2ccc(Cl)c(Cl)c2)CN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 27.2 %

Procedure:
This compound is prepared by the procedure described in step D of EXAMPLE 4 from 0.3 g of 4-benzylpiperidine, 0.8 g of the compound obtained in step C of EXAMPLE 4, 0.24 g of potassium iodide and 5 ml of DMF. The residue is chromatographed on silica H using DCM and then a DCM/MeOH mixture (96/4; v/v) as the eluent. The product obtained is taken up with a saturated solution of gaseous HCl in ether and the precipitate formed is wrung to give 0.13 g of the expected product. M.p.=124° C.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([OH:23])=[CH:6][CH:7]=[C:8]2[C:13]=1[O:12][C:11](=[O:14])[CH:10]=[C:9]2[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:2]=[CH2:3].[CH2:24]([CH:26]1[O:28][CH2:27]1)Cl>C(O)C>[CH2:1]([C:4]1[C:5]([O:23][CH2:24][CH:26]2[O:28][CH2:27]2)=[CH:6][CH:7]=[C:8]2[C:13]=1[O:12][C:11](=[O:14])[CH:10]=[C:9]2[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1c(O)ccc2c(OCc3ccccc3)cc(=O)oc12
Reactant: ClCC1CO1
Solvent: CCO
Product: C=CCc1c(OCC2CO2)ccc2c(OCc3ccccc3)cc(=O)oc12
Yield: 82 %

Procedure:
Reaction of 8-allyl-4-benzyloxy-7-hydroxycoumarin (12.33 g; 0.04 mole) with epichlorhydrin (25 ml) as described in Example 2(a) gave 11.97 g (82%) of product of m.p. (ethanol) 118°-121° C., νmax (mull) 1715, 1618, 1565 cm-1 (Found; C, 72.45; H, 5.53; C22H20O5 requires; C, 72.51; H, 5.53%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][S:8][C:9]2[N:14]=[C:13](Cl)[CH:12]=[C:11]([Cl:16])[N:10]=2)=[CH:5][CH:4]=1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=1[CH3:27]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C:9]2[N:10]=[C:11]([Cl:16])[CH:12]=[C:13]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=3[CH3:27])[N:14]=2)=[CH:17][CH:18]=1
Reactant: COc1ccc(CSc2nc(Cl)cc(Cl)n2)cc1
Reactant: Cc1cccc(N)c1C
Solvent: CC#N
Product: COc1ccc(CSc2nc(Cl)cc(Nc3cccc(C)c3C)n2)cc1

Procedure:
To a solution of 2-p-methoxybenzylthio-4,6-dichloro-pyrimidine (19.8 g) in acetonitrile (100 l) is added 2,3-xylidine (16 ml) and the resulting mixture is refluxed for 36 hours. The solid is filtered, washed with a little amount of acetonitrile, then the filtrate is concentrated to dryness. The residue is purified by chromatography on silica-gel. 17 g of the desired product are obtained. M.p. 118°-119° C. (benzene/hexane).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([NH:13][C:14]2[CH:15]=[N:16][CH:17]=[N:18][CH:19]=2)[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1.[CH3:20]I>C1COCC1.CCOC(C)=O>[F:3][C:4]1[CH:5]=[C:6]([N:13]([CH3:20])[C:14]2[CH:19]=[N:18][CH:17]=[N:16][CH:15]=2)[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1
Reactant: O=[N+]([O-])c1cc(F)cc(Nc2cncnc2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(c1cncnc1)c1cc(F)cc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 30.8 %

Procedure:
NaH (4.5 mg, 0.18 mmol, 1.1 eq) was added to a flame-dried round-bottom flask and anhydrous THF (0.4 mL) was added. The slurry was cooled to 0° C. and compound 30 (40 mg, 0.17 mmol, 1.0 eq) was added as a solution in THF (0.4 mL). After stirring at 0° C. for 30 minutes methyl iodide (12 μL, 0.18 mmol, 1.1 eq) was added and the reaction was allowed to warm to room temperature while stirring overnight. The reaction was diluted with EtOAc and washed with water (1×). The aqueous layer was back extracted (1×) with EtOAc and the combined organics were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 13 mg (31%) of the title compound as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.79 (s, 2H), 7.58 (dt, J=2.1, 8.5 Hz, 1H), 7.52 (t, J=1.8 Hz, 1H), 7.33 (dt, J=2.3, 11.2 Hz, 1H), 3.42 (s, 3H); ES-MS [M+1]+: 249.1.
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][CH:19]([CH3:24])[CH2:20][C:21]([NH2:23])=O)=[C:8]2[CH3:25])=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>O1CCOCC1>[Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][CH:19]([CH3:24])[CH2:20][C:21](=[S:37])[NH2:23])=[C:8]2[CH3:25])=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)c(CC(C)CC(N)=O)c(C)n2Cc1ccc(Br)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: COc1ccc2c(c1)c(CC(C)CC(N)=S)c(C)n2Cc1ccc(Br)cc1

