Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[C@@H:19]1[CH2:25][CH2:24][CH2:23][CH2:22][N:21]([CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[CH2:20]1>CCCCCC.CS(C)=O.C(=O)([O-])O.[Na+].C(OCC)(=O)C>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][CH2:26][N:21]2[CH2:22][CH2:23][CH2:24][CH2:25][C@@H:20]2[CH2:19][N:8]2[C:7]3[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=3[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]2=3)=[CH:33][CH:32]=1
Reactant: c1ccc2c(c1)COc1ccccc1N2
Reactant: Clc1ccc(CCN2CCCC[C@@H](Cl)C2)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Clc1ccc(CCN2CCCC[C@@H]2CN2c3ccccc3COc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
60% Sodium hydride (56 mg, 1.4 mmol) was washed with hexane under argon atmosphere, and then suspended in dimethyl sulfoxide (10 ml). The obtained suspension was stirred at room temperature for 30 minutes. 5,11-Dihydrodibenzo[b,e][1,4]oxazepine (250 mg, 1.27 mmol) was added to the suspension, and they were stirred at room temperature for 30 minutes and then at 50° C. for 30 minutes. A solution of (R)-3-chloro-1-(4-chlorophenethyl)homopiperidine (380 mg, 1.40 mmol) in dimethyl sulfoxide (5 ml) was added dropwise into the obtained solution, and they were stirred at 50° C. for 2 hours. The reaction liquid was distributed in saturated aqueous sodium hydrogencarbonate solution and ethyl acetate. The organic layer was dried, and the solvent was evaporated under reduce pressure. The obtained residue was subjected to silica gel column chromatography. The product was eluted with hexane and ethyl acetate (5:1) and then with hexane and ethyl acetate (2:1). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain (R)-5-[1-(4-chlorophenethyl)piperidine-2-ylmethyl]-5,11-dihydro-dibenzo[b,e][1,4]oxazepine in the form of a light yellow solid (160 mg, 29%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2=[N:9][C:10]([C:12]3[CH:13]=[CH:14][C:15]([CH3:19])=[C:16]([CH:18]=3)[NH2:17])=[CH:11][N:5]2[N:4]=1.C([O-])([O-])=O.[K+].[K+].[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1>C(#N)C>[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH:17][C:16]2[CH:18]=[C:12]([C:10]3[N:9]=[C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[N:4][N:5]4[CH:11]=3)[CH:13]=[CH:14][C:15]=2[CH3:19])=[CH:29][CH:28]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: COc1ccc2nc(-c3ccc(C)c(N)c3)cn2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc2nc(-c3ccc(C)c(NCc4ccc(F)cc4)c3)cn2n1
Reaction time: 0.5 h
Yield: 34.5 %

Procedure:
An 8 mL vial is charged with 5-(6-methoxyimidazo[2,1-f]pyridazin-2-yl)-2-methyl-aniline (20.3 mg, 0.08 mmol) in acetonitrile (0.5 mL), K2CO3 (13 mg) and 4-fluorobenzyl bromide (19 mg, 0.1 mmol). The mixture is stirred for 30 min then filtered, and the filtrate is added into water (10 mL). Solids precipitated and are collected by filtration to give the title compound (10 mg, 34% yield) (compound same as Example 102). LCMS m/z=363.3 [M+H]+, tR=2.57 min.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[CH2:17]([N:24]=[C:25]=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH2:17]([NH:24][C:25]([NH:16][C:10]1[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([C:3]2[N:4]([CH3:7])[N:5]=[CH:6][C:2]=2[Br:1])[CH:9]=1)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Reactant: O=C=NCc1ccccc1
Solvent: ClCCl
Product: COc1ccc(NC(=O)NCc2ccccc2)cc1-c1c(Br)cnn1C
Yield: 66.7 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.034 g, 0.12 mmol) was treated with benzyl isocyanate (0.017 g, 16.0 μL 0.13 mmol, 1.05 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.10 to afford Compound 74 (0.031 g, 0.08 mmol, 62%) as a solid film. LCMS m/z (%)=415 (M+H79Br, 86), 417 (M+H81Br, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.05 (s, 1H), 7.64 (dd, J=2.7, 9.0 Hz, 1H), 7.47 (s, 1H), 7.40 (d, J=2.7 Hz, 1H), 7.27-7.37 (m, 4H), 7.22 (t, J=7.0 Hz, 1H), 7.07 (d, J=9.0 Hz, 1H), 6.21 (s, 1H), 4.41 (d, J=4.0 Hz, 2H), 3.79 (s, 3H), 3.66 (s, 3H).
