Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[P:2]1(Cl)[N:7]=[P:6](Cl)(Cl)[N:5]=[P:4](Cl)(Cl)[N:3]=1.[C:13]1([CH3:19])[CH:18]=CC=C[CH:14]=1>>[CH2:14]([P:2]1([CH2:19][C:13](=[CH2:14])[CH3:18])[N:7]=[P:6]([CH2:14][C:13](=[CH2:19])[CH3:18])([CH2:14][C:13](=[CH2:19])[CH3:18])[N:5]=[P:4]([CH2:18][C:13](=[CH2:14])[CH3:19])([CH2:14][C:13](=[CH2:19])[CH3:18])[N:3]=1)[C:13](=[CH2:19])[CH3:18]
Reactant: Cc1ccccc1
Reactant: ClP1(Cl)=NP(Cl)(Cl)=NP(Cl)(Cl)=N1
Product: C=C(C)CP1(CC(=C)C)=NP(CC(=C)C)(CC(=C)C)=NP(CC(=C)C)(CC(=C)C)=N1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Furthermore, into the 5-liter flask as described above is put a solution of hexachlorocyclotriphosphazene in toluene (700 g (6.0 unit mol) of hexachlorocyclotriphosphazene, 3,500 mL of toluene). The slurry solution of 2-methyl-2-proper-1-ol sodium salt is added dropwise thereto at 5° C. or lower over 6 hours, followed by warming to 25° C. and stirring for 4 hours, to obtain a solution of hexamethallylcyclotriphosphazene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[C:5]([N:7]1[CH2:9][CH2:8]1)=[O:6].[NH:14]1[CH2:19][CH2:18][CH:17]([N:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[NH:22][C:21]2=[O:29])[CH2:16][CH2:15]1.CO.[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34]>CC(=O)C.C1C=CC=CC=1>[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34].[O:29]=[C:21]1[N:20]([CH:17]2[CH2:16][CH2:15][N:14]([CH2:8][CH2:9][NH:7][C:5](=[O:6])[C:4]3[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=3[O:2][CH3:1])[CH2:19][CH2:18]2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[NH:22]1
Reactant: COc1ccccc1C(=O)N1CC1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CC(C)=O
Solvent: c1ccccc1
Product: COc1ccccc1C(=O)NCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1

Procedure:
A mixture of 1.75 parts of 1-(2-methoxy-benzoyl)aziridine, 2.18 parts of 1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 1.6 parts of methanol and 10.8 parts of benzene is stirred and refluxed for 1.50 hours. The reaction mixture is cooled. After the addition of 2-propanone, the whole is acidified with ethanedioic acid. The formed ethanedioate salt is filtered off and crystallized from ethanol 70%, yielding 2.9 parts of N-{2-[4-(2,3-dihydro-2-oxo-1 H-benzimidazol-1-yl)-1-piperidinyl] ethyl}-2-methoxybenzamide ethanedioate; mp. 217.4° C.
Reaction SMILES: [C:1]([OH:24])(=O)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=[CH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[NH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.C1CCC(N=C=NC2CCCCC2)CC1>>[N:29]1[CH:30]=[CH:31][C:26]([NH:25][C:1](=[O:24])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22])=[CH:27][CH:28]=1
Reactant: CCCCCCCCCC=CC=CC=CC=CC=CC=CC(=O)O
Reactant: Nc1ccncc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)Nc1ccncc1
Yield: 90.6 %

