Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:25][C:26]4[CH2:27][NH:28][CH2:29][CH2:30][C:31]=4[N:32]=3)=[O:23])[CH2:18][CH2:17]1)(=[O:15])=[O:14])[CH:7]=[CH:6]2.C(N(CC)CC)C.ClC([O:43][CH2:44][CH3:45])=O.[BH4-].[Na+]>O1CCCC1.O>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:17][CH2:18][N:19]([C:22]([C:24]3[S:25][C:26]4[CH2:27][NH:28][CH:29]([CH2:45][CH2:44][OH:43])[CH2:30][C:31]=4[N:32]=3)=[O:23])[CH2:20][CH2:21]1)(=[O:14])=[O:15])[CH:7]=[CH:6]2
Reactant: CCOC(=O)Cl
Reactant: O=C(c1nc2c(s1)CNCC2)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=C(c1nc2c(s1)CNC(CCO)C2)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33 %

Procedure:
The crude product, which had been obtained by the reaction in the same manner as in Example B-32 by using 1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine hydrochloride (132 mg) and glyoxylic hydrate (82 mg) as starting materials, was suspended in tetrahydrofuran (50 ml). Triethylamine (0.22 ml) and ethyl chloroformate (0.03 ml) were added to the resulting suspension under ice cooling, followed by stirring at room temperature for 15 minutes. To the reaction mixture, sodium borohydride (50 mg) and water (10 ml) were added to the reaction mixture and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane, washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (dichloromethane˜dichloromethane:methanol 100:3), followed by dissolution in saturated hydrochloride in ethanol (1 ml). The resulting solution was then concentrated under reduced pressure. The concentrate was pulverized and washed in ethyl acetate, whereby the title compound (52 mg, 33%) was obtained.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].Br[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=1>>[OH:4][CH2:3][CH2:2][N:1]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=1)[CH2:5][CH2:6][OH:7]
Reactant: OCCNCCO
Reactant: N#Cc1ccc(CBr)cc1
Product: N#Cc1ccc(CN(CCO)CCO)cc1

Procedure:
4-{[Bis-(2-hydroxyethyl)-amino]-methyl}benzonitrile was prepared according to the general method as outlined in Example 1 (Step 4) starting from diethanolamine (10.2 g, 97 mmol) and α-bromo-p-tolunitrile (15.8 g, 81 mmol). Yield, (68%); white solid; mp 163° C. MS: 221.2 (M+H)+
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:11][N:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:20][C:21]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[CH:24][C:22]=1[NH2:23]>>[CH3:20][C:21]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[CH:24][C:22]=1[NH:23][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:11][N:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccc(Nc2cc(-c3ccccc3)on2)n1
Reactant: COc1cc(C)c(N)cc1OC
Product: COc1cc(C)c(Nc2nccc(Nc3cc(-c4ccccc4)on3)n2)cc1OC

Procedure:
The title compound was prepared by the method described in Example 1 using 2-chloro-N4-(5-phenylisoxazol-3-yl)-4-pyrimidineamine and 2-methyl-4,5-dimethoxyaniline.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH:5]([C:7]1[NH:8][CH:9]=[CH:10][CH:11]=1)O.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH2:5][C:7]1[NH:8][CH:9]=[CH:10][CH:11]=1
Reactant: Nc1cccc(C(O)c2ccc[nH]2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1cccc(Cc2ccc[nH]2)c1
Temperature: -5 °C
Reaction time: 9.5 h

