Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH:1]([N:14]1[CH2:17][CH:16]([O:18][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 18 h
Yield: 94.7 %

Procedure:
To a solution of 1-benzhydryl-3-hydroxyazetidine (4.78 g, 20 mmol) in dichloromethane (35 ml) was added triethylamine (2.43 g, 24 mmol) and cooled to 0° C. A solution of methanesulfonyl chloride (1.86 ml, 24 mmol) in dichloromethane (5 ml) was then introduced slowly, and the resulting suspension was stirred at room temperature for 18 h. The volatiles were evaporated, and the residue was extracted with a mixture of ether and ethyl acetate. The combined extract was filtered through Magnosol and the filtrate evaporated to give 6.01 g of a light yellow solid; MS (ES) m/z 318.0 (MH+).
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13]([N:15]1[CH2:19][CH2:18][C@@H:17]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([C:29]3[CH:30]=[C:31]4[C:35](=[CH:36][CH:37]=3)[NH:34][N:33]=[CH:32]4)(=[O:28])=[O:27])=[CH:22][CH:21]=2)[CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[CH3:13][N:15]1[CH2:19][CH2:18][C@@H:17]([C:20]2[CH:21]=[CH:22][C:23]([S:26]([C:29]3[CH:30]=[C:31]4[C:35](=[CH:36][CH:37]=3)[NH:34][N:33]=[CH:32]4)(=[O:27])=[O:28])=[CH:24][CH:25]=2)[CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(S(=O)(=O)c3ccc4[nH]ncc4c3)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CC[C@@H](c2ccc(S(=O)(=O)c3ccc4[nH]ncc4c3)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.8 %

Procedure:
Trifluoroacetic acid (3.4 mL) was added to a solution of (S)-3-[4-(1H-indazole-5-sulfonyl)-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (193.4 mg, 0.452 mmol) in DCM (3.4 mL) under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the residue was dissolved in acetonitrile (4 mL). Formaldehyde (37% in water, 0.181 mL) was added, under nitrogen atmosphere, to this material followed by sodiumcyanoborohydride (85 mg). The reaction mixture was stirred for 1.5 hour, and then a saturated solution of Na2CO3 was then added. The mixture was extracted with DCM, and the combined organic extracts were dried over Na2SO4, filtered, and evaporated under reduced pressure. The crude material was dissolved in HCl (2 M, 10 mL) and the resulting mixture was stirred for 8 hours. Solvent was evaporated under reduced pressure and the crude residue was purified via flash chromatography (DCM/MeOH/NH4OH) to give 89.2 mg of 5-[4-((S)-1-methyl-pyrrolidin-3-yl)-benzenesulfonyl]-1H-indazole which was treated with 1,4-dioxane (2 mL) and transformed into 83.3 mg of the corresponding hydrochloride salt by addition of HCl (4 M in 1,4-dioxane, 0.84 mL). MS (M+H)=342.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12]2[CH:13]=[C:14]([C:21]([OH:23])=O)[C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=2[O:10][C:9]([CH3:25])([CH3:24])[C:8]1=[O:26].[CH:27]([NH:30][CH:31]1[CH2:35][CH2:34][N:33]([C:36]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:37])[CH2:32]1)([CH3:29])[CH3:28]>>[CH:27]([N:30]([C:21]([C:14]1[C:15]([C:17]([F:20])([F:18])[F:19])=[CH:16][C:11]2[O:10][C:9]([CH3:25])([CH3:24])[C:8](=[O:26])[N:7]([CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:12]=2[CH:13]=1)=[O:23])[CH:31]1[CH2:35][CH2:34][N:33]([C:36]([O:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[O:37])[CH2:32]1)([CH3:29])[CH3:28]
Reactant: COCCCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)O)cc21
Reactant: CC(C)NC1CCN(C(=O)OCc2ccccc2)C1
Product: COCCCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)N(C(C)C)C3CCN(C(=O)OCc4ccccc4)C3)cc21

