Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][NH:13][CH3:14]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:13]([CH3:14])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Product: CN(C)S(=O)(=O)c1ccc(Br)cc1
Reaction time: 2 h
Yield: 94 %

Procedure:
4-Bromobenzenesulphonyl chloride (4.48 g, 18 mmol) was stirred in dichloromethane, and dimethylamine (40% aqueous solution, 10 ml) was added portionwise. The mixture was stirred for 2 h, washed with dilute hydrochloric acid, dried (Na2SO4) and evaporated to give the title compound (4.38 g, 94%) as a white solid.
Reaction SMILES: [OH:1][CH:2]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([CH3:26])[CH:17]=2)([CH2:14][CH3:15])[CH2:12][CH3:13])=[CH:7][C:6]=1[CH3:27].N1C=CN=C1.[CH3:37][C:38]([Si:41](Cl)([CH3:43])[CH3:42])([CH3:40])[CH3:39]>CN(C=O)C>[Si:41]([O:1][CH:2]([C:28]([CH3:29])([CH3:31])[CH3:30])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([CH3:26])[CH:17]=2)([CH2:12][CH3:13])[CH2:14][CH3:15])=[CH:7][C:6]=1[CH3:27])([C:38]([CH3:40])([CH3:39])[CH3:37])([CH3:43])[CH3:42]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc(C(=O)OC)c(C)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCC(CC)(c1ccc(OCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(C(=O)OC)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.9 %

Procedure:
To a solution of the methyl 4-(1-{4-[2-(hydroxy)-3,3-dimethyl-butoxy]-3-methylphenyl}-1-ethylpropyl)-2-methylbenzoate (4.79 g, 11.24 mmol), Example 1, in DMF (40 mL) is added imidazole (1.14 g, 16.87 mmol) followed by the addition of TBSCl (1.78 g, 11.80 mmol). The mixture is stirred at RT overnight and concentrated. The mixture is partitioned between 0.1 M HCl (100 mL) and EtOAc (100 mL). The aqueous layer is extracted with EtOAC. The combined organic layers is MgSO4 dried, concentrated, and chromatographed (10% EtOAc/Hex) to give the title compound (4.37 g, 72%).
Reaction SMILES: [O:1]=[C:2]1[NH:21][C:5]2=[N:6][C:7]3[CH:8]=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=O)=[CH:11][C:12]=3[CH:13]=[C:4]2[NH:3]1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[O:1]=[C:2]1[NH:21][C:5]2=[N:6][C:7]3[CH:8]=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH2:17][C:18]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[O:20])=[CH:11][C:12]=3[CH:13]=[C:4]2[NH:3]1
Reactant: O=C(O)CCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1
Reactant: C1CCNCC1
Product: O=C(CCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1)N1CCCCC1

Procedure:
This compound, m.p. 284.5°-285.5° C., was prepared analogous to Example 15 from 4-[(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]quinolin-7-yl)oxy]butyric acid and piperidine.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([NH:10][C:11](=[O:30])[C:12]3[CH:17]=[CH:16][C:15]([CH2:18][NH:19]C(OCC4C=CC=CC=4)=O)=[CH:14][CH:13]=3)=[C:4]2[CH:3]=[N:2]1.[ClH:31].CO.[H][H]>[C+4].[OH-].[Pd+2].[OH-].[OH-].[OH-].[OH-].[OH-].CO>[ClH:31].[ClH:31].[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([NH:10][C:11](=[O:30])[C:12]3[CH:17]=[CH:16][C:15]([CH2:18][NH2:19])=[CH:14][CH:13]=3)=[C:4]2[CH:3]=[N:2]1
Reactant: [H][H]
Reactant: O=C(NCc1ccc(C(=O)Nc2ccnc3[nH]ncc23)cc1)OCc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [C+4]
Solvent: CO
Product: NCc1ccc(C(=O)Nc2ccnc3[nH]ncc23)cc1

