Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Br:7][C:8]1[C:20]2[C:19]3[C:14](=[CH:15][C:16]([CH:21]=O)=[CH:17][CH:18]=3)[NH:13][C:12]=2[C:11]([C:23]([NH2:25])=[O:24])=[CH:10][CH:9]=1.O>C1COCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:7][C:8]1[C:20]2[C:19]3[C:14](=[CH:15][C:16]([CH:21]=[CH2:1])=[CH:17][CH:18]=3)[NH:13][C:12]=2[C:11]([C:23]([NH2:25])=[O:24])=[CH:10][CH:9]=1
Reactant: NC(=O)c1ccc(Br)c2c1[nH]c1cc(C=O)ccc12
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Step 1 A solution of potassium tert-butoxide (3.40 g, 30.3 mmol) in THF (249 mL) at 0° C. was treated with methyltriphenylphosphonium bromide (8.79 g, 24.60 mmol), forming a bright yellow suspension. After 1 h, 4-bromo-7-formyl-9H-carbazole-1-carboxamide (prepared according to the procedure of Step 1 of Example 41-1, 4 g, 9.46 mmol) was added, and the resulting suspension was warmed to rt and stirred for 3 h. Water was added and the mixture was extracted with EtOAc. The organic phase was washed with brine, dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from 70:30 hexane-EtOAc to EtOAc). The crude material was suspended in methanol, and the precipitate was collected by filtration and dried. The filtrate was concentrated to provide additional solid which was collected by filtration, dried and combined with the first crop to provide 4-bromo-7-vinyl-9H-carbazole-1-carboxamide as a light brown solid (1.66 g, ca. 90% purity, 50%). 1H NMR (400 MHz, DMSO-d6) δ 11.68 (1H, s), 8.52 (1H, d, J=8.3 Hz), 8.06-8.29 (1H, m), 7.79-7.88 (2H, m), 7.58 (1H, br. s.), 7.35-7.45 (2H, m), 6.78-6.98 (1H, m), 5.88 (1H, d, J=17.6 Hz), 5.32 (1H, d). Mass spectrum m/z 344, 346 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C@H:4]([CH2:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)[N:5]=C(OC)[C@@H](C(C)C)N=1.FC(F)(F)C(O)=[O:28]>O.C(#N)C>[NH2:5][C@@H:4]([CH2:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)[C:3]([O:2][CH3:1])=[O:28]
Reactant: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1Cc1ccc2ncccc2c1
Reactant: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: COC(=O)[C@@H](N)Cc1ccc2ncccc2c1
Temperature: 10 °C
Reaction time: 8 h

Procedure:
To a solution of #211 (7.3 g, 22.5 mmol, 1 eq.) in water (25 mL) and acetonitrile (80 mL) was added trifluoroacetic acid (9 mL) at 0° C. and the solution was stirred at 10° C. overnight. The organic layer was removed in vacuo and the remaining aqueous layer was basified to pH 9 with sodium carbonate, which was directly used for the next step.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[C:15]1[CH:16]=[CH:17][C:18]([N+:25]([O-:27])=[O:26])=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1.Cl>CN(C)C=O>[N+:25]([C:18]1[CH:17]=[CH:16][C:15]([CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])=[CH:20][C:19]=1[C:21]([F:22])([F:23])[F:24])([O-:27])=[O:26]
Reactant: O=[N+]([O-])c1ccc(Br)cc1C(F)(F)F
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 42.5 %