Procedure:
Using 4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid and benzyl 3-(isopropylamino)pyrrolidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 5.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH3:7])[C:4]([OH:6])=[O:5].[OH-].[Na+:11]>C(O)C>[OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH3:7])[C:4]([O-:6])=[O:5].[Na+:11]
Reactant: CC(CO)(CO)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(CO)(CO)C(=O)[O-]
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2,2-bis(hydroxymethyl)propionic acid (2.21 g) in ethanol (30 mL) was added 5N aqueous solution of sodium hydroxide (3.30 mL) and the mixture was stirred at room temperature for 5 minutes. The reaction mixture was concentrated to give the title compound.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[Br:7][C:8]1[CH:9]=[C:10]([S:15]([N:18]2[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]2)(=[O:17])=[O:16])[CH:11]=[CH:12][C:13]=1[F:14].O.CC1C=CC(S(O)(=O)=O)=CC=1.ClCCl>O>[Br:7][C:8]1[CH:9]=[C:10]([S:15]([N:18]2[CH2:19][CH2:20][CH:21]([O:24][CH:6]3[CH2:5][CH2:4][CH2:3][CH2:2][O:1]3)[CH2:22][CH2:23]2)(=[O:17])=[O:16])[CH:11]=[CH:12][C:13]=1[F:14]
Reactant: O=S(=O)(c1ccc(F)c(Br)c1)N1CCC(O)CC1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(c1ccc(F)c(Br)c1)N1CCC(OC2CCCCO2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 66.3 %

Procedure:
3,4-Dihydro-2H-pyran (0.28 mL, 3.1 mmol) was added dropwise to a 0° C. solution of Example 354a (0.51 g, 1.5 mmol), 4-methylbenzenesulfonic acid hydrate (0.59 g, 3.1 mmol), and dichloromethane (28 mL). The reaction mixture was stirred at ambient temperature for 5 hours. Water was added and the mixture was extracted with dichloromethane. The organic layer was washed with water, saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, dichloromethane/gradient with methanol) to afford the title compound (420 mg, 65.9% yield).
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.C(O)(=[O:14])C.OO>O1CCCC1>[F:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:14]
Reactant: CC(=O)O
Reactant: Cc1cccc(B(O)O)c1F
Agent: OO
Solvent: C1CCOC1
Product: Cc1cccc(O)c1F
Reaction time: 24 h
Yield: 98 %

Procedure:
To a solution of 2-fluoro-3-methyl-phenylboronic acid (25.0 g, 0.162 mol) in tetrahydrofuran (220 mL) was added glacial acetic acid (150 mL). The resulting mixture was cooled to 0° C. before hydrogen peroxide (50% aqueous solution, 30 mL) was added. The resulting mixture was allowed to come to room temperature and stirred for 24 h. The mixture was evaporated and the residue was dissolved in ethyl acetate, washed with hydrochloric acid (0.5N), water and brine. The organic phase was dried, filtered and evaporated which afforded 2-fluoro-3-methyl-phenol (20.0 g, 98%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C@:10]2([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[C:11](=[O:12])[C@@H:6]([C@:7]([CH3:28])([CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[C@@H:8]([O:18][CH2:19][O:20][CH3:21])[CH2:9]2)[C:5](=[O:29])[CH:4]=1.[Li+].CC([N-]C(C)C)C.[CH2:38](Br)[CH:39]=[C:40]([CH3:42])[CH3:41]>C1COCC1>[CH3:1][O:2][C:3]1[C@:10]2([CH2:13][CH:14]=[C:15]([CH3:16])[CH3:17])[C:11](=[O:12])[C@@H:6]([C@:7]([CH3:28])([CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[C@@H:8]([O:18][CH2:19][O:20][CH3:21])[CH2:9]2)[C:5](=[O:29])[C:4]=1[CH2:38][CH:39]=[C:40]([CH3:42])[CH3:41]
Reactant: CC(C)=CCBr
Reactant: COCO[C@H]1C[C@@]2(CC=C(C)C)C(=O)[C@H](C(=O)C=C2OC)[C@]1(C)CCC=C(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COCO[C@H]1C[C@@]2(CC=C(C)C)C(=O)[C@H](C(=O)C(CC=C(C)C)=C2OC)[C@]1(C)CCC=C(C)C
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 51.2 %

