Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:21]=3[NH:31][C:32]([C@H:34]3[CH2:39][CH2:38][C@H:37]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@H:14]2[CH3:46])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].I[CH3:52]>C1COCC1>[F:12][C:9]([F:11])([F:10])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([F:30])([F:28])[F:29])[CH:23]=[CH:22][C:21]=3[N:31]([CH3:52])[C:32]([C@H:34]3[CH2:39][CH2:38][C@H:37]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@H:14]2[CH3:46])[CH:4]=[C:3]([C:2]([F:1])([F:47])[F:48])[CH:8]=1
Reactant: CCOC(=O)C[C@H]1CC[C@H](C(=O)Nc2ccc(OC(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C[C@H]1CC[C@H](C(=O)N(C)c2ccc(OC(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A stirred solution of ethyl [trans-4-({[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethoxy)phenyl]amino}carbonyl)cyclohexyl]acetate (500 mg; 0.716 mmol) in anhydrous THF (10 mL) was cooled to 0° C. and treated with sodium hydride (60% in oil; 31.5 mg; 0.788 mmol). The resultant mixture was stirred at 0° C. for 30 min prior to addition of iodomethane (58 μL; 0.931 mmol). The reaction was stirred at room temperature for 14 h and quenched with H2O. The reaction was partitioned between EtOAc (50 mL) and H2O (50 mL) and the aqueous layer was extracted with EtOAc (3×50 mL). The combined extracts were washed with brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography, eluting with EtOAc/hexanes, and by chiral HPLC (chiralPak IA column, 10% iPrOH/heptane) to afford ethyl (trans-4-{[[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethoxy)phenyl](methyl)amino]carbonyl}cyclohexyl)acetate as a clear oil. LCMS=713.0 (M+1)+. 1H NMR (CDCl3, 500 MHz, mixture of atropisomers): δ 7.92 (s, 1 H), 7.80 (s, 1 H), 7.73 (s, 1H), 7.29-7.20 (m, 2 H), 7.17-7.15 (m, 1 H), 5.66 (d, J=8.3 Hz, 1 H), 4.95 (d, J=14.8 Hz, 1 H), 4.22 (d, J=16.7 Hz, 1 H), 4.14-4.06 (m, 2 H), 3.897 (d, J=14.7 Hz, 1 H), 3.39 (s, 3 H), 2.70-2.63 (m, 1 H), 2.22-2.18 (m, 1 H), 2.10-2.07 (m, 1 H), 2.00-1.52 (m, 8 H), 1.27-1.19 (m, 3 H), 1.16-1.08 (m, 1 H), 0.76-0.68 (m, 3 H).
Reaction SMILES: [C:1]([C:4](=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:3])[CH3:2].BrN1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH2:12]([C:11]1[O:3][C:1]([CH3:2])=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:10]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCC=C(C(C)=O)C(=O)OCC
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCCc1cc(C(=O)OCC)c(C)o1
Yield: 88.1 %

Procedure:
A mixture of 4.80 g (0.02 mole) ethyl 2-acetyl-2-decenoate and 3.56 g (0.02 mole) N-bromosuccinimide in 50 ml of carbon tetrachloride was heated at reflux for 12 hours. After cooling, the succinimide was removed by filtration and the solution concentrated by rotary evaporation. Distillation of the crude product gave 4.20 g (88%) of ethyl 5-hexyl-2-methyl-3-furoate, bp 107°-109° C. (0.4 mm).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[C:29]([O:30][CH3:31])=[C:28]([O:32][CH3:33])[CH:27]=[C:26]([CH3:34])[C:11]=1[C:12]([C:14]1[C:15]([Cl:25])=[N:16][C:17](Cl)=[CH:18][C:19]=1[C:20]([F:23])([F:22])[F:21])=[O:13]>CO.[C].[Pd]>[CH3:8][O:9][C:10]1[C:29]([O:30][CH3:31])=[C:28]([O:32][CH3:33])[CH:27]=[C:26]([CH3:34])[C:11]=1[C:12]([C:14]1[C:15]([Cl:25])=[N:16][CH:17]=[CH:18][C:19]=1[C:20]([F:23])([F:21])[F:22])=[O:13]
Reactant: COc1cc(C)c(C(=O)c2c(C(F)(F)F)cc(Cl)nc2Cl)c(OC)c1OC
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1cc(C)c(C(=O)c2c(C(F)(F)F)ccnc2Cl)c(OC)c1OC
Reaction time: 6.5 h
Yield: 54.5 %

