Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:15][C:16]1[C:21]([OH:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:17]=1[F:26].CCN(CC)CC>C(Cl)Cl>[F:15][C:16]1[C:21]([O:22][S:2]([C:5]2[CH:6]=[CH:7][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:13][CH:14]=2)(=[O:4])=[O:3])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:17]=1[F:26]
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(S(=O)(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1
Temperature: 25 °C
Yield: 85.7 %

Procedure:
To a solution of methyl 4-(chlorosulfonyl)benzoate (Preparation 2, 606 mg, 2.1 mmol, 1 eq) in DCM (35 ml) was added pentafluorophenol (412 mg, 2.2 mmol, 1.1 eq) and Et3N (540 mg, 5.4 mmol, 2.5 eq) and the reaction mixture stirred at room temperature until all of the starting material was consumed. The solvent was evaporated in vacuo and the residue redissolved in ethyl acetate (10 ml), washed with water (10 ml), saturated sodium hydrogen carbonate (10 ml), dried over sodium sulphate, filtered and evaporated to yield the title compound as a white solid (690 mg, 1.8 mmol, 85%).
Reaction SMILES: C(N[CH:5]([CH3:7])[CH3:6])(C)C.[Br:8][C:9]1[C:13]([Br:14])=[CH:12][S:11][CH:10]=1.ICCC>C1COCC1.CCCCCC>[Br:8][C:9]1[C:13]([Br:14])=[CH:12][S:11][C:10]=1[CH2:7][CH2:5][CH3:6]
Reactant: Brc1cscc1Br
Reactant: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCCI
Product: CCCc1scc(Br)c1Br
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
To a solution of diisopropylamine (2.7 mL, 19.4 mmol) in 50 mL of THF cooled to -78° C. was added 7.8 mL (2.5M in hexane, 19.4 mmol) of nbutyllithium, and the reaction was stirred for 0.5 hours. To the first solution was added 4.7 g (19.4 mmol) of 3,4-dibromothiophene (Aldrich), then the reaction mixture was stirred for 1 hour at -78° C. Iodopropane (2.8 mL, 29.1 mmol) was then added, the reaction stirred for 10 min at -78° C., then removed for the cooling bath and stirred for 2 hours at room temperature. The reaction was quenched with aqueous satd. NH4Cl, extracted with ether, washed with H2O and brine, and concentrated to give 5.27 g of crude 3,4-dibromo-2-propylthiophene. This compound (5.25 g, 18.5 mmol) was dissolved in 80 mL of ether and cooled to -78° C. n-Butyllithium (7.4 mL, 18.5 mmol) was added dropwise via syringe, and the resulting mixture was stirred at -78° C. for 20 min. DMF was added (1.86 mL, 24.03 mmol), and the reaction was stirred at -78° C. for 1 hour, then poured into water and extracted with ether. The extract was washed with water, dried over MgSO4, and concentrated in vacuo. Silica gel column chromatography afforded 0.63 g of the title compound. NMR (CDCl3) δ:10.07 (s, 1H), 7.09 (s, 1H), 3.20 (t, J=7 Hz, 2H), 1.74 (m, 2H), 1.02 (t, J=7 Hz, 3H).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2C=CC(O)=CC=2)(C)C)=[CH:4][CH:3]=1.C(Cl)Cl.[C:21](Cl)(Cl)=[O:22].C([N:27](CC)CC)C>[OH-].[Na+]>[OH:22][C:21]1[CH:11]=[CH:8][C:5]2[C:4](=[CH:3][CH:2]=[CH:7][CH:6]=2)[N:27]=1
Reactant: O=C(Cl)Cl
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: CCN(CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Oc1ccc2ccccc2n1

