Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:14][S:13][C:12]3=[N:15][CH:16]=[C:17]([C:18]([OH:20])=O)[N:11]23)=[CH:6][CH:5]=1)#[N:3].Cl.[Cl:22][C:23]1[CH:24]=[C:25]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][C:30]2=[O:35])[CH:26]=[CH:27][CH:28]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>>[ClH:22].[Cl:22][C:23]1[CH:24]=[C:25]([N:29]2[CH2:34][CH2:33][N:32]([C:18]([C:17]3[N:11]4[C:12]([S:13][CH2:14][CH:10]4[C:7]4[CH:6]=[CH:5][C:4]([C:2]#[N:3])=[CH:9][CH:8]=4)=[N:15][CH:16]=3)=[O:20])[CH2:31][C:30]2=[O:35])[CH:26]=[CH:27][CH:28]=1
Reactant: O=C1CNCCN1c1cccc(Cl)c1
Reactant: N#Cc1ccc(C2CSc3ncc(C(=O)O)n32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(C2CSc3ncc(C(=O)N4CCN(c5cccc(Cl)c5)C(=O)C4)n32)cc1

Procedure:
The carboxylic acid from Step D (5.14 g, 16.1 mmol), 1-(3-chlorophenyl)piperazin-2-one hydrochloride (3.97 g, 16.1 mmol) (prepared as described in U.S. Pat. No. 5,856,326), EDC hydrochloride (3.70 g, 19.3 mmol), HOBT (2.61 g, 19.3 mmol), and N,N-diisopropylethylamine (14.0 mL, 80.4 mmol) were stirred in dry, degassed DMF (50 mL) at 25° C. for 16 hours. The reaction was poured onto saturated aqueous sodium bicarbonate solution and extracted with methylene chloride (3×100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to provide a yellow oil. The crude product was purified by column chromatography (3→5% methanol/methylene chloride) and converted to the HCl salt to provide the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[C:5]([CH2:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1)([CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)C(OCC)=O)[CH3:2].[Cl-].[Li+]>CS(C)=O.O>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([CH2:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1)[CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:2]
Reactant: CCOC(=O)C(CCCCc1ccccc1)(Cc1cccc2ccccc12)C(=O)OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C(CCCCc1ccccc1)Cc1cccc2ccccc12
Yield: 89.6 %

Procedure:
To a solution of 2.76 g of 2-(1-naphthylmethyl)-2-(4-phenylbutyl)malonic acid diethyl ester in 20 ml of dimethyl sulfoxide and 0.5 ml of water was added 1.27 g of lithium chloride, and then the mixture was heated for 8 hours at from 180° to 190° C. After cooling, to the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 2.06 g of 2-(1-naphthylmethyl)-6-phenylhexanoic acid ethyl ester as a light brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]([NH:17][NH:18]C(OC(C)(C)C)=O)=[O:16])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[ClH:26]>C(OCC)(=O)C>[ClH:26].[ClH:26].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1)[C:15]([NH:17][NH2:18])=[O:16]
Reactant: COc1cc(C(=O)NNC(=O)OC(C)(C)C)ccc1-n1cnc(C)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)NN)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of tert-butyl 2-{[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]carbonyl}hydrazinecarboxylate (8.00 g) in ethyl acetate (50 mL) was added hydrogen chloride (4M ethyl acetate solution, 100 mL), and the mixture was stirred at room temperature overnight. Ethyl acetate was added to the reaction mixture, and the precipitate was collected by filtration. The solid was recrystallized from methanol/ethyl acetate to give the title compound (5.94 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=2)[CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:33]1([CH2:39][CH2:40][S:41][CH:42]([C:46](O)=[O:47])[C:43](O)=[O:44])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[OH:47][C:46]1[CH:16]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:10][CH:11]=2)[O:17][C:43](=[O:44])[C:42]=1[S:41][CH2:40][CH2:39][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Reactant: CC(=O)c1ccc(OCc2cccnc2)cc1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2ccc(OCc3cccnc3)cc2)cc(O)c1SCCc1ccccc1

