Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([CH2:21][CH:22]2[S:26][C:25](=[O:27])[NH:24][C:23]2=[O:28])[CH:18]=[C:17]([Cl:29])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:15][CH3:16])=[C:9]([S:11](Cl)(=[O:13])=[O:12])[CH:10]=1.[CH:30]1([NH2:33])[CH2:32][CH2:31]1.CN1CCOCC1>O1CCCC1>[CH:30]1([NH:33][S:11]([C:9]2[CH:10]=[C:5]([O:4][C:3]3[C:2]([Cl:1])=[CH:20][C:19]([CH2:21][CH:22]4[S:26][C:25](=[O:27])[NH:24][C:23]4=[O:28])=[CH:18][C:17]=3[Cl:29])[CH:6]=[CH:7][C:8]=2[O:15][CH3:16])(=[O:13])=[O:12])[CH2:32][CH2:31]1
Reactant: NC1CC1
Reactant: COc1ccc(Oc2c(Cl)cc(CC3SC(=O)NC3=O)cc2Cl)cc1S(=O)(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1ccc(Oc2c(Cl)cc(CC3SC(=O)NC3=O)cc2Cl)cc1S(=O)(=O)NC1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.7 %

Procedure:
To the title compound of Step E (38 mg, 0.08 mmol) in dry tetrahydrofuran (1 ml) at room temperature was added cyclopropylamine (8.0 mL, 0.12 mmol) and N-methylmorpholine (17 ml, 0.15 mmol). The reaction mixture was stirred at room temperature for two hours, quenched with 1N HCl (15 ml), and extracted with ethyl acetate (3×15 ml). The combined extracts were washed with 1N HCl (2×15 ml), brine (15 ml), dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative TLC (8% methanol in dichloromethane) to afford the title compound (16 mg, 41% yield). MS (APCI+) Calc: 516.0, Found: 516.9 (M+1).
Reaction SMILES: [NH:1]([C:37](OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=[O:38])[C@H:2]([C:10]([NH:12][C@H:13]([C:34]([OH:36])=[O:35])[CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[C:24]1[C:32](=[O:33])[CH2:31][C:28]([CH3:30])([CH3:29])[CH2:27][C:25]1=[O:26])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.N1CCCC[CH2:55]1.N[C@H](C(N[C@H](C(O)=O)CCCCNC(=C1C(=O)CC(C)(C)CC1=O)CC(C)C)=O)CC1C=CC=CC=1.C(OC(=O)C)(=O)C>>[NH:1]([C:37]([CH3:55])=[O:38])[C@H:2]([C:10]([NH:12][C@H:13]([C:34]([OH:36])=[O:35])[CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[C:24]1[C:25](=[O:26])[CH2:27][C:28]([CH3:29])([CH3:30])[CH2:31][C:32]1=[O:33])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)CC(NCCCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)=C1C(=O)CC(C)(C)CC1=O
Reactant: C1CCNCC1
Agent: CC(C)CC(NCCCC[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)O)=C1C(=O)CC(C)(C)CC1=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCCNC(CC(C)C)=C1C(=O)CC(C)(C)CC1=O)C(=O)O

Procedure:
To the deprotected Lys-resin sample was added Fmoc-Phe (8.8 mg, 33.2 μmol) in DCM/DMF and 1,3-diisopropylcarbodiimide (DIC) (3 μL, 20 μmol). The coupling reaction was continued for 2 h and ninhydrin tests gave negative amino group readings. The Fmoc-Phe-Lys(ivDde) on resin was then treated with photogenerated piperidine as described above. Upon completion of the reaction, the resin was washed with DCM/DMF. Capping of the NH2-Phe-Lys(ivDde)-resin was carried out for 1 h with acetic anhydride (470 μL, 5 mmol) and TEA (700 μL, 5 mmol) in 1.5 mL DMW to give Ac-Phe-Lys(ivDde)-resin.
Reaction SMILES: [H-].[Na+].[C:3](=[O:8])([O:6][CH3:7])OC.[Cl:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C:15](=[O:20])[CH2:14][CH2:13]2.C(O)(=O)C>C1(C)C=CC=CC=1.O>[Cl:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16]([C:3]([O:6][CH3:7])=[O:8])=[C:15]([OH:20])[CH2:14][CH2:13]2
Reactant: COC(=O)OC
Reactant: O=C1CCc2cc(Cl)ccc2C1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C1=C(O)CCc2cc(Cl)ccc21
Temperature: 0 °C
Yield: 63.8 %

