Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([S:23]([OH:26])(=O)=[O:24])=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:30])=O.CN(C=O)C>C1COCC1>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([S:23]([Cl:30])(=[O:26])=[O:24])=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)O)ccc1OCC2
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)Cl)ccc1OCC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 208.1 %

Procedure:
To a suspension of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene-9-sulfonic acid (228 mg, 0.61 mmol) in THF (15 mL) was added oxalyl chloride (257 μL, 3.04 mmol) and the resulting mixture stirred at RT for 15 min. The reaction mixture was cooled to 0° before DMF (126 μL, 1.69 mmol) was added and the resulting mixture warmed to RT after 10 min then stirred for a further 2 h. The reaction mixture was azeotroped with toluene affording 2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene-9-sulfonyl chloride (500 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:9])[NH:5][CH:6]=[CH:7][CH:8]=1.[H-].[Na+].Br[CH2:13][CH2:14][CH2:15][CH2:16][Cl:17]>CN(C)C=O>[Cl:17][CH2:16][CH2:15][CH2:14][CH2:13][N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]1=[O:9]
Reactant: COc1ccc[nH]c1=O
Reactant: ClCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccn(CCCCCl)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.6 %

Procedure:
3-Methoxy-1H-pyridin-2-one (20 mmol, 2.00 g) in 100 ml of N,N-dimethylformamide was added dropwise over the course of 10 minutes to a suspension of sodium hydride (20 mmol, 0.74 g, 60%, deoiled) in N,N-dimethylformamide (100 ml) at 10° C., and the mixture was then stirred at room temperature for 1 hour. Subsequently, 1-bromo-4-chlorobutane (20 mmol, 3.19 g) in 40 ml of N,N-dimethylformamide was added dropwise. The reaction mixture was then stirred at 95° C. After the reaction mixture had been concentrated, the remaining oil was suspended in diethyl ether. The resulting suspension was filtered and the filtrate was washed three times with water and then three times with a saturated aqueous sodium chloride solution. Drying of the organic phase over sodium sulfate was followed by removal of the desiccant by filtration and concentration. The resulting residue contained a mixture of O-alkylated and N-alkylated compound. Chromatography of the residue on silica gel (eluent: CH2Cl2/CH3OH: 0-2%) afforded 1.75 g of the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH3:11])[CH:5]=[C:4]([CH3:12])[C:3]=1[CH:13]=[CH:14][CH:15]1[CH2:20][CH2:19][CH:18]([CH:21]2[CH2:26][CH2:25][CH:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:23][CH2:22]2)[CH2:17][CH2:16]1.[H][H]>C1(C)C=CC=CC=1.[Pd]>[F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH3:11])[CH:5]=[C:4]([CH3:12])[C:3]=1[CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH:18]([CH:21]2[CH2:26][CH2:25][CH:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:23][CH2:22]2)[CH2:17][CH2:16]1
Reactant: [H][H]
Reactant: CCCCCC1CCC(C2CCC(C=Cc3c(C)cc(OCC)c(F)c3F)CC2)CC1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCCCCC1CCC(C2CCC(CCc3c(C)cc(OCC)c(F)c3F)CC2)CC1
Yield: 50.1 %

Procedure:
0.08 g of Pd/C was added to 1.65 g of the compound 1-3-3-10 having been dissolved in 12.5 mL of toluene and 12.5 mL of Solmix, and under a hydrogen atmosphere, the mixture was stirred at room temperature until hydrogen was not absorbed. Pd/C was removed, and the solvent was distilled off. The residue was purified by silica gel column chromatography and recrystallization to obtain 0.83 g of 1-(2,3-difluoro-4-ethoxy-6-methylphenyl)-2-(4-(4-pentylcyclohexyl)cyclohexyl)ethane (Compound 1-3-3-2) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[CH3:19][C:20]1[S:24][C:23]([S:25](Cl)(=[O:27])=[O:26])=[CH:22][CH:21]=1>>[F:8][C:7]1[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])=[C:5]([NH:18][S:25]([C:23]2[S:24][C:20]([CH3:19])=[CH:21][CH:22]=2)(=[O:27])=[O:26])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: Cc1ccc(S(=O)(=O)Cl)s1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(F)c(F)c2Nc2ccc(I)cc2F)s1