Procedure:
Sodium hydride (60% oiliness) (0.33 g, 8.25 mmol) was added in the dimethylformamide (20 mL) solution of diethyl malonate (1.23 mL, 8.14 mmol) while cooling the solution with ice, and the mixture was directly stirred for 4 hours. 5-bromo-2-nitrobenzotrifluoride (2.0 g, 7.41 mmol) was added in the reaction mixture while cooling it with ice, and the temperature was raised to room temperature and then the mixture was further heated and stirred at 70° C. for 3 hours. After the reaction solution was poured into ice water and acidified with 2N hydrochloric acid, the solution was extracted with ethyl acetate. After the organic layer had been washed with 5% sodium hydrogencarbonate aqueous solution and then with water and dried over anhydrous sodium sulfate, the solvents were concentrated under reduced pressure. The residue was subjected to silica gel column chromatograph (45 g) and was eluted with the mixture of ethyl acetate and n-hexane of 1:5 in mixing ratio. The eluted liquid was concentrated under reduced pressure and yellow oily diethyl 2-(4-nitro-3-trifluoromethyl-phenyl)-malonate (1.1 g, 42%) was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([N:12]1[N:16]=[C:15]2[CH:17]=[CH:18][CH:19]=[C:20]([Cl:21])[C:14]2=[N:13]1)[CH2:9][C:10]#[CH:11]>>[Cl:21][C:20]1[C:14]2[C:15](=[N:16][N:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[N:13]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: Brc1ccccn1
Reactant: C#CCCn1nc2cccc(Cl)c2n1
Product: Clc1cccc2nn(CCC#Cc3ccccn3)nc12
Yield: 28 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-pyridine (25 mg, 0.16 mmol) and 2-(but-3-ynyl)-4-chloro-2H-benzo[d][1,2,3]triazole (30 mg, 0.15 mmol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 12 mg (42 μmol, 29%) of 4-chloro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as an orange solid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.O1CCOCC1.[CH2:19]([NH:23][CH2:24][CH2:25][OH:26])[CH2:20][CH2:21][CH3:22]>O>[CH2:19]([N:23]([C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1)[CH2:24][CH2:25][OH:26])[CH2:20][CH2:21][CH3:22]
Reactant: CCCCNCCO
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Solvent: O
Solvent: C1COCCO1
Product: CCCCN(CCO)c1nc(OC)ccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 70 %

Procedure:
1.9 g (0.01 mol) of the product 2-chloro-3-nitro-6-methoxypyridine, 30 ml of dioxane, 5 ml of water and 2.62 ml (0.02 mol) of 2-butylaminoethanol are placed in a fully equipped round-bottomed flask. The mixture is refluxed for 2 hours with stirring and is then poured onto an ice/water mixture with stirring. The precipitate formed is filtered off by suction and dried under vacuum to constant weight. 1.9 g of yellow powder are obtained, ie a yield of 70%.
Reaction SMILES: [N:1]([C:4]1[S:8][C:7]2C[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:6]=2[C:5]=1[C:15]([O:17]C)=O)=[C:2]=[S:3].[CH3:19][C:20]1[N:21]=[CH:22][N:23]([CH2:25][CH2:26][CH2:27][NH2:28])[CH:24]=1>>[CH3:19][C:20]1[N:21]=[CH:22][N:23]([CH2:25][CH2:26][CH2:27][N:28]2[C:15](=[O:17])[C:5]3[C:6]4[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:7]=4[S:8][C:4]=3[NH:1][C:2]2=[S:3])[CH:24]=1
Reactant: Cc1cn(CCCN)cn1
Reactant: COC(=O)c1c(N=C=S)sc2c1CCCCCC2
Product: Cc1cn(CCCn2c(=S)[nH]c3sc4c(c3c2=O)CCCCC4)cn1

Procedure:
The compound was synthesized starting from methyl 4,5,6,7,8,9-hexahydro-2-isothiocyanatocycloocta[b]thiophene-3-carboxylate (0.100 g. 0.36 mmol) and 3-(4-methyl-1H-imidazol-1-yl)propan-1-amine (9) (0.049 g, 0.36 mmol) as described above.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[CH:11][C:10]=1/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])C1C=CC=CC=1>[C].[Pd].O1CCCC1>[CH2:16]([O:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:11]=1)[CH3:17]
Reactant: CCOC(=O)/C=C/c1cc(OCC)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cc(OCC)ccc1O
Yield: 94.2 %

