Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[C:9]([CH3:10])=[C:8]([C:11]([O:13]C)=[O:12])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([N:5]1[C:9]([CH3:10])=[C:8]([C:11]([OH:13])=[O:12])[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cnn(C(C)(C)C)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C(=O)O)cnn1C(C)(C)C

Procedure:
A solution of methyl 1-tert-butyl-5-methyl-1H-pyrazole-4-carboxylate in MeOH (20 mL) was treated with 2 M aqueous NaOH solution (7.95 mL, 15.9 mmol) for 48 h at room temperature. The solvent was removed under reduced pressure and the resulting residue was dissolved in H2O (20 mL). The resulting solution was then acidified to pH-2 using 2 M HCl. The resulting precipitate was isolated by filtration, washed once with H2O (20 mL), and the solid was dried under high vacuum to yield 1-tert-Butyl-5-methyl-1H-pyrazole-4-carboxylic acid. 1H-NMR (400 MHz, d6-DMSO) δ: 12.16 (br. s., 1H), 7.67 (s, 1H), 2.69 (s, 3H), 1.59 (s, 9H).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[N:9]1[CH:14]=[CH:13][CH:12]=[C:11](/[CH:15]=[CH:16]/[C:17]2[C:25]3[C:20](=[CH:21][C:22](/[CH:26]=[C:27]4/[C:28](=[O:36])[NH:29][C:30]5[C:35]/4=[CH:34][CH:33]=[CH:32][CH:31]=5)=[CH:23][CH:24]=3)[NH:19][N:18]=2)[CH:10]=1.[NH4+].[Cl-]>CN(C=O)C>[N:9]1[CH:14]=[CH:13][CH:12]=[C:11](/[CH:15]=[CH:16]/[C:17]2[C:25]3[C:20](=[CH:21][C:22]([C@H:26]4[C@@:27]5([C:35]6[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=6)[NH:29][C:28]5=[O:36])[CH2:2]4)=[CH:23][CH:24]=3)[NH:19][N:18]=2)[CH:10]=1
Reactant: C[S+](C)(C)=O
Reactant: O=C1Nc2ccccc2/C1=C\c1ccc2c(/C=C/c3cccnc3)n[nH]c2c1
Agent: [Cl-]
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2[C@]12C[C@H]2c1ccc2c(/C=C/c3cccnc3)n[nH]c2c1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 34.4 %

Procedure:
To a mixture of trimethylsulfoxonium iodide (176 mg, 0.8 mmol) and 60% NaH (96 mg, 2.4 mmol) in a RBF was added DMF (5 mL). The resulting mixture was stirred for 2 min at rt then cooled to 0° C. A solution of (E)-3-((3-((E)-2-(pyridin-3-yl)vinyl)-1H-indazol-6-yl)methylene)indolin-2-one (122 mg, 0.33 mmol)) in DMF (20 mL) was added via a pipet. After addition, the resulting mixture was heated at 55° C. (oil temp.) for 2 h and cooled to rt. Additional trimethylsulfoxonium iodide (176 mg, 0.8 mmol) and 60% NaH (96 mg, 2.4 mmol) were added and the resulting mixture was stirred O/N at rt and poured onto ice (80 mL). It was acidified with sat. NH4Cl and extracted with EtOAc (40 mL×3). The combined extracts were dried (Na2SO4) and concentrated to give a light brown liquid. This residue was purified by flash chromatography (eluent: CH2Cl2 to CH2Cl2/MeOH/Et3N=200:10:1) to give the crude title compound as a light yellow solid which was triturated with MeOH (5 mL) and suction filtered to give the title compound as a yellow solid (43 mg, 34%). 1H NMR (400 MHz, DMSO-d6) δ 13.21 (s, 1H), 10.64 (s, 1H), 8.86 (s, 1H), 8.45 (d, J=3.2 Hz, 1H), 8.15 (d, J=8.0 Hz, 1H), 8.09 (d, J=8.4 Hz, 1H), 7.65 (d, J=16.8 Hz, 1H), 7.49 (d, J=16.8 Hz, 1H, partially overlapping with the peak at 7.47 ppm), 7.47 (s, 1H, partially overlapping with the peak at 7.49 ppm), 7.40 (dd, J=8.0 Hz, J=4.8 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 6.99 (d, J=7.2 Hz, 1H), 6.86 (d, J=7.6 Hz, 1H), 6.53 (t, J=7.4 Hz, 1H), 6.01 (d, J=7.6 Hz, 1H), 3.21 (t, J=8.4 Hz, 1H), 2.32 (dd, J=7.6 Hz, J=4.8 Hz, 1H), 2.00 (dd, J=9.0 Hz, J=4.8 Hz, 1H); MS ESI 379.1 [M+H]+, calcd for [C24H18N4O+H]+ 379.1.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:7][C:8]([NH2:12])=[N:9]2)=[CH:4][CH:3]=1.[CH2:19]([O:21][C:22](=[O:27])[CH2:23][N:24]=[C:25]=[S:26])[CH3:20].C(N(C(C)C)CC)(C)C>>[CH2:19]([O:21][C:22](=[O:27])[CH2:23][NH:24][C:25]([N:16]1[CH2:17][CH2:18][N:13]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[C:8]([NH2:12])[CH:7]=2)[CH2:14][CH2:15]1)=[S:26])[CH3:20]
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Reactant: CCOC(=O)CN=C=S
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNC(=S)N1CCN(c2cc(N)nc3cc(Cl)ccc23)CC1

