Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:18])=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([OH:17])([CH3:16])[CH3:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:19]([O:21][CH2:22][C:23](Cl)=O)[CH3:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C>[Cl:18][C:3]1[C:2]2[N:1]=[C:20]([CH2:19][O:21][CH2:22][CH3:23])[N:12]([CH2:13][C:14]([CH3:16])([CH3:15])[OH:17])[C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1
Reactant: CC(C)(O)CNc1c(N)c(Cl)nc2ccccc12
Reactant: CCOCC(=O)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Product: CCOCc1nc2c(Cl)nc3ccccc3c2n1CC(C)(C)O
Reaction time: 120 h
Yield: 71.9 %

Procedure:
3-Amino-2-chloro-4-(2-hydroxy-2-methylpropylamino)quinoline (2.0 g, 7.5 mmol) was combined with acetonitrile (80 mL). Ethoxyacetyl chloride (0.92 g, 7.5 mmol) was added to the reaction mixture. After about 5 minutes a yellow precipitate formed. p-Toluenesulfonic acid (0.1 g) was added and the reaction mixture was heated to reflux. Refluxing was continued for about 120 hours at which time the reaction mixture was homogeneous. The reaction mixture was cooled and the acetonitrile was removed under vacuum. The resulting residue was dissolved in methylene chloride and washed with dilute ammonium hydroxide. The aqueous phase was extracted with methylene chloride (3×25 mL). The organic phases were combined, dried over magnesium sulfate and then concentrated to provide 2.6 g of crude product as a dark yellow solid. The crude product was recrystallized from t-butylmethyl ether to provide 1.8 g of a solid. The structure was confirmed by nuclear magnetic resonance spectroscopy.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:12](=[O:13])[C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[NH:9][CH2:8][C:7]1=[O:18].[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>O1CCOCC1>[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[N:25]1[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:12](=[O:13])[C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[NH:9][CH2:8][C:7]2=[O:18])[CH2:27][CH2:26]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: O=C1CNc2ccccc2C(=O)N1CCCCBr
Solvent: C1COCCO1
Product: O=C1CNc2ccccc2C(=O)N1CCCCN1CCN(c2ncccn2)CC1
Yield: 86.8 %

Procedure:
To a solution of 70 mg of the compound of Example 14 dissolved in 10 ml of dioxane was added 111 mg (3 equivalents) of 1-(2-pyrimidinyl)piperazine, and the mixture heated under reflux for 8 hours. The reaction treatment and purification were conducted in the same manner as in Example 17 to obtain 77.0 mg of the desired compound (yield 87%). The maleate was obtained by converting the product to maleate, followed by recrystallization from methylene chloride-ether.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[CH2:21][CH2:20][CH2:19][NH:18][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.Cl.O1CCOCC1>O1CCOCC1>[N:16]1[C:17]2[NH:18][CH2:19][CH2:20][CH2:21][C:22]=2[CH:23]=[CH:24][C:15]=1[CH2:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc3c(n2)NCCC3)CC1
Agent: Cl
Solvent: C1COCCO1
Product: c1cc2c(nc1CC1CCNCC1)NCCC2

Procedure:
A solution of 3-4 (1.6 g, 4.8 mmol) and dioxane (24 mL) at 0oC was treated with 4M HCl/dioxane (6.0 mL) followed by removal of the cooling bath. After 5 hr the reaction mixture was concentrated to give 3-5 as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](OCC)=[O:9])=[C:6]([N:13]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:5]=[C:4]([S:27][CH3:28])[N:3]=1.[Li+].CC([N-]C(C)C)C.O>O1CCCC1>[Cl:1][C:2]1[C:7]2[C:8](=[O:9])[CH:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:20][N:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:6]=2[N:5]=[C:4]([S:27][CH3:28])[N:3]=1
Reactant: CCOC(=O)CCN(c1ccccc1)c1nc(SC)nc(Cl)c1C(=O)OCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1CN(c2ccccc2)c2nc(SC)nc(Cl)c2C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 102.4 %