Reaction SMILES: [C:1]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][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][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([OH:49])=O)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(N(CC)CC)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH:68][CH2:69][C@@H:70]([C@@H:72]([C@@H:74]([CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][CH3:89])[OH:75])[OH:73])[NH2:71]>C(Cl)(Cl)Cl>[C:1]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][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][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([NH:71][C@H:70]([C@@H:72]([C@@H:74]([CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][CH3:89])[OH:75])[OH:73])[CH2:69][OH:68])=[O:49])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCC[C@@H](O)[C@@H](O)[C@@H](N)CO
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)[C@H](O)CCCCCCCCCCCCCC
Reaction time: 2 h
Yield: 29.6 %

Procedure:
A solution of 27-oleoyloxy-heptacosanoic acid (2 g; 2.89 mmoles) in chloroform (30 ml) and triethylamine (1.6 ml; 11.5 mmoles) was added in 30 minutes to a stirred solution of 0.5 grams of p-toluenesulphonyl chloride (0.5 g; 2.6 mmoles) in chloroform (40 ml) under nitrogen while keeping the temperature at 50° C. After stirring for 1 hour at 50° C. phytosphingosine (0.8 g; 2.52 mmoles) was added and stirring was continued for 2 hours at 50° C. After cooling the mixture was washed with 50 ml of 0.5 N hydrochloric acid, 50 ml of water and brine respectively. The organic layer was evaporated in vacuum and the residue was crystallized from 50 ml of warm 2-propanol under nitrogen giving 2.03 grams of the impure title compound. Purification over 40 grams of silica gel (Flash 30-60 μm) with chloroform/methanol=9/1 and subsequent crystallization from 40 ml of hot isopropanol gave 0.74 g of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16])=[C:13]([CH3:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:11](=[O:32])[NH:10]2)=[C:5]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:4]=1)#[N:2].[CH3:37][Si](C)(C)[N-][Si](C)(C)C.[Li+].IC>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16])=[C:13]([CH3:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:29])[F:31])[CH:23]=3)[C:11](=[O:32])[N:10]2[CH3:37])=[C:5]([S:33]([CH3:36])(=[O:34])=[O:35])[CH:4]=1)#[N:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: C=CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N[C@@H]1c1ccc(C#N)cc1S(C)(=O)=O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: C=CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)[C@@H]1c1ccc(C#N)cc1S(C)(=O)=O
Reaction time: 0.33 h
Yield: 59 %

Procedure:
The reaction was carried out under argon. Allyl (4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (260 mg, 0.5 mmol) was initially charged in THF (10 ml) at −78° C., and a 1 M solution of lithium hexamethyldisilazide (LiHMDS) in THF (0.6 ml; 1.2 eq.) was added. After 20 min of stirring, iodomethane (355 mg; 5 eq.) was added, and the mixture was stirred with gradual warming from −78° C. to RT for 16 h. The reaction mixture was then concentrated, and the residue was subjected to flash chromatography on silica gel (mobile phase: cyclohexane→cyclohexane/ethyl acetate 55:45). This gave the title compound as a solid (157 mg, 59% of theory).
