Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][C:10]([CH3:16])([CH3:15])[C:11]([O:13]C)=O)(C(C)(C)C)(C)C.[H-].[Na+].[C:19](#[N:21])[CH3:20]>C1(C)C=CC=CC=1>[OH:8][CH2:9][C:10]([CH3:15])([CH3:16])[C:11](=[O:13])[CH2:20][C:19]#[N:21]
Reactant: CC#N
Reactant: COC(=O)C(C)(C)CO[Si](C)(C)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(CO)C(=O)CC#N
Temperature: 90 °C
Reaction time: 6 h
Yield: 88.7 %

Procedure:
Methyl 3-(tert-butyldimethylsilyloxy)-2,2-dimethylpropanoate (0.63 g, 2.557 mmol) was added to toluene and NaH (0.4090 g, 10.23 mmol) and acetonitrile (0.534 mL, 10.23 mmol) and stirred overnight in a sealed vessel for 6 hours at 90° C. The solids were removed by filtration and rinsed with toluene. The toluene filtrate was concentrated, and the resulting solids were added to 3 N HCl, stirred for 30 minutes and then washed with ether. The mixture was concentrated and the resulting solids were rinsed several times with DCM. The DCM was dried over MgSO4, filtered and evaporated to provide the title compound as an oil (320 mg), which was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[O:10]CC)=[CH:4][CH:3]=1.[OH:14][CH:15]([C:21]([CH3:23])=[CH2:22])[C:16]([O:18]CC)=O.C(N(CCCC)CCCC)CCC.Cl>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:18])[C:15](=[C:21]([CH3:22])[CH3:23])[O:14][C:9]2=[O:10])=[CH:4][CH:3]=1
Reactant: C=C(C)C(O)C(=O)OCC
Reactant: CCOC(=O)Nc1ccc(C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCCCN(CCCC)CCCC
Product: CC(C)=C1OC(=O)N(c2ccc(C)cc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.3 %

Procedure:
Ethyl N-(4-methylphenyl)carbamate (2.87 g, 10 mmol), ethyl 2-hydroxy-3-methyl-3-butenoate (3.90 g, 30 mmol), tetrabutylammonium chloride (139 mg, 0.5 mmol) and tributylamine (92.7 mg, 0.5 mmol) were introduced into a flask (25 cc) equipped with a distillation unit, and the reaction was conducted at 200° C. for 8 hours. After the reaction solution was cooled to room temperature, toluene (20 mL) was added, and then the reaction solution was washed with water (20 mL), then 1N sodium hydroxide (20 mL) and 1N hydrochloric acid (20 mL). The organic layer was dried over magnesium sulfate. After the drying agent was filtered off, the filtrate was concentrated under reduced pressure. To the resulting oily crude product, methanol (3.5 mL) acidified with hydrochloric acid was added to form a homogeneous solution. Then, 6N hydrochloric acid (0.4 mL) was further added, and the solution was left to stand at room temperature. The precipitated crystals were collected by filtration, then washed with a 20:1 mixed solvent consisting of methanol and 6N hydrochloric acid and dried to obtain 3-(4-methylphenyl)-5-isopropylidene-1,3-oxazolidine-2,4-dione (1.07 g, yield 46.1%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C[S-].[Na+]>CN(C=O)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2/[CH:19]=[CH:20]/[C:21]2[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=2)(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: COc1ccc(S(=O)(=O)Nc2ccccc2/C=C/c2ccncc2)cc1
Agent: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(Nc1ccccc1/C=C/c1ccncc1)c1ccc(O)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 9.9 %