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine was reacted with 5-methylthiophene-2-sulfonyl chloride to obtain the title compound. 1H NMR (300 MHz, CDCl3): δ 7.34 (dd, J=0.9 & 10.2 Hz, 1H), 7.30 (ddd, J=2.1, 4.8 & 9.0 Hz, 1H), 7.25 (d, J=3.9 Hz, 1H), 7.07 (m, 2H), 6.65 (dd, J=1.2 & 3.9 Hz, 1H), 5.89 (dt, J=2.4, 8.7 & 17.4 Hz, 1H), 5.54 (br s, D2O exchangeable, 1H), 2.46 (s, 3H).
Reaction SMILES: [C:1]([O:11][CH2:12][CH:13]=[CH2:14])(=[O:10])/[CH:2]=[CH:3]/[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5].CCC(OO)=[O:18].C1C=CC=CC=1>>[C:4]([O:6][CH2:7][CH:8]=[CH2:9])(=[O:5])/[CH:3]=[CH:2]/[C:1]([O:11][CH2:12][CH:13]1[O:18][CH2:14]1)=[O:10]
Reactant: C=CCOC(=O)/C=C/C(=O)OCC=C
Reactant: CCC(=O)OO
Solvent: c1ccccc1
Product: C=CCOC(=O)/C=C/C(=O)OCC1CO1

Procedure:
9.8 kg (50 mol) of diallyl fumarate were reacted with 26.18 kg of a 22% strength solution of perpropionic acid in benzene (64 mol) at 60° C. in a manner analogous to that described in Example 1. After a reaction time of 6.8 hours, a percarboxylic acid conversion of 96.8% resulted. The conversion of diallyl fumarate was 90%. Allyl glycidyl fumarate was formed with a selectivity of 46.2% and diglycidyl fumarate was formed with a selectivity of 42.3%, in each case based on the diallyl fumarate reacted.
Reaction SMILES: [C:1]([C:3]1([NH:10][C:11](=[O:30])[CH:12]([CH2:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:13][C:14]([N:16]([CH2:21][CH3:22])[CH2:17][CH2:18][O:19]C)=[O:15])[CH2:5][CH:4]1[CH2:6]N(C)C)#[N:2].N1C=CC=CC=1.[O:37](S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O>ClCCl>[C:1]([C:3]1([NH:10][C:11](=[O:30])[CH:12]([CH2:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:13][C:14]([N:16]2[CH2:21][CH2:22][O:19][CH2:18][CH2:17]2)=[O:15])[CH2:5][CH:4]1[CH2:6][OH:37])#[N:2]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCN(CCOC)C(=O)CC(CC1CCCCC1)C(=O)NC1(C#N)CC1CN(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#CC1(NC(=O)C(CC(=O)N2CCOCC2)CC2CCCCC2)CC1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.3 %

Procedure:
To a stirred solution of the intermediate alcohol from Example 22 (1.1 g, 2.7 mmol) and pyridine (0.44 mL, 5.2 mmol) in dichloromethane (15 mL) at 0° C. was added Tf2O (0.67 mL, 4 mmol) slowly. The mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was washed with brine, dried (sodium sulfate) and purified by chromatography on silica gel (dichloromethane/MeOH=20/1) to give the title compound (0.35 g, 34.6%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](O)=O.[NH4+].[OH-]>>[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[NH:8][C:7]2[C:2]([N:1]=1)=[N:3][CH:4]=[CH:5][CH:6]=2
Reactant: Nc1cccnc1N
Reactant: O=C(O)c1ccccn1
Agent: [NH4+]
Agent: [OH-]
Product: c1ccc(-c2nc3ncccc3[nH]2)nc1
Temperature: 0 °C
Yield: 56.1 %