Procedure:
To the amide (530 mg, 1.30 mmol) of Example 90 in 1,4-dioxane (10.0 mL) was added the Lawesson reagent (310 mg, 0.767 mmol). After refluxing for 2 min, the solvent was evaporated in vacuo and the title product was purified by flash chromatography (30% EtOAc in hexane).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][C:15]#[N:16])[C:4]([CH3:7])=[CH:5][CH:6]=1.[C:17](OCC)(=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19].CC(C)([O-])C.[Na+]>C(O)C>[C:15]([CH:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[N:3]1[C:2]([CH3:1])=[CH:6][CH:5]=[C:4]1[CH3:7])[C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])#[N:16]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1ccc(C)n1-c1ccccc1CC#N
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=O)C(C#N)c1ccccc1-n1c(C)ccc1C

Procedure:
2-(2,5-Dimethylpyrrol-1-yl)phenylacetonitrile (15 mmol) and diethyl oxalate (4.38 g, 30 mml) were sequentially added neat washing with ethanol (15 mL) to a solution of sodium tert-butoxide (1.73 g, 18 mmol) in ethanol (15 mL). The reaction mixture was heated at reflux under a nitrogen atmosphere for 4.5 hours to provide a solution of ethyl 3-cyano-3-[2-(2,5-dimethylpyrrol-1-yl)phenyl]-2-oxopropionate in ethanol.
Reaction SMILES: CC(C)(OC([NH:7][CH:8]([C:19]([NH:21][C@@H:22]([C:24]([NH:26][CH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH2:28]1)=[O:25])[CH3:23])=[O:20])[CH2:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([OH:17])=[CH:12][C:11]=1[CH3:18])=O)C.[ClH:37]>>[ClH:37].[CH3:16][C:15]1[CH:14]=[C:13]([OH:17])[CH:12]=[C:11]([CH3:18])[C:10]=1[CH2:9][CH:8]([C:19]([NH:21][C@@H:22]([C:24]([NH:26][CH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH2:28]1)=[O:25])[CH3:23])=[O:20])[NH2:7]
Reactant: Cc1cc(O)cc(C)c1CC(NC(=O)OC(C)(C)C)C(=O)N[C@H](C)C(=O)NC1CCc2ccccc21
Agent: Cl
Product: Cc1cc(O)cc(C)c1CC(N)C(=O)N[C@H](C)C(=O)NC1CCc2ccccc21

Procedure:
The title compound of Example 18 was deblocked and converted to its HCl salt by the method of Example 6.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[N:30]=[C:29]([O:31][CH:32]3[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]3)[CH:28]=[CH:27][CH:26]=2)[N:4]=1)[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[C:29]([O:31][CH:32]3[CH2:33][CH2:34][NH:35][CH2:36][CH2:37]3)[N:30]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(Cc2cccc(OC3CCN(C(=O)OC(C)(C)C)CC3)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1nn(Cc2cccc(OC3CCNCC3)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reaction time: 1 h
Yield: 20.2 %

Procedure:
To tert-butyl 4-(6-((3-ethyl-4-(imidazo[1,2-a]pyridine-3-carboxamido)-1H-indazol-1-yl)methyl)pyridin-2-yloxy)piperidine-1-carboxylate (3 mg, 0.02 mmol) in DCM (1 mL) was added TFA (1 mL). The reaction mixture was stirred for one hour and concentrated. Silica gel chromatography of the crude material (DCM/MeOH/NH4OH 10:1:0.1) provided the desired product (2 mg). MS (ES+APCI) m/z=496 (M+H).
Reaction SMILES: C([O:5][C:6](=[O:72])[C@H:7]([CH2:63][CH2:64][C:65]([O:67]C(C)(C)C)=[O:66])[NH:8][C:9](=[O:62])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18](=[O:61])[CH2:19][CH2:20][S:21][CH2:22][CH:23]([O:43][C:44](=[O:60])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[CH2:24][O:25][C:26](=[O:42])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:12][CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:44]([O:43][CH:23]([CH2:24][O:25][C:26](=[O:42])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:22][S:21][CH2:20][CH2:19][C:18]([NH:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]([NH:8][C@H:7]([C:6]([OH:72])=[O:5])[CH2:63][CH2:64][C:65]([OH:67])=[O:66])=[O:62])=[CH:11][CH:12]=1)=[O:61])(=[O:60])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59]
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)NCc1ccc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1)OC(=O)CCCCCCCCCCCCCCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)NCc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A solution of 4-[6,7-bis(palmitoyloxy)-4-thiaheptanoylaminomethyl]benzoyl-glutamic acid di-t-butyl ester as obtained in Example 39 (325 mg) in dichloromethane (0.5 ml)-trifiuoroacetic acid (1 ml) was stirred at room temperature for 30 minutes. After solvent concentration under reduced pressure, the resulting residue was crystallized from methanol-water to yield the title compound (231 mg, yield 80%) as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:4]=[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8](CC3C=CC=CC=3)[C:7](=[O:22])[C:6]=12.Br.[OH-].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[N:3]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:4]=[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7](=[O:22])[C:6]=12
Reactant: Nc1c2c(=O)n(Cc3ccccc3)c3ccccc3c2nn1-c1ccccc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1c2c(=O)[nH]c3ccccc3c2nn1-c1ccccc1
Temperature: 100 °C
Yield: 24 %

