Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:3]=1[CH2:4][O:5][CH2:6][C@@H:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][NH:8]1.ClC1C=C(Cl)C=C(Cl)C=1[O:47][S:48](=O)(=[O:50])[NH2:49].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:3]=1[CH2:4][O:5][CH2:6][C@@H:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:9][N:8]1[S:48]([NH2:49])(=[O:50])=[O:47]
Reactant: Fc1cc(F)c(COC[C@@H]2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2)cc1F
Reactant: NS(=O)(=O)Oc1c(Cl)cc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NS(=O)(=O)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1COCc1cc(F)c(F)cc1F
Yield: 43.8 %

Procedure:
A solution of 567 mg (1.09 mmol) (2S,4R)-2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidine, 302 mg (1.09 mmol) sulfamic acid 2,4,6-trichloro-phenyl ester [Hedayatullah, M. & Hugueny, J. Phosphorus, Sulfur Silicon Relat. Elem. (1991), 61(1–2), 19–25.] and 0.15 ml triethylamine in 2 ml CH2Cl2 was heated for 1 h at reflux, evaporated and purified by flash column chromatography on silica gel with hexane/EtOAc (9:1 to 1:1) to give 286 mg (44%) (2S,4R)-2-(2,4,5-Trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidine-1-sulfonic acid amide. [Hedayatullah, M. & Hugueny, J. Phosphorus Sulfur (1985), 25(1), 33-8.] MS: 621 (M+Na+).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][C:8]2[O:12][C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=3)=[N:10][N:9]=2)=[CH:4][CH:3]=1.Cl[C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26]>N1C=CC=CC=1>[Cl:21][C:16]1[CH:15]=[C:14]([NH:13][C:11]2[O:12][C:8]([CH2:7][O:6][C:5]3[CH:22]=[CH:23][C:2]([NH:1][C:25](=[O:26])[O:27][CH:28]([CH3:30])[CH3:29])=[CH:3][CH:4]=3)=[N:9][N:10]=2)[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: CC(C)OC(=O)Cl
Reactant: Nc1ccc(OCc2nnc(Nc3ccc(Cl)c(Cl)c3)o2)cc1
Solvent: c1ccncc1
Product: CC(C)OC(=O)Nc1ccc(OCc2nnc(Nc3ccc(Cl)c(Cl)c3)o2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.5 %

Procedure:
To a stirred solution of 5-((4-aminophenoxy)methyl)-N-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-amine (130 mg, 0.370 mmol) in pyridine (1 mL) at 0° C., isopropyl chloroformate (1 M solution in toluene, 0.370 mL, 0.370 mmol) was added and the reaction was stirred at room temperature overnight. Solvent was removed under vacuum. The residue was filtered and purified by preparative HPLC to obtain isopropyl (4-((5-((3,4-dichlorophenyl)amino)-1,3,4-oxadiazol-2-yl)methoxy)phenyl)carbamate (0.03 g, 14%). 1H NMR: 400 MHZ, DMSO-d6: δ 1.24 (d, J=6.00 Hz, 6H), 4.87 (t, J=6.40 Hz, 1H), 5.26 (s, 2H), 6.99 (dd, J=2.40, 6.80 Hz, 2H), 7.39 (d, J=8.80 Hz, 1H), 7.47 (dd, J=2.80, 9.00 Hz, 1H), 7.61 (d, J=8.80 Hz, 1H), 7.88 (d, J=2.80 Hz, 1H), 9.40 (s, 1H), 11.00 (s, 1H). LCMS: RT 2.11 min. LCMS (ES-API), m/z 439.0 (M+H).
Reaction SMILES: C[N:2](C)[CH:3]=[N:4][C:5]([C:7]1[CH:8]=[C:9]2[N:15]([N:16]=1)[C:14]1[CH:17]=[C:18]([Br:21])[CH:19]=[CH:20][C:13]=1[O:12][CH2:11][CH2:10]2)=O.Cl.[CH:24]([NH:27]N)([CH3:26])[CH3:25]>C(O)(=O)C>[Br:21][C:18]1[CH:19]=[CH:20][C:13]2[O:12][CH2:11][CH2:10][C:9]3[N:15]([N:16]=[C:7]([C:5]4[N:27]([CH:24]([CH3:26])[CH3:25])[N:2]=[CH:3][N:4]=4)[CH:8]=3)[C:14]=2[CH:17]=1
Reactant: CC(C)NN
Reactant: CN(C)C=NC(=O)c1cc2n(n1)-c1cc(Br)ccc1OCC2
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(Br)ccc1OCC2
Temperature: 110 °C
Yield: 75.6 %

