Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].O[N:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14](=[O:21])[N:13]([CH3:22])[CH:12]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:11]1=[NH:29]>O.C(O)C>[NH2:29][C:11]1[CH:12]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:13]([CH3:22])[C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:10]=1
Reactant: CN1C(=O)c2ccccc2N(O)C(=N)C1c1ccccc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CN1C(=O)c2ccccc2N=C(N)C1c1ccccc1

Procedure:
A slow stream of a solution of 23.00 g (0.132 m) of sodium dithionite in 300 ml of water is added to a stirred solution of 16.87 g (0.06 m) of 1-hydroxy-2-imino-4-methyl-3-phenyl-1,2,3,4-tetrahydro-5H-1,4-benzodiazepine-5-one in 700 ml of ethanol. The reaction mixture is refluxed for 2 hours and then concentrated in vacuo, to about 200 ml. The resulting solution is extracted once with chloroform. Some solid crude product, formed during this extraction, is filtered off. The aqueous layer is made basic and extracted with chloroform. The organic solutions are combined, dried and concentrated to dryness in vacuo to give additional solid product. The solids are combined and recrystallized twice from ethanol/ether (the solution is filtered while hot to clarify) to give the pure product, 2-amino-3,4-dihydro-4-methyl-3-phenyl-5H-1,4-benzodiazepine-5-one m.p. 282° - 286° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([O:7][CH2:8][CH:9]=O)=[CH:5][CH:4]=1.N1CCC[C@@H]1C(O)=O.ClN1C(=O)CCC1=O.[Br:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[N:41]=[N:40][C:39]([NH2:42])=[N:38][CH:37]=2)=[CH:32][C:31]=1[F:43]>C(Cl)(Cl)Cl>[Br:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:37]=[N:38][C:39]3[N:40]([C:8]([O:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=4)=[CH:9][N:42]=3)[N:41]=2)=[CH:32][C:31]=1[F:43]
Reactant: Nc1ncc(-c2ccc(Br)c(F)c2)nn1
Reactant: COc1ccc(OCC=O)cc1
Agent: O=C(O)[C@H]1CCCN1
Agent: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc(Oc2cnc3ncc(-c4ccc(Br)c(F)c4)nn23)cc1
Temperature: 25 °C

Procedure:
To a cooled (0° C.) mixture of (4-methoxyphenoxy)acetaldehyde (33.2 mg, 0.2 mmol) and D-proline (4.6 mg, 0.04 mmol) in chloroform (1.0 mL) was added N-chlorosuccinimide (26.7 mg, 0.2 mmol) with stirring. The mixture was stirred at 0° C. for 30 min, then gradually warmed to ambient temperature for 2 h. To the reaction mixture was added 6-(4-bromo-3-fluorophenyl)-1,2,4-triazin-3-amine (26.9 mg, 0.1 mmol). The reaction mixture was stirred for 1 h and then the solvent was removed under reduced pressure. The residue was dissolved in isopropanol (2 mL) and heated to 100° C. overnight. After cooling, the mixture was filtered and the filtrate was purified by RP-HPLC (pH 10) to afford the desired product. LCMS: (M+H)=415.0/416.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[N:16][N:15]=[N:14]2)=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].[OH-].[Na+].O>CO.O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[N:16][N:15]=[N:14]2)=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(-n2cnnn2)ccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(-n2cnnn2)cc1C(=O)O
Reaction time: 4 h

Procedure:
Combine methyl 2-methoxy-5-(1H-tetrazol-1-yl)benzoate (2.86 g, 12.2 mmol) and a 1 M aqueous solution of sodium hydroxide (13.43 mL, 13.43 mmol) in methanol/water 100 mL, 5:1 vol./vol.). Heat to reflux. After 4 hours. concentrate in vacuo to remove most of the methanol, add water (50 mL), and adjust the pH to about 4 using a 1 M aqueous hydrochloric acid solution. Evaporate in vacuo to give a solid, slurry the solid with water, filter, and dry to give 2-methoxy-5-(1H-tetrazol-1-yl)benzoic acid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([CH3:11])([CH2:9]O)[C:5]([O:7][CH3:8])=[O:6].S(Cl)([Cl:14])=O.N1C=CC=CC=1>>[CH3:1][O:2][CH2:3][C:4]([CH3:11])([CH2:9][Cl:14])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COCC(C)(CO)C(=O)OC
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Product: COCC(C)(CCl)C(=O)OC
Temperature: 60 °C
Yield: 91 %