Procedure:
2.4 ml (17 mmol) of triethylamine and 0.3 g of 5% palladium carbon were added to a solution having 3.4 g (8.0 mmol) of 3-(2,3,4-trimethoxy-6-methylbenzoyl)-2,6-dichloro-4-trifluoromethylpyridine (compound No. 3) obtained in Synthesis Example 1 dissolved in 50 ml of methanol, followed by stirring under hydrogen atmosphere for 6.5 hours. The mixture was subjected to filtration, 50 ml of water was added thereto, and methanol was distilled off under reduced pressure. Extraction of ethyl acetate was carried out, the organic layer was dried over anhydrous sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure. The crude product thus obtained was purified by silica gel column chromatography to obtain 1.7 g (yield 55%) of 3-(2,3,4-trimethoxy-6-methylbenzoyl)-2-chloro-4-trifluoromethylpyridine (compound No. 11; m.p. 110-112° C.) and 1.1 g (yield 37%) of 3-(2,3,4-trimethoxy-6-methylbenzoyl)-4-trifluoromethylpyridine (compound No. 7; m.p. 59-62° C.).
Reaction SMILES: [CH2:1]([NH:3][S:4]([C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[C:9]([N+:14]([O-:16])=[O:15])[C:8]=1Cl)(=[O:6])=[O:5])[CH3:2].[H-].[Na+].[OH2:20]>>[CH2:1]([NH:3][S:4]([C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[C:9]([N+:14]([O-:16])=[O:15])[C:8]=1[OH:20])(=[O:6])=[O:5])[CH3:2]
Reactant: O
Reactant: CCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Agent: [H-]
Agent: [Na+]
Product: CCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O

Procedure:
Following the general hydrolysis procedure outlined in example 15, N-ethyl-2,6dichloro-3-nitrobenzenesulfonamide (1.16 g, 3.88mmol), 60% NaH (466 mg, 11.64 mmol) and water (70 μL, 3.88 mmol) were reacted. The crude product (1.34 g) was carried on to the next step without purification. 1H NMR (MeOD-d4): δ 8.07 (d, 1H), 7.25 (d, 1H), 3.05 (q, 2H), 1.12 (t, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:38])[CH:13]([N:20]2[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1)C.Cl[C:41]1C=CC(C2N(C(C3CCCCC3)C(O)=O)C3C=C(F)C(F)=CC=3N=2)=CC=1.NC1C=CC(C(OC)=O)=CC=1C>>[CH3:1][O:3][C:4](=[O:39])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:38])[CH:13]([N:20]2[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[C:7]([CH3:41])[CH:6]=1
Reactant: O=C(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: CCOC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Agent: COC(=O)c1ccc(N)c(C)c1
Product: COC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(C)c1

Procedure:
This compound was prepared in analogy to example 22, intermediate d, from [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid and methyl 4-amino-3-methylbenzoate.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[CH2:7][CH:8]1[C:13](=[O:14])[CH2:12][CH2:11][CH2:10][C:9]1=[O:15].[C-:20]#[N:21].[Na+].Cl>CS(C)=O>[C:20]([CH2:2][CH2:3][CH2:4][C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[CH2:7][CH:8]1[C:13](=[O:14])[CH2:12][CH2:11][CH2:10][C:9]1=[O:15])#[N:21]
Reactant: O=C1CCCC(=O)C1Cc1ccccc1CCCCl
Reactant: [C-]#N
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCCCc1ccccc1CC1C(=O)CCCC1=O
Temperature: 95 °C
Reaction time: 3 h

