Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][NH:10][C:4]=2[CH:3]=1.CCN(C(C)C)C(C)C.[CH3:20][Si:21]([CH2:24][CH2:25][O:26][CH2:27]Cl)([CH3:23])[CH3:22]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([CH2:27][O:26][CH2:25][CH2:24][Si:21]([CH3:23])([CH3:22])[CH3:20])[C:4]=2[CH:3]=1
Reactant: Clc1cc2[nH]ncc2cn1
Reactant: C[Si](C)(C)CCOCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1ncc2cnc(Cl)cc21
Temperature: 30 °C
Reaction time: 20 h
Yield: 93 %

Procedure:
To a solution of 6-chloro-1H-pyrazolo[4,3-c]pyridine (2.00 g, 13.1 mmol) and DIPEA (3 mL) in DCM (10 mL) was added SEMCl (3 mL). The mixture was stirred at 30° C. for 20 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography using EtOAc/Petroleum Ether (10%˜60%) as eluting solvents to afford 6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine as colorless oil (3.44 g, 93%). MS (ESI) m/z: 284 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH2:11])[CH:10]=1)[NH:7][C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:5]2.Br[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=3)[CH:10]=1)[NH:7][C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:5]2
Reactant: Nc1cc(Cl)cc2cc(-c3ccccc3)[nH]c12
Reactant: Cc1ccc(Br)nc1
Product: Cc1ccc(Nc2cc(Cl)cc3cc(-c4ccccc4)[nH]c23)nc1

Procedure:
7-Amino-5-chloro-2-phenyl-1H-indole prepared in Example 3 and 2-bromo-5-methyl-pyridine were reacted according to the same procedure as Example 113 to give the title compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]#[C:11][CH2:12][C@H:13]([OH:23])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.[CH3:33][O:34][CH2:35][CH2:36][O:37][CH2:38]Cl>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C:10]#[C:11][CH2:12][C@H:13]([O:23][CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38])[CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCOCCl
Reactant: O[C@@H](CC#CCOCc1ccccc1)COc1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCOCO[C@@H](CC#CCOCc1ccccc1)COc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.4 %

Procedure:
To an ice cooled solution of (2S)-6-benzyloxy-1-(4-fluorophenoxy)-hex-4-yn-2-ol (2 g, 6.4 mmol) in dry CH2Cl2 (8 ml) was added N-ethyldiisopropylamine (1.7 ml 9.5 mmol) and stirred for 10 minutes MEM-chloride (1.1 ml, 9.5 mmol) was added to the solution at 0° C. and stirred for 3 h at room temperature. The solvent was concentrated and the residue purified on a silica gel column using EtOAc-light petroleum (1:4) as eluent to yield (2S)-6-benzyloxy-1-(4-fluorophenoxy)-2-(methoxyethoxymethyloxy)-hex-4-yne (2.2 g, 85%) as a yellow colour liquid. TLC:ethyl acetate-light petroleum (1:3), Rf=0.5 1H NMR (CDCl3, 200 MHz): δ 2.65-2.75 (m, 2H), 3.39 (s, 3H), 3.55 (t, J=4.8 Hz, 2H 3.78 (t, J=4.8 Hz, 2H), 4.11 (s, 2H), 4.16 (m, 3H), 4.56 (s, 2H), 4.89 (s, 2H), 6.8-7.02 (m, 4H), 7.3-7.35 (m, 5H).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]([CH3:14])[CH2:10][C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[CH3:20]O>>[NH2:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]([CH3:14])[CH2:10][C:11]([O:13][CH3:20])=[O:12])=[CH:5][CH:4]=1
Reactant: CC(CC(=O)O)c1ccc(N)nc1
Reactant: CO
Agent: Cl
Agent: O=S(=O)(O)O
Product: COC(=O)CC(C)c1ccc(N)nc1