Procedure:
The methyl 2-methoxymethyl-2-methyl-3-hydroxypropionate was added at from 15° to 20° C. to 438 g (3.68 mol) of thionyl chloride, the temperature was then raised to 60° C. and the mixture was stirred until the evolution of gas had ended. Excess thionyl chloride was distilled off, 0.2 g (0.0025 mol) of pyridine was added to the residue, and the temperature was raised to 135° C. After the evolution of SO2 had ended, distillation gave 317.0 g (1.76 mol) of methyl 2-methoxymethyl-2-methyl-3chloropropionate of boiling point 94° C. 35 mbar, corresponding to a 91% yield, based on methyl 2-methoxymethyl-2-methyl-3-hydroxypropionate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].Cl.C[O:26][C:27](=[O:52])[CH:28]([NH:41][C:42](=[O:51])[C:43]1[C:48]([Cl:49])=[CH:47][CH:46]=[CH:45][C:44]=1[Cl:50])[CH2:29][C:30]1[O:34][N:33]=[C:32]([CH:35]([NH2:40])[CH2:36][CH:37]([CH3:39])[CH3:38])[CH:31]=1>>[Cl:50][C:44]1[CH:45]=[CH:46][CH:47]=[C:48]([Cl:49])[C:43]=1[C:42]([NH:41][CH:28]([CH2:29][C:30]1[O:34][N:33]=[C:32]([CH:35]([NH:40][C:21](=[O:23])[CH2:20][C:5]2[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:36][CH:37]([CH3:39])[CH3:38])[CH:31]=1)[C:27]([OH:52])=[O:26])=[O:51]
Reactant: COC(=O)C(Cc1cc(C(N)CC(C)C)no1)NC(=O)c1c(Cl)cccc1Cl
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Agent: Cl
Product: COc1cc(CC(=O)NC(CC(C)C)c2cc(CC(NC(=O)c3c(Cl)cccc3Cl)C(=O)O)on2)ccc1NC(=O)Nc1ccccc1C
Yield: 51 %

Procedure:
The title compound was prepared in the manner described in example 2B using 3-methoxy-4-(3-o-tolyl-ureido)-phenylacetic acid and 3-[3-(1-amino-3-methyl-butyl)-isoxazol-5-yl]-2-(2,6-dichloro-benzoylamino)-propionic acid methyl ester hydrochloride. 51% yield; white solid. MS (m/z) 724.2 and 726.2 (M+1). C. 3-[3-(1-Amino-3-methyl-butyl)-isoxazol-5-yl]-2-(2,6-dichloro-benzoylamino)-propionic acid methyl ester hydrochloride
Reaction SMILES: [C:1]1([CH3:10])[C:2]([N:7]=[C:8]=[O:9])=[CH:3][CH:4]=[CH:5][CH:6]=1.Cl.[NH2:12][CH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[C:16](=[O:32])[N:17]([CH:24]1[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:25]1=[O:31])[C:18]2=[O:23].C(N(CC)CC)C>C1COCC1>[O:31]=[C:25]1[CH:24]([N:17]2[C:16](=[O:32])[C:15]3[C:19](=[CH:20][CH:21]=[CH:22][C:14]=3[CH2:13][NH:12][C:8]([NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[CH3:10])=[O:9])[C:18]2=[O:23])[CH2:29][CH2:28][C:27](=[O:30])[NH:26]1
Reactant: Cc1ccccc1N=C=O
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccccc1NC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 72.4 %

