Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([O:22]CC)=O)[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:26][CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([NH:26][CH2:27][C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)=[O:22])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Reactant: NCc1cccnc1
Product: O=C(NCc1cccnc1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 3-(aminomethyl)pyridine employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (d6-DMSO) δ 12.32 (1H, br), 11.29 (1H, br), 10.17 (1H, br), 8.56 (1H, s), 8.44 (1H, br), 8.18 (1H, br), 7.73 (1H, m), 7.30-7.27 (4H, m), 7.14 (2H, t, J=8.6 Hz), 4.55 (2H, m), 4.01 (2H, s); ES+ MS: 405 (M+H+, 100).
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[Cl:32][C:33]1[CH:44]=[CH:43][CH:42]=[CH:41][C:34]=1[C:35](N(OC)C)=[O:36]>C1COCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([N:8]([C:7]2[C:2]([C:35](=[O:36])[C:34]3[CH:41]=[CH:42][CH:43]=[CH:44][C:33]=3[Cl:32])=[N:3][CH:4]=[C:5]([Cl:26])[CH:6]=2)[CH2:23][O:24][CH3:25])(=[O:11])=[O:10])=[CH:13][C:14]=1[C:19]([F:22])([F:21])[F:20]
Reactant: CON(C)C(=O)c1ccccc1Cl
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(=O)c1ccccc1Cl)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a magnetically stirred solution of N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-(trifluoromethyl)-benzenesulfonamide (1.5 g, 3.03 mmol) in anhydrous THF (15 mL) was added 2 M isopropylmagnesium chloride in THF (3.3mL, 6.6 mmol) at −20° C. The temperature was allowed to slowly rise to 10° and then 2-chloro-N-methoxy-N-methylbenzamide (1.2 g, 6.0 mmol) was added and the progress of the reaction was followed by LCMS. The reaction mixture was warmed to room temperature and stirred for 16 h. It was then quenched with saturated aqueous NH4Cl (50 mL), and extracted with ethyl acetate (3×100 mL). The combined extracts were dried (MgSO4), filtered and concentrated. The residue was purified by chromatography on silica gel using ethyl acetate-hexane mixtures (2:98, 5:95) to provide 4-chloro-N-[5-chloro-2-(2-chloro-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide mass spectrum m/z 574.8 (M+Na); 521.0 (M−31).
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[CH:13][N:12]=[C:11]2[CH3:15])=[CH:6][CH:5]=1.[OH-].[Na+]>CO.O>[CH3:15][C:11]1[N:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:16])=[O:2])=[CH:5][CH:6]=2)[CH:14]=[CH:13][N:12]=1
Reactant: COC(=O)c1ccc(-n2ccnc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nccn1-c1ccc(C(=O)O)cc1
Temperature: -15 °C

