Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:27]2[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]2)[CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:15])=[N:10][CH:9]=1)([CH3:6])[C:3]([OH:5])=[O:4].CO[C:36]([C:38]1(SC2SC(N)=NC=2)CCCC[CH2:39]1)=O.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[CH3:33][C@H:30]1[CH2:29][CH2:28][C@H:27]([N:16]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][C:2]3([C:3]([OH:5])=[O:4])[CH2:1][CH2:39][CH2:38][CH2:36][CH2:6]3)=[CH:9][N:10]=2)[CH2:32][CH2:31]1
Reactant: COC(=O)C1(Sc2cnc(N)s2)CCCCC1
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCCCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: C[C@H]1CC[C@H](N(CCCCc2ccccc2)C(=O)Nc2ncc(SC3(C(=O)O)CCCCC3)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-Methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-(4-phenyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-propionic acid using 1-(2-amino-thiazol-5-ylsulfanyl)-cyclohexanecarboxylic acid methyl ester prepared using the procedure for the preparation of 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34](Br)=[CH:33][C:32]=2[CH3:38])=[C:28]([CH:39]([CH3:41])[CH3:40])[NH:27][N:26]=1)(=[O:3])[CH3:2].[C:42]([OH:46])(=[O:45])[CH:43]=[CH2:44].C(O)(=O)CC=C>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34](/[CH:44]=[CH:43]/[C:42]([OH:46])=[O:45])=[CH:33][C:32]=2[CH3:38])=[C:28]([CH:39]([CH3:41])[CH3:40])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(Br)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: C=CC(=O)O
Agent: C=CCC(=O)O
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/C(=O)O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 4 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-bromo-2-methyl-phenyl)methyl]-5-isopropyl-1H-pyrazole and acrylic acid instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-bromophenyl)methyl]-5-isopropyl-1H-pyrazole and 3-butenoic acid, respectively.
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.Cl[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:8][CH:6]1[O:7][CH:2]([CH3:1])[CH2:3][N:4]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:5]1
Reactant: CCOC(=O)CCCl
Reactant: CC1CNCC(C)O1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CCN1CC(C)OC(C)C1

Procedure:
This intermediate (26.0 g.) was prepared using the procedure described in Example 4a except using 24.5 ml. (0.2 mole) of 2,6-dimethylmorpholine, 19.2 ml. (0.20 mole) of ethyl 3-chloropropionate, and 30.3 ml. (0.22 mole) of triethylamine in 60 ml. of toluene and was isolated as a colorless liquid boiling 88°-88.5° C. at 5 mm of Hg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([F:17])[CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[CH:8]([CH3:12])[C:9]([OH:11])=[O:10].[CH3:18]C(C)(C(OCC)=O)C(OCC)=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([F:17])[CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[C:8]([CH3:18])([CH3:12])[C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)C(C)(C)C(=O)OCC
Reactant: CC(C(=O)O)C(=O)NCc1cc(F)cc(F)c1
Product: CC(C)(C(=O)O)C(=O)NCc1cc(F)cc(F)c1

Procedure:
N-(3,5-Difluoro-benzyl)-2,2-dimethyl-malonamic acid was prepared in analogy to N-(3,5-difluoro-benzyl)-2-methyl-malonamic acid (example 1) from diethyl 2,2-dimethyl-malonate.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C:14]([F:25])([F:24])[C:15]([O:18][CH:19]([O:21][CH2:22][CH3:23])[CH3:20])([CH3:17])[CH3:16])(=O)=O)=CC=1.C(N(C(C)C)CC)(C)C.[I-:35].[Na+]>CC(C)=O>[CH2:22]([O:21][CH:19]([O:18][C:15]([CH3:17])([CH3:16])[C:14]([F:25])([F:24])[CH2:13][CH2:12][I:35])[CH3:20])[CH3:23]
Reactant: CCOC(C)OC(C)(C)C(F)(F)CCOS(=O)(=O)c1ccc(C)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)=O
Product: CCOC(C)OC(C)(C)C(F)(F)CCI
Temperature: 25 °C
Reaction time: 64 h

Procedure:
A mixture of 3.50 g (0.0087 mol) of 4-(1-ethoxyethoxy)-3,3-difluoro-4-methyl-1-pentanol 1-(4-methylbenzenesulfonate), 40 mL of acetone, 0.5 mL of diisopropylethylamine and 13.10 g (0.087 mol) of sodium iodide was stirred at 25° C. for 64 hr. The mixture was evaporated to dryness. The residue was partitioned between 5% aqueous sodium sulfite solution and methylene chloride. The organic phase was washed with saturated aqueous sodium bicarbonate solution. The organic phase was then dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The residue was chromatographed on 0.06-0.20 mm silica gel to yield 4-(1-ethoxyethoxy)-3,3-difluoro-1-iodo-4-methylpentane. NMR (CDCl3) δ4.98 (quartet, 1, J=7 Hz), 3.50 (quartet, 2, J=7 Hz), 3.28 (multiplet, 2), 2.60 (multiplet, 2), 1.32 (triplet, 6, J=1 Hz), 1.28 (doublet, 2, J=7 Hz), and 1.18 ppm (triplet, 3, J=7 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:29])[C:12]3[CH:26]=[C:25]([CH2:27]Cl)[S:24][C:13]=3[N:14]([CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.Cl.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]1[C@H:39]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[OH:40]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:29])[C:12]3[CH:26]=[C:25]([CH2:27][N:33]4[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]4[C@@H:39]([OH:40])[C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[S:24][C:13]=3[N:14]([CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:15]=2)=[O:9])=[CH:30][CH:31]=1
Reactant: O[C@@H](c1ccccc1)[C@H]1COCCN1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cn(CCN2CCOCC2)c2sc(CCl)cc2c1=O
Agent: Cl
Product: O=C(NCc1ccc(Cl)cc1)c1cn(CCN2CCOCC2)c2sc(CN3CCOC[C@@H]3[C@@H](O)c3ccccc3)cc2c1=O

Procedure:
Analogous to the procedures described in Example 15, N-(4-chlorobenzyl)-2-(chloromethyl)-7-(2-morpholin-4-ylethyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide (Preparation 23) is treated with (S)-(3R)-morpholin-3-yl(phenyl)methanol hydrochloride (Preparation 9) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH2:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH:14]([NH2:17])([CH3:16])[CH3:15]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:13][NH:17][CH:14]([CH3:16])[CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)N
Reactant: C=C(C(=O)OC)c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: COC(=O)C(CNC(C)C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 2-(4-chlorophenyl)acrylate (1.00 g, 5.09 mmol) was added as a solution in 2.5 mL of THF to a stirring solution of i-PrNH2 (650 uL, 7.63 mmol) in 10 mL of THF. The reaction was allowed to stir at room temperature overnight to completion by LCMS analysis. The solvent was removed under reduced pressure to give methyl 2-(4-chlorophenyl)-3-(isopropylamino)propanoate (LCMS (APCI+) [M−Boc+H]+ 256.1, Rt: 1.97 min), which was re-dissolved in 15 mL of DCM at room temperature. The Boc2O (1.29 mL, 5.59 mmol) was added to the stirring amine via pipette followed by a catalytic amount (1 mg) of DMAP. The reaction was allowed to stir overnight to completion by LCMS and TLC analysis of the mixture. The solution was concentrated in vacuo to afford methyl 3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoate as an oily residue (LCMS (APCI+) [M−Boc+H]+ 256.1, Rt: 4.13 min) which was re-dissolved in 12.0 mL of THF and 4.0 mL of water. The solution was treated with LiOH—H2O (1.07 g, 25.4 mmol) and allowed to stir for 4 hours to completion by LCMS analysis. The solution was diluted with water and washed with diethyl ether (discarded). The aqueous was treated with 1M HCl solution until pH 2-3 and extracted with ethyl acetate several times. The organics were combined, washed with brine, separated, dried over MgSO4, filtered, and concentrated in vacuo to afford 3-(tert-butoxycarbonykisopropyl)amino)-2-(4-chlorophenyl)propanoic acid as a colorless oil (1.04 g, 60%). LCMS (APCI+) [M−Boc+H]+ 242.0.