Procedure:
The title compound was prepared by Method A using 4'-(3-pyridinylmethoxy)acetophenone (1.14 g, 5.06 mmol), lithium bis(trimethylsilyl)amide (0.930 g, 5.56 mmol), chlorotrimethylsilane (0.705 mL, 5.56 mmol), THF (56 mL), and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. 178-179° C.; 1H NMR (400 MHz, DMSO-d6) δ2.76 (t, 2 H), 2.98 (t, 2 H), 5.25 (s, 2 H), 6.69 (s, 1 H), 7.21 (m, 7 H), 7.45 (q, 1 H), 7.77 (d, 2 H), 7.91 (d, 1 H), 8.57 (bs, 1 H), 8.70 (bs, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]([N:18]([CH3:20])[CH3:19])=O)[C:9]2([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].S(=O)(=O)(O)O>O1CCCC1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:9]2([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:16][N:18]([CH3:20])[CH3:19])=[CH:6][CH:7]=1
Reactant: CN(C)C(=O)C(c1ccc(N)cc1)C1(O)CCCCC1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CN(C)CC(c1ccc(N)cc1)C1(O)CCCCC1
Temperature: 0 °C
Reaction time: 5 h
Yield: 80.5 %

Procedure:
5.0 g (0.018 mole) of the above amide was dissolved in 300 ml of dry tetrahydrofuran and added dropwise to a mixture of 1.1 g of lithium aluminum hydride and 8.0 ml of concentrated sulfuric acid in 200 ml of tetrahydrofuran at 0° C. The mixture was stirred at 0° C. for five hours, then the excess reagent was destroyed by the dropwise addition of 4 ml of 50:50 THF-water, then 4 ml of 15% aqueous sodium hydroxide and finally 4 ml of water. The mixture was filtered and the precipitate washed several times with THF. The combined filtrates were evaporated and the residue recrystallized from isopropanol to give 3.8 g of the title compound as the free base. Treatment with excess oxalic acid in ethyl acetate gave the dioxalate, m.p. 105° C.(d).
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]2[O:12][CH:13]=[CH:14][N:15]=2)[CH:8]=[CH:7][C:6]=1[C:16]1[C:17]([S:22]([NH:25][C:26]2[O:30][N:29]=[C:28]([CH3:31])[C:27]=2[CH3:32])(=[O:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=1.C(N(CC)CC)C.[F:40][C:41]1[CH:49]=[CH:48][CH:47]=[CH:46][C:42]=1[C:43](Cl)=[O:44]>>[CH3:31][C:28]1[C:27]([CH3:32])=[C:26]([NH:25][S:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[O:12][CH:13]=[CH:14][N:15]=3)=[CH:10][C:5]=2[CH2:4][N:3]([CH3:2])[C:43](=[O:44])[C:42]2[CH:46]=[CH:47][CH:48]=[CH:49][C:41]=2[F:40])(=[O:24])=[O:23])[O:30][N:29]=1
Reactant: O=C(Cl)c1ccccc1F
Reactant: CNCc1cc(-c2ncco2)ccc1-c1ccccc1S(=O)(=O)Nc1onc(C)c1C
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2CN(C)C(=O)c2ccccc2F)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2'-[(methylamino)methyl]-N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide, monohydrochloride (25 mg, 0.053 mmol, prepared as described in Step (A) of Example 28), triethylamine (13.3 mg, 0.13 mmol) was added and followed by 2-fluorobenzoyl chloride (8.3 mg, 0.053 mmol). The reaction was stirred at room temperature overnight and concentrated. The residue was purified by preparative HPLC on an ODS S10 column using 29% solvent A (10% MeOH, 90% H2O, 0.1% TFA) and 71% solvent B (90% MeOH, 10% H2O, 0.1% TFA) to provide the title compound of this Example (20 mg, 68%) as a white solid, m.p. 127°-137° C. (amorphous).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)N)=[CH:4][CH:3]=1.CO[CH:21](OC)[CH2:22][CH2:23][CH2:24][NH:25][CH3:26]>>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:8]([CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:21]=[C:22]2[CH2:23][CH2:24][NH:25][CH3:26]
Reactant: NN(CCCc1ccccc1)c1ccc(Cl)cc1
Reactant: CNCCCC(OC)OC
Product: CNCCc1cn(CCCc2ccccc2)c2ccc(Cl)cc12