Procedure:
To a stirring solution of 4-(2-methyl-imidazol-1-yl)-benzoic acid methyl ester (250 mg) in MeOH (2 mL) add 10 M NaOH aqueous solution (2.3 mL) and stir the reaction at rt for 20 h. Dilute with water (25 mL) and cool to −15° C. Quench with careful dropwise addition of conc. HCl (2.2 mL) over 5 min to a final pH of 1-2. Wash the suspension with EtOAc (50 mL). Concentrate the aqueous layer to a solid, and further dry in vacuo under P2O5 to remove all moisture. Triturate the solid in MeOH and filter to remove inorganic salts, washing with MeOH. Concentrate the filtrate, triturate the residue in EtOAc/hexane, and filter, washing with hexane. Suspend the solid in 10% MeOH/EtOAc (20 mL) and stir/sonicate. Syringe filter the suspension to remove inorganics solids, concentrate the organic to a solid residue, and repeat this procedure. Triturate the organic residue in EtOAc/hexane and filter/dry the solid to afford the desired product 4-(2-methyl-imidazol-1-yl)-benzoic acid as a solid in 93% yield (238 mg, 1.06 mmol).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([OH:13])[C@@H:10]([O:14][CH2:15][CH:16]=[CH2:17])[CH2:9]1)=O)(C)(C)C.[ClH:18].O1CCOCC1>C(Cl)Cl>[ClH:18].[CH2:15]([O:14][C@H:10]1[CH2:9][NH:8][CH2:12][C@@H:11]1[OH:13])[CH:16]=[CH2:17]
Reactant: C=CCO[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C=CCO[C@H]1CNC[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(3S,4S)-3-Allyloxy-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester synthesized by the method described in the patent literature (DE4234330) (139 mg, 0.57 mmol) was dissolved in methylene chloride (2.4 ml). A 4 N solution of hydrochloric acid in dioxane (0.628 ml, 2.45 mmol) was added and the mixture was stirred at room temperature for two hours. The reaction solution was concentrated under reduced pressure to give (3S,4S)-4-allyloxy-pyrrolidin-3-ol hydrochloride (105 mg). This was used in the next reaction without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[C:31]([O:33][CH3:34])[C:30]([O:35][CH3:36])=[C:29]([O:37][CH3:38])[CH:28]=2)[O:24][C:25]=1[CH3:26].COC1C=C(C=C(OC)C=1OC)C=O.O=P(Cl)(Cl)Cl.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:28]=[C:29]([O:37][CH3:38])[C:30]([O:35][CH3:36])=[C:31]([O:33][CH3:34])[CH:32]=3)[O:24][C:25]=2[CH3:26])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Reactant: COc1cc(-c2nc(CCl)c(C)o2)cc(OC)c1OC
Agent: COc1cc(C=O)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)C(Cc1ccc(OCc2nc(-c3cc(OC)c(OC)c(OC)c3)oc2C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 1 f], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 34 b]) was reacted with 4-chloromethyl-5-methyl-2-(3,4,5-trimethoxy-phenyl)-oxazole (prepared from 3,4,5-trimethoxy-benzaldehyde and diacetyl monoxyme followed by treatment with POCl3 in analogy to the procedures described in examples 2 a] and b]) in the presence of cesium carbonate and potassium iodide to yield [rac]-2-ethoxy-3-{2-methyl-4-[5-methyl-2-(3,4,5-trimethoxy-phenyl)-oxazol-4-ylmethoxy]-phenyl}-propionic acid ethyl ester as yellow liquid.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10](=[O:29])[C@@H:11]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:20]([Cl:28])[CH:19]=2)[CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[N:7][CH:8]=1.[CH3:30][NH:31][CH3:32]>O1CCCC1>[Cl:28][C:20]1[CH:19]=[C:18]([C@@H:11]([CH2:12][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17]2)[C:10]([NH:9][C:6]2[CH:5]=[N:4][C:3]([CH2:2][N:31]([CH3:32])[CH3:30])=[CH:8][N:7]=2)=[O:29])[CH:23]=[CH:22][C:21]=1[S:24]([CH3:27])(=[O:26])=[O:25]
Reactant: CNC
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(CBr)cn2)cc1Cl
Solvent: C1CCOC1
Product: CN(C)Cc1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of N-(5-bromomethyl-pyrazin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (prepared as in Example 30, 138.5 mg, 0.28 mmol) in tetrahydrofuran (2.6 mL) was cooled to 0° C. and then was treated with a 2.0M solution of dimethylamine in tetrahydrofuran (275 μL, 0.55 mmol). The reaction was stirred at 0° C. for 30 min and then at 25° C. for 1 h. A second aliquot of a 2.0M solution of dimethylamine in tetrahydrofuran (275 μL, 0.55 mmol) was added, and the reaction was stirred at 25° C. for 1 h. A third aliquot of a 2.0M solution of dimethylamine in tetrahydrofuran (138 μL, 0.28 mmol) was added, and the reaction was stirred at 25° C. for 1.5 h, at which point, APCI-LRMS indicated the reaction had gone to completion. The reaction was concentrated in vacuo and then was diluted with ethyl acetate (50 mL), washed with water (25 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 100% methanol) afforded impure 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-dimethylaminomethyl-pyrazin-2-yl)-propionamide as an orange oil. This impure product was re-purified by reverse phase high-performance liquid chromatography (Waters symmetry packing, acetonitrile/water with 0.05% trifluoroacetic acid, 2% to 45% acetonitrile gradient). The fractions containing product were concentrated in vacuo to afford 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-dimethylaminomethyl-pyrazin-2-yl)-propionamide (50.4 mg, 39%) as a light yellow foam: mp 88.0–91.5° C. (foam to gel); (ES)+-HRMS m/e calcd for C22H29ClN4O3S (M+H)+ 465.1722, found 465.1726.
Reaction SMILES: C[C:2]1[C:3]([C:7]([OH:9])=O)=[CH:4][S:5][CH:6]=1.B.C1C[O:14][CH2:13]C1.CO>C1COCC1>[CH3:13][O:14][C:2]1[C:3]([CH2:7][OH:9])=[CH:4][S:5][CH:6]=1
Reactant: Cc1cscc1C(=O)O
Reactant: C1CCOC1
Agent: B
Solvent: CO
Product: COc1cscc1CO
Yield: 99.9 %