Procedure:
Reaction of docosahexaenoic acid (0.10 g, 0.30 mmol) with 4-aminopyridine (0.03 g, 0.30 mmol) was conducted according to the general amide coupling procedure using DCC to obtain the product as a yellow solid (0.11 g, 91%). EIMS m/z: 405 ([M]+).
Reaction SMILES: COC(=O)NC(C([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:20][C:19]2[CH2:21][O:22][C:23]3[CH:24]=[C:25]([C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[C:34]([C:39]6[NH:40][C:41]([CH:44]7[CH2:48][CH2:47][CH2:46][N:45]7[C:49](=[O:62])[CH:50]([NH:57][C:58]([O:60][CH3:61])=[O:59])[C:51]7[CH:56]=CC=C[CH:52]=7)=[N:42][CH:43]=6)[CH:35]=5)[CH:30]=4)[CH:26]=[CH:27][C:28]=3[C:18]=2[N:17]=1)=O)C(C)C.[CH3:64][O:65][C:66]([NH:68][CH:69]([C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1)[C:70]([OH:72])=O)=[O:67]>>[CH3:61][O:60][C:58](=[O:59])[NH:57][CH:50]([C:49]([N:45]1[CH2:46][CH2:47][CH2:48][CH:44]1[C:41]1[NH:40][C:39]([C:34]2[CH:33]=[CH:32][C:31]3[C:36](=[CH:37][CH:38]=[C:29]([C:25]4[CH:26]=[CH:27][C:28]5[C:18]6[NH:17][C:16]([CH:12]7[CH2:13][CH2:14][CH2:15][N:11]7[C:70](=[O:72])[CH:69]([NH:68][C:66]([O:65][CH3:64])=[O:67])[C:73]7[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=7)=[N:20][C:19]=6[CH2:21][O:22][C:23]=5[CH:24]=4)[CH:30]=3)[CH:35]=2)=[CH:43][N:42]=1)=[O:62])[CH:51]([CH3:56])[CH3:52]
Reactant: COC(=O)NC(C(=O)O)c1ccccc1
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc5c(c4)OCc4[nH]c(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)nc4-5)ccc3c2)[nH]1)c1ccccc1
Product: COC(=O)NC(C(=O)N1CCCC1c1nc2c([nH]1)-c1ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc1OC2)c1ccccc1

Procedure:
Synthesized similar to (1-{2-[7-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-3,4-dihydro-chromeno[3,4-d]imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester with the corresponding methoxycarbonylamino-phenyl-acetic acid replacement.
Reaction SMILES: CON(C)[C:4](=[O:39])[CH:5]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:17]=2)=[CH:11][C:10]=1[Cl:30].[CH3:41][Mg+].[Br-].O>C1COCC1>[CH2:23]([O:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][CH2:6][CH:5]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:4](=[O:39])[CH3:41])=[C:10]([Cl:30])[CH:11]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CON(C)C(=O)C(CCCc1ccc(Oc2cccc(OCc3ccccc3)c2)cc1Cl)NC(=O)OC(C)(C)C
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)C(CCCc1ccc(Oc2cccc(OCc3ccccc3)c2)cc1Cl)NC(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
The compound of Example 130-1 (570 mg) was dissolved in THF (15 mL). To this solution, a THF solution (2 mL) of 3 mol/L MeMgBr was added at 0° C. and the mixture was stirred for 3 hours. Following addition of water, the mixture was extracted with ethyl acetate and the extract was washed sequentially with water and a saturated aqueous solution of sodium chloride. The organic phase was then dried over anhydrous sodium sulfate. The solvent was removed and the residue was purified on a silica gel column chromatography (hexane:ethyl acetate=3:1) to give the desired product as a colorless oil (200 mg).
Reaction SMILES: C([O:8][CH2:9][C@H:10]([NH:27][C:28]1[N:36]=[CH:35][N:34]=[C:33]2[C:29]=1[NH:30][CH:31]=[N:32]2)[C:11]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]2[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:13]=2[N:12]=1)C1C=CC=CC=1.B(Br)(Br)Br.CO>C(Cl)Cl>[F:26][C:23]1[CH:24]=[CH:25][C:13]2[N:12]=[C:11]([CH:10]([NH:27][C:28]3[N:36]=[CH:35][N:34]=[C:33]4[C:29]=3[NH:30][CH:31]=[N:32]4)[CH2:9][OH:8])[N:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:14]=2[CH:22]=1
Reactant: Fc1ccc2nc([C@H](COCc3ccccc3)Nc3ncnc4nc[nH]c34)n(-c3ccccc3)c2c1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: OCC(Nc1ncnc2nc[nH]c12)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
To a solution of [(R)-2-benzyloxy-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]-(7H-purin-6-yl)amine (124 mg, 0.26 mmol) in anhydrous DCM (3 mL) at 0° C. under a nitrogen atmosphere was added boron tribromide (1.0M in DCM, 0.3 mL, 0.26 mmol) dropwise. The reaction mixture was slowly warmed to RT and stirred at RT for 1 h. Additional BBr3 (0.3 mL) was added and stirring continued for 1 h. MeOH was added then the volatiles removed under reduced pressure. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) to afford 172 (60 mg, 59%). LCMS (Method K): RT 3.11 min [M+H]+ 390.0. 1H NMR (DMSO-d6, 400 MHz): δ 12.93 (0.8H, s), 12.17 (0.2H, s), 8.27-8.01 (2H, m), 7.74-7.43 (6H, m), 7.16-7.01 (1H, m), 6.93-6.79 (1H, m), 5.56-5.31 (1H, m), 5.21-5.02 (1H, m), 3.95-3.74 (2H, m). Signals split due to presence of rotamers/tautomers
Reaction SMILES: C([O:8][C:9]1[C:18]2[C:13](=[C:14]([CH3:21])[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[N:12]=[C:11](Cl)[CH:10]=1)C1C=CC=CC=1.[CH:23]([C:26]1[CH:30]=[CH:29][NH:28][N:27]=1)([CH3:25])[CH3:24]>>[OH:8][C:9]1[C:18]2[C:13](=[C:14]([CH3:21])[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[N:12]=[C:11]([N:28]2[CH:29]=[CH:30][C:26]([CH:23]([CH3:25])[CH3:24])=[N:27]2)[CH:10]=1
Reactant: COc1ccc2c(OCc3ccccc3)cc(Cl)nc2c1C
Reactant: CC(C)c1cc[nH]n1
Product: COc1ccc2c(O)cc(-n3ccc(C(C)C)n3)nc2c1C
Temperature: 155 °C
Yield: 95 %

