Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[F:2][C:3]1[CH:4]=[N:5][C:6]([NH+:9]2[C:17]3[CH2:16][C@H:15]([CH3:18])[NH:14][CH2:13][C:12]=3[N:11]=[N:10]2)=[N:7][CH:8]=1.C(N(CC)CC)C.[F:26][C:27]1[C:35]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30].C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:2][C:3]1[CH:4]=[N:5][C:6]([N:9]2[C:17]3[CH2:16][C@H:15]([CH3:18])[N:14]([C:29]([C:28]4[CH:32]=[CH:33][CH:34]=[C:35]([C:36]([F:37])([F:38])[F:39])[C:27]=4[F:26])=[O:30])[CH2:13][C:12]=3[N:11]=[N:10]2)=[N:7][CH:8]=1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1F
Reactant: C[C@H]1CC2=C(CN1)N=N[NH+]2c1ncc(F)cn1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1Cc2c(nnn2-c2ncc(F)cn2)CN1C(=O)c1cccc(C(F)(F)F)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a solution of (S)-1-(5-fluoropyrimidin-2-yl)-6-methyl-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridinium chloride (0.575 g, 2.12 mmol) in CH2Cl2 (10 mL) was added triethylamine (1.18 mL, 8.50 mmol) followed by 2-fluoro-3-(trifluoromethyl)benzoyl chloride (0.625 g, 2.76 mmol). After stirring for 30 min at rt, sat NaHCO3 (20 mL) was added. The organic layer was separated and the water layer was extracted with CH2Cl2 two times. The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated. Chromatography on silica gel (0-100% ethyl acetatehexanes) provided the desired product as a white solid (0.837 g, 93%). MS (ESI) mass calcd. C18H13F5N6O, 424.11. m/z found, 425.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.75 (s, 2H), 7.81-7.49 (m, 2H), 7.46-7.30 (m, 1H), 5.92-5.66 (m, 0.5H), 5.68-5.55 (m, 0.5H), 4.81-4.54 (m, 1H), 4.37 (d, J=16.9 Hz, 0.5H), 4.30-4.18 (m, 0.5H), 3.58-3.40 (m, 0.8H), 3.34-3.12 (m, 1.2H), 1.43-1.12 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([CH3:10])=[CH:4][CH:3]=1.C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].[Br:35][C:36]1[CH:37]=[C:38](F)[C:39]([Cl:43])=[C:40]([F:42])[CH:41]=1>CS(C)=O.C1COCC1>[Br:35][C:36]1[CH:41]=[C:40]([F:42])[C:39]([Cl:43])=[C:38]([O:8][C:7]2[C:6]([F:9])=[C:5]([CH3:10])[CH:4]=[CH:3][C:2]=2[Cl:1])[CH:37]=1
Reactant: Cc1ccc(Cl)c(O)c1F
Reactant: Fc1cc(Br)cc(F)c1Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(Cl)c(Oc2cc(Br)cc(F)c2Cl)c1F
Temperature: 130 °C
Yield: 38.1 %

Procedure:
6-chloro-2-fluoro-3-methylphenol (9.96 g, 62.0 mmol) and 18-crown-6 (4.5 g, 17.03 mmol) were dissolved in dry DMSO (100 mL) and treated with 20% potassium t-butoxide in THF (34.8 g, 62.0 mmol) in THF for 15 minutes at room temperature. 5-bromo-2-chloro-1,3-difluorobenzene (14.11 g, 62.0 mmol) was added in one portion and the reaction mixture heated at 130° C. for 3 days. The reaction mixture was filtered through Celite™, cooled to ambient temperature and water was added to afford the crude product as a black precipitate which was filtered off, washed with water and air dried. The crude product was dissolved in DCM, dried over MgSO4, and filtered through a plug of 45 g silica gel which was eluted with 500 mL DCM. The filtrate was concentrated to an amber oil and crystallized by addition of EtOH (150 mL). The precipitate was cooled in an ice bath and filtered to afford 2-[(5-bromo-2-chloro-3-fluorophenyl)oxy]-1-chloro-3-fluoro-4-methylbenzene (8.7 g, 23.64 mmol, 38.1% yield) as a white solid. The mother liquor was concentrated to dryness and crystallized from IPA (70 mL) to give a second batch of the desired product (4.55 g, 12.36 mmol, 19.93% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.61 (dd, J=8.56, 1.97 Hz, 1H), 7.30-7.47 (m, 2H), 6.74 (s, 1H), 2.29 (d, J=1.56 Hz, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[CH:11][CH:10]=1)=[O:2].S([CH2:36][N+:37]#[C-:38])(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CO>[O:2]1[C:1]([C:3]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[C:17]3[C:18]([F:24])=[CH:19][CH:20]=[CH:21][C:22]=3[F:23])=[CH:11][CH:10]=2)=[CH:38][N:37]=[CH:36]1
Reactant: O=CC1=C(c2ccc(NC(=O)c3c(F)cccc3F)cc2)CCCC1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(Nc1ccc(C2=C(c3cnco3)CCCC2)cc1)c1c(F)cccc1F
Yield: 65 %