Procedure:
o-Tolyl isocyanate (0.4 g, 3.0 mmol) was added to a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.8 g, 2.3 mmol) and triethylamine (0.3 g, 3.2 mmol) in THF (40 mL) at 5° C. After stirring for 10 minutes at 5° C., the mixture was warmed to room temperature and stirred overnight. The mixture was concentrated, and the residue was stirred with 1N HCl (30 mL) for 30 minutes. The solid was collected and slurried with hot acetone (15 mL) to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-o-tolyl-urea (0.7 g, 72%) as a white solid: mp>260° C.; 1H NMR (DMSO-d6) δ 2.05-2.09 (m, 1H), 2.19 (s, 3H), 2.49-2.65 (m, 2H), 2.84-2.98 (m, 1H), 4.73 (d, J=5.9 Hz, 2H), 5.13-5.20 (dd, J=5.4 and 12.7 Hz, 1H), 6.85-7.19 (m, 4H), 7.77-7.92 (m, 5H), 11.15 (s, 1H); 13C NMR (DMSO-d6) δ 13.90, 17.99, 26.93, 34.68, 44.86, 116.73, 117.88, 118.14, 122.03, 123.05, 123.18, 126.06, 127.61, 129.69, 130.75, 133.93, '36.25, 151.47, 163.00, 163.56, 165.83, 168.76; Anal. calcd. for C22H20N4O5: C, 62.85; H, 4.79; N, 13.33. Found: C, 62.76; H, 4.75; N, 13.12.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[CH:21]1([NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Br)(=[O:27])=[O:26])[CH2:23][CH2:22]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:21]1([NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:12]2[CH2:11][CH2:10][N:9]([CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:14][CH2:13]2)(=[O:27])=[O:26])[CH2:23][CH2:22]1
Reactant: Clc1cccc(C(c2ccccc2)N2CCNCC2)c1
Reactant: O=S(=O)(CCCCCCBr)NC1CC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=S(=O)(CCCCCCN1CCN(C(c2ccccc2)c2cccc(Cl)c2)CC1)NC1CC1
Yield: 67 %

Procedure:
1-[(3-Chlorophenyl)phenylmethyl]piperazine (435.2 mg, 1.52 mmol) and N-cyclopropyl-6-bromohexanesulfonamide (474.5 mg, 1.67 mmol) were refluxed in toluene (15 ml) in the presence of triethylamine (169 mg, 1.67 mmol) for 42 hours. The reaction mixture was washed with water, and the organic layer was dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (20:1), to give N-cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulfonamide (499.0 mg) as an oil (yield based on 1-[(3-chlorophenyl)phenylmethyl]piperazine: 67.1%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([OH:6])=O.S(Cl)(Cl)=O.[NH2:11][C:12]1[C:13]([I:26])=[C:14]([C:23]([Cl:25])=[O:24])[C:15]([I:22])=[C:16]([C:20]=1[I:21])[C:17]([Cl:19])=[O:18]>CN(C=O)C>[CH3:1][O:2][CH2:3][C:4]([NH:11][C:12]1[C:20]([I:21])=[C:16]([C:17]([Cl:19])=[O:18])[C:15]([I:22])=[C:14]([C:13]=1[I:26])[C:23]([Cl:25])=[O:24])=[O:6]
Reactant: Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Reactant: COCC(=O)O
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COCC(=O)Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Temperature: 10 °C
Reaction time: 1 h

Procedure:
121.2 g. (1.6 mole) of methoxyacetic acid is dissolved in 400 ml. of dry DMF, cooled to 0° C., and within 60 minutes 116 ml. (1.6 mol) of thionyl chloride is added dropwise thereto. The mixture is stirred for 30 minutes at 10° C. and 138.3 g. (0.4 mol) of 5-amino-2,4,6-triiodoisophthalic acid dichloride is introduced into the reaction mixture and the latter is stirred for 20 hours at room temperature. The reaction solution is stirred into 10 l. of water, the precipitate is vacuum-filtered, washed with water, again stirred with water, vacuum-filtered, and dried at 50° C. under vacuum. Yield: 198 g. (0.296 mol)=74% of theory.
Reaction SMILES: [H-].[Na+].[C:3]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)(=[O:5])[CH3:4].[CH2:15](Br)[CH:16]=[CH2:17].O>CN(C=O)C>[C:3]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][CH2:17][CH:16]=[CH2:15])=[O:11])=[CH:8][CH:7]=1)(=[O:5])[CH3:4]
Reactant: C=CCBr
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1ccc(C(C)=O)cc1
Temperature: 25 °C