Procedure:
In DMF was dissolved 2.00 g of the (E)-4-[2-[2-[[(p-methoxyphenyl)sulfonyl]amino]phenyl]ethenyl]pyridine obtained in Example 3, followed by addition of 1.91 g of sodium methanethiolate, and the mixture was stirred at 100° C. overnight and then after-treated. The resulting crystals were recrystallized from methanol to provide 0.19 g of the title compound (white powders).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:48]1CCOC[CH2:49]1>>[S:8]1([C:3]2[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:49](=[O:48])[NH:11]1)(=[O:10])=[O:9]
Reactant: NS(=O)(=O)c1ccccc1Cl
Reactant: C1COCCO1
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: O=C1NS(=O)(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 90 mL glass pressure tube was charged in a nitrogen dry box with 2 g (10.4 mmol) of 2-chlorobenzenesulfonamide, 2.35 g (20.8 mmol) of triethylamine, 30 mg (0.067 mmol) of Pd(CH3CN)4 (BF4)2, 30 mg (0.073 mmol) of 1,3-bis(diphenyl-phosphino)propane (dppp) and 6 mL of dioxane. The resulting suspension was stirred at room temperature for 30 min, cooled to -80° C., evacuated and charged with 70 psia of CO. After stirring at room temperature for 30 min, the tube was heated with stirring at 120° C. for 48 hours (hrs). Upon cooling to room temperature, the pressure was 38 psia and much solid formed. The pressure was released, 20 mL of dioxane were added to the reaction mixture to redissolve the solid, and the precipitate was isolated by filtration and washed with 5 mL of dioxane, three times, to yield 0.95 g of HNEt3+Cl-. The reaction of Example 2 to this point can be also illustrated by the general formula provided in Example 1. The filtrate was combined with the washings and the solvent was removed in a vacuum to yield 2.84 g of almost pure saccharin salt A with [HN(C2H5)3 ]+ and Cl-. To this material were added 60 mL of water followed by 1.6 g of NaOH. The resulting solution was filtered, concentrated under vacuum, and 4 g of HCl 38% by weight of the solution were added. A copious white precipitate was formed, and isolated by filtration and washed with a small amount of cold water. 1.73 g (91.4% of the calculated amount of saccharin expected based on the measured amounts of the ingredients) of pure saccharin was obtained after vacuum drying. This reaction step from the saccharin salt to saccharin is illustrated by the following general formula: ##STR6##
Reaction SMILES: Cl.[CH2:2]([O:6][NH2:7])[CH:3]([CH3:5])[CH3:4].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[CH2:2]([O:6][NH:7][S:16]([C:13]1[CH:12]=[CH:11][C:10]([O:9][CH3:8])=[CH:15][CH:14]=1)(=[O:18])=[O:17])[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)CON
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)NOCC(C)C)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Isobutoxyamine hydrochloride (7.96 mmol, 1.0 g), 4-methoxybenzenesulfonyl chloride (7.24 mmol, 1.5 g), diisopropylethylamine (18.09 mmol, 3.15 mL) and anhydrous THF (15 mL) were combined under nitrogen. The reaction stirred at room temperature for 15 hours. The reaction solution was concentrated to a white solid and partitioned between ethyl acetate and 1N HCl. The organic layer was separated and washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated under vacuum to yield an off-white colored solid. Rf: 0.5 (2:1 hexanes/ethyl acetate); H1-NMR (CDCl3): δ 7.84 (2H,d), 6.99 (2H,d), 6.81 (1H,s), 3.87 (3H,s), 3.74 (2H,d), 1.90 (1H,septet), 0.86 (6H,d).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]([C:10]([C:12]2[CH:21]=[C:20]([CH3:22])[C:15]3[NH:16][C:17](=[O:19])[O:18][C:14]=3[CH:13]=2)=[O:11])[CH:5]=1.I[CH3:24]>CN(C=O)C>[Cl:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]([C:10]([C:12]2[CH:21]=[C:20]([CH3:22])[C:15]3[N:16]([CH3:24])[C:17](=[O:19])[O:18][C:14]=3[CH:13]=2)=[O:11])[CH:5]=1
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)[nH]c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.35 g (8.0 mmol) sodium hydride (55%, suspension in mineral oil) were added to 2.2 g (7.6 mmol) of 6-(6-chloropyrimidine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one in 10 mL N,N′-dimethylformamide. The reaction mixture was stirred for 30 min at RT. Then 0.95 mL (15.0 mmol) iodomethane were added and the mixture was stirred for 1 h at RT. The reaction mixture was combined with ice water, the aqueous phase was extracted several times with EtOAc. The combined organic phases were dried on sodium sulphate, filtered and concentrated to dryness by rotary evaporation. The residue was triturated with diethyl ether, suction filtered and dried.