Procedure:
The solution of Compound 100 (60 mg, 0.17 mmol), tosylmethylisocyanide (38 mg, 0.19 mmol) and K2CO3 (50 mg, 0.36 mmol) in MeOH (5 mL) were heated at 90° C. for 40 min before it was filtered and concentrated. The residue was dissolved in EtOAc (10 mL) and H2O (10 mL). The organic phase was collected, dried and concentrated. Column chromatography afforded Compound 23 (47, 65%). 1H NMR (300 MHz, CDCl3) δ 7.64-7.59 (m, 4 H), 7.46-7.40 (m, 1 H), 7.12 (d, J=8.7 Hz, 2 H), 7.01 (t, J=8.1 Hz, 2 H), 6.21 (s, 1 H), 2.49-2.40 (m, 4 H), 1.84-1.76 (m, 4 H); ESMS cacid (C22H18F2N2O2): 380.1; found: 381.1 (M+H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.Cl[CH2:17][C:18]1[N:22]=[C:21]([C:23]2[C:24]([CH3:29])=[N:25][O:26][C:27]=2[CH3:28])[O:20][N:19]=1>>[CH3:29][C:24]1[C:23]([C:21]2[O:20][N:19]=[C:18]([CH2:17][N:7]3[C:8]4[C:4](=[C:3]([C:2]([F:14])([F:1])[F:15])[C:11]([C:12]#[N:13])=[CH:10][CH:9]=4)[CH:5]=[CH:6]3)[N:22]=2)=[C:27]([CH3:28])[O:26][N:25]=1
Reactant: N#Cc1ccc2[nH]ccc2c1C(F)(F)F
Reactant: Cc1noc(C)c1-c1nc(CCl)no1
Product: Cc1noc(C)c1-c1nc(Cn2ccc3c(C(F)(F)F)c(C#N)ccc32)no1

Procedure:
Synthesized as described in Example 23 using 4-(trifluoromethyl)-1H-indole-5-carbonitrile and 3-(chloromethyl)-5-(3,5-dimethyl-4-isoxazolyl)-1,2,4-oxadiazole: MS (ES) m/z 388 (M+1).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:7][CH2:6]2.[I-].[Na+].C([N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)(=O)C.Cl>C(#N)C.C(O)C>[ClH:1].[NH:23]1[CH:27]=[CH:26][N:25]=[C:24]1[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:7][CH2:6]2
Reactant: CCOC(=O)C1CCc2cc(CCl)ccc2C1
Reactant: CC(=O)n1ccnc1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCO
Product: CCOC(=O)C1CCc2cc(Cc3ncc[nH]3)ccc2C1

Procedure:
The crude ethyl 6-(chloromethyl)-1,2,3,4-tetrahydro-2-naphthalenecarboxylate obtained in Referential Example 5 was dissolved in 100 ml of anhydrous acetonitrile and then 3.22 g of sodium iodide and 3.94 g of 1-acetylimidazole were added thereto. The resulting mixture was heated under reflux for 1.5 hours. The reaction mixture was concentrated in vacuo and 100 1 of mthanol as added to the residue. The mixture was stirred and concentrated in vacuo. Water was added to the residue. The mixture was neutralized by adding sodium bicarbonate and extracted with chloroform. The extract was washed with water, dried and then concentrated in vacuo. The residue was purified by silica gel column chromatography using a mixture of ethanol and chloroform (3:97 by volume) for elution to give an oily product. The product was suspended in ethanol, and an ethanolic solution of hydrogen chloride was added thereto. The mixture was concentrated to dryness in vacuo to give 4.8 g of ethyl 6-(1-imidazolylmethyl)-1,2,3,4-tetrahydro-2-naphthalenecarboxylate hydrochloride as colorless crystals with m.p. 170°-172 ° C.
Reaction SMILES: [Na+].[I-:2].CNCCNC.Br[C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([CH3:25])[CH2:21][CH2:20]2)=[C:12]([CH3:26])[CH:11]=1>O1CCOCC1.CCOC(C)=O.[Cu]I>[I:2][C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([CH3:25])[CH2:21][CH2:20]2)=[C:12]([CH3:26])[CH:11]=1
Reactant: [I-]
Reactant: Cc1cc(Br)ccc1NCCN1CCC(C)CC1
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(I)ccc1NCCN1CCC(C)CC1
Temperature: 110 °C
Reaction time: 20 h