Reaction SMILES: C1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9](CCCCCCCBr)[C:8]2=[O:32])C=CC=CC=1.[P:33]([O:40][CH2:41][CH3:42])([O:37]CC)[O:34][CH2:35][CH3:36]>C1(C)C(C)=CC=CC=1>[C:12]1([N:9]2[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:7]=[C:8]2[O:32][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:10][CH2:11][P:33]([O:34][CH2:35][CH3:36])(=[O:37])[O:40][CH2:41][CH3:42])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=c1n(CCCCCCCBr)c(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Reactant: CCOP(OCC)OCC
Solvent: Cc1ccccc1C
Product: CCOP(=O)(CCCCCCCOc1nc(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1)OCC

Procedure:
A mixture of 1,4,5-triphenyl-3-(7-bromoheptyl)-imidazol-2-one (1.0 g) and triethyl phosphite (1.66 g) was heated at reflux temperature in xylene (5 ml) for 40 hours. The solution was evaporated to an oil and re-evaporated from ethanol. The oil was partitioned between ether and water, the ether solution was separated, dried over magnesium sulphate and evaporated to an oil which was chromatographed on silica gel (ethyl acetate) to give diethyl 7-(1,4,5-triphenylimidazol-2-yl-oxy)heptanephosphonate as an oil which solidified on standing to a white solid (0.83 g; 75%), m.p. 76°-7° C. Found: C, 70.49; H, 7.40; N, 4.94%; C32H39N204P; Requires: C, 70.31; H, 7.19; N, 5.12%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:20](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH3:20])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(Br)cc(NC2CCCCC2)c1C
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Product: COC(=O)c1cc(Br)cc(N(C)C2CCCCC2)c1C
Temperature: 80 °C
Yield: 87 %

Procedure:
To a stirred solution of methyl 5-bromo-3-(cyclohexylamino)-2-methylbenzoate (2.75 g, 8.45 mmol) in acetonitrile (25 mL), cesium carbonate (5.45 g, 16.9 mmol) and methyl iodide (6 g, 42.3 mmol) were added; resulting solution was heated at 80° C. for 20 h. On completion, the solution was cooled to room temperature and filtered, and the residue was washed with ethyl acetate. The filtrate was concentrated and then purified by column chromatography to afford methyl 5-bromo-3-(cyclohexyl(methyl)amino)-2-methylbenzoate (2.5 g, 87%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Cl:10])[N:7]=[C:6](Br)[C:5]=1[NH2:12].[C:14](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1.O>O1CCOCC1>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Cl:10])[N:7]=[C:6]([CH3:14])[C:5]=1[NH2:12]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(Cl)nc(Br)c1N
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(Cl)nc(C)c1N
Temperature: 25 °C
Yield: 26.5 %

Procedure:
3-Amino-2-bromo-6-chloroisonicotinic acid methyl ester (500 mg), potassium carbonate (829 mg), tetrakis(triphenyl phosphine)palladium(0) and trimethylboroxine (276 mg) were suspended in dioxane (15 mL). Water (1.5 mL) was added and the mixture was degassed using subsequent evaporation and flushing with nitrogen (5×). The reaction mixture was stirred under reflux for 7 hours. After cooling to room temperature, the mixture was quenched with water and extracted 2× with ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4 and concentrated in vacuum. The residue was purified by column chromatography (silica 60, hexane/ethyl acetate=3:1, Rf=0.25) to afford 100 mg of the title compound of the formula