Procedure:
1.65 g (55 mmol) of sodium hydride (80% in oil) and 50 ml of DMF are introduced under a stream of nitrogen into a round-bottomed flask. 8.2 g (50 mmol) of 4-acetylbenzoic acid, dissolved in 100 ml of DMF, are added dropwise and the mixture is stirred at room temperature until gaseous evolution has ceased. 4.6 ml (55 mmol) of allyl bromide are then introduced and the mixture is stirred at room temperature for 24 hours. The reaction medium is poured into water, the mixture is extracted with ethyl ether and the organic phase is separated after settling has taken place, then dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column, eluting with a mixture of dichloromethane and hexane (80:20). After evaporation of the solvents, 7.2 g (71%) of allyl ester are collected in the form of a colorless oil.
Reaction SMILES: [CH:1](=O)[CH3:2].C(O)(=O)C.[NH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15](=[O:39])[C@@H:16]([N:18]2[CH2:22][CH2:21][C@H:20]([NH:23][S:24]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[C:32]([Cl:37])[CH:33]=4)[CH:28]=3)(=[O:26])=[O:25])[C:19]2=[O:38])[CH3:17])[CH2:10]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C([N+](CC)(CC)CC)C>C(Cl)Cl>[Cl:37][C:32]1[CH:33]=[C:34]2[C:29](=[CH:30][CH:31]=1)[CH:28]=[C:27]([S:24]([NH:23][C@H:20]1[CH2:21][CH2:22][N:18]([C@@H:16]([CH3:17])[C:15]([N:11]3[CH2:12][CH2:13][CH2:14][CH:9]([NH:8][CH2:1][CH3:2])[CH2:10]3)=[O:39])[C:19]1=[O:38])(=[O:26])=[O:25])[CH:36]=[CH:35]2
Reactant: C[C@@H](C(=O)N1CCCC(N)C1)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC[N+](CC)(CC)CC
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCNC1CCCN(C(=O)[C@H](C)N2CC[C@H](NS(=O)(=O)c3ccc4cc(Cl)ccc4c3)C2=O)C1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a solution of acetaldehyde (0.041 ml from a stock solution made up from 0.0127 l acetaldehyde dissolved in 1 ml DCM)) in dry DCM (0.4 ml) treated with acetic acid (0.1 ml from a stock solution made up from 0.0054 ml acetic acid dissolved in 1 ml DCM) was added N-{(3S)-1-[(1S)-2-(3-aminopiperidin-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl }-6-chloronaphthalene-2-sulfonamide [Example 365] (0.045 g) followed by tetraethylammonium triacetoxyborohydride (0.005 g). The mixture was stirred at room temperature, under nitrogen, for 60 h. DCM (1 ml) was added and the resultant solution washed with saturated sodium bicarbonate (1 ml) in a hydrophobic frit. The solvent was concentrated under reduced pressure and the residue purified by mass directed preparative h.p.l.c. to give the title compound (0.8 mg) as an oil.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH2:15]([O:22][C:23]1[C:28]2[C:29]([OH:32])=[N:30][O:31][C:27]=2[CH:26]=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O[CH2:34][CH2:35][CH:36]1[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:15]([O:22][C:23]1[C:28]2[C:29]([O:32][CH2:34][CH2:35][CH:36]3[CH2:37][CH2:38][N:39]([C:42]([O:44][C:45]([CH3:46])([CH3:48])[CH3:47])=[O:43])[CH2:40][CH2:41]3)=[N:30][O:31][C:27]=2[CH:26]=[CH:25][CH:24]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Oc1noc2cccc(OCc3ccccc3)c12
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(CCOc2noc3cccc(OCc4ccccc4)c23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.3 %

