Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH:11]2[C:16]([OH:18])=[O:17])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:32]([N:37]([CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C:38](Cl)=[O:39])[CH2:33][CH2:34][CH2:35][CH3:36]>C1COCC1>[CH2:41]([N:37]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:38]([N:13]1[CH2:14][CH2:15][N:10]([C:8](=[O:9])[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:11]([C:16]([OH:18])=[O:17])[CH2:12]1)=[O:39])[CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: O=C(O)C1CNCCN1C(=O)C(c1ccccc1)c1ccccc1
Reactant: CCCCCN(CCCCC)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)C(c2ccccc2)c2ccccc2)C(C(=O)O)C1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A mixture of 79 mg (0.24 mmole) of (±)-1-(diphenylacetyl)piperazine-2-carboxylic acid (from Example 2, Step A) and 2 ml of THF was treated with 49 mg (0.48 mmole) of triethylamine to give a solution which was cooled to 0° C. With stirring a solution of 61 mg (0.25 mmole) of dipentylcarbamoyl chloride (from Step A) in 0.5 ml of THF was added and the solution was briefly warmed to 50° C. and then stirred at 25° C. for 16 hours. The resulting mixture was filtered and the filtrate was concentrated in vacuo to an oil which was dissolved in 0.5 ml of methanol and was chromatographed over an 85×0.9 cm. LH-20 column with 1.7 ml fractions of methanol. Fractions 21-25 were combined and concentrated in vacuo to 70 mg (57%) of oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][C:5]1[N:6]=[CH:7][N:8]2[CH:12]=[C:11]([C:13]3[C@H:14]([CH3:27])[C@@H:15]4[C@@H:22]([C@H:23]([OH:25])[CH3:24])[C:21](=[O:26])[N:16]4[C:17]=3[C:18]([O-:20])=[O:19])[S:10][C:9]=12.[Na+:28].Cl.C(O[C:33](=[NH:35])[CH3:34])C>>[C:33]([NH:1][CH2:2][CH2:3][S:4][C:5]1[N:6]=[CH:7][N:8]2[CH:12]=[C:11]([C:13]3[C@H:14]([CH3:27])[C@@H:15]4[C@@H:22]([C@H:23]([OH:25])[CH3:24])[C:21](=[O:26])[N:16]4[C:17]=3[C:18]([O-:20])=[O:19])[S:10][C:9]=12)(=[NH:35])[CH3:34].[Na+:28]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3cn4cnc(SCCN)c4s3)[C@H](C)[C@H]12
Reactant: CCOC(C)=N
Agent: Cl
Agent: [Na+]
Product: CC(=N)NCCSc1ncn2cc(C3=C(C(=O)[O-])N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Yield: 19.3 %

Procedure:
The procedure of Example 12 was repeated, except that 44.0 mg of sodium (1S,5R,6S)-2-[7-(2-aminoethyl)thioimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate and 63 mg of ethylacetimidate hydrochloride were used as the starting compounds. Thus, 9.3 mg of the title compound was prepared.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OS(O)(=O)=O.[OH-].[Na+].CC[O:18][CH2:19][CH3:20]>>[CH:2]1([C@@H:19]([OH:18])[CH2:20][NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: NCc1ccccc1
Reactant: CCOCC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O[C@@H](CNCc1ccccc1)C1CCCCC1
Yield: 74 %

Procedure:
Following removal of the solvent under reduced pressure, the β-aminosulfate from the reaction of 1-(R)-cyclohexyl-l,2-cyclic sulfate (0.206 g, 1 mmol) and benzylamine (0.214 g, 2 mmol) was stirred with 20% H2SO4 (5 mL) and ether (5 mL) at room temperature (refluxing of the two phase mixture expedites the hydrolysis) for 12 hours. The organic phase was discarded and the aqueous phase was adjusted to pH 10 with 20% aq. NaOH and extracted with ether (3×20 mL). The combined organic phases were washed with brine (20 mL) and dried over Na2SO4. Concentration gave l(R)-cyclohexyl-2-benzylaminoethanol (0.117 g, 74%), mp. 56°-58° C., [α]22D=-1.2° (c 1, CHCI3 ; 1H NMR (CDCI3) δ 7.3 (S, 5 H), 3.75 (d, J 5.77 Hz, 2 H), 3.35 (m, 1 H), 2.75 (dd, J =2.5, 9.6 Hz, 2 H), 2.5 (dd, J 9.6, 13 Hz, 1 H), 1.9-1.5 (m, 5 H), 1.3-0.9 (m, 7 H).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].[CH3:16][O:17][C:18](=[O:38])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]OS(C)(=O)=O)[CH:22]=1>>[CH3:16][O:17][C:18](=[O:38])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:1][C:2]2[CH:12]=[CH:11][C:5]3[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=3[C:3]=2[CH2:13][CH2:14][CH3:15])[CH:22]=1
Reactant: COC(=O)CCc1cccc(OCCCCCOS(C)(=O)=O)c1
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Product: CCCc1c(OCCCCCOc2cccc(CCC(=O)OC)c2)ccc2c1OCCC2=O
Yield: 57 %