Procedure:
A mixture of ethyl (E)-3-(2-benzyloxy-5-ethoxyphenyl)-2-propenoate (4.58 g), 5% palladium carbon (6.0, g) and tetrahydrofuran (100 mL) was subjected to catalytic hydrogenation at room temperature and 1 atm. After filtering off the catalyst, the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to give ethyl 3-(5-ethoxy-2-hydroxyphenyl)propionate as a colorless oil (3.15 g, 94%) from a fraction eluted with ethyl acetate-hexane (1:6, v/v).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:11][C:10]([CH3:12])=[CH:9][C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.[Br:13]Br>ClCCl>[Br:13][C:9]1[C:4]2[N:5]=[C:6]([CH3:8])[N:7]=[C:2]([Cl:1])[C:3]=2[NH:11][C:10]=1[CH3:12]
Reactant: Cc1nc(Cl)c2[nH]c(C)cc2n1
Reactant: BrBr
Solvent: ClCCl
Product: Cc1nc(Cl)c2[nH]c(C)c(Br)c2n1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
4-Chloro-2,6-dimethyl-5H-pyrrolo[3,2-d]pyrimidine from example A7 (10.90 g; 60.00 mmol) is dissolved in dichloromethane (120 mL). The stirred mixture is cooled to −10° C. Br2 (3.08 mL; 60.00 mmol) dissolved in dichloromethane (20 mL) is added dropwise within 25 minutes. The re-suiting precipitate is collected by suction filtration, suspended in Na2SO3 (5% solution) (100 mL) and is stirred for 30 minutes at ambient temperature. After filtratrion the product is dissolved in acetonitrile (1000 mL), refluxed for one hour and filtered while still hot. The solvent is removed under reduced pressure until the product starts to precipitate. Precipitation of the product is completed by addition of cyclohexane and cooling to 0° C. for several hours. The solid is collected by suction filtration, washed with cyclohexane and dried in vacuum at 50° C. over night to yield the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])=[CH:6][CH:5]=[C:4]([CH3:18])[N:3]=1.[ClH:19].[C:20]1([CH2:26][C:27](=[NH:31])OCC)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[ClH:19].[F:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([F:16])[C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:27](=[NH:31])[CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:3][C:4]([CH3:18])=[CH:5][CH:6]=1
Reactant: Cc1ccc(OCc2c(F)cccc2F)c(N)n1
Reactant: CCOC(=N)Cc1ccccc1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(OCc2c(F)cccc2F)c(NC(=N)Cc2ccccc2)n1
Yield: 6.9 %

Procedure:
A mixture of 2-amino-3-(2,6-difluorobenzyloxy)-6-methyl-pyridine (5.0 g, 20 mmol) and ethyl phenylacetimidate hydrochloride (4.39 g, 22 mmol) in ethanol (80 ml) was heated under reflux for 2 hours. Evaporation of the solvent gave an oil which was purified by chromatography (silica, chloroform/methanol) and recrystallisation from ethanol/ether to obtain the product (0.56 g), m.p. 173°-177° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](O)[CH:6]=[C:5]([CH2:10][CH2:11][CH3:12])[N:4]=1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:7]1[CH:6]=[C:5]([CH2:10][CH2:11][CH3:12])[N:4]=[C:3]([S:2][CH3:1])[N:8]=1
Reactant: CCCc1cc(O)nc(SC)n1
Reactant: O=P(Cl)(Cl)Cl
Product: CCCc1cc(Cl)nc(SC)n1
Yield: 100 %

Procedure:
A suspension of 2-methylsulfanyl-6-propyl-pyrimidin-4-ol (15.5 g) in phosphorous oxychloride (160 mL) was refluxed for 6 hours. The solvent was distilled off under reduced pressure. The residue was diluted with dichloromethane and poured in ice. The layers were separated, then the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulphate, filtered and concentrated under reduced pressure to afford 4-chloro-2-methylsulfanyl-6-propyl-pyrimidine (17.5 g, 100%) as an orange oil.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:14].[P:15]([O:20]C)([O:18][CH3:19])[O:16][CH3:17]>>[O:14]=[C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12](=[O:13])[N:4]1[CH2:3][CH2:2][P:15](=[O:20])([O:18][CH3:19])[O:16][CH3:17]
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: COP(OC)OC
Product: COP(=O)(CCN1C(=O)c2ccccc2C1=O)OC
Yield: 61.2 %

Procedure:
A mixture of 2-(2-bromoethyl)isoindoline-1,3-dione (7.62 g, 30 mmol) and trimethyl phosphite (100 g) was refluxed under N2 atmosphere for 10 hours. Concentration and purification through column chromatography on silica gel (100% EtOAc) gave the desired product as a white solid (5.2 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[C:16]([O:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[CH:15][C:14]([O:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])=[CH:13][C:12]=2[O:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH3:40])[O:8][N:7]=1)=[O:5])C.[OH-].[K+:42].CCOCC>C(O)C>[CH3:40][O:39][CH2:38][CH2:37][O:36][CH2:35][O:34][C:12]1[CH:13]=[C:14]([O:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])[CH:15]=[C:16]([O:17][C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)[C:11]=1[C:9]1[O:8][N:7]=[C:6]([C:4]([O-:5])=[O:3])[CH:10]=1.[K+:42]
Reactant: CCOC(=O)c1cc(-c2c(OCOCCOC)cc(OCOCCOC)cc2Oc2ccc([N+](=O)[O-])cc2)on1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: COCCOCOc1cc(OCOCCOC)c(-c2cc(C(=O)[O-])no2)c(Oc2ccc([N+](=O)[O-])cc2)c1
Reaction time: 8 h
Yield: 77.6 %

