Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([C:25]2[CH:29]=[C:28]([C:30](O)=[O:31])[NH:27][N:26]=2)[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:33][C@@H:34]([CH3:50])[CH2:35][N:36]1[CH:40]=[CH:39][C:38]([C:41]2[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[C:43]([Cl:49])[CH:42]=2)=[N:37]1.CN(C=O)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:49][C:43]1[CH:42]=[C:41]([C:38]2[CH:39]=[CH:40][N:36]([CH2:35][C@@H:34]([NH:33][C:30]([C:28]3[NH:27][N:26]=[C:25]([C:23]4[N:22]=[CH:21][N:20]([C:1]([C:8]5[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=5)([C:14]5[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH:24]=4)[CH:29]=3)=[O:31])[CH3:50])[N:37]=2)[CH:48]=[CH:47][C:44]=1[C:45]#[N:46]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1cc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)n[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)n[nH]1
Yield: 128.7 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from 3-(1-trityl-1H-imidazol-4-yl)-1H-pyrazole-5-carboxylic acid (2.493 mmol, 1048 mg) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-benzonitrile (1.918 mmol, 500 mg) using a mixture of DCM (10 ml) and DMF (1 ml) as the solvent. HBTU (0.384 mmol, 145 mg) was used instead of HOBt. The reaction mixture was diluted with DCM and washed with 1 M Na2CO3 and water. The separated organic phase was dried, filtered and evaporated. 1.637 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.12 (d, 3H), 4.17-4.52 (m, 3H), 6.75 (bs., 1H), 6.92 (d, 1H), 7.12-7.19 (m, 7H), 7.35-7.53 (m, 12H), 7.80 (d, 1H), 7.97 (bs, 1H), 8.04 (s, 1H), 8.21 (d, 1H), 13.38 (bs., 1H).
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[N:32]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:18]4[CH:19]=[N:20][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22](=[O:23])[C:17]=4[C:16]=3[CH:41]=O)[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1.[Br-].[CH:44]1([CH2:47][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:46][CH2:45]1>>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[N:32]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:38])[CH3:39])[C:18]4[CH:19]=[N:20][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22](=[O:23])[C:17]=4[C:16]=3[CH:41]=[CH:47][CH:44]3[CH2:46][CH2:45]3)[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:2][CH2:3]1
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(C=O)c(-c3ccc(OC(F)F)c(OC4CC4)c3)n2COCC[Si](C)(C)C)c1=O
Reactant: c1ccc([P+](CC2CC2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Product: C[Si](C)(C)CCOCn1ncc2c(c(C=CC3CC3)c(-c3ccc(OC(F)F)c(OC4CC4)c3)n2COCC[Si](C)(C)C)c1=O
Yield: 71.2 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Example 68-(a) except for using 0.62 g (1.00 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-formyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in the same manner as in Example 15-(a), and using 1.19 g (3.00 mmol) of cyclopropylmethyltriphenylphosphonium bromide in place of butyltriphenylphosphonium bromide, whereby 0.47 g of the title compound was obtained as a colorless oil. (Yield: 71%)
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Cl.[S:13]([O-:16])([O-:15])=[O:14].[Na+:17].[Na+]>O>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][S:13]([O-:16])(=[O:15])=[O:14].[Na+:17]
Reactant: FC(F)(F)c1cccc(CCl)c1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=S(=O)([O-])Cc1cccc(C(F)(F)F)c1
Yield: 90.5 %

