Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][Si](C)(C)C)=[C:7]2[N:6]=[C:5]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[CH:4]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CO.CC(OC)(C)C>[C:12]([C:11]1[CH:10]=[N:9][N:8]2[C:3]([C:2]([F:1])([F:29])[F:28])=[CH:4][C:5]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[N:6][C:7]=12)#[CH:13]
Reactant: C[Si](C)(C)C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Temperature: 0 °C
Reaction time: 6 h
Yield: 85.5 %

Procedure:
To a solution of 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-3-trimethylsilanylethynyl-pyrazolo[1,5-a]pyrimidine (Example C.1 step 3a) (13.65 g, ca. 26 mmol) in THF (40 mL) and MeOH (100 mL) at 0° C. was added K2CO3 (362 mg, 10 mol %), and the mixture was stirred at 0° C. for 6 h. Diluted with TBME and ice water, separated phases, washed organic layer with brine, dried over Na2SO4. Removal of the solvent in vacuum left a dark brown solid, which was purified by silica gel column chromatography with heptane/EtOAc 9:1 followed by trituration with heptane to give the 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (7.90 g, 89%) as a yellow solid. MS (ISP) 356.0 [(M+H)+]; mp 138° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]([C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=1)[CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[C:11]1[C:15](=[O:30])[C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=1)(=O)=O.[C:39]1([C:45]23[CH2:52][CH2:51][N:48]([CH2:49][CH2:50]2)[CH2:47][CH2:46]3)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(#N)C>[Cl-:37].[C:39]1([C:45]23[CH2:52][CH2:51][N+:48]([CH2:6][CH2:7][CH:8]([C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=4)[CH2:9][N:10]4[CH:14]=[CH:13][N:12]=[C:11]4[C:15](=[O:30])[C:16]4[CH:17]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:19]=[C:20]([C:22]([F:24])([F:23])[F:25])[CH:21]=4)([CH2:47][CH2:46]2)[CH2:49][CH2:50]3)[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: c1ccc(C23CCN(CC2)CC3)cc1
Reactant: CS(=O)(=O)OCCC(Cn1ccnc1C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccc(Cl)c(Cl)c1
Solvent: CC#N
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nccn1CC(CC[N+]12CCC(c3ccccc3)(CC1)CC2)c1ccc(Cl)c(Cl)c1
Product: [Cl-]
Yield: 87.3 %

Procedure:
1-Methanesulphonyloxy-3-(3,4-dichlorophenyl)-4-{2-[3,5-bis(trifluoromethyl)benzoyl]imidazol-1-yl}butane (0.7 g) (see Preparation 85) and 4-phenylquinuclidine (0.32 g) (see J. Org. Chem., 22, 1484,(1957)) were dissolved in acetonitrile (10 ml) and the mixture heated under reflux for 18 hours. The solvent was removed under reduced pressure and the resulting residue dissolved in dichloromethane and washed twice with 2N aqueous hydrochloric acid solution. The organic phase was then dried over anhydrous sodium sulphate and the solvent removed under reduced pressure to give a residue which was chromatographed on silica gel eluting with a solvent gradient of 95:5 changing to 90:10, by volume, dichloromethane:methanol to give 4-phenyl-1-(3-[3,4-dichlorophenyl]-4-{2-[3,5-bis(trifluoromethyl)benzoyl]imidazol-1-yl}butyl)quinuclidinium chloride (0.37 g) as a white foam.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.ClCCl.[NH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[N:32]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>O>[N:32]1([C:23]2[CH:24]=[CH:25][C:26]([C:28]([F:30])([F:31])[F:29])=[CH:27][C:22]=2[NH:21][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: Nc1cc(C(F)(F)F)ccc1N1CCCCCC1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cc(C(F)(F)F)ccc1N1CCCCCC1)c1ccncc1
Yield: 97 %