Procedure:
A mixture of 4-benzyloxy-2-chloro-7-methoxy-8-methylquinoline (63, 1.00 g, 3.19 mmol) and 3-isopropylpyrazole was heated at 155° C. for 12 h. Then, the reaction mixture was partitioned between AcOEt and water, dried (Na2SO4) and evaporated. The residue was purified by column chromatography (AcOEt/CH2Cl2, 1:1) to give 900 mg (95%) of the target product 64 as a yellowish powder: m/z=298 (M+H)+.
Reaction SMILES: [Na+].[CH:2]1([N:5]2[C:13]3[C:8](=[C:9]([O:41][CH3:42])[CH:10]=[C:11]([C:14]([N:16]4[CH2:21][CH2:20][C:19]5([CH2:30][C:29](=[O:31])[C:28]6[C:23](=[CH:24][CH:25]=[C:26]([C:32]7[CH:33]=[N:34][CH:35]=[C:36]([CH:40]=7)[C:37]([O-:39])=[O:38])[CH:27]=6)[O:22]5)[CH2:18][CH2:17]4)=[O:15])[CH:12]=3)[C:7]([CH3:43])=[CH:6]2)[CH2:4][CH2:3]1.Cl>CO.O>[CH:2]1([N:5]2[C:13]3[C:8](=[C:9]([O:41][CH3:42])[CH:10]=[C:11]([C:14]([N:16]4[CH2:17][CH2:18][C:19]5([CH2:30][C:29](=[O:31])[C:28]6[C:23](=[CH:24][CH:25]=[C:26]([C:32]7[CH:33]=[N:34][CH:35]=[C:36]([CH:40]=7)[C:37]([OH:39])=[O:38])[CH:27]=6)[O:22]5)[CH2:20][CH2:21]4)=[O:15])[CH:12]=3)[C:7]([CH3:43])=[CH:6]2)[CH2:3][CH2:4]1
Reactant: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4cncc(C(=O)[O-])c4)ccc2O3)cc2c1c(C)cn2C1CC1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4cncc(C(=O)O)c4)ccc2O3)cc2c1c(C)cn2C1CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of the compound of Example 23 in MeOH (25 mL) and H2O (25 mL) was added 4 mL of 1N HCl aqueous at 0° C. 60 mL of MeOH was added thereto and the mixture was stirred at r.t. for 3 hours. The precipitate was filtered and dried at 60° C. in vacuo to give the title compound as a colorless solid. 1H-NMR (400 MHz, DMSO-d6) δ: 13.56 (1H, s), 9.09 (1H, d, J=2.2 Hz), 9.03 (1H, d, J=2.2 Hz), 8.41 (1H, dd, J=2.2, 2.2 Hz), 8.07-8.03 (2H, m), 7.29-7.25 (1H, m), 7.14 (1H, d, J=1.0 Hz), 7.00 (1H, d, J=1.0 Hz), 6.51 (1H, d, J=1.0 Hz), 4.41-4.10 (1H, br m), 3.83 (3H, s), 3.51-3.41 (1H, br m), 3.51-3.26 (3H, br m), 2.96 (2H, s), 2.31 (3H, s), 2.13-1.74 (4H, br m), 1.06-0.85 (4H, m); MS [M+H]+=566.
Reaction SMILES: CC[N:3]([CH2:6]C)CC.P(N=[N+]=[N-])(OC1C=CC=CC=1)(OC1C=CC=CC=1)=[O:9].[CH3:27][C:28]1[CH:29]=[N:30][NH:31][C:32]=1[C:33]1[C:34](C(O)=O)=[CH:35][C:36]2[C:41]([CH:42]=1)=[CH:40][CH:39]=[CH:38][CH:37]=2>C1C=CC=CC=1>[CH3:27][C:28]1[C:32]2[N:31]([C:6](=[O:9])[N:3]=[C:34]3[C:33]=2[CH:42]=[C:41]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]2=[CH:35]3)[NH:30][CH:29]=1
Reactant: CCN(CC)CC
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: Cc1cn[nH]c1-c1cc2ccccc2cc1C(=O)O
Solvent: c1ccccc1
Product: Cc1c[nH]n2c(=O)nc3cc4ccccc4cc3c12
Temperature: 50 °C
Yield: 67.2 %