Procedure:
A mixture containing 50 g of 3-trifluoromethylbenzyl chloride and 32.4 g of sodium sulfite in 200 ml of water was refluxed for five hours and then concentrated by evaporation. The concentrate was then filtered to collect the precipitate (product). The precipitate was then washed with ethyl ether and then dried in a vacuum oven affording 61 g of sodium 3-trifluoromethylbenzylsulfonate.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[CH:31]=O>>[CH3:20][O:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:31][C:22]2[CH:23]=[CH:24][C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:21]=2)[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1ccc2ccccc2c1
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1ccc2ccccc2c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with commercially available 2-naphthaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.95 min.; [M+H]+: 390.17 g/mol.
Reaction SMILES: [F:1][CH:2]([F:21])[C:3]1[C:8]([C:9]([O:11]CC)=[O:10])=[CH:7][C:6]([CH2:14][NH:15][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])=[CH:5][N:4]=1.O.[OH-].[Li+].Cl>O1CCOCC1>[F:21][CH:2]([F:1])[C:3]1[C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]([CH2:14][NH:15][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])=[CH:5][N:4]=1
Reactant: CCOC(=O)c1cc(CNC(=O)C(C)C)cnc1C(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)C(=O)NCc1cnc(C(F)F)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
Dissolve ethyl 2-(difluoromethyl)-5-{[(2-methylpropanoyl)amino]methyl}pyridine-3-carboxylate (414 g, 1.38 mol, 1.0 equiv) in 1,4-dioxane (4.97 L). Add water (2.48 L) and lithium hydroxide (125.6 g, 2.96 mol, 2.5 equiv); then stir the resulting mixture for 60 min at room temperature. Concentrate the 1,4-dioxane solution to ½ volume under reduced pressure, and add hydrochloric acid (5 N, 1.16 L, 5.79 mol, 4.2 equiv) slowly to maintain temperature at less than 20° C. until the pH is 2. Collect the solids by filtration; air dry for 18 hours; and then in a vacuum oven at 40° C. for 18 hours to give a white solid, (355.4 g, 94.7% yield). MS (m/z) 303 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].C(N(C(C)C)C(C)C)C.[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([I:23])=[CH:18][N:17]=1>C(#N)C>[Cl:15][C:16]1[N:21]=[C:20]([NH:1][CH2:2][CH2:3][CH2:4][OH:5])[C:19]([I:23])=[CH:18][N:17]=1
Reactant: Clc1ncc(I)c(Cl)n1
Reactant: NCCCO
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: OCCCNc1nc(Cl)ncc1I
Yield: 95 %

Procedure:
In analogy to GP 2 reaction of 3-amino-1-propanol (0.38 ml, 5 mmol) in the presence of N-ethyldiisopropylamine (1.74 ml, 10 mmol) in 150 ml acetonitrile with 2,4-dichloro-5-iodo-pyrimidine (1.51, 5.5 mmol) provided the target compound after column chromatography in 95% yield.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([N:11]=[C:12]=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2].[F:27][CH2:28][CH2:29][NH2:30]>CC#N>[C:1]([O:4][C@H:5]1[C@H:10]([NH:11][C:12]([NH:30][CH2:29][CH2:28][F:27])=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N=C=S)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NCCF
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](NC(=S)NCCF)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.9 %

Procedure:
To a stirred solution of (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-isothiocyanato-tetrahydro-2H-pyran-2,4,5-triyl triacetate (0.54 g, 1.39 mmol) in CH3CN, was added neat 2-fluoroethanamine (0.28 g, 2.79 mmol), dropwise. The reaction was stirred at room temperature until complete by TLC (3 h). The reaction was washed with a minimal amount of saturated aqueous NaHCO3 (15 mL). The aqueous layer was then extracted three times with DCM, and the organic layers were combined, dried with MgSO4, filtered and concentrated. The concentrated mixture was purified via flash column chromatography in a solvent system of EtOAc and hexanes (1:1), providing (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-(3-(2-fluoroethyl)thioureido)-tetrahydro-2H-pyran-2,4,5-triyl triacetate (0.358 g, 57% yield). 1H NMR (500 MHz, CDCl3) δ 1.23 (t, 2H, J=7.3 Hz), 2.02 (s, 3H), 2.05 (s, 3H), 2.10 (s, 3H), 2.11 (s, 3H), 3.85-3.88 (m, 2H), 4.07-4.12 (m, 1H), 4.25 (dd, 1H, J=4.6, 12.5 Hz), 4.47-4.53 (m, 1H), 4.54-4.63 (m, 1H), 5.14 (t, 1H, J=9.7 Hz), 5.25 (t, 1H, J=5.4 Hz), 5.73 (d, 1H, J=8.6 Hz), 6.50 (d, 1H, J=9.3 Hz), 6.68 (t, 1H, J=5.4 Hz).
Reaction SMILES: C(OP([CH2:9]/[C:10](/[CH3:17])=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:18]([O:22][C:23]1[CH:32]=[C:31]2[C:26]([C:27]([CH:35]([CH3:37])[CH3:36])=[CH:28][C:29]([CH3:34])([CH3:33])[O:30]2)=[CH:25][C:24]=1/[C:38](/[CH3:43])=[C:39](/[F:42])\[CH:40]=O)[CH2:19][CH2:20][CH3:21]>>[CH2:18]([O:22][C:23]1[CH:32]=[C:31]2[C:26]([C:27]([CH:35]([CH3:36])[CH3:37])=[CH:28][C:29]([CH3:33])([CH3:34])[O:30]2)=[CH:25][C:24]=1/[C:38](/[CH3:43])=[C:39](/[F:42])\[CH:40]=[CH:9]\[C:10](\[CH3:17])=[CH:11]\[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCOc1cc2c(cc1/C(C)=C(/F)C=O)C(C(C)C)=CC(C)(C)O2
Reactant: CCOC(=O)/C=C(\C)CP(=O)(OCC)OCC
Product: CCCCOc1cc2c(cc1/C(C)=C(F)\C=C\C(C)=C\C(=O)OCC)C(C(C)C)=CC(C)(C)O2