Procedure:
As described for example 159, 7-chloro-4-(1-piperazinyl)-2-quinolinamine, isothiocyanato-acetic acid-ethy ester, and diisopropylethyl amine, are reacted to give the product as a white solid. LC-MS: 407 (M++1). 1H NMR (DMSO-d6): δ 1.16 (t, 3H), 3.05 (br.s, 4H), 4.01 (br.s, 4H), 4.06 (q, 2H), 4.20 (d, 2H), 6.24 (s, 1H), 6.47 (br.s, 2H), 7.08 (dd, 1H), 7.36 (d, 1H), 7.76 (d, 1H), 8.23 (dd, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][NH2:7])=[O:5].[CH3:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1>[OH-].[Na+]>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][NH:7][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][C:13]([CH3:12])=[CH:14][CH:15]=1)=[O:5]
Reactant: NNC(=O)c1ccccc1Cl
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(C(=O)NNC(=O)c2ccccc2Cl)cc1
Yield: 45.7 %

Procedure:
2-Chlorobenzhydrazide (38.8 g) was dissolved in sodium hydroxide solution (9.18 g in 125 ml water). The solution was stirred and 4-methylbenzoyl chloride (35.2 g) added dropwise. The mixture was then stirred for 2 hours and the solid which precipitated was filtered off, washed with water and recrystallised from ethanol to give 30.0 g of the desired product, mp 204°-206° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH:6]=[CH:7][CH:8]=O.S([O-])([O-])(=O)=O.[Mg+2].[CH3:21][NH2:22]>C1C=CC=CC=1>[CH3:21][NH:22][CH2:8][CH:7]=[CH:6][C:5]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1ccc(C=CC=O)cc1OC
Reactant: CN
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: c1ccccc1
Product: CNCC=Cc1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The starting material is prepared as follows: To the mixture of 19.2 g of 3,4-dimethoxycinnamaldehyde, 24 g of magnesium sulfate and 100 ml of benzene, 6.2 g of methylamine in 120 ml of benzene are added and the suspension is stirred at room temperature for 8 hours. It is filtered and the filtrate added dropwise to the solution of 3.8 g of sodium borohydride in 200 ml to anhydrous ethanol while stirring and cooling with ice. Stirring is continued over night at room temperature, the mixture cooled again, 25 ml of concentrated hydrochloric acid are added and the solution evaporated under reduced pressure. The residue is taken up in 150 ml of water the solution washed with diethyl ether, made basic with sodium hydroxide and the mixture extracted with diethyl ether. The extract is dried and evaporated, to yield the N-methyl-3,4-dimethoxycinnamylamine as an oil; the cyclamate thereof melts at 145°-147°.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[CH2:11]1)(C)(C)C>CO>[CH3:18][C:12]1([CH3:19])[CH2:11][CH:10]([CH2:9][CH2:8][NH2:7])[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13]1
Reactant: CC1(C)CC(CCNC(=O)OC(C)(C)C)CC(C)(C)N1
Solvent: CO
Product: CC1(C)CC(CCN)CC(C)(C)N1
Reaction time: 1 h
Yield: 140.8 %