Procedure:
456 g of bisphenol A and 559 g of 2-[4-hydroxyphenyl]-2-[5-(8-hydroxyquinolyl)]-propane are dissolved in 4 kg of 9% strength sodium hydroxide solution and 9 kg of methylene chloride are then added. 562.8 g of phosgene are introduced with vigorous stirring and 60 ml of a 4% strength triethylamine solution are then added dropwise. The mixture is stirred for a further hour and if necessary sufficient sodium hydroxide solution is added for the pH of the solution to remain constant at 13. The phases are separated and the aqueous phase is tested for complete conversion. The organic phase is extracted once with 5% strength H3PO4, washed with water until neutral and subsequently dried over sodium-sulphate. The organic phase is concentrated and the short-chain polycarbonate with hydroxyquinoline end groups is obtained direct by precipitation in methanol. ηrel : 1.038 (ηrel is measured in CH2Cl2 at 20° C.; 0.5 g solved in 100 g solution); nitrogen analysis: N2 2.56%; phenolic OH: 2.8%. The molecular weight calculated from these values is Mn = 1178.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[CH:17]=[C:18]([S:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:19]=[N:20][C:21]=3[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I([O-])(=O)(=O)=[O:40].[Na+].CO>O.C(OCC)(=O)C>[C:1]1([CH:7]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[CH:17]=[C:18]([S@:32]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[O:40])[N:19]=[N:20][C:21]=3[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](Nc1nccc(-c2cc(Sc3ccccc3)nnc2-c2cccc(C(F)(F)F)c2)n1)c1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(Nc1nccc(-c2cc([S@@](=O)c3ccccc3)nnc2-c2cccc(C(F)(F)F)c2)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.3 %

Procedure:
Compound 86 (70 mg, 0.132 mmol), sodium periodate (28 mg, 0.132 mmol), methanol (2 mL) and water (250 μL) were combined at 0° C. under Argon. After 0.5 h, the mixture was warmed to room temperature and stirred for 24 h. An additional portion of sodium periodate (28 mg, 0.132 mmol) was added and heated to 60° C. for 48 h. Ethyl acetate and water were added. The layers were separated and the organic portion was dried with anhydrous sodium sulfate. The solvent was removed in vacuo and the remaining residue was purified by flash column chromatography (hexane:ethyl acetate 50:50) to give 20 mg (0.036 mmol, 28%) of Compound 87 as a foam.
Reaction SMILES: [OH-].[Na+].O.[F:4][C:5]1[CH:40]=[CH:39][C:8]([CH2:9][C:10]2([C:35]([O:37]C)=[O:36])[CH2:15][CH2:14][CH2:13][CH:12]([NH:16][C:17]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][N:23]=[C:22]4[C:28]3[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[CH:29]=3)=[O:18])[CH2:11]2)=[CH:7][CH:6]=1.Cl>CO.C1COCC1>[F:4][C:5]1[CH:40]=[CH:39][C:8]([CH2:9][C:10]2([C:35]([OH:37])=[O:36])[CH2:15][CH2:14][CH2:13][CH:12]([NH:16][C:17]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][N:23]=[C:22]4[C:28]3[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[CH:29]=3)=[O:18])[CH2:11]2)=[CH:7][CH:6]=1
Reactant: COC(=O)C1(Cc2ccc(F)cc2)CCCC(NC(=O)c2ccc3[nH]nc(-c4ccnc(C)c4)c3c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(-c2n[nH]c3ccc(C(=O)NC4CCCC(Cc5ccc(F)cc5)(C(=O)O)C4)cc23)ccn1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
Sodium hydroxide in water (4 M solution, 1 ml, 4 mmol) was added into a solution of methyl 1-(4-fluorobenzyl)-3-(3-(2-methylpyridin-4-yl)-1H-indazole-5-carboxamido)cyclohexanecarboxylate (0.32 mmol) in methanol (0.5 ml) and THF (2 ml). The reaction solution was stirred at 70° C. for 16 h, and 1.0 N HCl solution was added dropwise to adjust pH to 4. The resulting solution was extracted with EtOAc (10 ml, twice). The combined organic layers were dried over sodium sulfate, filtered, concentrated, and purified using HPLC to give the titled compound. LC-MS: 487.21 [M+11]. LC/MS RT=2.36 min.
Reaction SMILES: [H-].[Na+].[CH:3]12[CH2:8][CH:7]1[C:6](=[O:9])[NH:5][C:4]2=[O:10].Br[CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>CN(C)C=O.O>[CH:14]1([CH2:13][CH2:12][N:5]2[C:6](=[O:9])[CH:7]3[CH:3]([CH2:8]3)[C:4]2=[O:10])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C1NC(=O)C2CC12
Reactant: BrCCC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1C2CC2C(=O)N1CCC1CCCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium hydride (0.11 g) was added to a solution of 3-azabicyclo[3.1.0]hexane-2,4dione (0.3 g) and 1-bromo-2-cyclohexylethane (0.52 g) in dimethylformamide (5 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The mixture was diluted with water (15 ml) and then extracted with toluene (20 ml). The organic extract was washed with water (15 ml), dried (MgSO4) and evaporated in vacuo. The residue was purified by Kugelrohr distillation (boiling point 130-140° C. @ 0.1 mmHg) to give the title compound as a colourless oil.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1)=O.[NH:18]1[CH2:22][CH2:21][NH:20][C:19]1=[S:23].C(O)C>C(O)(=O)C>[BrH:1].[Cl:17][C:12]1[CH:11]=[C:10]([C:5]2([C:3]3[N:20]4[CH2:21][CH2:22][N:18]=[C:19]4[S:23][CH:2]=3)[CH2:9][CH2:8][CH2:7][CH2:6]2)[CH:15]=[CH:14][C:13]=1[Cl:16]
Reactant: S=C1NCCN1
Reactant: O=C(CBr)C1(c2ccc(Cl)c(Cl)c2)CCCC1
Solvent: CC(=O)O
Solvent: CCO
Product: Br
Product: Clc1ccc(C2(C3=CSC4=NCCN34)CCCC2)cc1Cl
Temperature: 25 °C