Procedure:
A mixture of 3-amino-5-benzyl-2-phenyl-2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (0.26 g), 48% aqueous hydrobromic acid (8 ml) and acetic acid (1.3 ml) was heated at 100° C. for 36 hours. After cooling, ice was added thereto, and basified by adding an 11N aqueous sodium hydroxide solution. The precipitated crystal was collected by filtration, washed with water and dried. Methanol and ethyl acetate were added to the crystal, and the mixture was heated under reflux for 10 minutes. After cooling, the precipitated crystal was collected by filtration to obtain the target compound (47 mg).
Reaction SMILES: [C:1]12([C:11]([NH:13][NH:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[S:16])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH-].[Na+].N#N>>[C:1]12([C:11]3[N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:15]([SH:16])=[N:14][N:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(NNC(=S)Nc1ccccc1)C12CC3CC(CC(C3)C1)C2
Agent: N#N
Agent: [Na+]
Agent: [OH-]
Product: Sc1nnc(C23CC4CC(CC(C4)C2)C3)n1-c1ccccc1

Procedure:
A mixture of 1-(1-adamantylcarbonyl)-4-phenylthiosemicarbazide (C) (1.48 g) and 2 N NaOH (45 mL) was heated for I h under reflux in a N2 atmosphere and filtered. The filtrate was acidified with conc HCl to pH 4. The precipitated solid was filtered, washed with water and dried to give 5-(1-adamantyl)-4-phenyl-4H-1,2,4-triazole-3-thiol (11). MS: 312 (M+1).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=1>[O-2].[O-2].[Mn+4].C(OCC)(=O)C>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]=[O:15])=[CH:12][CH:13]=1
Reactant: OCc1ccc(CCC2CCCO2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: O=Cc1ccc(CCC2CCCO2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.1 %

Procedure:
To an ethyl acetate (50 mL) solution of (4-(2-(tetrahydrofuran-2-yl)-ethyl)-phenyl)methanol (600 mg, 2.91 mmol) described in Manufacturing Example 82-1-2 was added active manganese dioxide (10 g, 115 mmol), which was stirred for 12 hours at room temperature. The reaction liquid was suction filtered through a Celite pad, and washed with ethyl acetate (50 mL). The filtrate was concentrated under a reduced pressure to obtain the title compound (565 mg, 95%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]([C:13]1[CH:21]=[C:20]2[C:16]([C:17]3[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:18]=3[NH:19]2)=[C:15]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([S:33]([CH2:36][CH3:37])(=[O:35])=[O:34])[CH:28]=2)[CH:14]=1)=[O:12]>C(Cl)Cl>[CH3:9][O:10][C:11]([C:13]1[CH:21]=[C:20]2[C:16]([C:17]3[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:18]=3[NH:19]2)=[C:15]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([S:33]([CH2:36][CH3:37])(=[O:35])=[O:34])[CH:28]=2)[C:14]=1[Br:1])=[O:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCS(=O)(=O)c1cccc(-c2cc(C(=O)OC)cc3[nH]c4ncc(C)cc4c23)c1
Solvent: ClCCl
Product: CCS(=O)(=O)c1cccc(-c2c(Br)c(C(=O)OC)cc3[nH]c4ncc(C)cc4c23)c1
Temperature: 30 °C
Reaction time: 18 h
Yield: 23.8 %

Procedure:
N-Bromosuccinimide (59 mg, 0.33 mmol) was added to a solution of Compound 132 (128 mg, 0.31 mmol) in CH2Cl2 (3 mL) at r.t. The reaction was stirred for 18 h at 30° C. and was then concentrated in vacuo. Purification by prep-HPLC gave 36 mg (24%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ 12.28 (br s, 1H), 8.23 (s, 1H), 8.15-8.19 (m, 2H), 7.98 (s, 1H), 7.87 (t, 1H, J=7.6 Hz), 7.72 (d, 1H, J=7.6 Hz), 7.08 (s, 1H), 4.03 (s, 3H), 3.22 (q, 2H, J=7.2 Hz), 2.34 (s, 3H), 1.33 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for C22H19BrN2O4S, 487, 489; found 487, 489.