Procedure:
Isonicotinoyl chloride hydrochloride (704 mg, 3.95 mmol, commercially available product) and triethylamine (823 μl, 5.94 mmol) were sequentially added at 0° C. to a dichloromethane (6 ml) solution of 1-[2-amino-4-(trifluoromethyl)phenyl]-hexahydro-1H-azepine (512 mg, 1.98 mmol), obtained as described in Referential Example 4-2. The resulting mixture was stirred for one and a half hours. Water was added to the mixture, and the resulting mixture was extracted three times with dichloromethane. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30 g, hexane/ethyl acetate=2/1). Thus, N-[2-(1-hexahydro-1H-azepinyl)-5-(trifluoromethyl)phenyl]isonicotinamide (GIF-0618) (697 mg, 97.0%) was yielded as a colorless solid.
Reaction SMILES: C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[CH2:16]([N:18]1[C:24]2[CH:25]=[CH:26][C:27]([NH2:29])=[CH:28][C:23]=2[O:22][CH2:21][CH2:20][CH2:19]1)[CH3:17].Cl[C:31]1[N:36]=[C:35]([NH:37][C@@H:38]2[CH2:43][CH2:42][CH2:41][CH2:40][C@H:39]2[NH:44][S:45]([CH3:48])(=[O:47])=[O:46])[C:34]([Cl:49])=[CH:33][N:32]=1.C(=O)([O-])[O-]>C(O)(C)C>[Cl:49][C:34]1[C:35]([NH:37][C@@H:38]2[CH2:43][CH2:42][CH2:41][CH2:40][C@H:39]2[NH:44][S:45]([CH3:48])(=[O:47])=[O:46])=[N:36][C:31]([NH:29][C:27]2[CH:26]=[CH:25][C:24]3[N:18]([CH2:16][CH3:17])[CH2:19][CH2:20][CH2:21][O:22][C:23]=3[CH:28]=2)=[N:32][CH:33]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: CCN1CCCOc2cc(N)ccc21
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Product: CCN1CCCOc2cc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)ccc21

Procedure:
10-Camphorsulfonic acid (86 mg, 0.37 mmol) was added to 9-Ethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-3-ylamine (65 mg, 0.34 mmol) and N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (110 mg, 0.34 mmol) in Isopropyl alcohol (3 mL). The mixture was irradiated in a CEM microwave (130° C., 30 min). The mixture was conc. and purified by HPLC, conc., neutralized with MP-Carbonate (2.69 mmol/g loading; 0.50 g, 1.345 mmol), filtered and conc. to give N-{(1R,2R)-2-[5-Chloro-2-(9-ethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-3-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide as a light green foam, MP: 108-110° C., LCMS: 495 (M+H); 1H-NMR (DMSO): 9.01 (s, 1H), 7.90 (s, 1H), 7.41 (s, 1H), 7.15 (m, 2H), 6.75 (d, 1H, J=8.4 Hz), 6.67 (d, 1H, J=6.3 Hz), 3.98 (m, 2H), 3.79 (m, 1H), 3.32 (m, 1H), 3.12 (m, 2H), 3.06 (m, 2H), 2.90 (s, 3H), 2.14 (m, 1H), 2.02 (m, 1H), 1.90 (m, 2H), 1.69 (m, 2H), 1.32 (m, 4H), 1.10 (t, 3H, J=7.0 Hz).
Reaction SMILES: OC(=CC([O-])=O)C.CS(Cl)(=O)=O.C(C1SC2C(C(=O)N2C(=C(OS(C)(=O)=O)C)C(OC(C2C=CC=CC=2)C2C=CC=CC=2)=O)N=1)C1C=CC=CC=1.N1CCOCC1.[CH2:58]([C:65]1[S:71][CH:70]2[CH:67]([C:68](=[O:97])[N:69]2[C:72](=[C:89]([N:91]2[CH2:96][CH2:95][O:94][CH2:93][CH2:92]2)[CH3:90])[C:73]([O:75][CH:76]([C:83]2[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=2)[C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)=[O:74])[N:66]=1)[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1.[Br:98]Br>N1C=CC=CC=1.C(N(CC)CC)C>[CH2:58]([C:65]1[S:71][CH:70]2[CH:67]([C:68](=[O:97])[N:69]2[C:72](=[C:89]([N:91]2[CH2:92][CH2:93][O:94][CH2:95][CH2:96]2)[CH2:90][Br:98])[C:73]([O:75][CH:76]([C:83]2[CH:84]=[CH:85][CH:86]=[CH:87][CH:88]=2)[C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)=[O:74])[N:66]=1)[C:59]1[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=1
Reactant: BrBr
Reactant: CC(=C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C2N=C(Cc3ccccc3)SC21)N1CCOCC1
Agent: CC(O)=CC(=O)[O-]
Agent: CC(OS(C)(=O)=O)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C2N=C(Cc3ccccc3)SC21
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1COCCN1
Product: O=C(OC(c1ccccc1)c1ccccc1)C(=C(CBr)N1CCOCC1)N1C(=O)C2N=C(Cc3ccccc3)SC21
Reaction time: 3.5 h
Yield: 70 %