Procedure:
10.1 g (252 mmol) of 60% sodium hydride in oil, 621 ml of toluene and 14.18 ml (163 mmol) of dimethyl carbonate are introduced into a 2 l reactor. The reaction mixture is stirred at reflux for 1 h. A solution of 15.2 g (84 mmol) of 6-chloro-3,4-dihydro-1H-naphthalen-2-one in 268 ml of toluene is subsequently added. The reaction mixture is heated at reflux for 24 h. The reaction mixture is subsequently cooled to 0° C. and then acidified by addition of 92 ml of acetic acid. 114 ml of water are added and the separated organic phase is separated by settling and washed with three times 150 ml of water and then with 100 ml of a saturated aqueous sodium chloride solution. The organic phase is subsequently dried over magnesium sulphate and then concentrated under reduced pressure. The residue is purified by chromatography on a silica column (elution being carried out with a mixture of cyclohexane and of dichloromethane) to result in 12.8 g (53.6 mmol) of the expected product used as is in the following stage.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])([OH:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.[CH2:19]([S:22](Cl)(=[O:24])=[O:23])[CH2:20][CH3:21]>>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:3]([OH:10])([CH2:2][NH:1][S:22]([CH2:19][CH2:20][CH3:21])(=[O:24])=[O:23])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1
Reactant: NCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: CCCS(=O)(=O)Cl
Product: CCCS(=O)(=O)NCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl

Procedure:
Following the procedure described in example 1 but using 3-amino-2-(2,4-dichlorophenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol and propanesulfonylchloride, the title compound was obtained in a similar yield: mp 128°-129° C.; 1H NMR (80 MHz, CDCl3)δ(TMS) 7.99 (s, 1H, CH=N), 7.83 (s, 1H, CH=N), 7.62 (d, J=8.5 Hz, 1H, arom), 7.4-7.1 (m, 2H, arom), 5.00 (AB system, Δv=0.56, J=14.5 Hz, 2H, CH2 -Tr), 4.91 (m, 1H, NH, 4.1-3.5 (m, 2H, CH2NH), 3.1-2.8 (m, 2H, CH2S), 2.1-1.5 (m, 2H, CH2CH2S), 1.00 (t, J=7.5 Hz, 3H, Me). Anal calcd. for C14H18Cl2N4O3S: C 42.76%; H 4.61%; N 14.25%. Found: C 42.61%; H 4.77%; N 14.08%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]3([NH:24][C:25](=[O:27])[CH3:26])[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18][CH2:17]3)=[CH:10][CH:9]=2)=[C:4]([F:28])[CH:3]=1.[CH3:29][C:30]1[CH:35]=[CH:34][C:33]([SH:36])=[CH:32][CH:31]=1.C(N(C(C)C)CC)(C)C.O>O1CCOCC1.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.C(Cl)(Cl)Cl.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[F:28][C:4]1[CH:3]=[C:2]([S:36][C:33]2[CH:34]=[CH:35][C:30]([CH3:29])=[CH:31][CH:32]=2)[CH:7]=[CH:6][C:5]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]2([NH:24][C:25](=[O:27])[CH3:26])[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18][CH2:17]2)=[CH:10][CH:9]=1
Reactant: Cc1ccc(S)cc1
Reactant: CC(=O)NC1(CCc2ccc(-c3ccc(Br)cc3F)cc2)COC(C)(C)OC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(=O)NC1(CCc2ccc(-c3ccc(Sc4ccc(C)cc4)cc3F)cc2)COC(C)(C)OC1
Yield: 89.2 %

Procedure:
A solution of N-{5-[2-(4′-bromo-2′-fluorobiphenyl-4-yl)ethyl]-2,2-dimethyl-1,3-dioxan-5-yl}acetamide (1.17 g) of Reference Example 10, 4-methylbenzenethiol (316 mg), diisopropylethylamine (672 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (67.3 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (77.5 mg) in 1,4-dioxane (10 mL) was heated under reflux for 8 hr under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (1.12 g) as pale-yellow crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.[Cl:11][C:12]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:13]=1[CH2:14][CH2:15][NH2:16].C(=O)(O)[O-].[Na+].O>C(O)C>[Cl:8][C:6]1[N:5]=[C:4]([O:9][CH3:10])[N:3]=[C:2]([NH:16][CH2:15][CH2:14][C:13]2[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:12]=2[Cl:11])[CH:7]=1
Reactant: NCCc1ccc(Cl)cc1Cl
Reactant: COc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1nc(Cl)cc(NCCc2ccc(Cl)cc2Cl)n1

