Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:27])=[C:6]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:17]=3[CH:18]=[CH:19][C:20]([CH3:26])=[N:21]4)[CH2:12][CH2:11]2)[CH:7]=1.[CH3:28][S:29]([NH2:32])(=[O:31])=[O:30]>>[F:27][C:5]1[CH:4]=[CH:3][C:2]([NH:32][S:29]([CH3:28])(=[O:31])=[O:30])=[CH:7][C:6]=1[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][C:20]([CH3:26])=[N:21]3)[CH2:12][CH2:11]1
Reactant: Cc1ccc2c(N3CCN(CCc4cc(Br)ccc4F)CC3)cccc2n1
Reactant: CS(N)(=O)=O
Product: Cc1ccc2c(N3CCN(CCc4cc(NS(C)(=O)=O)ccc4F)CC3)cccc2n1
Yield: 69 %

Procedure:
The title compound was prepared in 69% yield according to the general procedure for the preparation of amides, ureas and carbamates (Method A) starting from 5-{4-[2-(5-bromo-2-fluorophenyl)ethyl]-1-piperazinyl}-2-methylquinoline and methanesulfonamide.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5]/[C:6]/2=[CH:11]\[C:12](Cl)=[O:13].[CH:15]1([NH2:18])[CH2:17][CH2:16]1>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5]/[C:6]/2=[CH:11]\[C:12]([NH:18][CH:15]1[CH2:17][CH2:16]1)=[O:13]
Reactant: O=C(Cl)/C=C1\CCc2c(Cl)cccc21
Reactant: NC1CC1
Solvent: ClCCl
Product: O=C(/C=C1\CCc2c(Cl)cccc21)NC1CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 76.4 %

Procedure:
An ice cold solution of (E)-2-(4-choro-1-indanylidene)acetyl chloride (2.95 g, 0.013 mol ) in dichloromethane (30 mL) was treated with cyclopropylamine (1.48 g, 0.026 mol, Aldrich) and the mixture was stirred for 4 h. The mixture was concentrated in vacuo and the residue was taken up in a mixture of ethyl acetate and 5% aqueous sodium bicarbonate. The ethyl acetate phase was washed with 5% aqueous sodium bicarbonate, saturated aqueous NaCl and dried (Na2SO4). Filtration and concentration gave 3.5 g of crude oil product. Chromatography on Silca gel with ethyl acetate: hexanes (1:1) as eluent and trituration of the resulting solid with hexanes gave 2.46 g (76%) of (E)-2-(4-chloro-1-indanylidene)-N-cyclopropylacetamide as an off-white solid: m.p., 140°-142° C.; NMR (DMSO-d6): d 8.16, d, 1H, NH), 7.29-7.51 (m, 3H, Ar), 6.34 (t, 1H, =CH), 2.93-3.07, 3.18-3.31 (2m's, 4H 2XCH2), 2.72 (m, 1H, CH), 0.62-0.72, 0.39-0.47 (2m's, 4H, 2XCH2); steady-state nOe: irradiation at 6.34 d, observed 20.3% nOe at 7.46 d.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH2:15])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.Cl[C:20]1[C:25]([C:26]#[N:27])=[CH:24][N:23]=[C:22]2[S:28][C:29]3[CH2:30][N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:32][CH2:33][C:34]=3[C:21]=12>>[C:26]([C:25]1[C:20]([NH:15][C:11]2[CH:10]=[C:9]3[C:14](=[CH:13][CH:12]=2)[N:6]([CH2:5][C:4]2[CH:16]=[CH:17][CH:18]=[C:2]([F:1])[CH:3]=2)[N:7]=[CH:8]3)=[C:21]2[C:34]3[CH2:33][CH2:32][N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30][C:29]=3[S:28][C:22]2=[N:23][CH:24]=1)#[N:27]
Reactant: Nc1ccc2c(cnn2Cc2cccc(F)c2)c1
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3ncc(C#N)c(Cl)c23)C1
Product: CC(C)(C)OC(=O)N1CCc2c(sc3ncc(C#N)c(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)C1