Reaction SMILES: [CH2:1]([N:8]1[C:16]([C:17]2[CH:33]=[CH:32][C:20]([O:21][C:22]3[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=3)[C:25]([O:27]C)=O)=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:11]([C:34]([F:37])([F:36])[F:35])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-]#N.[Na+].[CH3:41][NH:42][CH3:43]>CO>[CH2:1]([N:8]1[C:16]([C:17]2[CH:33]=[CH:32][C:20]([O:21][C:22]3[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=3)[C:25]([N:42]([CH3:43])[CH3:41])=[O:27])=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:11]([C:34]([F:36])([F:35])[F:37])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(Oc2ccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3ccccc3)cc2)c1
Reactant: CNC
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Product: CN(C)C(=O)c1cccc(Oc2ccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3ccccc3)cc2)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
This compound was prepared from Example 912. Methyl 3-{4-[2-benzyl-7-(trifluoromethyl)-2H-indazol-3-yl]phenoxy}benzoate (49 mg, 0.0971 mmol) was dissolved in a 2M solution of dimethylamine in methanol (1.5 mL), 0.5 mg of sodium cyanide was added and the reaction mixture was stirred at 60° C. overnight. The solvent was evaporated, the residue dissolved in CH2Cl2 and washed with brine. The combined organic phases were dried, evaporated and the crude material was purified by HPLC using a gradient with an acidic mobile phase on an ACE-C8 column to afford 9 mg of analytically pure product.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:30])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](Cl)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:31][N:32]([CH3:44])[C:33]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)=[O:34].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(=O)([O-])O.[Na+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:1]([O:8][CH2:9][C:10]1([CH3:30])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:38]5[CH:39]=[CH:40][C:35]([C:33]([N:32]([CH3:44])[CH3:31])=[O:34])=[CH:36][CH:37]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CN(C)C(=O)c1ccc(B(O)O)cc1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(Cl)cc4)CC3)n2CCS1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CN(C)C(=O)c1ccc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)cc1
Temperature: 25 °C
Yield: 110.3 %

Procedure:
A solution of the compound (232 mg, 0.5 mmol) obtained in Example 1-2), 4-(N,N-dimethylaminocarbonyl)phenylboronic acid (96 mg, 0.5 mmol), tris(dibenzylideneacetone)dipalladium(0) (23 mg, 0.05 mmol), tricyclohexylphosphine (17 mg, 0.12 mmol), and tripotassium phosphate (186 mg, 0.85 mmol) in dioxane (2 mL) and water (1 mL) was stirred at 140° C. for 2 h under microwave irradiation. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 30:70, gradient) to obtain the title compound (318 mg, quant.) as a light yellow oily substance.
Reaction SMILES: CN(C)C=O.[H-].[Na+].[F:8][C:9]([F:23])([F:22])[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[NH:17][O:18][C:19](=[O:21])[N:20]=2)[CH:11]=1.[Cl-].[NH4+].[CH3:26][CH2:27][O:28][CH2:29]C>>[CH2:27]([O:28][CH2:29][N:20]1[C:19](=[O:21])[O:18][N:17]=[C:16]1[C:12]1[CH:11]=[C:10]([C:9]([F:8])([F:22])[F:23])[CH:15]=[CH:14][N:13]=1)[CH3:26]
Reactant: O=c1nc(-c2cc(C(F)(F)F)ccn2)[nH]o1
Reactant: CCOCC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOCn1c(-c2cc(C(F)(F)F)ccn2)noc1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Into 2 ml of N,N-dimethylformamide was suspended 0.05 g of sodium hydride (60% oily), and 0.2 g of 3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one was added at room temperature. After stirring for 10 minutes, 0.12 g. of chloromethyl=ethyl=ether was added at 0° C., the mixture was stirred at 60° C. for 3 hours, and the reaction solution was allowed to cool to room temperature, and poured into an aqueous saturated ammonium chloride solution, followed by extraction with tert-butyl=methyl=ether three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.21 g of 4-ethoxymethyl-3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one (present compound (7)).