Procedure:
To a stirred solution of 5-{2,4-bis[(2-methoxyethoxy)methoxy]-6-(4-nitrophenoxy)phenyl}isoxazole-3-carboxylic acid ethyl ester (15.6 g., 27.7 mmol) in ethanol (75 mL) was added a solution of 1 M KOH (55.5 mL, 55 mmol, 2 eq.) in ethanol at room temperature. After stirring overnight, the precipitate was collected and washed with a small volume of ethanol, then with ether to provide the title compound (12.3 g, 77% yield).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[C:7]([NH:10][CH2:11][C@@H:12]1[O:16][C:15](=[O:17])[N:14]([C:18]2[CH:23]=[CH:22][C:21]([S:24][CH2:25][CH2:26][OH:27])=[C:20]([F:28])[CH:19]=2)[CH2:13]1)(=[O:9])[CH3:8]>O.CO>[C:7]([NH:10][CH2:11][C@@H:12]1[O:16][C:15](=[O:17])[N:14]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH2:25][CH2:26][OH:27])=[O:2])=[C:20]([F:28])[CH:19]=2)[CH2:13]1)(=[O:9])[CH3:8]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(SCCO)c(F)c2)C(=O)O1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=O)NC[C@H]1CN(c2ccc(S(=O)CCO)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium periodate (0.014 g, 0.065 mmol) in water (0.5 mL) was added to 5-(S)-acetamidomethyl-3-[4′-(2″-hydroxyethyl)thio-3′-fluorophenyl]-oxazo-lidine-2-one (0.020 g, 0.061 mmol) in methanol (1 mL), and the mixture was stirred at r.t. overnight. Solvent was removed under vacuum, and the residue dissolved in ethyl acetate (ca. 5 mL). Resulting solution was washed with water, brine, and dried (MgSO4). Solvent was removed under vacuum, and the crude product purified by TLC (eluent: 10% methanol in dichloromethane). Yield 0.018 g (86%). MS (m/z): 345 [M+H]+. 1H NMR.
Reaction SMILES: [Cl:1][C:2]1[C:22](F)=[CH:21][C:5]2[C:6]3[C:7](=[O:20])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][N:10]([CH3:14])[C:11]=3[CH:12]=[N:13][C:4]=2[C:3]=1[F:24].[F:25][C:26]1[CH:27]=[C:28]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:29]=[CH:30][C:31]=1[CH3:32]>CS(C)=O>[Cl:1][C:2]1[C:22]([N:36]2[CH2:35][CH2:34][N:33]([C:28]3[CH:29]=[CH:30][C:31]([CH3:32])=[C:26]([F:25])[CH:27]=3)[CH2:38][CH2:37]2)=[CH:21][C:5]2[C:6]3[C:7](=[O:20])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][N:10]([CH3:14])[C:11]=3[CH:12]=[N:13][C:4]=2[C:3]=1[F:24]
Reactant: Cc1ccc(N2CCNCC2)cc1F
Reactant: CCOC(=O)c1cn(C)c2cnc3c(F)c(Cl)c(F)cc3c2c1=O
Solvent: CS(C)=O
Product: CCOC(=O)c1cn(C)c2cnc3c(F)c(Cl)c(N4CCN(c5ccc(C)c(F)c5)CC4)cc3c2c1=O
Temperature: 80 °C
Reaction time: 20 h
Yield: 42.8 %