Procedure:
A solution of 4,6-dichloro-2-methoxypyrimidine (0.7 g), 2,4-dichlorophenethylamine (0.82 g) and sodium bicarbonate (0.88 g) in ethanol (25 mL) is heated at 80° C. for three hours and poured into water (400 mL). The resulting solid is filtered and air dried to afford (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(2,4-dichloro-phenyl)-ethyl]-amine.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C@H:4](/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11](Cl)=[O:12].[CH:15]([OH:18])([CH3:17])[CH3:16]>C1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:14])[C@H:4](/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11]([O:18][CH:15]([CH3:17])[CH3:16])=[O:12]
Reactant: CC(C)O
Reactant: COC(=O)/C=C/[C@@H]1[C@@H](C(=O)Cl)C1(C)C
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: COC(=O)/C=C/[C@@H]1[C@@H](C(=O)OC(C)C)C1(C)C

Procedure:
Using the procedure of Example 3, 2.7 g of (1R,trans) 2,2-dimethyl-3-[(E)-3-methoxy-3-oxo-1-propenyl]-cyclopropane-1-carboxylic acid chloride in benzene and 1 ml of isopropanol were reacted to obtain 1.7 g of isopropyl (1R,trans) 2,2-dimethyl-3-[(E)-3-methoxy-3-oxo-1-propenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+84° (c=1.25% in chloroform).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13].[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=[C:17]1[S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1.CCOC(C)=O>[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=[C:17]1[S:25]([NH:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])(=[O:27])=[O:26]
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Reactant: COC(=O)CCSc1ccc(Cl)cc1N
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)CCSc1ccc(Cl)cc1NS(=O)(=O)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 72 h
Yield: 52.4 %

Procedure:
To a solution of methyl 3-((2-amino-4-chlorophenyl)thio)propanoate (412 mg, 1.67 mmol) in pyridine (2 ml) was added 1-benzofuran-2-sulfonyl chloride (363 mg, 1.67 mmol). The reaction was stirred at room temperature for 72 hours, diluted with EtOAc and extracted with HCl, brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (10-20% EtOAc in hexane) to yield the title compound (373 mg, 52%).
Reaction SMILES: C([O:3][P:4](/[CH:9]=[CH:10]\[CH2:11][CH2:12][O:13][N:14]1[CH:22]=[N:21][C:20]2[C:15]1=[N:16][CH:17]=[N:18][C:19]=2[NH2:23])([O:6]CC)=[O:5])C.Br[Si](C)(C)C>ClCCl>[P:4](/[CH:9]=[CH:10]\[CH2:11][CH2:12][O:13][N:14]1[CH:22]=[N:21][C:20]2[C:15]1=[N:16][CH:17]=[N:18][C:19]=2[NH2:23])([OH:5])([OH:6])=[O:3]
Reactant: CCOP(=O)(/C=C\CCOn1cnc2c(N)ncnc21)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: Nc1ncnc2c1ncn2OCC/C=C\P(=O)(O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.9 %