Procedure:
A solution of (RS) 3-(6-amino-pyrid-3-yl)-butanoic acid hydrochloride (12.0 g, Reference Example 20) in methanol (300 mL) was treated with concentrated sulphuric acid (3.0 mL) then heated at reflux temperature for 8 hours. The reaction mixture was concentrated, then basefied with 5% aqueous sodium bicarbonate and then extracted with ethyl acetate . The extracts were washed with water, then with brine, then dried over magnesium sulphate and then evaporated to give the title compound (7.6 g) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C@:3]([CH3:16])([CH2:12][CH2:13][CH2:14][CH3:15])[C@H:4]([OH:11])[C:5]#[C:6][Si](C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][O:2][C@:3]([CH3:16])([CH2:12][CH2:13][CH2:14][CH3:15])[C@H:4]([OH:11])[C:5]#[CH:6]
Reactant: CCCC[C@@](C)(OC)[C@H](O)C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#C[C@@H](O)[C@@](C)(CCCC)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
Dissolve (3R,4R)-4-methoxy-4-methyl-l-trimethylsilyl-l-octyn-3-ol (40mg, 0.17 mmol) in tetrah place under an argon atmosphere. Add, by dropwise addition, tetra-n-butylammonium fluoride (1.4 mL of a lM solution in tetrahydrofuran, 1.4 mmol). Stir for 1 hour at room temperature and partition between methylene chloride and water. Separate the organic phase, wash with saturated aqueous sodium chloride and dry (MgSO4). Evaporate the solvent in vacuo to give the title compound as a thick clear oil (21 mg, 75%).
Reaction SMILES: O[C:2]1([C:12]([NH2:14])=[O:13])[CH:10](O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C(N(CC)CC)C.[C:22](Cl)(=[O:24])[CH3:23]>ClC(Cl)Cl>[C:22]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10][C@H:2]1[C:12]([NH2:14])=[O:13])(=[O:24])[CH3:23]
Reactant: NC(=O)C1(O)Nc2ccccc2C1O
Reactant: CC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)N1c2ccccc2C[C@H]1C(N)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
2,3-Dihydroxy-1H-indole-2-carboxamide (0.030 mol) was suspended in trichloromethane (400 ml). The mixture was cooled to 0° C. Triethylamine (0.045 mol) was added. Acetyl chloride (0.045 mol) was added over 2 minutes. After 30 minutes, TLC showed the reaction was incomplete. While the flask was still cool, more Triethylamine (6.26 ml) was added, followed 15 minutes later with more acetyl chloride (3.21 ml). TLC showed the reaction was still incomplete. The reaction was continued to allow to stir, cooled to 0° C., and more triethylamine (6.26 ml) was added. Over 2 minutes, more acetyl chloride (3.21 ml) was added neat. TLC showed 80% completion after 60 minutes, and no progress after 30 more minutes. A third portion of acetyl chloride and triethylamine was added. After an additional 15 minutes, ice cold water (200 ml) was added. The mixture was stirred for 10 minutes, filtered, and rinsed with water (3×100 ml) and trichloromethane (2×75 ml). The sample was allowed to dry overnight, yielding 4.71 g of (S)-1-acetyl-2,3-dihydro-1H-indole-2-carboxamide (intermediate 1, mp. >260° C.). b) Intermediate (1) (0.02022 mol) was suspended in DCM (175 ml). The mixture was cooled to 0° C. Triethylamine (0.06066 mol) was added neat. Trichloroacetyl chloride (0.03033 mol) in DCM (20 ml) was added dropwise over 20 minutes. After 2 hours, ice water (200 ml) was added, the phases separated and the organic phase reextracted with 3 N HCl and then with a saturated aqueous NaHCO3 solution. The organic phase was dried, filtered, and stripped to leave 4.61 g brown solid. The solid was triturated with ice cold diethylether (30 ml), filtered, and rinsed with ice cold diethylether (twice), yielding 3.12 g (83%) of (S)-1-acetyl-2,3-dihydro-1H-indole-2-carbonitrile (intermediate 2, mp. 134-135° C.). c) Intermediate (2) (0.0151 mol) was suspended in diethylether (200 ml). Ethanol (0.0214 mol) was added, and the mixture was cooled to 0° C. HCl (gas) was bubbled in for 45 minutes. The mixture was removed from the ice bath and stirred. After 20 minutes, a residue collected on the wall sides. The walls were scratched, and a white solid precipitated out. After 1 hour the sample was filtered, rinsed with diethylether, air dried quickly, yielding 3.99 g of (S)-ethyl 1-acetyl-2,3-dihydro-1H-indole-2-carboximidate monohydrochloride (intermediate 3). In analogy, ethyl 1-acetyl-2,3-dihydro-1H-indole-2-carboximidate monohydrochloride (intermediate 6) was prepared starting from 1-acetyl-2,3-dihydro-1H-indole-2-carbonitrile.
Reaction SMILES: C[O:2][C:3](=[O:14])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Br:13].[OH-].[Na+].O.Cl>CO>[Br:13][C:7]1[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:6]=1/[CH:5]=[CH:4]/[C:3]([OH:14])=[O:2]
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)/C=C/c1ccc(Cl)cc1Br