Procedure:
To an ice-cooled solution of ethyl 4-chloro-6-((3-ethoxy-3-oxopropyl)(phenyl)amino)-2-(methylthio)pyrimidine-5-carboxylate (23.0 g, 54.25 mmol) in tetrahydrofuran (400 mL), LDA [generated at 0° C. using diisopropylamine (25.37 mL, 179.4 mmol) and n-BuLi (74.2 mL, 173.9 mmol) in tetrahydrofuran (300 mL)] was added dropwise. The reaction mixture was further stirred for additional 1 h and water (500 mL) was added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted using EtOAc (200 mL×2). The combined organic layer was washed with water (500 mL) and brine (500 mL); dried over anhydrous sodium sulphate and concentrated under reduced pressure to give crude product. Crude product from two batches of the same size were combined and purified by silica gel column chromatography (polarity) to provide ethyl 4-chloro-2-(methylthio)-5-oxo-8-phenyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-6-carboxylate (21 g, 51.2% yield). 1H NMR (400 MHz, CDCl3): δ 7.48-7.43 (m, 2H), 7.37-7.28 (m, 3H), 4.37 (dd, J=7.2, 13.6 Hz, 1H), 4.27 (q, J=7.2 Hz, 2H), 4.11 (dd, J=4.8, 13.6 Hz, 1H), 3.75 (dd, J=4.8, 7.2 Hz, 1H), 2.17 (s, 3H), 1.29 (t, J=7.2 Hz, 3H). LCMS [M+H]: 378
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:19])[N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[CH:3]=1.C1C(=O)N(Br)C(=O)C1.C1CCN2C(=NCCC2)CC1>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:19])[N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[CH:3]=1
Reactant: O=C1CCc2c(-c3ccccc3Cl)cc(Cl)nc2N1c1ccccc1Cl
Agent: O=C1CCC(=O)N1Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClC(Cl)(Cl)Cl
Product: O=c1ccc2c(-c3ccccc3Cl)cc(Cl)nc2n1-c1ccccc1Cl
Reaction time: 2 h
Yield: 69 %

Procedure:
7-Chloro-1,5-bis(2-chlorophenyl)-3,4-dihydro[1,8]naphthyridin-2(1H)-one (220 mg, 0.545 mmol) in carbon tetrachloride (3 ml) was treated with NBS (110 mg; 0.618 mmol) and AlBN (1 mg) and heated under reflux for 1 h. Further NBS (110 mg, 0.618 mmol) and AlBN (2 mg) were added and heating under reflux continued for a further 2 h. DBU (0.2 ml) was added, the mixture cooled, filtered, and further carbon tetrachloride (3 ml) added, followed by 2M hydrochloric acid (3 ml). The mixture was purified by column chromatography over silica (20 g) eluting with cyclohexane-ethyl acetate (100:0-60:40) to afford the title compound as a white solid (151 mg, 69%).
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:18])[NH:6][C:7](=[O:17])[NH:8][C:9]=1[S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:3])[CH3:2].[C:19]([CH:23]1[CH2:27][C:26](CBr)=[C:25]([CH2:30][O:31][SiH](C)C)[CH2:24]1)(C)(C)C>>[OH:31][CH2:30][CH:25]1[CH2:24][C:23]([CH2:19][N:8]2[C:9]([S:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:18])[NH:6][C:7]2=[O:17])=[CH:27][CH2:26]1
Reactant: CC(C)c1c(Sc2ccccc2)[nH]c(=O)[nH]c1=O
Reactant: C[SiH](C)OCC1=C(CBr)CC(C(C)(C)C)C1
Product: CC(C)c1c(Sc2ccccc2)n(CC2=CCC(CO)C2)c(=O)[nH]c1=O
Yield: 29.5 %

Procedure:
5-Isopropyl-6-phenylthio-2,4-pyrimidinedione and [(4-t-butyldimethylsilyl-oxymethylcyclopent-1-en-1-yl)methyl bromide were reacted by the same way with the example 6 to obtain the titled compound (67 mg)
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1)=[O:3].[H-].[Na+].[C:13](=O)([O:17]CC)[O:14][CH2:15][CH3:16]>>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH2:1][C:13]([O:14][CH2:15][CH3:16])=[O:17])=[CH:5][CH:6]=1
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(=O)c1ccc(Cl)cc1
Reaction time: 48 h