Procedure:
A mixture of 22 g (0.079 mol) of 2-[2-(3-chloropropyl)benzyl]-1,3-cyclohexanedione 3 and 15.5 g (0.316 mol) of NaCN in 250 ml of dry dimethyl sulfoxide was stirred at 95° C. for 3 hours. The reaction was filtered while hot to remove NaCl, and the dimethyl sulfoxide was distilled out under high vacuum. The residue was dissolved in 400 ml H2O, filtered through a diatomaceous earth filter aid (celite) to give a red solution and neutralized by the rapid addition of 40 ml concentrated HCl. The precipitate was recrystallized twice from ethyl acetate to give 16 g of the cyanodione, IIa, mp 143° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Cl)[CH:16]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[O:25][CH3:24])[CH:16]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CCl)c1
Reactant: COc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: COCCOC
Product: COc1ccccc1Cc1cccc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)c1
Yield: 37.4 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-3-(2-methoxybenzyl)benzamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(chloromethyl)benzamide (0.075 g; 0.216 mmol), 2-methoxyphenylboronic acid (0.0339 g; 0.216 mmol), tetrakis(triphenylphosphine)palladium(0) (0.013 g; 0.011 mmol), sodium carbonate (0.0457 g; 0.432 mmol), sodium iodide (0.0647 g; 0.431 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) furnished 0.0338 g (38%) of the title compound as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:7][C@H:6]1[CH3:20])=[O:4].[CH2:21]([O:23][C:24](=[O:37])[CH2:25][CH2:26][C:27]([C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=1[OH:36])=[O:28])[CH3:22].C1CN2C(=NCCC2)NC1>C(#N)C>[CH2:21]([O:23][C:24](=[O:37])[CH2:25][CH2:26][C:27]([C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=1[O:36][CH2:2][C:3]([N:5]1[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:7][C@H:6]1[CH3:20])=[O:4])=[O:28])[CH3:22]
Reactant: CCOC(=O)CCC(=O)c1cc(Cl)ccc1O
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)CCl
Agent: C1CN=C2NCCCN2C1
Solvent: CC#N
Product: CCOC(=O)CCC(=O)c1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 45 %

Procedure:
A solution of 2-chloro-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.11 g, 0.36 mmol), 4-(5-chloro-2-hydroxy-phenyl)-4-oxo-butyric acid ethyl ester (0.11 g, 0.43 mmol) and 1,5,7-triazabicyclo[4,4,0]dec-5-ene bound to polystyrene crosslinked with 2% DVB (0.21 g, 0.54 mmol) in acetonitrile (1.8 mL) was stirred at ambient temperature for 12 hours. The reaction mixture was filtered through a glass frit, concentrated in vacuo and purified via flash chromatography on silica gel to give the title compound (0.084 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:18]([NH2:20])=O)=[N:4][C:5]([S:8][CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)=[CH:6][CH:7]=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:18]#[N:20])=[N:4][C:5]([S:8][CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)=[CH:6][CH:7]=1
Reactant: NC(=O)c1nc(SCc2cc(F)cc(F)c2)ccc1N
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: N#Cc1nc(SCc2cc(F)cc(F)c2)ccc1N
Temperature: 140 °C
Yield: 106.5 %

Procedure:
A mixture of 3-amino-6-(3,5-difluorobenzylthio)picolinoamide (2.37 mmol, 0.7 g) and P2Cl5 (9.48 mmol, 1.346 g), 20 ml of toluene and 1 ml of ionic solvent (1-butyl-3-methylimidazolium tetrafluoroborate) are placed in a microwave reactor and then heated at 140° C. for 30 minutes. The crude reaction product is then concentrated under reduced pressure and the orange crystals thus obtained are redissolved in ethyl acetate and washed using saturated aqueous NaHCO3 solution. The organic phase is dried on magnesium sulfate and then concentrated to yield 0.7 g of a brown oil. This crude reaction product is purified by silica gel chromatography (AcOEt/heptane+0.1% of NEt3) to yield, after concentration, 0.15 g (23%) of orange crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:3]=1[NH:4][C:5]1[S:9][C:8]2[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:7]=2[C:6]=1[C:16](OCC)=O.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C1(OC)C=CC=CC=1>[Ti](Cl)(Cl)(Cl)Cl>[F:25][C:22]1[CH:23]=[CH:24][C:2]2[N:1]=[C:16]([N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)[C:6]3[C:7]4[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:8]=4[S:9][C:5]=3[NH:4][C:3]=2[CH:21]=1
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1c(Nc2cc(F)ccc2N)sc2cc(OC)ccc12
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: COc1ccccc1
Product: COc1ccc2c3c(sc2c1)Nc1cc(F)ccc1N=C3N1CCN(C)CC1