Procedure:
In analogy to Example 54A, the title compound was synthesized from 1-(3-fluorobenzyl)-1H-indazol-5-amine from Example 8A (138 mg, 0.57 mmol) and tert-butyl 4-chloro-3-cyano-5,8-dihydrothieno[2,3-b:5,4-c′]dipyridine-7(6H)-carboxylate (200 mg, 0.57 mmol) from Example 53A to yield 234 mg (74%).
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([CH3:23])=[CH:6][C:7]([CH3:22])([CH3:21])[NH:8]2.[C:24]1([OH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[C:3]([CH2:2][O:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:22])([CH3:21])[CH:6]=[C:5]2[CH3:23]
Reactant: COc1ccccc1-c1ccc2c(c1CCl)C(C)=CC(C)(C)N2
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccccc1-c1ccc2c(c1COc1ccccc1)C(C)=CC(C)(C)N2
Temperature: 80 °C
Reaction time: 5 h
Yield: 38.9 %

Procedure:
A mixture of 5-chloromethyl-6-(2-methoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound 5-1, 52 mg, 0.16 mmol), phenol (42 μL, 0.48 mmol) and potassium carbonate (88 mg, 0.64 mmol) was suspended in anhydrous N,N-dimethylformamide (2 mL), and stirred 80° C. for 5 hours. After cooling down, the reaction mixture was diluted with ethyl acetate (60 mL). The whole was washed with water (50 mL) and saturated brine (30 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (24 mg) as a colorless oil. (Yield 39%)
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:5](O)=[O:6].[CH3:12][CH2:13][OH:14]>>[OH:6][C:5]1[C:4]2[C:3](=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:2]([CH3:1])[C:13](=[O:14])[CH:12]=1
Reactant: CCO
Reactant: CNc1ccccc1C(=O)O
Product: Cn1c(=O)cc(O)c2ccccc21

Procedure:
This was prepared from N-methyl anthranilic acid (22.04g. 0.146 mole) as described in example 30a., m.p. (EtOH) 270°-273°C. (Found; C, 68.59; H, 5.44; N, 7.73; C10H9NO2 requires; C, 58.56; H, 5.18; N, 8.00%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:15])=[C:7]([CH:14]=1)[C:8]([O:10]C(C)C)=[O:9])=[CH2:2].I[C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1>>[OH:15][C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[CH:2][C:17]2[CH:18]=[CH:19][C:20]([S:23]([NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)(=[O:25])=[O:24])=[CH:21][CH:22]=2)=[CH:14][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: C=Cc1ccc(O)c(C(=O)OC(C)C)c1
Reactant: O=S(=O)(Nc1ccccn1)c1ccc(I)cc1
Product: O=C(O)c1cc(C=Cc2ccc(S(=O)(=O)Nc3ccccn3)cc2)ccc1O
Yield: 40 %

Procedure:
Isopropyl 5-ethenyl-2-hydroxybenzoate was reacted with 4-iodo-N-(2-pyridinyl)benzenesulfonamide similarly to the procedure of Example 5c. After the reaction, the solvent was evaporated, toluene was added and the suspension filtered and washed with toluene. After drying on the filter and washing with water the material was hydrolyzed and precipitated similarly to the procedure of Example 3c. Yield 40%
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13](=O)[CH2:14][CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O)[CH:7]=[CH:6]2.[CH3:25][NH2:26]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[N:26]([CH3:25])[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:14]=1)[CH:7]=[CH:6]2
Reactant: CN
Reactant: COc1ccc2cc(C(=O)CCC(=O)c3ccccc3)ccc2c1
Product: COc1ccc2cc(-c3ccc(-c4ccccc4)n3C)ccc2c1
Yield: 84.7 %