Procedure:
A mixture of 9-bromo-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-2-carboxylic acid 1-dimethylaminomethylideneamide (1.27 g, 3.5 mmol), isopropylhydrazine hydrochloride (0.48 g, 4.37 mmol) and glacial acetic acid (6 mL) was heated at 110° C. for 6.5 h, then cooled and concentrated in vacuo. The resultant residue was dissolved in aqueous sodium bicarbonate and DCM and the phases were separated. The aqueous phase was extracted several times with DCM, the combined organic extracts dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 30 to 70% ethyl acetate in cyclohexane) to give 9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene (0.99 g, 76%). LCMS: RT=5.07 min, M+H+=374/376. 1H NMR δ (ppm)(CDCl3): 8.07 (1 H, d, J=2.41 Hz), 7.96 (1 H, s), 7.39 (1 H, dd, J=8.63, 2.43 Hz), 7.08 (1 H, d, J=8.63 Hz), 6.91 (1 H, s), 5.73-5.65 (1 H, m), 4.53 (2 H, t, J=5.91 Hz), 3.18 (2 H, t, J=5.91 Hz), 1.60 (6 H, d, J=6.62 Hz)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].[NH:34]1[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36][CH2:35]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([N:34]2[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36][CH2:35]2)=[O:32])[C:25]=1[CH3:33])(=[O:11])=[O:12]
Reactant: Cc1cccc(C)c1CS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c(C)c(C(=O)O)c1C)C(=O)N2
Reactant: OC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1CS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c(C)c(C(=O)N3CCC(O)CC3)c1C)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-[5-(2,6-dimethyl-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (120 mg, 0.26 mmol), piperidin-4-ol (1.2 eq.), HOBt (1.21 eq.), EDAC.HCl (1.2 eq.) and TEA (3 eq.) in DMF (0.2 M) was stirred at rt for overnight. The reaction was concentrated, diluted with DCM, washed with water, dried and concentrated. The residue was triturated with ethyl ether to give the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:33])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][N:14]([C:25]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[O:26])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.Br[C:35]1[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][N:36]=1.CCN(C(C)C)C(C)C>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:33])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][N:14]([C:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:35]4[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][N:36]=4)[CH2:29][CH2:28]3)=[O:26])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCNCC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(c3ccc(C(F)(F)F)cn3)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 80 °C

Procedure:
A mixture of 100 mg (0.2 mmol) [(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester (example 265, c), 68 mg (0.3 mmol) 2-bromo-5-(trifluoromethyl)pyridine and 131 mg (1 mmol) DIPEA in 8 mL acetonitrile was heated to 80° C. for 18 h. The mixture was evaporated and the residue subjected to column chromatography on silica eluting with a gradient formed from ethyl acetate and heptane to yield after evaporation of the product containing fractions 70 mg (54%) of the title compounds as white foam. MS m/e: 639.1 [M+H]F.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[N:13][C:12]=2[CH3:21])[CH:5]=[CH:6][C:7]=1[Cl:8].[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1>>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[N:13][C:12]=2[CH3:21])=[CH:3][C:2]=1[NH:1][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][C:24]([F:23])=[CH:25][CH:26]=1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(N)c1
Reactant: O=C(O)c1ccc(F)cc1
Product: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(NC(=O)c2ccc(F)cc2)c1