Reaction SMILES: [CH3:1][C:2]([CH3:20])([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[C:18]([NH2:19])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:3].Br[CH2:22][CH:23]=[CH2:24].C(#N)C>ClCCl.C(=O)([O-])[O-].[K+].[K+]>[CH3:3][C:2]([CH3:20])([O:4][C:5]([N:7]1[CH2:8][CH2:9][N:10]([C:13]2[C:18]([NH:19][CH2:24][CH:23]=[CH2:22])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:11][CH2:12]1)=[O:6])[CH3:1]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncccc2N)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: C=CCNc1cccnc1N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
A mixture of 1-[1,1-dimethylethoxycarbonyl]-4-[3-amino-2-pyridinyl]-piperazine (International Publication 88/08424, 2.78 g), 3-bromopropene (1.87 g), anhydrous potassium carbonate (3.3 g) and acetonitrile (100 ml) is refluxed for 36 hr. The mixture is cooled and then diluted with dichloromethane and aqueous potassium carbonate solution. The phases are separated and the organic phase is washed with saline and than concentrated in vacuo. Purification by flash column chromatography (2% methanol/chloroform) provided of the title compound. Capillary GC analysis (HP1 column, initial temperature at 100° for 1 min, then programmed to rise 20° per minute to 250°) gave a peak at 6.06 (96%) minutes.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH:2]1[CH:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18]O)[CH2:13][CH2:12]1.CCN(S(F)(F)[F:26])CC.O>ClCCl>[O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH:2]1[CH:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][F:26])[CH2:13][CH2:12]1
Reactant: CCN(CC)S(F)(F)F
Reactant: OCCC1CCC(C2COC3(CCCCC3)O2)CC1
Solvent: O
Solvent: ClCCl
Product: FCCC1CCC(C2COC3(CCCCC3)O2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The above 2-(4-(1,4-dioxaspiro[4.5]decyl)cyclohexyl)ethanol (20 g, 70.8 mmol) was dissolved in dichloromethane (70 ml), followed by dropwise adding to the solution, DAST (13 g, 80.7 mmol), stirring at 0° C. for one hour, adding water to the reaction solution, washing the resulting organic layer successively with a saturated aqueous solution of sodium bicarbonate and water, distilling off the solvent, purifying the residue according to column chromatography using heptane/ethyl acetate as a developing solvent, on silica gel, to obtain 1-(4-(1,4-dioxaspiro[4,5]decyl)cyclohexyl)-2-fluoroethane, adding thereto formic acid (80 ml), refluxing the mixture for 2 hours, extracting the resulting product with toluene, washing the extraction solution successively with a saturated aqueous solution of sodium bicarbonate, distilling off the solvent, to isolate 4-(4-(2-fluoroethyl)cyclohexyl)cyclohexanone (8.0 g, 35.3 mmol). The yield of this product from 2-(4-(1,4-dioxaspiro[4,5]decyl)cyclohexyl)ethanol was 49.9%.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][NH:8][C:7]=12.[H-].[Na+].[C:13](O)(=O)C>CN(C=O)C>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][N:8]([CH3:13])[C:7]=12
Reactant: Clc1nccc2cc[nH]c12
Reactant: CC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2ccnc(Cl)c21
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a solution of 259 (250mg, 1.64 mmol) in DMF (16 mL) at 0° C. was added NaH (197 mg, 4.92 mmol, 60% in mineral oil), and the mixture was stirred for 30 min, followed by addition of Mel (112 □L, 1.80 mmol). The reaction mixture was stirred at room temperature for 2 h before acetic acid (1 mL) was added. Solvents were removed under reduced pressure, the residue was partitioned between water and EtOAc. Organic phase was collected, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column chromatography, eluent EtOAc/hexane (1:1), to afford the title compound 263 (200 mg, 92% yield) as an off-white solid. MS (m/z): 167.1(M+H) (found).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][C:7]=1[O:19][CH3:20].[CH2:21]([C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([C:28]1[CH:29]=[CH:30][C:31]([O:34][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][C:7]=2[O:19][CH3:20])=[CH:32][CH:33]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COc1cc(CC(OC)C(=O)O)ccc1OCCCBr
Reactant: Oc1ccc(Cc2ccccc2)cc1
Product: COc1cc(CC(OC)C(=O)O)ccc1OCCCOc1ccc(Cc2ccccc2)cc1