Procedure:
A 2-(3'-amino-α-hydroxybenzyl)pyrrole is dissolved in an inert organic solvent (such as a lower alkanol, preferably methanol), cooled to about -20° to 10° C., preferably -5° C., and treated with a molar excess of a reducing agent (such as sodium cyanoborohydride in glacial acetic acid). The reaction mixture is allowed to warm to about ambient temperature and is stirred for a period of about 0.5 to 36 hours, preferably 1 to 18 hours, and most preferably about 2 hours. The reaction is then quenched (e.g., with saturated sodium carbonate) and extracted with ethyl acetate. The extract is washed with water, dried and evaporated in vacuo, and then purified, e.g., by column chromatography over slica gel, to obtain the 2-(3'-aminobenzyl)pyrrole of Formula 11.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH2:15])[CH:9]=1.[NH:16]1[C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([NH2:25])[C:19]=2[CH:18]=[N:17]1.CCO>C([O-])(O)=O.[Na+]>[NH2:15][C:10]1[N:11]=[C:12]([CH3:14])[N:13]=[C:8]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:2]=2[NH:25][C:20]2[C:19]3[CH:18]=[N:17][NH:16][C:24]=3[CH:23]=[CH:22][CH:21]=2)[CH:9]=1
Reactant: Cc1nc(N)cc(-c2cnccc2Cl)n1
Reactant: Nc1cccc2[nH]ncc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1nc(N)cc(-c2cnccc2Nc2cccc3[nH]ncc23)n1
Temperature: 160 °C
Yield: 44.1 %

Procedure:
A glass microwave reaction vessel was charged with 6-(4-chloropyridin-3-yl)-2-methylpyrimidin-4-amine (22 mg, 100 μmol), 1H-indazol-4-amine (27 mg, 199 μmol, Bionet) and EtOH (1 mL). The reaction mixture was stirred and heated in a Smith Synthesizer® microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) at 160° C. for 30 min. The reaction mixture was diluted with saturated NaHCO3 (2 mL) and extracted with EtOAc (3×20 mL). The organic extract was washed with saturated NaCl (2 mL), dried over Na2SO4, filtered, concentrated and the residue was purified by silica gel chromatography, eluting with 10% MeOH/CH2Cl2/1% NH4OH to give N-(3-(6-amino-2-methylpyrimidin-4-yl)pyridin-4-yl)-1H-indazol-4-amine (14 mg, 44% yield). 1H NMR (300 MHz, CD3OD) δ 8.71 (s, 1H); 8.19 (d, J=6.14 Hz, 1H); 7.34-7.53 (m, 2H); 7.29 (d, J=7.02 Hz, 1H); 7.18 (d, J=6.28 Hz, 1H); 6.90 (s, 1H); 2.59 (s, 3H). m/z (ESI, +ve ion) 318 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.S(Cl)(Cl)=O.[NH2:16][C:17]1[N:22]=[C:21]([C:23]2[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=2)[C:20]([C:35]#[N:36])=[CH:19][N:18]=1.N1C=CC=CC=1>ClCCl>[C:35]([C:20]1[C:21]([C:23]2[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=2)=[N:22][C:17]([NH:16][C:9](=[O:11])[CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[I:1])=[N:18][CH:19]=1)#[N:36]
Reactant: O=C(O)Cc1ccccc1I
Reactant: COc1cc(-c2nc(N)ncc2C#N)cc(OC)c1OC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(-c2nc(NC(=O)Cc3ccccc3I)ncc2C#N)cc(OC)c1OC

Procedure:
From 2-iodophenylacetic acid, thionyl chloride and N,N-in dichloromethane. Then treatment with 2-amino-5-cyano-4-(3,4,5-trimethoxyphenyl)pyrimidine and pyridine in dichloromethane. ES-MS m/e (%): 553 (M+Na+, 15), 531 (M+H+, 100).
Reaction SMILES: O.[Cl:2][C:3]([Cl:8])([Cl:7])[CH:4]([OH:6])[OH:5].[CH2:9](O)[CH2:10][CH2:11][CH3:12].[CH3:14][C:15]1C=CC(S(O)(=O)=O)=[CH:17][CH:16]=1>C1C=CC=CC=1>[CH2:9]([O:5][CH:4]([O:6][CH2:14][CH2:15][CH2:16][CH3:17])[C:3]([Cl:8])([Cl:7])[Cl:2])[CH2:10][CH2:11][CH3:12]
Reactant: CCCCO
Reactant: OC(O)C(Cl)(Cl)Cl
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCCCOC(OCCCC)C(Cl)(Cl)Cl
Reaction time: 10 h