Procedure:
Following General Procedure O, ethyl 4-(diethoxyphosphoryl)-3-methyl-but-2E-enoate (183 mg, 0.70 mmol) and (2E)-3-(7-butoxy-4-isopropyl-2,2-dimethyl-2H-chromen-6-yl)-2-fluoro-but-2-enal (Compound 100, 86 mg, 0.24 mmol) were reacted to give the title compound as a yellow oil after purification by flash chromatography (silica gel, 5% ethyl acetate in hexane).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)=[C:4]([CH3:30])[CH:3]=1.[NH2:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34]>C1COCC1>[CH3:35][C:32]([NH:31][C:12]1[N:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[CH3:30])[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[C:10]=2[N:11]=1)([CH3:36])[CH2:33][OH:34]
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccccc1F
Reactant: CC(C)(N)CO
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1-c1nc(NC(C)(C)CO)nc2c1ccc(=O)n2-c1ccccc1F
Reaction time: 72 h

Procedure:
The product of Example 59 (200 mg, 0.47 mmol) and 2-amino-2-methyl-1-propanol (94 mg, 1 mmol) were dissolved in THF (10 ml) and stirred under Ar at 50° for 3 days. The solvents were removed in vacuo, and the residue was partitioned between EtOAc and H2O. The organic phase was washed with H2O, satd aq NaCl, dried over anhyd Na2SO4, filtered and evaporated to give the crude product. Flash chromatography eluted with 0-15% EtOAc/CH2Cl2 gave the title compound as a light-yellow amorphous solid. mp 106-112°, LC MS m/z=437 (MH+) Retention time=1.94 min.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([S:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[CH3:20])=O.[NH2:21][C:22]([NH2:24])=[S:23]>CCO>[CH3:20][C:6]1[CH:7]=[C:8]([S:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:9]=[C:10]([CH3:11])[C:5]=1[C:3]1[N:21]=[C:22]([NH2:24])[S:23][CH:2]=1
Reactant: Cc1ccc(Sc2cc(C)c(C(=O)CBr)c(C)c2)cc1
Reactant: NC(N)=S
Solvent: CCO
Product: Cc1ccc(Sc2cc(C)c(-c3csc(N)n3)c(C)c2)cc1
Yield: 100 %