Procedure:
(E)-3-(2-Bromo-4-chlorophenyl)-acrylic acid methyl ester (6.8 g, 17.4 mmol) was dissolved in MeOH (175 ml) and treated with 2N NaOH (13 ml; 26 mmol) and water (87 ml) for 1 hour at 50° C. The mixture was acidified with 2N HCl (15 ml) and extracted with TBME twice. The combined organic phases were dried over Na2SO4 and evporated to dryness to yield the title compound as a solid, which was recrystallised from TBME/hexanes to yield the title compound as colorless crystals (4.4 g, 90%).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:3]#[N:4].[C:11]([CH2:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16])(=O)[CH3:12]>C(O)C>[NH2:4][C:3]1[C:14]([C:15](=[O:16])[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:11]([CH3:12])[NH:1][C:2]=1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(=O)CC(=O)Nc1ccccc1
Reactant: N#CC(N)c1ccccc1
Solvent: CCO
Product: Cc1[nH]c(-c2ccccc2)c(N)c1C(=O)Nc1ccccc1

Procedure:
This compound is prepared starting from 2-amino-2-phenylacetonitrile and α-acetyl-N-phenyl-acetamide, and is obtained with a 73% overall yield, m.p. 271°-73° C. (from ethanol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:16][CH2:15][CH2:14][NH:13]2)=[CH:8][CH:7]=1.[C:18](#[N:21])[CH:19]=[CH2:20]>>[CH3:1][O:2][C:3](=[O:17])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH2:20][CH2:19][C:18]#[N:21])=[CH:8][CH:7]=1
Reactant: C=CC#N
Reactant: COC(=O)/C=C/c1ccc(C2CCCN2)cc1
Product: COC(=O)/C=C/c1ccc(C2CCCN2CCC#N)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.1 %

Procedure:
A mixture of (E)-3-(4-pyrrolidin-2-yl-phenyl)-acrylic acid methyl ester (1.0 g, 4.3 mmol), acrylonitrile (1.1 g, 22 mmol) and silica gel (4 g, grade 62 60-200 mesh 150 Å) was stirred at room temperature for 24 h. The reaction mixture was purified via silica gel column chromatography to give (E)-3-{4-[1-(2-cyano-ethyl)-pyrrolidin-2-yl]-phenyl}-acrylic acid methyl ester (1.2 g, 98%) as a colorless oil. LCMS (m/z): 285.1 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]([OH:30])=O)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.[NH2:32][CH2:33][C@H:34]([OH:39])[C:35]([F:38])([F:37])[F:36].CCN=C=NCCCN(C)C.Cl>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]([NH:32][CH2:33][C@H:34]([OH:39])[C:35]([F:38])([F:37])[F:36])=[O:30])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=2)[CH:11]=1
Reactant: NC[C@H](O)C(F)(F)F
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)O)[nH]2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)NC[C@H](O)C(F)(F)F)[nH]2)c1
Reaction time: 2 h
Yield: 64.8 %