Procedure:
To 2-(2,2,6,6-tetramethylpiperidin-4-ylidene)-ethylamine (0.480 g, 2.63 mmol) in MeOH (5 mL) is added 10% Pd/C (48 mg) and 5 N HCl (2.63 mL, 13.2 mmol). At 50 psi hydrogen gas at 50° C. the reaction mixture is stirred for 18 hours. The reaction is filtered to remove the catalyst and resubjected to the reaction conditions using RhClPPh3 (0.26 mmol). Due to incomplete reaction the mixture is diluted with water, concentrated to remove any organic solvent, filtered to remove any solids, and then concentrated again. The residue is dissolved in acetic acid and resubjected to the hydrogenation conditions using 100 mg of palladium black and 50 psi hydrogen gas at 50° C. for 18 hours. The mixture of products is not easily purified, so the crude mixture is treated with di-tert-butyl dicarbonate in dichloromethane and then purified by silica gel chromatography using a high enough percentage of 2 M NH3 in MeOH in dichloromethane to isolate 240 mg of [2-(2,2,6,6-tetramethyl-piperidin-4-yl)-ethyl]-carbamic acid tert-butyl ester. [2-(2,2,6,6-Tetramethyl-piperidin-4-yl)-ethyl]-carbamic acid tert-butyl ester (240 mg, 0.844 mmol) is dissolved in 2:1 MeOH:dichloromethane (10.5 mL) and HCl (g) is bubbled for 5 minutes. After 1 hour, the reaction mixture is concentrated to give a foam (219 mg). The foam is dissolved in MeOH and loaded onto an SCX 5 g resin column. The column is washed with MeOH, then the product is released with 7 M NH3 in MeOH. After concentration the title compound is obtained and used without further purification (138 mg).
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[C@H:11](CC([O-])=O)[C@H:10](CC([O-])=O)[C@H:9](CC([O-])=O)[C@@H:8]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][O:41][Si](C(C)(C)C)(C)C)=[CH:34][CH:33]=3)[CH:25]=2)[O:7]1)(=[O:3])[CH3:2].[C:49]([OH:52])(=[O:51])[CH3:50]>C1COCC1.O>[C:49]([O:52][C@H:11]1[C@H:10]([O:51][C:49](=[O:52])[CH3:50])[C@@H:9]([O:4][C:1](=[O:3])[CH3:2])[C@H:8]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][OH:41])=[CH:34][CH:33]=3)[CH:25]=2)[O:7][C@@H:6]1[CH2:5][O:4][C:1](=[O:3])[CH3:2])(=[O:51])[CH3:50]
Reactant: CC(=O)OC[C@@H]1O[C@H](c2ccc(Cl)c(Cc3ccc(OCCO[Si](C)(C)C(C)(C)C)cc3)c2)[C@@H](CC(=O)[O-])[C@@H](CC(=O)[O-])[C@H]1CC(=O)[O-]
Reactant: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCCO)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 82 %