Procedure:
A reaction mixture containing 2-bromo-1-(2,6-dimethyl-4-(p-tolylthio)phenyl)ethanone (394.8 mg, 1.1 mmol, 1.0 equiv) and thiourea (86.04 mg, 1.1 mmol, 1.0 equiv) in EtOH (10.0 mL) was heated at reflux for 16 h. The solution was concentrated under reduced pressure, and the residue was re-dissolved in EtOAc (50 mL). The solution was washed with saturated aqueous NaHCO3 (30 mL), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (5.0% EtOAc in hexanes as eluant) to provide 4-(2,6-dimethyl-4-(p-tolylthio)phenyl)thiazol-2-amine (371.9 mg, 1.1 mmol) as yellow solids in >99% yield: 1H NMR (DMSO-d6, 500 MHz) δ 7.27 (d, J=8.0 Hz, 2 H), 7.21 (d, J=8.0 Hz, 2 H), 6.97 (s, 2 H), 6.87 (s, 2 H), 6.36 (s, 1 H), 2.30 (s, 3 H), 2.05 (s, 6 H); ESI-MS: m/z 327.0 (M+H)+.
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].[O:7]1[C:11]2([CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1.O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:1]=[C:14]1[CH2:15][CH2:16][C:11]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)[O-]
Reactant: O=C1CCC2(CC1)OCCO2
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
In a reactor under nitrogen atmosphere, 200 mL of THF was added to 41.2 g of methyltriphenylphosphonium bromide, and the mixture was cooled to −20° C., to which 12.9 g of t-BuOK was added, followed by stirring for 1 hour. A solution containing 15.0 g of 1.4-dioxaspiro[4.5]decan-8-one dissolved in 200 mL of THF was added dropwise thereto, followed by stirring at −20° C. for 1 hour. The temperature of the reaction mixture was increased to room temperature, and 200 mL of water was added to the reaction mixture, followed by extracting three times with 300 mL of toluene. The resulting organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was concentrated to about 200 mL under reduced pressure, and the concentrated solution was placed in 1,000 mL of hexane, followed by removing deposited solid matters. The solvent was distilled off from the resulting solution under reduced pressure, and the residue was purified by silica gel column chromatography to provide 10.6 g of 8-methylene-1,4-dioxaspiro[4.5]decane.
Reaction SMILES: F[C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][C:9]2[CH:24]=[CH:23][CH:22]=[CH:21][C:10]=2[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=2)=[O:12])=[O:7])=[C:4]([O:27][CH:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]2)[CH:3]=1.[OH:41][CH:42]1[CH2:47][CH2:46][CH2:45][NH:44][CH2:43]1>>[C:37]([O:36][C:34]([N:31]1[CH2:30][CH2:29][CH:28]([O:27][C:4]2[CH:3]=[C:2]([N:44]3[CH2:45][CH2:46][CH2:47][CH:42]([OH:41])[CH2:43]3)[CH:26]=[CH:25][C:5]=2[C:6]([NH:8][C:9]2[CH:24]=[CH:23][CH:22]=[CH:21][C:10]=2[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=2)=[O:12])=[O:7])[CH2:33][CH2:32]1)=[O:35])([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(F)ccc2C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Reactant: OC1CCCNC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCCC(O)C3)ccc2C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Yield: 34 %

Procedure:
Using methods substantially equivalent to those described in Example 4-F, except that the reaction was quenched with water and the resulting precipitate was collected, 2-[2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(3-hydroxypiperidin-1-yl)-benzoylamino]-N-(5-chloropyridin-2-yl)-benzamide (166 mg, 0.26 mmol, 34%) was prepared from 2-[4-fluoro-2-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)benzamide and 3-hydroxypiperidine.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].S(Cl)([Cl:17])=O>>[CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([Cl:17])=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=S(Cl)Cl
Reactant: CCCCOc1ccc(C(=O)O)cc1
Product: CCCCOc1ccc(C(=O)Cl)cc1

Procedure:
Heated at reflux a solution of 75 g (0.39 mole) of 4-n-butoxybenzoic acid in 250 ml of thionyl chloride for 3 hrs. Removed by vacuum distillation the excess thionyl chloride to give 84 g of a brown colored liquid.
Reaction SMILES: CN(C=O)C.Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[O:12][C@H:11]([CH3:18])[CH2:10]2.Br[Zn][CH2:21][CH:22]1[O:26][CH2:25][CH2:24][O:23]1>CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:23]1[CH2:24][CH2:25][O:26][CH:22]1[CH2:21][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[O:12][C@H:11]([CH3:18])[CH2:10]2
Reactant: C[C@@H]1Cc2cc(Br)ccc2C(=O)O1
Reactant: Br[Zn]CC1OCCO1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H]1Cc2cc(CC3OCCO3)ccc2C(=O)O1
Temperature: 110 °C