Reaction SMILES: Cl.[C:2]1([CH2:8][N:9]2[CH2:14][CH2:13][C:12]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)([C:15](N)=[O:16])[CH2:11][CH2:10]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:29].[Na+]>O>[C:2]1([CH2:8][N:9]2[CH2:10][CH2:11][C:12]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)([C:15]([OH:16])=[O:29])[CH2:13][CH2:14]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)C1(Nc2cccc(C(F)(F)F)c2)CCN(Cc2ccccc2)CC1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)C1(Nc2cccc(C(F)(F)F)c2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To 792 parts of concentrated hydrochloric acid solution are added 100 parts of 1-(phenylmethyl)-4-{[3-(trifluoromethyl)phenyl]amino}-4-piperidinecarboxamide. The whole is heated to reflux temperature while stirring. 230 Parts of water are added followed by the addition of anti-foam. Stirring at reflux is continued for 3.50 h. After cooling to room temperature, the reaction mixture is poured into a vessel and 200 parts of water are added. The whole is strongly alkalized with sodium hydroxide while stirring vigorously: a precipitate is formed. The supernatant aqueous phase is decanted and the residual precipitate is dissolved in water. The resulting solution is cooled and acidified with acetic acid (pH=about 7), whereupon the product is precipitated. It is filtered off and boiled in N,N-dimethylformamide. After cooling, the product is filtered off again, washed successively with ethanol and 2,2'-oxybispropane and dried. The less pure fraction is crystallized from N,N-dimethylformamide. The pure product is filtered off, washed successively with ethanol and with N,N-dimethylformamide, and dried at 140° C., yielding 1-(phenylmethyl)-4-[3-(trifluoromethyl)phenylamino] -4-piperidinecarboxylic acid; mp. 264.3° C.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])([CH3:7])[C:4]([OH:6])=[O:5].[CH3:11][Si](C=[N+]=[N-])(C)C>ClCCl.C(OCC)C>[F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])([CH3:7])[C:4]([O:6][CH3:11])=[O:5]
Reactant: CC(C)(C(=O)O)C(F)(F)F
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)C(C)(C)C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Reaction was carried out in two separate batches, employing 5 g of 3,3,3-trifluoro-2,2-dimethylpropionic acid in each batch. To a stirred solution of 3,3,3-trifluoro-2,2-dimethylpropionic acid (5 g, 32 mmol) in anhydrous dichloromethane (20 mL) at 0° C. (under an argon atmosphere), was added dropwise a solution of (trimethylsilyl)diazomethane (18 mL of a 2M solution in diethyl ether, 35 mmol) (gas evolution observed). The resulting yellow solution was allowed to warm to rt and stirred for a further 48 h. An additional 5 mL of 2M (trimethylsilyl)diazomethane solution (10 mmol) was added, and stirring continued for a further 5 h whereupon a further 6 mL of 2 M (trimethylsilyl)diazomethane solution (12 mmol) was added. After stirring for a further 15 h, the reaction mixture was concentrated in vacuo (keeping bath temperature below 30° C.). The resulting oil was redissolved in diethyl ether (200 mL), washed with saturated sodium hydrogencarbonate solution (100 mL), separated, and dried over MgSO4. Filtration followed by concentration in vacuo (keeping bath temperature below 30° C.) gave crude product. Crude product from both batches were combined to afford crude methyl 3,3,3-trifluoro-2,2-dimethylpropanoate (7.69 g) as a yellow oil which was taken on without further purification. 1H NMR (300 MHz, CDCl3) δ 3.86 (s, 3H), 1.40 (s, 6H).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1([CH3:14])[O:9][C:8]2[CH:10]=[CH:11][S:12][C:7]=2[C:6](=[O:13])[CH2:5]1.O>C(O)C>[OH:13][CH:6]1[CH2:5][C:4]([CH3:14])([CH3:3])[O:9][C:8]2[CH:10]=[CH:11][S:12][C:7]1=2