Procedure:
A 1 dram vial equipped with a stir bar is charged with 12.6 mg (0.031 mmol, 1 equiv.) of starting material 50 followed by 660 μL of THF. The solution is cooled to −78° C. prior to the addition of 124 μL of LDA (0.50 M, 0.062 mmol, 2 equiv.). The mixture was then stirred for 20 minutes followed by the addition of 18 μL (0.155 mmol, 5 equiv.) of prenyl bromide. Stirring was continued for an additional 20 minutes at which time the reaction was quenched by the addition of 500 μL of saturated aqueous ammonium chloride. The reaction was transferred to a separatory funnel in diethyl ether, and the organic layer was washed twice with water, dried with MgSO4, and concentrated in vacuo. The crude product was purified by silica gel chromatography (Rf=0.25 in 9:1 hexane:ethyl acetate), affording 7.5 mg (51% yield) of 54 as a clear oil. 1H NMR (500 MHz, CDCl3) δ ppm 5.07 (t, J=7.0 Hz, 1H), 5.04-4.94 (m, 2H), 4.58 (dd, J=7.0, 47.1 Hz, 2H), 3.95 (s, 3H), 3.60 (dd, J=5.3, 11.4 Hz, 1H), 3.33 (s, 3H), 3.25 (s, 1H), 3.13 (d, J=6.4 Hz, 2H), 2.50 (dd, J=6.2, 14.7 Hz, 1H), 2.42-2.28 (m, 2H), 2.25 (dd, J=5.2, 13.4 Hz, 1H), 1.96-1.84 (m, 1H), 1.77 (dd, J=11.5, 13.3 Hz, 1H), 1.71-1.61 (m, 18H), 1.58-1.51 (m, 2H), 1.30-1.23 (m, 2H), 1.18 (dt, J=4.3, 12.8 Hz, 2H), 0.91 (s, 3H). HRMS-ESI (m/z): [M+H]+ calculated for C29H44O5, 473.3262. found 473.3250.
Reaction SMILES: [N:1]1[C:14]2[C:5](=[C:6]3[C:11](=[CH:12][CH:13]=2)[CH2:10][CH2:9][CH:8]([CH2:15][OH:16])[O:7]3)[CH:4]=[CH:3][CH:2]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[N:1]1[C:14]2[C:5](=[C:6]3[C:11](=[CH:12][CH:13]=2)[CH2:10][CH2:9][CH:8]([CH2:15][O:16][S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[O:7]3)[CH:4]=[CH:3][CH:2]=1
Reactant: OCC1CCc2ccc3ncccc3c2O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CCc3ccc4ncccc4c3O2)cc1
Reaction time: 120 h
Yield: 45.8 %

Procedure:
(7,8-Dihydro-6H-5-oxa-1-aza-phenanthren-6-yl)-methanol (0.27 g, 1.3 mmole) was dissolved in 75 mL of methylene chloride and p-toluenesulfonyl chloride (0.60 g, 3.1 mmole) added. The mixture was placed in an ice/isopropanol bath and first N,N-diisopropylethylamine (0.55 mL, 3.1 mmole) and then N,N-dimethyaminopyridine added. The mixture was allowed to stir under nitrogen for 5 days. It was washed with 150 mL portions of 2 N aqueous HCl, saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuum to an orange oil. Column chromatography on silica gel with 0-5% methanol/methylene chloride gave 0.22 g of the title compound. 1H-NMR (CDCl3): doublet 8.8 δ (1 H); doublet 8.25 δ (1 H); doublet 7.8 δ (2 H); doublet 7.6 δ(1 H); multiplet 7.3 δ (4 H); multiplet 4.4 δ (1 H); doublet 4.3 δ (2 H); multiplet 2.9 δ (2 H); singlet 2.4 δ (3 H); multiplet 2.0 δ (2 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:4]=1[CH2:5][NH:6][C:7]([NH:9][C@H:10]([C:14](OC)=[O:15])[CH:11]([CH3:13])[CH3:12])=[O:8].C(N(CC)CC)C>CO>[CH3:1][O:2][C:3]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:14](=[O:15])[C@H:10]([CH:11]([CH3:13])[CH3:12])[NH:9][C:7]1=[O:8]
Reactant: COC(=O)[C@@H](NC(=O)NCc1ccc(OC)cc1OC)C(C)C
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc(CN2C(=O)N[C@@H](C(C)C)C2=O)c(OC)c1
Yield: 113.6 %

