Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)/[C:8]([O:10]CC)=[O:9])[N:6]=1.[OH-].[Na+]>C(O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)/[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCOC(=O)/C(=N\OCC1CC1)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1nc(/C(=N/OCC2CC2)C(=O)O)cs1
Reaction time: 40 h
Yield: 84.2 %

Procedure:
Ethyl 2-(2-aminothiazol-4-yl)-(Z)-2 -cyclopropylmethoxyiminoacetate (1.12 g) was suspended in ethanol (9 ml) and sodium hydroxide (1N; 9 ml) added. The mixture was stirred at room temerature for 40 h, acidified to pH2.8 and the ethanol removed. The precipitated solid was filtered off, washed with a little cold water, and dried in vacuo to give a white solid (845 mg) νmax (Nujol) 3350, 1640 br, and 1580 cm-1 ; δH [(CD3)2SO] inter alia 3.92 (2H, d, J 7 Hz), 6.82 (1H, s), and 7.20 (3H, very broad s, excn. D2O).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[C:16]([F:24])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][N:7]=1.[Li+].[OH-]>C1COCC1.CO>[NH2:1][C:2]1[C:3]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[C:16]([F:24])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][N:7]=1
Reactant: COC(=O)c1ccc(-c2nc(C3CCOCC3)cnc2N)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ncc(C2CCOCC2)nc1-c1ccc(C(=O)O)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-2-fluorobenzoate (104 mg, 0.314 mmol) in THF (698 μL) and MeOH (349 μL) was added LiOH (1 M solution) (565 μL, 0.565 mmol). The reaction mixture was stirred for 1 h at room temperature. The reaction mixture was quenched with 1N HCl solution up to pH 5, and worked up with EtOAc. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered off, and concentrated in vacuo. The crude product was used for the next step. LCMS (m/z): 318.3 (MH+), 0.5 min.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11](N1C=CN=C1)=[S:12].Cl.[CH3:19][O:20][C:21](=[O:31])[CH:22]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH2:23]>CN(C)C=O>[CH3:19][O:20][C:21](=[O:31])[CH:22]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH:23][C:11]([NH:10][C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)=[S:12]
Reactant: S=C(Nc1nc2ccccc2s1)n1ccnc1
Reactant: COC(=O)C(N)Cc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccccc1)NC(=S)Nc1nc2ccccc2s1
Temperature: 25 °C
Yield: 70.5 %

Procedure:
A solution of 1-[(2-benzothiazolyl)thiocarbamoyl]imidazole (1.30 g, 5.0 mmol) and DL-phenylalanine methyl ester hydrochloride (1.08 g, 5.0 mmol) in N,N-dimethylformamide (50 mL) was heated at 90° C. for 3 h. The reaction was cooled to room temperature, solvent removed under reduced pressure, recrystalllized from ethyl ether-hexanes to provide 1.31 g (70%) of the titled product:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7]([CH3:12])=[C:6]2[CH2:13][C:14]([O:16]C)=[O:15].[CH3:18][O:19][C:20]1[C:27]([O:28][CH3:29])=[C:26]([O:30][CH3:31])[CH:25]=[CH:24][C:21]=1[CH:22]=O.C[O-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[CH:22][C:21]1[CH:24]=[CH:25][C:26]([O:30][CH3:31])=[C:27]([O:28][CH3:29])[C:20]=1[O:19][CH3:18])[C:7]([CH3:12])=[C:6]2[CH2:13][C:14]([OH:16])=[O:15]
Reactant: COc1ccc(C=O)c(OC)c1OC
Reactant: COC(=O)CC1=C(C)Cc2ccc(OC)cc21
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc2c(c1)C(CC(=O)O)=C(C)C2=Cc1ccc(OC)c(OC)c1OC
Reaction time: 0.5 h