Procedure:
The starting material is prepared as follows: A solution of 96.6 g of 4-chloro acetophenone in 300 ml of diethyl carbonate is added dropwise to a suspension of 34 g sodium hydride (55% in mineral oil, washed twice with diethyl ether) in 400 ml of diethyl carbonate at ice bath temperature, then at room temperature for 2 days. To the dark solution is then added crushed ice and 5N hydrochloric acid to adjust the pH to 6-7. After dilution with diethyl ether, the layers are separated, the organic phase washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. After removal of the solvents, the oily ethyl 3-(4-chloro-phenyl)-3-oxo-propionate is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[NH:19]1[C:27]2[C:22](=[CH:23][C:24](B(O)O)=[CH:25][CH:26]=2)[CH:21]=[CH:20]1>>[NH:19]1[C:27]2[C:22](=[CH:23][C:24]([C:2]3[CH:3]=[C:4]([N:8]4[CH2:16][CH:15]5[CH2:17][N:11]6[CH2:12][CH:13]([CH2:18][CH:9]4[CH2:10]6)[CH2:14]5)[CH:5]=[N:6][CH:7]=3)=[CH:25][CH:26]=2)[CH:21]=[CH:20]1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Product: c1cc2cc(-c3cncc(N4CC5CC6CC4CN(C6)C5)c3)ccc2[nH]1

Procedure:
The title compound was prepared from the product of Example 65A and 1H-indol-5-ylboronic acid according to General Method B: LC-MS Method D (ESI+) m/z 344.0 (M+H)+, retention time 1.30 minutes.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:8][C@@H:9]([OH:13])[CH2:10][CH:11]=[CH2:12].C(N(CC)CC)C.C(#N)C>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2](/[CH:12]=[CH:11]/[CH2:10][C@H:9]([OH:13])[CH3:8])[CH:3]=1
Reactant: Brc1cccnc1
Reactant: C=CC[C@@H](C)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[C@@H](O)C/C=C/c1cccnc1
Temperature: 140 °C
Yield: 65.1 %

Procedure:
A mixture of 3-bromopyridine (9.17 g, 58.04 mmol), (2R)-4-penten-2-ol (600 g 69.65 mmol), palladium(II) acetate (130 mg, 0.58 mmol), tri-o-tolylphosphine (710 mg, 2.32 mmol), triethylamine (34.7 mL, 249.5 mmol), and acetonitrile (35 mL) was heated in a sealed glass tube at 140° C. for 14 h. The reaction mixture was cooled to ambient temperature, diluted with water, and extracted with chloroform (3×200 mL). The combined chloroform extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporation to give 6.17 g (65.2%) of a pale-yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:15][N:14]3[C:10]([S:11][CH2:12][CH2:13]3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C[Al](C)C.C([O:22][C:23]([C:25]1[N:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:28]=[C:27]([CH3:36])[CH:26]=1)=O)C>ClCCl>[CH3:36][C:27]1[CH:26]=[C:25]([C:23]([NH:1][C:2]2[CH:3]=[C:4]([CH:8]3[CH2:15][N:14]4[C:10]([S:11][CH2:12][CH2:13]4)=[N:9]3)[CH:5]=[CH:6][CH:7]=2)=[O:22])[N:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:28]=1
Reactant: Nc1cccc(C2CN3CCSC3=N2)c1
Reactant: CCOC(=O)c1cc(C)nn1-c1ccccc1
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1cc(C(=O)Nc2cccc(C3CN4CCSC4=N3)c2)n(-c2ccccc2)n1
Yield: 73.6 %