Procedure:
A mixture of 2-bromo-1-[1-(3,4-dichlorophenyl)cyclopentyl]ethanone (0.5 g), imidazolidine-2-thione (0.16 g), ethanol (3 ml) and acetic acid (2 ml) was heated under reflux for 18 hours then allowed to cool to ambient temperature. The solvents were removed in vacuo and the residue crystallised from a 1:1 mixture of ethyl acetate and ethanol. The resulting product was collected by filtration, washed with ethanol (3 ml) and dried in vacuo at 60° C. to give 3-[1-(3,4-dichlorophenyl)cyclopentyl]-5,6-dihydroimidazo[2,1-b]thiazole hydrobromide as white microneedles (0.27 g), m.p. 230-232° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([C:14]([N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])=[O:15])[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[C-:23]#[N:24].[Na+]>CS(C)=O>[C:23]([CH2:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([C:14]([N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])=[O:15])[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:24]
Reactant: [C-]#N
Reactant: CCCN(CCC)C(=O)c1cc(CBr)cc(C(=O)OCC)c1
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCN(CCC)C(=O)c1cc(CC#N)cc(C(=O)OCC)c1
Reaction time: 3.5 h

Procedure:
A mixture of ethyl 3-[(dipropylamino)carbonyl]-5-(hydroxymethyl)benzoate (1.5 g) and phosphorous tribromide (0.95 mL) is stirred in dichloromethane (10 mL) and heated at 50 degrees C. for 4 hours and then cooled and partitioned between dichloromethane and water. The organic phase is separated and washed with aqueous sodium bicarbonate and then dried over magnesium sulfate and taken to dryness to give ethyl 3-(bromomethyl)-5-[(dipropylamino)carbonyl]benzoate, high resolution MS MH+=370.1020. Ethyl 3-(bromomethyl)-5-[(dipropylamino)carbonyl]benzoate (1.4 g) and sodium cyanide (0.2 g) are stirred in dry DMSO (25 mL) at 20–25 degrees C. for 3.5 hours and the mixture is then partitioned between ethyl acetate, water and saline. The organic layer is separated and dried over magnesium sulfate and taken to dryness under reduced pressure to give ethyl 3-(cyanomethyl)-5-[(dipropylamino)carbonyl]benzoate. Ethyl 3-(cyanomethyl)-5-[(dipropylamino)carbonyl]benzoate (0.6 g) is hydrolyzed with lithium hydroxide monohydrate (0.1 g) in ethanol and water at 20–25 degrees C. overnight and then added to water (50 mL). The pH is adjusted to 4 using concentrated hydrochloric acid and the mixture is partitioned between ethyl acetate, water, and saline. The organic phase is separated and dried over magnesium sulfate and taken to dryness under reduced pressure to give 3-(cyanomethyl)-5-[(dipropylamino)carbonyl]benzoic acid, MS M+H=287.2.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:8]=2[C:9](O)=[O:10])=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+]>C1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:8]=2[CH2:9][OH:10])=[CH:17][CH:18]=1
Reactant: Cc1ccc(Oc2ccc(C)cc2C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc(Oc2ccc(C)cc2CO)cc1

