Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH:22](/B(O)O)=[CH:23]\[CH2:24][CH2:25][CH2:26][CH3:27].[ClH:31]>CCOCC>[ClH:31].[CH:22](/[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1)=[CH:23]\[CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CN1CCN(CCCNc2ccc3ncc(Br)n3n2)CC1
Reactant: CCCC/C=C/B(O)O
Agent: Cl
Solvent: CCOCC
Product: CCCC/C=C/c1cnc2ccc(NCCCN3CCN(C)CC3)nn12
Yield: 35 %

Procedure:
Prepared from the product of step A and (E)-1-hexeneboronic acid according to general procedure 2. The free-base was converted to the HCl salt with 2N HCl in Et2O to provide the title compound (60 mg, 35%) as a brown solid; 1H NMR (500 MHz, CD3OD) δ 7.59 (d, J=9.7 Hz, 1H), 7.50 (s, 1H), 6.77-6.69 (m, 2H), 6.61 (d, J=16.2 Hz, 1H), 3.45 (t, J=6.7 Hz, 2H), 3.35 (m, 2H), 3.13-2.69 (m, 11H), 2.29 (q, J=6.7 Hz, 2H), 2.02-1.93 (m, 2H), 1.53-1.38 (m, 4H), 0.96 (t, J=7.1 Hz, 13C NMR (125 MHz, CD3OD) δ 155.6, 137.1, 133.8, 128.9, 127.2, 125.0, 116.5, 114.6, 56.3, 54.5, 51.8, 44.1, 40.4, 34.4, 32.9, 26.2, 23.4, 14.4; HPLC tR=8.7 min (Luna), 95.1%; ES-MS: (M+H)=357 m/z.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][C:10]([O:12]C)=[O:11])=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CO>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:3][CH:2]=1
Reactant: COC(=O)CCCc1ccncc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCc1ccncc1

Procedure:
A solution of ester 10-4 (10.0 g, 56 mmol), 1N NaOH (84 ml, 84 mmole) and CH3OH (200 ml) was stirred at ambient temperature for 1.0 h. Concentrated HCl (7.0 ml, 84 mmol) was added followed by concentration. The residue was dissolved in CHCl3, dried (MgSO4) and concentrated to give acid 10-5 as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:6]1)=[O:4].[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:21][C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[F:18])=[CH:15][CH:16]=2)[CH2:6]1)=[O:4]
Reactant: Fc1ccccc1CBr
Reactant: COC(=O)C1CC(=O)N(c2ccc(O)cc2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)C1CC(=O)N(c2ccc(OCc3ccccc3F)cc2)C1
Yield: 82 %

Procedure:
In an analogous manner to that described in Example 13 a), the alkylation of the (RS)-1-(4-hydroxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester [Example 2 b)] with 2-fluorobenzyl-bromide using cesium carbonate as the base at RT yields (RS)-1-[4-(2-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methyl ester as a light yellow solid (yield 82% of theory).
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:23]2[CH2:25][CH2:24]2)[C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#[N:2].[OH:26][NH:27][C:28](=N)[CH2:29][CH2:30][CH:31]=[CH2:32]>>[CH2:29]([C:28]1[N:2]=[C:1]([N:3]2[CH2:4][CH2:5][CH:6]([N:9]([CH:23]3[CH2:25][CH2:24]3)[C:10](=[O:22])[C:11]3[CH:12]=[CH:13][C:14]([C:17]4[O:21][CH:20]=[N:19][CH:18]=4)=[CH:15][CH:16]=3)[CH2:7][CH2:8]2)[O:26][N:27]=1)[CH2:30][CH:31]=[CH2:32]
Reactant: C=CCCC(=N)NO
Reactant: N#CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Product: C=CCCc1noc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)n1