Procedure:
In the same manner as in Example 1 and using ethyl 2-(2-amino-5-fluoroanilino)-6-methoxybenzo[b]thiophene-3-carboxylate, 1-methylpiperazine, anisole and titanium tetrachloride, 8-fluoro-3-methoxy-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine is obtained.
Reaction SMILES: C(NC(C)C)(C)C.[Li].C([Li])CCC.C(NC(C)C)(C)C.[CH3:21][N:22]1[C:26]([CH2:27]O)=[CH:25][N:24]=[C:23]1[N+:29]([O-:31])=[O:30].C1(C)C=CC(S([Cl:41])(=O)=O)=CC=1>CCCCCC.O1CCCC1.CN(C)C=O>[Cl:41][CH2:27][C:26]1[N:22]([CH3:21])[C:23]([N+:29]([O-:31])=[O:30])=[N:24][CH:25]=1
Reactant: Cn1c(CO)cnc1[N+](=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Li]
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cn1c(CCl)cnc1[N+](=O)[O-]
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 48.8 %

Procedure:
A lithium diisopropylamine solution (prepared from 65 ml of a 2.2 molar solution of butyl lithium in hexane and 14.5 g of diisopropylamine in 150 ml of tetrahydrofuran) was added dropwise at a temperature of -60° C. within 15 minutes to a solution of 22 g of 1-methyl-2-nitroimidazole-5-methanol in 300 ml of tetrahydrofuran and 150 ml of dimethylformamide. The mixture was stirred at -60° C. for 30 minutes and treated with 28 g of p-toluenesulphonyl chloride in 150 ml of tetrahydrofuran. After removing the cooling, warming to room temperature and adding 300 ml of ice/water, the mixture was extracted three times with 300 ml of ethyl acetate each time. The combined extracts were washed with 150 ml of saturated sodium chloride solution and evaporated under reduced pressure. The residue was purified on 800 g of silica gel with ethyl acetate/dichloromethane (1:3, v/v). After a forerun of 1.5 l, the next 1.5 l were collected and evaporated. Recrystallization from 70 ml of toluene yielded 12 g (50%) of 5-(chloromethyl)-1-methyl-2-nitroimidazole, m.p. 100°-101° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[C:16]([OH:18])=[CH:15][CH:14]=[CH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:21]I>CN(C)C=O>[CH2:1]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[C:16]([O:18][CH3:21])=[CH:15][CH:14]=[CH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cccc2cccc(Cc3ccccc3)c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc2cccc(Cc3ccccc3)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
100 g of 8-benzyl-1-naphthol was dissolved in 300 ml of N,N-dimethylformamide to give a solution. 24.2 g of sodium hydride (55% suspension in oil) was added to the solution under cooling with ice. The obtained mixture was stirred at room temperature for 30 minutes. Methyl iodide was added to the resulting mixture under cooling with ice. The obtained mixture was stirred for 30 minutes under cooling with ice and poured onto ice-water. The obtained mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride twice, dried over anhydrous magnesium sulfate and distilled in a vacuum to remove the solvent. The residue was purified by silica gel column chromatography (developer: 5% ethyl acetate/hexane) to give 73 g of the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[CH:2]1.Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:40][C@@H:41]([CH3:57])[CH2:42][N:43]1[CH:47]=[CH:46][C:45]([C:48]2[CH:55]=[CH:54][C:51]([C:52]#[N:53])=[C:50]([Cl:56])[CH:49]=2)=[N:44]1>CN(C=O)C.O>[Cl:56][C:50]1[CH:49]=[C:48]([C:45]2[CH:46]=[CH:47][N:43]([CH2:42][C@@H:41]([NH:40][C:6]([C:4]3[N:3]=[CH:2][NH:1][CH:5]=3)=[O:8])[CH3:57])[N:44]=2)[CH:55]=[CH:54][C:51]=1[C:52]#[N:53]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1c[nH]cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1c[nH]cn1
Reaction time: 45 h