Procedure:
5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxylic acid (408 mg, 0.94 mmol) synthesized in Example (18a), (2S)-3-amino-1,1,1-trifluoro-2-propanol (177 mg, 1.37 mmol) and 4-dimethylaminopyridine (224 mg, 1.87 mmol) were dissolved in dichloromethane (20 mL), and WSCI.HCl (193 mg, 1.01 mmol) was added at room temperature, followed by stirring for 2 hours under nitrogen atmosphere. The reaction solution was diluted with dichloromethane (200 mL), washed with 1N hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=50%-70%) to afford the desired product (339 mg, yield 67%) as a white amorphous substance.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][CH2:26][NH2:27]>>[Cl:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:27][CH2:26][CH2:25][C:21]2[S:20][CH:24]=[CH:23][CH:22]=2)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2Cl)cn1
Reactant: NCCc1cccs1
Product: NC(=O)c1ccc(Oc2ccc(CNCCc3cccs3)cc2Cl)cn1
Yield: 72.9 %

Procedure:
Using a method similar to Example 405, using 5-(2-chloro-4-formylphenoxy)pyridine-2-carboxamide (0.0388 g, 0.140 mmol) and 2-(2-thienyl)ethylamine (0.018 g, 0.140 mmol) gives the title compound (0.0396 g, 72.8%): TOF MS ES+ 388.1 (M+H)+. HRMS calcd for C19H19N2O2ClS 388.0887 (M+H)+, found 388.0866, time 0.39 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=7.6 min, 100% purity.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[O:10][C:11]3[C:12]([N:17]=2)=[N:13][CH:14]=[CH:15][CH:16]=3)[CH:6]=[CH:7][CH:8]=1)#[N:2]>O=[Pt]=O.C(O)(=O)C>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([C:9]2[O:10][C:11]3[C:12]([N:17]=2)=[N:13][CH:14]=[CH:15][CH:16]=3)[CH:6]=[CH:7][CH:8]=1
Reactant: N#Cc1cccc(-c2nc3ncccc3o2)c1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: NCc1cccc(-c2nc3ncccc3o2)c1

Procedure:
A mixture of 2-(3-cyanophenyl)oxazolo[4,5-b]pyridine (2.2 g., 0.01 m.), 200 ml. of glacial acetic acid and 1.0 g. of PtO2 catalyst is reacted in a 40 p.s.i. hydrogen atmosphere at room temperature until the theoretical amount of hydrogen has been absorbed. The mixture is filtered, the acetic acid removed in vacuo to yield 2-[3-(aminomethyl)phenyl]oxazolo[4,5-b]pyridine.
Reaction SMILES: [C:1]([CH2:13][C:14]([O:16]CC)=O)(=O)[C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1.[CH2:19]([NH:21][C:22]([NH:24][CH2:25][CH3:26])=[O:23])[CH3:20].C(O)C>Cl.O>[CH2:19]([N:21]1[C:1]([C:2]2[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=2)=[CH:13][C:14](=[O:16])[N:24]([CH2:25][CH3:26])[C:22]1=[O:23])[CH3:20]
Reactant: CCNC(=O)NCC
Reactant: CCOC(=O)CC(=O)c1ccc(OC)c(OC)c1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCn1c(-c2ccc(OC)c(OC)c2)cc(=O)n(CC)c1=O
Temperature: 120 °C
Yield: 26.5 %