Procedure:
To a solution of methyl 5-methoxy-2-methyl-3-indenylacetate 8.7 g (0.037 mol) and 2,3,4-trimethoxybenzaldehyde, 7.99 g (1.1 equivalent) is added 16+ml (2.0+equivalents) of 25% methanolic sodium methoxide. The mixture is stirred at reflux under nitrogen for 2 hours. An equal volume of water is added dropwise and refluxing continues for 30 min. The solution is cooled, diluted with water and extracted with ether (3×). Residual ether is blown off with nitrogen, and then the aqueous solution is acidified with 50% glacial acetic acid. The precipitated product is collected and washed thoroughly with water. The crude product is crystallized to give 5-methoxy-2-methyl-1-(2,3,4-trimethoxybenzylidene)-3-indenyl-acetic acid. (R and R1 =H, R2 =OCH3, R3 and R4 =H, R5, R6 and R7 =OCH3, R8 =CH3, o=1, M=OH)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].[I:13]N1C(=O)CCC1=O.O.C(OCC)C>CN(C)C=O>[I:13][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][N:8]=1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2[nH]nc(I)c2c1
Temperature: 80 °C
Reaction time: 7 h
Yield: 91.3 %

Procedure:
To a solution of 17.0 g of 5-nitroindazole in 100 ml dimethylformamide was added 24.6 g of N-iodosuccinimide at room temperature, and the mixture was stirred at 80° C. for 7 hours. After standing to cool, to the reaction mixture were added 150 ml of water and 200 ml of diethyl ether, and the resulting crystals were collected by filtration. The crystals were sequentially washed with water, isopropanol and diethyl ether, to give 27.5 g of the title compound as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH:4]=[CH:5][CH:6]=O.[NH2:12][NH:13][C:14]([NH2:16])=[S:15]>>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH:4]=[CH:5][CH:6]=[N:12][NH:13][C:14]([NH2:16])=[S:15]
Reactant: NNC(N)=S
Reactant: O=CC=Cc1ccccc1Cl
Product: NC(=S)NN=CC=Cc1ccccc1Cl
Yield: 55 %

Procedure:
The compound is prepared according to the method described in Example 1A from 2-chlorocinnamaldehyde (0.15 mmol) and from thiosemicarbazide (0.15 mmol). Yield 55%.
Reaction SMILES: C([O:4][CH2:5][CH:6]1[CH:11]=[CH:10][C@H:9]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][O:7]1)(=O)C>[Pd].CO>[OH:4][CH2:5][CH:6]1[O:7][CH2:8][C@@H:9]([NH:12][C:13](=[O:14])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])[CH2:10][CH2:11]1
Reactant: CC(=O)OCC1C=C[C@H](NC(=O)OC(C)(C)C)CO1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CCC(CO)OC1
Reaction time: 4 h
Yield: 26 %

Procedure:
{(5S)-5-[(tert-Butoxycarbonyl)amino]-5,6-dihydro-2H-pyran-2-yl}methyl acetate (from example 19, step 5) (3.47 g, 12.8 mmol) and 10% palladium on carbon (1.4 g) in methanol (60 mL) was stirred under a H2 balloon at room temperature for 2 h. The reaction mixture was filtered and the filtrate was treated with 1.0 M sodium hydroxide in water (12 mL). After stirring for 4 h, the reaction solution was concentrated and diluted with ethyl acetate. The organic layer was separated and washed with brine, dried over Na2SO4, and concentrated. The residue was purified with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (0.77 g, 26%). LCMS calculated for C6H14NO2 (M−100+H)+: m/z=132.1. Found: 132.1.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([CH:24]=O)[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.[C:28]1([CH3:37])[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][NH2:36])=[CH:30][CH:29]=1.C([BH3-])#N.[Na+].C(O)(=O)C>C1COCC1>[F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([CH2:24][NH:36][CH2:35][CH2:34][C:31]3[CH:32]=[CH:33][C:28]([CH3:37])=[CH:29][CH:30]=3)[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1
Reactant: O=CC1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: Cc1ccc(CCN)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1ccc(CCNCC2CCN(C(=O)c3cc4ccccc4n3Cc3ccc(F)cc3)CC2)cc1
Reaction time: 14 h