Procedure:
A solution of 2,3-diaminopyridine (1.1 g, 10 mmol) and 2-picolinic acid (1.23 g, 10 mmol) in polyphosphoric acid (10 ml) was heated to 160° C. for 4 hours. The hot solution was poured into ice water and the pH adjusted to pH 9 with conc. NH4OH. The resulting precipitate was filtered and air dried. This crude product was recrystallized from EtOH to give 1.1 g (56%) of the title compound, m.p. 139°-142° C. Anal. Calcd for C11H8N4 : C, 67.34; H, 4.11; N, 28.36. Found: C, 66.88; H, 4.17; N, 8.36.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[N:3][CH:2]=1.CCN(C(C)C)C(C)C.[N+:19]([CH2:21][C:22]([O:24][CH3:25])=[O:23])#[C-:20].C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[O:9][CH:20]=[N:19][C:21]=2[C:22]([O:24][CH3:25])=[O:23])=[N:3][CH:2]=1
Reactant: [C-]#[N+]CC(=O)OC
Reactant: O=C(O)c1ccncn1
Agent: O=C([O-])O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ncoc1-c1ccncn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of pyrimidine-4-carboxylic acid (261 mg, 2.00 mmol) and DIPEA (0.52 mL, 2.96 mmol) in DMF (8 mL) was added methyl isocyanoacetate (0.28 mL, 2.93 mmol) at rt. The resulting yellow solution was stirred at rt for 5 min and cooled to 0° C. DPPA (0.54 mL, 2.43 mmol) was then added and the resulting solution was stirred at 0° C. for 1 h and at rt for 30 min. Aq. sat. NaHCO3-solution was added and the mixture extracted with EtOAc (4×). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. Purification by FC (hept/EtOAc 9:1 to 100% EtOAc) yielded methyl 5-(pyrimidin-4-yl)oxazole-4-carboxylate. LC-MS conditions A: tR=0.68 min, [M+H]+=206.43.
Reaction SMILES: [Cl:1][C:2]1[C:21]([Cl:22])=[CH:20][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([C:15](O)=[O:16])=[CH:11][C:10]=3[O:18][CH3:19])[NH:8][C:4]=2[CH:3]=1.Cl.CN(C)CCCN=C=NCC.[CH3:35][N:36]1[C:41]([CH3:43])([CH3:42])[CH2:40][CH:39]([NH2:44])[CH2:38][C:37]1([CH3:46])[CH3:45]>CN(C=O)C.C1COCC1.C1COCC1>[Cl:1][C:2]1[C:21]([Cl:22])=[CH:20][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([NH:44][CH:39]4[CH2:38][C:37]([CH3:45])([CH3:46])[N:36]([CH3:35])[C:41]([CH3:43])([CH3:42])[CH2:40]4)=[O:16])=[CH:11][C:10]=3[O:18][CH3:19])[NH:8][C:4]=2[CH:3]=1
Reactant: CN1C(C)(C)CC(N)CC1(C)C
Reactant: COc1cc(C(=O)O)ccc1-c1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc(C(=O)NC2CC(C)(C)N(C)C(C)(C)C2)ccc1-c1nc2cc(Cl)c(Cl)cc2[nH]1
Reaction time: 1 h
Yield: 47.6 %

Procedure:
A solution of 5,6-dichloro-2-(4-carboxy-2-methoxyphenyl)benzimidazole (0.8 g, 2,36 mmol), prepared as described in Preparation 6,1-hydroxybenzotriazole (0.32 g, 2.36 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.56 g, 2.9 mmol) in 80 ml of DMF/THF (50:50) was refluxed for 5 h. A solution of 1,2,2,6,6-pentamethyl-4-aminopiperidine (0.5 g, 2.9 mmol) in THF (5 ml) was added dropwise and the reaction was refluxed for additional 3 h. After cooling, solvent was removed under reduced pressure and the residue was treated with 1N NaOH (10 ml) and extracted with dichloromethane (50 ml). The organic layer was washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was triturated with diisopropyl ether (150 ml), stirred for 1 h, filtered to give 0.55 g of the title compound (yield 47.6%), mp=285–286° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]=[O:10])=[C:4](Cl)[N:3]=1.CCN(C(C)C)C(C)C.[N:21]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([N:24]2[CH2:23][CH2:22][N:21]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25]2)[C:5]([CH:9]=[O:10])=[C:6]([Cl:8])[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Nc1nc(Cl)c(C=O)c(Cl)n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2nc(N)nc(Cl)c2C=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 2-amino-4,6-dichloropyrimidine-5-carboxaldehyde (3.84 g, 20 mmol) and DIPEA (5.2 mL, 30 mmol) in DMF was added tert-butyl piperazine-1-carboxylate (3.73 g, 20 mmol) portionwise. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residue obtained was precipitated with H2O. The precipitate was collected, washed with water and dried in vacuo, to provide the title compound as a white solid in quantitative yield. MS (m/z) 342 [M+H]+.
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].[CH3:6][C@H:7]([O:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[C:14]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=3)=[C:25]([CH3:37])[CH:24]=1)=[N:15][CH:16]=[N:17]2)[CH2:8][NH:9][CH3:10]>>[OH:3][CH2:2][C:1]([N:9]([CH3:10])[CH2:8][C@@H:7]([O:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[C:14]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=3)=[C:25]([CH3:37])[CH:24]=1)=[N:15][CH:16]=[N:17]2)[CH3:6])=[O:5]
Reactant: O=C(O)CO
Reactant: CNC[C@H](C)Oc1cccc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(C)c3)c12
Product: Cc1ccc(Oc2ccc(Nc3ncnc4cccc(O[C@@H](C)CN(C)C(=O)CO)c34)cc2C)cn1
Yield: 46 %