Procedure:
Diisopropyl azodicarboxylate (3.2 mL, 17 mmol) was added to a mixture of 4-(benzyloxy)-1,2-benzisoxazol-3-ol (2.7 g, 11 mmol, EXAMPLE 7, Step 1), tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (3.1 g, 14 mmol), and triphenylphosphine (4.3 g, 17 mmol) in toluene (11 mL) at 0° C. The mixture was stirred at room temperature for 16 h, and concentrated in vacuo to give a yellow oil. The residual oil was purified by silica gel column chromatography (hexane/ethyl acetate 4:1) to give 3.8 g (76%) of the title compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.C(N(CC)CC)C.[NH:17]1[CH:26]2[CH:21]([CH2:22][CH2:23][CH2:24][CH2:25]2)[CH2:20][CH2:19][CH2:18]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([N:17]2[C@@H:26]3[C@@H:21]([CH2:22][CH2:23][CH2:24][CH2:25]3)[CH2:20][CH2:19][CH2:18]2)=[O:9])[CH:3]=1
Reactant: O=C(O)c1csc(Br)c1
Reactant: C1CCC2NCCCC2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(c1csc(Br)c1)N1CCC[C@@H]2CCCC[C@@H]21
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.5 %

Procedure:
5-Bromothiophene-3-carboxylic acid (0.5 g, 2.4 mmol) was dissolved in acetonitrile (10 mL) and triethylamine (7.1 mmol). Decahydroquinoline (3:2 mixture of cis- and trans-isomers; 4.8 mmol) and HATU (2.4 mmol) were added and the reaction stirred at room temperature overnight. The solvent was evaporated and the residue dissolved in DCM and washed with water. After drying with anhydrous magnesium sulphate, the solution was filtered and evaporated and the residue purified by flash chromatography on silica, eluting with 0-40% ethyl acetate in cyclohexane. The fractions containing the desired product were combined and evaporated to give the title compound as a white crystalline solid (0.39 g). LCMS m/z 330.11 [M+H]+ RT=4.07 min (Analytical Method 4).
Reaction SMILES: S(C)C.[CH3:4][C:5]1[N:6]=[C:7]([NH:10][C:11]2[N:16]=[CH:15][C:14]([S:17][CH:18]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[CH:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)=[CH:13][C:12]=2[O:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[S:8][CH:9]=1.[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48]>>[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].[CH3:4][C:5]1[N:6]=[C:7]([NH:10][C:11]2[C:12]([O:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[CH:13][C:14]([S:17][CH:18]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)=[CH:15][N:16]=2)[S:8][CH:9]=1
Reactant: Cc1csc(Nc2ncc(SC(c3ccccn3)C3CCN(C(=O)OC(C)(C)C)CC3)cc2Oc2ccccc2)n1
Solvent: CSC
Solvent: O=C(O)C(F)(F)F
Product: Cc1csc(Nc2ncc(SC(c3ccccn3)C3CCNCC3)cc2Oc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Placed Me2S (0.0072 g, 0.12 mmol) in Trifluoroacetic acid (10 mL) followed by tert-butyl 4-((6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)(pyridin-2-yl)methyl)piperidine-1-carboxylate (0.068 g, 0.12 mmol) stirred at ambient temperature for 30 minutes, then concentrated to give the title compound (0.086 g, 90% yield). 1H NMR (d6-DMSO) δ 8.52 (bs, 1H), 8.42 (m, 1H), 8.17 (bs, 1H), 8.00 (d, 1H), 7.70 (dt, 1H), 7.41 (t, 2H), 7.25-7.16 (m, 3H), 6.92 (d, 2H), 6.90 (s, 1H), 6.63 (s, 1H), 4.22 (d, 1H), 3.32 (d, 1H), 3.17 (d, 1H), 2.98-2.74 (m, 2H), 2.30 (m, 2H), 2.23 (s, 3H), 1.45 (m, 2H), 1.30 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[C:16]([O:20][CH3:21])(=[O:19])[CH2:17][SH:18]>CN(C=O)C.O>[NH2:9][C:8]1[C:3]2=[N:4][CH:5]=[CH:6][CH:7]=[C:2]2[S:18][C:17]=1[C:16]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)CS
Reactant: N#Cc1ncccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1sc2cccnc2c1N
Temperature: 40 °C
Reaction time: 3 h