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[OH:16][C:17]([C:45]1[CH:46]=[C:47]2[C:52](=[CH:53][CH:54]=1)[CH:51]=[C:50](O)[CH:49]=[CH:48]2)([C:21]1[N:22]=[CH:23][N:24]([C:26]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=1)[CH:18]([CH3:20])[CH3:19]>N1C=CC=CC=1.O>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:50]1[CH:49]=[CH:48][C:47]2[C:52](=[CH:53][CH:54]=[C:45]([C:17]([OH:16])([C:21]3[N:22]=[CH:23][N:24]([C:26]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:25]=3)[CH:18]([CH3:19])[CH3:20])[CH:46]=2)[CH:51]=1)(=[O:5])=[O:4]
Reactant: CC(C)C(O)(c1ccc2cc(O)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: O
Product: CC(C)C(O)(c1ccc2cc(OS(=O)(=O)C(F)(F)F)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Trifluoromethanesulfonic anhydride (9.1 mL) was added dropwise to a solution of 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthol (27.0 g) in pyridine (200 mL) at 0° C. The reaction mixture was stirred for 1 h at 0° C., diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated. The residue was purified by silica gel column chromatography (eluent; hexane-ethyl acetate=1:1). Crystallization from diisopropyl ether gave the titled compound (29.6 g) as a colorless powder.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]1[CH:19]=[CH:18][C:14]2[S:15][CH:16]=[CH:17][C:13]=2[CH:12]=1)(=O)=O.[CH2:20]([NH:23][CH2:24][CH2:25][CH3:26])[CH2:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[S:15]1[CH:16]=[CH:17][C:13]2[CH:12]=[C:11]([CH2:10][CH2:9][O:8][CH2:7][CH2:6][N:23]([CH2:24][CH2:25][CH3:26])[CH2:20][CH2:21][CH3:22])[CH:19]=[CH:18][C:14]1=2
Reactant: CCCNCCC
Reactant: CS(=O)(=O)OCCOCCc1ccc2sccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCN(CCC)CCOCCc1ccc2sccc2c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
In 8 mL of N,N-dimethylformamide is dissolved 0.80 g of 2-(2-benzo[b]thiophen-5-ylethoxy)ethyl methanesulfonate, to which are added 0.73 mL of dipropylamine and 0.74 g of potassium carbonate. The resulting mixture is stirred at 80° C. for 3 hours. The reaction mixture is introduced into a mixture of water and ethyl acetate, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by column chromatography (eluent:chloroform:methanol=10:1). Thus, 0.60 of N-[2-(2-benzo[b]thiophen-5-ylethoxy)ethyl]-N,N-dipropylamine is obtained as an oily product.
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=2)[C:7]([CH3:19])=[N:6][C:5]=1[CH3:20])(=[O:3])[NH2:2].[Cl:21][C:22]1[CH:27]=[C:26](OS(C(F)(F)F)(=O)=O)[C:25]([Cl:36])=[CH:24][C:23]=1[CH2:37][C:38]([O:40][CH3:41])=[O:39].C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Li+]>COCCOC.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>[C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:26]3[CH:27]=[C:22]([Cl:21])[C:23]([CH2:37][C:38]([O:40][CH3:41])=[O:39])=[CH:24][C:25]=3[Cl:36])=[CH:12][CH:11]=2)[C:7]([CH3:19])=[N:6][C:5]=1[CH3:20])(=[O:3])[NH2:2]
Reactant: COC(=O)Cc1cc(Cl)c(OS(=O)(=O)C(F)(F)F)cc1Cl
Reactant: Cc1nc(C)c(-c2ccc(B(O)O)cc2)nc1C(N)=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: [Cl-]
Solvent: COCCOC
Product: COC(=O)Cc1cc(Cl)c(-c2ccc(-c3nc(C(N)=O)c(C)nc3C)cc2)cc1Cl
Temperature: 85 °C
Reaction time: 17 h
Yield: 32.7 %

Procedure:
A solution of 4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)phenylboronic acid (Intermediate 5-1; 312 mg, 1.15 mmol) and methyl 2-(2,5-dichloro-4-(trifluoromethylsulfonyloxy)phenyl)acetate (Intermediate 4-2; 375 mg, 1.02 mmol) and 2M sodium carbonate (0.830 mL, 1.66 mmol), tetrakis(triphenylphosphine)palladium(0) (73.2 mg, 0.06 mmol) and lithium chloride (76 mg, 1.79 mmol) in DME (10 mL) was degassed and then stirred at 85° C. for 17 hours. The reaction mixture was concentrated and diluted with EtOAc (75 mL), and washed sequentially with 2M HCl (25 mL) and saturated brine (25 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2,5-dichlorobiphenyl-4-yl)acetate (148 mg, 32.6%) as a yellow solid.
