Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].[OH-].[Na+].Cl>CN(C=O)C.O>[OH:2][C:1]1[CH:8]=[CH:7][C:5]([O:6][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1
Reactant: Oc1ccc(O)cc1
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 13.4 %

Procedure:
To a mixture of hydroquinone(24 g, 0.22 mol) and ethyl bromoacetate(24 mL, 0.22 mol) in DMF(300 mL) was added 10 M aq. NaOH(22 mL, 0.22 mol). The mixture was stirred at 0° C. for 1 h, diluted with H2O, acidified with 6M aq. HCl and extracted with EtOAc. The EtOAc extract was dried(anhydrous MgSO4) and concentrated in vacuo. The residue was swished with Et2O to give ethyl 4-hydroxyphenoxy-acetate(5.8 g) as a white powder.
Reaction SMILES: COC[O:4][C:5]1[C:13]2[CH:12]=[C:11]([C:14]([OH:16])=O)[S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.P(C#N)(OCC)(OCC)=O>>[OH:4][C:5]1[C:13]2[CH:12]=[C:11]([C:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: COCOc1cccc2sc(C(=O)O)cc12
Reactant: C1COCCN1
Agent: CCOP(=O)(C#N)OCC
Product: O=C(c1cc2c(O)cccc2s1)N1CCOCC1
Yield: 105.9 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 16 using 4-(methoxymethyloxy)benzo(b)thiophene-2-carboxylic acid (3.5 g), morpholine (1.0 g) and diethyl cyanophosphate (3.1 g), 4-(4-hydroxybenzo(b)thiophene-2-carbonyl)morpholine (3.2 g) was obtained as a brown oil. By the reactions in the same manner as in Starting Material Synthesis Example 1 using the brown oil (2.0 g) and (S)-glycidyl nosylate (2.1 g), the title compound (2.0 g) was obtained as brown crystals.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18](=[O:29])[C@@H:19]([NH:23][S:24]([CH2:27][CH3:28])(=[O:26])=[O:25])[CH:20]([CH3:22])[CH3:21])=[CH:11][C:10]=1[O:30][CH3:31])C1C=CC=CC=1.[H][H]>O1CCCC1.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18](=[O:29])[C@@H:19]([NH:23][S:24]([CH2:27][CH3:28])(=[O:26])=[O:25])[CH:20]([CH3:21])[CH3:22])=[CH:11][C:10]=1[O:30][CH3:31]
Reactant: CCS(=O)(=O)N[C@H](C(=O)NCCc1ccc(OCc2ccccc2)c(OC)c1)C(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCS(=O)(=O)N[C@H](C(=O)NCCc1ccc(O)c(OC)c1)C(C)C

Procedure:
14.5 g of (S)-2-(ethylsulfonylamino)-3-methyl-butyric acid N-[2-(4-benzyloxy-3-methoxyphenyl)-ethyl]-amide (Ex. P-1. 1) are dissolved in 420 ml of tetrahydrofuran and shaken together with 3 g of palladium-on-carbon (5%) in a duck-shaped hydrogenation vessel for 5 hours in a hydrogen atmosphere at normal pressure. The catalyst is then removed by filtration. The filtrate is concentrated. The residue is purified by flash-chromatography on silica gel using ethyl acetate/n-hexane 3:1, yielding (S)-2-(ethylsulfonylamino)-3-methyl-butyric acid N-[2-(4-hydroxy-3-methoxyphenyl)ethyl]-amide in the form of a colourless oil.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[NH2:8][CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:11]([CH3:25])([CH3:24])[CH2:10]1>CC(C)=O>[CH:18]1([O:17][N:12]2[C:11]([CH3:24])([CH3:25])[CH2:10][CH:9]([NH:8][C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7])[CH2:14][C:13]2([CH3:16])[CH3:15])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: O=C1CCC(=O)O1
Reactant: CC1(C)CC(N)CC(C)(C)N1OC1CCCCC1
Solvent: CC(C)=O
Product: CC1(C)CC(NC(=O)CCC(=O)O)CC(C)(C)N1OC1CCCCC1
Temperature: 25 °C

Procedure:
A solution of 1.0 gram (10.0 mmol) of succinic anhydride in 25 ml of acetone is added to a solution of 2.64 gram (10.0 mmol) of 4-amino-1-cyclohexyloxy-2,2,6,6-tetramethylpiperidine (as prepared in Example 6B) in 10 ml of acetone. The reaction mixture is stirred for sixteen hours at room temperature and then concentrated to form a white solid. Purification by flash chromatography (silica gel; 9:1 ethyl acetate:ethanol) and recrystallization from heptane:ethyl acetate affords the title compound as a white solid melting at 136°-138° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C@@H:4]([NH:25]C(OC(C)(C)C)=O)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13](=[O:16])[NH:14][CH3:15])=[C:8]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:7]=1.C(OCC)C.[Cl:39]CCl>O1CCOCC1>[Cl-:39].[CH2:18]([O:17][C:8]1[CH:7]=[C:6]([CH2:5][C@H:4]([NH3+:25])[C:3]([O:2][CH3:1])=[O:33])[CH:11]=[CH:10][C:9]=1[O:12][C:13](=[O:16])[NH:14][CH3:15])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: ClCCl
Reactant: CNC(=O)Oc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)cc1OCc1ccccc1
Solvent: C1COCCO1
Solvent: CCOCC
Product: CNC(=O)Oc1ccc(C[C@H]([NH3+])C(=O)OC)cc1OCc1ccccc1
Product: [Cl-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-3-(3-benzyloxy-4-methylcarbamoyloxy-phenyl)-2-tert-butoxycarbonylamino-propionic acid methyl ester (0.90 g) in dichloromethane (12 ml) cooled with an ice-bath was added 4 MHCl in dioxane (6 ml). The mixture was stirred at 0° C. for 2 h. Diethyl ether was added and a white solid was precipitated. (S)-2-(3-Benzyloxy-4-methylcarbamoyloxy-phenyl)-1-methoxycarbonyl-ethyl-ammonium chloride was obtained as white solid by filtration, 0.83 g. 1H NMR (400 MHz, d6-DMSO) 2.64 (s, 3H), 3.10 (m, 2H), 3.68 (s, 3H), 4.33 (m, 1H), 5.10 (s, 2H), 6.79 (m, 1H), 7.04-7.12 (m, 2H), 7.32-7.45 (m, 5H), 7.60 (m, 1H), 8.64 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:18]([CH2:31][CH3:32])=[CH:19][C:20]([CH:27]4[CH2:30][CH2:29][CH2:28]4)=[C:21]([CH:26]=3)[C:22]([NH:24][NH2:25])=[O:23])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].C(=O)(O)[O-].[Na+].[N:38]#[C:39]Br>O1CCOCC1>[NH2:38][C:39]1[O:23][C:22]([C:21]2[C:20]([CH:27]3[CH2:30][CH2:29][CH2:28]3)=[CH:19][C:18]([CH2:31][CH3:32])=[C:17]([CH:26]=2)[C:15]([N:12]2[CH2:11][CH2:10][CH:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)[CH2:14][CH2:13]2)=[O:16])=[N:24][N:25]=1
Reactant: CCc1cc(C2CCC2)c(C(=O)NN)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCc1cc(C2CCC2)c(-c2nnc(N)o2)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-ethylbenzohydrazide (compound 215.6, 600 mg, 1.39 mmol, 1.00 equiv) in 1,4-dioxane (10 mL) was added 10 mL of an aqueous solution of sodium bicarbonate (350 mg, 4.17 mmol, 1.00 equiv). Cyanogen bromide (220 mg, 2.08 mmol, 1.50 equiv) was added to the reaction mixture dropwise. The reaction mixture was stirred at 25° C. for 2 h, then quenched with 20 mL of FeSO4 (aq., sat.) and diluted with DCM. The resulting mixture was stirred vigorously then filtered through celite and washed with 1 M FeSO4, water, and ethyl acetate. The layers were separated and the aqueous phase was extracted with 2×50 mL of DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. This resulted in 600 mg (95%) of 4-(1-(5-(5-amino-1,3,4-oxadiazol-2-yl)-4-cyclobutyl-2-ethylbenzoyl)piperidin-4-yl)benzonitrile as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][C:12]=2[CH3:13])[C:5]([C:14]#[N:15])=[C:4](SC)[N:3]=1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([NH:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:14]#[N:15])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][C:12]=2[CH3:13])[N:7]=1
Reactant: NCc1ccccc1
Reactant: CSc1nc(N)nc(-c2occc2C)c1C#N
Solvent: COCCOC
Product: Cc1ccoc1-c1nc(N)nc(NCc2ccccc2)c1C#N

Procedure:
From 2-amino-4-(3-methyl-furan-2-yl)-6-methylsulfanyl-pyrimidine-5-carbonitrile and benzylamine in DME. EI-MS m/e (%): 305 (M+, 40), 304 ([M—H]+, 100).