Procedure:
4-Imidazolecarboxylic acid (1.00 g, 8.9 mmol) was dissolved in dry DMF (35 ml). Dry 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 2.31 g, 12.0 mmol), HOBt (1.84 g, 12.0 mmol), and DIPEA (4.7 ml, 3.46 g, 26.8 mmol) were added at RT. After stirring for 15 min (S)-4-[1-(2-aminopropyl)-1H-pyrazol-3-yl]-2-chlorobenzonitrile of Example 34© (2.44 g, 9.4 mmol) in dry DMF (15 ml) was added to the solution at RT. Then the solution was stirred for 45 h. Water was added and the product was extracted into ethyl acetate. The organic phase was washed with brine and water, dried and evaporated. The crude product was purified by triturating in hot DCM. The product was filtered and washed with heptane. 1H NMR (400 MHz, DMSO-d6): 1.08 (3H, d), 4.30 (1H, distorted dd), 4.41 (2H, m), 6.95 (1H, d), 7.57 (1H, s), 7.75 (1H, d), 7.85 (1H, d), 8.01 (2H, m), 8.21 (1H, s), 8.30 (1H, d), 12.47 (1H, broad s).
Reaction SMILES: C(N(CCCC)CCCC)CCC.[CH2:14]([OH:20])[C:15]1[O:19][CH:18]=[CH:17][CH:16]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[C:21]([O:20][CH2:14][C:15]1[O:19][CH:18]=[CH:17][CH:16]=1)(=[O:23])[CH3:22]
Reactant: OCc1ccco1
Reactant: CC(=O)OC(C)=O
Solvent: CCCCN(CCCC)CCCC
Product: CC(=O)OCc1ccco1
Yield: 98.2 %

Procedure:
First 111.2 g (0.600 mole) tributyl amine and then 196.2 g (2.00 mole) distilled furfuryl alcohol were added to 224.6 g (2.20 mole) acetic anhydride. The temperature was allowed to rise to 35° C and was maintained at that for 5 hours. The mixture weighed 528.7 g and its concentration was 52.05%, i.e., the yield was 98.2%. The crude product was washed 3 times with 200 ml water. 5 ml HCl had been added to the second washing water. 264.7 g furfuryl acetate was obtained and its concentration was 95.6%, i.e., the yield was 90.3%.
Reaction SMILES: CO[C:3](=[O:44])[C:4]1[C:5](=[CH:10][C:11]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:32][CH:31]=2)=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)[CH:13]=1)[C:6](OC)=[O:7].[NH3:45]>C(O)CO>[CH2:22]([O:21][C:18]1[CH:17]=[CH:16][C:15]([NH:14][C:12]2[CH:13]=[C:4]3[C:3](=[O:44])[NH:45][C:6](=[O:7])[C:5]3=[CH:10][C:11]=2[NH:29][C:30]2[CH:31]=[CH:32][C:33]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:34][CH:35]=2)=[CH:20][CH:19]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1cc(Nc2ccc(OCc3ccccc3)cc2)c(Nc2ccc(OCc3ccccc3)cc2)cc1C(=O)OC
Reactant: N
Solvent: OCCO
Product: O=C1NC(=O)c2cc(Nc3ccc(OCc4ccccc4)cc3)c(Nc3ccc(OCc4ccccc4)cc3)cc21
Reaction time: 16 h