Reactant: CC1(C)CC(=O)c2sccc2O1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC1(C)CC(O)c2sccc2O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium borohydride (0.97 g, 25.5 mmol) was added to a solution of 5,6-dihydro-5,5-dimethyl-7H-thieno-[3,2-b]pyran-7-one (3.1 g, 17.0 mmol) in ethanol (50 mL) and stirred at rt for 2 h. An additional 0.97 g of sodium borohydride was added and the mixture was stirred 16 h. The mixture was poured into water and extracted with dichloromethane. The dichloromethane solution was washed with water (5×) and dried over magnesium sulfate. The solvent was evaporated in vacuo to give the product, 2.96 g (95%), as a brown oil: IR (neat): 3373, 2976, 1561 and 1400 cm-1 ; MS: m/z 185 (MH+); 1H NMR (CDCl3): δ1.34 (s, 3H), 1.45 (s, 3H), 1.87 (m, 1H), 1.94 (d, J=7.0 Hz, 1H, exchanges with D2O), 2.16 (m, 1H), 4.88 (m, 1H), 6.57 (d, J=5.4 Hz, 1H), 7.13 (d, J=5.4 Hz, 1H). This oil was used without further purification in the next step.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[CH2:6][N:7]([CH:12]([CH3:14])[CH3:13])[S:8](=[O:11])(=[O:10])[NH:9][C:4]=2[CH:3]=1.[H-].[Na+].Br[CH2:20][CH2:21][Cl:22].O>CN(C=O)C>[Cl:22][CH2:21][CH2:20][N:9]1[C:4]2[CH:3]=[C:2]([F:1])[CH:16]=[CH:15][C:5]=2[CH2:6][N:7]([CH:12]([CH3:14])[CH3:13])[S:8]1(=[O:11])=[O:10]
Reactant: CC(C)N1Cc2ccc(F)cc2NS1(=O)=O
Reactant: ClCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)N1Cc2ccc(F)cc2N(CCCl)S1(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3,4-dihydro-7-fluoro-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide(1.48 g, 6.07 mmol) in dry DMF (15 ml) was added via a cannula to a flask containing sodium hydride (175 mg, 7.28 mmol) and DMF (2 ml) in Argon atmosphere, and stirred for 2 hours at room temperature when 1-bromo-2-chloroethane (7.28 mmol, 605 μl) was added dropwise. The mixture was stirred overnight at room temperature and water (75 ml) added. The product was extracted with EtOAc (3×50 ml) and the combined organic extracts were washed with water (1×100 ml) and then brine (1×100 ml), dried over sodium sulphate and solvent evaporated at reduced pressure. The residue was purified by flash chromatography on silica gel (EtOAc:Hexanes 1:4) affording pure 1-(2-chloroethyl)-3,4-dihydro-7-fluoro-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].N1C=CC=CC=1.Cl[C:17]([O:19][CH:20]([Cl:22])[CH3:21])=[O:18]>CCOCC>[C:17](=[O:18])([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[O:19][CH:20]([Cl:22])[CH3:21]
Reactant: CCCCCCCCO
Reactant: CC(Cl)OC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCCCCCCOC(=O)OC(C)Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.4 %

Procedure:
To a stirring solution of dry n-octanol (6.42 g, 49.3 mmol) and pyridine (3.90 g, 49.3 mmol) in anhydrous ether (75 mL) was added at 0° C. alpha-chloroethyl chloroformate (prepared according to U.K. Pat. No. 1,426,717; 7.00 g, 49.3 mmol). The mixture was stirred vigorously for three hours at 25° C. then filtered. The filtrate was concentrated in vacuo and distilled at 102°-107° C. (2 mm) affording 8.1 g title product as a clear oil (34.2 mmol, 69.4%): 1H NMR (CDCl3) delta 0.44-2.03 (m, 15H), 1.60 (d, J=6 Hz, 3H), 3.94 (t, J=7 Hz, 2H), 6.18 (q, J=6 Hz, 1H).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:11]([CH:13]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][CH2:14]1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CC(O)=O>[C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH:10][CH2:11][CH:13]2[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:15][CH2:14]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC(C=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCCC(CN[C@@H]2C[C@H]2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 13.1 %

Procedure:
A mixture of [trans-2-phenylcyclopropyl]amine (496 mg, 3.72 mmol), 1,1-dimethylethyl 4-formylhexahydro-1H-azepine-1-carboxylate (871 mg, 3.83 mmol) and AcOH (1 μL, 0.017 mmol) in chloroform (5 mL) was stirred at room temperature for 18 hours. Sodium triacetoxyborohydride (950 mg, 4.48 mmol) was added and stirring continued for 18 hours. Upon completion, saturated NaHCO3 was added to the reaction mixture and the mixture was extracted with THF—CHCl3 (2×50 mL). The organics were combined, dried over Na2SO4 and concentrated. The residue was adsorbed onto silica and purified via column chromatography on the ISCO Companion (gradient 0-40% 80:20:2 [CHCl3/MeOH/NH4OH]/CHCl3; 40 g column) to afford the desired product (168 mg, 12%) as a pale yellow oil LC-MS (ES) m/z=345 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.Cl.[Cl:12][C:13]1[C:17]([Cl:18])=[C:16]([CH3:19])[NH:15][C:14]=1[C:20]([NH:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:21]>CN(C=O)C.O>[Cl:12][C:13]1[C:17]([Cl:18])=[C:16]([CH3:19])[NH:15][C:14]=1[C:20]([NH:22][CH:23]1[CH2:28][CH2:27][N:26]([C:2]2[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=2)[CH2:25][CH2:24]1)=[O:21]
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)c(Cl)c1Cl
Reactant: COc1nc(Cl)nc(Cl)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc(Cl)nc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)n1

Procedure:
A solution of 2,4-dichloro-6-methoxy-1,3,5-triazine (commercially available) (0.05 g, 0.32 mmol) in DMF (0.5 ml) was added to a solution of 3,4-dichloro-5-methyl-N-piperidin-4-yl-1H-pyrrole-2-carboxamide hydrochloride (Intermediate 1, 0.1 g, 0.32 mmol) and TEA (0.06 g, 0.64 mmol) in DMF (1.5 ml). The resultant mixture was stirred for 1 h at room temperature, then was diluted with water and extracted with EtOAc. During the aqueous workup, some of the product precipitated and was collected by suction filtration. The organic extract was dried over magnesium sulphate, filtered and concentrated to give the desired product with small amount of impurities.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([CH2:17][N:18]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[C:19](=[O:27])[C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[O:16])=[CH:10][CH:9]=2)[N:7]=1.[Br:35]Br>C(O)(=O)C.O>[ClH:1].[NH2:2][C:3]1[S:4][C:5]([Br:35])=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]([CH2:17][N:18]([C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[C:19](=[O:27])[C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[O:16])=[CH:12][CH:13]=2)[N:7]=1
Reactant: Nc1nc(-c2ccc(NC(=O)CN(C(=O)c3ccc(F)cc3)c3ccc(F)cc3)cc2)cs1
Reactant: BrBr
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc(-c2ccc(NC(=O)CN(C(=O)c3ccc(F)cc3)c3ccc(F)cc3)cc2)c(Br)s1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
N-{[4-(2-aminothiazol-4-yl)phenylcarbamoyl]methyl}-4-fluoro-N-(4-fluorophenyl)benzamide monohydrochloride (200 mg) was dissolved in a mixed solvent of acetic acid (10 ml) and water (5 ml), mixed with bromine (20 μl) under ice-cooling and then stirred at room temperature for 5 minutes. The reaction solution was concentrated under a reduced pressure, and the residue was dissolved in ethyl acetate (30 ml)-saturated sodium bicarbonate aqueous solution (20 ml). The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate and then concentrated under a reduced pressure. The residue was dissolved in ethyl acetate (5 ml) and mixed with 4 M hydrogen chloride in ethyl acetate solution (0.15 ml), and the thus precipitated solid was collected by filtration, dried and then recrystallized from methanol-ether, thereby obtaining 184 mg of N-{[4-(2-amino-5-bromothiazol-4-yl)phenylcarbamoyl]methyl}-4-fluoro-N-(4-fluorophenyl)benzamide monohydrochloride (colorless powder).