Procedure:
N-(3-amino-4-chlorophenyl)-2-methyl-6-(trifluoromethyl)nicotinamide (0.15 mmol) was used in general procedure 2 with 4-fluorobenzoic acid (0.167 mmol). The product was purified by RP-HPLC to give N-(4-chloro-3-(4-fluorobenzamido)phenyl)-2-methyl-6-(trifluoromethyl)-nicotinamide. MS (Q1) 452.0 (M)+
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5](=[C:12]1[CH:17]2[CH2:18][CH:14]3[CH:15]([CH2:16]2)[CH:13]13)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20]>C1C=CC=CC=1>[CH2:19]([N:21]([CH2:22][CH3:23])[CH2:2][CH2:3][O:4][C:5](=[C:12]1[CH:17]2[CH2:18][CH:14]3[CH:15]([CH2:16]2)[CH:13]13)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:20]
Reactant: CCNCC
Reactant: ClCCOC(=C1C2CC3C(C2)C13)c1ccccc1
Solvent: c1ccccc1
Product: CCN(CC)CCOC(=C1C2CC3C(C2)C13)c1ccccc1

Procedure:
A solution of 14 g. (53.6 mMol) of β-chloroethyl-{α-[tricyclo-(2.2.1.02.6)hept-3-ylidene]-benzyl}-ether and 20 g. (0.273 mol) of diethyl amine in 130 ml. of benzene was heated for 5 hours to 140° C. in a 0.5 liter autoclave. After cooling, the diethyl amine hydrochloride was filtered off under suction, benzene and diethyl amine distilled off in vacuo and the residue left subjected to acid-alkaline working up. The basic fraction was fractionated in vacuo.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH3:31])[C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[CH:16][C:10]=2[CH2:9]1)C1C=CC=CC=1>CO.O1CCCC1.[OH-].[OH-].[Pd+2]>[CH3:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([C:15]2[N:14]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH3:31])[C:11]3[CH2:12][CH2:13][NH:8][CH2:9][C:10]=3[CH:16]=2)=[CH:22][CH:21]=1
Reactant: COc1ccc(-c2cc3c(n2-c2ccccc2C)CCN(Cc2ccccc2)C3)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-c2cc3c(n2-c2ccccc2C)CCNC3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
5-Benzyl-2-(4-methoxyphenyl)-1-(2-methylphenyl)4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine (5.6 g, 14 mmol; prepared by methods as described in Example 1) was added to a suspension of palladium hydroxide on carbon (20%, 1.52 g, 2 mmol) in dry methanol (130 mL) and tetrahydrofuran (100 mL) under argon. The mixture was degassed by vacuum, and purged by argon several times. Then, the flask was fitted with a balloon containing hydrogen gas, and the mixture was stirred under H2 at rt overnight. The reaction mixture was filtered through Celite, and the filtrate evaporated to provide the product (4.3 g, 98%). LC-MS m/z (MH+) 409.2, retention time 2.30 min (method 2).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([CH:15]=[C:16](Br)Br)[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.CN1C(=O)N(C)CCC1.Br[CH2:35][CH2:36][O:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][O:39]1.[NH4+].[Cl-]>C1COCC1>[C:1]([O:5][C:6](=[O:19])[N:7]([CH3:8])[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]#[C:16][CH2:35][CH2:36][O:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][O:39]2)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: BrCCOC1CCCCO1
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C=C(Br)Br)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C#CCCOC2CCCCO2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 10.0 g (25.2 mmol) of trans-[4-(2,2-Dibromo-vinyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester in 400 ml THF was treated at −78° C. with 33.0 ml (68.3 mmol) of BuLi (ca 1.6 M in hexane) and stirred for 2 h, then 27.8 ml (230.4 mmol) of DMPU were added and 10 min later 19.0 ml (125.9 mmol) of 2-(2-bromoethoxy)tetrahydro-2H-pyran dissolved in 20 ml were dropped in during 20 min. The reaction was warmed up to RT and stirred over night (approx. 16 h). An aqueous solution of saturated NH4Cl was added and the mixture was extracted with Et2O (3×). The organic phase was washed with H2O (2×), aqueous 10% NaCl and dried with Na2SO4, filtered and evaporated to give after flash column chromatography on silica gel (hexane/EtOAc 19:1 to 3:1) 3.5 g (38%) of trans-Methyl-{4-[4-(tetrahydro-pyran-2-yloxy)-but-1-ynyl]-cyclohexyl}-carbamic acid tert-butyl ester, MS: 366 (MH+).
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH2:3][C:4]([C:6]1[S:7][CH:8]=[CH:9][C:10]=1[C:11](O)=[O:12])=O.[CH3:15][NH:16][NH2:17]>C(O)C.C(OCC)(=O)C>[CH3:15][N:16]1[C:11](=[O:12])[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[C:4]([CH2:3][CH:2]([CH3:14])[CH3:1])=[N:17]1
Reactant: CNN
Reactant: CC(C)CC(=O)c1sccc1C(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)Cc1nn(C)c(=O)c2ccsc12