Procedure:
The procedure described in Example 1 was repeated using glycolic acid and 5-[(1S)-1-methyl-2-(methylamino)ethoxy]-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine to give the title compound in 46% yield; NMR spectrum (CDCl3) 1.55 (d, 3H), 2.30 (s, 3H), 2.53 (s, 3H), 2.96 (s, 3H), 3.59 (dd, 1H), 4.16-4.07 (m, 3H), 5.08 (m, 1H), 6.92 (d, 1H), 7.02 (d, 1H), 7.09 (d, 1H), 7.14 (d, 1H), 7.50 (m, 2H), 7.65 (m, 2H), 8.28 (s, 1H), 8.61 (s, 1H), 9.87 (s 1H); Mass spectrum: MH+ 488.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([O:18][C:19](=[O:29])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=1)C>CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][C:11]([C:13]([NH:28][C:24]3[CH:23]=[C:22]([CH2:21][CH2:20][C:19]([OH:29])=[O:18])[CH:27]=[CH:26][CH:25]=3)=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCc1cccc(N)c1
Reactant: O=C(O)c1ccc(-c2ccc(F)cc2)o1
Solvent: CCOC(C)=O
Product: O=C(O)CCc1cccc(NC(=O)c2ccc(-c3ccc(F)cc3)o2)c1

Procedure:
Carboxylic acid (76) (53 mg, 0.26 mmol) was coupled to aniline (124) (50 mg, 0.26 mmol) using Method C. During this reaction, hydrolysis occurred. The acid was re-dissolved in EtOAc (2 ml) and the organic layer was washed with 1M HCl (2×1 ml), dried (Na2SO4), filtered and the solvent removed in vacuo. The solid was recrystallised from a hot 10% EtOH in H2O mixture to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:11]([OH:13])[CH3:12])[C:9]#[N:10])=[CH:4][CH:3]=1.[CH3:14][C:15](C)=[O:16]>CCCCCC>[C:15]([O:13][CH:11]([CH3:12])[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:9]#[N:10])(=[O:16])[CH3:14]
Reactant: CC(O)C(C#N)c1ccc(Cl)cc1
Reactant: CC(C)=O
Solvent: CCCCCC
Product: CC(=O)OC(C)C(C#N)c1ccc(Cl)cc1
Yield: 85 %

Procedure:
This ester was prepared using the procedure described in Example 5, except 2-(4-chlorophenyl)-3-hydroxybutanenitrile was used in place of 2-(2-chloro-5-(difluoromethoxy)phenyl)-3-hydroxypropanenitrile. The preparation of 2-(4-chlorophenyl)-3-hydroxybutanenitrile is described in Example 17. The recovered ester product was a mixture of diastereoisomers (85% yield), Rf 0.29 and 0.35 (silica gel, acetone:hexane=1:3).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[CH3:23][O:24][CH2:25][CH2:26][NH:27][CH3:28]>>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:27]([CH2:26][CH2:25][O:24][CH3:23])[CH3:28])=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: CNCCOC
Reactant: BrCCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Product: COCCN(C)CCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
According to the method in example 4, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and N-(2-methoxyethyl)methylamine were converted to yield [4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl]-(2-methoxy-ethyl)-methyl-amine, MS: 450 (MH+, 1Br).
Reaction SMILES: [SH2:1].[S].[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)=[CH2:4]>>[N:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH:3]([SH:1])[CH3:4]
Reactant: C=Cc1ccccn1
Reactant: S
Agent: [S]
Product: CC(S)c1ccccn1