Procedure:
To a solution of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-(4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)benzyl)-4-chlorophenyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate (2.59 g, 3.66 mmol) in THF:Water (1:1, 36 mL) was added acetic acid (54 mL) at 0° C. The reaction mixture was stirred at r.t. for 24 h. After completion of reaction, as confirmed by TLC, the reaction mixture was evaporated in vacuo and the residue obtained was purified by column chromatography (silica gel, 4:6 Ethyl acetate:Pet. Ether) to afford title compound (1.8 g, 82%).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH3:14]>>[NH2:14][C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: N
Reactant: O=[N+]([O-])c1ccc2nc(Cl)sc2c1
Product: Nc1nc2ccc([N+](=O)[O-])cc2s1

Procedure:
Various processes for the preparation of 2-amino-6-nitrobenzothiazole are known. For example Pubbl. ist. chim. univ. Bologna No. 2, 3-10 (1943); Chemical Abstracts 41:754 discloses the chlorination of 2-mercaptobenzothiazole to give 2-chlorobenzothiazole which is then treated with nitric and sulfuric acids to give 2-chloro-6-nitrobenzothiazole. The 2-chloro-6-nitrobenzothiazole is then treated with alcoholic ammonia under pressure at 140° to give 2-amino-6-nitrobenzothiazole. No yields are stated in the English abstract.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH:12]3[CH2:13][CH2:14][CH:9]([CH:10]=[CH:11]3)[N:8]2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:2]=1>C(O)(=O)C.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH:12]3[CH2:11][CH2:10][CH:9]([CH2:14][CH2:13]3)[N:8]2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:2]=1
Reactant: CCOC(=O)N1C2C=CC(CC2)C1c1cccnc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)N1C2CCC(CC2)C1c1cccnc1
Yield: 98 %

Procedure:
A solution of the (+/-)-endo and (+/-)-exo isomers of 3-(3-pyridyl)-2-carboethoxy-2-azabicyclo[2.2.2]oct-5-ene, compound (II), (750 mg, 2.90 mmol) in glacial acetic acid (0.5 mL) and Pd/C (10%) was shaken under a H2 atmosphere in a Parr apparatus for 2 hours. The catalyst was removed by Alteration over a bed of Celite and the filterate was basified by addition of a solution of 40% of NaOH in water. The aqueous basic solution was extracted with dichloromethane (4×20 mL) to give 740 mg (98%) of compound (XII). 1H NMR (CDCl3 ): δ 8.48 (m, 2H), 7.60 (m. 2H), 4.78 and 4.67 (m,1H), 4.30 (m, 1H), 4.13 and 4.10 (q, 2H), 2.19 (m, 2H), 1.90 (m, 3H), 1.63 (m, 4H,), 1.28 and 0.90 (t, 3H).
Reaction SMILES: O1CCOC[CH2:2]1.Br[C:8]1[CH:9]=[C:10]([CH2:17][N:18]2[CH:23]=[N:22][C:21]([N:24]3[CH2:29][CH2:28][N:27]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)[CH2:26][CH2:25]3)=[N:20][C:19]2=[O:37])[S:11][C:12]=1[C:13]([F:16])([F:15])[F:14].B(OC)(OC)OC.C(=O)([O-])[O-].[Na+].[Na+]>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].O>[F:36][C:33]1[CH:34]=[CH:35][C:30]([N:27]2[CH2:28][CH2:29][N:24]([C:21]3[N:22]=[CH:23][N:18]([CH2:17][C:10]4[S:11][C:12]([C:13]([F:16])([F:15])[F:14])=[C:8]([CH3:2])[CH:9]=4)[C:19](=[O:37])[N:20]=3)[CH2:25][CH2:26]2)=[CH:31][CH:32]=1
Reactant: O=c1nc(N2CCN(c3ccc(F)cc3)CC2)ncn1Cc1cc(Br)c(C(F)(F)F)s1
Reactant: C1COCCO1
Agent: [Pd]
Agent: COB(OC)OC
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: Cc1cc(Cn2cnc(N3CCN(c4ccc(F)cc4)CC3)nc2=O)sc1C(F)(F)F
Temperature: 100 °C
Reaction time: 3 h
Yield: 13 %