Procedure:
Et3N (300 μL, 2.152 mmol) and (PhO)2PON3 (440 μL, 2.064 mmol) were added to a C6H6 (10.0 mL) suspension of 3-(4-methylpyrazol-5-yl)-2-naphthoic acid (Preparation 10) (257 mg, 1.019 mmol), and the mixture was heated at 50° C. for 2 hr. The volatile component was removed in vacuo, and the resulting yellow solid was dissolved in o-dichlorobenzene (8.0 mL) and heated at 150° C. for 4 hr. During the latter heating, there was a gradual evolution of gas accompanied by the formation of a suspension. The reaction mixture was allowed to cool to RT, and the precipitate was filtered and washed with copious ether to afford the title compound as a fluffy light-yellow solid (170.8 mg, 67%). 1H NMR (DMSO, δ=2.50): 11.86 (s, 1H), 8.57 (s, 1H), 8.13 (d, J=8.2, 1H), 7.99 (s, 1H), 7.92 (d, J=8.3, 1H), 7.22 (s, 1H), 7.56 (app t, J=7.21, 1H), 7.49 (app t, J=7.48, 1H), 2.60 (s, 3H). (ESI) m/z (M+H)+=250.00.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:17]=[C:16]([O:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=2)[CH:15]=[CH:14][C:13]=1[CH3:29].C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[C:27]([C:24]1[CH:25]=[CH:26][C:21]([CH2:20][CH2:19][O:18][C:16]2[CH:15]=[CH:14][C:13]([CH3:29])=[C:12]([NH:11][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[CH:17]=2)=[CH:22][CH:23]=1)#[N:28]
Reactant: Cc1ccc(OCCc2ccc(C#N)cc2)cc1N
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1ccc(OCCc2ccc(C#N)cc2)cc1NS(=O)(=O)c1ccccc1
Reaction time: 8 h
Yield: 98.7 %

Procedure:
Benzenesulfonyl chloride (22 μL; 0.17 mmol) was added to a cold solution (ice:water temperature) of amino-5-[2-(4-cyanophenyl)ethoxy]-2-methylbenzene (0.041 g; 0.16 mmol; from step (ii) above) in pyridine (4 mL) The reaction flask was left overnight in a refrigerator. NaHCO3/aq (sat.) was added and the solution extracted twice with EtOAc. The combined organic phases were washed with water, HCl/aq (2M) and water. Drying (MgSO4) and evaporation of the solvent in vacuo afforded 0.062 g (100%) of the sub-title compound.
Reaction SMILES: [OH-:1].[Na+].C([CH2:5][CH2:6][CH:7]1[CH:13]=[CH:12][N:11]([C:14](=[O:36])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:35])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:17][CH:16]=2)[C:10]2[CH:37]=[CH:38][CH:39]=[CH:40][C:9]=2[S:8]1)#N.[CH3:41][OH:42]>>[C:41]([CH2:5][CH2:6][CH:7]1[CH:13]=[CH:12][N:11]([C:14](=[O:36])[C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22](=[O:35])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:19][CH:20]=2)[C:10]2[CH:37]=[CH:38][CH:39]=[CH:40][C:9]=2[S:8]1)([OH:42])=[O:1]
Reactant: N#CCCC1C=CN(C(=O)c2ccc(NC(=O)c3ccccc3-c3ccccc3)cc2)c2ccccc2S1
Reactant: CO
Reactant: [OH-]
Agent: [Na+]
Product: O=C(O)CCC1C=CN(C(=O)c2ccc(NC(=O)c3ccccc3-c3ccccc3)cc2)c2ccccc2S1
Temperature: 25 °C