Procedure:
The reaction using hydrogen sulfide as the sulfur-containing compound is as follows. That is, vinyl pyridine is reacted with hydrogen sulfide to obtain pyridylethanethiol represented by the above general formula (3) as the pyridylethylthio compound.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][NH:18][CH2:19][C:20]3[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][N:36]=1>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=3)[C:39]([C:38]3[CH:37]=[N:36][C:35]([OH:34])=[CH:43][CH:42]=3)=[O:40])=[CH:32][CH:33]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)c1ccc(O)nc1
Reactant: CCCCc1ccc(C#Cc2ccc(CNCc3ccc(OCC(=O)OC)cc3)cc2)cc1
Product: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(OCC(=O)OC)cc3)C(=O)c3ccc(O)nc3)cc2)cc1

Procedure:
The titled compound was prepared following the procedure H using methyl {4-[({4-[(4-butylphenyl)ethynyl]benzyl}amino)methyl]phenoxy}acetate and 6-hydroxynicotinic acid as a colorless oil (95%). HPLC, Rt: 4.86 min (Purity: 88%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C@@H:18]3[CH:23]4[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]4)[CH2:19]3)=[O:17])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH2:26]([N:28]=[C:29]=[O:30])[CH3:27]>C1COCC1.CN(C=O)C>[CH2:26]([NH:28][C:29](=[O:30])[O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([C@@H:18]3[CH:23]4[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]4)[CH2:19]3)=[O:17])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1)[CH3:27]
Reactant: CCN=C=O
Reactant: O=C(Nc1ccc(-c2ccc(CO)cc2)cc1)[C@H]1CN2CCC1CC2
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCNC(=O)OCc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
35 mg (0.10 mmol) of (3R)-N-[4′-(hydroxymethyl)-1,1′-biphenyl-4-yl]-1-azabicyclo-[2.2.2]octane-3-carboxamide are dissolved in 1 ml of a 1:1 THF/DMF mixture. 17 mg (0.21 mmol) of ethyl isocyanate are added, and the mixture is stirred at 60° C. overnight. The solvent is removed under reduced pressure, and the crude product is purified by preparative HPLC. 24 mg (55% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:11][C:12]1[CH:27]=[CH:26][C:15]([C:16]([NH:18][C@H:19]([C:22]([O:24][CH3:25])=[O:23])[CH2:20][OH:21])=O)=[CH:14][CH:13]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]2[O:21][CH2:20][CH:19]([C:22]([O:24][CH3:25])=[O:23])[N:18]=2)=[CH:26][CH:27]=1
Reactant: COC(=O)[C@H](CO)NC(=O)c1ccc(Cc2nc3ccccc3n2C)cc1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: COC(=O)C1COC(c2ccc(Cc3nc4ccccc4n3C)cc2)=N1
Temperature: 60 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
A stirred solution of methyl N-{4-[(1-methyl-1H-benzimidazol-2-yl)methyl]-benzoyl}-serinate (0.2 g, 0.55 mmol, 1.0 eq) in THF was treated with Burgess reagent (0.156 g, 0.65 mmol) and molecular sieves (1 g), stirred at 60° C. for 2 h, cooled to room temperature and concentrated under reduced pressure. The resultant residue was purified by column chromatography (silica, CHCl3:MeOH 5%) to afford the title compound in 52% yield, identified by NMR and mass spectral analyses. 1H NMR (400 MHz, DMSO-d6): 7.95 (s, 1H), 7.84 (d, J=8 Hz, 1H), 7.57 (d, J=8 Hz, 1H), 7.48 (d, J=8 Hz, 1H), 7.39 (d, J=8 Hz, 2H)), 7.16-7.21 (m, 1H), 5.60 (m, 1H), 4.95 (t, J=8.4 Hz, 1H), 4.57-4.60 (m, 1H), 4.38 (s, 2H), 4.26 (t, J=8.4 Hz, 1H), 3.78 (s, 3H). LCMS (ESI+) 350 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[C:10](=[O:11])[CH2:9][NH:8][S:7]1(=[O:13])=[O:12].[C:20]([O:24][C:25](=[O:35])[NH:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33]O)=[CH:29][CH:28]=1)([CH3:23])([CH3:22])[CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:20]([O:24][C:25](=[O:35])[NH:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:33][N:8]2[CH2:9][C:10](=[O:11])[N:6]([CH2:5][C:4]3[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:3]=3[O:2][CH3:1])[S:7]2(=[O:13])=[O:12])=[CH:31][CH:32]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: COc1ccc(CN2C(=O)CNS2(=O)=O)c(OC)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CO)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)CN(Cc3ccc(NC(=O)OC(C)(C)C)cc3)S2(=O)=O)c(OC)c1
Reaction time: 16 h