Reaction SMILES: C([CH2:3][C@@H:4]([NH:8][C:9]1[CH:14]=[CH:13][C:12](C(F)(F)F)=CC=1)[CH:5]([CH3:7])C)#N.[OH-:19].[Li+].Cl.[O:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[N:8]1([C:4]2[CH:5]=[CH:7][C:24]([CH2:25][C:26]([OH:22])=[O:19])=[CH:23][CH:3]=2)[CH2:9][CH2:14][CH2:13][CH2:12]1
Reactant: [OH-]
Reactant: C1CCOC1
Reactant: CC(C)[C@@H](CC#N)Nc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Li+]
Product: O=C(O)Cc1ccc(N2CCCC2)cc1
Reaction time: 5 h

Procedure:
Methyl 4-(pyrrolidin-1-yl)phenylacetate (0.13 g, 0.59 mmol) obtained in Step 1 was dissolved in tetrahydrofuran (1.2 mL), 1 M aqueous lithium hydroxide solution (1.2 mL) was added, and the mixture was stirred for 5 hrs. The mixture was neutralized with 1 N aqueous hydrogen chloride solution (1.2 mL), and the solvent was evaporated to give a crude product of the title compound, which was used for the synthesis of A-54.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:25](C4CCCCO4)[NH:24][CH2:23][C:12]=3[C:13](=[O:22])[N:14]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:15]=2[CH:16]=1.N1C=CC=CC=1C1C=CC2C3C(=CN(C4CCCCO4)N=3)C(=O)N(CC(F)(F)F)C=2C=1.Cl.O1CCOCC1>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[NH:25][N:24]=[CH:23][C:12]=3[C:13](=[O:22])[N:14]([CH2:17][C:18]([F:20])([F:19])[F:21])[C:15]=2[CH:16]=1
Reactant: O=c1c2c(c3ccc(-c4ccccn4)cc3n1CC(F)(F)F)N(C1CCCCO1)NC2
Agent: Cl
Agent: O=c1c2cn(C3CCCCO3)nc2c2ccc(-c3ccccn3)cc2n1CC(F)(F)F
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=c1c2cn[nH]c2c2ccc(-c3ccccn3)cc2n1CC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7-(pyrid-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-5-(2,2,2-trifluoroethyl)-2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one and 7-(pyrid-2-yl)-2-(tetrahydro-2H-pyran-2-yl)-5-(2,2,2-trifluoroethyl)-2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (60 mg, 0.14 mmol) in 1 mL of DCM is added a 4M solution of anhydrous hydrogen chloride in dioxane (350 μL, 1.40 mmol). After stirring for 1 hour at room temperature, the suspension is filtered and the solid is dried under vacuum to give 59 mg of 7-(pyrid-2-yl)-5-(2,2,2-trifluoroethyl)-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one in the form of a beige-coloured powder (hydrochloride, 0.88 H2O; quantitative yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:27])=[C:6]([C:8]([NH:20]S(C(C)(C)C)=O)([CH2:18][F:19])[CH2:9][S:10]([C:13]([C:16]#[N:17])([CH3:15])[CH3:14])(=[O:12])=[O:11])[CH:7]=1.Cl>O1CCOCC1>[NH2:17][C:16]1[C:13]([CH3:15])([CH3:14])[S:10](=[O:12])(=[O:11])[CH2:9][C@@:8]([C:6]2[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[F:27])([CH2:18][F:19])[N:20]=1.[NH2:17][C:16]1[C:13]([CH3:15])([CH3:14])[S:10](=[O:12])(=[O:11])[CH2:9][C@:8]([C:6]2[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[F:27])([CH2:18][F:19])[N:20]=1
Reactant: CC(C)(C)S(=O)NC(CF)(CS(=O)(=O)C(C)(C)C#N)c1cc(Br)ccc1F
Agent: Cl
Solvent: C1COCCO1
Product: CC1(C)C(N)=N[C@@](CF)(c2cc(Br)ccc2F)CS1(=O)=O
Product: CC1(C)C(N)=N[C@](CF)(c2cc(Br)ccc2F)CS1(=O)=O
Temperature: 100 °C
Yield: 73 %
Yield: 78 %

Procedure:
To a solution of N-(2-(5-bromo-2-fluorophenyl)-1-((2-cyanopropan-2-yl)sulfonyl)-3-fluoropropan-2-yl)-2-methylpropane-2-sulfinamide (45 g, 93 mmol) in dioxane (800 mL) was added hydrochloric acid, 4.0M solution in 1,4-dioxane (107 mL, 428 mmol). The reaction mixture was heated to 100° C. for 2 d. The reaction was allowed to cool to RT, concentrated, and dried under high vacuum to give a light brown solid. The solids were triturated in DCM, filtered, rinsed, and dried to give a white solid. The compound was separated into its enantiomers via prep-scale supercritical fluid chromatography using a Chiralpak AD-H column with an isocratic 75% carbon dioxide/25% methanol with 0.2% ammonia solvent system to yield (R)-5-amino-3-(5-bromo-2-fluorophenyl)-3-(fluoromethyl)-6,6-dimethyl-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide (41.4 g, 109 mmol, 78% yield) and (S)-5-amino-3-(5-bromo-2-fluorophenyl)-3-(fluoromethyl)-6,6-dimethyl-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide (38.6 g, 101 mmol, 73%) LC/MS (ESI+) m/z=380.9; 382.9 for both diastereomers. (M+H; 2 bromine isotopes).
Reaction SMILES: [Cl:1][C:2]1[C:28]([CH3:29])=[CH:27][C:5]2[N:6]([C@@H:9]3[O:26][CH2:25][C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]3[O:11][C:12](=[O:14])[CH3:13])[CH:7]=[N:8][C:4]=2[CH:3]=1.[Br:30]N1C(=O)CCC1=O>O1CCCC1>[Br:30][C:7]1[N:6]([C@@H:9]2[O:26][CH2:25][C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]2[O:11][C:12](=[O:14])[CH3:13])[C:5]2[CH:27]=[C:28]([CH3:29])[C:2]([Cl:1])=[CH:3][C:4]=2[N:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](OC(C)=O)CO[C@H]1n1cnc2cc(Cl)c(C)cc21
Solvent: C1CCOC1
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](OC(C)=O)CO[C@H]1n1c(Br)nc2cc(Cl)c(C)cc21
Yield: 68.8 %

Procedure:
The title compound was prepared according to General Procedure IV using) 5-Chloro-6-methyl-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-benzimidazole (0.12 g, 0.28 mmol), 20 ml tetrahydrofuran (Aldrich Sure Seal, Milwaukee), and a total of 2.0 g (11 mmol) of N-bromosuccinimide that was added over 2 h. The product from work-up by General Procedure IV was partially purified on a silica gel column (2.5×20 cm, 230-400 mesh) with dichloromethane containing 0.5% methanol to give 2-Bromo-5-chloro-6-methyl-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-benzimidazole (0.097 g) of sufficient purity for the next step; 1H NMR (DMSO-d6) δ7.99 (s,1H), 7.66 (s, 1H), 5.93-5.90 (d, 1H, J=8.9 Hz), 5.69-5.62 (m, 3H), 4.02-3.92 (m, 2H), 2.41 (s, 3H), 2.20 (s, 3H), 1.99 (s, 3H), 1.73 (s, 3H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[S:20]([Cl:24])(Cl)(=[O:22])=[O:21].[NH2:25][C:26]1[C:31]([CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:30][CH:29]=[CH:28][C:27]=1S(O)(=O)=O.C(N(CCCC)CCCC)CCC>ClCCl>[NH2:25][C:26]1[C:31]([CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:30][CH:29]=[CH:28][C:27]=1[S:20]([Cl:24])(=[O:22])=[O:21]
Reactant: O=S(=O)(Cl)Cl
Reactant: Nc1c(C2CCCC2)cccc1S(=O)(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCN(CCCC)CCCC
Product: Nc1c(C2CCCC2)cccc1S(=O)(=O)Cl
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2.42 g (9.2 mmol) of triphenylphosphine in 5 ml of dichloromethane is added dropwise, at 0° C. under a nitrogen atmosphere, 0.70 ml (8.8 mmol) of sulphuryl chloride. The reaction medium is left stirring for 10 minutes at 0° C., followed by addition over 5 minutes of a solution containing 1.06 g (4.4 mmol) of 2-amino-3-cyclopentylbenzenesulphonic acid and 1.04 ml of tributylamine in 3 ml of dichloromethane. The mixture is brought to room temperature and is left at this temperature for 2 hours, then it is purified by chromatography on a column of silica gel, eluting with a dichloromethane/pentane mixture (1:1).