Procedure:
4-Methylthiophene-3-carboxylic acid (158 mg, 1.00 mmol) was reduced with BH3-THF (1.0M in THF, 3.0 mL, 3.0 mmol) in THF (2 mL) at room temperature and treated with MeOH to give (4-methoxy-thiophen-3-yl)-methanol as an oil (144 mg, 100%) after work-up.
Reaction SMILES: [CH3:1][C:2]([CH3:28])([O:4][C:5]([NH:7][C:8]([CH3:27])([CH3:26])[C:9]([NH:11][C@H:12]([CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[C:13]([OH:15])=O)=[O:10])=[O:6])[CH3:3].Cl.[NH:30]1[CH2:35][CH2:34][C:33]2([CH2:40][C:39](=[O:41])[C:38]3[CH:42]=[CH:43][CH:44]=[CH:45][C:37]=3[O:36]2)[CH2:32][CH2:31]1>>[O:41]=[C:39]1[C:38]2[CH:42]=[CH:43][CH:44]=[CH:45][C:37]=2[O:36][C:33]2([CH2:34][CH2:35][N:30]([C:13]([C@H:12]([NH:11][C:9](=[O:10])[C:8]([NH:7][C:5]([O:4][C:2]([CH3:28])([CH3:1])[CH3:3])=[O:6])([CH3:27])[CH3:26])[CH2:16][C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][CH:18]=3)=[O:15])[CH2:31][CH2:32]2)[CH2:40]1
Reactant: O=C1CC2(CCNCC2)Oc2ccccc21
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: Cl
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N1CCC2(CC1)CC(=O)c1ccccc1O2

Procedure:
This intermediate was prepared from α(R)-[[2-[[(1,1-dimethylethoxy)carbonyl]amino]-2,2-dimethyl-1-oxoethyl]amino]-1H-indole-3-propanoic acid (903 mg, 2.3 mmol) and spiro[2H-1-benzopyran-2,4'-piperidin]-4(3H)-one, hydrochloride (535 mg, 2.11 mmol) (Elliott, J., et al, J. Med. Chem. 1992, 35, 3973-3976) by the procedure described in Example 25, Step A (1.25 g, 100%).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[O:3]1.[H-].[Na+].Cl[CH2:20][CH2:21][N:22]([CH3:24])[CH3:23]>CN(C=O)C>[CH3:23][N:22]([CH3:24])[CH2:21][CH2:20][O:15][C:12]1[CH:13]=[CH:14][C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10][CH:11]=1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: CN(C)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (258 mg, 0.509 mmol) in DMF (10 mL) was added 60% NaH (204 mg, 5.09 mmol) and 2-chloro-N,N-dimethylethylamine (220 mg, 1.527 mmol). The resulting solution was stirred at 60° C. overnight, cooled to the ambient temperature, quenched with aqueous NH4Cl, and extracted with EtOAc. The combined extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography to give the title compound (100 mg, 29% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([N:12]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34]C2CCCCO2)=[CH:30][C:29]=1[Cl:41])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:15][CH:14]=1)(=[O:11])=[O:10].Cl>C(O)C.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([N:12]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][C:29]=1[Cl:41])[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][CH2:25][CH2:26]2)=[CH:17][CH:18]=1)(=[O:10])=[O:11]
Reactant: O=S(=O)(c1ccc(Cl)cc1Cl)N(Cc1ccc(OC2CCCCO2)cc1Cl)c1ccc(OCCN2CCCC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=S(=O)(c1ccc(Cl)cc1Cl)N(Cc1ccc(O)cc1Cl)c1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 34.8 %