Procedure:
Analogously to Example 1, 294.4 mg (0.5 mmol) of 4,5-bis(4-benzyloxy-anilino)phthalic acid dimethyl ester in 22 ml of ethylene glycol are heated at 120°, ammonia gas being passed through the mixture, with stirring, for 16 hours. The reaction mixture is cooled and extracted with ethyl acetate. The ethyl acetate phases are washed in succession three times with water and once with saturated sodiumchloride solution, dried with sodium sulfate and concentrated by evaporation. The evaporation residue is chromatographed on silica gel withdichloromethane/methanol 50:1 and the product fractions are combined and concentrated by evaporation, yielding the title compound in the form of red crystals, m.p. 187°-189° C., FAB-MS: 542 [M+ +H].
Reaction SMILES: CC(=CCCC(C)=CCCC(=[O:13])C)C.O[C:16]1([CH3:32])[CH2:25][CH2:24][CH:23]2[C:18](C)([CH2:19][CH2:20][CH2:21][C:22]2([CH3:27])[CH3:26])[CH:17]1CCO>>[CH3:17][C:16]([CH:25]=[CH:24][CH:23]([CH:22]([CH3:27])[CH3:26])[CH2:18][CH2:19][C:20](=[O:13])[CH3:21])=[CH2:32]
Reactant: CC1(C)CCCC2(C)C1CCC(C)(O)C2CCO
Reactant: CC(=O)CCC=C(C)CCC=C(C)C
Product: C=C(C)C=CC(CCC(C)=O)C(C)C

Procedure:
2,6-dimethyl-2,6-undecadiene-10-one; 2-methyl-5-isopropyl acetophenone; 2-hydroxy-2,5,5,8a-tetramethyl-1-(2-hydroxyethyl)-decahydronaphthalene;
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([CH3:12])[C:10]#[N:11])[CH:5]=[CH:6][CH:7]=1.[CH:13]([O-])=[O:14].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:13]([C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([CH3:12])[C:10]#[N:11])[CH:5]=[CH:6][CH:7]=1)=[O:14]
Reactant: O=C[O-]
Reactant: CC(C#N)Cc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Product: CC(C#N)Cc1cccc(C=O)c1
Reaction time: 0.5 h

Procedure:
A 3-neck flask equipped with a condenser and 2 septa was flushed with N2, then the flask was charged with 0.6 g (2.7 mmol) 3-(3-bromophenyl)-2-methylpropionitrile (9-2), 0.275 g (4 mmol) sodium formate, 0.155 g (0.13 mmol) tetrakis(triphenylphosphine)Palladium and flushed with CO from a balloon for 5 min. The solids were suspended in 10 mL DMF and CO continued to bubble into the liquid. The flask was heated in an oil bath at 100′ for 20 min then 110′ while stirring. The color changed from yellow to a deep orange color after 1.5 h, and HPLC/MS analysis showed no starting material and one major product. The reaction was cooled and quenched with brine. The product was extracted into EtOAc, dried over Na2SO4, filtered and concentrated. The product was dissolved in 1 mL CH2Cl2 and purified on an Isco automated system affixed with a Biotage Flash 25(M) cartridge eluted with 0-50% EtOAc in hexane at 25 mL/min over 15 min and hold for 30 min. The product eluted last. MS 174.1 NB#212867-104
Reaction SMILES: I[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:3]=1.[Cl:22][C:23]1[N:28]=[C:27](Cl)[CH:26]=[CH:25][N:24]=1>>[Cl:22][C:23]1[N:28]=[C:27]([C:2]2[N:3]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=2)[CH:26]=[CH:25][N:24]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(I)n2)cc1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)n3)n2)cc1

Procedure:
The title compound was prepared from 2-iodo-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example A.4) (1.0 g, 2.39 mmol) and 2,4-dichloro-pyrimidine (0.356 g, 2.39 mmol) according to the general procedure IVc. Obtained as an off-white solid (0.49 g, 50%). MS (EI) 404.1 [(M)+]; mp 152° C.