Procedure:
A sealed tube was charged with aryl bromide, palladium(II) acetate (0.028 g, 0.124 mmol) and commercially available tri-t-butylphosphine-BF4 complex (0.072 g, 0.25 mmol) and sealed. The tube was evacuated and refilled with nitrogen before DMF (12 ml) and (3R)-6-bromo-3-methyl-3,4-dihydro-1H-isochromen-1-one (0.75 g, 3.1 mmol) were added followed by commercially available bromo(1,3-dioxolan-2-ylmethyl)zinc (6.2 ml, 3.1 mmol). The tube was heated to 110° C. in the microwave for 75 minutes, after which it was cooled, diluted with EtOAc, filtered, concentrated and purified via MPLC (20-50% E/H) to afford (3R)-6-(1,3-dioxolan-2-ylmethyl)-3-methyl-3,4-dihydro-1H-isochromen-1-one.
Reaction SMILES: [OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH3:17])[C:3]=1[C:18](OCC)=[O:19].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:31]=[C:32]([NH2:35])[S:33][CH:34]=2)=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[N:31]=[C:32]([NH:35][C:18]([C:3]3[N:4]([CH3:17])[S:5](=[O:16])(=[O:15])[C:6]4[C:10]5[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=5[S:8][C:7]=4[C:2]=3[OH:1])=[O:19])[S:33][CH:34]=2)=[CH:28][CH:29]=1
Reactant: Nc1nc(-c2ccc(Cl)cc2)cs1
Reactant: CCOC(=O)C1=C(O)c2sc3ccccc3c2S(=O)(=O)N1C
Product: CN1C(C(=O)Nc2nc(-c3ccc(Cl)cc3)cs2)=C(O)c2sc3ccccc3c2S1(=O)=O
Yield: 40 %

Procedure:
Prepared analogous to Example 1 from ethyl 4-hydroxy-2-methyl-2H-[1]-benzothieno [2,3-e]-1,2-thiazine-3-carboxylate-1,1-dioxide and 4-(4-chlorphenyl)-2-thiazolamine with a yield of 40% of theory.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C:11](=[O:13])[N:10]([CH:14]([C:20](OCC)=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])(=[O:35])=[O:34])=[CH:29][C:28]=1[Cl:48]>C1(C)C(C)=CC=CC=1>[Cl:48][C:28]1[CH:29]=[C:30]([S:33]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])(=[O:35])=[O:34])[CH:31]=[CH:32][C:27]=1[NH:26][C:20](=[O:21])[CH:14]([N:10]1[C:11](=[O:13])[CH2:12][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]1=[O:25])[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCCCCCCCCCCCS(=O)(=O)c1ccc(N)c(Cl)c1
Reactant: CCOC(=O)C(C(=O)OCC)N1C(=O)CN(Cc2ccccc2)C1=O
Solvent: Cc1ccccc1C
Product: CCCCCCCCCCCCS(=O)(=O)c1ccc(NC(=O)C(C(=O)OCC)N2C(=O)CN(Cc3ccccc3)C2=O)c(Cl)c1
Temperature: 70 °C

Procedure:
Diethyl 2-(3-benzyl-2,5-dioxo-1,3-diazolidin-1-yl)-malonate (19.3 g, 55.5 mmol) and (4-amino-3-chloro-phenyl)dodecylsulphone (20.0 g,56.0 mmol) were added to xylene (100 ml) and refluxed under Dean and Stark conditions for 80 hr, occasionally removing a small amount of distillate and replenishing the solvent as necessary. The reaction was followed by TLC (1:2 ethyl acetate:60-80° C. petroleum ether), the Rf of the product being between that of the two starting materials. The xylene was removed on the rotary evaporator and the residual yellowish oil stirred with 60-80° C. petroleum ether (100 ml), allowed to settle and decanted from the oil. This removed some front-running impurities. On standing the oil solidified to a crystalline mass which was crystallized from toluene and petrol to give a white solid, 17.0 g, 46%.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].[K+].[Br-]>CCOC(C)=O.CCCCCCC>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:32]3[CH2:31][CH2:30][N:29]([C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])[CH2:34][CH2:33]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)Oc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)CC1
Yield: 59 %