Procedure:
A solution of 121 g. of 2-(4-methyl-phenoxy)-5-methyl-benzoic acid in 600 ml. of tetrahydrofuran is slowly added dropwise, with cooling in an icebath, to 420 ml. of a 70% solution of sodium dihydro-bis(1-methoxyethoxy)-aluminate in benzene and stirred for an additional hour at room temperature. To the obtained clear solution, 800 ml. of 20% aqueous sodium hydroxide solution are carefully added dropwise. Then, the organic phase is separated. The aqueous phase is extracted three additional times with ether. The organic extracts are washed with saturated sodium chloride solution and the latter dried over sodium sulfate. After evaporation of the ether, there is obtained 2-(4-methylphenoxy)-5-methyl-benzyl alcohol as an oil.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]2[N:15]=[N:16][C:17]([C:20](=[O:27])[NH:21][CH2:22][CH2:23][CH:24]3[CH2:26][CH2:25]3)=[CH:18][CH:19]=2)[CH2:9]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.C1(CCNC(C2N=NC(NC3CCNC3)=CC=2)=O)CC1.[F:55][C:56]([F:67])([F:66])[C:57]1[CH:65]=[CH:64][CH:63]=[CH:62][C:58]=1C(Cl)=O>ClCCl.C(N(CC)CC)C>[CH:24]1([CH2:23][CH2:22][NH:21][C:20]([C:17]2[N:16]=[N:15][C:14]([NH:13][CH:10]3[CH2:11][CH2:12][N:8]([C:6](=[O:7])[C:58]4[CH:62]=[CH:63][CH:64]=[CH:65][C:57]=4[C:56]([F:67])([F:66])[F:55])[CH2:9]3)=[CH:19][CH:18]=2)=[O:27])[CH2:25][CH2:26]1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C(=O)NCCC3CC3)nn2)C1
Agent: O=C(NCCC1CC1)c1ccc(NC2CCNC2)nn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCCC1CC1)c1ccc(NC2CCN(C(=O)c3ccccc3C(F)(F)F)C2)nn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54 %

Procedure:
3-[6-(2-Cyclopropylethylcarbamoyl)pyridazin-3-ylamino]pyrrolidine-1-carboxylic acid tert-butyl ester was treated with trifluoroacetic acid in dichloromethane (15 mL). The isolated 6-(pyrrolidin-3-ylamino)pyridazine-3-carboxylic acid (2-cyclopropylethyl)-amide (0.053 g, 0.19 mmol) was dissolved in dichloromethane (10 mL) and then 2-trifluoromethylbenzoyl chloride (0.040 g, 0.19 mmol) was added at ambient temperature in the presence of triethylamine (0.2 mL). The mixture was stirred at ambient temperature for 15 minutes. The solvent was evaporated and the residue was purified by column chromatography. The title compound was obtained as a white powder in 54% yield (0.046 g). 1H NMR (300 MHz, CDCl3) δ 8.01 (d, J=10.0 Hz, 1H), 7.7 (m, 2H), 7.6 (t, J=7.0 Hz, 1H), 7.5 (m, 2H), 6.7 (d, J=10.0 Hz, 1H), 6.2 (m, 1H), 4.8 (m, 1H), 3.9-3.60 (m, 2H), 3.5-3.4 (m, 2H), 2.4 (m, 1H), 2.2 (m, 1H), 1.4 (t, J=7.0 Hz, 2H), 0.7 (m, 1H), 0.4 (m, 2H), 0.07 (m, 2H). MS (ES+) m/z 448.1 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH:4]=O.[O:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]1.[S-:17][C:18]#[N:19].[K+].II>>[C:2]([C:3]1[S:17][C:18](=[NH:19])[N:16]([CH2:15][CH2:14][N:11]2[CH2:12][CH2:13][O:8][CH2:9][CH2:10]2)[CH:4]=1)([CH3:7])([CH3:6])[CH3:1]
Reactant: NCCN1CCOCC1
Reactant: N#C[S-]
Reactant: CC(C)(C)CC=O
Agent: II
Agent: [K+]
Product: CC(C)(C)c1cn(CCN2CCOCC2)c(=N)s1