Procedure:
Into an apparatus supplied with a Dean-Stark water separator 7 g of chloral hydrate, 10 g of butyl alcohol, 0.1 g of 4-methyl-benzene-sulphonic acid and 50 ml of benzene are weighed. The mixture is heated on a water-bath and the water separation is continued for 10 hours. The benzene is washed with water and sodium hydrogen carbonate, then distilled off and the product is vacuum distilled.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][CH:7]=1.C([Li])CCC.CN(C)[CH:22]=[O:23].[BH4-].[Na+]>O.CO.C(OCC)C>[O:8]([C:5]1[N:6]=[CH:7][C:2]([CH2:22][OH:23])=[CH:3][CH:4]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc(Oc2ccccc2)nc1
Agent: [BH4-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CO
Product: OCc1ccc(Oc2ccccc2)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 356.9 %

Procedure:
To a diethyl ether (30.0 mL) solution of 5-bromo-2-phenoxy-pyridine (1.02 g, 4.08 mmol) described in Manufacturing Example 40-1-1 was added dropwise n-butyl lithium (2.55 M n-hexane solution, 1.92 mL, 4.90 mmol) on a dry ice-ethanol bath (−78° C.) under nitrogen atmosphere, which was stirred for 30 minutes at −78° C. Thereafter, N,N-dimethylformamide (378 μL, 4.90 mmol) was added dropwise, which was stirred for 10 minutes at −78° C. Then, sodium borohydride (309 mg, 8.16 mmol) and methanol (15.0 mL) were added, which was stirred for 20 minutes at room temperature. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:1) to obtain the title compound (2.93 g, 66.5%).
Reaction SMILES: [CH2:1](O[CH:4](OCC)[CH:5]([Cl:7])[Cl:6])C.[CH2:11]([SH:15])[CH2:12][CH2:13][SH:14]>C1C=CC=CC=1>[Cl:7][CH:5]([Cl:6])[CH:4]1[S:15][CH2:11][CH2:12][CH2:13][S:14]1.[S:14]1[CH2:13][CH2:12][CH2:11][S:15][CH2:1]1
Reactant: SCCCS
Reactant: CCOC(OCC)C(Cl)Cl
Solvent: c1ccccc1
Product: C1CSCSC1
Product: ClC(Cl)C1SCCCS1
Yield: 126.4 %

Procedure:
In 100 ml of benzene, 9.4 g of dichloroacetaldehyde diethylacetal was reacted with 5.4 g of propane-1,3-dithiol. After distilling off the benzene/ethanol azeotrope at 68° C., there was obtained a yield of 10.2 g of the title compound, nD30 1.5850. The structure was supported by analytical data.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]#[N:10])[CH:5]=[N:6][C:7]=1Cl.[CH3:11][S-:12].[Na+]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]#[N:10])[C:5]([S:12][CH3:11])=[N:6][CH:7]=1
Reactant: C[S-]
Reactant: N#Cc1cnc(Cl)c(Cl)c1
Agent: [Na+]
Solvent: CS(C)=O
Product: CSc1ncc(Cl)cc1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.4 %

Procedure:
5,6-Dichloro-3-pyridinecarbonitrile (1.73 g, 0.01 mol) was dissolved with stirring in dimethyl sulphoxide (25 mL) and sodium methanethiolate (0.77 g, 0.011 mol) added. The reaction mixture was stirred at room temperature for two hours and poured onto ice (100 g). The mixture was extracted with dichloromethane (50 mL), and the organic extract washed with water (100 mL), and brine, and dried over anhydrous sodium sulphate. Evaporation of the solvent under reduced pressure and recrystallisation of the residue from ethyl acetate:hexane gave the desired product (1.3 g, 71%) as a cream solid, MP 147-9° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]3[CH2:16][NH:15][CH2:14][CH2:13][N:12]3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:8][CH:9]=2)[CH:4]=[N:3]1.Br[C:25]1[S:26][C:27]2[C:33]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)=[C:32]([C@H:41]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[C:42]([O:44][CH2:45][CH3:46])=[O:43])[C:31]([CH3:52])=[CH:30][C:28]=2[N:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:48]([O:47][C@@H:41]([C:32]1[C:31]([CH3:52])=[CH:30][C:28]2[N:29]=[C:25]([N:15]3[CH2:14][CH2:13][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:11]([C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:2]([CH3:1])[N:3]=[CH:4]5)[CH2:16]3)[S:26][C:27]=2[C:33]=1[C:34]1[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=1)[C:42]([O:44][CH2:45][CH3:46])=[O:43])([CH3:49])([CH3:50])[CH3:51]
Reactant: Cn1ncc2cc(C3CNCCN3C(=O)OC(C)(C)C)ccc21
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(N3CCN(C(=O)OC(C)(C)C)C(c4ccc5c(cnn5C)c4)C3)sc2c1-c1ccc(Cl)cc1
Temperature: 140 °C