Procedure:
The title B compound, 2-(2,4-dimethoxybenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (98 mg, 0.34 mmol) and (4-hydroxymethylphenyl)carbamic acid t-butyl ester (153 mg, 0.68 mmol) and triphenylphosphine (180 mg, 0.68 mmol) are dissolved in THF (10 mL) with stirring under argon atmosphere. The reaction is cooled in an ice/water bath and diethyl azodicarboxylate (0.107 mL, 0.68 mmol) dissolved in THF (0.107 mL) is added dropwise. After 16 h, the solvent is evaporated and the residue is taken up in a minimal amount of CH2Cl2 and chromatographed on silica gel with a gradient from 1 to 5% EtOAc in CH2Cl2 over 15 min to give {4-[5-(2,4-dimethoxybenzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-phenyl}-carbamic acid t-butyl ester as an oil: [M+NH4]+=509.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[SH:7][CH2:8][CH2:9][C:10]([N:12]1[CH2:19][CH2:18][CH2:17][C@H:13]1[C:14]([OH:16])=[O:15])=[O:11]>C(=O)(O)[O-].[Na+]>[CH2:5]([O:4][C:2]([S:7][CH2:8][CH2:9][C:10]([N:12]1[CH2:19][CH2:18][CH2:17][C@H:13]1[C:14]([OH:16])=[O:15])=[O:11])=[O:3])[CH3:6]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)CCS
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)SCCC(=O)N1CCC[C@H]1C(=O)O
Reaction time: 1 h

Procedure:
Ethyl chloroformate (1.2 g.) is added to a solution of 3-mercaptopropanoyl-L-proline (2.03 g.) in normal sodium bicarbonate (30 ml.) and the mixture is stirred vigorously at 5° for one hour, and for two hours at room temperature. After acidification with concentrated hydrochloric acid, the mixture is extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate, and concentrated to dryness to yield 1-[3-[[(ethoxy)carbonyl]thio]propanoyl]-L-proline.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12]([N:14]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:15][CH2:16][CH2:17][O:18][C:19]1[C:24]2[C:25]([CH2:31][OH:32])=[C:26]([C:28]([OH:30])=[O:29])[O:27][C:23]=2[CH:22]=[CH:21][CH:20]=1)=[O:13])([CH3:10])([CH3:9])[CH3:8].CI.Cl>CN(C=O)C>[CH3:1][O:29][C:28]([C:26]1[O:27][C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([O:18][CH2:17][CH2:16][CH2:15][N:14]([C:12]([O:11][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:13])[C:33]([CH3:36])([CH3:35])[CH3:34])[C:24]=2[C:25]=1[CH2:31][OH:32])=[O:30]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N(CCCOc1cccc2oc(C(=O)O)c(CO)c12)C(C)(C)C
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1oc2cccc(OCCCN(C(=O)OC(C)(C)C)C(C)(C)C)c2c1CO
Reaction time: 8 h
Yield: 71.6 %

Procedure:
To a suspension of potassium carbonate (4.0 mg) and 4-[3-(tert-butoxycarbonyl-tert-butyl-amino)-propoxy]-3-hydroxymethyl-benzofuran-2-carboxylic acid (5.0 mg) in dry DMF (0.8 ml) was added methyl iodide (48 μl) at room temperature and the mixture was stirred overnight. The solvent was evaporated in vacuo to give the crude material as a white heavy syrup, which was then treated with 0.1N HCl (10 ml). The product was extracted with ethyl acetate (10 ml) three times and washed with saturated sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography developed by hexane-ethyl acetate to give 4-[3-(tert-butoxycarbonyl-tert-butyl-amino)-propoxy]-3-hydroxymethyl-benzofuran-2-carboxylic acid methyl ester (3.7 mg) as a white solid. FAB-MS: m/z 436 (MH+); 1H-NMR (CDCl3): δ 1.42-1.48 (18H, m), 2.11 (2H, quintet, J=7.3 Hz), 3.54 (2H, t, J=7.3 Hz), 4.07 (1H, t, J=6.9 Hz), 4.12 (2H, t, J=7.3 Hz), 4.48 (3H, s), 5.22 (2H, d, J=6.9 Hz), 6.68 (1H, d, J=7.9 Hz), 7.18 (1H, d, J=7.9 Hz), 7.40 (1H, dd, J=7.9 Hz, 7.9 Hz).