Procedure:
To 6-(m-aminophenyl)-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole (1.43 g; 6.5 mmol) in dry dichloromethane (30 ml) under nitrogen at room temperature was added trimethylaluminium (10 ml; 25% in hexane). After 30 mins 3-methyl-1-phenylpyrazole 5-carboxylic acid ethyl ester (1.5 g, 6.5 mmol) in dry dichloromethane (5 ml) was added and the mixture heated under reflux for 24 hr. The reaction was quenched by the slow addition of hydrochloric acid (20 ml; 2 N aqueous), the resulting two phase system basified with aqueous ammonia solution (5 N) and extracted with chloroform (3×200 ml). After drying (MgSO4) the combined organic phases were concentrated in vacuo to afford an oil which was separated by column chromatography on alumina eluting with chloroform. The major band was further purified by column chromatography on silica gel (60-120 mesh) eluting with chloroform to afford the amide (1.93 g; 62%) which was converted into its hydrochloride salt by the addition of isopropanolic hydrogen chloride. Recrystallisation from ethanol afforded the pure salt (0.7 g).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][OH:20])[CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C.O>[Cl:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([N:12]3[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][OH:20])[CH2:14][CH2:13]3)[S:3][C:4]=2[CH:10]=1
Reactant: OCCC1CCNCC1
Reactant: Clc1ccc2nc(Cl)sc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: OCCC1CCN(c2nc3ccc(Cl)cc3s2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2,6-dichlorobenzothiazole (3.00 g; 14.7 mmol), 4-piperidine ethanol (2.09 g; 16.2 mmol), potassium carbonate (2.33 g; 16.2 mmol) and anhydrous N,N-dimethylformamide (15 ml) was stirred at room temperature for 16 hours. Water and ethyl acetate were added to the reaction solution. The organic layer was separated, washed with brine, dried over anhydrous sodium sulphate, and evaporated under reduced pressure. The precipitate was washed with diisopropyl ether to give 6-chloro-2-[4-(2-hydroxyethyl)piperidine-1-yl]benzothiazole as green crystal (2.92 g; 67%).
Reaction SMILES: CCCCCCCCCCCCCCCC(OC[C@@H](OC(CCCCCCCCCCCCCCC)=O)COC(CCC(O)=O)=O)=[O:17].ON1C(=O)CCC1=O.[CH2:56]1[CH2:61][CH2:60][CH:59]([N:62]=[C:63]=[N:64][CH:65]2[CH2:70][CH2:69][CH2:68][CH2:67][CH2:66]2)[CH2:58][CH2:57]1>CN(C1C=CN=CC=1)C.C(#N)C>[C:63]([NH:62][CH:59]1[CH2:58][CH2:57][CH2:56][CH2:61][CH2:60]1)([NH:64][CH:65]1[CH2:70][CH2:69][CH2:68][CH2:67][CH2:66]1)=[O:17]
Reactant: CCCCCCCCCCCCCCCC(=O)OC[C@H](COC(=O)CCC(=O)O)OC(=O)CCCCCCCCCCCCCCC
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: O=C1CCC(=O)N1O
Solvent: CC#N
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 5 h

Procedure:
To a cooled (0 to 5° C.) solution of 1,2-dipalmitoyl-sn-glycero-3-succinate (66.8 mg), N-hydroxy-succinimide (11.5 mg), DMAP (2 mg) and acetonitrile (40 mL) in a 100 mL round bottom flask was added dropwise a solution of DCC (20.6 mg) in acetonitrile (10 mL). The resulting mixture was stirred for 5 hours. The solid material which formed during the reaction (dicyclohexylurea) was removed by filtration and the filtrate was concentrated in vacuo to yield 78 mg of N-DPGS-succinimide as a white product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:13]3[S:14][C:15]([Cl:18])=[CH:16][CH:17]=3)=[N:10][NH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].ClC1[CH:31]=[C:30]([C:32]2C(C3SC(Cl)=CC=3)=NN(CC(C)C)C=2)[CH:29]=CN=1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:12]=[N:11][N:10]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:9]=2[C:13]2[S:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)Cn1cc(-c2ccnc(Cl)c2)c(-c2ccc(Cl)s2)n1
Reactant: Clc1cc(-c2c[nH]nc2-c2ccc(Cl)s2)ccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)Cn1ncc(-c2ccnc(Cl)c2)c1-c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of 2-chloro-4-[3-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]pyridine (6.7 mmol) in 53 mL N,N-dimethylformamide were added bromoisobutyle (10.1 mmol) and cesium carbonate (7.4 mmol). The reaction mixture was stirred overnight at room temperature and the solvent was then evaporated. The residue was diluted with water and extracted three times with ethyl acetate. The combined organic extracts were dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (heptane:ethyl acetate 1:0 to 1:1) to afford 2.21 g of a mixture of 2-chloro-4-[1-isobutyl-3-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]pyridine and 2-chloro-4-[1-isobutyl-5-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]pyridine (8:2; 88% yield). The mixture was used as such in the next step.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][S:26]([C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35]C)=[O:34])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[C:15]1[CH2:39][CH2:40][NH:41][S:42]([CH2:45][C:46]1[CH:51]=[CH:50][C:49]([Cl:52])=[C:48]([Cl:53])[CH:47]=1)(=[O:44])=[O:43])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[OH-].[Na+]>CO>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][S:26]([C:29]2[CH:38]=[CH:37][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[C:15]1[CH2:39][CH2:40][NH:41][S:42]([CH2:45][C:46]1[CH:51]=[CH:50][C:49]([Cl:52])=[C:48]([Cl:53])[CH:47]=1)(=[O:43])=[O:44])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)CCc2c(CCNS(=O)(=O)Cc3ccc(Cl)c(Cl)c3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(S(=O)(=O)CCc2c(CCNS(=O)(=O)Cc3ccc(Cl)c(Cl)c3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 93 %