Procedure:
A 6.6N NaOH solution (0.5 ml) was added to a mixture of Compound 30 as prepared in Example 17 (0.05 g, 0.096 mM) in methanol. The mixture was stirred at reflux overnight, cooled to room temperature and evaporated in vacuo. The residue was diluted with water and enough 6N HCl was added drop-wise to precipitate the product. The solid product was collected by filtration and dried. m/z (MH+)537
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[CH3:20][O:21][NH2:22].CCN(C(C)C)C(C)C>>[CH3:20][O:21][NH:22][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1
Reactant: CON
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: CONC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, methoxyamine and DIEA to give 2-methoxyamino-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 286 (MH+).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=[O:5])#[N:2].CO[CH:16]=[CH:17][C:18](=O)[CH3:19].N12CCN(CC1)CC2.CO/C=C/C(=O)C.Cl>COCCOCCO>[F:13][C:10]1[CH:9]=[CH:8][C:7]([N:6]2[C:18]([CH3:19])=[CH:17][CH:16]=[C:3]([C:1]#[N:2])[C:4]2=[O:5])=[CH:12][CH:11]=1
Reactant: N#CCC(=O)Nc1ccc(F)cc1
Reactant: COC=CC(C)=O
Agent: C1CN2CCN1CC2
Agent: CO/C=C/C(C)=O
Agent: Cl
Solvent: COCCOCCO
Product: Cc1ccc(C#N)c(=O)n1-c1ccc(F)cc1
Temperature: 120 °C
Yield: 31.2 %

Procedure:
A solution of 2-cyano-N-(4-fluorophenyl)acetamide (15 g, 84.2 mmol), 4-methoxybut-3-en-2-one (12.6 g, 125.9 mmol) and 1,4-diazabicyclo[2.2.2]octane (9.4 g, 84.2 mmol) in 2-(2-methoxyethoxy)ethanol (150 mL) was stirred with heating at 120° C. for 5 hr. (3E)-4-Methoxybut-3-en-2-one (4.2 g, 41.9 mmol) and 1,4-diazabicyclo[2,2,2]octane (4.7 g, 41.9 mmol) were further added to the reaction mixture, and the mixture was stirred with heating at 120° C. for 1 hr. 2N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The obtained solid was washed with ethyl acetate to give the title compound (6 g, 31%) as a pale-brown solid.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:4]=[C:5]([NH2:9])[S:6][C:7]=1[CH3:8].C(N(CC)CC)C.[C:17]12([C:27](Cl)=[O:28])[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2>C1COCC1>[CH3:2][C:3]1[N:4]=[C:5]([NH:9][C:27]([C:17]23[CH2:26][CH:21]4[CH2:20][CH:19]([CH2:25][CH:23]([CH2:22]4)[CH2:24]2)[CH2:18]3)=[O:28])[S:6][C:7]=1[CH3:8]
Reactant: Cc1nc(N)sc1C
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nc(NC(=O)C23CC4CC(CC(C4)C2)C3)sc1C
Yield: 74 %

Procedure:
To a solution of 4,5-dimethyl-thiazol-2-ylamine hydrochloride (1.65 g, 10.0 mmol) in THF (100 mL) was added triethylamine (4.2 mL, 30 mmol) and adamantane-1-carbonyl chloride (2.2 g, 11 mmol). The mixture was heated at reflux overnight and then concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with 1M NaHCO3, dried (Na2SO4), filtered and concentrated. Purification by column chromatography (SiO2, 10% ethyl acetate:90% hexanes) afforded 2.15 g (74%) of the title compound. MS (ESI+) m/z 291 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][O:23]COC)=[CH:17][CH:16]=2)(O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][OH:23])=[CH:19][CH:20]=2)=[CH:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCOCCc1ccc(C2(O)CCN(Cc3ccccc3)CC2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: OCCc1ccc(C2=CCN(Cc3ccccc3)CC2)cc1
Yield: 24.2 %

Procedure:
To a solution of 1.0 g of 1-benzyl-4-[4-[2-(methoxymethoxy)ethyl]phenyl]piperidin-4-ol in 30 ml of toluene was added 2.0 g of p-toluenesulfonic acid. Then the resulting mixture was heated under reflux for 1 hour while eliminating the water thus formed with a Dean Stark trap. Then the reaction mixture was brought back to room temperature and a saturated aqueous solution of sodium bicarbonate was added thereto. Then it was extracted with ethyl acetate, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 0.2 g of the title compound as a brown oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][N:10]=[C:11](Cl)[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])O.[K+].CO[C:25]([CH:27]([CH3:29])[CH3:28])=[CH2:26]>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:25]([CH:27]([CH3:29])[CH3:28])=[CH:26][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:10]1
Reactant: CCOC(=O)C(Cl)=NNc1ccc(Cl)cc1Cl
Reactant: C=C(OC)C(C)C
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1cc(C(C)C)n(-c2ccc(Cl)cc2Cl)n1
Temperature: 25 °C