Procedure:
2-(3-Methyl-1-oxobutyl)thiophene-3-carboxylic acid (5.3 g) prepared in a) above was dissolved in ethanol (30 ml) and methylhydrazine (1.5 ml) added. The resultant mixture was heated to reflux for 10 hours. The reaction mixture was evaporated and the residue obtained was dissolved in ethyl acetate. The organic phase was washed twice with dilute hydrochloric acid, twice with saturated sodium hydrogen carbonate solution and once with brine, then dried and evaporated. Purification by chromatography eluting with iso-hexane/ethyl acetate (2:1 to 1:1) gave the sub-title compound as an oil (3.05 g).
Reaction SMILES: [N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=3)[N:9]=[C:8]2[CH:23]2[CH2:28][CH2:27][N:26]([C:29]3[N:34]=[CH:33][N:32]=[C:31]([NH2:35])[C:30]=3Br)[CH2:25][CH2:24]2)[CH2:4][CH2:3][CH2:2]1.C(OC([N:44]1[CH:48]=[C:47](B2OC(C)(C)C(C)(C)O2)[CH:46]=[N:45]1)=O)(C)(C)C>>[N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=3)[N:9]=[C:8]2[CH:23]2[CH2:28][CH2:27][N:26]([C:29]3[N:34]=[CH:33][N:32]=[C:31]([NH2:35])[C:30]=3[C:47]3[CH:48]=[N:44][NH:45][CH:46]=3)[CH2:25][CH2:24]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Nc1ncnc(N2CCC(c3nc(-c4ccc(F)c(C(F)(F)F)c4)cn3CCN3CCC3)CC2)c1Br
Product: Nc1ncnc(N2CCC(c3nc(-c4ccc(F)c(C(F)(F)F)c4)cn3CCN3CCC3)CC2)c1-c1cn[nH]c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
A mixture of 6-{4-[1-(2-Azetidin-1-yl-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-bromo-pyrimidin-4-ylamine (100.00 mg; 0.18 mmol; 1.00 eq.), 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazole-1-carboxylic acid tert-butyl ester (77.63 mg; 0.26 mmol; 1.50 eq.), and in dioxane 2 ml and water 0.15 ml was degas, added Pd(t-Bu3)2 13 mg, stirred at 50° C. for overnight. Added methanol 5 ml, 4.0M HCl in dioxane 5 ml, stirred at RT for 4 hr, removed off solvent and purified by prep HPLC, collected title compound 15 mg, yield 12.7%. LC-MS: (M+1=556, obsd.=556).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:13])[C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[N+:14]([O-])([OH:16])=[O:15]>S(=O)(=O)(O)O>[N+:14]([C:8]1[CH:7]=[C:6]([CH:9]([CH3:13])[C:10]([OH:12])=[O:11])[CH:5]=[CH:4][C:3]=1[O:2][CH3:1])([O-:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(C(C)C(=O)O)cc1
Agent: O=S(=O)(O)O
Product: COc1ccc(C(C)C(=O)O)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 6 h