Procedure:
Using the procedure of example 11 and starting with 0.28 g (1.4 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one and 0.48 g (1.4 mmol) of 3-[[5-[(methylsulfonyl)oxy]pentyl]oxy]benzenepropanoic acid methyl ester (from example 67), 3-[5-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]pentyloxy]benzenepropanoic acid methyl ester was obtained in 57% yield (0.36 g) as a yellow oil. This diester (0.79 mmol) was saponified with 2 mL of 3N aqueous lithium hydroxide in 20 mL of tetrahydrofuran, at room temperature, for 22 hr. Work-up as in example 4 gave crystalline 3-[5-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]pentyloxy]benzenepropanoic acid. Recrystallization from ethyl acetate-hexane gave 0.30 g (86%) of a colorless solid, mp 124°-125° C.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[SH:7]CC(OC)=O.Cl.[CH3:14][CH2:15][O:16][CH2:17]C>>[O:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH2:14][C:15]([O:16][CH3:17])=[S:7]
Reactant: COC(=O)CS
Reactant: CCOCC
Reactant: C1=COCCC1
Agent: Cl
Product: COC(=S)CC1CCCCO1
Reaction time: 8 h

Procedure:
Dihydropyran (19 g, 230 mmol) was added dropwise to a solution of methyl mercaptoacetate (20 g, 188 mmol) in anhydrous ether (40 cm3) cooled in ice. Hydrogen chloride was passed into this solution until it began to feel warm and then the mixture was left to stand at room temperature overnight. Volatile components were removed under reduced pressure (50° C. at 20 mmHg) to give the methyl tetrahydropyran-2-ylthioacetate in essentially quanitative yield. This material was sufficiently pure to be used without further purification.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)(=[O:8])=[O:7].Cl[C:17]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:18]=1[C:19]#[N:20].O>CN(C=O)C>[C:19]([C:18]1[CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=[CH:24][C:17]=1[N:5]([O:4][CH3:3])[S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)(=[O:8])=[O:7])#[N:20]
Reactant: CONS(=O)(=O)c1ccc(C)cc1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CON(c1ccc([N+](=O)[O-])cc1C#N)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Yield: 68.1 %

Procedure:
To a suspension of sodium hydride (60%, 0.09 g (2.25 mmol)) in 3.0 ml of DMF, N-methoxy-p-toluenesulfonamide (0.45 g (2.20 mmol)) was added under cooling with ice and with stirring. To the resulting mixture, after 15 minutes' stirring under cooling with ice, 2-chloro-5-nitrobenzonitrile (0.37 g (2.03 mmol)) was added and the mixture was stirred under cooling with ice for one hour and at room temperature for 18 hours. The reaction mixture was then poured into water and extracted with diethyl ether. The extract was washed twice with water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate-hexane (1:5) as eluent to give 0.48 g (68%) of the title compound as pale yellow crystals.
Reaction SMILES: [CH3:1][CH:2]([O:9][N:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][C:13](=O)[CH2:12][C:11]1([CH3:20])[CH3:19])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:21]([NH2:33])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[CH3:1][CH:2]([O:9][N:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][CH:13]([NH:33][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:12][C:11]1([CH3:20])[CH3:19])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCCCCCCCCCCCN
Reactant: CC(ON1C(C)(C)CC(=O)CC1(C)C)c1ccccc1
Product: CCCCCCCCCCCCNC1CC(C)(C)N(OC(C)c2ccccc2)C(C)(C)C1