Procedure:
The title compound is prepared by General Method 10 using 1-(4-chlorophenyl)-1-(3-phenylpropyl)hydrazine (Example 9) and 4,4-dimethoxy-N-methylbutan-1-amine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH2:10][NH2:11])[CH:8]=1)([O-:3])=[O:2].CN1C(=O)CCC1.Cl[C:20]1[N:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[N:21]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH3:29][O:28][C:22]1[CH:23]=[C:24]([O:26][CH3:27])[N:25]=[C:20]([NH:11][CH2:10][CH2:9][N:7]2[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[N:6]2)[N:21]=1
Reactant: COc1cc(OC)nc(Cl)n1
Reactant: NCCn1cc([N+](=O)[O-])cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: COc1cc(OC)nc(NCCn2cc([N+](=O)[O-])cn2)n1
Temperature: 150 °C

Procedure:
A microwave tube was charged with 2-(4-nitro-1H-pyrazol-1-yl)ethanamine (1.92 g, 5.52 mmol), NMP. (15 mL), 2-chloro-4,6-dimethoxypyrimidine (1.16 g, 6.62 mmol) and K2CO3 (4.19 g, 30.34 mmol). The resulting mixture was heated to 150° C. for 20 min in the microwave (no cooling). The reaction mixture was diluted with DCM and washed with water. The org. layer was separated and the aq. layer was extracted with DCM (2×) The combined organic layers were washed with brine, dried (MgSO4), filtered and the solvent was removed under reduced pressure. Purification was performed by FC (EtOAc/hept 6:4) to obtain 4,6-dimethoxy-N-(2-(4-nitro-1H-pyrazol-1-yl)ethyl)pyrimidin-2-amine. LC-MS conditions A: tR=0.33 min, [M+H]+=no ionization.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([OH:15])=O)=[CH:7]2)([O-:3])=[O:2].Cl.CN(C)CCCN=C=NCC.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>ClCCl>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([C:13]([C:8]2[NH:9][C:10]3[C:6]([CH:7]=2)=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=3)=[O:15])[CH2:31][CH2:30]1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CN1CCN(C(=O)c2cc3cc([N+](=O)[O-])ccc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 5-nitroindole-2-carboxylic acid (4.38 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 4.89 g) in dichloromethane (150 mL) was treated with N-methylpiperazine (2.83 mL) and stirred at ambient temperature for 16 h. The reaction mixture was poured into dichloromethane (200 mL), washed with water, saturated sodium hydrogencarbonate solution and then brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-10% 2 M ammonia in methanol/dichloromethane) to give the title compound (1.8 g). 1H NMR (400 MHz, CDCl3): δ 10.97 (br s, 1H), 8.58 (d, J=2.15 Hz, 1H), 8.11 (dd, J=2.15, 7.04 Hz, 1H), 7.44 (d, J=9.00 Hz, 1H), 6.89 (s, 1H), 3.95 (br m, 4H), 2.52 (t, J=4.89 Hz, 4H), 2.34 (s, 3H). MS (electrospray): exact mass calculated for C14H16N4O3, 288.12; m/z found, 289.1 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[C:13](O)(=[O:17])[C:14]([CH3:16])=[CH2:15]>CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>[C:1]([C:5]1[CH:10]=[C:9]2[C:8]([CH2:15][CH:14]([CH3:16])[C:13]2=[O:17])=[CH:7][C:6]=1[O:11][CH3:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccccc1C(C)(C)C
Reactant: C=C(C)C(=O)O
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: COc1cc2c(cc1C(C)(C)C)C(=O)C(C)C2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 1-tert-butyl-2-methoxybenzene (32.8 g, 0.2 mol) and methacrylic acid (21.5 g, 0.25 mol) was added at 60° C. to a well stirred Eaton reagent (55 g P2O5 and 280 ml of methanesulfonic acid). After 1 h of stirring the reaction mixture was cooled, poured into ice water, and extracted with benzene (3×200 ml). The combined organic layer was washed with water, aq. NaHCO3, dried over MgSO4, evaporated and distilled at 145-150° C./0.7 Torr. Yield 20 g (43%).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[N:11]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:19][CH:18]=3)[C:10]([S:29][CH2:30][CH3:31])=[N:9][C:8]=2[C:7]1=[O:32]>C(O)=O>[CH2:30]([S:29][C:10]1[N:11]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:27])([F:28])[F:26])=[CH:19][CH:18]=2)[C:12](=[O:16])[C:13]2[CH:14]=[CH:15][NH:6][C:7](=[O:32])[C:8]=2[N:9]=1)[CH3:31]
Reactant: CCSc1nc2c(=O)n(Cc3ccc(OC)cc3OC)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Solvent: O=CO
Product: CCSc1nc2c(=O)[nH]ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 83.1 %