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([O:14][CH2:15][CH3:16])[CH:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:22].C(OCC)(=O)C>C(Cl)Cl>[CH2:15]([O:14][C:5]1[CH:4]=[C:3]([S:2]([CH3:1])=[O:22])[CH:13]=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:16]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1ccc(SC)cc1OCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(S(C)=O)cc1OCC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 60.7 %

Procedure:
To a cooled solution of ethyl 4-methylthio-2-ethoxybenzoate (1.1 g, 4.6 mmol) in methylene chloride (40 mL) was added 3-chloroperoxybenzoic acid (1.1 g, 4.5 mmol, 77%) in several portions. The reaction mixture was stirred at 0° C. for 15 min, after which TLC (50% ethyl acetate in hexanes) showed consumption of starting material. The reaction mixture was quenched with a solution of sodium thiosulfate and neutralize with a solution of sodium bicarbonate. The product was extracted three times with methylene chloride. The organic layer was washed with sodium bicarbonate, dried over magnesium sulfate, and concentrated. Purification of the crude residue by flash column chromatography (silica gel, eluting with 50% ethyl acetate in hexanes) gave ethyl 2-ethoxy-4-methanesulfinylbenzoate as a yellow oil (0.70 g, 58%). LC-MS: 257.2 [(M+H)+].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([F:58])[C:5]([S:52]([CH:55]2[CH2:57][CH2:56]2)(=[O:54])=[O:53])=[C:6]([CH2:8][N:9]([CH3:51])[C:10]([CH:12]([NH:24][C:25]2[CH:26]=[C:27]3[C:32](=[C:33]([F:35])[CH:34]=2)[C:31]([N:36]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[N:30][CH:29]=[CH:28]3)[C:13]2[CH:18]=[CH:17][C:16]([C@@H:19]([CH3:22])[CH2:20][OH:21])=[C:15]([CH3:23])[CH:14]=2)=[O:11])[CH:7]=1.[C:59](Cl)(Cl)=[O:60]>C(#N)C.ClCCl>[C:39]([O:38][C:37]([N:36]([C:31]1[C:32]2[C:27](=[CH:26][C:25]([NH:24][C@H:12]3[C:10](=[O:11])[N:9]([CH3:51])[CH2:8][C:6]4[CH:7]=[C:2]([CH:3]=[C:4]([F:58])[C:5]=4[S:52]([CH:55]4[CH2:57][CH2:56]4)(=[O:53])=[O:54])[NH:1][C:59](=[O:60])[O:21][CH2:20][C@H:19]([CH3:22])[C:16]4[CH:17]=[CH:18][C:13]3=[CH:14][C:15]=4[CH3:23])=[CH:34][C:33]=2[F:35])[CH:28]=[CH:29][N:30]=1)[C:44](=[O:45])[O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:43])([CH3:41])([CH3:40])[CH3:42]
Reactant: O=C(Cl)Cl
Reactant: Cc1cc(C(Nc2cc(F)c3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)N(C)Cc2cc(N)cc(F)c2S(=O)(=O)C2CC2)ccc1[C@@H](C)CO
Solvent: CC#N
Solvent: ClCCl
Product: Cc1cc2ccc1[C@@H](C)COC(=O)Nc1cc(F)c(S(=O)(=O)C3CC3)c(c1)CN(C)C(=O)[C@@H]2Nc1cc(F)c2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc2c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 25.8 %

Procedure:
A solution of 11F (163 mg, 0.198 mmol) in acetonitrile (3 mL) and dichloromethane (6 mL) was cooled to 0° C. To this solution was added phosgene (20% in toluene) (0.108 mL, 0.218 mmol). The mixture was stirred at 0° C. for 5 min, and rt for 1 h. The mixture was bubbled with Ar for 10 min to remove excess phosgene. The resulting solution was added dropwise over 3 h via a syringe pump into a solution of TEA (0.276 mL, 1.978 mmol) in CH2Cl2 (260 mL) at rt. The solution was stirred for 16 h. Solvent was removed and the crude product was purified by flash chromatography to give a mixture of diastereoisomers (102 mg, 60.7% yield). The diastereoisomers were separated by a prep chiral HPLC equipped with an IA column to give 11G (43 mg, 0.051 mmol, 43.0% yield). MS (ESI) m/z: 850.1 [M+1]+.