Procedure:
The title compound, a colorless oil, is prepared from 1-alpha-methylbenzyloxy-2,2,6,6-tetramethylpiperidin-4-one and dodecylamine according to the procedure given in Example 35.
Reaction SMILES: [F:1][CH:2]([F:23])[C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([CH2:17]Cl)=[C:5]([C:19]([F:22])([F:21])[F:20])[N:4]=1.[I-:24].[Na+]>CC(C)=O>[F:1][CH:2]([F:23])[C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([CH2:17][I:24])=[C:5]([C:19]([F:22])([F:21])[F:20])[N:4]=1
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(CCl)c1CC(C)C
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(CI)c1CC(C)C

Procedure:
Reaction of methyl 2-(difluoromethyl)-5-(chloromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (U.S. Pat. No. 5,169,432 example 3) with sodium iodide in refluxing acetone according to the procedure known to those in the art yielded the product.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[CH2:2][C:3]([NH:5][CH2:6][C:7]([OH:9])=[O:8])=[O:4].[C:17]([OH:23])([C:19]([F:22])([F:21])[F:20])=[O:18]>C(Cl)Cl>[C:17]([OH:23])([C:19]([F:22])([F:21])[F:20])=[O:18].[NH2:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([OH:9])=[O:8])=[O:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)NCC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC(=O)NCC(=O)O
Reaction time: 1 h

Procedure:
A 100 mL media bottle equipped with a septum cap and stir bar was charged with of t-BOC-GlyGly-Ama-diEt (5.12 g, 13.14 mmol) and CH2Cl2(15 mL). With vigorous stirring, TFA (25 mL in 25 mL CH2Cl2) was added dropwise. After 1 hour the reaction was complete, the TFA was removed in vacuo and the trifluoroacetate salt precipitated with Et2O. The TFA-GlyGly-Ama-diEt salt was collected by filteration, washed with Et2O and recrystallized from absolute EtOH:ether (7:3 v/v). The white crystals were dried in vacuo to give 5.21 g of product: 1H NMR (DMSO-d6) δ 8.96 (br d, 1, —NHCH—), 8.63 (br t, 1, —NHCH2—), 8.02 (v br s, 3, NH3CH2), 5.09 (d, 1, CH(CO2Et), 4.12−4.24 (m, 4, OCH2CH3), 3.94 (br d, 2, —NHCH2—), 3.59 (br s, 2, —NHCH2—), 1.21 (t, 6, OCH2CH3). 13C NMR (CDCl3) δ 168.8, 166.4, 158.3, 158.0, 119.3, 115.4, 61.9, 56.3, 41.5, 13.9.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][C@@H:21]3[CH3:26])[C:11]3[CH2:17][CH2:16][N:15]([CH:18]=[O:19])[CH2:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.[O:27]1CCOC[CH2:28]1.C(N(CC)CC)C.C(Cl)(Cl)=O.[CH2:44]([CH2:46][NH2:47])[OH:45]>C1(C)C=CC=CC=1>[CH:18]([N:15]1[CH2:16][CH2:17][C:11]2[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][C@@H:21]3[CH3:26])=[N:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:28]([NH:47][CH2:46][CH2:44][OH:45])=[O:27])=[CH:7][CH:6]=3)=[N:13][C:12]=2[CH2:14]1)=[O:19]
Reactant: C1COCCO1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(N)cc2)nc2c1CCN(C=O)C2
Reactant: NCCO
Agent: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NCCO)cc2)nc2c1CCN(C=O)C2
Temperature: 50 °C
Reaction time: 8 h

Procedure:
(S)-2-(4-aminophenyl)-4-(3-methylmorpholino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carbaldehyde (0.100 g, 0.000283 mol) in dry 1,4-Dioxane (2.00 mL, 0.0256 mol) was added Triethylamine (0.0434 mL, 0.000311 mol) followed by 20% Phosgene in toluene (1:4, Phosgene:Toluene, 0.170 mL). The reaction mixture was heated at 50° C. for 1 hour. The reaction mixture was cooled to room temperature and then added ethanolamine (0.1020 mL, 0.001690 mol). The reaction mixture was stirred overnight. The reaction mixture was concentrated and purified by HPLC. LC/MS-m/z+441.2 (M+H)+
Reaction SMILES: [F-:1].[K+].[CH2:3]([N:10]1[CH2:18][C:17]2[C:12](=[C:13](I)[CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.COC(=O)[C:24](Cl)([F:26])[F:25]>CN(C=O)C.[Cu]I>[CH2:3]([N:10]1[CH2:18][C:17]2[C:12](=[C:13]([C:24]([F:26])([F:1])[F:25])[CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [F-]
Reactant: O=C1c2c(I)cccc2CN1Cc1ccccc1
Reactant: COC(=O)C(F)(F)Cl
Agent: [Cu]I
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2c(cccc2C(F)(F)F)CN1Cc1ccccc1
Temperature: 140 °C
Yield: 41.2 %