Procedure:
In a similar manner as described in step 4 of Example 1, the title compound was prepared from 1-(6-methoxy-2-naphthyl)-4-phenylbutane-1,4-dione (3.00 g, 9.42 mmol), prepared in step 3 of Example 1, and methyl amine (8 M solution in EtOH, 100 mL, 800 mmol). Isolation of the solids by vacuum filtration gave 2-(6-methoxy-2-naphthyl)-1-methyl-5-phenyl-1H-pyrrole as a white solid (2.5 g, 85%), mp 197–198° C. Elemental Analysis for C22H19NO Calc'd: C, 84.31; H, 6.11; N, 4.47. Found: C, 84.47; H, 6.08; N, 4.41.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:29])[CH2:7][CH2:8][CH2:9][NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][NH:21]C(OC(C)(C)C)=O)=[CH:13][CH:12]=1)C.Cl>O.C1COCC1>[NH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][CH2:9][CH2:8][CH2:7][C:6]([OH:29])=[O:5])=[CH:12][CH:13]=1
Reactant: CCOC(=O)CCCNc1ccc(CCCCNC(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NCCCCc1ccc(NCCCC(=O)O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 128.6 %

Procedure:
2.5N aqueous NaOH (1.2 mL) was added to a solution of 4-[4-(4-tert-butoxycarbonylaminobutyl)phenylamino]butyric acid ethyl ester 420 (0.45 g, 1.18 mmol) dissolved in a mixture of water (25 mL) and THF (30 mL). The reaction was stirred for 2 h. 12 N HCl was added dropwise until pH 3. The solvent was evaporated in vacuo. The residue was cooled to 0° C. and a solution of TFA/dichloromethane (10 mL) was added. The reaction was stirred for 30 minutes. The solvent was evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 4:1:0.1, chloroform/methanol/concentrated ammonium hydroxide, v/v) to provide 460 (0.38 g, 100%). 1H NMR (300 MHz, CD3OD) δ 1.61 (m, 4H), 1.82 (m, 2H), 2.29 (t, 2H), 2.50 (m, 2H), 2.88 (m, 2H), 3.09 (t, 2H), 6.58 (d, 2H), 6.92 (d, 2H). m/z (ESI) 251.
Reaction SMILES: CC([N:5]([C@@H:9]([CH2:23][CH:24]([CH3:26])[CH3:25])/[CH:10]=[CH:11]/[C:12]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]1)=[O:13])C(=O)[O-])(C)C.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28]>C(Cl)Cl>[F:30][C:29]([F:32])([F:31])[C:27]([OH:33])=[O:28].[N:14]1([C:12](=[O:13])/[CH:11]=[CH:10]/[C@@H:9]([NH2:5])[CH2:23][CH:24]([CH3:26])[CH3:25])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]1
Reactant: CC(C)C[C@@H](/C=C/C(=O)N1CCc2ccccc21)N(C(=O)[O-])C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C[C@H](N)/C=C/C(=O)N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 17.5 h

Procedure:
To a solution of 1,1-dimethylethyl[(1S,2E)-4-(2,3-dihydro-1H-indol-1-yl)-1-(2-methylpropyl)-4-oxo-2-buten-1-yl]carbamate (3.21 g, 8.95 mmol) in CH2Cl2 (10.0 mL) was added TFA (10 mL, 130 mmol). The reaction mixture was stirred for 17.5 h at RT and then concentrated under reduced pressure and dried under high vacuum to afford the title compound. LC-MS m/z 259 (M+H)+, 0.76 min (ret time).
Reaction SMILES: C(O[CH:5]1[O:18][C@@H:17]([C:19]([F:22])([F:21])[F:20])[C@@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@@H:7]([O:8][C:9](=[O:11])[CH3:10])[CH2:6]1)(=O)C.[BrH:23].C(O)(=O)C>>[C:9]([O:8][C@@H:7]1[C@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@H:17]([C:19]([F:22])([F:21])[F:20])[O:18][C@@H:5]([Br:23])[CH2:6]1)(=[O:11])[CH3:10]
Reactant: Br
Reactant: CC(=O)OC1C[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H](C(F)(F)F)O1
Solvent: CC(=O)O
Product: CC(=O)O[C@H]1[C@@H](OC(C)=O)C[C@H](Br)O[C@H]1C(F)(F)F