Procedure:
To a solution of crude 2,4-dichloro-N-[2-chloro-4-(tetrahydro-pyran-2-yloxy)-benzyl]-N-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-benzenesulfonamide (0.096 g, 0.15 mmol) in 4 mL absolute ethanol was added 1 mL of 1.2N HCl. The reaction mixture was stirred at room temperature for 24 hr. and was diluted with 10 mL saturated aqueous sodium bicarbonate. The aqueous solution was washed with methylene chloride (2×10 mL). The combined organic layers were dried (sodium sulfate), filtered, and concentrated. The residue was purified by preparative TLC (1.0 mm silica gel layer, elution with 10% methanol/ethyl acetate) to afford 0.029 g of the title compound. MS 557.3 (M+1)+
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:37])[N:17]([CH2:28][C@H:29]([NH2:36])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([CH:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:38][C:39]1[C:47]2[C:42](=[CH:43][C:44]([C:48](O)=[O:49])=[CH:45][CH:46]=2)[NH:41][CH:40]=1>>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:37])[N:17]([CH2:28][C@H:29]([NH:36][C:48]([C:44]3[CH:43]=[C:42]4[C:47]([C:39]([Cl:38])=[CH:40][NH:41]4)=[CH:46][CH:45]=3)=[O:49])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([CH:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc2c(Cl)c[nH]c2c1
Reactant: CC(C)N1CCC(CN(C[C@H](N)c2ccccc2)C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Product: CC(C)N1CCC(CN(C[C@H](NC(=O)c2ccc3c(Cl)c[nH]c3c2)c2ccccc2)C(=O)OCC2c3ccccc3-c3ccccc32)CC1

Procedure:
Using coupling method A, crude N-[(R)-2-amino-2-phenyl-ethyl]-N-(1-isopropylpiperidin-4-ylmethyl)carbamic acid 9H-fluoren-9-ylmethyl ester (980 mg, 2.0 mmol) and 3-chloro-indole-6-carboxylic acid (462 mg, 2.4 mmol) afforded, after purification (SiO2: 0 to 30% isopropylamine in 1:1 hexane:EtOAc), 300 mg (23%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-])=O)=[O:5])[CH3:2].[Cl:20][C:21]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:22]=1[CH2:23][NH2:24]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:24][CH2:23][C:22]1[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:21]=1[Cl:20])=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:17])=[O:5])[CH3:2]
Reactant: NCc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Product: CCOC(=O)c1cnc2c(N)cccc2c1NCc1ccc(Cl)cc1Cl
Yield: 88 %

Procedure:
The compound prepared in Example 3 was reacted with 2,4-dichloro-benzylamine according to the method as described in Example 4 and the obtained compound was treated as described in Example 14 to prepare the title compound (yield 88%).
Reaction SMILES: [NH2:1][C:2](=[O:15])[C@H:3]([NH:7]C(=O)OC(C)(C)C)[CH2:4][O:5][CH3:6].[ClH:16]>O1CCOCC1>[ClH:16].[NH2:7][C@H:3]([CH2:4][O:5][CH3:6])[C:2]([NH2:1])=[O:15]
Reactant: COC[C@@H](NC(=O)OC(C)(C)C)C(N)=O
Agent: Cl
Solvent: C1COCCO1
Product: COC[C@@H](N)C(N)=O