Procedure:
CuI (0.057 g, 0.3 mmol) and potassium fluoride (0.017 g, 0.3 mmol) were added under N2 atmosphere to a stirred solution of 2-benzyl-7-iodo-2,3-dihydro-isoindol-1-one (0.089 g, 0.25 mmol) and chloro-difluoro-acetic acid methyl ester (0.053 mL, 0.5 mmol) in DMF (3 mL). The mixture was heated at 140° C. for 5-8 h. The reaction was cooled and the solvent evaporated. Silica gel column chromatography of the resulting material using 30% ethyl acetate in hexane afforded 2-benzyl-7-trifluoromethyl-2,3-dihydro-isoindol-1-one (0.03 g, 41%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.28 (s, 2H), 4.79 (s, 2H), 7.33 (m, 5H), 7.59 (m, 2H), 7.76 (d, 1H). GC-MS: m/z 291 (M)+, 270 (M−20)+.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[N:25]1[C:30]2=[N:31][C:32]3[C:33](=[C:34]([CH:38]=O)[CH:35]=[CH:36][CH:37]=3)[N:29]2[CH2:28][CH2:27][CH2:26]1>O1CCCC1.O>[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[N:25]1[C:30]2=[N:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34](/[CH:38]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:33]=3[N:29]2[CH2:28][CH2:27][CH2:26]1
Reactant: O=Cc1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C/c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reaction time: 0.17 h
Yield: 75.7 %

Procedure:
Sodium hydride (60% in oil, 230 mg, 5.76 mmol) was added to a stirred solution of ethyl (diethoxyphosphoryl)acetate (1.94 g, 8.67 mmol) in tetrahydrofuran (14 mL) at 0° C. After stirring 10 min, 1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (1.00 g, 2.88 mmol) in tetrahydrofuran (1.0 mL) was added to the mixture, and the mixture was stirred at room temperature for 12 hr. The mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was washed with diisopropyl ether to give the title compound as a colorless powder (908 mg, 2.18 mmol, 76%).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.Br[C:16]1[S:17][CH:18]=[CH:19][N:20]=1>>[OH:1][C:2]1([C:16]2[S:17][CH:18]=[CH:19][N:20]=2)[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: Brc1nccs1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2nccs2)CC1
Yield: 80 %

Procedure:
Obtained in 80% yield by an analogous method to Example 323, preparation of starting materials, starting from tert-butyl 4-oxo-1-piperidinecarboxylate and 2-bromothiazole.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([O-:19])=[O:18])=[CH:13][CH:12]=1.[Na+]>CS(C)=O.C(OCC)(=O)C.[Cu]I>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: O=S([O-])c1ccc(Br)cc1
Reactant: O=Cc1cccc(I)c1
Agent: [Cu]I
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=Cc1cccc(S(=O)(=O)c2ccc(Br)cc2)c1
Temperature: 110 °C
Yield: 35.8 %