Procedure:
1-(1-(4-fluorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carbaldehyde (46 mg, 0.126 mmol) was dissolved in THF (2 mL) and 2-(p-tolyl)ethanamine (0.030 mL, 0.189 mmol) was added. The solution was stirred at rt for 10 h, at which time the THF was removed in vacuo and the residue dissolved in EtOH (5 mL), and sodium cyanoborohydride (24 mg, 0.349 mmol) and a catalytic drop of glacial acetic acid were added. Stirring was permitted for 14 h, at which time the solvent was removed in vacuo, the residue was taken up in EtOAc. The organic phase was washed with 10% aq. sodium carbonate, dried over magnesium sulfate, and concentrated. Purification was accomplished via silica gel flash chromatography (30 g silica gel, 5:95 7M methanolic ammonia:ethyl acetate.) The title compound was obtained as a yellow oil. (Yield: 26 mg, 0.054 mmol, 43%) 1H NMR (400 MHz, CDCl3) 7.62, 7.36, 7.29-7.20, 7.17-7.07, 6.90, 6.58, 5.46, 4.62, 4.08, 2.89-2.65, 2.42, 2.31, 1.60, 1.01, 0.64
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]([NH2:13])[C:8]2([CH3:12])[CH2:11][O:10][CH2:9]2)=[CH:4][CH:3]=1.C([O:16][C:17]1[C:20](=[O:21])[C:19](=O)[C:18]=1[NH:23][C:24]1[C:25]([OH:33])=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([OH:29])=[O:28])C>CO>[OH:33][C:25]1[C:24]([NH:23][C:18]2[C:17](=[O:16])[C:20](=[O:21])[C:19]=2[NH:13][CH:7]([C:5]2[O:6][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:8]2([CH3:12])[CH2:9][O:10][CH2:11]2)=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([OH:29])=[O:28]
Reactant: CCOc1c(Nc2cccc(C(=O)O)c2O)c(=O)c1=O
Reactant: Cc1ccc(C(N)C2(C)COC2)o1
Solvent: CO
Product: Cc1ccc(C(Nc2c(Nc3cccc(C(=O)O)c3O)c(=O)c2=O)C2(C)COC2)o1
Temperature: 50 °C
Reaction time: 168 h
Yield: 44.2 %