Procedure:
Commercially available 3,3-dimethylbutanal (Aldrich), 2-morpholinoethanamine (Aldrich), potassium thiocyanate (Aldrich) and iodine (EMD chemicals) were processed using the method described in Example 315A to afford the title compound. MS (ESI+) m/z 270 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[C:21]([CH3:24])[S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH:25]([C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]2)=[CH:29][CH:28]=1)=O.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CCO.CN(C=O)C.C(Cl)Cl.N>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[C:21]([CH3:24])[S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:25]([C:27]3[CH:28]=[CH:29][C:30]([N:33]4[CH2:34][CH2:35][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:37][CH2:38]4)=[CH:31][CH:32]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1nc(CN2CCN(c3c(Br)cnc(N)c3[N+](=O)[O-])CC2)cs1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)cc2)CC1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: ClCCl
Product: Cc1nc(CN2CCN(c3c(Br)cnc4[nH]c(-c5ccc(N6CCN(C(=O)OC(C)(C)C)CC6)cc5)nc34)CC2)cs1
Temperature: 85 °C
Yield: 43.9 %

Procedure:
To a mixture of 5-bromo-4-(4-((2-methylthiazol-4-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.062 g, 0.15 mmol) in EtOH (2.6 mL) and DMF (0.35 mL), tert-butyl 4-(4-formylphenyl)piperazine-1-carboxylate (0.044 g, 0.165 mmol) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.45 mL, 0.45 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v 96:4) to give the title compound as a off-white solid (0.043 g, 47%); 1H-NMR (500 Mz, DMSO-d6): δ 1.43 (s, 9H, C(CH3)3), 2.61-2.70 (m, 7H), 3.22-3.31 (m, 4H), 3.43-3.52 (m, 4H), 3.60-3.68 (m, 6H), 7.07 (d, J=9.0 Hz, 2H, ArH, C6H4), 7.32 (s, 1H, thiazole 5-H), 8.04 (d, J=8.5 Hz, 2H, ArH, C6H4), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.22 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z) 4.01 min—653/655 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 653.2022, calculated for C30H38BrN8O2S (M+H)+: 653.2019.
Reaction SMILES: [C:1]([N:8]([CH3:16])[C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:18][NH:19][O:20][CH3:21].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CCN(C(C)C)C(C)C.C(OCC)C>[CH3:21][O:20][N:19]([CH3:18])[C:13](=[O:15])[C@H:9]([CH:10]([CH3:11])[CH3:12])[N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH3:16]
Reactant: CC(C)[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 75.3 %