Procedure:
Methyl 4-({2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoate (1 eq), THF (0.1M), MeOH (1 mL/1 mL THF), and NaOH (1N) (11 eq) were stirred together overnight. Solvents were removed and the resulting residue was taken up in water. The solution was acidified with 1N HCl and collected resulting precipitate by filtration. Obtained 4-({2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoic acid (white-yellow solid) in 93% yield. HRMS calc for [C38H33Cl3N2O6S2−H] 793.07728 found 793.07629
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][N:4]=[N:3]1.C([Mg]Cl)(C)C.CON(C)[C:15](=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22][CH3:23])[CH:17]=1.Cl>C1COCC1>[CH3:23][S:22][C:18]1[CH:17]=[C:16]([C:15]([C:6]2[N:2]([CH3:1])[N:3]=[N:4][N:5]=2)=[O:24])[CH:21]=[CH:20][CH:19]=1
Reactant: CON(C)C(=O)c1cccc(SC)c1
Reactant: Cn1cnnn1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CSc1cccc(C(=O)c2nnnn2C)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 43 %

Procedure:
To a stirred solution of 1-methyl-1H-tetrazole (4.20 g, 50 mmol) in anhydrous THF (200 mL), cooled to 0° C. with a brine/ice bath, was added dropwise a solution of isopropylmagnesium chloride (2 M in THF, 30 mL, 60.2 mmol). After the addition was over, the resulting cloudy suspension was stirred for 15 min at 0° C. A solution of N-methoxy-N-methyl-3-(methylsulfanyl)benzamide (10.2 g, 39 mmol) in THF (80 mL) was then added dropwise while keeping the internal temperature below 5° C. The reaction mixture was then allowed to warm up and stirred overnight at room temperature. Aq. HCl (1 M, 65 mL) was added to the reaction mixture, the layers were separated, the water phase was extracted with ethyl acetate (3×50 mL) and the combined organic layers were dried over MgSO4. Purification on silica gel afforded [3-(methylsulfanyl)phenyl](1-methyl-1H-tetrazol-5-yl)methanone as a yellow solid [5.95 g, yield 43%; HPLC/MS: m/z=235 (M+H); logP(HCOOH)=2.52].
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]3[O:15][C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[N:18]=3)=[CH:13][C:8]=2[N:7]=[C:6]1[CH3:23].[C:24]1(=[O:30])[O:29][C:27](=[O:28])[CH2:26][CH2:25]1.C(N(CC)CC)C.C(Cl)(Cl)Cl>O>[O:30]=[C:24]([NH:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]3[O:15][C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[N:18]=3)=[CH:13][C:8]=2[N:7]=[C:6]1[CH3:23])[CH2:25][CH2:26][C:27]([OH:29])=[O:28]
Reactant: O=C1CCC(=O)O1
Reactant: Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1CCNC(=O)CCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.2 %