Procedure:
A solution of methyl N-[(2,4-dimethoxybenzyl)carbamoyl]-L-valinate (4.2 g) and triethylamine (1.3 g) in methanol was stirred while heating to reflux for 5 hr. After the solvent was distilled off under reduced pressure, the residue was purified by column chromatography (NH silica gel cartridge, hexane/ethyl acetate) to afford (5S)-3-(2,4-dimethoxybenzyl)-5-(propan-2-yl)imidazolidine-2,4-dione (4.3 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[N:18]2.[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[N:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=2)[CH2:29][CH2:28]1>C(Cl)Cl.CO>[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[N:39]=[CH:38][C:37]([NH:40][C:23]([C:20]3[CH:21]=[CH:22][C:13]([C:3]4[C:4]([Cl:12])=[C:5]([O:10][CH3:11])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=4[Cl:1])=[C:14]4[C:19]=3[N:18]=[CH:17][CH:16]=[CH:15]4)=[O:24])=[CH:36][CH:35]=2)[CH2:29][CH2:28]1
Reactant: CN1CCN(Cc2ccc(N)cn2)CC1
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)O)c3ncccc23)c1Cl
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)nc3)c3ncccc23)c1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 5-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid (Step 159.1), 6-(4-methyl-piperazin-1-ylmethyl)-pyridin-3-ylamine (Step 39.1), and stirring the reaction mixture for 3 h at rt. Title compound: ESI-MS: 566.0 [M+H]+; tR=3.64 min (System 1); TLC: Rf=0.24 (DCM/MeOH, 9:1).
Reaction SMILES: [Li+].[C:2]([CH2:4][CH2:5][CH:6]([P:11]([O:16]CC)([O:13]CC)=[O:12])[S:7]([O-:10])(=[O:9])=[O:8])#[N:3].[H][H]>N.[Rh]>[NH2:3][CH2:2][CH2:4][CH2:5][CH:6]([P:11]([OH:16])([OH:13])=[O:12])[S:7]([OH:10])(=[O:8])=[O:9]
Reactant: [H][H]
Reactant: CCOP(=O)(OCC)C(CCC#N)S(=O)(=O)[O-]
Agent: [Rh]
Agent: N
Agent: [Li+]
Product: NCCCC(P(=O)(O)O)S(=O)(=O)O

Procedure:
The hydrogenation of 3-cyano-1-diethoxyphosphinylpropanesulfonic acid lithium salt is carried out using the hydrogenation technique of Freifelder (J. Am. Chem. Soc., 82, 2386 (1960)). The cyano compound (2.62 g; 0.01 mole) is placed in 20 ml of 10% methanolic ammonia. Rhodium on alumina (5%) catalyst (0.5 g) is added, and the mixture is hydrogenated at 40 PSI on a Parr apparatus for several hours (until uptake of hydrogen is complete). The catalyst is filtered off, and the filtrate is evaporated dry. The product is hydrolyzed by dissolving the residue in 25 ml of 6N HCl and refluxing the solution for 12-24 hours. It is then evaporated to dryness under vacuum on a rotary evaporator. Distilled water (25 ml) is added, and the solution is again evaporated dry. The resulting residue is dissolved in a few ml H2O, and ethanol is added to precipitate a solid. This is recrystallized from water/ethanol to yield 4-amino-1-phosphonobutanesulfonic acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH2:8])=[CH:3][CH:2]=1.Cl[C:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:11]>ClCCl>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:10](=[O:11])[O:12][C:13]2[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=2)=[CH:3][CH:2]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCc1ccncc1
Solvent: ClCCl
Product: O=C(NCc1ccncc1)Oc1ccc([N+](=O)[O-])cc1