Procedure:
A solution of (R)-tert-butyl 1-amino-3-methoxy-1-oxopropan-2-ylcarbamate (342 mg, 1.57 mmol) in 4N HCl in dioxane (5 mL) was stirred at room temperature for 18 h. It was then concentrated in vacuo to give (R)-2-amino-3-methoxypropanamide hydrochloride (260 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6]2)=[CH2:2].Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+]>CO>[CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)/[C:8](=[N:14]/[OH:15])/[CH2:7][CH2:6]2)=[CH2:2]
Reactant: NO
Reactant: C=Cc1ccc2c(c1)CCC2=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=Cc1ccc2c(c1)CC/C2=N\O
Temperature: 60 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
To a mixture of 5-vinyl-2,3-dihydro-1H-inden-1-one (Preparation 87A, 1.05 g, 6.64 mmol), hydroxylamine hydrochloride (0.553 g, 7.96 mmol) and methanol (20 mL) at room temperature was added sodium acetate (0.653 g, 7.96 mmol). The reaction mixture was stirred at 60° C. for 1 hr and at room temperature overnight. The heterogeneous mixture was concentrated and water (20 mL) was added. The mixture was heated to ˜60° C. and then cooled. The solid was filtered, washed with a mixture of water and ethanol (1:1) and dried to give (E)-5-vinyl-2,3-dihydro-1H-inden-1-one oxime (1.13 g, 6.52 mmol, 98% yield) as a yellow solid. The product had an HPLC ret. time=2.72 min. (condition C); LC/MS M+1=174.3.
Reaction SMILES: CO[CH:3]=[CH:4][CH:5]([O:8][CH3:9])OC.[S:10]1(=[O:21])(=[O:20])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12](=[O:19])[CH2:11]1>>[CH3:9][O:8]/[CH:5]=[CH:4]/[CH:3]=[C:11]1/[S:10](=[O:20])(=[O:21])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12]/1=[O:19]
Reactant: O=C1CS(=O)(=O)c2ccccc21
Reactant: COC=CC(OC)OC
Product: CO/C=C/C=C1\C(=O)c2ccccc2S1(=O)=O
Temperature: 90 °C
Yield: 75.1 %

Procedure:
A mixture of 1,3,3-trimethoxypropene (2.64 g, 20 mmol) and 1.82 g (10 mmol) of 1-benzothiophen-3(2H)-one 1,1-dioxide was heated at 90° C. for 12 h. The solid formed was recrystallized from MeOH to give 1.88 g (75% yield) of final product. 1H NMR (400 MHz, CDCl3): δ 4.02 (s, 3H, OCH3), 6.51 (t, 3JH—H=12.3 Hz, 1H), 7.51-8.11 (m, 6H). GC-MS (70 eV) m/e (relative intensity): 250 (65, M+), 219 (100, (M−OCH3)+).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]([C:17](=[O:28])[C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[C:15]([CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[CH:14]=[C:13]2[C:8]=1[C:9](=[O:36])[CH2:10][C:11]([CH3:35])([CH3:34])[O:12]2)(=O)=O.[F:39][C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:29]1([C:15]2[CH:14]=[C:13]3[C:8]([C:9](=[O:36])[CH2:10][C:11]([CH3:34])([CH3:35])[O:12]3)=[C:7]([C:43]3[CH:44]=[CH:45][C:40]([F:39])=[CH:41][CH:42]=3)[C:16]=2[C:17](=[O:28])[C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:22][CH:23]=2)[CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC1(C)CC(=O)c2c(cc(C3CCCC3)c(C(=O)c3ccc(C(F)(F)F)cc3)c2OS(=O)(=O)C(F)(F)F)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CC1(C)CC(=O)c2c(cc(C3CCCC3)c(C(=O)c3ccc(C(F)(F)F)cc3)c2-c2ccc(F)cc2)O1

Procedure:
In a flask which had been dried by heating, 250 mg (0.44 mmol) of 7-cyclopentyl-2,2-dimethyl-4-oxo-6-[4-(trifluoromethyl)benzoyl]-3,4-dihydro-2H-chromen-5-yl trifluoromethanesulfonate (Example 10A), 81 mg (0.58 mmol) of 4-fluorophenylboronic acid, 160 mg (0.75 mmol) of potassium phosphate and 56 mg (0.05 mmol) of tetrakis(triphenylphosphine)palladium(0) are initially charged, and the apparatus is flushed by repeated evacuation and venting with argon. 4 ml of dioxane are then added, the apparatus is closed and the reaction mixture is heated under reflux overnight. The mixture is cooled and filtered through a layer of silica gel, the filter cake is washed thoroughly with ethyl acetate and the filtrate is concentrated. The crude product is purified on silica gel (mobile phase: cyclohexane→cyclohexane/ethyl acetate 10:1→5:1). This gives 194 mg (86% of theory) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].[CH3:12][O:13][CH2:14][CH2:15]Br.CCOC(C)=O>CN(C=O)C.[I-].[K+]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH2:15][CH2:14][O:13][CH3:12]
Reactant: O=[N+]([O-])c1ccc(Br)c(O)c1
Reactant: COCCBr
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOc1cc([N+](=O)[O-])ccc1Br
Temperature: 70 °C
Yield: 90.6 %