Procedure:
73 mg (0.386 mmol) of CuI, 1.16 g (7.71 mmol) of NaI, and N,N′-dimethylethane-1,2-diamine were added under argon to a solution of 1.20 g (3.86 mmol) of (4-bromo-2-methylphenyl)-[2-(4-methylpiperidin-1-yl)ethyl]amine in 3.9 mL of 1,4-dioxane and the mixture was stirred for 20 hours at 110° C. The reaction mixture was cooled to RT and diluted with EtOAc. The organic phase was washed with 10% aqueous ammonia, dried over magnesium sulfate, and evaporated down in vacuo. Yield: 1.22 g (88% of theoretical); C15H23IN2 (M=358.261); calc.: molpeak (M+H)+: 359; found: molpeak (M+H)+: 359; HPLC-MS: 6.24 minutes (method A).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[O:11][C:12]([NH:14][C:15]([CH3:29])([C:26]([OH:28])=O)[CH2:16][C:17]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=1)=[O:13])[CH2:8]2.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:52][CH2:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][N:56]=1>C(OCC)(=O)C.CN(C)C=O>[NH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([CH2:16][C:15]([NH:14][C:12](=[O:13])[O:11][CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)([CH3:29])[C:26](=[O:28])[NH:52][CH2:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][N:56]=2)=[CH:18]1
Reactant: CC(Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)O
Reactant: NCCc1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)NCCc1ccccn1
Reaction time: 2 h
Yield: 72186 %

Procedure:
To a solution of 2-adamantyloxycarbonyl-α-methyl-DL-tryptophan (0.400 g, 1.01 mmol) in ethyl acetate (6 mL) and N,N-dimethylformamide (4 mL) under nitrogen atmosphere was added 1-hydroxybenzotriazole (0.138 g, 1.02 mmol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.198 g, 1.03 mmol). This mixture was stirred 2 hours and 2 (2-aminoethyl)pyridine (0.16 mL, 1.3 mmol) was added. After stirring an additional 18 hours, the resulting mixture was diluted with ethyl acetate (20 mL), and washed with aqueous 1N citric acid, aqueous saturated sodium bicarbonate, and brine solutions. The organic phase was dried over MgSO4, concentrated, and purified by flash chromatography (SiO2, 230-400 mesh, ethyl acetate eluant). After concentration, the residue was dried under vacuum at 60° C. for 48 hours to provide 0,365 g (72%) of product; 1H NMR (CDCl3) δ1.40-1.60 (2H, m), 1.56 (3H, s), 1.65-1.95 (12H, m), 2.88 (2H, t, J 6 Hz), 3.39 (2H, d, J 5 Hz), 3.50-3.70 (2H, m), 4.75 (1H, br s), 5.35 (1H, br s), 6.40 (1H, d, J 2 Hz), 7.00-7.20 (4H, m), 7.22-7.35 (2H, m), 7.52-7.60 (2H, m), 8.20 (1H, br s), 8.40-8.45 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:39])[C@:10]3([C@@H:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=4[F:22])[C@H:13]([C:23]([NH:25][C:26]4[S:27][CH:28]=[C:29]([C:31]([OH:33])=O)[N:30]=4)=[O:24])[NH:12][C@H:11]3[CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:5]2=[CH:4][CH:3]=1.CC[N:42]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH4+].[Cl-].C(N(CC)CC)C>CN(C=O)C>[C:31]([C:29]1[N:30]=[C:26]([NH:25][C:23]([CH:13]2[NH:12][CH:11]([CH2:34][C:35]([CH3:37])([CH3:38])[CH3:36])[C:10]3([C:5]4[C:6](=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:9]3=[O:39])[CH:14]2[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[F:22])=[O:24])[S:27][CH:28]=1)(=[O:33])[NH2:42]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2nc(C(=O)O)cs2)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)CC1NC(C(=O)Nc2nc(C(N)=O)cs2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 80 °C