Procedure:
453 mg (2.5 mmol, 1.5 eq) of C-(5-methylfuran-2-yl)-C-(3-methyloxetan-3-yl)methylamine were added to 471 mg (1.7 mmol, 1 eq) of 3-(2-ethoxy-3,4-dioxocyclobut-1-enylamino)-2-hydroxybenzoic acid dissolved under hot conditions in 50 ml of methanol. The reaction medium was heated at 50° C. for 18 hours and then at 60° C. for 7 days. The methanol was evaporated off and the residue was chromatographed on silica gel (column puriFlash IR50SI-120G, Spot II) eluted with dichloromethane/methanol (gradient). The solid was taken up with a little ethyl acetate, filtered and dried under vacuum at 55° C. 310 mg of 2-hydroxy-3-(2-{[(5-methylfuran-2-yl)-(3-methyloxetan-3-yl)methyl]amino}-3,4-dioxocyclobut-1-enylamino)benzoic acid were obtained in the form of a brown solid. (Mp=180-185° C.). Yield=44%. LC/MS: 97.08% [412].
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.CC1(C)O[C:17](=[O:18])[CH2:16][C:14](=[O:15])[O:13]1>O>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]2[C:3]=1[O:10][C:17](=[O:18])[C:16]([C:14]([OH:15])=[O:13])=[CH:5]2
Reactant: O=Cc1cccc(Br)c1O
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: O
Product: O=C(O)c1cc2cccc(Br)c2oc1=O
Temperature: 75 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
3-bromohydroxybenzaldehyde (139.5 mg, 0.69 mmol) and Meldrum's acid (100 mg, 0.69 mmol) were combined in H2O (1 mL). The solution was stirred at 75° C. for 2 h. After cooling to room temperature, the precipitate was filtered and dried at suction to give 135.0 mg of 8-bromo-3-carboxy-coumarin in an 73% yield.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([O:4][C:5](=[O:20])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([CH3:19])[C:16]([OH:18])=O)=[CH:10][CH:9]=1)[CH3:3].CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:37]([N:40]1[C:47]([NH2:48])=[C:46]([NH2:49])[C:44](=[O:45])[N:43]([CH2:50][CH2:51][CH3:52])[C:41]1=[O:42])[CH2:38][CH3:39]>O1CCCC1.CN(C)C=O.C(Cl)(Cl)Cl>[NH2:48][C:47]1[N:40]([CH2:37][CH2:38][CH3:39])[C:41](=[O:42])[N:43]([CH2:50][CH2:51][CH3:52])[C:44](=[O:45])[C:46]=1[NH:49][C:16](=[O:18])[CH:15]([CH3:19])[CH2:14][C:11]1[CH:10]=[CH:9][C:8]([O:7][CH2:6][C:5]([O:4][C:2]([CH3:1])([CH3:3])[CH3:21])=[O:20])=[CH:13][CH:12]=1
Reactant: CC(Cc1ccc(OCC(=O)OC(C)(C)C)cc1)C(=O)O
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCCn1c(N)c(NC(=O)C(C)Cc2ccc(OCC(=O)OC(C)(C)C)cc2)c(=O)n(CCC)c1=O
Temperature: -20 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
Dissolve (-)-4-[[2-(1,1-dimethylethoxy)-2-oxoethyl]oxy]-alpha-methyl-benzenepropanoic acid (1.92 g, 6.52 mmol) in tetrahydrofuran (50 mL) and treat with N-methylmorpholine (0.77 mL, 6.52 mmol). Cool to -20° C. and treat with isobutyl chloroformate (0.86 mL, 6.52 mmol). Stir for 1 hour and add a solution of 1,3-dipropyl-5,6-diaminouracil (1.48 g, 6.52 mmol) in dimethylformamide (4 mL). Stir at -20° C. for 3 hours and warm to room temperature. Stir for 2 hours and dilute with chloroform (400 mL). Separate the organic phase and wash with saturated sodium hydrogen carbonate (300 mL), then brine (2×400 mL). Dry (Na2SO4) and evaporate the solvent in vacuo to give 4.31 g crude product. Purify by flash chromatography (10→15→20% isopropanol/hexane) to give the title compound (2.16 g, 66%); [α]d 20 =-45.8 ° (C=1.00, CHCl3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[CH2:11][C:10](=O)[CH2:9]1.Cl.[NH2:17][CH2:18][C:19]#[C:20][CH3:21].O1CCCC1>C(N(CC)CC)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:9][C:10]2[N:17]=[CH:18][CH:19]=[C:20]([CH3:21])[C:11]=2[C:12](=[O:14])[CH2:13]1
Reactant: CC#CCN
Reactant: O=C1CC(=O)CC(c2ccccc2F)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccnc2c1C(=O)CC(c1ccccc1F)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.9 %

Procedure:
To a mixture of 5-(2-fluorophenyl)cyclohexane-1,3-dione (0.98 g), 1-amino-2-butyne hydrochloride (0.5 g), molecular sieves 4A (2 g) and tetrahydrofuran (20 ml) was added triethylamine (0.48 g), and the mixture was stirred at room temperature for 1 hour, refluxed for 12 hours and cooled. Insoluble materials were filtered off. Under reduced pressure, the solvent was evaporated, and the residue was stirred for 6 hours at 220° C. and cooled, to which were added ethyl acetate and sodium hydrogen carbonate solution. The organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtOAc/hexane) to give oil of 7-(2-fluorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.35 g).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1[C:21](O)=[O:22])=[O:7])([CH3:4])[CH3:3].C1CCC(N=C=NC2CCCCC2)CC1.[CH3:39][C:40]1([CH3:48])[O:45][C:44](=[O:46])[CH2:43][C:42](=[O:47])[O:41]1>ClCCl.CN(C1C=CN=CC=1)C>[CH3:39][C:40]1([CH3:48])[O:45][C:44](=[O:46])[C:43](=[C:21]([OH:22])[CH:9]2[CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15])[CH2:12][CH2:13][N:8]2[C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7])[C:42](=[O:47])[O:41]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(C(=O)O)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(C(O)=C2C(=O)OC(C)(C)OC2=O)C1
Reaction time: 0.25 h
Yield: 5.8 %