Procedure:
A stirred suspension of 1 g of ethyl 8-chloro-7,9-difluoro-4-methyl-1-oxo-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylate and 1.2 g of 1-(3-fluoro-4-methylphenyl)piperazine in 15 cm3 of dimethyl sulphoxide was heated to a temperature in the region of 80° C. After 20 hours, 0.6 g of 1-(3-fluoro-4-methylphenyl)piperazine was added and the heating was continued for an additional 8 hours. After 28 hours, the reaction mixture was cooled and then filtered. The precipitate was washed twice with 10 cm3 of water, twice with 5 cm3 of ethanol, and twice with 5 cm3 of diisopropyl ether. 0.64 g of ethyl 8-chloro-7-fluoro-9-[4-(3-fluoro-4-methylphenyl)piperazin-1-yl]-4-methyl-1-oxo-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylate was obtained in the form of a greenish-yellow solid, which melted at 350° C. with decomposition.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[C:12](OC)(=[O:16])[CH:13]([CH3:15])O.C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:11])[O:10][CH:13]([CH3:15])[C:12]=1[OH:16]
Reactant: O=C(O)Cc1ccccc1F
Reactant: COC(=O)C(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC1OC(=O)C(c2ccccc2F)=C1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
To 2-fluorophenylacetic acid (25 g, 0.16 mol) and methyl lactate (17 g, 0.16 mol) in THF (600 ml) was added 1,3-dicyclohexylcarbodiimide (34 g, 0.16 mol) and 4-dimethylaminopyridine (0.99 g, 8.1 mmol) at 5° C. The mixture was allowed to warm to room temperature and stirred under nitrogen overnight. The solvent was removed in vacuo, then the residue was taken up in diethyl ether (300 ml), and the resulting slurry was filtered to remove insoluble material. The filtrate was concentrated in vacuo, and the residual oil was dissolved in potassium tert-butoxide solution (162 ml of a 1.0 M solution in tert-butanol). The mixture was stirred at reflux for 16 h and was allowed to cool to room temperature. Water (300 ml) was added, and the solution was washed with diethyl ether (2×100 ml). The aqueous solution was acidified to pH 1 with 5 N hydrochloric acid. The product formed an immiscible oil, which solidified upon standing. This was collected by filtration, washed with water and dried at 50° C., yielding 3-(2-fluorophenyl)-4-hydroxy-5-methyl-5H-furan-2-one as a pale yellow solid (23.2 g). 1H NMR (400 MHz, CDCl3) δ 1.46 (3H, d, J=6.7 Hz), 5.00 (1H, q, J=6.7 Hz), 7.22 (2H, m), 7.39 (2H, m), 12.50 (1H, br s).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18].C([O-])([O-])=O.[K+].[K+]>CC(=O)CC>[F:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[O:10][CH2:9][CH2:8][N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: Fc1ccc(OCCBr)c(F)c1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Fc1ccc(OCCN2CCNCC2)c(F)c1
Yield: 73 %

Procedure:
A mixture of piperazine (8.7 g, 101.26 mmol) in butanone (70 ml), 4-(2-bromo-ethoxy)-1,3-difluoro benzene (6.0 g, 25.31 mmol), anhydrous K2CO3 (3.5 g, 25.31 mmol) and KI (4.2 g, 25.31 mmol) was refluxed under nitrogen for 18 hours. The mixture was then cooled and filtered and the solvent removed in vacuo. The residue was dissolved in CH2Cl2 (200 ml) and washed with water (50 ml). Drying and removal of the solvent followed by chromatography (CH2Cl2:CH3OH:NH4OH 10:1) afforded desired product in 73% yield.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[C:8]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])=[N:9][N:10]([CH3:11])[C:5]2=[C:4](O)[CH:3]=1.P(Cl)(Cl)([Cl:23])=O>>[CH3:1][C:2]1[N:7]=[C:6]2[C:8]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])=[N:9][N:10]([CH3:11])[C:5]2=[C:4]([Cl:23])[CH:3]=1
Reactant: Cc1cc(O)c2c(n1)c(-c1ccc(Cl)cc1Cl)nn2C
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(Cl)c2c(n1)c(-c1ccc(Cl)cc1Cl)nn2C
Temperature: 25 °C

Procedure:
Intermediate (10) was refluxed in the presence of phosphorous oxychloride (45 ml) for 4 hours. The reaction mixture was cooled to room temperature, concentrated and partitioned between ethyl acetate and saturated sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried, concentrated, and the residue was purified over silica gel (eluent: 10% diethyl ether/hexanes), yielding 5-methyl-7-chloro-1-methyl-3-(2,4-dichlorophenyl)-pyrazolo[4,3-b]pyridine (intermediate 11).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]=[CH:17][CH:18]=[CH:19][C:20]([O:22]C)=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Na].O>CO>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]=[CH:17][CH:18]=[CH:19][C:20]([OH:22])=[O:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C=CC=Cc1ccccc1CNC(=O)OC(C)(C)C
Agent: [Na]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccccc1C=CC=CC(=O)O
Temperature: 0 °C
Yield: 85.5 %