Procedure:
Step (12'): Compound 77 (the mixture of the aforesaid anomers) is brominated in its solution in hydrogen bromide-acetic acid by a conventional method, whereby there is obtained 3,4-di-O-acetyl-2,6-dideoxy-6,6,6-trifluoro-α-L-lyxo-hexopyranosyl bromide [Compound 78 of the formula ##STR118## as a 1-bromo sugar. While, when Compound 77 is reacted with iodotrimethylsilane in anhydrous toluene, there is produced a corresponding 1-iodo sugar.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([NH2:11])[N:3]=1.O.[C:13]1([C:19]([CH:21]=O)=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C.[Ni]>[C:13]1([C:19]2[N:1]=[C:2]3[N:3]=[C:4]([NH2:11])[CH:5]=[CH:6][C:7]3=[N:8][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccc([N+](=O)[O-])c(N)n1
Reactant: O=CC(=O)c1ccccc1
Agent: [Ni]
Solvent: CCO
Solvent: O
Product: Nc1ccc2ncc(-c3ccccc3)nc2n1

Procedure:
A solution of 1.22 g of 2,6-diamino-3-nitropyridine (7.92 mmol) in 210 ml of ethanol is hydrogenated with Raney nickel as catalyst at 50° C. and 5 bar. After the hydrogenation is complete, the catalyst is filtered off with suction through a glass fibre filter. Before the filtration, 1.68 g of phenylglyoxal hydrate (11.03 mmol) are introduced into 50 ml of ethanol in the receiver. The catalyst is then filtered off under nitrogen as protective gas, and the hydrogenation solution is sucked directly into the reaction flask. The greenish blue reaction mixture is heated under reflux under nitrogen for 30 min. The mixture is allowed to cool, and the solvent is removed in vacuo. A dark brown solid is finally obtained. Purification by column chromatography on silica gel (mobile phase dichloromethane/methanol mixture) affords a pale yellow crystalline solid.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[S:27]([C:31]1[CH:32]=[C:33]([NH2:37])[CH:34]=[CH:35][CH:36]=1)(=[O:30])(=[O:29])[NH2:28]>>[S:27]([C:31]1[CH:32]=[C:33]([NH:37][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:26])([F:1])[F:25])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])[CH:34]=[CH:35][CH:36]=1)(=[O:29])(=[O:30])[NH2:28]
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) and 3-sulfamoyl-phenylamine [commercially available] according to general procedure II. Yellow solid. MS (ISP) 529.0 [(M+H)+]; mp 155° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[O:17]1[CH:21]=[CH:20][CH2:19][CH2:18]1>O.C1COCC1>[Cl:2][C:3]1[C:4]([O:11][CH2:12][C:13]([F:15])([F:14])[F:16])=[C:5]([NH:9][N:10]=[CH:21][CH2:20][CH2:19][CH2:18][OH:17])[CH:6]=[CH:7][CH:8]=1
Reactant: C1=COCC1
Reactant: NNc1cccc(Cl)c1OCC(F)(F)F
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: OCCCC=NNc1cccc(Cl)c1OCC(F)(F)F
Reaction time: 3 h