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-tert-butoxycarbonyl-piperazin, yield 59% (recrystallized from EtOAc-heptane 1:1). White crystals, m.p. 165–166° C.; 1H NMR (CDCl3) □ 8.45–8.42 (m, 1H), 7.92–7.87 (m, dd-like, 1H), 7.21–7.12 (AB-system, 4H), 7.03–6.98 (m, d-like, 1H), 3.72–3.45 (br m, 8H), 1.49 (s, 9H); 13C-NMR (CDCl3) □ (ref. CDCl3 77.00 ppm):165.71, 154.56, 153.51, 150.21, 148.34, 145.43 (q, J=4.4 Hz), 136.701 (q, J=3 Hz), 123.65 (q, J=271.5 Hz), 122.86, 122.24, 121.62 (q, J=33 Hz), 11.20, 80.32, 44.38, 43.78, 44.6–42.3 (br), 28.36 ppm; IR (KBr) □ 1722 (C═O), 1691(C═O) cm−1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[Cl:10][C:11]1[C:12]([N:16]=[C:17]=[S:18])=[CH:13][S:14][CH:15]=1>C1COCC1>[NH2:9][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[NH:8][C:17]([NH:16][C:12]1[C:11]([Cl:10])=[CH:15][S:14][CH:13]=1)=[S:18]
Reactant: S=C=Nc1cscc1Cl
Reactant: Nc1ccc(F)cc1N
Solvent: C1CCOC1
Product: Nc1cc(F)ccc1NC(=S)Nc1cscc1Cl
Reaction time: 8 h

Procedure:
4-Fluoro-1,2-phenylendiamine (900 mg) was dissolved in THF (25 ml) and 4-chloro-3-thienylisothiocyanat (example 52c), dissolved in THF (15 ml), was added with stirring. The solution was stirred for about 3 h at room temperature and stood overnight. Then the reaction mixture was concentrated und the residue purified by preparative HPLC. The product containing fractions were combined, the acetonitrile was removed, the aqueous residue made basic and three times extracted with ethyl acetate. The organic layers were combined, dried (MgSO4) and filtered. After removal of the solvent the desired product (625 mg) was obtained.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]=[C:10]([C:14]2([CH3:19])[O:18][CH2:17][CH2:16][O:15]2)[CH2:9]1)C1C=CC=CC=1.Cl[C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22]>C1(C)C=CC=CC=1>[CH2:24]([O:23][C:21]([N:8]1[CH2:13][CH2:12][CH:11]=[C:10]([C:14]2([CH3:19])[O:15][CH2:16][CH2:17][O:18]2)[CH2:9]1)=[O:22])[CH:25]=[CH2:26]
Reactant: C=CCOC(=O)Cl
Reactant: CC1(C2=CCCN(Cc3ccccc3)C2)OCCO1
Solvent: Cc1ccccc1
Product: C=CCOC(=O)N1CCC=C(C2(C)OCCO2)C1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(1-benzyl-1,2,5,6-tetrahydropyridin-3-yl)-2-methyl-1,3-dioxolane (7.8 g) in toluene (70 ml) was added allyl chloroformate (3.9 ml) and the mixture was stirred at 60° C. for 30 minutes. The reaction mixture was then concentrated and the residue was purified by column chromatography to give 2-(1-allyloxycarbonyl-1,2,5,6-tetrahydropyridin-3-yl)-2-methyl-1,3-dioxolane (6.95 g).
Reaction SMILES: [C:1]([N:18](CC(C)C)[CH2:19][C:20]([OH:22])=[O:21])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].S(Cl)(Cl)=O.CN(C=O)C>ClCl>[NH:18]([C:1]([O:3][CH2:4][CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:2])[C@H:19]([C:20]([OH:22])=[O:21])[CH2:4][CH:5]([CH3:17])[CH3:6]
Reactant: CC(C)CN(CC(=O)O)C(=O)OCC1c2ccccc2-c2ccccc21
Agent: ClCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reaction time: 5 h

Procedure:
FMOC-Leu*-Cl was prepared by dissolving FMOC-N-isobutylglycine (150 mg, 0.42 mmol) in CH2 Cl2 (2.8 mL), and adding thionyl chloride (309 μL, 4.2 mmol) and 3 μL DMF (0.04 mmol). The reaction mixture was stirred for 5 hours and concentrated in vacuo, repeatedly dissolving in CH2 Cl2 (3××) to provide FMOC-Leu*-Cl as a colorless oil (146 mg, 92%): IR (cm−1) -1804, 1720, 1715. FMOC-Phe*-Cl was similarly prepared.