Procedure:
7-(2,4-Dimethoxybenzyl)-2-(ethylsulfanyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]-3,7-dihydropyrido[3,4-d]pyrimidine-4,8-dione (219 mg) was dissolved in formic acid (5 ml), and the solution was stirred at 100° C. for 3 hr, allowed to be cooled to room temperature, and concentrated under reduced pressure. To the residue was added toluene, and the mixture was again concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate), and recrystallized from a mixed solvent of ethyl acetate/hexane/methanol to give the title compound (132 mg).
Reaction SMILES: [CH:1]([N:14]1[C:18]2=[N:19][C:20]([CH3:24])=[CH:21][C:22]([CH3:23])=[C:17]2[C:16]([C:25]#[N:26])=[C:15]1/[CH:27]=[CH:28]/[C:29]([O-:31])=O)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:38][C:39]([CH3:44])([CH3:43])[CH2:40][CH2:41][NH2:42].C(N(CC)CC)C>C1COCC1.O.CN(C=O)C>[CH:1]([N:14]1[C:18]2=[N:19][C:20]([CH3:24])=[CH:21][C:22]([CH3:23])=[C:17]2[C:16]([C:25]#[N:26])=[C:15]1/[CH:27]=[CH:28]/[C:29]([NH:42][CH2:41][CH2:40][C:39]([CH3:44])([CH3:43])[CH3:38])=[O:31])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)[O-])n(C(c3ccccc3)c3ccccc3)c2n1
Reactant: CC(C)(C)CCN
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)NCCC(C)(C)C)n(C(c3ccccc3)c3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2E)-3-(1-benzhydryl-3-cyano-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl)propenoate (200 mg, 0.506 mmol) in THF (2 ml) were added DMF (0,01 ml) and oxalylchloride (0.053 ml, 0.607 mmol), the mixture was stirred at room temperature 1 hour, and the solvent was distilled off under reduced pressure. The residue was added under ice-cooling to a solution of 3,3-dimethylbutylamine (0.103 mg, 0.760 mmol), triethylamine (0.177 ml, 1.27 mmol) and THF (4 ml), and the mixture was stirred under ice-cooling for 1 hour. After stirring at room temperature for 4 hours, the reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give the objective product as a solid material. The resultant material was recrystallized from hexane and ethyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](OS(C(F)(F)F)(=O)=O)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:24])[CH:11]=2)[CH:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.B(O)(O)[C:46]1[CH:51]=[CH:50][C:49]([S:52]([NH:55][CH:56]2[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]2)(=[O:54])=[O:53])=[CH:48][CH:47]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:46]2[CH:51]=[CH:50][C:49]([S:52](=[O:54])(=[O:53])[NH:55][CH:56]3[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]3)=[CH:48][CH:47]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:24])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(OS(=O)(=O)C(F)(F)F)c1C
Reactant: O=S(=O)(NC1CCCCC1)c1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(=O)(=O)NC3CCCCC3)cc2)c1C
Temperature: 25 °C
Yield: 31.1 %