Procedure:
To a solution of rac-2-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-thiazole-4-carboxylic acid (40 mg, 0.07 mmol) prepared in Example 197 in anhydrous DMF (2 mL) were added EDCI (26 mg, 0.13 mmol), HOBt (18 mg, 0.13 mmol), NH4Cl (36 mg, 0.67 mmol), and triethylamine (14 mg, 0.13 mmol) sequentially. The reaction mixture was heated at 80° C. for 1 h. The mixture was cooled to room temperature, then partitioned between ethyl acetate and water. The organic layer was separated, and aqueous layer was extracted with ethyl acetate twice. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (25-100% EtOAc in dichloromethane) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-carbamoyl-thiazol-2-yl)-amide as a off white solid (12 mg, 30%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[N+:9]([O-:11])=[O:10].II.[I:14]([O-])(=O)=O.[Na+].O>C(O)(=O)C.S(=O)(=O)(O)O>[I:14][C:7]1[C:2]([CH3:1])=[C:3]([N+:9]([O-:11])=[O:10])[C:4](=[O:8])[NH:5][CH:6]=1
Reactant: [O-][I+2]([O-])[O-]
Reactant: Cc1cc[nH]c(=O)c1[N+](=O)[O-]
Agent: II
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(I)c[nH]c(=O)c1[N+](=O)[O-]
Temperature: 75 °C
Reaction time: 8 h

Procedure:
To a solution of 4-methyl-3-nitro-2-pyridone (2.00 g, 13 mmol) in acetic acid (12 mL) and concentrated sulfuric acid (1.6 ml,) was added iodine (1.32 g) and sodium iodate (0.55 g). The mixture was heated at 75° C. for 2.5 hours and then stirred at rt overnight. Water (100 mL) was added, and the precipitated 5-iodo-4-methyl-3-nitro-2-pyridone was collected by filtration (2.97 g, 82%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:5]([C:15]([N:17]2[CH2:22][CH:21]=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)=[O:16])[C@@H:4]([C:29]([O:31][CH3:32])=[O:30])[CH2:3]1.O1CCCC1.[N:38]1[CH:43]=[CH:42][C:41](O)=[CH:40][CH:39]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[C:23]1([C:20]2[CH2:21][CH2:22][N:17]([C:15]([C@@H:5]3[C@@H:4]([C:29]([O:31][CH3:32])=[O:30])[CH2:3][C@H:2]([O:1][C:41]4[CH:42]=[CH:43][N:38]=[CH:39][CH:40]=4)[CH2:7][N:6]3[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:16])[CH2:18][CH:19]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)[C@H]1C[C@@H](O)CN(C(=O)OC(C)(C)C)[C@@H]1C(=O)N1CC=C(c2ccccc2)CC1
Reactant: Oc1ccncc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H]1C[C@H](Oc2ccncc2)CN(C(=O)OC(C)(C)C)[C@@H]1C(=O)N1CC=C(c2ccccc2)CC1
Temperature: 70 °C

Procedure:
To a solution of 1-tert-butyl 3-methyl(2S,3S,5R)-5-hydroxy-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]piperidine-1,3-dicarboxylate (100 mg, 0.0002 mol) in tetrahydrofuran (0.912 mL, 0.0112 mol) was added 4-pyridinol (25.7 mg, 0.000270 mol), triphenylphosphine (70.8 mg, 0.000270 mol), followed by diisopropyl azodicarboxylate (0.0532 mL, 0.000270 mol). The mixture was heated at 70 Celsius overnight. After concentrated to dry, the mixture was purified on silica gel, eluting with 0 to 40% EtOAc in hexane, to afford the desired ether compound (56 mg, 50%). MS (ESI): (M+H)+=522.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:15])[NH:13][C:12](=S)[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(OO)(C)(C)C.[NH4+:22].[OH-]>CO.N>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:15])[CH2:9][O:10][CH2:11][C:12]([NH2:22])=[N:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: CC1(c2cccc(Br)c2)COCC(=S)N1
Agent: CC(C)(C)OO
Agent: N
Agent: [OH-]
Solvent: CO
Product: CC1(c2cccc(Br)c2)COCC(N)=N1
Reaction time: 8 h