Procedure:
A stirred mixture of 0.85 g (2.7 mmol) of methyl 5-[2-(tert-butoxycarbonylaminomethyl)phenyl]-2,4-pentadienoate, 1.17 g (11 mmol) of sodium carbinate, 15 ml of water and 15 ml of methanol was heated at reflux for 2 hours. After the produced methanol was distilled off, the solution was cooled to 0° C. and carefully acidified with 1N hydrochloric acid. The resulting mixture was extracted with methylene chloride and the extracts were washed with brine, dried (Na2SO4) and concentrated. Recrystallization of the residue from 1:3 methylene chloride:hexane gave 0.7 g (86%) of the product as crystals, mp 179°-182° C. (dec).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][CH2:8][C:7](=[O:11])[C:6]=2[CH:12]=1.C(O)(=O)C.[N-:17]=[N+]=[N-].[Na+].S(=O)(=O)(O)O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][CH2:8][C:7](=[O:11])[NH:17][C:6]=2[CH:12]=1
Reactant: O=C1CCSc2ccc(F)cc21
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1CCSc2ccc(F)cc2N1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 75.1 %

Procedure:
6-fluoro-2,3-dihydro-4H-1-benzothiopyran-4-one (100 mg, 0.54 mmol ) was dissolved in acetic acid (0.5 mL, 1.1 eq), sodium azide (71.2 mg, 1.1 mmol) was added and mixture was heated to 50° C. Sulfuric acid (0.13 mL, 4.3 eq) was added slowly and stirred at 50° C. for 1.5 hours. Ice chips (150 mg) were added and a green solid precipitated, this was filtered, washed with water and dried to give 7-fluoro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (80 mg, 24%). 1H NMR (CDCl3, 300 MHz): δ 7.77 (s-broad, 1H), 7.69 (t, 1H, J=7.3 Hz), 6.94-6.82 (m, 2H), 3.42 (t, 2H, J=7 Hz), 2.63 (t, 2H, J=6.7 Hz) ppm.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].Cl.[F:19][C:20]([F:33])([F:32])[C:21]1[S:25][C:24]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:23][CH:22]=1>>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:29]1[CH2:30][CH2:31][N:26]([C:24]2[S:25][C:21]([C:20]([F:33])([F:19])[F:32])=[CH:22][N:23]=2)[CH2:27][CH2:28]1)=[O:9])([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: FC(F)(F)c1cnc(N2CCNCC2)s1
Agent: Cl
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(C(F)(F)F)s2)CC1
Yield: 28 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-(5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride. The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in pentane to yield the title compound as a white crystalline solid (yield 28%). MS (m/e): 478.3 (M+H+, 100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([C:13]1[N:18]=[C:17]([O:19]C)[CH:16]=[C:15]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[C:35]5[C:30](=[N:31][CH:32]=[CH:33][CH:34]=5)[NH:29][C:28]4=[O:36])[CH2:23][CH2:22]3)[CH:14]=1)=[O:12])[CH2:6][CH2:5]2.Cl.N1C=CC=CC=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([C:13]1[NH:18][C:17](=[O:19])[CH:16]=[C:15]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[C:35]5[C:30](=[N:31][CH:32]=[CH:33][CH:34]=5)[NH:29][C:28]4=[O:36])[CH2:23][CH2:22]3)[CH:14]=1)=[O:12])[CH2:6][CH2:5]2
Reactant: COc1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)cc(C(=O)N2CCc3cc(F)ccc32)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)cc(=O)[nH]1)N1CCc2cc(F)ccc21
Reaction time: 0.03 h

Procedure:
A well stirred mixture of 40 mg (0.082 mmol) 1-[6′-(5-fluoro-2,3-dihydro-indole-1-carbonyl)-2′-methoxy-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-yl]-1,3-dihydro-imidazo-[4,5-b]pyridin-2-one and 0.020 g (1.7 mmol) pyridine hydrochloride was kept in a melt for 2 min using a hot air blower. After the reaction had cooled the mixture was dissolved in DMF and purified by preparative HPLC. The product-containing fractions were combined and lyophilised.