Procedure:
3-Iodobenzaldehyde (1.0 g, 4.3 mmol), copper(I) iodide (2.45 g, 12.9 mmol) and sodium 4-bromophenylsulfinate (1.55 g, 5.59 mmol) were combined in dimethylsulfoxide (8.6 mL) and heated to 110° C. for 4 hours. The cooled reaction mixture was diluted with ethyl acetate and filtered through Hyflo®. The filtrate was washed with water (×2) and brine and dried over MgSO4. The solvent was removed in vacuo and the residue purified by flash column chromatography on silica, eluting with 25% ethyl acetate/isohexane, to give 3-[(4-bromophenyl)sulfonyl]benzaldehyde (0.5 g, 35%). δH (400 MHz, d6 DMSO): 10.09 (1H, s), 8.47–8.44 (1H, m), 8.29–8.25 (1H, m), 8.21 (1H, d, J=7.6 Hz), 7.96–7.94 (2H, m), 7.88–7.84 (3H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:32]([O:33][CH3:34])=[CH:31][C:6]2[CH2:7][C:8](=[O:30])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:29])[CH2:16][CH2:17][S:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[OH:35]O>>[CH3:1][O:2][C:3]1[C:32]([O:33][CH3:34])=[CH:31][C:6]2[CH2:7][C:8](=[O:30])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:29])[CH2:16][CH2:17][S:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)=[O:35])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: OO
Reactant: COc1ccc(SCCN(C)CCCN2CCc3cc(OC)c(OC)cc3CC2=O)cc1OC
Product: COc1ccc(S(=O)CCN(C)CCCN2CCc3cc(OC)c(OC)cc3CC2=O)cc1OC

Procedure:
The title compound is prepared from N-[3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-propyl]-N-[2-(3,4-dimethoxyphenylthio)-ethyl]-methylamine and hydrogen peroxide analogously to Example 4.
Reaction SMILES: Br[C:2]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]2[O:6][CH2:7][C:8]([CH3:10])([CH3:9])[C:4]=2[CH:3]=1.C([Sn](CCCC)(CCCC)[C:22]1[O:23][CH:24]=[CH:25][CH:26]=1)CCC>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.C1(C)C=CC=CC=1>[C:13]([C:11]1[C:5]2[O:6][CH2:7][C:8]([CH3:10])([CH3:9])[C:4]=2[CH:3]=[C:2]([C:22]2[O:23][CH:24]=[CH:25][CH:26]=2)[CH:12]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: CC(C)(C)c1cc(Br)cc2c1OCC2(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(-c2ccco2)cc2c1OCC2(C)C
Temperature: 25 °C
Yield: 43.5 %

Procedure:
A mixture of 5-bromo-7-tert-butyl-2,3-dihydro-3,3-dimethylbenzo[b]furan (1.13 g, 4.0 mmol), 2-(tributylstannyl)furan (1.71 g, 4.8 mmol), tetrakis(triphenylphosphine)palladium (0.46 g, 0.4 mmol), and 20 mL of toluene is heated under argon at reflux for 30 min. The reaction mixture is cooled to room temperature, concentrated in vacuo, diluted with ether, washed with 10% aqueous ammonium hydroxide solution and with brine, dried over anhydrous magnesium sulfate, and concentrated to give a dark oil. Purification by flash column chromatography on silica gel (1% ethyl acetate-hexane) yields about 0.47 g (43%) of the title compound as a light yellow oil.
Reaction SMILES: CO[C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[C:15]([Cl:18])=[C:14]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:22]=3)[N:13]=[C:12]2[CH3:28])[CH:5]=1.[OH-].[Na+].[C:32](N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:45][N:46](C)[OH:47].C(N(CC)CC)C>O1CCCC1>[Cl:18][C:15]1[C:16](=[O:17])[N:11]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=2[CH3:10])[C:3]([N:46]([O:47][CH3:32])[CH3:45])=[O:29])[C:12]([CH3:28])=[N:13][C:14]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:22]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(C)n3)c(Cl)c2=O)c1
Reactant: CN(C)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(C)n3)c(Cl)c2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
To a solution of 3-[5-chloro-2-methyl-4-(6-methyl-pyridin-2-ylmethoxy)-6-oxo-6H-pyrimidin-1-yl]-4-methyl-benzoic acid methyl ester from Step A (108 mg, 0.26 mmol) in tetrahydrofuran (1 mL) was added 1N sodium hydroxide (1 mL) and the solution stirred at ambient temperature for eighteen hours. The solution was concentrated in vacuo and the aqueous residue was acidified to pH=2 using 1M HCl. The solution was extracted with ethyl acetate, washed with water and dried over magnesium sulfate. The slurry was filtered and concentrated to give an orange oil which was used without any additional purification. To a solution of the crude acid in tetrahydrofuran (2 mL) was added 1,1′-carbonyldiimidazole (63 mg, 0.39 mmol). After stifling at ambient temperature for one hour, N,N-dimethylhydroxylamine HCl (38 mg, 0.39 mmol) and triethylamine (0.07 mL, 0.52 mmol) were added. The solution continued to stir for eighteen hours. The solution was partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium bicarbonate, water, and brine and dried over magnesium sulfate. The slurry was filtered and concentrated to provide the amide as a light brown oil (73 mg, 63%). MS (M+H): 443
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].BrC1[CH:27]=[CH:26][C:25]2[C:24]3[C:19](=[CH:20][C:21](Br)=[CH:22][CH:23]=3)[NH:18][C:17]=2[CH:16]=1.[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(O)C>[C:1]1([C:7]2[CH:27]=[CH:26][C:25]3[C:24]4[C:19](=[CH:20][C:21]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[CH:22][CH:23]=4)[NH:18][C:17]=3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccccc1
Reactant: OB(O)c1ccccc1
Reactant: Brc1ccc2c(c1)[nH]c1cc(Br)ccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: c1ccc(-c2ccc3c(c2)[nH]c2cc(-c4ccccc4)ccc23)cc1
Temperature: 25 °C