Procedure:
The mixture of tert-butyl 2-(1-methyl-1H-indazol-5-yl)piperazine-1-carboxylate (10 mg, 0.03 mmol), (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (15 mg, 0.03 mmol), and potassium carbonate (41 mg, 0.3 mmol) in DMF (0.5 mL) was heated at 140° C. for 4 hours. The mixture was cooled, and was quenched with water. The mixture was extracted with ethyl acetate, and the organic phase was washed with water and brine, and was dried with sodium sulfate. Concentration and purification by reverse phase HPLC gave tert-butyl 4-(6-((S)-1-tert-butoxy-2-ethoxy-2-oxoethyl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-2-yl)-2-(1-methyl-1H-indazol-5-yl)piperazine-1-carboxylate. LCMS-ESI+: calc'd for C39H47ClN5O5S2: 732.3 (M+H+); Found: 732.2 (M+H+).
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].Br.Cl[C:10]1[CH:11]=[C:12]([CH3:20])[C:13]2[N:14]([C:16]([NH2:19])=[N:17][N:18]=2)[N:15]=1>CN(C=O)C>[CH:1]1([CH2:4][O:5][C:10]2[CH:11]=[C:12]([CH3:20])[C:13]3[N:14]([C:16]([NH2:19])=[N:17][N:18]=3)[N:15]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(Cl)nn2c(N)nnc12
Reactant: OCC1CC1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(OCC2CC2)nn2c(N)nnc12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Cyclopropylmethanol (2.99 ml) was initially charged in DMF (30 ml), admixed under argon with sodium hydride (907 mg) and stirred at 50° C. for 1 h. Subsequently, 6-chloro-8-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine hydrobromide (W2.002; 2.0 g) were dissolved in DMF (30 ml) and one equivalent of the alkoxide solution was added. After stirring at 50° C. for one hour, two further equivalents of alkoxide solution were added and the mixture was stirred further at 50° C. The reaction mixture was then dried and purified using silica gel (80 g cartridge, dichloromethane/methanol gradient of 0-10% in 40 min). 620 mg of the title compound were obtained. LC-MS rt: 0.57 min [M+H]+: 220.1 (met. b)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](I)=[CH:9][N:10]=2)[CH:7]=1.C([Mg]Br)(C)C.[C:17](Cl)(=[O:21])[O:18][CH2:19][CH3:20].C(=O)(O)[O-].[Na+]>O1CCCC1.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:17]([O:18][CH2:19][CH3:20])=[O:21])=[CH:9][N:10]=2)[CH:7]=1
Reactant: CCOC(=O)Cl
Reactant: Brc1ccc2ncc(I)n2c1
Agent: CC(C)[Mg]Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cnc2ccc(Br)cn12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A mixture of 9.69 g 6-bromo-3-iodoimidazo[1,2-a]pyridine (compound in Production Example 49) and 450 mL anhydrous tetrahydrofuran was added little by little to 4.5 mL isopropyl magnesium bromide (0.75 M tetrahydrofuran solution) under ice-cooling in a stream of nitrogen. Then, this reaction solution was returned to room temperature and stirred for 1.5 hours. The reaction solution was cooled to −60° C. or less in a dry ice/acetone bath, 50 mL solution of 4.5 mL ethyl chlorocarbonate in anhydrous tetrahydrofuran was added dropwise thereto over 30 minutes, and the temperature of the reaction solution was increased to 0° C. After saturated sodium bicarbonate was added to the reaction solution, ethyl acetate and water were added thereto, and the organic layer was separated. The aqueous layer was saturated with common salt and then extracted with ethyl acetate. The combined organic layer was washed with brine and then dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was evaporated. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 5.09 g of the title compound as white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[N:21]=[CH:20][C:19]([CH2:22][N:23]5[CH2:27][CH2:26][CH2:25][C:24]5=[O:28])=[CH:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:31])[CH:3]=1.CCN(C(C)C)C(C)C.Cl[C:42](OC1C=CC([N+]([O-])=O)=CC=1)=[O:43].Cl.[CH3:55][S:56]([C:59]1[CH:60]=[C:61]([CH:63]=[CH:64][CH:65]=1)[NH2:62])(=[O:58])=[O:57]>C1COCC1>[F:31][C:4]1[CH:3]=[C:2]([NH:1][C:42]([NH:62][C:61]2[CH:63]=[CH:64][CH:65]=[C:59]([S:56]([CH3:55])(=[O:57])=[O:58])[CH:60]=2)=[O:43])[CH:30]=[CH:29][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][N:23]4[CH2:27][CH2:26][CH2:25][C:24]4=[O:28])=[CH:20][N:21]=3)[S:15][C:8]=12
Reactant: CS(=O)(=O)c1cccc(N)c1
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCCC5=O)cn4)sc23)c(F)c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1cccc(NC(=O)Nc2ccc(Oc3ccnc4cc(-c5ccc(CN6CCCC6=O)cn5)sc34)c(F)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