Procedure:
A stirred solution of (6-fluoro-3-methyl-4-trifluoromethanesulfonyloxy-naphthalen-2-yl)-acetic acid methyl ester (0.10 g, 0.26 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Triphenylphosphine (0.016 g, 0.06 mmol), palladium (II) acetate (0.007 g, 0.03 mmol), 4-N-cyclohexylsulfamoylphenylboronic acid (0.099 g, 0.35 mmol) and a 2 M aqueous solution of sodium carbonate (0.5 mL, 1.0 mmol) were added simultaneously to the reaction mixture at room temperature under argon. The reaction mixture was refluxed for 2 hours and then cooled to room temperature. Water was added and the mixture was extracted twice with ethyl acetate. The collected organic extracts were washed with water and then brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (Biotage, 5-10% ethyl acetate-hexane) to afford [4-(4-cyclohexylsulfamoyl-phenyl)-6-fluoro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (0.038 g, 33%) as a solid. MS calcd. for C26H27FNO4S [(M−H)−] 468, obsd. 468.4.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH:25]=O)[CH:8]=2)[N:3]=1.[CH2:31]([NH:33][CH2:34][CH2:35][OH:36])[CH3:32].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O1CCCC1.O>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:22]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH2:25][N:33]([CH2:34][CH2:35][OH:36])[CH2:31][CH3:32])[CH:8]=2)[N:3]=1
Reactant: CCNCCO
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccccc3C=O)ccc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCCl
Product: CCN(CCO)Cc1ccccc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
200 mg of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]benzaldehyde are dissolved in 10 ml of 1,2-dichloroethane and 10 ml of tetrahydrofuran. 99 μl of 2-(ethylamino)ethanol and 29 μl of glacial acetic acid are added, and the mixture is stirred at 60° C. for 6 h. After cooling to 25° C., 226 mg of sodium triacetoxyborohydride are added and stirred at 25° C. for a further 12 h. The mixture is poured into water, extracted three times with dichloromethane, and the combined organic phases are dried over sodium sulfate. After filtration, the filtrate is evaporated to dryness and purified by chromatography (reversed phase HPLC).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.C(N([CH2:15][CH3:16])CC)C.[C:17]([O:20][CH2:21][CH3:22])(=O)[CH3:18]>C(OC(C)COC)(=O)C>[CH:16]1([CH2:18][CH2:17][O:20][CH:21]([O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=2)[CH3:22])[CH2:15][CH2:4][CH2:3][CH2:2][CH2:9]1.[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: CCN(CC)CC
Agent: C=Cc1ccc(O)cc1
Solvent: COCC(C)OC(C)=O
Product: C=Cc1ccc(OC(C)OCCC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
p-Hydroxystyrene (VP-8000, produced by Nippon Soda Co., Ltd.) in an amount of 70 g was dissolved in 320 g of propylene glycol monomethyl ether acetate (PGMEA) with heating, dehydrated by vacuum distillation, and then cooled to 25° C. To this solution, 0.35 g of pyridinium p-toluenesulfonate and 22.4 g of cyclohexane ethanol were added, and further 17.5 g of t-butyl vinyl ether was added at a slow speed. In the resulting mixture, reaction was run for 5 hours at 20° C. Thereafter, the reaction solution was admixed with 0.28 g of triethylamine and 320 ml of ethyl acetate, and washed with 150 ml each of distilled water for three times. Therefrom, the solvent was distilled away, and the residue was concentrated. The thus obtained oil was dissolved in 100 ml of acetone, and poured slowly into 2 liter of distilled water. As a result, a powdery matter separated out. This powdery matter was filtered off and dried to yield 54 g of the desired resin.
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:20][CH2:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1>>[C:22]1([C:21]2[NH:20][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:2]=2)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: NCc1cccc2ccccc12
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc([N+](=O)[O-])cc1
Product: CCOC(=O)c1nc(-c2cccc3ccccc23)[nH]c1-c1ccc([N+](=O)[O-])cc1
Yield: 24.7 %