Procedure:
One dissolves diphenylmethyl α-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-hydroxy-ethylideneacetate (4.84 g) in tetrahydroufran (60 ml), cools to -20° C., adds triethylamine (2.84 ml) with stirring, adds dropwise methanesulfonyl chloride (0.82 ml) to the yellow solution, and lets react for 30 minutes. To the produced solution of diphenylmethyl α-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-methanesulfonyloxyethylidene)acetate, one adds morpholine (0.96 ml) at -40° C., stirs for 3.5 hours, adds pyridine (0.77 ml) to the produced solution of diphenylmethyl α-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-morpholinoethylidene)acetate, cools to -40° C., adds bromine (0.49 ml), and stirs for 30 minutes, to give diphenylmethyl α-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl] -α-(2-bromo-1-morpholinoethylidene)acetate. To this solution, one adds dropwise 5% hydrochloric acid (72 ml) and methanol (60 ml), stirs for 3 hours at room temperature, and keeps in a refrigerator overnight. The reaction mixture is evaporated to give residue which is dissolved in methylene chloride, washed with water, dried over sodium sulfate, and evaporated. Purification of the obtained residue (5.83 g) by chromatography over silica gel containing 10% water (150 g) gives from the fraction eluted with a mixture of benzene and ethyl acetate (4:1) diphenylmethyl 7-phenylacetamido-3-hydroxy-3-cephem-4-carboxylate (3.51 g) by recrystallization from n-hexane. m.p. 93°-96° C. Yield: 70%. IR: νmaxCHCl3 3410, 1782, 1674, 1610 cm-1. NMR: δCDCl3 3.20s2H, 3.64s2H, 4.97d(4 Hz)1H, 5.66dd(9:4)1H, 6.77d(9 Hz)1H, 6.90s1H, 7.35 ml 5H.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.Cl.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1.NC1C=CC(C(F)(F)F)=CC=1>CO.C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:18][CH:17]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CSc1ncnc2cc(N)ncc12
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Nc1cc2ncnc(Nc3ccc(C(F)(F)F)cc3)c2cn1
Temperature: 180 °C
Reaction time: 0.03 h
Yield: 63.2 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (390 mg, 2.03 mmol), 4-aminobenzotrifluoride hydrochloride (0.40 g, 2.02 mmol) and 4-aminobenzotrifluoride (1.61 g, 10.0 mmol) is stirred at 180° C. for 2 min. The resulting product is neutralized with excess NaHCO2, dissolved in MeOH/CHCl3, dried onto alumina and chromatographed over alumina (4-7% MeOH/CH2Cl2) to give 7-amino-4-(4-trifluoromethylanilino)pyrido[4,3-d]pyrimidine (390 mg, 63%) as a cream solid. Analytically pure material was obtained by further chromatography over silica gel (5% MeOH/CH2Cl2) to give pale yellow needles. 1H NMR (DMSO) δ 10.09 (1H, brs), 9.40 (1H, s), 8.48 (1H, s), 8.13 (2H, d, J=8.2 Hz), 7.74 (2H, d, J=8.7 Hz), 6.72 (2H, brs), 6.40 (1H, s).
Reaction SMILES: [CH3:1][OH:2].[OH-:3].[Na+].Cl[CH2:6][C:7]1[O:8][CH:9]=[CH:10][CH:11]=1>O>[O:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[CH2:6][C:1]([OH:3])=[O:2]
Reactant: CO
Reactant: [OH-]
Reactant: ClCc1ccco1
Agent: [Na+]
Solvent: O
Product: O=C(O)Cc1ccco1
Yield: 57 %