To a solution of 104 (50 mg, 0.115 mmol) in THF (2.3 mL) under nitrogen at −78° C. was added DIPEA (201 μl, 1.151 mmol) followed by 4-nitrophenyl chloroformate (116 mg, 0.575 mmol). The reaction mixture was kept at −78° C. over 1 hour. 3-(Methylsulfonyl)aniline hydrochloride (143 mg, 0.690 mmol) was added at −78° C. and the reaction mixture was allowed to warm to room temperature slowly. The reaction mixture was then quenched by addition of methanol, concentrated, dissolved in ethyl acetate, and successively washed with NH4Cl and NaHCO3, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by Biotage (SNAP 25 g cartridge; MeOH/DCM: 0/100 to 20/80 over 20 CV), to afford the title compound 105 (14.8 mg, 0.023 mmol, 20% yield) as beige solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.28 (s, 1H), 9.21 (s, 1H), 8.54 (d, J=5.6 Hz, 1H), 8.53 (d, J=2.4 Hz, 1H), 8.36 (s, 1H), 8.27 (d, J=8.4 Hz, 1H), 8.18 (t, J=2.0 Hz, 1H), 7.82-7.74 (m, 2H), 7.70 (dt, J=8.0, 1.6 Hz, 1H), 7.59 (t, J=8.0 Hz, 1H), 7.55 (dt, J=8.0, 1.6 Hz, 1H), 7.47 (t, J=8.8 Hz, 1H), 7.31 (d, J=8.8 Hz, 1H), 6.69 (d, J=5.2 Hz, 1H), 4.46 (s, 2H), 3.40-3.28 (m, 2H, hidden under water peak), 3.21 (s, 3H), 2.31 (t, J=8.0 Hz, 2H), 1.95 (quint, J=7.6 Hz, 2H). MS (m/z): 632.5 (M+H).
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][C:13]3=[O:18])[CH:7]=[CH:6][C:5]=12.I[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH2:20][CH2:21][C:22]4[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=4)[CH2:14][C:13]3=[O:18])[CH:7]=[CH:6][C:5]=12
Reactant: O=C1CNCCN1CCc1ccc2nonc2c1
Reactant: O=[N+]([O-])c1ccc(CCI)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CN(CCc2ccc([N+](=O)[O-])cc2)CCN1CCc1ccc2nonc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-[2-(2,1,3-Benzoxadiazol-5-yl)ethyl]piperazin-2-one (20 mg, 0.081 mmol) in DMF (1 mL) was added 1-(2-Iodoethyl)-4-nitrobenzene (27 mg, 0.097 mmol) and K2CO3 (45 mg, 0.32 mmol). The mixture was allowed to stir at RT for 16 hours. LC showed product formation. The desired product was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 396 [M+1]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:18][O:19][C:20](=[O:32])[CH:21]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22][SH:23].C(OCC)(=O)C>CN(C=O)C.CCCCCCC>[CH3:18][O:19][C:20](=[O:32])[C@@H:21]([NH:24][C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:22][S:23][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1
Reactant: COC(=O)C(CS)NC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CSCc1ccc(N)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A mixture of 1-bromomethyl-4-nitro-benzene (2.15 g, 9.95 mmol), cesium carbonate (6.49 g, 19.9 mmol) and 2-tert-butoxycarbonylamino-3-mercapto-propionic acid methyl ester (2.46 g, 10.5 mmol) in DMF (25 mL) was stirred at room temperature. Upon completion of the reaction (TLC control: 30% ethyl acetate in heptane), the reaction mixture was quenched with water (50 mL) and extracted with diethyl ether (3×50 mL). The combined extract was washed sequentially with water and brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification by flash chromatography (SiO2; 30% ethyl acetate in heptane as eluent) yielded the thioether as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[C:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:9][C:8](Br)=[C:7]2[C:3]=1[CH2:4][CH2:5][CH2:6]2.[Li][CH2:22][CH2:23][CH2:24][CH3:25].[CH2:26]([OH:37])[C@H:27]1[O:33][C:31](=[O:32])[C@H:30]([OH:34])[C@@H:29]([OH:35])[C@@H:28]1[OH:36]>C1COCC1>[CH2:22]([O:34][C@@H:30]1[C@@H:29]([O:35][CH2:22][C:23]2[CH:4]=[CH:5][CH:6]=[CH:25][CH:24]=2)[C@H:28]([O:36][CH2:22][C:23]2[CH:13]=[CH:12][CH:17]=[CH:25][CH:24]=2)[C@@H:27]([CH2:26][O:37][CH2:11][C:10]2[CH:9]=[CH:8][CH:7]=[CH:3][CH:2]=2)[O:33][C:31]1([C:8]1[CH:9]=[C:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:2]([Br:1])=[C:3]2[C:7]=1[CH2:6][CH2:5][CH2:4]2)[OH:32])[C:23]1[CH:16]=[CH:15][CH:14]=[CH:25][CH:24]=1
Reactant: O=C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: COc1ccc(Cc2cc(Br)c3c(c2Br)CCC3)cc1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(Cc2cc(C3(O)O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Br)CCC3)cc1
Reaction time: 0.75 h