Procedure:
Add 80 ml of toluene, 20 ml of ethanol, and 40 g of 2M sodium carbonate aqueous solution to 6.50 g of 2,7-dibromocarbazole, 7.32 g of phenyl boronic acid, 0.734 g of tetrakis triphenyl phosphine palladium; reflux the mixture for three hours while heating in nitrogen atmosphere followed by cooling down to room temperature; filter the mixture to remove insoluble matters; distill away the solvent to obtain 4.15 g of pale bark powder of 2,7-diphenyl carbazole; mix 4.01 g of the thus obtained 2,7-diphenyl carbazole, 4.37 g of 4-(8-hydroxyoctyloxy)iodine benzene, 3.45 g of potassium carbonate, 0.5 g of copper powder, and 20 ml of nitrobenzene; reflux the mixture for seven hours while heating in nitrogen atmosphere followed by cooling down to room temperature; filter the mixture to remove insoluble matters; distill away the solvent; next, refine the resultant with silica gel column chromatography using a liquid mixture of ethyl acetate and hexane as an eluting solution to obtain 2.0 g of a pale bark oily matter of 2.7-diphenyl-N-[4-(8-hydroxyoctyloxyphenyl)]carbazole; and then, tosylate, thioacetylate, and hydrolyze the thus obtained 2.7-diphenyl-N-[4-(8-hydroxyoctyloxyphenyl)]carbazole in the same manner as in Synthesis of Carbazole Derivative 2 to obtain 2,7-diphenyl-N-[4-(8-mercaptooctyloxyphenyl)]carbazole (hereinafter referred to as carbazole derivative 5) having a colorless needle-like crystal represented by the chemical structure 11.
Reaction SMILES: C(O[CH2:4][NH:5][C:6]1[CH:28]=[CH:27][C:9]([C:10]([NH:12][CH2:13][C:14]2[S:15][C:16]([O:19][C:20]3[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=3)=[CH:17][CH:18]=2)=[O:11])=[CH:8][N:7]=1)C.[BH4-].[Na+].O.C(OCC)(=O)C>CS(C)=O>[CH3:4][NH:5][C:6]1[CH:28]=[CH:27][C:9]([C:10]([NH:12][CH2:13][C:14]2[S:15][C:16]([O:19][C:20]3[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=3)=[CH:17][CH:18]=2)=[O:11])=[CH:8][N:7]=1
Reactant: CCOCNc1ccc(C(=O)NCc2ccc(Oc3cccc(C)c3)s2)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CNc1ccc(C(=O)NCc2ccc(Oc3cccc(C)c3)s2)cn1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 88.2 %

Procedure:
To a solution of 6-(ethoxymethyl-amino)-N-(5-m-tolyloxy-thiophen-2-ylmethyl)-nicotinamide described in Example A-155 (70 mg, 0.17 mmol) in dimethylsulfoxide (5 mL) was added sodium borohydride (20 mg, 0.51 mmol), and the solution was stirred for 20 minutes at 120° C. Water and ethyl acetate were added to the reaction solution, which was then partitioned, the organic layer was washed with brine once. The organic layer was passed through a glass filter lined with NH silica gel, and eluted thoroughly with ethyl acetate. The solvent was evaporated in vacuo, and the title compound (53 mg, 0.15 mmol, 88.2%) was obtained as a light brown solid.