Reaction SMILES: OC1C2N=NNC=2C=CC=1.C(N=C=NC(C)C)(C)C.[C:20](O)(=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[C:29]1([C:35]2[C:39]([NH2:40])=[C:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[NH:37][N:36]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl.C(#N)C.O>[C:29]1([C:35]2[C:39]([NH:40][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:38]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[NH:37][N:36]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(O)c1ccccc1
Reactant: Nc1c(-c2ccccc2)n[nH]c1-c1ccccc1
Agent: CC(C)N=C=NC(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: c1ccc(CNc2c(-c3ccccc3)n[nH]c2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
574 mg of hydroxybenzotriazole and 822 μl of diisopropylcarbodiimide were added to a solution of 260 mg of benzoic acid in 10 ml of methylene chloride, after which 500 mg of 3,5-diphenyl-1H-pyrazol-4-ylamine in 2 ml of acetonitrile were added dropwise, at 0° C.; the mixture was then stirred at room temperature (RT) for 12 hours (h), after which water was added and the whole was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue contained the title compound and was used in the following reaction without further purification.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[F:19])[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20]Br.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].[OH-].[NH4+]>CN(C)C=O.O>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[F:19])[C:12]([Br:20])=[CH:11]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrBr
Reactant: O=S(=O)(c1ccccc1)n1ccc2cccc(F)c21
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(c1ccccc1)n1cc(Br)c2cccc(F)c21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.3 %

Procedure:
The suspension was then diluted with water (200 ml), extracted with tert-butyl methyl ether (3×100 ml) and the combined organic layers washed with water (3×100 ml), dried with sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography eluting with 20% (v/v) ethyl acetate in isohexane to afford 1-benzenesulfonyl-7-fluoroindole as a colourless solid (3.96 g, 14.4 mmol). To a solution of 1-benzenesulfonyl-7-fluoroindole (2.0 g, 7.27 mmol) in dimethylformamide (10 ml) was added a solution of bromine (0.75 ml, 14.55 mmol) in dimethylformamide (25 ml) dropwise over 3 min. The mixture was then stirred at room temperature for 10 min and poured onto a mixture of sodium metabisulphite (2 g), ammonium hydroxide solution (3 ml), water (100 ml) and crushed ice (100 g). The resulting suspension was stirred until all colour had discharged and extracted into tert-butyl methyl ether (2×100 ml). The combined organic layers were washed with water (2×100 ml), dried with sodium sulfate and the solvent removed in vacuo to afford 1-benzenesulfonyl-3-bromo-7-fluoroindole as a salmon coloured solid (2.35 g, 6.64 mmol).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:19][CH:20]1[CH2:22][CH2:21]1)[CH:13]([OH:18])[C:14]([O:16]C)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].Cl>C1COCC1.O>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:19][CH:20]1[CH2:21][CH2:22]1)[CH:13]([OH:18])[C:14]([OH:16])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(O)[C@H](CC1CC1)NC(=O)OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(N[C@@H](CC1CC1)C(O)C(=O)O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a solution of the methyl ester of Step 2 (400 mg; 1.3 mmol) in THF (8 mL) and water (6.63 mL) was added LiOH (1 N; 1.37 mL). The reaction mixture was stirred for 30 minutes and then acidified with 1.0 N HCl to pH=3≈4. The mixture was extracted with EtOAc (20 mL, twice). The combined organic layer was washed with water, brine, and then concentrated in vacuo to afford the title compound (370 mg). (M+1) 294.
Reaction SMILES: [Cl:1][CH:2]([CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3](Cl)=[O:4].[NH2:15][CH2:16][CH2:17][CH:18]1[O:22][CH2:21][CH2:20][O:19]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:1][CH:2]([CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([NH:15][CH2:16][CH2:17][CH:18]1[O:22][CH2:21][CH2:20][O:19]1)=[O:4]
Reactant: O=C(Cl)C(Cl)COCc1ccccc1
Reactant: NCCC1OCCO1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(NCCC1OCCO1)C(Cl)COCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 65.9 %

Procedure:
A solution of 69.63 g of 2-chloro-3-(phenylmethoxy)propanoyl chloride (prepared according to the procedure described in Inorg. Chem., 31. 2422, 1992) (0.299 mol) in 90 ml of CHCl3 was added to a solution of 35.49 g of 2-(2-aminoethyl)-1,3-dioxolane (prepared according to the procedure described in EXAMPLE 4) (0.303 mol) and to 60.3 g of triethylamine (83 ml; 0.596 mol) in 100 ml of CHCl3 under inert atmosphere, keeping the temperature at 0°-5° C. The reaction mixture was stirred for 5 h at 25° C., then was washed with H2O. The organic phase was dried and evaporated to dryness, the residue was purified by flash chromatography. 61.68 g of the desired product (0.197 mol) were obtained.