Procedure:
To a cold (0° C.) solution of N-Boc-N-methylvaline (11) (5.0 g, 21.6 mmol), N,O-dimethylhydroxylamine hydrochloride (2.8 g, 28 mmol), and PyBOP® (11.2 g, 22 mmol) in CH2Cl2 (22 mL) was added DIEA (8.4 mL, 75 mmol). After 1 min., the reaction mixture was warmed to room temperature and stirring was continued for 1 h. If the pH value of the mixture was less than 7, the mixture could be treated with a few drops DIEA to allow the reaction to go to completion. The mixture was poured into 200 mL of diethyl ether and the resultant mixture was washed successively with 3 N hydrochloric acid (3×30 mL), saturated aqueous sodium hydrogen carbonate solution (3×30 mL), and saturated aqueous sodium chloride (3×30 mL). The organic layer was dried with magnesium sulfate and the solvent was evaporated, followed by chromatography of the crude product (silica gel, 1:3 diethyl ether-pet. ether), afforded 12 (4.46 g, 75% yield) as a colourless oil. 1H-NMR (200 MHz, CDCl3): 0.84 (d, J=6.6 Hz, 4H, (CH3)2), 0.85 (d, J=6.6 Hz, 2H, (CH3)2), 1.41 (s, 6H, Boc-(CH3)3), 1.44 (s, 3H, Boc-(CH3)3), 2.15-2.30 (m, 1H, CH), 2.75 (s, 1H, NCH3), 2.78 (s, 2H, NCH3), 3.10 (bs, 3H, NCH3), 3.64 (s, 1H, OCH3), 3.68 (s, 2H, OCH3), 4.66 (d, J=10 Hz, 0.4H, CH), 4.95 (d, J=10 Hz, 0.6H, CH); Exact mass calc'd for C13H27N2O4 (M+H)+: 275.19708. Found (DCI): 275.19710. Optical rotation obtained was [α]25 +128.3 (c 2.9, CHCl3).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl.[NH2:27][C@@H:28]1[CH2:33][CH2:32][C@H:31]([OH:34])[CH2:30][CH2:29]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[NH3:16].[OH:34][C@@H:31]1[CH2:32][CH2:33][C@H:28]([NH:27][C:10](=[O:12])[C:9]2[CH:13]=[CH:14][CH:15]=[N:16][C:8]=2[O:7][C:6]2[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:18][CH:17]=2)[CH2:29][CH2:30]1
Reactant: N[C@H]1CC[C@@H](O)CC1
Reactant: CSc1ccc(Oc2ncccc2C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1ccc(Oc2ncccc2C(=O)N[C@H]2CC[C@@H](O)CC2)cc1
Product: N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-(4-Methylsulfanyl-phenoxy)-nicotinic acid (500 mg, 1.91 mmol) was dissolved in dimethylformamide (10 ml) and triethylamine (800 μl, 5.74 mmol) was added followed by cis-4-aminocyclohexanol hydrochloride (290 mg, 1.91 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (404 mg, 2.10 mmol) and 1-hydroxybenzotriazole (284 mg, 2.10 mmol). The reaction was stirred under nitrogen at room temperature for 18 h and the solvent was removed under reduced pressure. The residue was partitioned between sat. sodium bicarbonate solution (25 ml) and ethyl acetate (20 ml) and the aqueous phase was extracted with ethyl acetate (2×20 ml). The combined organic extracts were washed with water (10 ml), brine (10 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol:concentrated aqueous ammonia (97.5:2.5:0.25 changing to 97:3:0.3, by volume) to give N-(cis-4-hydroxy-cyclohexyl)-2-(4-methylsulfanyl-phenoxy)-nicotinamide (620 mg) as a white solid.
Reaction SMILES: Cl.[OH:2][CH:3]1[CH2:8][NH:7][CH2:6][C:5]2[S:9][CH:10]=[CH:11][C:4]1=2.C(=O)([O-])[O-].[K+].[K+].[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)(Cl)Cl>[OH:2][CH:3]1[CH2:8][N:7]([S:19]([CH3:18])(=[O:21])=[O:20])[CH2:6][C:5]2[S:9][CH:10]=[CH:11][C:4]1=2
Reactant: CS(=O)(=O)Cl
Reactant: OC1CNCc2sccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)N1Cc2sccc2C(O)C1
Reaction time: 2 h
Yield: 76 %

Procedure:
To a mixture of 4-hydroxy-4,5,6,7-tetrahydro-thieno-[2,3-c]pyridine hydrochloride (50 g; 0.26 mole), chloroform (200 ml) and saturated aqueous potassium carbonate solution (100 ml) is added dropwise a solution of methanesulfonyl chloride (30 g; 0.26 mole) in chloroform (50 ml), at room temperature and with vigorous mechanical stirring. Stirring is continued a further 2 hours at room temperature. After decantation, the chloroform phase is washed with dilute hydrochloric acid, then with water, and is dried over anhydrous sodium sulfate. Evaporation of the solvent, in vacuo, leaves crystals which are recrystallized from methanol. Light brown crystals; M.p.=140° C. (methanol); Yield: 76%.