Procedure:
To a solution of (Z)-9-[4-(diethoxyphosphoryl)-but-3-enyloxy]adenine (145 mg, 425 μmol) in dichlormethane (10 ml) was added bromotrimethylsilane (1.29 g, 8.48 mmol) and the resulting solution was stirred at room temperature under dry nitrogen for 18 hr. The solvent was removed and the residue was azeotroped with methanol (×5). The residue was purified by column chromatography on reverse phase silica gel eluting with water to give (Z)-9-(4-phosphonobut-3-enyloxy]adenine as a white solid (98 mg, 81%), m.p. 238° C.; λmax (MeOH) 260 (13,515)nm; υmax (KBr) 3420, 3200, 3085, 2970, 1700, 1610, 1485, 1415 and 1335 cm-1 ; δH [(CD3)2SO] 2.94 (2H, m, CH2), 4.43 (2H, t, J 7 Hz, CH2O ), 5.77 (1H, dd, J 14 Hz and 17 Hz, PCH=CH), 6.40 (1H, ddt, J 7 Hz, 14 Hz and 47 Hz, PCH=CH), 7.40 (2H, br.s, NH2). 8.15 (1H, s, H-2/H-8), 8.42 (1H, s, H-2/H-8); FABMS (thioglycerol) 286 (NH+) (Found: C, 36.71; H, 4.16; N, 23.96%. C9H12N5O4P.0.4H20 requires C, 36.96; H, 4.41; N, 23.95%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[CH3:23][C:24]1[O:28][C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]3[CH:39]=[CH:38][S:37][CH:36]=3)[CH:30]=2)=[N:26][C:25]=1[CH2:40][CH2:41]OS(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:41][CH2:40][C:25]2[N:26]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]4[CH:39]=[CH:38][S:37][CH:36]=4)[CH:30]=3)[O:28][C:24]=2[CH3:23])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccc(-c4ccsc4)c3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(Cc1ccc(OCCc2nc(-c3cccc(-c4ccsc4)c3)oc2C)cc1)Oc1ccccc1
Temperature: 55 °C
Reaction time: 16 h

Procedure:
3-(4-Hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester (495 mg, 1.7 mmol) (see Ex. 1, Part C), toluene-4-sulfonic acid 2-[5-methyl-2-(3-thiophen-3-ylphenyl)oxazol-4-yl]ethyl ester (2.2 mmol) and Cs2CO3 (700 mg, 2.2 mmol) are combined in anhydrous DMF (25 mL) and stirred for 16 h at 55° C. under an atmosphere of nitrogen. The mixture was then cooled and diluted with ethyl acetate (100 mL), and washed with water then brine. The organic layer was dried with Na2SO4 and concentrated in vacuo to a viscous yellow oil. The residue was purified by flash column chromatography (100 g silica, 60×15 mL fractions, gradient elution 0–20% ethyl acetate in hexanes) to provide the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 7.90 (dt, J=7.6 Hz, J=1.2 Hz, 1H), 7.64 (dt, J=7.6 Hz, J=1.2 Hz, 1H), 7.56–7.55 (m, 1H), 7.48–7.39 (m, 3H), 7.23–7.14 (m, 5H), 6.96 (t, J=7.2 Hz, 1H), 6.83–6.81 (m, 4H), 4.24 (t, J=6.8 Hz, 2H), 4.12 (q, J=7.2 Hz, 2H), 3.26 (d, J=14.0 Hz, 1H), 3.10 (d, J=14.0 Hz, 1H), 3.00 (t, J=6.4 Hz, 2H), 2.39 (s, 3H), 1.38 (s, 3H) 1.21 (t, J=7.2 Hz, 3H); MS (EI) 568.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]2[S:21][C:20]([S:22](Cl)(=[O:24])=[O:23])=[C:19]([CH3:26])[C:18]=2[CH:27]=1>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]2[S:21][C:20]([S:22]([NH:1][C:2]3[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=3)(=[O:24])=[O:23])=[C:19]([CH3:26])[C:18]=2[CH:27]=1
Reactant: CCOC(=O)c1sc(N)nc1C
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Product: CCOC(=O)c1sc(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)nc1C
Yield: 18 %

Procedure:
The product was prepared from ethyl 2-amino-4-methyl-1,3-thiazole-5-carboxylate (9 mg, 0.050 mmol) and 5-chloro-3-methylbenzothiophene-2-sulfonyl chloride (14 mg, 0.050 mmol) according to the General Procedure 9, described in Example 123, using a slightly modified reaction temperature of 60° C. and a reaction time of one week. The title compound was obtained in 18% yield (3.9 mg). 1H NMR (500 MHz, CDCl3) δ ppm 1.34 (t, J=7.15 Hz, 3 H) 2.60 (s, 3 H) 2.61 (s, 3 H) 4.30 (q, J=7.15 Hz, 2 H) 7.42 (dd, J=8.63, 2.01 Hz, 1 H) 7.66 (dd, J=8.63, 0.50 Hz, 1 H) 7.70 (dd, J=2.01, 0.50 Hz, 1 H). MS (ESI+) m/z 431 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[F:14][C:13]([F:15])([F:16])[CH2:12][CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(OCCC(F)(F)F)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(OCCC(F)(F)F)cc1
Yield: 36.8 %