Procedure:
To a mixture of ethyl veratroylacetate (10 g) and N,N'-diethylurea (5.06 g) were added conc. hydrochloric acid (1 drop) and ethanol (1 ml). The mixture was heated at 120° C. for 3.5 hours under reduced pressure. To the residue was added another conc. hydrochloric acid (2 drops) and the mixture was heated again at 120° C. for 4 hours under reduced pressure. To the reaction mixture was added water and extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated under reduced pressure. The residue was triturated with a mixture of diisopropyl ether and ethyl acetate to give 1,3-diethyl-6-(3,4-dimethoxyphenyl)-2,4(1H,3H)-pyrimidinedione (3.20 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7](Br)[N+:6]=1[O-:12])(=[O:3])[CH3:2].[SH-:13].[Na+].Cl>C(O)C>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([SH:13])[N+:6]=1[O-:12])(=[O:3])[CH3:2]
Reactant: [SH-]
Reactant: CC(=O)Nc1cccc(Br)[n+]1[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=O)Nc1cccc(S)[n+]1[O-]
Temperature: 60 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
More specifically, the mercapto pyridine-1-oxide derivatives of the instant invention are prepared from known starting materials. 2-amino-6-bromopyridine which may be prepared by hydrogen bromide induced cyclization of 3-hydroxyglutaronitriles, a method described in U.S. Pat. No. 3,096,337, or by any other known process, is dissolved in an excess amount of acetic anhydride and heated at 70° C. for 45 minutes and the excess acetic anhydride is hydrolyzed by the addition of 300 ml. water, to give a substantially quantitative yield (95%) of 2-acetamido-6-bromopyridine which has a melting point of 159.2°-160.0° C. The 2-acetamido-6-bromopyridine is oxidized by heating a solution thereof in glacial acetic acid with an excess of peracetic acid at 70° C. for 2 hours and at 55° C. for 19 hours. The reaction mixture is diluted with 1600 ml. water and concentrated in vacuum, unreacted material removed by filtration, and the solvent evaporated from the filtrate, giving an 83% yield of impure 2-acetamido-6-bromopyridine-1-oxide which is purified and recrystallized from 2-propanol to yield fine white needles having a melting point of 180.0°-180.5° C. The mercapto derivative of 2-acetamido-6-bromopyridine-1-oxide may be prepared by reaction with an excess of sodium hydrosulfide (M NaSH) in an aqueous-ethanol medium while stirring for 5 hours at 60° C. and overnight at room temperature, adding concentrated hydrochloric acid dropwise to the cold yellow solution and collecting the light yellow solid by filtration, purifying by recrystallization from 2-propanol and obtaining pale yellow crystals having a melting point of 172.8°-173.5° C. A 79% yield of 2-acetamido-6-mercaptopyridine-1-oxide is obtained with the aforedefined process.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][CH2:7][CH2:8][C:9]1[CH:13]=[CH:12][S:11][CH:10]=1)=O.P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH3:1][O:2][CH2:3][C:4]1[C:10]2[S:11][CH:12]=[CH:13][C:9]=2[CH2:8][CH2:7][N:6]=1
Reactant: COCC(=O)NCCc1ccsc1
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: COCC1=NCCc2ccsc21

Procedure:
15.6 g (78.3 mmol) 2-methoxy-N-(2-thiophen-3-yl-ethyl)-acetamide are dissolved in 350 ml chloroform and combined with 35.8 ml (391.4 mmol) phosphorus oxychloride while cooling with an ice bath. The ice bath is removed and the mixture is refluxed for 5 hours. Then it is carefully added to 600 ml of warm sodium hydroxide solution (4N) and the aqueous phase is extracted three times with ethyl acetate. The combined organic phases are dried on sodium sulphate, filtered and evaporated down i. vac. The crude product is purified by flash chromatography on silica gel (eluant DCM/methanol 98:2→95:5).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]([F:20])([F:19])[O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([O:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:10]([F:9])([F:19])[F:20])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)Oc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 97.6 %

Procedure:
Benzyl bromide (66.17 ml, 95.35 g, 0.56 mol) was added to a mixture of 4-(trifluoromethoxy)phenol (90.26 g, 0.51 mol) and potassium carbonate (140.97 g, 1.2 mol) in dimethylformamide (160 ml) and the mixture was stirred at room temperature for 72 hours. The mixture was poured into water (1.5 l) and extracted with ethyl acetate (3×500 ml). The combined organic fractions were washed with aqueous sodium carbonate (saturated, 500 ml), dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (133.5 g, 99%). 1H NMR (360 MHz, CDCl3)δ7.39 (5H, m), 7.14 (2H, d, J=9.0 Hz), 6.95 (2H, d, J=9.0 Hz), and 5.05 (2H, s).
Reaction SMILES: Cl.[CH2:2]([NH2:13])[CH2:3][C:4]1[CH:12]=[CH:11][C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=1.C(N(CC)CC)C.[Cl:21][CH2:22][C:23](Cl)=[O:24]>C(Cl)Cl>[Cl:21][CH2:22][C:23]([NH:13][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=1)=[O:24]
Reactant: O=C(Cl)CCl
Reactant: NCCc1ccc2c(c1)OCO2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)NCCc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.5 %