Procedure:
10% Palladium hydroxide carbon (250 mg) was added to a mixture of N-(1H-pyrazolo[3,4-b]pyridin-4-yl)-4-benzyloxycarbonylaminomethylbenzamide (540 mg), 15% hydrochloric acid-methanol (3 ml) and methanol (10 ml), and the mixture was stirred in a stream of hydrogen at 40° C. for 2 hours. After the reaction, the catalyst was removed by filtration, and the mixture was concentrated under reduced pressure. The obtained crystals were recrystallized from ethanol-ethyl acetate to give 330 mg of N-(1H-pyrazolo[3,4-b]pyridin-4-yl)-4-aminomethylbenzamide dihydrochloride.
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH:5]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:4].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:37](=[O:38])[CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[N:34]([CH3:43])[C:33]2=[O:44])=[CH:28][C:27]=1[CH:45]=O>CO>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:37](=[O:38])[CH:36]=[C:35]([C:39]([F:41])([F:42])[F:40])[N:34]([CH3:43])[C:33]2=[O:44])=[CH:28][C:27]=1[CH:45]=[CH:5][C:3](=[O:4])[CH2:2][Cl:1]
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)CCl
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c(C=O)c2)c1=O
Solvent: CO
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c(C=CC(=O)CCl)c2)c1=O
Reaction time: 10 h

Procedure:
4.6 g of chloroacetylmethylenetriphenylphosphorane were added to a solution of 3.3 g of 3-[4-chloro-3-formylphenyl]-2,4-dioxo-1-methyl-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine in 100 ml of methanol, and stirring was carried out for 10 hours at room temperature. The precipitate which had separated out was isolated, washed with petroleum ether and dried.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]1([C:17]([O:19][CH3:20])=[O:18])[C:11](=[O:12])[CH2:10][CH2:9][C:8]2[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=2[O:6]1.[BH4-].[Na+].O>CO>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]1([C:17]([O:19][CH3:20])=[O:18])[CH:11]([OH:12])[CH2:10][CH2:9][C:8]2[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=2[O:6]1
Reactant: COC(=O)C1(CCCCl)Oc2ccccc2CCC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)C1(CCCCl)Oc2ccccc2CCC1O

Procedure:
To a suspension of 2.0 g of methyl 2-(3-chloropropyl)-3-oxo-2,3,4,5-tetrahydro-1-benzoxepin-2-carboxylate obtained in Reference Example 1 in 30 ml of methanol, sodium borohydride is added in small portions with stirring and under ice-cooling. After completion of the reaction, the reaction mixture is treated with water and extracted with ethyl acetate. The organic layer is washed with water, dried, and evaporated under reduced pressure. The residue is purified by column chromatography on silica gel (eluant: hexane:ethyl acetate=3:1→1:1). From the first fraction eluted, methyl 2-(3-chloropropyl)-3-hydroxy-2,3,4,5-tetrahydro-1-benzoxepin-2-carboxylate (A isomer) is obtained as a colorless oil. Mass spectrum m/e: 298, 300 (M+). IR νmaxneat cm-1 : 3500 (OH), 1735. NMR(CDCl3) δ: 2.0 (6H, multiplet), 3.0(2H, multiplet), 3.5 (2H, triplet, ClCH2 --), 3.70 (3H, s, OCH3), 4.18 (1H, multiplet, C3 --H).
Reaction SMILES: [Cl:1][CH:2]([CH:7]=[C:8]([Cl:10])[Cl:9])[CH2:3][C:4](O)=[O:5].S(Cl)([Cl:13])=O>>[Cl:1][CH:2]([CH:7]=[C:8]([Cl:10])[Cl:9])[CH2:3][C:4]([Cl:13])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CC(Cl)C=C(Cl)Cl
Product: O=C(Cl)CC(Cl)C=C(Cl)Cl

Procedure:
205.6 g (1.19 mols) of 2,4,4-trichlorobut-3-enecarboxylic acid [produced according to Monateshefte d. Chemie, 98, 2138 (1967)] is heated with 290 ml of thionyl chloride for 5 hours at 85° C. The reaction solution is concentrated by evaporation and subsequently distilled to obtain 209.7 g of 2,4,4-trichlorobut-3-enecarboxylic acid chloride; b.p. 75°-76° C./20 mm Hg. The spectroscopic data of the substance obtained agree with those of the products obtained according to (a).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([NH:15][C:16](=[O:25])[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1.[N+:26]([C:29]1[CH:30]=[C:31]([S:35](Cl)(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1)([O-:28])=[O:27]>>[N+:26]([C:29]1[CH:30]=[C:31]([S:35]([NH:1][C:2]2[CH:3]=[C:4]([CH2:8][CH:9]([NH:15][C:16](=[O:25])[CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=2)(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1)([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: CCOC(=O)C(Cc1cccc(N)c1)NC(=O)CCc1ccccc1
Product: CCOC(=O)C(Cc1cccc(NS(=O)(=O)c2cccc([N+](=O)[O-])c2)c1)NC(=O)CCc1ccccc1