Procedure:
To a solution of 2-bromo-5-nitrophenol (7.24 g, 33.2 mmol) (Method 9) in anhydrous DMF was added 2-methoxy-1-bromoethane (6.92 g, 49.8 mmol) and a catalytic amount of potassium iodide (˜100 mg). The reaction was heated at 70° C. for 4 h before being allowed to cool to rt. The reaction was then poured into a separatory funnel and partitioned between EtOAc (˜250 mL) and water (˜250 mL). The organic phase was dried over Na2SO4 and conc in vacuo giving the crude title compound which was taken up in a minimum volume of warm EtOAc. The resulting solution was cooled in an ice bath and hexanes were slowly added to induce crystallization. The resulting precipitate was isolated via vacuum filtration through a fritted funnel and air dried to give pure title compound (8.3 g, 91%). 1H NMR: (300 MHz) 7.87-7.92 (m, 2H), 7.76 (dd, 1H), 4.35 (t, 2H), 3.73 (t, 2H), 3.35 (s, 3H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[OH-].[Na+].Br[CH2:9][CH2:10][CH2:11][Cl:12]>CC(C)=O>[Cl:12][CH2:11][CH2:10][CH2:9][N:2]([CH3:1])[CH2:3][CH2:4][OH:5]
Reactant: ClCCCBr
Reactant: CNCCO
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CN(CCO)CCCCl
Yield: 56.5 %

Procedure:
2-(Methylamino)-ethanol (1.0 g, 13.3 mmol), acetone (20 ml, 20 vol), 5M NaOH solution (3.19 ml, 1.2 eq.) and 1-bromo-3-chloropropane (6.28 g, 39.9 mmol, 3 eq.) were reacted together according to general procedure A to give the title compound (1.14 g, 55%) as a colourless oil.
Reaction SMILES: Cl.[CH:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH:3]1[NH:12][C:13](=[O:23])[CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][NH:17][S:16]1(=[O:22])=[O:21])[CH2:9]2.C([O-])([O-])=O.[K+].[K+].Br[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C>[CH:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH:3]1[NH:12][C:13](=[O:23])[CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][N:17]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[S:16]1(=[O:22])=[O:21])[CH2:9]2
Reactant: O=C(CN1CCCNS1(=O)=O)NC1C2CC3CC(C2)CC1C3
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CN1CCCN(Cc2ccccc2)S1(=O)=O)NC1C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 4 h
Yield: 94 %

Procedure:
To N-(adamantan-2-yl)-2-(1,1-dioxido-1,2,6-thiadiazinan-2-yl)acetamide hydrochloride (50 mg, 0.135 mmol) in DMF (1 mL), were added K2CO3 (93.3 mg, 0.675 mmol) and (bromomethyl)benzene (46.2 mg, 0.27 mmol). The reaction mixture was agitated for 4 hr at room temperature and extracted with ethyl acetate and brine. The organic layer was dried over MgSO4 and the residue was purified by silica gel column chromatography to yield N-(adamantan-2-yl)-2-(6-benzyl-1,1-dioxido-1,2,6-thiadiazinan-2-yl)acetamide (53 mg, 94%, white solid). 1H NMR (300 MHz, DMSO-d6): δ 7.72-7.69 (brd, 1H), 7.39-7.28 (m, 5H), 4.17 (s, 2H), 3.86-3.83 (m, 1H), 3.79 (s, 2H), 3.46-3.42 (m, 2H), 3.17-3.14 (m, 2H), 1.93-1.89 (m, 2H), 1.80-1.67 (m, 12H), 1.52-1.48 (m, 2H).