Procedure:
The 3-chloro-2-(2,2,2-trifluoroethoxy)phenylhydrazine hydrochloride (13.3 g, 48 mmol) was dissolved in H2O (133 mL) and THF (133 mL). Dihydrofuran (3.75 mL, 48 mmol) was added in one portion, and the reaction mixture was stirred for 3 hours. After this time, the organic layer was separated and the aqueous layer extracted with Et2O (250 mL). The combined organic layers were washed with brine (250 mL), dried (MgSO4), and concentrated to afford 14 g (98%) of a 3:1 mixture of E:Z isomers of 4-[3-chloro-2-(2,2,2-trifluoroethoxy)phenylhydrazono]-1-butanol as an orange oil which was used without further purification.
Reaction SMILES: CC([N:5]([C@H:9]([CH2:21][N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=O)[CH2:18]Br)=[CH:13][CH:12]=1)[C:6](=[O:8])[O-:7])(C)C.[NH2:33][C:34]1[C:39]([CH:40]([OH:42])[CH3:41])=[CH:38][CH:37]=[CH:36][N:35]=1.C(=O)(O)[O-].[Na+]>C(O)(C)C>[O:31]=[C:30]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](=[O:32])[N:22]1[CH2:21][C@@H:9]([NH:5][C:6](=[O:8])[O:7][C:11]([CH3:16])([CH3:12])[CH3:10])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:33]=[C:34]3[C:39]([CH:40]([OH:42])[CH3:41])=[CH:38][CH:37]=[CH:36][N:35]3[CH:18]=2)=[CH:15][CH:16]=1
Reactant: CC(C)(C)N(C(=O)[O-])[C@@H](Cc1ccc(C(=O)CBr)cc1)CN1C(=O)c2ccccc2C1=O
Reactant: CC(O)c1cccnc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CC(O)c1cccn2cc(-c3ccc(C[C@@H](CN4C(=O)c5ccccc5C4=O)NC(=O)OC(C)(C)C)cc3)nc12
Yield: 174.7 %

Procedure:
A mixture of 1,1-dimethylethyl{(1S)-2-{4-(bromoacetyl)phenyl]-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}carbamate (1.90 g, 3.79 mmol), 1-(2-amino-3-pyridinyl)ethanol (0.523 g, 3.79 mmol), and solid sodium bicarbonate (0.398 g, 4.72 mmol) in isopropanol (24 mL) was refluxed for 3.0 h. The mixture was concentrated in vacuo and the residue dissolved in ethyl acetate, washed with water and saturated sodium chloride, dried (Na2SO4), and concentrated to give the title compound (1.79 g, 87%) as a light pink solid. MS (ES+) m/e 541 [M+H]+.
Reaction SMILES: [OH-].[K+].NC1[S:5][C:6]2[C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1>O.O1CCOCC1>[NH2:8][C:7]1[C:6]([SH:5])=[C:12]([CH:11]=[CH:10][CH:9]=1)[C:13]([OH:15])=[O:14]
Reactant: COC(=O)c1cccc2nc(N)sc12
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Nc1cccc(C(=O)O)c1S
Temperature: 25 °C