Procedure:
Corresponding to Example 3c, 1.2 g of (6b) were reacted with 3-nitrophenylsulphonyl chloride. A solid was obtained (yield: 1.54 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:14]=1[NH2:15]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:15][C:14]1[CH:16]=[C:17]([C:20]([F:21])([F:22])[F:23])[CH:18]=[CH:19][C:13]=1[Cl:12])=[O:9]
Reactant: Nc1cc(C(F)(F)F)ccc1Cl
Reactant: O=C(O)c1cc(Br)ccc1O
Product: O=C(Nc1cc(C(F)(F)F)ccc1Cl)c1cc(Br)ccc1O
Yield: 34.2 %

Procedure:
Using 5-bromosalicylic acid and 2-chloro-5-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 1(1) gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:11])[CH:9]=O)=[CH:4][CH:3]=1.[C:12]([CH:17]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:14][CH2:15][CH3:16])=[O:13]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:11])[CH:9]=[CH:17][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1
Reactant: CC(C=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)C=CC(C)c1ccc(Cl)cc1

Procedure:
The synthesis of intermediates leading to different values of m and X is within the capability of one skilled in the art. Example 3 details the method of making the compound wherein X is --CH(CH3)-- and m is 2. This synthesis starts with the reduction of 2-(4-chlorophenyl)propionic acid with lithium aluminum hydride, producing 2-(4-chlorophenyl)propanol. Oxidation of this alcohol with pyridinium chlorochromate in methylene chloride produces 2-(4-chlorophenyl)propionaldehyde. This aldehyde is then reacted with (carbethoxymethylene)triphenylphosphorane, yielding ethyl 4-(4-chlorophenyl)-2-pentenoate. Hydrogenation of this ester in the presence of platinum oxide produces ethyl 4-(4-chlorophenyl)pentanoate which is then hydrolyzed with sodium hydroxide to the corresponding pentanoic acid (II). The remaining steps of this synthesis are shown in Schema 1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].I[CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH2:11][CH3:12])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CCI
Reactant: Cc1ccc(O)cc1Br
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(C)c(Br)c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 54.3 %