Procedure:
5.23g of 2-(4-methoxyphenyl)propionic acid was added gradually under cooling in a mixture of 27.5g of nitric acid and 19.9g of sulfuric acid. After the mixture was stirred at -10° C to -5° C for 6 hours, the mixture was poured into ice-water. The thus obtained oily substance was extracted with ethyl acetate. The extract was dried over magnesium sulfate and distilled off. The residue was purified by means of silica gel chromatography to give the object compound having m.p. 89° - 90° C in a yield of 5.0g (76%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[Cl:11][C:12]1[CH:19]=[C:16]([CH:17]=O)[C:15]([OH:20])=[CH:14][CH:13]=1>C(O)C>[OH:20][C:15]1[CH:14]=[CH:13][C:12]([Cl:11])=[CH:19][C:16]=1[CH:17]=[N:10][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([Cl:8])=[CH:6][C:5]=1[N:9]=[CH:17][C:16]1[CH:19]=[C:12]([Cl:11])[CH:13]=[CH:14][C:15]=1[OH:20]
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: O=Cc1cc(Cl)ccc1O
Solvent: CCO
Product: Oc1ccc(Cl)cc1C=Nc1cc(Cl)c(Cl)cc1N=Cc1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 144 h

Procedure:
A slurry of 177.0 g (1.0 mole) of 4,5-dichloro-o-phenylenediamine in 750 ml. ethanol was added to a warm near solution of 313.1 g (2.0 mole) of 5-chlorosalicylaldehyde in 2250 ml. of ethanol with mechanical stirring in a 5000 ml, 3-neck flask. A brown solution formed, and a light brown solid began to precipitate after 10-15 minutes. Stirring at room temperature was continued for six days. Thin-layer chromatography indicated that the reaction was substantially complete at the end of six days.
Reaction SMILES: [H-].[Na+].[N:3]1[C:8]2[S:9][C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[NH:12][C:13](=[O:14])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH2:19](I)[CH3:20].O>CN(C)C=O>[CH2:19]([N:12]1[C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[S:9][C:8]2[N:3]=[CH:4][CH:5]=[CH:6][C:7]=2[C:13]1=[O:14])[CH3:20]
Reactant: CCI
Reactant: O=C1Nc2ccccc2Sc2ncccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1C(=O)c2cccnc2Sc2ccccc21
Temperature: 50 °C

Procedure:
Sodium hydride (1.05 g of a 50% suspension in mineral oil) was added to a suspension of pyrido[2,3-b][1,5]benzothiazepin-5(6H)-one (4.0 g, 0.0175 mol) in 100 ml of dimethylformamide and the resulting mixture stirred until the evolution of gas stopped, at which time the mixture was heated to 50° C. for 30 min. After cooling to room temperature, ethyl iodide (5.46 g, 0.035 mol) was slowly added and the reaction mixture allowed to stir for 2 hours. Crushed ice was added to decompose unreacted sodium hydride. Water was then added and the product was extracted with ether, dried (anhydrous sodium sulfate) and concentrated in vacuo. After washing the solid residue with hexane, it was recrystallized from ethyl acetate/hexane to give 0.66 g (14% of theory) of product as yellow crystals, m.p. 148°-149° C.
Reaction SMILES: [CH2:1](O)[C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].P(Br)(Br)[Br:17]>CCOCC.N1C=CC=CC=1>[Br:17][CH2:1][C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCC/C=C\CCCCC#CCO
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCCC/C=C\CCCCC#CCBr
Yield: 219.3 %

Procedure:
By the procedure of example 14, 3.82 g (18.34 mmol) of (Z)-8-tetradecen-2-yn-1-ol, 72 mg of dry pyridine, and 1.66 g (6.12 mmol) of phosphorous tribromide were reacted in 20 ml of ether under reflux for 2.0 h. It was worked up as described in example 14 to give 3.83 g of crude product. It was purified by evaporative distillation at 105° C.-120° C./0.25 mm to yield 3.64 g (73% by weight yield) of (Z)-1-bromo-8-tetradecen-2-yne as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][N:11]([C:22](=[O:23])[C:21]3[CH:25]=[CH:26][C:18]([Cl:17])=[CH:19][CH:20]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Product: O=C(c1ccc(Cl)cc1)N1CCC(CCO)(c2ccc(Cl)c(Cl)c2)C1

Procedure:
Prepare by the method of example 3.1 using 2-[3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (2 mmol) and 4-chlorobenzoyl chloride (2 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [OH:1][OH:2].[C:3]1(=[O:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>O>[CH2:6]1[CH2:7][CH2:8][C:3]([O:1][O:2][C:3]2([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)([OH:9])[CH2:4][CH2:5]1
Reactant: O=C1CCCCC1
Reactant: OO
Solvent: O
Product: OC1(OOC2(O)CCCCC2)CCCCC1
Reaction time: 8 h