Procedure:
The title compound is prepared from N-(1-cyano-piperidin-4-yl)-N-cyclopropyl-4-oxazol-5-yl-benzamide and N-hydroxy-pent-4-enamidine following a procedure analogous to that described in Example 1. LC (method 1): tR=1.19 min; Mass spectrum (ESI+): m/z=434 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]3[N:14]=[C:15]([CH3:26])[N:16]=[C:17]([N:18]4[CH2:23][CH2:22][CH:21]([CH2:24][OH:25])[CH2:20][CH2:19]4)[C:12]=3[C:11]([CH3:27])=[CH:10]2)=[C:4]([CH3:28])[CH:3]=1.[P:29](Cl)([O:34][CH2:35][CH3:36])([O:31][CH2:32][CH3:33])=[O:30]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:32]([O:31][P:29](=[O:30])([O:34][CH2:35][CH3:36])[O:25][CH2:24][CH:21]1[CH2:22][CH2:23][N:18]([C:17]2[C:12]3[C:11]([CH3:27])=[CH:10][N:9]([C:5]4[C:6]([CH3:8])=[CH:7][C:2]([Br:1])=[CH:3][C:4]=4[CH3:28])[C:13]=3[N:14]=[C:15]([CH3:26])[N:16]=2)[CH2:19][CH2:20]1)[CH3:33]
Reactant: CCOP(=O)(Cl)OCC
Reactant: Cc1nc(N2CCC(CO)CC2)c2c(C)cn(-c3c(C)cc(Br)cc3C)c2n1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOP(=O)(OCC)OCC1CCN(c2nc(C)nc3c2c(C)cn3-c2c(C)cc(Br)cc2C)CC1
Temperature: 25 °C
Yield: 47.4 %

Procedure:
Under nitrogen atmosphere, to a solution of {1-[7-(4-bromo-2,6-dimethylphenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]piperidin-4-yl}methanol (0.50 g) and 4-dimethylaminopyridine (0.55 g) in CH2Cl2 (50 mL) at 0° C. diethyl chlorophosphate (0.38 g) was added dropwise and the reaction is slowly heated up to room temperature. The reaction mixture is poured on ice-water and extracted with CH2Cl2. After the usual work-up the residue is purified over silica gel on a glass filter (eluent: CH2Cl2/MeOH=98:2) yielding product 3-017 (0.31 g).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([N:12]3[CH2:17][CH2:16][C:15]4([C:29]5[CH:28]=[N:27][N:26]([CH3:30])[C:25]=5[C:24]5[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=5[O:18]4)[CH2:14][CH2:13]3)=[O:11])[C:4]=2[N:3]=[CH:2]1.[H-].[Na+].[CH3:33]I>C1COCC1.CO>[CH3:33][N:3]1[C:4]2[C:9]([C:10]([N:12]3[CH2:17][CH2:16][C:15]4([C:29]5[CH:28]=[N:27][N:26]([CH3:30])[C:25]=5[C:24]5[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=5[O:18]4)[CH2:14][CH2:13]3)=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[CH:2]1
Reactant: CI
Reactant: Cn1ncc2c1-c1ccccc1OC21CCN(C(=O)c2cccc3[nH]cnc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1ncc2c1-c1ccccc1OC21CCN(C(=O)c2cccc3ncn(C)c23)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (1H-benzo[d]imidazol-4-yl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone (21 mg, 0.052 mmol) in dry THF (0.2 mL) under N2 was added NaH (1.9 mg, 0.079 mmol) at 0° C. After 30 min, MeI (3.3 μL, 0.052 mmol) was added and the mixture was stirred at 0° C. for 1 h. The reaction mixture was quenched with water and the solvent removed under vacuum to yield a crude residue that was taken up in methanol and purified by reverse phase HPLC to give (3-methylbenzoimidazol-4-yl)-(1-methyl-1H-Spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone. ESI-MS m/z talc. 413.5, found 414.5 (M+1)+. Retention time: 1.13 minutes (3 min run).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:8]1.Br[C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([CH3:33])[N:24]=1>>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][N:17]([C:23]2[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[C:25]([CH3:33])[N:24]=2)[CH2:16][CH2:15]3)[CH2:8]1
Reactant: Cc1cc(C(F)(F)F)cc(Br)n1
Reactant: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCNC3)C1
Product: Cc1cc(C(F)(F)F)cc(N2CCc3cc(N4CC[C@H](N5CCC[C@@H]5C)C4)ccc3C2)n1