Procedure:
To a stirred solution of 3-bromo-4-methyl-phenol (1.2 g, 6.42 mmol) in anhydrous DMF (12 mL), was added iodoethane (1.55 mL, 19.25 mmol) and potassium carbonate (1.06 g, 7.7 mmol). The resulting mixture was left to stir at 80° C. for 18 h. It was allowed to cool to room temperature, poured into brine and extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate and filtered. The filtrate was evaporated and the crude residue was purified by silica gel chromatography (25 g SiO2) eluting with iso-hexane. Evaporation of desired fractions gave 2-bromo-4-ethoxy-1-methyl-benzene (D64) (0.7500 g, 3.4869 mmol, 54.3% yield) as colourless oil;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[C:4]=1[C:5]([OH:7])=[O:6].C(Cl)(Cl)[Cl:17]>>[Cl:17][C:11]1[C:3]([O:2][CH3:1])=[C:4]([C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: COc1ccc(OC)c(C(=O)O)c1OC
Reactant: ClC(Cl)Cl
Product: COc1cc(Cl)c(OC)c(C(=O)O)c1OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
2,5,6-trimethoxybenzoic acid 5.0 g (0.024 mol) was suspended in 75 ml of CHCl3 and cooled to 0° C. 1.9 ml (0.024 mol) of SO2Cl2 was added under N2 -atm. The reaction was stirred for 2 hr and allowed to slowly attain room temperature. The reaction mixture was diluted 100 ml CHCl3 and washed with 200 ml H2O. The aqueous layer was washed with 50 ml CHCl3 and the combined organic layer was dried (Na2SO4) and the solvent was evaporated. Gave 5.5 g (95%) of 3-chloro-2,5,6-trimethoxybenzoic acid (oil). Mw: 246.7.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[C:6]([N+:17]([O-:19])=[O:18])[CH:5]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.Cl[CH2:45][C:46]1[CH:55]=[CH:54][C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[N:47]=1>CCCCCC.C(OCC)(=O)C.C(#N)C>[N+:17]([C:6]1[CH:5]=[C:4]([C:1](=[O:3])[CH3:2])[CH:9]=[CH:8][C:7]=1[C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:45][C:46]2[CH:55]=[CH:54][C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[N:47]=2)=[CH:14][CH:15]=1)([O-:19])=[O:18]
Reactant: ClCc1ccc2ccccc2n1
Reactant: CC(=O)c1ccc(-c2ccc(O)cc2)c([N+](=O)[O-])c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(-c2ccc(OCc3ccc4ccccc4n3)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of the phenol (4.4 g, 17.12 mmole) of Step B, powdered anhydrous potassium carbonate (2.37 g, 17.12 mmole), 18-crown-6 (0.453 g, 1.71 mmole) and acetonitrile (38 mL) is stirred at room temperature under nitrogen for 15 minutes. 2-Chloromethylquinoline (3.34 g, 18.83 mmole, free base freshly prepared from the hydrochloride salt) is added and the mixture is refluxed for 10 hours. (TLC, 7:3 hexane-ethyl acetate). A 10% excess of potassium carbonate, 18-crown-6 and the chloromethylquinoline is added and reflux continued for another 4 hours. The solvent is removed and the residue is diluted with water and extracted with ethyl acetate (3x). The extracts are washed and dried (MgSO4). The residue is flash chromatographed (on silica Merck 60, preabsorbed in dichloromethane and eluted in order of increasing polarity with 7:3, 1:1 and 1:3 hexane-ethyl acetate followed by pure ethyl acetate) to provide the pure title compound (2.59 g). Recrystallization from toluene yields a yellow solid, m.p. 160°-162° C. (2.05 g, 30%).
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[NH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[O:4]1[CH2:9][CH2:10][N:5]([CH2:6][CH2:7][OH:8])[CH2:2][CH2:3]1
Reactant: C1COCCN1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCCN1CCOCC1
Temperature: 25 °C
Yield: 83.4 %

Procedure:
A mixture of 2-bromoethanol (27.9 g, 223 mmol), morpholine (40 g, 459 mmol) and K2CO3 (48.4 g, 350 mmol) in CH3CN (30 mL) was refluxed for 3 h. The mixture was then cooled to rt and filtered. The filtrate was concentrated in vacuo to give the title compound as a yellow solid (24.40 g, 83%), which was used for next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[C:5]#[N:6].C([O-])([O-])=[O:14].[K+].[K+].C(N)(N)=O.OO.C(Cl)Cl>CC(C)=O.O.O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[C:5]([NH2:6])=[O:14]
Reactant: N#Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: O=C([O-])[O-]
Agent: NC(N)=O
Agent: OO
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: O
Product: NC(=O)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-fluoro-4-nitrobenzonitrile (15 g, 90.3 mmol) and K2CO3 (25.03 g, 181.1 mmol) in 100 mL of acetone/water (4:1) was added urea hydrogen peroxide adduct (16.99 g, 180.6 mmol) and the reaction stirred overnight at ambient temperature. DCM (100 mL) and water (500 mL) were added to the reaction mixture, the solution partitioned and the organic layer separated. The aqueous layer was extracted with DCM (3×100 mL) and the combined organic portions, washed with brine (100 mL), filtered through Celite and passed through a PTFE separation frit. The solvent was concentrated in vacuo and the title compound obtained as an orange solid (10 g, 60% yield) after recrystallisation from EtOAc/petroleum ether (40-60° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([C:8]2[C:12]([NH:13]C(=O)OC(C)(C)C)=[CH:11][N:10]([CH3:21])[N:9]=2)[CH:7]=1.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([C:8]2[C:12]([NH2:13])=[CH:11][N:10]([CH3:21])[N:9]=2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1-c1nn(C)cc1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(Cl)cc1-c1nn(C)cc1N
Temperature: 25 °C
Reaction time: 9 h