Procedure:
The title compound was prepared from 3-[4-(3-Bromo-propoxy)-3-methoxy-phenyl]-2-methoxy-propionic acid and 4-benzylphenol following the Standard Procedure J. MS (ES) for C27H30O6 [M+NH4]+: 468, [M+Na]+: 473.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[C:4]([CH3:11])[N:3]=1.[CH2:12]([NH2:15])[CH2:13][CH3:14]>O1CCOCC1>[CH3:11][C:4]1[N:3]=[C:2]([NH:15][CH2:12][CH2:13][CH3:14])[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=1
Reactant: CCCN
Reactant: Cc1cc(C(=O)O)nc(Cl)n1
Solvent: C1COCCO1
Product: CCCNc1nc(C)cc(C(=O)O)n1

Procedure:
A solution of 2-chloro-6-methylpyrimidine-4-carboxylic acid (100 mg, 0.58 mmol) and propylamine (0.48 mL) in dioxane (1 mL) is stirred at 70° C. for 18 h. The reaction mixture is concentrated and purified by prep. HPLC (X-Bridge) to give 6-methyl-2-propylamino-pyrimidine-4-carboxylic acid (81 mg) as a yellow crystalline solid; LC-MS: tR=0.56 min, [M+H]+=196.08; 1H NMR (D6-DMSO): δ 0.89 (t, J=7.3 Hz, 3H), 1.53 (m, 2H), 2.32 (s, 3H), 3.25 (m, 2H), 6.92 (s, 1H), 7.36 (s br, 1H), 13.2 (s br, 1H).
Reaction SMILES: C([Li])(C)(C)C.BrC1C(C)=CC(C)=CC=1C.[CH3:16][O:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1.[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[C:28]2=[O:35]>CCCCC.C1COCC1>[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[C:28]2([OH:35])[C:19]1[C:18]([O:17][CH3:16])=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: COc1cccnc1
Agent: Cc1cc(C)c(Br)c(C)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: COc1cccnc1C1(O)C(=O)Nc2ccc(Cl)cc21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A 1.7 M solution of tert-butyllithium in pentane (57.8 mL) was added to THF (200 ml) at −78° C. 2-Bromomesitylene (3.6 mL) was added dropwise, keeping the temperature below −60° C., and the mixture stirred at −78° C. for 1 h. 3-Methoxypyridine (3.6 mL) was added dropwise at −78° C. and then the mixture was stirred between −30° C. and −20° C. The reaction mixture was re-cooled to −78° C. and a slurry of 5-chloroisatin (3.26 g) in THF (100 mL) was added portionwise, keeping the temperature below −60° C. The reaction mixture was stirred at −78° C. for 1 h. The cooling bath was removed and the reaction mixture was stirred for 30 min. The reaction mixture was quenched with 10% aqueous ammonium chloride solution and extracted several times with ethyl acetate. The combined organic layers were washed with water, dried over magnesium sulfate and evaporated to low volume. Upon standing, 1.05 g of a cream-colored solid separated which was filtered off, washed with ethyl acetate and dried in vacuo.
Reaction SMILES: [CH3:1][C@@H:2]1[O:9]C(=O)[C@H](C)[O:5][C:3]1=[O:4].[C:11]([O:16][CH2:17][CH2:18][OH:19])(=[O:15])[C:12]([CH3:14])=[CH2:13]>>[C:11]([O:16][CH2:17][CH2:18][OH:19])(=[O:15])[C:12]([CH3:14])=[CH2:13].[C:3]([O-:5])(=[O:4])[CH:2]([CH3:1])[OH:9]
Reactant: C[C@@H]1OC(=O)[C@H](C)OC1=O
Agent: C=C(C)C(=O)OCCO
Product: CC(O)C(=O)[O-]