Procedure:
A solution of pyridin-4-ylmethanamine (505 uL, 5 mmol) and p-nitrophenyl chloroformate (1.0 g, 5 mmol) in dichloromethane (20 mL) was stirred at room temperature for 5 h. Upon completion, the product was collected by vacuum filtration, washed with dichloromethane and purified by preparative HPLC (10-90% acetonitrile in water) to provide 4-nitrophenyl pyridin-4-ylmethylcarbamate as a white solid. MS=274 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[CH2:5][C:4](=[O:13])[CH:3]=1.[OH-].[K+]>C(O)C.C1(C)C=CC=CC=1>[O:9]1[CH:10]=[CH:11][CH:12]=[C:8]1[CH:6]1[CH2:7][C:2]2[N:1]=[CH:7][CH:2]=[C:3]([CH3:4])[C:3]=2[C:4](=[O:13])[CH2:5]1
Reactant: NC1=CC(=O)CC(c2ccco2)C1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccnc2c1C(=O)CC(c1ccco1)C2
Temperature: 115 °C
Yield: 124.8 %

Procedure:
In a mixture of ethanol (30 ml) and toluene (90 ml) was dissolved 1-amino-5-(2-furyl)cyclohexen-3-one (1.25 g), and to the solution were added 3-oxobutylaldehydedimethylacetal (2.36 g) and granulated potassium hydroxide (390 mg). The mixture was stirred at 115° C. (bath temperature), and to the mixture was added granulated potassium hydroxide (80 mg), 30 minutes later; 1 hour later; and 1.5 hours later; respectively. The reaction solution was stirred at the same temperature for 1 hour. The reaction solution was cooled, and concentrated under reduced pressure, and to the residue was added ethyl acetate (50 ml) and water (15 ml). The mixture was shaken and the separated upper layer was washed with saturated brine. Under reduced pressure, ethyl acetate was evaporated, and the residue was purified with silica gel column chromatography (EtOAc/hexane) and eluted with ethyl acetate/hexane to give 7-(2-furyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (1.0 g) as colorless crystals.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[S:21][C:22]([C:25]2[NH:26][C:27]([CH:30]([C:38]3[CH:43]=[CH:42][C:41]([S:44]([CH:47]4[CH2:49][CH2:48]4)(=[O:46])=[O:45])=[CH:40][CH:39]=3)[CH2:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:28][CH:29]=2)=[N:23][N:24]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH:47]1([S:44]([C:41]2[CH:42]=[CH:43][C:38]([CH:30]([C:27]3[NH:26][C:25]([C:22]4[S:21][C:20]([CH2:19][OH:18])=[N:24][N:23]=4)=[CH:29][CH:28]=3)[CH2:31][CH:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[CH:39][CH:40]=2)(=[O:45])=[O:46])[CH2:49][CH2:48]1
Reactant: CC(C)(C)[Si](OCc1nnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3nnc(CO)s3)[nH]2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.2 %