Procedure:
100 ml of CH3OH, 7 g of AMBERLYST A 26 type (III) and 0.75 g of NaCo(CO)4 were introduced into the equipment of Example 1. It was left under stirring for 15 minutes whereupon 10 ml of H2O were added. Successively, maintaining the pH at a value of from 10.5 to 11 with a NaOH solution at 30%, 9 g of 2-chloromethylfuran were dropped in 2 hours at a temperature of 25°-30° C. At the end of the reaction, it was filtered from the resin and by operating as described in Example 1, 5.6 g of 2-furanacetic acid were isolated (yield=57% referred to the starting product).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[OH:16][CH:17]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:19]2[CH2:20][CH2:21][CH2:22][CH:17]([OH:16])[CH2:18]2)=[O:15])=[CH:6][CH:7]=1
Reactant: OC1CCCNC1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Product: Cc1ccc(-c2oncc2C(=O)N2CCCC(O)C2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 3-hydroxypiperidine (6.1 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (0.6 mg). HRMS calcd for C16H18N2O3: 286.1317, found 286.1315.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:11][C:12]([C:16]#[N:17])=[N:13]2)=[CH:8][CH:7]=1)=[N+:2]=[N-:3].[CH2:24]([C:26]([OH:31])([CH2:29][CH3:30])[C:27]#[CH:28])[CH3:25].C(N(C(C)C)CC)(C)C>C1COCC1.[Cu](I)I>[CH2:27]([C:26]([C:24]1[N:3]=[N:2][N:1]([CH2:4][CH2:5][C:6]2[CH:15]=[C:14]3[C:9]([C:10]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:11][C:12]([C:16]#[N:17])=[N:13]3)=[CH:8][CH:7]=2)[CH:25]=1)([OH:31])[CH2:29][CH3:30])[CH3:28]
Reactant: C#CC(O)(CC)CC
Reactant: N#Cc1cc(-c2ccccc2)c2ccc(CCN=[N+]=[N-])cc2n1
Agent: I[Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC(O)(CC)c1cn(CCc2ccc3c(-c4ccccc4)cc(C#N)nc3c2)nn1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 7-(2-azidoethyl)-4-phenylquinoline-2-carbonitrile (128 mg, 0.43 mmol), 3-ethylpent-1-yn-3-ol (63 mg, 0.56 mmol), copper iodide (58 mg, 0.65 mmol) and diisopropylethylamine (375 μL, 2.2 mmol) in THF (5 mL) was stirred at rt for 6 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification on silica gel (eluting with acetone/dichloromethane, 2:8) gave the title compound. MS (+ESI): 394 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:36][CH3:37])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:38].ClC1C=C(C=CC=1)C(OO)=[O:44]>C(Cl)Cl.CCOC(C)=O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:36]([CH3:37])=[O:44])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:38]
Reactant: CSc1nc(-c2cc(C(=O)NCc3ccccc3)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc(C(=O)NCc2ccccc2)cc1-c1nc(S(C)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reaction time: 0.17 h

Procedure:
3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methyl-N-(phenylmethyl)benzamide (0.12 g 0.227 mmol) was dissolved in CH2Cl2 (5 mL) and 50-60% 3-chloroperoxybenzoic acid (0.106 g, 0.34 mmol) was added and the mixture stirred for 10 min. The solvents were pumped off, and the residue taken up in EtOAc and washed with H2O, brine, dried over anhydrous Na2SO4 filtered and evaporated. The crude product which contained a small amount of sulfone, was flashed on silica gel (20 g) eluted with a hexane to EtOAc gradient to isolate the title compound. mp (dec) 268-270° C. LC-MS m/z 545 (M+H)+, 1.87 min (ret time).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([O:17][CH2:16]1)[C:10]([F:15])([F:14])[C:11]([NH2:13])=[O:12].C(=O)([O-])[O-].[K+].[K+].[NH:24]1[CH:28]=[N:27][CH:26]=[N:25]1.Cl>CN(C)C=O.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:17])([CH2:16][N:24]1[CH:28]=[N:27][CH:26]=[N:25]1)[C:10]([F:15])([F:14])[C:11]([NH2:13])=[O:12]
Reactant: c1nc[nH]n1
Reactant: NC(=O)C(F)(F)C1(c2ccc(Cl)cc2Cl)CO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)C(F)(F)C(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Yield: 40.2 %

Procedure:
In 8 ml of N,N-dimethylformamide was dissolved 0.8 g of 3-(2,4-dichlorophenyl)-3,4-epoxy-2,2-difluorobutanamide. To the resulting solution were added 0.59 g of anhydrous potassium carbonate and 0.29 g of 1,2,4-triazole. The mixture was subjected to reaction at 80°-90° C. for 1 hour. The solvent was removed by distillation under reduced pressure. To the residue obtained were added 10 ml of ethyl acetate and 10 ml of water. The mixture was adjusted to pH 1.0 with 2N hydrochloric acid. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography (eluant: chloroform/methanol=100/1) to obtain 0.40 g of 3-(2,4-dichlorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanamide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][NH:25][CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[O-:29][C:30]#[N:31].[Na+].C(O)(=O)C.CN(C=O)C>O>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:26][CH3:27])[C:30]([NH2:31])=[O:29])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: N#C[O-]
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCC)ccc1OC
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(N)=O)c1
Reaction time: 1 h