Procedure:
A 1,4-dioxane (2.0 mL)-water (0.25 mL) solution of 1-{[4-bromo-5-(trifluoromethyl)thiophen-2-yl]methyl}-4-[4-(4-fluorophenyl)piperazin-1-yl]-1,3,5-triazin-2(1H)-one (50.9 mg, 0.0982 mmol) synthesized in Synthesis Example 154, tetrakis(triphenylphosphine)palladium (0) (11.6 mg, 0.0100 mmol), trimethyl borate (41 μL, 0.295 mmol), and sodium carbonate (20.8 mg, 0.196 mmol) was stirred in nitrogen atmosphere at 100° C. for 3 hours. After the completion of the reaction, to the reaction solution, water was added and a deposited solid was smeared on silica gel. The resultant mixture was eluted with ethyl acetate and the resultant eluate was concentrated under reduced pressure. The resultant solid was purified by silica gel column chromatography to obtain the title compound (5.82 mg, yield: 13%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([O:16][Si](C(C)(C)C)(C)C)[CH2:13][CH:12]1[C:24]([C:26]1[C:34]2[C:29](=[CH:30][C:31]([F:35])=[CH:32][CH:33]=2)[NH:28][CH:27]=1)=[O:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([OH:16])[CH2:13][CH:12]1[C:24]([C:26]1[C:34]2[C:29](=[CH:30][C:31]([F:35])=[CH:32][CH:33]=2)[NH:28][CH:27]=1)=[O:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CC(C(=O)c2c[nH]c3cc(F)ccc23)N(C(=O)OCc2ccccc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(c1c[nH]c2cc(F)ccc12)C1CC(O)CN1C(=O)OCc1ccccc1
Reaction time: 9 h
Yield: 24.6 %

Procedure:
To a solution containing 3 (227 g) in THF (600 mL) was added 1 M TBAF in THF (160 mL) at ambient temperature. After 9 h, another 20 mL of the 1 M TBAF/THF solution was added. After ca. 48 h, the reaction mixture was concentrated in vacuo and then redissolved in EtOAc (600 mL). The organic solution was washed with water (310 mL) and the product precipitated to form a thick suspension which was filtered (slow). The solids were washed with EtOAc (165 mL in portions) and dried to provide 43 g of 4. The combined filtrate was concentrated in vacuo to precipitate an additional 4.8 g of 4 after drying. 1H NMR (300 MHz, d6-DMSO), mixture of rotomers: δ12.08 (br s, 1H), 8.43 (d, J=10.5 Hz, 1H), 8.16 (ddd, J=5.4, 8.7, 14.1 Hz, 1H), 7.36-7.31 (m, 2H), 7.27 (app. d, J=10.2 Hz, 1H), 7.09-6.93 (m, 4H), 5.24 (dt, J=8.1, 15.6 Hz, 1H), 5.14 (br s, 1H), 5.04 (app. d, J=6.4 Hz, 1H), 4.90 (app. dd, J=13.4, 28.4 Hz, 1H), 4.30 (br s, 1H), 3.58-3.43 (m, 2H), 2.27 (m, 1H), 1.93 (m, 1H) ppm; 13C NMR (75 MHz, d6-DMSO), mixture of rotomers: δ194.0, 193.6, 159.9 (d, JCF=235.2 Hz), 154.6 (d, JCF=9.6 Hz), 138.1, 137.5 (d, JCF=26.9 Hz), 136.0, 129.0, 128.5, 128.1 (d, JCF=40.0 Hz), 123.4, 123.3, 123.0, 122.9, 114.4 (d, JCF=11.7 Hz), 110.6 (d, JCF=23.7 Hz), 99.3 (d, JCF=25.2 Hz), 69.5, 68.8, 66.4, 66.3, 61.4, 61.1, 56.2, 55.7 ppm. Mass spectrum (ESI), m/z 382.6 [(M)+; calcd for C21H19FN2O4: 382.3].
Reaction SMILES: [Li]CCCC.[CH2:6]([N:13]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:27][CH:28]([CH3:32])[C:29](Cl)=[O:30]>C1COCC1>[CH2:20]([N:13]([CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C@H:14]([C:29](=[O:30])[CH:28]([CH3:32])[CH3:27])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)CN(Cc1ccccc1)Cc1ccccc1
Reactant: CC(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](C(=O)C(C)C)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 116.1 %