Procedure:
To a solution of bromide 6 (3.21 g, 8.10 mmol) in anhydrous THF (28.3 mL) was added dropwise n-BuLi (2.5 M in hexane, 3.40 mL, 8.51 mmol) at −78° C. under nitrogen atmosphere, and the mixture was stirred for 0.5-1 h at the same temperature. Then a solution of perbenzylated gluconolactone 13 (4.37 g, 8.10 mmol) in THF (9.6 mL) was added dropwise, and the mixture was stirred for 3 h at the same temperature. The reaction mixture was quenched with saturated NH4Cl solution (30 mL) and extracted with EtOAc (100 mL). The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to provide the crude intermediate 16, which was used without further purification (6.96 g, 8.13 mmol, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[S:10][CH:11]=[CH:12][N:13]=1.[CH3:20][I:21]>C(O)C>[I-:21].[CH3:20][N+:13]1[CH:12]=[CH:11][S:10][C:9]=1[NH:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:3][C:2]=1[Cl:1]
Reactant: CI
Reactant: CCOC(=O)Cc1ccc(Nc2nccs2)c(Cl)c1
Solvent: CCO
Product: CCOC(=O)Cc1ccc(Nc2scc[n+]2C)c(Cl)c1
Product: [I-]

Procedure:
A mixture of ethyl 2-[3-chloro-4-(N-thiazol-2-ylamino)phenyl]acetate (8.9 g), methyl iodide (44 ml) and ethanol (44 ml) is heated at 50°-55° C for 42 hours with stirring. The ethanol and methyl iodide are evaporated and the residue is washed with ether and kept at room temperature to give a precipitate. The precipitate is washed with ethyl acetate and cold acetone successively and recrystallized from acetone to give 3-methyl-2-[2-chloro-4-(ethoxycarbonylmethyl)anilino]-thiazolium iodide (6.6 g) melting at 147°-148° C.