Procedure:
To a stirring solution of tert-butyl 3-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazol-4-ylcarbamate (543.2 mg, 1.608 mmol, 1 eq) was added hydrogen chloride (5.0 mL of a 4.0 M solution in 1,4-dioxane, 0.020 mol, 12 eq). The reaction mixture was stirred at room temperature for 9 hours and then evaporated to dryness. The solid residue was partitioned between dichloromethane and a saturated aqueous solution of sodium bicarbonate. The aqueous portion was extracted once more with dichloromethane, and the combined organic extracts dried over magnesium sulfate and concentrated to give 3-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazol-4-amine, which was carried forward without purification. LCMS (ESI) m+H=238.2; 1H NMR (400 MHz, CDCl3) δ: 7.53 (s, 1H), 7.28 (d, 1H), 7.02 (s, 1H), 6.91 (d, 1H), 3.91 (d, 2H), 3.87 (s, 3H), 3.84 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]([NH2:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.C1COCC1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>O>[F:1][C:2]1[C:3]([C:8]#[N:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1ncccc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ncccc1F
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
30 g of 3-Fluoropyridine-2-carboxamide (C), 120 mL of THF and 768.5 mL of TEA were taken in a reaction flask and cooled to 0-5° C. To this mixture, 72.2 mL of Trifluoroacetic anhydride (in 30 mL of THF) was added dropwise over a period of 30 minutes keeping the reaction temperature below 5° C. (0° C. to 5° C.) and the RM was stirred for 2 hours 30 minutes at a temperature below 10° C. (5° C. to 10° C.). After completion of the reaction, 150 mL of 20% Na2CO3 solution was added dropwise to the RM while maintaining the temperature below 10° C. (5° C. to 5° C.), followed by addition of 360 mL of purified water. The RM was brought to room temperature (RT) and extracted with dichloromethane (MDC) and the organic layer was washed with 300 mL purified water, 150 mL of 2% dil HCl, followed by purified water and brine. The organic layer was dried over Na2SO4 and distilled under vacuum, resulting in the titled compound as a dark brown viscous oily mass. Crude Yield: 22-24 g.
Reaction SMILES: [C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25]OS(C4C=CC(C)=CC=4)(=O)=O)[CH:21]=3)[NH:16][N:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1COCC1.[CH3:42][NH:43][CH3:44]>>[CH3:42][N:43]([CH3:44])[CH2:25][CH2:24][O:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][N:15]=[C:14]2[S:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)(=[O:13])=[O:12]
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)cc1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc2[nH]nc(S(=O)(=O)c3cccc4ccccc34)c2c1
Temperature: 25 °C
Yield: 73.4 %

Procedure:
A solution of toluene-4-sulfonic acid 2-[3-(naphthalene-1-sulfonyl)-1H-indazol -5-yloxy]-ethyl ester (0.382 g, 0.731 mmol) in 2.0 M dimethylamine in THF (8 mL, 16 mmol) was stirred for 4 hours at 70° C. in a sealed tube. After cooling to ambient temperature, the reaction mixture was concentrated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with water and brine, dried with anhydrous magnesium sulfate, filtered and concentrated. Drying at 80° C. for 20 minutes in vacuo yielded dimethyl-{2-[3-(naphthalene-1-sulfonyl)-1H-indazol -5-yloxy]-ethyl}-amine as a light yellow solid (0.212 g, 73.4%). Methanol, chloroform and etheric hydrochloride were added. The resulting solution was concentrated and dried for 15 hours at 78° C. in vacuo. The hydrochloride as a buff foam (0.217 g) was obtained. Mass Spectrum (+EI, [M+H]+) m/z 396. 1HNMR (500 MHz, DMSO-d6): δ14.20 (s, 1H), 10.05 (s, 1H), 8.74-8.77 (m, 1H), 8.52 (dd, 1H, J=7.44 Hz and 1.22 Hz), 8.27 (d, 1H, J=8.17 Hz), 8.03-8.05 (m, 1H), 7.70-7.74 (m, 1H), 7.56-7.65 (m, 3H), 7.37 (d, 1H, J=2.20 Hz), 7.15-7.18 (m, 1H), 4.37-4.39 (m, 2H), 3.51 (t, 2H, J=4.76 Hz), 2.83 ppm (s, 6H). Elemental Analysis for C21H21N3O3S.1.00 mol HCl.0.70 mol H2O: Calcd: C, 56.74; H, 5.31; N, 9.45; Found: C, 56.72; H, 5.33; N, 9.06.
Reaction SMILES: O[CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8]([C:10]1[CH:34]=[CH:33][C:13]2[N:14]([CH3:32])[C:15]([NH:17][C:18]3[S:19][C:20]4[CH:26]=[C:25]([O:27][C:28]([F:31])([F:30])[F:29])[CH:24]=[CH:23][C:21]=4[N:22]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9].COCCN(S(F)(F)[F:45])CCOC>>[F:45][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8]([C:10]1[CH:34]=[CH:33][C:13]2[N:14]([CH3:32])[C:15]([NH:17][C:18]3[S:19][C:20]4[CH:26]=[C:25]([O:27][C:28]([F:30])([F:31])[F:29])[CH:24]=[CH:23][C:21]=4[N:22]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCOCCO)ccc21
Reactant: COCCN(CCOC)S(F)(F)F
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCOCCF)ccc21