Procedure:
Dextran-(2-hydroxyethylmethacrylate)-lactate (Dex-lactateHEMA) macromer was synthesized according to a published method (Wolthuis, et al. Polymer, 1997, 38, 6235-6242). For example, L-lactide and 2-hydroxyethyl methacrylate (HEMA) with 1:1 molar ratio were first reacted at 110° C. for one hour in the presence of catalyst SnOct2 to obtain HEMA-lactate. Secondly, N,N′-carbonyldiimidazole (CDI) was reacted with the above HEMA-lactate product at 1:1 feeding molar ratio at room temperature in THF for 16 h to obtain HEMA-lactateCl. Finally, a calculated amount of dextran was reacted with HEMA-lactateCI (HEMAlactateCI:glucopyranose=7:1 molar ratio) in the presence of catalyst 4-(N,N-dimethylamino) pyridine (DMAP) in dimethyl sulfoxide (DMSO) at room temperature for four days to obtain the Dex-lactateHEMA macromer. The average length of lactate spacer (DPav) is equal to 3, and degree of substitute (DS; amount of methacrylate groups per 100 dextran glucopyranose residues) is equal to 4.6.
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]([NH:11][C:12](=[O:29])[NH:13][C:14]2[CH:28]=[CH:27][C:17]([O:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:16][CH:15]=2)=[O:10])=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[SH2:36]>C(N(CC)CC)C>[C:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]([NH:11][C:12](=[O:29])[NH:13][C:14]2[CH:28]=[CH:27][C:17]([O:18][CH2:19][C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])=[CH:16][CH:15]=2)=[O:10])=[CH:5][CH:4]=1)(=[S:36])[NH2:2]
Reactant: S
Reactant: CC(C)(C)OC(=O)COc1ccc(NC(=O)NC(=O)c2ccc(C#N)nc2)cc1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)COc1ccc(NC(=O)NC(=O)c2ccc(C(N)=S)nc2)cc1

Procedure:
In a similar manner to Example 1, starting material step (b), the product of step (a) (2.29 g), pyridine (105 ml), triethylamine (15 ml) and H2S gas were reacted to give t-butyl 4-[3-(6-thiocarbamoylpyrid-3-ylcarbonyl)ureido]phenoxyacetate (2.76 g) as a yellow solid: m.p. 248°-249° C. (decomposes); NMR Spectrum (DMSO-d6) 1.44 (9H, s), 4.62 (2H, s), 6.90 (2H, d), 7.49 (2H, d), 8.48 (1H, dd), 8.58 (1H, d), 9.10 (1H, d), 10.02 (1H, bs), 10.30 (1H, br s), 10.49 (1H, s), 11.30 (1H, s); Mass Spectrum m/Z 431 (M+H)+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.N1C=CC=CC=1.[C:19]([N:29]1[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]1)([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>O1CCCC1>[C:19]([N:29]1[CH2:30][CH2:31][C:32]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)([OH:35])[CH2:33][CH2:34]1)([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]
Reactant: Brc1cccnc1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(OCc1ccccc1)N1CCC(O)(c2cccnc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.8 %

Procedure:
To a cooled solution (-78° C.) of n-butyllithium (2.0M in hexane, 12.9 mL, 28.3 mmol, 1.2 eq) in tetrahydrofuran (200 mL) under nitrogen was added 3-bromopyridine (2.27 mL, 23.6 mmol, 1.1 eq). The solution became a dark green color as the pyridine was added. The reaction was stirred at this temperature for 1h, at which time 1-carbobenzyloxy-4-piperidone (described in example 87c) (5.00 g, 21.4 mmol) was added as a tetrahydrofuran solution (20 mL). The cooling bath was removed and the reaction warmed to room temperature, stirring at that temperature for 18 h. The reaction was quenched by the addition of water (125 mL) and the aqueous phase extracted with ethyl acetate (3×75 mL). Combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and reduced to an oil. The reaction product was purified by flash chromatography over silica gel (300 mL, eluent: ethyl acetate) to yield 5.00 g (75%) of the title compound as an oil. TLC analysis (Rf 0.10, ethyl acetate). MS (CI, CH4) m/z 313 (M+1,100), 341 (M+29,15), 295 (15).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].I[CH2:15][CH3:16].[H-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:15][CH3:16])[CH:6]=1)=[O:4]
Reactant: CCI
Reactant: COC(=O)c1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCn1cc(C(=O)OC)c2ccccc21
Yield: 77.6 %