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1B(O)O.[O:21]=[S:22]1(=[O:39])[CH2:27][CH2:26][N:25]2[CH2:28][CH2:29][CH2:30][C@@H:31]([C:32]3[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=3)[C:24]2=[N:23]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC#N.C(O[Cu]OC(=O)C)(=O)C>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[O:38][C:35]1[CH:34]=[CH:33][C:32]([C@H:31]2[C:24]3=[N:23][S:22](=[O:39])(=[O:21])[CH2:27][CH2:26][N:25]3[CH2:28][CH2:29][CH2:30]2)=[CH:37][CH:36]=1
Reactant: O=S1(=O)CCN2CCC[C@@H](c3ccc(O)cc3)C2=N1
Reactant: OB(O)c1cc(C(F)(F)F)ccc1Cl
Agent: CC(=O)O[Cu]OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: c1ccncc1
Solvent: CC#N
Product: O=S1(=O)CCN2CCC[C@@H](c3ccc(Oc4cc(C(F)(F)F)ccc4Cl)cc3)C2=N1
Temperature: 25 °C
Reaction time: 48 h
Yield: 0.6 %

Procedure:
Diacetoxycopper (907 mg) was added to a mixture of pyridine (0.606 mL), 2-chloro-5-(trifluoromethyl)phenylboronic acid (459 mg), 4-[(9S)-2,2-dioxido-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazin-9-yl]phenol (700 mg) and cesium carbonate (814 mg) in MeCN (25 mL). The mixture was stirred at room temperature under a dry atmosphere with anhydrous calcium chloride tube for 2 days. The insoluble material was removed by filtration, and the filtrate was diluted with water, and extracted with EtOAc. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. Silica-gel was added and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) and concentrated in vacuo to give the title compound (5.9 mg) as pale yellow gum.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:18]([C:29]#[N:30])[CH:17]=1.O>CN(C)C(=O)C>[C:23]1([S:22][C:19]2[CH:20]=[CH:21][C:16]([NH:15][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[CH:17][C:18]=2[C:29]#[N:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: N#Cc1cc(N)ccc1Sc1ccccc1
Reactant: CC(O)(C(=O)O)C(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Solvent: O
Product: CC(O)(C(=O)Nc1ccc(Sc2ccccc2)c(C#N)c1)C(F)(F)F
Temperature: 60 °C
Reaction time: 1 h
Yield: 158.7 %

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (2.16 g 13.7 mmol) in N,N-dimethylacetamide (20 mL) was rapidly added thionyl chloride (1.73 g, 14.5 mmol) and the mixture (a precipitate formed after a few minutes) stirred at -20° C. to -10° C. for 1 hour. (4-Amino-2-cyanophenyl)phenyl sulfide (2.08 g, 9.2 mmol) was then added in one portion and the mixture allowed to stir at room temperature overnight. The solution was poured into 500 mL of water and extracted with two 100 mL portions of ethyl ether. The oil obtained-on removal of the ethyl ether was chromatographed on 325 g of silica gel using an ethyl ether (0%, 5%, 10% and 20%) in methylene chloride gradient. The proper fractions were combined, the solvent removed in vacuo and the residue heated overnight at 60° C./0.1 mm to yield 5.35 g (93%) of N-(4-phenylthio-3-cyanophenyl)-3,3,3,-trifluoro-2-hydroxy-2-methylpropanamide, mp 124°-126° C. 1H--NMR (300 MHz, d6 --DMSO): 1.59 (s, 3H, CH3), 7.32-7.47 (m, 6H, aromatic), 7.59 (s, 1H, OH), 8.07 (dd 1H, J=8.8, 2.3 Hz, aromatic), 8.33 (d, 1H, J=2.3 Hz, aromatic), 10.48 (s, 1H, NH). MS (CI, CH4): 367(M+1).