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-(2-fluoro-ethoxy)-ethyl]-amide (53 mg) was prepared by following General Procedure H starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-(2-hydroxy-ethoxy)-ethyl]-amide (50 mg) and bis(2-methoxyethyl)aminosulfur trifluoride (47 uL). LC/MS: m/z 498.9. 1H NMR (DMSO-d6, 400 MHz): δ 12.39 (bs, 1H), 8.51 (s, 1H), 8.09 (s, 1H), 7.93 (s, 1H), 7.86-7.62 (m, 2H), 7.49 (d, 1H), 7.36 (d, 1H), 4.63-4.46 (m, 1H), 3.80-3.69 (m, 2H), 3.68-3.52 (m, 6H), 3.46 (q, 2H).
Reaction SMILES: O[CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.O>C(Cl)Cl>[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:3]1[CH2:4][CH2:5][CH2:6][CH:2]=1
Reactant: OC1CCCC1c1ccccn1
Solvent: ClCCl
Solvent: O
Product: C1=C(c2ccccn2)CCC1
Temperature: 170 °C
Reaction time: 60 h
Yield: 52.5 %

Procedure:
In an autoclave, 60.0 g (368 mM) of 1-hydroxy-2-(2-pyridyl)cyclopentane was placed and stirred for 60 hours at 170° C., followed by cooling, addition of water and extraction with methylene chloride. The organic layer was dried with anhydrous sodium sulfate, followed by distilling-off of the solvent under reduced pressure and then purification by silica gel column chromatography (eluent: hexane/ethyl acetate=8/1) to obtain 28.0 g of liquid 1-(2-pyridyl)cyclopentene (Yield: 52.5%).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3](=[O:22])/[CH:4]=[CH:5]/[C:6]1[N:7]=[C:8]([CH3:21])[N:9](S(C2C=CC(C)=CC=2)(=O)=O)[CH:10]=1>N1C=CC=CC=1.C(OC(=O)C)(=O)C>[CH3:23][N:2]([CH3:1])[C:3](=[O:22])/[CH:4]=[CH:5]/[C:6]1[N:7]=[C:8]([CH3:21])[NH:9][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(/C=C/C(=O)N(C)C)nc2C)cc1
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: Cc1nc(/C=C/C(=O)N(C)C)c[nH]1
Reaction time: 1 h
Yield: 63.3 %

Procedure:
A solution of (E)-N,N-dimethyl-3-[2-methyl-1-(4-methylbenzenesulphonyl)-1H-imidazol-4-yl]-2-propenamide (1.0 g) in pyridine (5 ml) and acetic anhydride (10 ml) was stirred at room temperature for 16 h. The reaction mixture was evaporated in vacuo, methanol (15 ml) was added and stirring was continued for 1 h. The mixture was evaporated in vacuo and the resulting gum partitioned between potassium carbonate solution (ca. 25% saturated) (30 ml) and chloroform (4×25 ml). The combined organic layers were dried, evaporated in vacuo and the residue triturated with ether (30 ml) to give the title compound (340 mg) as a solid, t.l.c. (ether:methanol 9:1), Rf 0.07.