Procedure:
In a round bottomed flask, at −78° C., under argon atmosphere, a solution of DIPA (1.6 ml, 9.3 mmol) in dry THF (40 ml) was treated with n-BuLi (2.5 M in n-hexane, 3.4 ml, 8.5 mmol). After 30 min a solution of ethyl 2-(dibenzylamino)-acetate [prepared as described in Example 47, step 1] (2.2 g, 7.8 mmol) in dry THF (40 ml) was added dropwise via cannula. After 15 min, 2-methyl-propanoyl chloride (2.4 mL, 23.3 mmol) was added dropwise at −78° C. and the mixture stirred for 10 min at rt. The reaction was then quenched with H2O, and Et2O was subsequently added. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give a crude product, as an oil. Purification by column chromatography using a Teledyne ISCO apparatus, eluting with Cy:AcOEt (98:2) gave a crude compound (3.2 g) as a mixture of two tautomers (ketone:enol=ca. 65:35), as a colorless oil, which was used without further purification in the following step. Ketone isomer: MS (ESI) m/z: 354 [M−H]+; (ESI) m/z: 352 [M−H]−. 1H NMR (DMSO-d6) δ 0.86 (d, J=6.73 Hz, 3H), 0.91 (d, J=7.01 Hz, 3H), 1.22 (t, J=7.11 Hz, 3H), 2.99 (hept, J=6.90 Hz, 1H), 3.78 (d, J=14.11 Hz, 2H), 3.84 (d, J=14.13 Hz, 2H), 4.10-4.24 (m, 2H), 4.29 (s, 1H), 7.17-7.48 (m, 10H). Enol isomer: MS (ESI) m/z: 354 [M−H]+; (ESI) m/z: 352 [M−H]−. 1H NMR (DMSO-d6) δ 0.48 (s, 3H), 0.50 (s, 3H), 1.43 (t, J=7.09 Hz, 3H), 3.16-3.28 (m, 1H), 3.90 (d, J=12.66 Hz, 2H), 3.96 (d, J=12.66 Hz, 2H), 4.38 (q, J=7.08 Hz, 2H), 7.10-7.46 (m, 10H), 12.32 (s, 1H).
Reaction SMILES: S1CCNC1.NO.[C:8]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:13]=[CH:12][C:11]([S:14]([N:17]2[CH2:21][CH2:20][S:19][CH:18]2[C:22]([NH:24][CH:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:26][CH2:27][OH:28])=[O:23])(=[O:16])=[O:15])=[CH:10][CH:9]=1.[C:41]1(O)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:8]1([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:13]=[CH:12][C:11]([S:14]([N:17]2[CH2:21][CH2:20][S:19][CH:18]2[C:22]([NH:24][CH:25]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:26][CH2:27][O:28][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:23])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: Oc1ccccc1
Reactant: O=C(NC(CCO)c1ccccc1)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1
Agent: C1CSCN1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: NO
Solvent: C1CCOC1
Product: O=C(NC(CCOc1ccccc1)c1ccccc1)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 40 %