Procedure:
28.9 g of potassium hydroxide (85%), dissolved in 38 ml of water, are added dropwise to 3:5 g of methyl 2-amino-benzothiazole-7-carboxylate in 38 ml of dioxane under a nitrogen atmosphere in the course of 20 minutes, while stirring and cooling with ice, such that the internal temperature of 25° C. is not exceeded. Thereafter, the mixture is refluxed at a bath temperature of 140° C., and towards the end of the reaction the internal temperature is increased to 170° C. and dioxane is distilled off by means of a descending condenser. The mixture is then cooled to 0° C. and filtered under a nitrogen atmosphere and the residue is rinsed with 30. ml of ice-water. The title compound can be isolated from the filtrate by acidification to pH 5.5, with severe cooling and stirring at a maximum of 0° C., and extraction with ethyl acetateltetrahydrofuran (8:2) and washing with concentrated sodium chloride solution. Because of the risk of the formation of the disulfide, the potassium salt in the filtrate (potassium 3-amino-2-mercapto-benzoate) is preferably further reacted directly.
Reaction SMILES: [F:1][C:2]1([F:31])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3[C:19]4[C:14](=[N:15][CH:16]=[C:17]([C:20]5[CH:21]=[N:22][N:23]([CH:25]6[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]6)[CH:24]=5)[CH:18]=4)[NH:13][CH:12]=3)=[CH:10][C:4]=2[O:3]1.C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[F:31][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3[C:19]4[C:14](=[N:15][CH:16]=[C:17]([C:20]5[CH:21]=[N:22][N:23]([CH:25]6[CH2:26][CH2:27][N:28]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:29][CH2:30]6)[CH:24]=5)[CH:18]=4)[NH:13][CH:12]=3)=[CH:10][C:4]=2[O:3]1
Reactant: FC1(F)Oc2ccc(-c3c[nH]c4ncc(-c5cnn(C6CCNCC6)c5)cc34)cc2O1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(n2cc(-c3cnc4[nH]cc(-c5ccc6c(c5)OC(F)(F)O6)c4c3)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 324 (50 mg, 0.1182 mmol) in DCM was added triethylamine (17.9 mg, 0.1773 mmol). Methane sulfonyl chloride 342 (13.5 mg, 0.1182 mmol) was added to the reaction and stirred for 2 h at rt. The reaction mixture was diluted with dichloromethane and washed with water twice. The organic layer was dried over sodium sulphate and concentrated to get the crude, which was purified by flash column using 100-200 mesh silica gel. The compound was eluted at 2% methanol in chloroform as off white coloured solid 3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-5-(1-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine 343. 1H NMR (400 MHz, DMSO) δ: 11.94 (s, 1H), 8.55 (d, 1H), 8.39 (m, 2H), 8.03 (s, 1H), 7.88 (d, 1H), 7.78 (d, 1H), 7.58 (m, 1H), 7.44 (d, 1H), 4.31 (m, 1H), 3.66 (m, 2H), 2.95 (s, 3H), 2.16 (m, 2H), 2.01 (m, 2H) and MS ES+502.1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH2:14]([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[CH3:15]>ClCCl>[N:8]1[CH:5]=[CH:4][C:14]([N:16]2[CH2:19][CH2:20][CH:6]([CH2:7][C:2]([O:1][C:2]3[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=3)=[O:1])[CH2:18][CH2:17]2)=[CH:15][CH:9]=1
Reactant: CCN(CC)CC
Reactant: COC(=O)CNc1ccc(O)cc1
Solvent: ClCCl
Product: COC(=O)CNc1ccc(OC(=O)CC2CCN(c3ccncc3)CC2)cc1
Reaction time: 16 h

Procedure:
A solution of the foam in dry dichloromethane (5 ml) was added dropwise to a stirred solution of methyl N-(4-hydroxyphenyl)glycinate (210 mg) and triethylamine (0.33 ml) in dry dichloromethane (10 ml) and the mixture stirred for 16 hours. The mixture was diluted with dichloromethane, washed with water, dried and evaporated. Purification by flash chromatography on silica, eluting with 0-10% v/v methanol/dichloromethane and trituration of the resulting gum with diethyl ether gave the title compound, 80 mg, as a white solid: m.p. 120°-122° C.; NMR(d6DMSO), δ 8.13(2H,d), 6.84(2H,d), 6.81(2H,d), 6.54(2H,d), 6.01(1H,t), 3.96(2H,bd), 3.90(2H,d), 3.66(3H,s), 2.90(2H,dt), 2.50(2H,d +DMSO), 2.07(1H,m), 1.81(2H,bd), 1.30(2H,dq); m/e 384(M+H)+ ; calculated for C21 H25N3O4. 0.5 H2O: C, 64.3; H, 6.6; N, 10.7. found: C, 64.2; H, 6.3; N, 10.7%.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9](=O)[CH3:10])=[C:4]([F:12])[CH:3]=1.O.[NH2:14][NH2:15]>C(O)C>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5](/[C:9](=[N:14]/[NH2:15])/[CH3:10])=[C:4]([F:12])[CH:3]=1
Reactant: CC(=O)c1cc(F)c(Br)cc1F
Reactant: NN
Solvent: CCO
Solvent: O
Product: C/C(=N\N)c1cc(F)c(Br)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.9 %