Procedure:
To a mixture of 3-chloropyridine-2-carbonitrile (C-1) (1.01 g, 7.29 mmol) and K2CO3 (1.10 g, 7.96 mmol) in DMF (10 mL) and water (1 mL) was added methyl thioglycolate (0.709 mL, 7.93 mmol) dropwise. The reaction mixture was stirred at 40° C. for 3 h. The mixture was quenched with cold water (70 mL) and placed on ice to enhance precipitation. The precipitate was collected by filtration to afford the title compound. MS (m/z): 209 (M+1)+.
Reaction SMILES: [CH:1]1([C@H:7]2[C:12]3[NH:13][C:14]4[C:19]([C:11]=3[CH2:10][C@H:9]([C:20](OC)=[O:21])[NH:8]2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:24]([N:31]=[C:32]=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([N:31]1[C:20](=[O:21])[C@H:9]2[N:8]([C@@H:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:12]3[NH:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:11]=3[CH2:10]2)[C:32]1=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)[C@H]1Cc2c([nH]c3ccccc23)[C@H](C2CCCCC2)N1
Reactant: O=C=NCc1ccccc1
Product: O=C1[C@@H]2Cc3c([nH]c4ccccc34)[C@H](C3CCCCC3)N2C(=O)N1Cc1ccccc1

Procedure:
The same method as employed in the preparation of Example 1 but starting from trans methyl 1,2,3,4-tetrahydro-1-cyclohexyl-9H-pyrido[3,4-b]indole-3-carboxylate (see J. Cook et al., Heterocycles, 4(7), 1249-1255 (1976)) and benzyl isocyanate gave after recrystallization from methanol, the title compound as white crystals m.p.: 130-135° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.[Cl:13][C:14]1[CH:19]=[C:18]([S:20]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)(=[O:22])=[O:21])[CH:17]=[CH:16][C:15]=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([O:8][C:15]2[CH:16]=[CH:17][C:18]([S:20]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)(=[O:21])=[O:22])=[CH:19][C:14]=2[Cl:13])[CH:7]=1
Reactant: O=C(O)Cc1cc(O)cc(Cl)c1
Reactant: O=S(=O)(Cc1ccc(F)cc1)c1ccc(F)c(Cl)c1
Product: O=C(O)Cc1cc(Cl)cc(Oc2ccc(S(=O)(=O)Cc3ccc(F)cc3)cc2Cl)c1

Procedure:
The title compound was prepared as described in example 2 step (iii) but instead using the product from example 18 step (iv) and the product from step (i).
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:11][OH:12])[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][OH:10])[CH:4]=1.[CH2:13]([O:29][CH2:30][CH:31]([O:34][CH3:35])[CH2:32]O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].O>CN(C)C=O>[CH2:13]([O:29][CH2:30][CH:31]([O:34][CH3:35])[CH2:32][O:10][CH2:9][C:5]1[CH:4]=[C:3]([CH2:11][OH:12])[CH:8]=[CH:7][CH:6]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCCCCOCC(CO)OC
Reactant: OCc1cccc(CO)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCOCC(COCc1cccc(CO)c1)OC
Reaction time: 18 h

Procedure:
To a suspension of 2.8 g of sodium hydride in 25 ml of dimethylformamide was added at 0° C. over 30 minutes a solution of 1,3-benzenedimethanol in 75 ml of dimethylformamide. After 30 minutes a solution of 3-(hexadecyloxy)-2-methoxy-1-propanol, 4-methyl benzene sulfonate in 25 ml of dinethylformamide was added over 30 minutes. After stirring 18 hours the mixture was poured into water and extracted with ethylacetate. The solution was dried and the product was purified by chromatography giving 4.7 g.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].C(N(CC)CC)C.[Br:15][CH2:16][C:17](Cl)=[O:18]>C(OCC)C>[Br:15][CH2:16][C:17]([N:4]([CH2:5][CH2:6][CH3:7])[CH2:1][CH2:2][CH3:3])=[O:18]
Reactant: CCCNCCC
Reactant: O=C(Cl)CBr
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCN(CCC)C(=O)CBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
To a mixture of dipropylamine (10.1 g), triethylamine (10.1 g) and anhydrous diethyl ether (80 ml) is added dropwise a solution of bromoacetyl chloride (15.8 g) in anhydrous diethyl ether (40 ml) while the temperature of the mixture is kept at -40° C. After addition, the temperature is gradually raised, and the mixture is stirred at room temperature for one hour. The reaction mixture is filtered, and the filtrate is concentrated under reduced pressure, and purified by distillation under reduced pressure to give the desired compound (14 g), b.p. 100-103° C./1 mmHg.