Procedure:
To a solution of 2-({[tert-butyl(diphenyl)silyl]oxy}methyl)-5-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)-1,3,4-thiadiazole (122 mg) in tetrahydrofuran (1.2 mL) was added tetrabutylammonium fluoride (0.44 mL: 1M tetrahydrofuran solution), and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, and washed with saturated brine. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (51.3 mg, yield 63%) was obtained as white crystals from a fraction eluted with ethyl acetate-hexane (19:1, volume ratio). melting point 208.5-208.6° C. MS: 474 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)=[C:19]([O:30][CH2:31][CH2:32][O:33][C:34]3[N:39]=[CH:38][C:37]([CH:40](O)[CH3:41])=[CH:36][N:35]=3)[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)=[C:19]([O:30][CH2:31][CH2:32][O:33][C:34]3[N:35]=[CH:36][C:37]([CH2:40][CH3:41])=[CH:38][N:39]=3)[N:18]=[CH:17][N:16]=2)(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ncc(C(C)O)cn2)c1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCc1cnc(OCCOc2ncnc(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)c2Oc2cccc(OC)c2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
To a solution of 4-tert-butyl-N-[6-{2-(5-(1-hydroxyethyl)pyrimidin-2-yloxy)ethoxy}-5-(3-methoxyphenoxy)pyrimidin-4-yl]benzenesulfonamide (150 mg) in methylene chloride (3 ml) is added thionyl chloride (90 mg), and the mixture is reacted at room temperature for 0.5 hour. The reaction solution is concentrated to dryness under reduced pressure, and to the residue are added 10% palladium-carbon (30 mg), triethylamine (76 mg) and ethanol (3 ml), and the mixture is stirred at room temperature for two hours under hydrogen atmosphere (1 atm). The catalyst is removed by filtration, and the filtrate is concentrated to dryness under reduced pressure. The residue is extracted with ethyl acetate, and the ethyl acetate layer is washed, dried, and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform/ethyl acetate=10:1), and recrystallized from ethyl acetate/n-hexane to give 4-tert-butyl-N-[6-{2-(5-ethylpyrimidin-2-yloxy)ethoxy}-5-(3-methoxyphenoxy)pyrimidin-4-yl]benzenesulfonamide (137 mg) as crystals.
Reaction SMILES: [CH:1]#[C:2][CH3:3].[CH3:4][O:5][C:6](=[O:16])[C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9](I)[C:8]=1[NH2:15]>C(N(CC)CC)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:4][O:5][C:6](=[O:16])[C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]([C:1]#[C:2][CH3:3])[C:8]=1[NH2:15]
Reactant: COC(=O)c1cc(Cl)cc(I)c1N
Reactant: C#CC
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC#Cc1cc(Cl)cc(C(=O)OC)c1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
Propyne (excess ca 3 ml) was condensed onto a cold (−78° C.) solution of 2-amino-5-chloro-3-iodobenzoic acid methyl ester (500 mg, 1.61 mmol) in triethylamine (10 ml) in a Parr pressure reaction vessel. To this solution was added copper (I) iodide and bis(triphenylphosphine)palladium (II) chloride and the pressure tube was then sealed and stirred at rt for 4 h. The solvent was then removed in vacuo and the residue was purified by flash column chromatography (9:1 cyclohexane:EtOAc) to give 2-amino-5-chloro-3-prop-1-ynylbenzoic acid methyl ester (340 mg, 95%) as an off white solid. 1H NMR (CDCl3, 300 MHz): δ 7.76 (d, J=2.5 Hz, 1H), 7.33 (d, J=2.5 Hz, 1H), 6.37 (br s, 2H), 3.87 (s, 3H), 2.13 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:26])[CH2:15][N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[NH:18][C:17]3=[O:25])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:27][CH3:28].IC.[C:31]([O-])([O-])=O.[Cs+].[Cs+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:26])[CH2:15][N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]([CH3:31])[C:17]3=[O:25])[CH2:12][CH2:13]2)=[CH:4][C:3]=1[O:27][CH3:28]
Reactant: COc1cc(N2CCN(C(=O)Cn3c(=O)[nH]c4ccccc43)CC2)ccc1Cl
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN1CCCC1=O
Product: COc1cc(N2CCN(C(=O)Cn3c(=O)n(C)c4ccccc43)CC2)ccc1Cl

Procedure:
In a 4 mL vial was added 1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-1,3-dihydro-benzoimidazol-2-one (19) (10 mg, 0.025 mmol, 1.0 equiv), 5 μL of iodomethane (0.081 mmol, 3.26 equiv), 25 mg Cs2CO3 (0.075 mmol, 3.00 equiv) and 150 μL of NMP. A stir bar was placed in the vial and the vial was then capped. The resultant mixture stirred at 60° C. overnight. The crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield 1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3-methyl-1,3-dihydro-benzoimidazol-2-one (20): HPLC retention time, 2.14 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 414.9, found, 415.5.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12](=[O:14])[NH:11][C:10]=2[CH:15]=1)(=[O:5])[CH3:4]>C(Cl)Cl.C(O)(=O)C>[Br:1][CH2:4][C:3]([C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12](=[O:14])[NH:11][C:10]=2[CH:15]=1)=[O:5]
Reactant: BrBr
Reactant: CC(=O)c1ccc2sc(=O)[nH]c2c1
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(CBr)c1ccc2sc(=O)[nH]c2c1
Yield: 58.8 %

Procedure:
Bromine (2.4 g) was added to the solution of 5-acetyl-2-benzothiazolinone (2.9 g) in a mixture of methylene chloride (60 ml) and acetic acid (10 ml) at 32° C. to 35° C. with stirring and the mixture was stirred at the same temperature for an hour. The resulting precipitate was collected by filtration, washed with methylene chloride and dried over phosphorus pentoxide to give 5-bromoacetyl-2-benzothiazolinone (2.4 g). mp 249° C. (dec.)