Procedure:
Ethyl 2-hydroxyimino-3-(4-nitrophenyl)-3-oxopropionate (10.0 g) and 1-aminomethylnaphthalene (6.4 g) were reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give ethyl 2-(1-naphthyl)-5-(4-nitrophenyl)imidazole-4-carboxylate (3.6 g). 3.0 g therefrom was dissolved in ethyl alcohol (100 ml) and 1 M sodium hydroxide solution (20 ml) was added. The mixture was reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 2-(1-naphthyl)-5-(4-nitrophenyl)imidazole-4-carboxylic acid (3.4 g), melting point 161° C. (decomposition).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[CH2:11][CH2:12][CH2:13][Cl:14].C1C=CC=CC=1.[H-].[Na+]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O>[Cl:14][CH2:13][CH2:12][CH2:11][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: ClCCCBr
Reactant: c1ccc2[nH]ccc2c1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: c1ccccc1
Product: ClCCCn1ccc2ccccc21
Reaction time: 1 h
Yield: 83 %

Procedure:
To a stirred mixture of 58.5 g of 1H-indole, 107.5 ml of 1-bromo-3-chloropropane, 15 mg of N,N,N-triethylbenzenemethanaminium chloride and 450 ml of benzene were added dropwise, during a period of 30 minutes, 250 ml of a sodium hydride dispersion 60% at 40° C. Upon completion, stirring was continued for 1 hour at 40° C. Another amount of 15 ml of 1-bromo-3-chloropropane was added and stirring was continued for 1 hour at 50° C. After cooling, the reaction mixture was poured into water. The product was extracted with benzene. The extract was separated, dried, filtered and evaporated. The residue was distilled, yielding 80 ml (83%) of 1-(3-chloropropyl)-1H-indole (interm. 10); bp. 120-125° C.
Reaction SMILES: [CH3:1][C:2]1([CH2:18][C:19]([O:21]CC)=[O:20])[C:10]2[S:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH2:5][CH2:4][O:3]1.[OH-].[Na+]>CO>[CH3:1][C:2]1([CH2:18][C:19]([OH:21])=[O:20])[C:10]2[S:9][C:8]([C:11]3[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=3)=[N:7][C:6]=2[CH2:5][CH2:4][O:3]1
Reactant: CCOC(=O)CC1(C)OCCc2nc(-c3ccc(Cl)cc3)sc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(CC(=O)O)OCCc2nc(-c3ccc(Cl)cc3)sc21

Procedure:
The latter ester is dissolved in methanol (500 ml) followed by the addition of sodium hydroxide (80 g) and the resulting mixture is heated at reflux temperature for 5 hr. The solvent is removed by distillation, water is added to the residue and the solution is extracted with ether. The aqueous basic phase is mixed with ether and the mixture is acidified with dilute hydrochloric acid. The organic phase is separated, washed with saturated sodium chloride solution, dried over sodium sulfate, and evaporated under reduced pressure. The residue is crystallized from chloroform-ether to give the title compound; mp 162°-164° C., γmaxCHCl3 2900 and 1705 cm-1.