Procedure:
1-(2-Aminoethyl)-5-(benzoxazol-2-yl)-2-methylbenzimidazole hydrochloride (see Working Example 56) (0.20 g, 0.6 mmol), succinic anhydride (0.06 g, 0.6 mmol), triethylamine (0.22 g, 2.2 mmol) and CHCl3 (2 mL) were added together, and after stirring for 1 hour at room temperature this was heated to reflux with stirring for 1 hour. After cooling, water was added and back-extraction was carried out. The aqueous layer obtained was concentrated, and the residue was reslurried in methanol. After the precipitated crystals were filtered, they were dried to yield the title compound (0.13 g, 69% yield) as white crystals.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].N1C=CN=C1.[C:21]([Si:25]([CH3:28])([CH3:27])Cl)([CH3:24])([CH3:23])[CH3:22]>C(Cl)Cl>[Si:25]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)NCCCCCCO
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCCCO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 87 %

Procedure:
To a solution of tert-butyl 6-hydroxyhexylcarbamate (21 mmol) in CH2Cl2 (30 ml) was added imidazole (27 mmol) at 0° C. The reaction mixture was kept at 25° C. and stirred for 20 min, then cooled to 0° C. To the resulting reaction mixture was added tert-butyldimethylchlorosilane (23 mmol) dropwise over 30 min at 0° C. The reaction mixture was allowed to warm to 25° C. and stirred for 16 h and then filtered. The filtrate was washed with 1 N HCl (2×25 ml) and brine (30 ml), dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by SiO2 flash column (eluent: petroleum ether and then CH2Cl2). Yield 6.53 g (87% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([NH2:15])=[O:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[CH3:31])[CH2:26]Br>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[CH3:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[CH3:31])[CH2:26][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([C:13]([NH2:15])=[O:14])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: NC(=O)c1cc(-c2ccc(O)cc2)no1
Reactant: Cc1ccc(CBr)cc1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: Cc1ccc(COc2ccc(-c3cc(C(N)=O)on3)cc2)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.2 %

Procedure:
3-(4-Hydroxy-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 2; 50 mg, 0.24 mmol), K2CO3 (37 mg, 0.27 mmol) and tetrabutylammonium iodide (9 mg, 0.024 mmol) were taken up in DMF (2.4 mL). 3,4-Dimethylbenzyl bromide (77 mg, 0.27 mmol) was added and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was purified by high-throughput purification to give 3-[4-(3,4-dimethyl-benzyloxy)-phenyl]-isoxazole-5-carboxylic acid amide (8.7 mg, 11%). LRMS (ESI+): m/z [M+H+CH3CN]+ 364.2.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][CH2:13][C:14]2[N:15]=[CH:16][S:17][CH:18]=2)[CH2:8][CH2:7]1)[CH3:5].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:40][C:41]1[CH:49]=[C:48]([CH3:50])[C:44]([C:45](O)=[O:46])=[C:43]([CH3:51])[N:42]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:40][C:41]1[CH:49]=[C:48]([CH3:50])[C:44]([C:45]([NH:1][CH2:2][CH2:3][CH:4]([N:6]2[CH2:11][CH2:10][CH:9]([NH:12][CH2:13][C:14]3[N:15]=[CH:16][S:17][CH:18]=3)[CH2:8][CH2:7]2)[CH3:5])=[O:46])=[C:43]([CH3:51])[N:42]=1
Reactant: Cc1cc(Cl)nc(C)c1C(=O)O
Reactant: CC(CCN)N1CCC(NCc2cscn2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Cl)nc(C)c1C(=O)NCCC(C)N1CCC(NCc2cscn2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.9 %

Procedure:
Following general procedure E: to a stirred solution of [1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-thiazol-4-ylmethyl-amine (0.320 g. 1.19 mmol), EDCI (0.252 g, 1.31 mmol) and HOBt (0.177 g, 1.31 mmol) in DMF (5 ml) was added 6-chloro-2,4-dimethyl-nicotinic acid (0.243 g, 1.31 mmol) followed by DIPEA (343 μL, 1.78 mmol) and the resulting mixture was stirred at 25° C. for 16 hours. Standard workup and purification by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 93:5:2) afforded 6-chloro-2,4-dimethyl-N-(3-{4-[(thiazol-4-ylmethyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide (0.42 g, 81%) as a colorless oil.