Procedure:
(2′-Ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (0.202 g, 0.51 mmol) and sodium cyanate (0.052 g, 0.77 mmol) were combined in H2O (2 mL). Acetic acid (0.04 mL, 0.77 mmol) was added, and the reaction was stirred for 1 hour. DMF (1 mL) was added to facilitate stirring, and the reaction was stirred for 1.5 hours. The solution was extracted with EtOAc, and the combined organic layers were dried and concentrated to give the title compound.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:15][C:16]([CH:18]1[CH2:22][CH2:21][CH:20]([O:23][Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])[CH2:19]1)=[O:17])[CH3:14].[CH:34](=[O:36])[CH3:35]>O1CCCC1>[CH2:13]([O:15][C:16]([C:18]1([CH:34]([OH:36])[CH3:35])[CH2:22][CH2:21][CH:20]([O:23][Si:24]([CH:25]([CH3:26])[CH3:27])([CH:31]([CH3:32])[CH3:33])[CH:28]([CH3:30])[CH3:29])[CH2:19]1)=[O:17])[CH3:14]
Reactant: CC=O
Reactant: CCOC(=O)C1CCC(O[Si](C(C)C)(C(C)C)C(C)C)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C1(C(C)O)CCC(O[Si](C(C)C)(C(C)C)C(C)C)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
A cooled (−78° C.) solution of N,N-diisopropylamine (4.4 mL, 31.285 mmol) in anhydrous tetrahydrofuran (60 mL) was treated with n-butyllithium (2.5 M in hexanes, 11.7 mL, 29.329 mmol). After stirring at −78° C. for 30 min, the reaction mixture was treated with a solution of 3-triisopropylsilanyloxy-cyclopentanecarboxylic acid ethyl ester (6.15 g, 19.553 mmol) in anhydrous tetrahydrofuran (20 mL). After stirring at −78° C. for 40 min, the reaction mixture was treated with neat acetaldehyde (3.3 mL, 58.659 mmol). The cooling bath was removed and the reaction was stirred at room temperature for 50 min then quenched at 0° C. with a saturated solution of ammonium chloride (100 mL). The aqueous layer was extracted with dichloromethane (2×). The organics were combined, filtered through a phase separator and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 100 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 4:1 to afford the title compound (6.61 g, 94%) as a light yellow oil and as a complex mixture of diastereoisomers.
Reaction SMILES: O1C=CC2C=C(C3CO3)C=CC1=2.N1C=CC=C(CO)C=1.[S:21]1[CH:25]=[CH:24][C:23]2[CH:26]=[C:27]([CH:30]3[CH2:32][O:31]3)[CH:28]=[CH:29][C:22]1=2.[CH:33]([N:35]1[CH2:40][CH2:39][N:38]([CH:41]=[O:42])[CH2:37][CH:36]1[CH2:43][OH:44])=[O:34]>>[S:21]1[CH:25]=[CH:24][C:23]2[CH:26]=[C:27]([CH:30]([OH:31])[CH2:32][O:44][CH2:43][CH:36]3[CH2:37][N:38]([CH:41]=[O:42])[CH2:39][CH2:40][N:35]3[CH:33]=[O:34])[CH:28]=[CH:29][C:22]1=2
Reactant: O=CN1CCN(C=O)C(CO)C1
Reactant: c1cc2cc(C3CO3)ccc2s1
Agent: OCc1cccnc1
Agent: c1cc2cc(C3CO3)ccc2o1
Product: O=CN1CCN(C=O)C(COCC(O)c2ccc3sccc3c2)C1