Procedure:
Thiazolidine intermediates of general structure (XXVI), e.g., 3-([1,1′-biphenyl]-4-ylsulfonyl)-N-(3-hydroxy-1-phenylpropyl)-1,3-thiazolidine-2-carboxamide (1.0 g, 1.0 eq, 2.07 mmol) was dissolved in 20 ml dry THF under nitrogen. Phenol (252 mg, 1.5 eq, 2.69 mmol), diethylazodicarboxylate (470 mg, 1.5 eq, 2.69 mmol) and triphenyl phosphine polymer bound (1.0 g, 1.5 eq, 2.70 mmol) were then added and the reaction mixture was shaken for 12 hours at RT. Triphenyl phosphine resin was filtered off and the THF solution evaporated in vacuo. The residue was taken up in DCM and washed twice with saturated sodium carbonate solution and then water. The organic layer was dried with magnesium sulfate and concentrated in vacuo to give a crude product which was purified on silica gel using cyclohexane/ethyl acetate(8/2) as eluent, affording the desired products of general structure (XXVII), e.g., 3-([1,1′-biphenyl]-4-ylsulfonyl)-N-[3-phenoxy-1-phenylpropyl]-1,3-thiazolidine-2-carboxamide as a white oil in 40% yield and 95.5% purity by HPLC.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][CH2:21]Br)[C:9]=2[C:10]=1[CH:11]1[CH2:13][CH2:12]1)=[O:5])[CH3:2].[NH2:23][CH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1>C(O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][CH2:21][NH:23][CH2:24][C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[C:9]=2[C:10]=1[CH:11]1[CH2:13][CH2:12]1)=[O:5])[CH3:2]
Reactant: NCc1cccnc1
Reactant: CCOC(=O)c1oc2cccc(OCCCBr)c2c1C1CC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1oc2cccc(OCCCNCc3cccnc3)c2c1C1CC1
Temperature: 70 °C

Procedure:
To a solution of 4-(3-bromo-propoxy)-3-cyclopropyl-benzofuran-2-carboxylic acid ethyl ester (92 mg) in ethanol (4 ml) was added 3-aminomethylpyridine (500 μl) and heated at 70° C. overnight. The mixture was diluted with ethyl acetate (10 ml) and washed with saturated aqueous ammonium chloride solution (5 ml) and water (5 ml), then dried over anhydrous sodium sulfate, concentrated in vacuo to dryness. The residue was purified by silica gel column chromatography developed by dichloromethane-methanol to give 3-cyclopropyl-4-{3-[(pyridin-3-ylmethyl)-amino]-propoxy}-benzofuran-2-carboxylic acid ethyl ester as a pale yellow oil (108 mg). ESI-MS: m/z 395 (MH+); 1H-NMR (CDCl3): δ 0.95-1.08 (4H, m), 1.44 (3H, t, J=7.3 Hz), 2.10 (2H, quintet, J=6.3 Hz), 2.54-2.60 (1H, m), 2.89 (2H, t, J=6.3 Hz), 3.85 (2H, s), 4.17 (2H, t, J=6.3 Hz), 4.45 (2H, q, J=7.3 Hz), 6.63 (1H, d, J=7.9 Hz), 7.13 (1H, d, J=7.9 Hz), 7.21-7.34 (2H, m), 7.68 (1H, d, J=7.9 Hz), 8.48 (1H, dd, J=1.7 Hz, 4.9 Hz), 8.56 (1H, d, J=1.7 Hz).
Reaction SMILES: [OH:1][C@H:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][NH:4][C:5]([C:7]1[N:8]=[N:9][C:10](Cl)=[CH:11][CH:12]=1)=[O:6].[N:20]1([C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:36])[F:35])=[O:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[OH:1][C@H:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][NH:4][C:5]([C:7]1[N:8]=[N:9][C:10]([N:23]2[CH2:24][CH2:25][N:20]([C:26](=[O:27])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:35])[F:36])[CH2:21][CH2:22]2)=[CH:11][CH:12]=1)=[O:6]
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Reactant: O=C(NC[C@H](O)c1ccccc1)c1ccc(Cl)nn1
Product: O=C(NC[C@H](O)c1ccccc1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use (R)-6-chloropyridazine-3-carboxylic acid (2-hydroxy-2-phenylethyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white powder (64.5% yield). 1H NMR (500 MHz, CDCl3) δ 8.28, 8.05, 7.76, 7.64, 7.58, 7.44-7.32, 7.29, 7.00, 4.96, 4.08, 3.92-3.68, 3.61, 3.36.