Reaction SMILES: Br[CH2:2][C:3]1[NH:7][C:6](=[O:8])[NH:5][C:4]=1[C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1.[C:19]1([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].[ClH:37]>CC(O)C.O.C(O)C>[ClH:37].[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]([C:4]2[NH:5][C:6](=[O:8])[NH:7][C:3]=2[CH2:2][N:28]2[CH2:29][CH2:30][CH:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:26][CH2:27]2)=[O:18])=[CH:11][CH:12]=1
Reactant: COc1ccc(C(=O)c2[nH]c(=O)[nH]c2CBr)cc1
Reactant: c1ccc(C2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Solvent: CCO
Product: COc1ccc(C(=O)c2[nH]c(=O)[nH]c2CN2CCC(c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4.7 g (15 mmole) of 5-(bromomethyl)-1,3-dihydro-4-(4-methoxybenzoyl)-2H-imidazol-2-one, 2.5 g (16 mmole) of 4-phenylpiperidine, 2.1 g (15 mmole) of potassium carbonate and 75 ml of ethanol is stirred at 25° C. for 16 hours. Water (100 ml) is added and a precipitate forms. This is separated by filtration and washed with water. It is then suspended in 2-propanol and 1 equivalent of hydrogen chloride in 2-propanol is added. The resulting solid is separated by filtration and recrystallized from 2-propanol containing a little water to give 1,3-dihydro-4-(4-methoxybenzoyl)-5-[(4-phenyl-1-piperidinyl)methyl]-2H-imidazol-2-one hydrochloride melting at about 230° C. with decomposition.
Reaction SMILES: C(NCC)C.[CH2:6]([O:8][C:9](=[O:22])[CH:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1)[C:11](O)=O)[CH3:7].C=O>O>[Cl:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH2:14][C:10](=[CH2:11])[C:9]([O:8][CH2:6][CH3:7])=[O:22]
Reactant: CCOC(=O)C(Cc1cccc(Cl)c1)C(=O)O
Agent: C=O
Solvent: O
Solvent: CCNCC
Product: C=C(Cc1cccc(Cl)c1)C(=O)OCC

Procedure:
Diethylamine (27.6 g, 39 ml) is added dropwise with shaking to 3-chlorobenzylmalonic acid monoethyl ester (90.0 g) [Chem. Ber. 92, 203 (1959)], in a flask cooled in a water bath. Aqueous formaldehyde (37%, 38 ml) is added dropwise with shaking and cooling as before. Gas is evolved, and the reaction mixture becomes lighter in color. The mixture is stirred at room temperature for 65 hours, then water (500 ml) is added, and the solution extracted with ether (2×350 ml). The combined ether solutions are washed with water (300 ml), 3N HCl (2×200 ml) and water (300 ml). The ether solution is dried over magnesium sulfate, and the solvent removed under reduced pressure to give ethyl α-(3-chlorobenzyl)acrylate as a yellow oil, NMR (CDCl3)δ: 7.15 (m, 4H), 6.22 (s, 1H), 5.45 (m, 1H), 4.13 (q, 2H), 3.58 (s, 2H), 1.23 (t, 3H).