Procedure:
A flask was charged with 1H-indole-3-carboxylic acid methyl ester (2 g, 11.41 mmol) and iodoethane (4.4 g, 28.5 mmol) in dry THF (25 mL). The mixture was stirred in a water bath and a 60% dispersion of sodium hydride (0.68 g, 17.12 mmol) in mineral oil was added in portions over 5 minutes. The reaction stirred for 48 hours and was quenched by careful addition of water. The mixture was extracted with dichloromethane (2×100 mL), dried over sodium sulfate and evaporated under reduced pressure. The crude product was purified by silica flash chromatography (10% ethyl acetate/heptane) to give 1-ethyl-1H-indole-3-carboxylic acid methyl ester (1.8 g). 1H NMR [CDCl3]: δ 8.22-8.15 (m, 1H), 7.87 (s, 1H), 7.42-7.33 (m, 1H), 7.31-7.25 (m, 2H), 4.22 (q, 2H), 3.92 (s, 3H), 1.52 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]1.[C:15](#N)[CH3:16].C(=O)([O-])[O-].[K+].[K+].ICC>O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:14])[CH2:13][CH2:12][N:11]([CH2:15][CH3:16])[CH2:10]1
Reactant: CC#N
Reactant: OC1(c2cccc(Cl)c2Cl)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCI
Product: CCN1CCC(O)(c2cccc(Cl)c2Cl)C1
Temperature: 25 °C

Procedure:
In a sealed tube a mixture of 3-(2,3-dichlorophenyl)pyrrolidin-3-ol (0.35 g, 1.51 mmol), acetonitrile (20 mL), potassium carbonate (0.019 g, 3.77 mmol) and iodoethane (0.24 g, 1.51 mmol) was stirred at ambient temperature over night, additional iodoethane (0.02 mL) was added and the resulting mixture was stirred over night. Water (50 mL) was added, the aqueous phase was extracted with tert-butyl methyl ether (2×50 mL) and the combined organic phase was dried (MgSO4) and evaporated. Purification by flash column chromatography on silica gel (ethyl acetate/methanol, 1:0 to 1:1) gave the title compound (0.13 g). The amine was converted to the oxalic acid salt and recrystallized from methanol/ethanol/diethyl ether: M.p. 206-207° C.; MS m/z (relative intensity, 70 eV) 259 (M+, 5), 173 (7), 145 (6), 72 (23), 71 (bp).
Reaction SMILES: [Br:1][C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:11][O:12]C(Cl)Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:7]2[C:8]([CH:11]=[O:12])=[CH:9][S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COC(Cl)Cl
Reactant: Brc1cccc2sccc12
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=Cc1csc2cccc(Br)c12
Reaction time: 0.5 h
Yield: 44.7 %

Procedure:
4-Bromobenzothiophene (1.80 g, 8.45 mmol) and dichloromethyl methyl ether (1.46 g, 12.7 mmol) were dissolved in anhydrous DCM (100 mL). Titanium tetrachloride (2.40 g, 12.7 mmol) was added, turning the solution dark. After 30 minutes at room temperature, the reaction was poured into a mixture of saturated aqueous NaHCO3 and ice. The mixture was stirred for about 30 minutes and then was extracted with DCM (2×150 mL). The extracts were concentrated and chromatographed (0 to 15% ethyl acetate in hexane) to yield 4-bromobenzothiophene-3-carboxaldehyde (0.910 g). The 4-bromobenzothiophene-3-carboxaldehyde (0.910 g, 3.77 mmol) and sulfamide (3.0 g, 31 mmol) were combined in anhydrous ethanol (25 mL) and heated to reflux for three days. The reaction was cooled to room temperature and sodium borohydride (0.157 g, 4.15 mmol) was added. After five hours, water (50 ml) was added and the solution was extracted with chloroform (3×50 mL). The extracts were concentrated, suspended in a minimal amount of DCM, and filtered to yield the title compound as a yellow solid.