Procedure:
nitro-4-(3,3,3-trifluoro-propoxy)-benzene (1.4 g) in methanol (50 ml) was hydrogenated over Pd/C at RT and at atmospheric pressure for 12 h. The catalyst was filtered off and the solvent was removed in vacuo to give the desired 4-(3,3,3-trifluoro-propoxy)-phenylamine (0.45 g) as a light brown solid. MS (ESI, m/e): 206.1 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:16]([Cl:26])=[C:17]3[C:22](=[CH:23][C:24]=2[Cl:25])[CH:21]=[N:20][CH:19]=[CH:18]3)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:26][C:16]1[C:15]([O:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[C:24]([Cl:25])[CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][N:20]=[CH:21]2
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2c(Cl)cc3cnccc3c2Cl)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1cc2cnccc2c(Cl)c1OC1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
150 mg 4-(5,7-Dichloro-isoquinolin-6-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (377, already partially deprotected) were dissolved in 10 ml of dichloromethane and 1 ml of trifluoroacetic acid is added at 0° C. The solution is stirred for 2 h at room temperature. For working up, 50 ml Dichloromethane were added and the solution was washed with saturated NaHCO3-solution. The layers were separated and the aqueous phase was extracted once with Dichloromethane. The combined organic layers were again washed with saturated NaHCO3-solution, dried with MgSO4 and evaporated. The residue was purified by preparative HPLC. The product fractions were evaporated and the residue dissolved in 2 N HCl. After evaporation, the title compound was isolated as HCl-salt. Rt=0.90 min (Method #2). Detected mass: 297.1/299.1 (M+H+).
Reaction SMILES: [C:1]([C:3]([C@H:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2].[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:26][CH2:27]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:3]([C@H:16]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:27][CH2:26][C:25]2[CH:29]=[CH:30][C:31]([Cl:32])=[C:23]([Cl:22])[CH:24]=2)[CH2:17]1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2]
Reactant: N#CC(c1ccccc1)(c1ccccc1)[C@H]1CCCNC1
Reactant: Clc1ccc(CCBr)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CC(c1ccccc1)(c1ccccc1)[C@H]1CCCN(CCc2ccc(Cl)c(Cl)c2)C1

Procedure:
A mixture containing 3-(R)-(+)-(1-cyano-1,1-diphenylmethyl)piperidine (0.28 g), 3,4-dichlorophenethyl bromide (0.255 g), anhydrous potassium carbonate (0.3 g) and acetonitrile (10 ml) was heated under reflux for 8 hours. The mixture was partitioned between dichlorometbane (30 ml) and 10% aqueous potassium carbonate (20 ml), the layers separated and the aqueous layer extracted with dichloromethane (3×70 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated inn vacuo to give an oil which was purified by column chromatograpby on silica eluting with dichloromethane containing hexane (30%). The product-containing fractions were combined and concentrated in vacuo to give an oil which was crystallised from acetonitrile to give the title compound, yield 0.233 g, m.p. 139°-142° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]([OH:20])=O)[CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([NH2:24])[CH2:22][CH3:23].C(N(CC)CC)C.CN(C1C=CC=CN=1)C>C(Cl)Cl.C(OCC)(=O)C>[CH2:21]([NH:24][C:18]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:17]2)=[O:20])[CH2:22][CH3:23]
Reactant: CCCN
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc(C(=O)O)cc2C1
Agent: CN(C)c1ccccn1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCNC(=O)c1ccc2c(c1)CC(NC(=O)OC(C)(C)C)C2
Yield: 63.6 %

Procedure:
2-(tert-butoxycarbonylamino)-5-carboxyindan (30 mg, 0.11 mmol) synthesized in Reference Production Example 4, n-propylamine (20 μl, 0.24 mmol), triethylamine (0.20 ml, 1.4 mmol), propanephosphonic acid anhydride (0.3 ml) (see Japanese Unexamined Patent Publication (Kokai) No. 55-100346), and dimethylaminopyridine (acatalytic amount) in methylene chloride (0.25 ml) were stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate, and then washed with, in the order of, an aqueous solution of saturated potassium hydrogen sulfate, brine, an aqueous solution of saturated sodium hydrogen carbonate, and brine, and then was dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel chromatography (hexane:ethyl acetate=4:1 to 3:7) to obtain N-propyl-2-(tert-butoxycarbonylamino)-5-indan carboxamide (22 mg, 0.070 mmol) having the following physical properties:
Reaction SMILES: [OH:1][CH2:2][P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>ClCCl.O>[O:1]([CH2:2][P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6])[Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: CCOP(=O)(CO)OCC
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOP(=O)(CO[Si](C)(C)C(C)(C)C)OCC