Procedure:
To a solution of 5-(3-bromo-phenyl)-5-methyl-morpholine-3-thione (5 g, 17.5 mmol) in MeOH/NH3 (110 ml) were added at room temperature t-BuOOH (28 ml, 65%) and NH4OH (47 ml, 25%). The mixture was stirred overnight, quenched with aqueous Na2S2O3 solution, concentrated in vacuo to remove the methanol solution and extracted with EtOAc (3×30 ml). The organic phase was dried with Na2SO4 and concentrated in vacuo to give the crude product, which was purified by preparative HPLC [column: Venusil XBP-C18, 250×21.2 mm, 10 μm; injection volume: 10 ml/injection; mobile phase: CH3CN/H2O=10 to 35% (0.1% formic acid) gradient for 15 min, washed with 95% CH3CN for 4 min, back to 10% balance for 4 min] to give the title compound in the form of a formic acid salt. 1H-NMR (300 MHz, DMSO-d6): 9.99 (s, 1H), 8.39 (s, 1H), 7.65 (s, 1H), 7.55 (d, 1H), 7.47 (d, 1H), 7.39 (t, 1H), 4.46 (s, 2H), 4.05 (d, 1H), 3.85 (d, 1H), 1.55 (s, 3H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[O:12][CH3:13].C(=O)([O-])[O-].[K+].[K+]>S(=O)(=O)(O)O>[CH3:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([N+:1]([O-:4])=[O:2])[C:11]=1[O:12][CH3:13]
Reactant: O=[N+]([O-])O
Reactant: COc1ccncc1C
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COc1c(C)cncc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 30 %

Procedure:
30 ml of 100% nitric acid is added to 150 ml of 98% sulphuric acid with stirring and cooling. To this solution is added dropwise 3.2 g (26 mmol) of 3-methyl-4-methoxy pyridine. The mixture is stirred at 80° C. for 2.5 hours, cooled down and added cautiously to a mixture of 400 g of crushed ice and 300 g of potassium carbonate with external cooling. 125 g more of potassium carbonate is added, and the suspension is filtered. The cake is washed with around 11 of diethyl ether. The filtrate layers are separated, the ethereal layer is dried, filtered off and concentrated to give 2.9 g (30% yield) of a yellow oil (M+1=169) (purity #80%, used with no further purification).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]([C:28]1[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][C:29]=1[S:35][CH3:36])[C:11]1[C:12](=[O:27])[CH2:13][CH2:14][C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1.[C:37](N1C=CN=C1)(N1C=CN=C1)=[O:38]>C(#N)C>[Br:34][C:31]1[CH:32]=[CH:33][C:28]([CH:10]2[NH:9][C:37](=[O:38])[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:26])[F:24])[CH:18]=3)[C:15]3[CH2:14][CH2:13][C:12](=[O:27])[C:11]2=3)=[C:29]([S:35][CH3:36])[CH:30]=1
Reactant: CSc1cc(Br)ccc1C(N)C1=C(Nc2cccc(C(F)(F)F)c2)CCC1=O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CSc1cc(Br)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylamine (250 μL, 1.81 mmol) is added to a mixture of 2-(amino(4-bromo-2-(methyl-thio)phenyl)methyl)-3-(3-(trifluoromethyl)phenyl amino)cyclopent-2-enone hydrochloride (intermediate 20.5, 4.08 g, 7.23 mmol based on 90% purity) and 1,1′-carbonyldiimidazole (1.46 g, 9.04 mmol) in acetonitrile (54 mL), and the mixture is stirred at room temperature for 1 h. All volatiles are removed under reduced pressure, and the residue is treated with water. The precipitate is filtered and purified by flash chromatography on silica (gradient dichloromethane to dichloromethane/methanol 95:5). Yield: 3.04 g; ESI mass spectrum: [(79Br)-M+H]+=497, [(81Br)-M+H]+=499; Retention time HPLC: 0.65 min (X011_S03).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])=[CH:8][C:7]=1[Cl:19].[F:20][C:21]([F:32])([F:31])[C:22]1[CH:23]=[CH:24][C:25]([C:28](O)=[O:29])=[N:26][CH:27]=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>C(Cl)(Cl)Cl>[Cl:19][C:7]1[CH:8]=[C:9]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])[CH:10]=[C:11]([Cl:12])[C:6]=1[O:5][CH2:4][CH2:3][CH2:2][NH:1][C:28](=[O:29])[C:25]1[CH:24]=[CH:23][C:22]([C:21]([F:31])([F:20])[F:32])=[CH:27][N:26]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cn1
Reactant: NCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(NCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Yield: 10.4 %