Procedure:
The title compound was synthesized in substantially the same way as Example 1 by condensation of 6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-1,2,3,4-tetrahydro-isoquinoline with 2-Bromo-6-methyl-4-trifluoromethyl-pyridine.
Reaction SMILES: [CH2:1]([NH:8][C@@H:9]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:24]=[C:25]([C@@H:29]2[CH2:31][O:30]2)[CH:26]=[CH:27][CH:28]=1>C(O)C>[CH2:1]([N:8]([C@@H:9]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=1)[CH2:10][OH:11])[CH2:31][C@@H:29]([C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([Cl:22])[CH:24]=1)[OH:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc([C@@H]2CO2)c1
Reactant: O=[N+]([O-])c1ccc(C[C@@H](CO)NCc2ccccc2)cc1
Solvent: CCO
Product: O=[N+]([O-])c1ccc(C[C@@H](CO)N(Cc2ccccc2)C[C@H](O)c2cccc(Cl)c2)cc1
Temperature: 25 °C
Yield: 59.1 %

Procedure:
To a suspension of (25)-2-(benzylamino)-3-(4-nitrophenyl)-1-propanol (6.0 g) in ethanol (60 ml) was added (2R)-2-(3-chlorophenyl)oxirane (4.86 g) and the mixture was refluxed for 23 hours. After cooling to room temperature, the solvent was removed by evaporation and the residue was chromatographed on silica gel (eluent: hexane/ethyl acetate=2/1) to give the (2S)-2-[N-benzyl-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-3-(4-nitrophenyl)-1-propanol (5.46 g) as a yellow crystalline solid.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10](=[O:42])[CH:11]([N:15]1[C@H:18]([S:19][S:20][C:21]2[S:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[N:25]=2)[C@@H:17]([O:30][C:31](=[O:40])[CH2:32][O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:16]1=[O:41])[C:12](=[CH2:14])[CH3:13]>C(Cl)Cl>[CH3:8][O:9][C:10](=[O:42])[C:11]([N:15]1[C@H:18]([S:19][S:20][C:21]2[S:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[N:25]=2)[C@@H:17]([O:30][C:31](=[O:40])[CH2:32][O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:16]1=[O:41])=[C:12]([CH3:14])[CH3:13]
Reactant: C=C(C)C(C(=O)OC)N1C(=O)[C@H](OC(=O)COc2ccccc2)[C@H]1SSc1nc2ccccc2s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(=C(C)C)N1C(=O)[C@H](OC(=O)COc2ccccc2)[C@H]1SSc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.4 ml of triethylamine is added to a solution of 1.28 g (2.41 mmole) of 2-[(3S,4R)-4-(benzthiazol-2-yldithio)-3-phenoxyacetoxy-2-oxoazetidin-1-yl]-3-methylenebutyric acid methyl ester in 30 ml of methylene chloride and the mixture is stirred at room temperature for 30 minutes. The reaction mixture is diluted with 50 ml of methylene chloride, washed in succession with 2N hydrochloric acid, water and sodium chloride solution, dried over sodium sulphate and freed from solvent in vacuo. The residue is purified by chromatography over silica gel with toluene/ethyl acetate (19:1) and yields the title compound in the form of a faint yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[C:11]([CH3:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:19]1([C@@H:24]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][C:30]=3[O:36][CH3:37])[CH2:25]2)[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH:35][C:32]2[CH:33]=[CH:34][C:29]([N:26]3[CH2:27][CH2:28][C@@H:24]([N:19]4[CH2:20][CH2:21][CH2:22][CH2:23]4)[CH2:25]3)=[C:30]([O:36][CH3:37])[CH:31]=2)=[O:15])=[C:11]([CH3:18])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(N)ccc1N1CC[C@@H](N2CCCC2)C1
Reactant: Cc1cc(OCc2ccccc2)ccc1C(=O)O
Product: COc1cc(NC(=O)c2ccc(OCc3ccccc3)cc2C)ccc1N1CC[C@@H](N2CCCC2)C1

Procedure:
According to Method P, 4-benzyloxy-2-methyl-benzoic acid was reacted with (R)-4-[1,3′]bipyrrolidinyl-1′-yl-3-methoxy-phenylamine. In this way the product was obtained with molecular weight 485.63 (C30H35N3O3); MS (ESI): 486 (M+H+).
Reaction SMILES: [N:1]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][C@@H:3]2[CH2:6][NH:7][CH2:8][C@H:2]12.[H-].[Na+].I[CH2:26][CH3:27]>C1COCC1.O>[CH2:26]([N:7]1[CH2:6][C@@H:3]2[C@@H:2]([N:1]([C:9]3[CH:10]=[CH:11][C:12]([C:15]4[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=4)=[CH:13][CH:14]=3)[CH2:5][CH2:4]2)[CH2:8]1)[CH3:27]
Reactant: CCI
Reactant: N#Cc1ccc(-c2ccc(N3CC[C@@H]4CNC[C@@H]43)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCN1C[C@H]2CCN(c3ccc(-c4ccc(C#N)cc4)cc3)[C@H]2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.6 %