Procedure:
1-(4-bromo-2,5-difluorophenyl)ethanone (500 mg, 1.042 mmol) was dissolved in ethanol (10 mL), then hydrazine hydrate (57.4 mg, 1.147 mmol) added and stirred at RT for 16 hr. A pale yellow solid was filtered off and the filtrate was concentrated under reduced pressure to obtain the crude title compound as a brown-yellow solid (249 mg, 54% yield); 1H NMR (500 MHz, CHLOROFORM-d)delta 2.13 (3H, d, J=2.99 Hz), 7.28 (1H, dd, J=9.85, 5.60 Hz), 7.34 (1H, dd, J=9.14, 6.62 Hz).
Reaction SMILES: [H-].[Na+].CCCCC.[C:8]([C:13]1[CH:27]=[CH:26][C:16]([CH2:17]P(=O)(OCC)OCC)=[CH:15][CH:14]=1)([O:10][CH2:11][CH3:12])=[O:9].[CH3:28][C:29]([C:31]1[CH:40]=[C:39]2[C:34]([C:35]([CH3:43])([CH3:42])[CH2:36][CH2:37][N:38]2[CH3:41])=[CH:33][CH:32]=1)=O>CN(C)C=O>[CH3:41][N:38]1[C:39]2[C:34](=[CH:33][CH:32]=[C:31]([C:29]([CH3:28])=[CH:17][C:16]3[CH:15]=[CH:14][C:13]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:27][CH:26]=3)[CH:40]=2)[C:35]([CH3:42])([CH3:43])[CH2:36][CH2:37]1
Reactant: CCOC(=O)c1ccc(CP(=O)(OCC)OCC)cc1
Reactant: CC(=O)c1ccc2c(c1)N(C)CCC2(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C=C(C)c2ccc3c(c2)N(C)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.2 %

Procedure:
2.9 g of a 50% suspension of sodium hydride in mineral oil were suspended in 30 ml of dimethylformamide after two-fold washing with pentane and treated dropwise at room temperature with a solution of 17.3 g of diethyl (4-carbethoxybenzyl)phosphonate in 50 ml of dimethylformamide. After stirring at room temperature for 1 hour, a solution of 5 g of 1,2,3,4-tetrahydro-1,4,4-trimethyl-7-quinolinyl methyl ketone in 50 ml of dimethylformamide was added dropwise thereto. The reaction mixture was heated to 50° C. for 1 hour, poured on to ice/water and extracted with ethyl acetate. The brownish oil obtained after drying and evaporation of the organic phase was chromatographed (silica gel, eluting agent hexane/ethyl acetate=9:1) and gave 4.2 g of ethyl p-[2-(1,2,3,4-tetrahydro-1,4,4-trimethyl-7-quinolinyl)propenyl]benzoate as a slightly yellow, viscous oil.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([OH:17])=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[CH:12]=1.[N+:18]([O-])([OH:20])=[O:19]>O>[Cl:6][C:7]1[CH:8]=[C:9]([N+:18]([O-:20])=[O:19])[C:10]([OH:17])=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[CH:12]=1
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1cc(Cl)ccc1O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Nc1cc(Cl)cc([N+](=O)[O-])c1O
Temperature: 25 °C

Procedure:
224.5 g of sulphuric acid (50% w/w) was dissolved in 300 ml of water and cooled to 25° C. while stirring under a mild nitrogen purge. 185.1 g (1 mole) of N-(5-chloro-2-hydroxyphenyl)acetamide prepared according to Example 1a was added to the diluted sulphuric acid and mixed intensively. 4 ml of nitric acid 65% w/w was added to the foam formed on top of the reaction mixture at low stirring speed. The stirring speed was increased and 75 ml of nitric acid 65% w/w was added in 45 minutes, while maintaining the temperature between 23 and 26° C. The mixture was stirred vigorously for an additional 1 hour at 23-26° C. Then the mixture was cooled to 0-5° C. and vigorously stirred at this temperature for 1 hour. The solid was filtered off quickly, washed three times with 300 ml of cold water, sucked for at least 30 minutes and dried at 50° C. and 100 mbar under a gentle nitrogen stream till dry.