Procedure:
To homopiperonylamine hydrochloride (2.14 g, 10.6 mmol) (a compound of formula (Y7)) in CH2Cl2 (20 mL) in an ice bath was added triethylamine (3.1 mL, 21 mmol) and chloroacetyl chloride (0.85 mL, 10 mmol) (a compound of formula (Y6)). After warming to ambient temperature and stirring for 16 hours, the reaction was partitioned with 1 N HCl. The organic layer was separated, washed with aqueous bicarbonate, dried (Na2SO4), and the solvent was removed in vacuo to give 1.8 g of 2-chloro-N-[2-(1,3-benzodioxol-5-yl)ethyl]acetamide, a compound of formula (Y8).
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH:3]=[CH:4][C:5]([O:7][CH3:8])=[O:6].C(N(CC)CC)C.[Cl:17][C:18]1[CH:26]=[C:25]([Cl:27])[C:24]([F:28])=[CH:23][C:19]=1[C:20](Cl)=[O:21]>O1CCOCC1>[CH3:1][N:2]([CH3:9])[CH:3]=[C:4]([C:20](=[O:21])[C:19]1[CH:23]=[C:24]([F:28])[C:25]([Cl:27])=[CH:26][C:18]=1[Cl:17])[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C(Cl)c1cc(F)c(Cl)cc1Cl
Reactant: COC(=O)C=CN(C)C
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)C(=CN(C)C)C(=O)c1cc(F)c(Cl)cc1Cl
Yield: 89.1 %

Procedure:
First a solution of 12.9 g of methyl 3-dimethylaminoacrylate in 25 ml of dioxane is added dropwise, and then 10.5 g of triethylamine are added to a solution of 22.75 g of 2,4-dichloro-5-fluorobenzoyl chloride in 80 ml of anhydrous dioxane, while cooling in ice and stirring. The mixture is stirred at room temperature for 3 hours, heated at 50°-60° C. for 1 hour, and the solvent is removed by distillation in vacuo and the residue is taken up in methylene chloride/H2O. The phases are separated, and the aqueous solution is again extracted with methylene chloride. The combined organic phases are washed with water, dried with sodium sulphate, and the methylene chloride is removed in vacuo. The crystalline residue is recrystallized from methanol/water. 28.5 g of methyl 3-dimethylamino-2-(2,4-dichloro-5-fluorobenzoyl)acrylate of melting point 107°-109° C. are obtained.
Reaction SMILES: [C:1]([CH:4]1[C:8](=[O:9])[CH2:7][CH2:6][C:5]1=[O:10])(=[O:3])[CH3:2].[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][C:13]=1[O:20][CH3:21].N1CCOCC1.Cl>CS(C)=O>[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[CH:2][C:1]([CH:4]2[C:8](=[O:9])[CH2:7][CH2:6][C:5]2=[O:10])=[O:3])=[CH:14][C:13]=1[O:20][CH3:21]
Reactant: CC(=O)C1C(=O)CCC1=O
Reactant: COc1cc(C=O)ccc1O
Agent: Cl
Solvent: CS(C)=O
Solvent: C1COCCN1
Product: COc1cc(C=CC(=O)C2C(=O)CCC2=O)ccc1O

Procedure:
2-Acetyl-1,3-cyclopentanedione (3.03 g.) was treated with 4-hydroxy-3-methoxybenzaldehyde (5.05 g.) in 50 ml. of dimethylsulfoxide at 80° C for 13 minutes in the presence of 4 ml. of morpholine. After cooling, 80 ml. of 1 N hydrochloric acid was added to the reaction mixture, depositing a crystalline product. The solid was collected by filtration, and washed with water and ethanol successively, and it was then dried. The Claiseu-Schmidt condensation product, 2-(4-hydroxy-3-methoxycinnamoyl)-1,3-cyclopentanedione, (1.3 g.) was obtained in an orange crystalline form, which showed mp. 274°- 275° C after recrystallization from dioxane.