Procedure:
The product of Example 1E (22 mg, 0.076 mmole) was dissolved in 2.5 ml anhydrous THF under nitrogen. Sodium hydride (95%, 4 mg, 0.167 mmole) was added and the mixture was stirred at room temperature for 1 hour. Iodoethane (18 μl, 0.225 mmole) was added and the mixture was stirred at room temperature over night. The mixture was diluted with water and extracted with dichloromethane (3×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (eluting with a mixture of 0.2% ammonium hydroxide and 2% methanol in dichloromethane) to provide the title compound (11 mg, 46%). 1H NMR (CDCl3) δ ppm 7.64 (d, J=1.36 Hz, 4H) 7.50 (d, J=8.82 Hz, 2H) 6.65 (d, J=8.82 Hz, 2H) 4.14-4.23 (m, 1H) 3.47-3.60 (m, 1H) 3.27-3.39 (m, 1H) 2.92-3.04 (m, 1H) 2.70-2.81 (m, 1H) 2.38-2.67 (m, 5H) 2.11-2.25 (m, 1H) 1.89-2.03 (m, 1H) 1.08 (t, J=7.12 Hz, 3H); MS (M+H)+=318.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]CC(OC[C@H]1O[C@H](O[C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O)=O>O>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCCC(=O)OC[C@H]1O[C@H](O[C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O
Solvent: O
Product: CCCCCCCCCC

Procedure:
Sucrose monolaurate (SM-1200, produced by Mitsubishi Chemical Foods K.K.) dissolved in distilled water uniformly, and n-decane (guaranteed reagent, produced by Tokyo Kasei Kogyo K.K.) were put in a test tube with a screw closure, and 0.5% by volume of adsorbent cotton (adsorbent cotton according to Japanese Pharmacopeia, produced by Toei K.K.) was added thereto. The system was emulsified by shaking by hand at 25° C. to prepare an oil-in-water emulsion composition, then the cotton was taken out.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]#[N:9].[O-]CC.[Na+].[CH2:14]([O:16][C:17](=[O:21])[CH:18]=[N+:19]=[N-:20])[CH3:15].C(=O)=O>C(O)C.O>[NH2:9][C:8]1[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:20][NH:19][C:18]=1[C:17]([O:16][CH2:14][CH3:15])=[O:21]
Reactant: N#CCc1ccccn1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: CC[O-]
Agent: O=C=O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1[nH]nc(-c2ccccn2)c1N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
2-Pyridylacetonitrile (10 ml, 94.0 mmol) was added dropwise over 20 minutes to an ice-cooled solution of sodium ethoxide (34 ml, 2.76M, 94.0 mmol) in ethanol (50 ml), and the mixture stirred at 0° C. for 30 minutes. Ethyldiazoacetate (9.9 ml, 94.0 mmol) was added dropwise over 15 minutes and the reaction allowed to warm to room temperature and stirred for a furter 18 hours. Water (300 ml) was added, the mixture neutralised with solid carbon dioxide, and the resulting precipitate filtered and dried to afford the title compound, (13.0 g, 60%) as a brown solid.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([Br:30])[CH:24]=2)=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:32]([C:35]1[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[C:37]([OH:44])[CH:36]=1)(=[O:34])=[O:33]>>[CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][S:32]([C:35]3[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[C:37]([OH:44])[CH:36]=3)(=[O:34])=[O:33])=[C:25]([Br:30])[CH:24]=2)=[CH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: Oc1ccc(-c2ccc(-c3c(Cc4ccccc4)sc4ccccc34)cc2)cc1Br
Product: O=C(O)c1ccc(S(=O)(=O)Oc2ccc(-c3ccc(-c4c(Cc5ccccc5)sc5ccccc45)cc3)cc2Br)cc1O