Procedure:
The same procedure as in Production Example 43 was repeated, except that the 2-(benzo[b]furan-5-yl)oxirane and the 3-pyridinemethanol were replaced by 2-(benzo[b]thiophen-5-yl)oxirane and 1,4-diformyl-2-piperazinemethanol, respectively, to obtain oily 1-(benzo [b]thiophen-5-yl)-2-[(1,4-diformylpiperazin-2-yl)methoxy]ethanol (compound No. 354).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([F:20])[C:5]2[N:6]([CH2:11][CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])[C:7]([CH2:9]Cl)=[N:8][C:4]=2[CH:3]=1.ClC1C=C(F)C2N(CCC(F)(F)F)C(CCl)=NC=2C=1.[CH3:40][S:41]([C:44]1[C:52]2[C:47](=[CH:48][N:49]=[CH:50][CH:51]=2)[NH:46][N:45]=1)(=[O:43])=[O:42].CS(C1C2C(=CN=CC=2)NN=1)(=O)=O>>[Cl:1][C:2]1[CH:19]=[C:18]([F:20])[C:5]2[N:6]([CH2:11][CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])[C:7]([CH2:9][N:46]3[C:47]4=[CH:48][N:49]=[CH:50][CH:51]=[C:52]4[C:44]([S:41]([CH3:40])(=[O:42])=[O:43])=[N:45]3)=[N:8][C:4]=2[CH:3]=1
Reactant: Fc1cc(Cl)cc2nc(CCl)n(CCCC(F)(F)F)c12
Reactant: CS(=O)(=O)c1n[nH]c2cnccc12
Agent: Fc1cc(Cl)cc2nc(CCl)n(CCC(F)(F)F)c12
Product: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)cc(F)c3n2CCCC(F)(F)F)c2cnccc12

Procedure:
The title compound was prepared in analogy to Example 5-1 by using 5-chloro-2-(chloromethyl)-7-fluoro-1-(4,4,4-trifluorobutyl)-1H-benzo[d]imidazole and 3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine 5-chloro-2-(chloromethyl)-7-fluoro-1-(3,3,3-trifluoropropyl)-1H-benzo[d]imidazole and 3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:10])[C:6]=1[C:7]([NH2:9])=[O:8].CCN(CC)CC.CN(C1C=CC=CN=1)C.[CH3:27][O:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32]>C(Cl)Cl.O>[CH3:27][O:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH3:10])[C:6]=1[C:7]([NH2:9])=[O:8])=[O:32]
Reactant: COc1ccccc1C(=O)Cl
Reactant: Cc1csc(N)c1C(N)=O
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1C(=O)Nc1scc(C)c1C(N)=O
Reaction time: 1 h
Yield: 43.6 %

Procedure:
A solution of 2-amino-4-methylthiophene-3-carboxamide (0.47 g, 3 mmol), Et3N (0.46 mL, 3.3 mmol), and dimethylaminopyridine (0.073 g, 0.64 mmol) in CH2Cl2 (10.0 mL) was cooled in an ice bath, and 2-methoxybenzoyl chloride (513 mg, 3.0 mmol) was added dropwise to this mixture. The reaction was stirred for 1 h, and water (20 mL) was added. The insoluble solids were filtered, and the layers were separated. The organic layer was dried and the solvent removed under vacuum to give a residue which was purified with silica gel using EtOAc-hexanes to give 2-(2-methoxybenzamido)-4-methylthiophene-3-carboxamide (0.38 g, 44% yield). LC/MS: m/z 291.1 (M+H)+ at 2.59 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=O.Cl.[CH3:8][C:9]1[CH:13]=[C:12]([NH2:14])[S:11][N:10]=1.C(N(CC)CC)C>ClCCl.O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][NH:14][C:12]1[S:11][N:10]=[C:9]([CH3:8])[CH:13]=1
Reactant: COCC(=O)Cl
Reactant: Cc1cc(N)sn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCNc1cc(C)ns1

Procedure:
From methoxyacetyl chloride and 3-methyl-isothiazol-5-ylamine hydrochloride with triethylamine in dichloromethane. Then treatment with a borane-dimethyl sulphide complex in tetrahydrofuran.
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[O:15]1[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]1>>[N+:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:4]([O:21][CH:18]2[CH2:19][CH2:20][O:15][CH2:16][CH2:17]2)[C:5]=1[C:6]#[N:7])([O-:14])=[O:13]
Reactant: OC1CCOCC1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: N#Cc1c(OC2CCOCC2)cccc1[N+](=O)[O-]
Yield: 100 %

Procedure:
Prepared as in Example 166d from 2,6-dinitrobenzonitrile and tetrahydro-2H-pyran-4-ol in 100% yield as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ 1.69 (m, 2H), 2.03 (m, 2H), 3.56 (m, 2H), 3.87 (m, 2H), 4.98 (sept, J=3.8 Hz, 1H), 7.90 (m, 3H).