Procedure:
To a stirred solution of diethyl hydroxylmethylphosphonate (2.13 g, 12.7 mmol), triethylamine (2.12 ml, 15.2 mmol) and dimethylaminopyridine (77 mg, 0.63 mmol) in dichlormethane at 0° C. under argon, at r.t., was added t-butyldimethylsilyl chloride (1.85 g, 12.8 mmol) in dichloromethane (5 ml). After 14 hr the resulting slurry was poured into water (100 ml) and extracted with dichloromethane (2×100 ml). The organic extracts were dried (Na2SO4), concentrated in vacuo and the resulting oil chromatographed on silica gel eluted with ethylacetate:hexanes (1:1, v:v) to afford the title compound as a clear oil.
Reaction SMILES: [H][H].[C:3]1([C:9](O)([CH3:11])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>>[C:3]1([CH:9]([CH3:11])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: CC(C)(O)c1ccccc1
Product: CC(C)c1ccccc1

Procedure:
The 6–20 mesh particles of reduced catalyst, prepared by the afore-mentioned procedure are loaded onto bed supports made of porous plate or screen in a distillation reactor in a nitrogen filled environment. Glass wool can also be used to support the catalyst particles. Hydrogen gas is added via a regulator to the apparatus to maintain a pressure between 0–450 psig, (typically between 0–150 psig). The flow rate is adjusted to maintain twice the amount of hydrogen required for the reaction stoichiometry. A feed stream containing alkylphenyl alcohol, such as a stream containing (e.g.10–40 weight %) of 2-phenyl-2-propanol (cumyl alcohol), is fed into the distillation reactor from below the catalyst beds. The bottom section of the distillation reactor is lowered into a heater and then the temperature is raised until the liquid refluxes in the distillation reaction zone containing the catalyst. Lower boiling alkylbenzene, such as cumene, and water are distilled out from the top of the column. Additional alkylphenyl alcohol, such as a cumyl alcohol-containing stream, is continually added with a slight molar excess of hydrogen to replace the amount of alkylphenyl alcohol, such as cumyl alcohol, that is converted to alkylbenzene, such as cumene, and distilled off. The alkyl benzene product, such as cumene, easily separates from the denser water phase. It is optionally dried further with molecular sieves or other suitable drying agents. The alkylbenzene, such as cumene, produced has a purity of more than 98 wt. %, preferably more than 99 wt. %. No measurable alkylphenyl alcohol, such as cumyl alcohol (<0.01 wt. %) is found in the alkylbenzene, such as cumene product. When desired, the bottoms can be removed, optionally diluted with cumene and sent to a fixed bed hydrogenation reactor to make additional alkyl benzene, such as cumene.
Reaction SMILES: N(=[S:3]1[CH2:8][C:7](=[O:9])C=CN1)O.[NH2:10][C:11](C)(C)[CH:12]=[N:13][OH:14].ClCl.SCC(OCC)=O.[OH-].[Na+]>O>[N:13](=[C:12]1[CH2:11][NH:10][C:7](=[O:9])[CH2:8][S:3]1)[OH:14]
Reactant: O=C1C=CNS(=NO)C1
Reactant: CC(C)(N)C=NO
Agent: CCOC(=O)CS
Agent: ClCl
Agent: [Na+]
Solvent: O
Product: O=C1CSC(=NO)CN1
Temperature: 0 °C

Procedure:
The oximino-thiazin-5-one compounds used as starting materials in preparing the compounds of this invention can be prepared by the methods disclosed in U.S. Pat. No. 4,071,627. In one method, a solution of α-aminoisobutyraldoxime and water is stirred and cooled to 0° C. Chlorine is added to the solution and the mixture is stirred. Ethyl mercaptoacetate and a base, such as sodium hydroxide, are added to produce an oximino-tetrahydro-1,4-thiazin-5-one.