Procedure:
To a solution of 1,4-bis{[(1,1-dimethylethyl)oxy]carbonyl}-2-piperazinecarboxylic acid (may be prepared as described in Intermediate 1; 14.58 g) in dichloromethane (500 mL) was added DMAP (8.09 g) and then DCC (13.66 g). The reaction was stirred for 15 minutes and then 2,2-dimethyl-1,3-dioxane-4,6-dione (9.54 g) (Meldrum's acid) was added. The reaction was stirred at room temperature for 20 h. A solid was present, which was filtered off and the product was found to be in the filtrate. The filtrate was washed with water (2×200 mL) and brine (200 mL) before it was dried (Na2SC4), filtered and the solvent removed under vacuum. The crude material was then redissolved in DCM (500 mL) and 50 mL removed and this was washed with 1M HCl (2×20 mL) before the organic phase was dried (Na2SC4), filtered and the solvent removed under vacuum to give the title compound (1.16 g). This process removed the DMAP impurity. The process was repeated with the remaining DCM solution, washing with 1M HCl (2×300 mL) before the solution was dried (Na2SC4), filtered and the solvent removed under vacuum to give the title compound as yellow viscous oil (16.65 g).
Reaction SMILES: [SH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][SH:7].[OH-].[Na+].Cl[CH2:11][CH2:12][OH:13]>C(O)C>[SH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][S:7][CH2:11][CH2:12][OH:13]
Reactant: SCCOCCS
Reactant: OCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OCCSCCOCCS
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
2-Mercaptoethyl ether (53.8 ml; 0.434 mol) was added to a solution of sodium hydroxide (17.36 g; 0.434 mol) in ethanol (300 ml) at ambient temperature and stirred for 15 min. 2-Chloroethanol (29.1 ml; 0.434 mol) was added to the solution at ambient temperature and after addition was complete the stirred solution was heated to 80° C. for 1 hr. The reaction mixture was then cooled to ambient temperature and the solid sodium chloride separated by filtration. The filtrate was transferred to a distillation apparatus and ethanol and unreacted 2-mercaptoethyl ether removed under vacuum (the latter distilling at 62° C. and 0.4 mbar). Fractional distillation of the remaining product yielded 2-[2-(2-mercapto-ethoxy)-ethylsulfanyl]-ethanol at 128° C. and 0.3 mbar. Pure fractions were combined to afford 2-[2-(2-mercapto-ethoxy)-ethylsulfanyl]-ethanol (31 g; 0.17 mol; 39% yield) as a colourless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.C[O:16][B:17](OC)[O:18]C.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.O>[CH3:9][S:8][C:5]1[CH:6]=[CH:7][C:2]([B:17]([OH:18])[OH:16])=[CH:3][CH:4]=1
Reactant: CSc1ccc(Br)cc1
Reactant: COB(OC)OC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CSc1ccc(B(O)O)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 36 %

Procedure:
A stirred solution of 4-bromothioanisole (5.0 g, 0.0246 mol) in anhydrous tetrahydrofuran (THF) was chilled to −78° C. under a nitrogen atmosphere. A 2.5 M solution of n-butyl lithium (12 mL, 0.030 mol) in hexanes was added dropwise to the chilled solution. When the addition was complete, the reaction mixture was stirred at −78° C. for about 45 minutes. Trimethylborate (8.5 mL, 0.0748) was introduced via syringe. The reaction mixture was then allowed to warm to room temperature overnight. The room temperature solution was treated successively with 10% aqueous sodium hydroxide solution (50 mL) and water (33.5 mL) and stirred at room temperature for 1 hour. The reaction mixture was lowered to about pH=4-5 using 10% aqueous citric acid and the THF was removed under reduced pressure. The aqueous residue was saturated with sodium chloride and extracted with ethyl acetate. The organic extract was dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure to provide a white solid which was washed with hexanes to provide the product as a white solid (yield: 1.5 g; 36%). mp 170° C. 1H NMR (300 MHz, DMSO-d6) δ 2.47 (s, 3H), 7.20 (d, J=8 Hz, 2H), 7.71 (d, J=8 Hz, 2H), 7.96 (br s, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:16]3[S:20][N:19]=[CH:18][N:17]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:36][C:37]1[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[CH:39][C:38]=1B(O)O.C(Cl)Cl>O1CCOCC1.O.CCCCCCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:36][C:37]1[CH:42]=[C:41]([C:43]([F:44])([F:45])[F:46])[CH:40]=[CH:39][C:38]=1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:16]3[S:20][N:19]=[CH:18][N:17]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1Br
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4Br)nccc3c2)cc1
Temperature: 100 °C
Reaction time: 0.58 h
Yield: 87.9 %