Procedure:
In a 200 ml, 3-neck round-bottom flask equipped with a magnetic stirring bar, two addition funnels, and a thermometer, was placed 20.45 ml. of 30% hydrogen peroxide. One addition funnel was charged with 41.3 ml. of distilled cyclohexanone and the other with 82.6 ml of water. The contents of the two addition funnels were discharged gradually and constantly into the stirred round-bottom flask whose contents were kept at a constant temperature of about 25°-26° C. No exothermicity was noted. After both addition funnels were emptied into the round-bottom flask stirring was continued overnight.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].Br[C:7]([CH3:28])([CH3:27])[C:8]([NH:10][C:11]1[O:15][N:14]=[C:13]([C:16]([CH3:26])([CH3:25])[CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH:12]=1)=[O:9].C(OCC)C>CN(C=O)C>[CH3:26][C:16]([C:13]1[CH:12]=[C:11]([NH:10][C:8]([C:7]([S:3][C:1](=[O:4])[CH3:2])([CH3:28])[CH3:27])=[O:9])[O:15][N:14]=1)([CH3:25])[CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1
Reactant: CC(C)(Br)C(=O)Nc1cc(C(C)(C)COC2CCCCO2)no1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(=O)SC(C)(C)C(=O)Nc1cc(C(C)(C)COC2CCCCO2)no1
Temperature: 25 °C
Reaction time: 12 h
Yield: 58.6 %

Procedure:
Potassium thioacetate (6.6 g, 58.0 mmol) is added at 0° C. to a solution of 2-bromo-N-{3-[1,1-dimethyl-2-(tetrahydro-pyran-2-yloxy)-ethyl]-isoxazol-5-yl}-2-methyl-propionamide (15.0 g, 38.6 mmol) in DMF (150 mL). After stirring the reaction mixture at room temperature for 12 h, ice water and diethyl ether are added. The two phases are separated, the organic layer is washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the crude product that is purified by silica gel chromatography to afford 8.7 g of thioacetic acid S-(1-{3-[1,1-dimethyl-2-(tetrahydro-pyran-2-yloxy)-ethyl]-isoxazol-5-ylcarbamoyl}-1-methyl-ethyl) ester as a pale yellow solid. Yield: 58%; m/z 383 [M−H]; 1H NMR (250 MHz, CHLOROFORM-d) δ ppm 1.35 (6H, d, J=8.07 Hz), 1.45-1.88 (12H, m), 2.37 (3H, s), 3.30-3.58 (2H, m), 3.69-3.87 (2H, m), 4.58 (1H, t), 6.35 (1H, s), 9.44 (1H, br. s.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[C:12]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)(=[O:14])[CH3:13].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[C:12]([N:15]1[CH2:20][CH2:19][N:18]([CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:17][CH2:16]1)(=[O:14])[CH3:13]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(=O)N1CCN(Cc2cccc([N+](=O)[O-])c2)CC1
Reaction time: 8 h

Procedure:
3-Nitrobenzaldehyde (2.04 g, 13.5 mmol) was dissolved in 50 ml 1,2-dichloroethane. 1-Acetylpiperazine 1.90 g, 14.9 mmol) and sodium triacetoxyborohydride (3.15 g, 14.9 mmol) were added followed by the addition of 0.100 ml of acetic acid. The reaction was allowed to proceed overnight (18 hours) and was then quenched with half-saturated NaHCO3 (aq). The mixture was extracted 3× with DCM and the organic extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (eluting with 95:5 DCM/MeOH) to afford 1-acetyl-4-(3-nitrobenzyl)piperazine (5-2). 1H NMR (300 MHz, CDCl3) δ 8.22 (s, 1H), 8.13 (dd, J=1.2, 8.3 Hz, 1H), 7.66 (d, J=7.6 Hz, 1H), 7.50 (t, J=7.9 Hz, 1H), 3.63 (t, J=5.2 Hz, 2H), 3.61 (s, 2H), 3.48 (t, J=4.8 Hz, 2H), 2.44 (m, 4H), 2.08 (s, 3H).