Procedure:
1550 g of ethyl 2-chloroglyoxalate 2,4-dichlorophenylhydrazone are dissolved in 1000 g of 2-methoxy-3-methylbut-1-ene and a total of 600 g of potassium hydrogen-carbonate in 500 ml of water is added continuously at 70°-80° C. such that a pH of about 8-8.5 is always maintained. After a total reaction time of 4 hours, the excess enol ether (465 g) is distilled off and the reaction mixture is adjusted to a pH of 0.5 using 190 ml of hydrochloric acid. After heating to reflux for 1 hour, the mixture is cooled to room temperature and the precipitated crystallizate is filtered off with suction.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:9][N:8]([CH2:10][CH2:11][CH:12]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:31])[F:30])[CH:23]=3)[CH:18]([CH3:33])[C:17]2=[O:34])[C:13]([OH:15])=O)[CH2:7][CH2:6][C:3]21[CH2:5][CH2:4]2.Cl.[CH3:36][NH:37][CH3:38].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[OH:1][C@@H:2]1[CH2:9][N:8]([CH2:10][CH2:11][CH:12]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:31])[F:30])[CH:23]=3)[CH:18]([CH3:33])[C:17]2=[O:34])[C:13]([N:37]([CH3:38])[CH3:36])=[O:15])[CH2:7][CH2:6][C:3]21[CH2:5][CH2:4]2
Reactant: CC1C(=O)N(C(CCN2CCC3(CC3)[C@H](O)C2)C(=O)O)CCN1c1cccc(OC(F)(F)F)c1
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1C(=O)N(C(CCN2CCC3(CC3)[C@H](O)C2)C(=O)N(C)C)CCN1c1cccc(OC(F)(F)F)c1
Yield: 71.4 %

Procedure:
To a solution of 4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-2-[3-methyl-2-oxo-4-(3-trifluoromethoxy-phenyl)-piperazin-1-yl]-butyric acid (example 48; 40 mg, 82 μmol) in N,N-dimethylformamide (1.5 mL) was added dimethylamine hydrochloride (10 mg, 0.12 mmol), triethylamine (33 mg, 0.33 mmol) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (38 mg, 99 μmol), then after 1 h the reaction mixture was partitioned between EtOAc and sat. aq. NaHCO3 solution. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated. Chromatography (IST Isolute® Flash NH2; EtOAc) afforded the title compound (30 mg, 71%). Colorless oil, MS: 513.5 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]2[O:22][CH2:23][CH2:24][N:25]=2)[CH:18]=[C:17]([Cl:26])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[O:14][N:13]=[C:12]([CH2:15][OH:16])[CH:11]=1.[C:27]([O:30][CH2:31][CH2:32][O:33][CH2:34]Br)(=[O:29])[CH3:28].[H-].[Na+]>>[C:27]([O:30][CH2:31][CH2:32][O:33][CH2:34][O:16][CH2:15][C:12]1[CH:11]=[C:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][O:4][C:3]2[C:2]([Cl:1])=[CH:20][C:19]([C:21]3[O:22][CH2:23][CH2:24][N:25]=3)=[CH:18][C:17]=2[Cl:26])[O:14][N:13]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)OCCOCBr
Reactant: OCc1cc(CCCCCOc2c(Cl)cc(C3=NCCO3)cc2Cl)on1
Agent: [H-]
Agent: [Na+]
Product: CC(=O)OCCOCOCc1cc(CCCCCOc2c(Cl)cc(C3=NCCO3)cc2Cl)on1

Procedure:
5-{5-[2,6-Dichloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]pentyl}-3-isoxazolylmethoxymethoxyethyl acetate [XXIV; n=5, R1 and R2 =Cl] was prepared from 4.0 g of 5-{5-[2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]pentyl}-3-isoxazolemethanol (Example 116) and 2.0 g of 2-acetoxyethoxymethyl bromide [CH3COCH2CH2OCH2Br] in the presence of sodium hydride according to the procedure of Example 117, and was obtained in the form of a colorless oil (2.4 g).