Procedure:
The title compound was prepared from 4′-(2-benzyl-benzo[b]thiophen-3-yl)-3-bromo-biphenyl-4-ol and 4-chlorosulfonyl-2-hydroxy-benzoic acid, in substantially the same manner, as described in Example 1 step g, and was obtained as an off-white solid, mp 117-119° C.; MS m/e 669 (M-H)+;
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23](OCC)=[O:24])[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[N:29]1[CH:34]=[CH:33][C:32]([CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[CH:31][CH:30]=1>C(O)C>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:22][N:21]=[C:20]([C:23]([N:38]3[CH2:39][CH2:40][CH:35]([C:32]4[CH:31]=[CH:30][N:29]=[CH:34][CH:33]=4)[CH2:36][CH2:37]3)=[O:24])[N:19]=2)[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: c1cc(C2CCNCC2)ccn1
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: CCO
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CCC(c3ccncc3)CC2)no1
Yield: 60.1 %

Procedure:
A solution of ethyl 5-{(1R)-1 -[2-(tert-butoxy)-2-oxoethyl]4-cyclohexylbutyl}-1,2,4-oxadiazole-3-carboxylate (Preparation 3) (0.50 g, 1.27 mmol) in ethanol (10 ml) was treated with 4-(4-pyridinyl)piperidine (Monatsh.Chem.; 3; 1882; 867) (0.41 g, 2.54 mmol) and the resulting mixture was heated under reflux under a nitrogen atmosphere for 72 hours. Further 4-(4-pyridinyl)piperidine (0.21 g, 1.27 mmol) was added and the mixture heated under reflux for 24 hours. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The layers were separated and the aqueous layer extracted with ethyl acetate. The combined organic layers were washed sequentially with water and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol (99:1) gradually changing to dichloromethane:methanol (95:5) to afford the title compound as a pale yellow oil (0.39 g).
Reaction SMILES: [SH:1][CH2:2][C:3]1[N:4]=[C:5]([CH3:13])[S:6][C:7]=1[C:8](OCC)=[O:9].O>O1CCCC1>[SH:1][CH2:2][C:3]1[N:4]=[C:5]([CH3:13])[S:6][C:7]=1[CH:8]=[O:9]
Reactant: CCOC(=O)c1sc(C)nc1CS
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(CS)c(C=O)s1
Reaction time: 4 h

Procedure:
10 mmol of ethyl 4-(mercaptomethyl)-2-methyl-1,3-thiazole-5-carboxylate was dissolved in 100 ml of dried tetrahydrofuran, then 42 ml of 0.5M SDBBA solution was gradually added with keeping the temperature at −30 to −20° C. After the adding, the reaction was carried out for 4 hours at −20° C. Then 20 ml of water was added into the reaction system to stop the reaction and then an organic layer was separated. To the remaining water phase, sodium hydrogen carbonate was added until the pH of the water phase reached a value of 8 to 9. The product was extracted and separated into an organic layer using ethyl acetate. This organic layer and the previous organic layer were mixed together and dried under sodium sulfate. The solvent was evaporated out and then the product was purified using a column separation with solvents of ethylacetate and hexane, obtaining 4-(mercaptomethyl)-2-methyl-1,3-thiazole-5-carbaldehyde.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH3:22])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([NH:32][CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])=[O:31])=[CH:26][CH:25]=1>>[CH:1]1([CH:7]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]([NH:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:31])=[CH:28][CH:29]=2)[C:9]2[C:10]([CH3:22])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(-n2cc(C(O)C3CCCCC3)c(C)n2)cc1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Product: COc1ccc(-n2cc(C(Nc3ccc(C(=O)NCCC(=O)O)cc3)C3CCCCC3)c(C)n2)cc1
Yield: 39.6 %