Procedure:
To a mixture of 0.96 g of 4-(3-aminopropyloxy)-3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)benzene, 0.53 g of 5-(trifluoromethyl)-2-pyridinecarboxylic acid, 0.37 g of triethylamine and 10 ml of chloroform was added 0.64 g of WSC hydrochloride, while stirring at room temperature. After stirring at room temperature for 6 hours, the reaction mixture was concentrated to give a residue. The residue was subjected to silica gel chromatography, which afforded 0.15 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(3-(5-(trifluoromethyl)picolinamido)propoxy)benzene (10% yield), m.p., 55.1° C.
Reaction SMILES: [C:1]1([S:7][CH:8]([CH:16]([S:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:17]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)O)[CH:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.O>O1CCOCC1>[C:25]1([S:24][CH:16]2[CH:8]([S:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:9]([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)[O:10][CH:17]2[C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: OC(c1cccs1)C(Sc1ccccc1)C(Sc1ccccc1)C(O)c1cccs1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O
Product: c1ccc(SC2C(c3cccs3)OC(c3cccs3)C2Sc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a suspension of 2,3-bis(phenylthio)-1,4-di(2-thienyl)-1,4-butanediol (54.0 g, 114.9 mmol) in 350 ml dioxane there is added 8.70 g conc. sulfuric acid in 4 almost equal portions with a 45 minutes interval between each addition. The rather thick suspension is stirred mechanically for 4 days at room temperature whereby a clear solution is obtained. The solution is poured into 500 ml water and the product is extracted with 2×300 ml toluene. The organic layer is washed with 2×250 ml water, then dried and rotary evaporated. A quantity of 50 ml ether, followed by 200 ml methanol as well as some seed crystals are stirred into the residue. The crystallized product is filtered off and washed with methanol. It weighs 21.83 g. The filtrate is rotary evaporated and the residue is chromatographed on an aluminum oxide column (16×3 cm) using a 1/1 mixture of toluene and hexane as the eluent, thus obtaining a fraction with an additional amount of the product. This fraction is rotary evaporated and the residue is dissolved in some ether. Methanol is added while stirring, whereupon 3,4-bis(phenylthio)-2,5-di(2-thienyl)-tetrahydrofuran crystallizes. It is isolated in the usual way and weighs 7.04 g. The total yield is 28.87 g (63.9 mmol, 56%).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[C:15]2[C:14](=O)[NH:13][C:12]([S:17][CH3:18])=[N:11][C:10]=2[NH:9][CH:8]=1)(=[O:3])[CH3:2].N.P(Cl)(Cl)([Cl:22])=O>>[C:1]([O:4][CH2:5][CH2:6][C:7]1[C:15]2[C:14]([Cl:22])=[N:13][C:12]([S:17][CH3:18])=[N:11][C:10]=2[NH:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: CSc1nc2[nH]cc(CCOC(C)=O)c2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: N
Product: CSc1nc(Cl)c2c(CCOC(C)=O)c[nH]c2n1
Temperature: 47.5 °C
Reaction time: 0.17 h
Yield: 54 %

Procedure:
The above pyrrolopyrimidinone (1.2) (3.7 g, 13.8 mmol) was suspended in phosphoryl chloride (20 ml) and the solution heated at 45-50° C. overnight. The solution was cooled and poured onto ice and stirred for 10 mins and then neutralised with concentrated ammonia solution. The solid was filtered and recrystallised from methanol to give a yellow-brown solid which was chromatographed (CHCl3/2% MeOH) to give the product as a pale brown solid, yield 1.3 g. Unreacted starting material was eluted from the column in CHCl3/5% MeOH, yield 1.44 g. Overall yield 54%. δH ([2H6]-DMSO) 12.24 (1 H, br s, NH), 7.38 (1 H, s, 6-H), 4.26 (2 H, t J 6.8 Hz, OCH2), 3.08 (2 H, t J 6.8 Hz, OCH2CH2), 2.52 (3 H, s, CH3S), 1.98 (3 H, s, CH3CO) ppm. UV λmax (nm) 314 (4800), 254 (28300), 222 (13000). pH 12 λmax 291 (5100), 257 (26700). Accurate mass measurement 285.0339, C11H12CIN3O2S requires 285.0356.