Procedure:
A glass pressure tube was charged with 1-chloro-N-(4-methoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (690 mg, 1.54 mmol), potassium carbonate (107 mg, 7.72 mmol), 2-bromo-4-(trifluoromethyl)phenylboronic acid (498 mg, 1.85 mmol), tetrakis(triphenylphosphine)palladium(0) (178 mg, 0.154 mmol) in dioxane (10.300 mL) and water (5.15 mL). The reaction was purged with argon. The tube was sealed and heated in an oil bath at 100° C. After 35 min, the reaction was cooled down to room temperature. The mixture was extracted with EtOAc (3×30 mL). The organic layers were separated, combined, dried over MgSO4, filtered and concentrated to afford a yellow residue. The residue was absorbed onto a plug of silica gel and purified by chromatography through a silica gel column (40 g), eluting with a gradient of 0% to 20% DCM in heptane to remove PPh3 and then 20 to 90% DCM in heptane to provide 1-(2-bromo-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (0.86 g, 1.353 mmol) as a yellow solid. MS (ESI): 634.0 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 3.64 (s, 3H), 5.24 (s, 2H), 6.78 (d, J=8.90 Hz, 2H), 7.27 (d, J=8.80 Hz, 2H), 7.69 (d, J=10 Hz, 1H), 7.75 (d, J=8 Hz, 1H), 7.91-7.99 (m, 2H), 8.23-8.26 (m, 2H), 8.46 (s, 1H), 8.81-8.84 (m, 2H).
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:36][C:37]1[CH:38]=[CH:39][C:40]([O:54][CH2:55][CH2:56][CH3:57])=[C:41]([C:43]2[NH:48][C:47](=[O:49])[C:46]([CH2:50][CH3:51])=[C:45]([CH2:52][CH3:53])[N:44]=2)[CH:42]=1>ClCCl>[CH2:52]([C:45]1[N:44]=[C:43]([C:41]2[CH:42]=[C:37]([NH:36][C:12]([CH2:11][CH2:10][CH2:9][NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])=[O:14])[CH:38]=[CH:39][C:40]=2[O:54][CH2:55][CH2:56][CH3:57])[NH:48][C:47](=[O:49])[C:46]=1[CH2:50][CH3:51])[CH3:53]
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Reactant: CCCOc1ccc(N)cc1-c1nc(CC)c(CC)c(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCCOc1ccc(NC(=O)CCCNC(=O)OC(C)(C)C)cc1-c1nc(CC)c(CC)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 41.1 %

Procedure:
N-Boc-4-aminobutyric acid (203 mg, 1 mmol) was dissolved in dichloromethane (50 ml), and added with EDCI (180 mg, 1 mmol) and HOBT (135 mg, 1 mmol), followed by stirring at room temperature for 12 h. The compound of example 42 (300 mg, 1 mmol) was added thereinto and the stirring continued at room temperature for 6 h. The reaction mixture was washed with water (50 ml) and saturated saline (50 ml) respectively. The organic layer was dried with anhydrous sodium sulfate, and concentrated, and the residue was passed through a silica gel column to give the white title compound (200 mg, yield: 41%). 1H NMR (CDCl3) δ: 9.00 (1H, br), 8.39 (1H, d), 8.09 (1H, dd), 6.99 (1H, d), 4.83 (1H, t), 4.14 (2H, t), 3.27 (2H, m), 2.65 (2H, q), 2.59 (2H, q), 2.41 (2H, t), 1.97 (2H, m), 1.89 (2H, m), 1.48 (9H, s), 1.29 (3H, t), 1.14 (3H, t), 1.13 (3H, t).