Procedure:
Using cyclohexyl[1-(4-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]methanol (0.68 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.55 g) synthesized in Example 1(2) and in the same manner as in Example 1(7), the title object compound (0.44 g, 39%) was obtained as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[C:19]([CH:21]([CH3:23])[CH3:22])[CH:18]=[CH:17][C:16]=2[O:24][CH3:25])=[C:11]([CH2:26]O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:30])=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[C:19]([CH:21]([CH3:23])[CH3:22])[CH:18]=[CH:17][C:16]=2[O:24][CH3:25])=[C:11]([CH2:26][Cl:30])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C(C)C)cc1-c1ccc(OCc2ccccc2)cc1CO
Solvent: ClCCl
Product: COc1ccc(C(C)C)cc1-c1ccc(OCc2ccccc2)cc1CCl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(4-Benzyloxy-5′-isopropyl-2′-methoxy-biphenyl-2-yl)-methanol (1.10 g) is dissolved in methylene chloride (10 ml), and thereto is added thionyl chloride (332 μl) and the mixture is stirred at room temperature for 30 minutes. The reaction solution is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (hexane:ethyl acetate=1:0→9:1) to give 4-benzyloxy-2-chloromethyl-5′-isopropyl-2′-methoxy-biphenyl (1.15 g). MS (m/z): 345
Reaction SMILES: Cl[C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.[CH2:19]([O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=1)[CH3:20]>>[CH2:19]([O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:2]2[CH:17]=[C:6]3[C:7]4[C:12]([CH2:13][CH2:14][N:5]3[C:4](=[O:18])[N:3]=2)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=4)[CH:24]=1)[CH3:20]
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: COc1ccc2c(c1)CCn1c-2cc(Cl)nc1=O
Product: CCOC(=O)c1cccc(Nc2cc3n(c(=O)n2)CCc2cc(OC)ccc2-3)c1

Procedure:
The title compound was prepared from 2-chloro-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (4) and 3-amino-benzoic acid ethyl ester as in Example 1 d. 1H-NMR (400 MHz, d0-DMSO) δ 9.84 (s, 1H), 8.26 (s, 1H), 8.21 (d, 1H), 7.70 (d, 1H), 7.62 (d, 1H), 7.49 (t, 1H), 7.05-6.97 (2H), 6.36 (s, 1H), 4.33 (q, 2H), 3.99 (t, 2H), 3.85 (s, 3H), 2.97 (t, 2H) and 1.34 (t, 3H); MS (ESI) (M+H)+ 392.
Reaction SMILES: C[C@H]1[O:7][C@@H]2O[C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O[C@H]5[C@H](O)[C@@H](O)[C@@H](O[C@H]6[C@H](O)[C@@H](O)[C@@H](O[C@H]7[C@H](O)[C@@H](O)[C@@H](O[C@H]8[C@H](O)[C@@H](O)[C@@H](O[C@H]1[C@H](O)[C@H]2O)O[C@@H]8COCCCCS([O-])(=O)=O)O[C@@H]7CO)O[C@@H]6CO)O[C@@H]5CO)O[C@@H]4CO)O[C@@H]3CO.[Na+].[OH-].[Na+].[OH:88][NH:89][S:90]([C:93]1C=[CH:97][CH:96]=[C:95](S(C)(=O)=O)[CH:94]=1)(=[O:92])=[O:91]>O>[OH:88][NH:89][S:90]([C:93]1[O:7][C:96]([CH3:97])=[CH:95][CH:94]=1)(=[O:92])=[O:91]
Reactant: CS(=O)(=O)c1cccc(S(=O)(=O)NO)c1
Reactant: C[C@H]1O[C@@H]2O[C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O[C@H]5[C@H](O)[C@@H](O)[C@@H](O[C@H]6[C@H](O)[C@@H](O)[C@@H](O[C@H]7[C@H](O)[C@@H](O)[C@@H](O[C@H]8[C@H](O)[C@@H](O)[C@@H](O[C@H]1[C@H](O)[C@H]2O)O[C@@H]8COCCCCS(=O)(=O)[O-])O[C@@H]7CO)O[C@@H]6CO)O[C@@H]5CO)O[C@@H]4CO)O[C@@H]3CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(S(=O)(=O)NO)o1

Procedure:
Additionally, a sample of the compound of formula (1) was prepared in water to determine the approximate solubility of the compound in the absence of excipients (e.g., CAPTISOL®). A concentration of approximately 300 mg/mL was achieved, not accounting for the volume contribution of the compound. The pH of the sample was determined to be 2.8, which was adjusted to the target of 4.0 using 0.1 N NaOH. Upon pH adjustment, precipitation of a small amount of solid was observed. The clear solution was diluted in acetonitrile and analyzed by HPLC, resulting in an observed solution concentration of 268 mg/mL. A similar analysis was performed for the compound of formula (2). The compound of formula (2) has a solubility of approximately 10 mg/mL.